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WO2025015254A2 - Therapeutic agent composition and method of use of combination therapy for treatment of mild cognitive impairment - Google Patents

Therapeutic agent composition and method of use of combination therapy for treatment of mild cognitive impairment Download PDF

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Publication number
WO2025015254A2
WO2025015254A2 PCT/US2024/037745 US2024037745W WO2025015254A2 WO 2025015254 A2 WO2025015254 A2 WO 2025015254A2 US 2024037745 W US2024037745 W US 2024037745W WO 2025015254 A2 WO2025015254 A2 WO 2025015254A2
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effective amount
cpg
disease
cyclic
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WO2025015254A3 (en
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Lloyd Tran
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention generally relates to novel cyclic dipeptides compounds structurally related to diketopiperazines and methods for their therapeutic use.
  • the present invention generally relates to the use of cyclic prolyl glycine (“cyclic GP” or “cPG”) and cPG analogues and cPG compounds, pharmacologically effective analogues thereof, and pharmaceutical compositions thereof in combination with specific binding members such as antibodies, or active fragments thereof, such as but not limited to monoclonal antibody Lecanemab, in the treatment and prevention of progression of cognitive impairment and related neurodegenerative disorders and psychological disorders such as but not limited mild cognitive impairment such as but no limited to as related to Alzheimer’s Disease.
  • Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level. Mild cognitive impairments are those involving impairments of memory and other cognition functions ons, beyond the age norm but not leading to the characteristic of dementia.
  • MCI MCI ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • Dementia is an overall term that describes a group of symptoms associated with a decline in memory or other thinking skills severe enough to reduce a person's ability to perform everyday activities. Alzheimer's disease accounts for 60 to 80 percent of these types of cases. Vascular dementia, which occurs after a stroke, is the second most common dementia type. But there are many other conditions that can cause symptoms of dementia, including some that are reversible, such as thyroid problems and vitamin deficiencies.
  • dementia While symptoms of dementia can vary greatly, at least two of the following core mental functions are to be significantly impaired to be considered dementia: memory, communication and language, ability to focus and pay attention, reasoning and judgment, and visual perception.
  • AD Alzheimer's disease
  • AD is a progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, plaiming, language, and perception.
  • the growth in the prevalence of Alzheimer’s disease over the next few decades is anticipated to result in great pressure on the social and health-care systems of developed and developing economies alike.
  • therapies that halt, substantially slow, slow or otherwise ameliorate the progression, symptoms, or provide comfort or palli ative care of this disease and related diseases.
  • AD treatments include the cholinesterase inhibitors donepezil rivastigmine, and galantamine, that are purported to address cholinergic deficits in AD by increasing acetylcholine levels in the central nervous system (CNS), and the N-methyl-D- aspartate antagonist memantine.
  • Memantine was approved in 2003, and is the most recently approved novel medication for AD; it is postulated to work by binding preferentially to N- methyl-D-aspartate (NMDA) receptor-operated cation channels to block persistent activation by the excitatory amino acid glutamate.
  • NMDA N- methyl-D-aspartate
  • Aducanumab an anti-amyloid beta-directed antibody
  • AP brain amyloid-beta
  • anti-Ap monoclonal antibodies studied in AD have had negative studies in Phase 3 development; however, differences in enrollment criteria, study design, and trial endpoints make it difficult to compare them to the aducanumab program.
  • anti-Ap monoclonal antibodies related to binding at different epitopes and selectivity for different Ap variants (e.g., monomers, soluble oligomers, aggregated forms) (Linse et al. 2020).
  • the degrees of amyloid reduction in these studies have been variable.
  • Monoclonal antibodies directed against aggregated forms of beta amyloid can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.
  • ARIA amyloid related imaging abnormalities
  • ARIA-E ARIA with edema
  • ARIA-H ARIA with hemosiderin deposition
  • ARIA was observed in 12% of participants treated with lecanemab 10 mg/kg biweekly (20 out of 161) compared to 5% participants on placebo (13 out of 245).
  • ARIA-E was observed in 10% of treated participants compared to 1% of participants on placebo.
  • Symptomatic AREA occurred in 3% (5 out of 161 ) of participants treated with lecanemab 10 mg/kg biweekly in Study 201 sponsored by Eisai and in none of the participants on placebo.
  • Lecanemab was to be discontinued if ARIA occurred. Limited data are available from the open label extension phase of Study 201 on the safety of continued dosing after ARIA-E with Lecanemab. Infusion-related reactions occurred in 20% of patients on lecanemab 10 mg/kg biweekly versus 3% in placebo. Infusion reactions were mild (56%) or moderate (44%) in severity, and 88% occurred at the time of the first infusion. Symptoms included fever and flu-like symptoms (chills, generalized aches, feeling shaky and joint pain). The most common adverse drug reactions with lecanemab are ARIA-E, infusion related reactions, and headache. All occurred in at least 10% of participants on the proposed dose of lecanemab 10 mg/kg biweekly and at least 2% more frequently than placebo in the controlled period of Study 201.
  • Figure 1 generally illustrates time for rats to reach the platform-in Morris Water Maze (MWM) Model of Learning and Memory Used to Assess Effects of cyclic Prolyl Glycine (cPG), Lecanemab and Donanemab and the combination of cPG + Lecanemab and cPG + Donanemab
  • MMM Morris Water Maze
  • Figure 2 generally illustrates adjusted mean change from baseline to week 12 in the NPI-NH psychosis score (cPG vs. Placebo).
  • Figure 3 generally illustrates adjusted mean change from baseline to week 12 in the NPI-NH psychosis score (cPG, Lecanemab vs Placebo, and cPG + Lecanemab vs. Placebo).
  • the present invention recognizes that there is a long felt need for the treatment of mild cognitive impairment.
  • the present invention includes several general and useful aspects, including but not limited to:
  • a first aspect of the present invention generally relates to a method of treating, relieving, or alleviating mild cognitive impairment in a subject.
  • a second aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease in a subject.
  • a third aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject
  • a fourth aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject.
  • a fifth aspect of the present in venti on generally relates to a method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject.
  • the combined treatment is believed to also induce neurogenesis and compared the effects of the combined treatment with NA-831 or LEQ alone.
  • the administrations of combined treatment with NA-831 and LEQ led to increased survival of newly proliferating and differentiated neuronal cells compared with NA-831 or LEQ alone.
  • Hippocampal neurogenesis plays a key role in long-term memory and cognitive function.
  • brain-derived neurotrophic factor (BDNF) is reported to be one of the most important factors in inducing neurogenesis, and there is a report that NA-831 increases the expression level of BDNF.
  • BDNF contributes to neurogenesis of dentate gyrus granule cells. This is a very important topic because neurogenesis of granule cells is thought to be relevant to learning, depression, and possibly other aspects of neurological and psychiatric function (Eisch, 2002; Jacobs et al., 2000). Furthermore, the results suggest that it might be possible to use BDNF in the future to increase granule cell numbers after neuronal loss. Especially promising is the fact that isolated administration of BDNF to one area of the hippocampus appeared to have widespread effects throughout both hippocampi. This could be favorable therapeutically.
  • Neuropsychiatric symptoms are almost ubiquitous in people with dementia, with prevalence estimates as high as 97% (Steinberg, M. et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study, hit. J. Geriatr. Psychiatry 23, 170-177 (2008).
  • AD Alzheimer’s Disease
  • NPS neurosenors
  • Symptom severity can increase and decrease.
  • Neurotic symptoms which consist of hallucinations and delusions, are among the most clinically relevant NPS, and are associated with hospitalization or institutionalization, cognitive and functional impairment, accelerated cognitive decline and mortality, as well as caregiver distress.
  • antipsychotics are commonly used to treat psychosis in patients with Alzheimer’s disease, no drug is approved for treating psychosis in Alzheimer’s disease.
  • Antipsychotic use in people with Alzheimer’s disease is associated with side- effects that include accelerated decline in cognition; increased serious medical adverse events, such as stroke, bronchopneumonia, and pulmonary embolism; and increased short- term mortality. Therefore, although psychosis has a major impact in people with Alzheimer’s disease, no safe or effective pharmacological treatment is approved, leaving a key unmet treatment need. (Ismail, Z., Creese, B., Aarsland, D. et al. Psychosis in Alzheimer disease — mechanisms, genetics and therapeutic opportunities. Nat Rev Neurol 18, 131—144 (2022). https://doi.org/10.1038/s41582-021-00597-3).
  • the present invention provides a preferred embodiment of a combination therapy of NA-831 and a specific binding member or active fragment thereof, such as but not limited to the monoclonal antibody Lecanemab, to reduce the side effects of Lecanemab while enhancing the efficacy of both drugs for the treatment of Alzheimer’s Disease psychosis.
  • cyclic Prolyl Glycine compounds suitable for the drug combination therapy with a specific binding member such as an antibody or active fragment thereof, such as a monoclonal antibody, such as Lecanemab, for treatment and prevention of disease and injury in animals and humans.
  • the cyclic PG being preferably selected from the group that includes cPG, cPG analogues, cPG peptidomimetics and relating compounds which promote or cause the formation of cPG or cPG analogues in vivo.
  • a further aspect the invention relates to a method of restoring the myelination of axons in a mammal in need of restored myelination due to neural injury or disease, comprising administering a therapeutic amount of a cPG compound, where a cPG compound comprises cPG, a biologically active cPG analogue such as c(PG)3 and cGAL, a biologically active cPG peptidomimetic, a compound that increases the concentration of cPG, or a compound that increases the concentration of cPG analogues, effective to restore myelination of axons in a mammal, hi one aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound comprises stimulation of astrocytes to promote remyelination. In another aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of
  • the method of restoring myelination of axons to a mammal in need of restored myelination further comprises administering a therapeutic amount of a cPG compound in combination with a compound selected from IGF-I or an interferon.
  • the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound in combination with IGF-I or an interferon to stimulate astrocytes to promote remyelination.
  • the methods to treat or prevent cell damage and death in response to injury and disease comprises administration of a therapeutic amount of a cPG compound, preferably but not limited to an amount from between about 10 pg to about 150 mg of cPG per kg of body weight of the mammal.
  • a suitable dosage for administration of cPG can be, for example, preferably but not limited to between about 0.1 mg to about 100 mg per kilogram of body weight, between about 1 mg to about 100 mg per kilogram of body weight, between about 5 mg and about 70 mg per kilogram of body weight, between about 10 mg to about 50 mg per kilogram of body weight, or between about 20 mg to about 40 mg per kilogram of body weight.
  • the dose, route of administration, and regime of cPG may be different for different diseases, disorders, and conditions.
  • mild cognitive impairment may have a lower dose using the same or different route of administration than for Alzheimer’s disease.
  • a typical dosage for patient with mild cognitive impairment may be between about 10 mg to about 50 mg per day administered orally (taking 1 capsule of 20 mg or 2 capsules per day per doctor prescription).
  • a more severe Alzheimer’s Disease or severe Traumatic Brain injury patent may be administered intravenously in a range from between about 50 mg to about 300 mg per day.
  • the particulars of the dose, route of administration, and regime for a particular disease, disorder, or condition can be evaluated in general or for a particular subject or patient.
  • the method of restoring myelination of axons to a mammal in need of restored myelination further comprises administering a therapeutic amount of a cPG compound in combination with IGF-1 from about 1 mg to about 10 mg of IGF-I per 1 Kg body weight of the mammal or an interferon from about 1.0 pg to about 10 pg of IGF-I per Kg of body weight of the mammal.
  • the interferon is interferon beta.
  • a suitable dosage for administration of cPG can be, for example, preferably but not limited to between about 0.1 mg to about 100 mg per kilogram of body weight, between about 1 mg to about 100 mg per kilogram of body weight, between about 5 nig and about 70 mg per kilogram of body weight, between about 10 mg to about 50 mg per kilogram of body weight, or between about 20 mg to about 40 mg per kilogram of body weight.
  • the dose, route of administration, and regime of cPG may be different for different diseases, disorders, and conditions.
  • mild cognitive impairment can have a lower dose using the same or different route of administration than for Alzheimer’s disease.
  • a typical dosage for patient with mild cognitive impairment can be between about 10 mg to about 40 mg per day administered orally (taking 1 capsule of 20 mg or 2 capsules per day per doctor prescription).
  • a more severe Alzheimer’s Disease or severe Traumatic Brain injury patent can be administered intravenously in a range from between about 50 mg to about 300 mg per day.
  • the particulars of the dose, route of administration, and regime for a particular disease, disorder, or condition can be evaluated in general or for a particular subject or patient.
  • the cPG compound is administered to the mammal through a shunt into a ventricle of the mammal.
  • the cPG compound is administered to the mammal by peripheral administration.
  • the present invention provides a method of treatment for stimulating mature astrocytes to promote myelin production after hypoxic-ischemic injury’ including the step of increasing the active concentration of cPG and/or the concentration of analogues of cPG in the CNS of mammals.
  • IGF-I itself that is increased within the CNS of the mammal.
  • This can be effected by direct administration of a cPG compound such as cPG, c(PG)3 or cGAL or cGMeP and indeed this is preferred.
  • a cPG compound such as cPG, c(PG)3 or cGAL or cGMeP and indeed this is preferred.
  • the administration of compounds that indirectly increase the effective amount of IGF-I is in no way- excluded.
  • Tire active compound (IGF-I or its analogue or its mimetic) can be administered alone, or as is preferred, a part of a pharmaceutical composition.
  • composition can be administered directly to the CNS.
  • the latter route of administration can involve, for example, lateral cerebroventricular injection, focal injection or a surgically inserted shunt into the lateral cerebroventricle of the brain of the patient.
  • the stimulation and promotion of myelin production in oligodendrocytes and the support, stimulation and promotion of remyelination by mature astrocytes is promoted through the administration of cPG compounds in the prophylaxis or therapy of demyelinating diseases such as multiple sclerosis.
  • present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of cyclic GP or its analogues with structural formulas given above to treat a disease, disorder, or condition, including but not limited to Alzheimer’s disease and its related conditions such an impairment of cognitive function.
  • the present invention provides methods of treating an animal having a cognitive impairment, comprising administration to that animal an effective amount of a composition comprising cyclic GP or its analogues.
  • the animal to be treated is a human.
  • One aspect of the present invention is generally directed to therapeutic treatments of neurological diseases and injuries.
  • the present invention is not limited to any specific mechanisms of action and may, in part be based on inducing neurogenesis, in particular. neural stern cell, or progenitor cell proliferation, the proliferation of neural stem cell.
  • cyclic Prolyl Glycine and it analogues f‘cPG compounds”) act as key neurogenesis modulating agents that facilitate and induce proliferation and'or differentiation in neural cells.
  • Neurogenesis is defined herein as proliferation, differentiation, migration, or survival of a neural cell in vivo or in vitro.
  • the neural cell can be an adult, fetal, or embryonic neural stern cell or progenitor cell.
  • Neurogenesis also refers to a net increase in cell number or a net increase in cell survival.
  • neural stem cell would include, at least, all brain stem cells, all brain progenitor cells, and all brain precursor ceils.
  • GPCRs G-proteih coupled receptors
  • GPCRs G-protein -coupled receptors
  • GPLR G protein-linked receptors
  • the ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins.
  • GPCRs in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate.
  • G protein-coupled receptors are involved in many diseases, and are also the target of approximately 34% of all modem medicinal drugs.
  • One aspect of the present invention includes, and not being limited by any proposed mechanisms, that cPG and its analogues can act as a neurogenesis modulating agents that modulate intracellular levels of cAMP and/or Ca 2 ⁇ cPG has been shown chemically and biologically to be capable of increasing cAMP (e.g., by increasing synthesis or decreasing breakdown) and/or Ca 2 ” (e.g., by increasing influx or decreasing efflux).
  • One aspect of the present invention describes a new method for promoting regeneration of damaged nerve tissue, compri sing administering an effective amoun t of cyclo Prolyl Glycine (cPG), and its analogues, which can reduce the rate of growth of glial cells to facilitate the growth of nerve tissue.
  • cPG cyclo Prolyl Glycine
  • Neurons are closely surrounded by glial cells or astrocytes.
  • One of the difficulties in achieving regeneration of neurons after they have been damaged or severed is that the glial cells proliferate and form a barrier to the regenerating neurons. The result is that the further movement of the neurons toward anticipated attachment sites is blocked and regeneration of structure and function ceases. It has been observed that formation of astrocytic and connective tissue scars and progressive necrosis have negative impact on the regeneration of neuronal functions.
  • one aspect of the present invention is a method for promoting regeneration of damaged nerve tissue in a mammal (such as a human), comprising administering an effective amount of cPG compounds (cPG and its analogues) to the damage site.
  • a mammal such as a human
  • Some objectives of the experiments provided herein is to provide enablement for a method of regenerating neurons and gl ial cells or a method of repairing damaged neurons and glial cells as claimed.
  • cyclic Prolyl Glycine and its pharmaceutically active analogues act as a neuronal modulating agents in order to treat depression and other psychological disorders.
  • the A-methyl- aspartate receptor (“NMDA receptor'’), is a glutamate receptor and ion channel protein found in nerve cells.
  • the NMDA receptor is one of three types of ionotropic glutamate receptors, the others being the AMP A and kainate receptors.
  • the NMDA receptor is activated when glutamate and glycine bind to it. and when activated it allows positively charged ions to flow through the cell membrane.
  • NMDA receptor channels play an important role in synaptic plasticity and synapse formation underlying memory, learning and formation of neural networks during development in the central nervous system (CNS). Over activation of the receptor, causing excessive influx of Ca 2 b can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.
  • the NMDA receptor is an ion channel protein receptor that is activated when glycine and glutamate bind to it.
  • the receptor is a heteromeric complex that interacts with multiple intracellular proteins by three different subunits: NR1, NR2 and NR3.
  • NR1 has eight different subunits generated by alternative splicing from a single gene. There are four different NR2 subunits (A-D), and NR3A and NR3B subunits have been reported.
  • Six separate genes encode for NR2 and NR3. [Loftis J. M., Janowsky A. (2003). ''The N- methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications” (Pharmacol Ther. 97 (1): 55-85. doi: 10.1016/s0163- 7258(02)00302-9).
  • NMDA receptors in particular NR2B subunit- containing channels
  • NR2B subunit- containing channels have been investigated as therapeutic agents for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437).
  • the NR2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangement.
  • the basic structure and functions associated with the NMDA receptor can be attributed to the NR2B subunit.
  • NR2B N- terminal domain of NR2B.
  • the NR2 subunit acts as the binding site for glutamate, one of the predominant excitatory neurotransmitter receptors in the mammalian brain.
  • glutamate one of the predominant excitatory neurotransmitter receptors in the mammalian brain.
  • NR2B has been associated with age- and visual-experience-dependent plasticity’ in the neocortex of rats, where an increased NR2B/NR2A ratio correlates directly with the stronger excitatory LTP in young animals. This is thought to contribute to experience- dependent refinement of developing cortical circuits.
  • GPCRs G protein-coupled receptors
  • GPLR G protein-Linked receptors
  • GPCRs in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate. G protein-coupled receptors are involved in many diseases and are also the target of approximately 34% of all modern medicinal drugs.
  • cyclic Prolyl Glycine and its pharmaceutically active analogues act as a neuronal modulating agents in order to treat depression and other psychological disorders.
  • One possible mechanism though expressly not being limited to any mechanism, is the modulation of intracellular levels ofcAMP and/or Ca 2+ .
  • cPG has been shown chemically and biologically to be capable of increasing cAMP (e.g., by increasing synthesis or decreasing breakdown) and/or Ca 2 '’’ (e.g., by increasing influx or decreasing efflux).
  • cyclic Prolyl Glycine and its pharmaceutically active analogues have been shown to selectively bind the N-terminal domain of NR2B, which might sustain an antidepressant response in human.
  • cPG cyclic Prolyl Glycine
  • cPG compounds which are ligands for the NR2B receptor and can be useful for the treatment of various disorders of the central nervous system.
  • the cPG compounds provide advantages for pharmaceutical uses, for example, wdth regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • patients are given the combination of substances at pharmaceutically effective dosage levels using appropriate routes of administration and regime.
  • the substances can be administered in the form of a single dosage unit in which the active ingredients are combined with a suitable carrier; or they may be given in separate dosage units in which the active materials are individually combined with a suitable carrier.
  • the administration may be simultaneous or at selected time intervals.
  • the administration is preferably orally and the carrier or carriers are selected with this in mind. While this is the case, other modes of administration of both substances as well as mixed modes with the individual materials is considered part of the present invention.
  • the dosage levels of the materials will vary with the particular material being used and the severity of the condition of the patient being treated.
  • the cyclic Prolyl Glycine (cPG) is used in amounts ranging from about 0.1 mg to about 10 mg per kg of body weight. It is recommended to administer orally with a dose of about 20 mg to about 80 mg per day and can be up to about 100 mg per day for some severe cases per physician’s prescription order.
  • compositions of the present invention are prepared by utilizing the active ingredients in association with the pharmaceutical carriers conventionally employed wi th such materials.
  • the compositions of the present invention are in general contemplated for administration orally to achieve an antidepressant effect. This may be in any of the dosage forms such as tablets, capsules, powders, suspensions, solutions, syrups and the like, including sustained release preparations.
  • dosage form as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosage, each unit containing a predetermined quantity of active material in association with the required diluent, carrier or vehicle. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units.
  • Ampules for parenteral application can be prepared and preferably contain water soluble salts of the active substances and possible buffer substances in aqueous solution.
  • care must be taken to insure stability of the active materials.
  • compositions are prepared in the manner indicated above. These individual compositions can then be administered as such or combined into a single-dosage unit while maintaining the separate identity, as for example in a multilayer tablet or single capsule containing both components in a plurality of discrete particles.
  • the present invention recognizes that there is a long felt need for the treatment of mild cognitive impairment.
  • the present invention includes several general and useful aspects, including but not limited to:
  • a first aspect of the present invention generally relates to a method of treating, relieving, or alleviating mild cognitive impairment in a subject.
  • a second aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease in a subject.
  • a third aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject
  • a fourth aspect of the presen t i nvention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject
  • a fifth aspect of the present invention generally relates to a method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject
  • a first aspect of the present invention includes a method of treating, relieving, or alleviating mild cognitive impairment in a subject, including: a) providing a subject in need of treating, relieving, or alleviating mild cognitive impairment; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the mild cognitive impairment; further wherein the subject
  • An aspect of the present invention includes wherein the mild cogniti ve impairment is related to Alzheimer’s Disease.
  • Another aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is from about 1 pg to about 100 mg per kg of bodyweight.
  • a further aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is administered at an amount from about 0.1 mg to about 10 mg/kg per day, from about 0.5 mg to about 20 mg/kg per day, from about 0.2 mg to about 40 mg/kg per day, from about 5 mg to about 50 mg/kg per day, or from about 10 micrograms to about 100 mg/kg per day.
  • An additional aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound has a lower limit of about 0.1 milligrams per kilogram mass (mg, kg) of the mammal and an upper limit of about 10 mg/kg of the subject.
  • An aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is from about 20 mg and about 80 mg per day, or from about 20 mg and about 100 mg per day.
  • Another aspect of the present invention includes wherei n the administeri ng of the pharmaceutically effective amount of the cPG compound is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
  • a further aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is in combination with artificial cerebrospinal fluid.
  • An additional aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is intravenous.
  • An aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is combined with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF-II), or a combination thereof.
  • a neuroprotective agent insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF-II)
  • Another aspect of the present in vention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is combined with the administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof
  • a further aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is combined with administration of an anti-inflammatory agent.
  • An additional aspect of the present invention includes wherein the cPG compound is provided in aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.
  • an aspect of the present invention includes wherein the cPG compound includes one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or a combination thereof.
  • Another aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.
  • a further aspect of the present invention includes wherein the cPG compound is in the form of a tablet, capsule, or a combination thereof.
  • An additional aspect of the present invention includes wherein the specific binding member includes a receptor, receptor agonist, polypeptide, ligand, antibody, polyclonal antibody, monoclonal antibody, humanized antibody, an active fragment thereof, or a combination thereof.
  • An aspect of the present invention includes wherein the specific binding member includes Lecanemab, Aducanumab, Donanemab, Crenezumab, Semorinemab, Gantenerumab an active fragment thereof, or a combination thereof.
  • Another aspect of the present invention includes wherein the specific binding is biding with Amyloid p soluble protofibrils.
  • a further aspect of the present invention includes wherein the specific binding is binding with Amyloid P (Ap42) soluble protofibrils.
  • An additional aspect of the present invention includes wherein the operably binds is binding with Amyloid p soluble protofibrils to modulate at least one activity thereof.
  • the modulation of an activity relates to the ability to provide a desired effect, such as but not limited to a pharmaceutical effect, such as but not limited to a pharmaceutical effect as described or demonstrated herein.
  • An aspect of the present invention includes wherein the operably binds is binding with Amyloid [3 (A
  • Another aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is from about Ipg to about 100 mg per kg of body weight.
  • a further aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is administered at an amount from about 0.1 mg to about 10 mg/kg per day, from about 0.5 mg to about 20 mg/kg per day, from about 0.2 mg to about 40 mg/kg per day, from about 5 mg to about 50 mg/kg per day, or from about 10 micrograms to about 100 mg/kg per day.
  • An additional aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member has a lower limit of about 0.1 milligrams per kilogram mass (mg/kg) of the mammal and an upper limit of about 100 mg/kg of the subject.
  • An aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is from about 20 mg and about 80 mg per day, or from about 20 mg and about 100 per day.
  • Another aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
  • a further aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is in combination with artificial cerebrospinal fluid.
  • An additional aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is intravenous.
  • An aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is combined with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF -II), or a combination thereof.
  • a neuroprotective agent insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF -II)
  • Another aspect of the present invention includes wherein the administering of the pharmaceutically effective amoun t of the specific binding member is combined with the administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof.
  • a further additional aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is combined with administration of an anti-inflammatory agent.
  • An additional aspect of the present invention includes wherein the administering of the pharmaceutically effecti ve amount of the specific binding member Lecanemab (Leqembi®) at a dose of 10 mg/kg, once every two weeks, in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier, such as 0.9% sodium chloride injection.
  • a pharmaceutically acceptable carrier such as 0.9% sodium chloride injection.
  • An aspect of the present invention includes wherein the specific binding member is provided in aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.
  • Another aspect of the present invention includes wherein the specific binding member includes one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or a combination thereof.
  • a further aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracisternal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.
  • An additional aspect of the present invention includes wherein the specific binding member is in the form of a tablet, capsule, nasal spray, injectable, intravenous infusion, or a combination thereof.
  • An aspect of the present invention includes wherein the subject is a mammal.
  • Another aspect of the present invention includes wherein the subject is a subject is human.
  • a further aspect of the present invention includes wherein the effective amount that together treat the subject for mild cognitive impairment is from about 0.1 mg/kg to about 20 mg/kg body weight of cPG in combination with from about 1 gg to about 100 mg per kg of body weight of a specific binding member.
  • An additional aspect of the present in vention includes wherein the treating, relieving, or alleviating is treating.
  • To treat a condition means to heal the disease, disorder, or condition, so that the patient recovers completely and no longer has the symptoms of the disease, disorder, or condition.
  • To treat can include mitigation, delay the onset of the disease, relieve the disease, alleviate the symptoms of the disease, or a combination thereof. These are distinct from the concept of cure, which relates to the end of the disease from a subject, or as the term is known in the art, particularly in the medical field.
  • An aspect of the present invention includes wherein the treating, relieving, or alleviating is relieving.
  • Another aspect of the present invention includes wherein the treating, relieving, or alleviating is alleviating.
  • alleviate means to make it less severe or serious and more bearable of the above problems and symptoms.
  • a second aspect of the present invention includes a method of treating, relieving, or alleviating Alzheimer’s Disease in a subject, includes: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the Alzheimer’s Disease; further where
  • a third aspect of the present invention includes a method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject, including: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease Psychosis; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2 -Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the
  • a fourth aspect of the present invention includes a method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject, including: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease behaviours, aggression, agitation, anger, apathy, or a combination thereof; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPGj or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl- Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with A$ soluble proto
  • a fifth aspect of the present invention includes a method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject, including: a) providing a subject in need of treating, relieving, or alleviating Early Onset Alzheimer’s Disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Metliyl-Proline (cPMeG), or a combination thereof, col lectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the
  • cyclic Prolyl Glycine (“cyclic PG 5 ’ or “cPG”) has the following structure;
  • the present invention includes novel diketopiperazines that are structurally related to cPG.
  • One aspect of this invention provides novel cyclic compounds having the structural formula and substituents described below.
  • R can be an Alkyl” which refers to a saturated branched, straight chain or cyclic hydrocarbon radical.
  • exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopiopyimethyl, hexyl and the like.
  • R can be an Ally, which refer to a group is a substituent with the structural formula I hC CH Cl IJL where R is the rest of the molecule.
  • R is a methyl
  • an aspect of the present invention that includes Cyclic Glycyl- 2- Alkyl Proline is (8aS)-Methyl-hexahydropyrrolo[l,2-a]pyrazine- 1,4-dione, which is referred to as Cyclic Glycyl-2-Methyl-Pro!ime or cyclicGMeP or cGMeP.
  • c(PG)3 and cGAL can be prepared by methods such as are already well- known to persons of ordinary skill in the art of peptide and modified peptide synthesis. See for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer- Verlag 1993. Synthesis of the diketopiperazine compounds of this invention may be by solution-phase synthesis as discussed in the Examples or via the solid-phase synthesis method exemplified by Merrifield et al. 1963 J. Amer. Chem. Soc.: 85, 2149-2156. Specific examples of diketopiperazme synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and references therein. A person of ordinary skill in the art will have no difficulty, taking account of that skill and the knowledge available, and of this disclosure, in developing one or more suitable synthetic methods for compounds of this invention.
  • Structure 4 one possible structure for cyclic (glvcyl-L-prolylglvcyl-L-prolylglvcyl- L-prolyl).
  • CYCLIC Peptides VII The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences- by Charles M. Deber and Elkan R. Blout.
  • the material was then dissolved in a minimum of DMF.
  • the white microcrystalline precipitate was shown to be Cyc/o(glycyl-L -prolyl-glycyl-L - prolyl-glycyl-L -prolyl) (155 mg, with 28% yield), formed complexed with DMF. Crystallization from methanol-ether of 100 mg of this material gave crystalline cyclo(Pro- Gly)s (55 mg) free of DMF.
  • cPG analogues is cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L- prolyl) or being abbreviated as cyclic(tri(Pro-Gly)) or referred herein as c(PG)3.
  • cPG analogues is cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline referred herein as “cGAL.”
  • cPG compounds Collectively the cPG, c(PG)3, cGAL, and Cyclic Glycyl-2-Methyl-Proline, and their pharmaceutically acceptable salts, are referred herein collectively as the “cPG compounds.”
  • Cyclic Glycyl-2-Methyl-Proline is a compound belong to the cyclic Glycyl- 2 -Alkyl Proline) group of compounds.
  • any of the cPG compounds, derivatives thereof, analogs thereof, and the like as disclosed herein or otherwise known in the art can be provided in the form of a pharmaceutically acceptable salt.
  • the cPG compounds are administered in a pharmaceutically acceptable composition such as a pharmaceutically acceptable carrier.
  • composition additional! ⁇ ' includes a therapeutic amount of a cPG compound in combination with a compound selected from growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-11 (IGF-II), GPE, transforming growth factor-ill, activin, growth hormone, nerve growth factor, growth hormone binding protein, JQF-binding proteins (especially JGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor.
  • growth factors and associated derivatives IGF-I
  • IGF-II insulin-like growth factor-11
  • GPE transforming growth factor-ill
  • activin growth hormone, nerve growth factor, growth hormone binding protein, JQF-binding proteins (especially JGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4
  • Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-1 (FHF-1) FHF-2 FHF-3 and FHF-4, karatinocyte growth factor 2, glial-activating factor, FGF- 10 and FGF- 16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial-cell line derived neurotrophic factor, activity -dependant neurotrophic factor, cytokine leukaemia inhibiting factor, oncostatin M, interleukin), P,a,x or consensus interferon, TNF- a; clomethiazole; kynurenic acid, Semax, FK506 [tacrolimus], L-threo-l-pheyl-2- decanoylamino-3 -morpholino- 1 -propanol, andrenocorticotropin-(4-9_ analogue [ORG2766] and dizolcipine [
  • Lecanemab or BAN2401 is the humanized Immunoglobulin G (IgG 1) version of the mouse monoclonal antibody mAb'l 58, which selectively binds to large, soluble A[3 protofibrils.
  • IgG 1 Humanized Immunoglobulin G
  • mAb'l 58 This therapeutic antibody grew out of the discovery of the “Arctic” mutation in amyloid precursor protein (APP), which leads to a form of clinically typical Alzheimer's disease that is marked by particularly high levels of Ap protofibrils and relative absence of amyloid plaques (see Nilsberth et al., 2001).
  • mAbl58 was originally developed at Uppsala University, Sweden.
  • Lecanemab targets soluble Ap aggregates (oligomers and protofibrils) with high selectivity.
  • Lecanemab showed a high selectivity' for protofibrils versus monomers with an about 2300- and about 14,300-fold stronger binding to protofibrils (small and large, respectively) than to monomers when analyzed by SPR.
  • Oligomerization of the amyloid P-protein (Ap) is believed to be a critical event in the development of Alzheimer’s Disease (AD).
  • Ap is found primarily as either a 40- or 42- amino acid peptide, differing only in the addition of two hydrophobic residues (141 and A42) to the C -terminus of the former. This small difference in primary structure translates into large differences in the oligomerization patterns of Ap40 and Ap42.
  • CTFs C -terminal fragments
  • Ap(31-42), Ap(30-42) and Ap(39-42) inhibited 100%, 80% and 80% of Ap- induced toxicity, respectively.
  • both AP(31-42) and AP(39-42) formed non-toxic heterooligomers with Ap42 monomers, tire mechanism was different: Ap(31-42) was a stronger inhibitor of intermolecular interactions among Ap42 monomers, whereas AP(39- 42) was a stronger inhibitor of intramolecular interactions within Ap42 monomers.
  • Wu C Murray MM, Bernstein SL, Condron MM, Bitan G, Shea JE, Bowers MT.
  • Ap is a proteolytic product of amyloid precursor protein by p- and y-secretases.
  • the imprecise cleavage of y-secretase at C-terminus of Ap sequence results in two major Ap isofomis: Ap42 (42 residues long) and Ap40 (40 residues long).
  • Ap42 has two extra residues at the C-terminus.
  • the concentration of Ap40 in cerebral spinal fluid has been found to be several-fold more than that of Ap42.
  • Ap42 is the major component of amyloid plaques in AD brains. (Gu L, Guo Z. Alzheimer's Ap42 and Ap40 peptides form interlaced amyloid fibrils. J Neurochem. 2013 Aug;126(3):305-I 1.
  • Lecanemab targets AP’s N-terminus (residues 1-16'), overlapping with fibrinogen’s binding site on Ap. Lecanemab blocked Ap42 binding to fibrinogen in a dose-dependent manner, while human IgG had no effect.
  • the Ap42 preparation used was comprised of curvy linear aggregates (small protofibrils) 30-90 nm in length.
  • Lecanemab Blocks the Effects of the Ap/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture. bioRxiv [Preprint]. 2024 Jan 21:2024.01.20.576458. doi: 10.1101/2024.01.20.576458. Update in: Proc Natl Acad Sei U S A. 2024 Apr 23;121(17):e2314450121. doi: 10.1073/pnas.2314450121. PMID: 38293058; PMCID: PMC 10827200.).
  • soluble oligomeric Ap was proposed to be toxic through binding to a variety of receptors, including lipids, proteoglycans, and proteins, such as the Ap-binding p75 neurotrophin receptor (P75NRT), the low-density lipoprotein receptor-related protein (LRP), cellular prion protein (PrPc), metabotropic glutamate receptors (mGluR5), a subunit containing nicotinic acetylcholine receptor ( «7nAChR), N-methyl-D-aspartic acid receptor (NMDAR), P-adrenergic receptor (P-AR), erythropoietin-producing hepatoma cell line receptor (EphR), and paired immunoglobulin-like receptor B (PirB)97.
  • P75NRT Ap-binding p75 neurotrophin receptor
  • LRP low-density lipoprotein receptor-related protein
  • PrPc cellular prion protein
  • mGluR5 met
  • the Ap/Ap receptor interactions are proposed to generate and transduce neurotoxic signals into neurons, causing cellular defects such as mitochondrial dysfunction and the ER stress response. In addition, some Ap receptors are most likely to internalize Ap into neurons to display distinct cellular defects. (Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017 Sep;38(9):1205-1235. doi: 10. 1038/aps.2017.28. Epub 2017 Jul 17.
  • a potential binding of IGF- 1 and its analogue, NA-831 with Lecanemab would potentially provide advantages over monotherapy of Lecanemab or NA-831 alone.
  • ARIA-E amyloid -related imaging abnormalities, mainly with edema
  • the main risk factors identified for developing ARIA-E have been antibody dose and the presence of the apolipoprotein E4 (ApoE4 ) allele.
  • ApoE4 apolipoprotein E4
  • the exact mechanism for the occurrence of ARIA-E has not been elucidated, but probable explanations involve direct binding of Ap antibodies to cerebral amyloid angiopathy (CAA).
  • CAA is a pathology consisting of fibrillar Ap, mainly Ap 1 -40 deposited in the blood vessel walls and is a common occurrence in AD.
  • Lecaneniab-irmb is a recombinant human immunoglobulin gamma 1 (IgG 1 ) monoclonalantibody targeting aggregated soluble and insoluble forms of amyloid beta. It is expressed in a Chinese hamster ovary (CHO) cell line.
  • Lecanemab-irmb inj ection is a preservative-free, sterile, clear to opalescent, and colorless to yellow solution for intravenous infusion after dilution. It is supplied in single-dose vials available in concentrations of 500 mg/5.0 mL (100 mg/mL) or 200 mg/2 mL (100 mg/mL).
  • Lecanemab a humanized IgG I monoclonal antibody that binds with high affinity to Ap soluble protofibrils, has been tested in persons with early Alzheimer’s disease.
  • a multicenter, double-blind, phase 3 trial was conducted over 18 months involving 1795 participants 50 to 90 years of age with early Alzheimer’s disease.
  • the primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating- Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment).
  • CDR-SB Clinical Dementia Rating- Sum of Boxes
  • CDR-SB scores increased from a baseline of 3.2 to 4.41 in the lecanemab group, a change of 1.21 ; and increased to 4.86 in the placebo group, a change of 1.65.
  • the -0.45 difference (4.41 -4.86) between the groups is often represented as 27% less cognitive decline (0.45/1.65), indicating the clinical benefit of Lecanemab treatment. This percentage is mis-leading and an erroneous conclusion based on the use of the wrong denominator.
  • the actual CDR-SB scores give lecanemab a clinical benefit of 9.3% (0.45/4.86), and not 27%. This smaller value is unlikely to make any difference for people living w id 1 , early AD
  • Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events.
  • Lecanemab was approved by the FDA on July 6, 2023, even though it was recommended that longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.
  • LEQ Lecanemab
  • AD Alzheimer’s disease
  • a combination therapy includes LEQ at reduced dose at 5 mg/kg administered intravenously, in addition to cPG administered orally at reduced dose of about 0.5 mg/kg.
  • a patient is administered about 5 mg/ kg of Lecanemab intravenously biweekly, in addition to take between about 30 to about 60 mg of cPG orally per day.
  • the combined treatment resulted in a marked improvement in. cognitive impairment after a 12-month treatment.
  • repositioning anti-diabetic drugs for dementia aligns with the concept of repositioning anti-diabetic drugs for dementia, as the insulin/IGF-1 signaling pathway has been implicated in many dementia subtypes.
  • repositioning anti-diabetic drags such as IGF-1 for disease modifying therapies (DMT) against multiple subtypes of dementia appears to be a reasonable approach.
  • DMT disease modifying therapies
  • cPG can cross the blood brain barrier and has been shown to exhibit neuroprotection and neurogenesis properties.
  • the combination therapy of cPG compounds and Lecanemab can be used in the treatment or prevention of cell damage or cell death in response to diseases and injury resulting from septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, allograft rejection, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataract, retinal disorders, age-related macular degeneration, optic neuritis ileitis, inflammation induced by overproduction of inflammatory cytokines
  • cPG compound can be used in the restoration of myelination where depletion due to trauma, toxin exposure, asphyxia or hypoxia-ischemia, perinatal hypoxic- ischemic injury, injury to or disease of the w'hite matter of the CNS, acute brain injury, chronic neurodegenerative disease including multiple sclerosis, and demyelinating diseases and disorders including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, Devic's disease, the leucodystrophies; non-inflammatory involvement: progressive multifocal leukoencephalopathy, and central pontine myelinolysis.
  • the cPG compound can be administered at between about 1 ug to about 150 mg per kilogram of bodyweight.
  • a suitable dosage for administration of cPG can be, for example, preferably but not limited to between about 0. ling to about 100 mg per kilogram of body weight, between about 1 mg to about 100 mg per kilogram of body weight, between about 5 mg and about 70 mg per kilogram of body weight, between about 10 mg to about 50 mg per kilogram of body weight, or between about 20 mg to about 40 mg per kilogram of bodyweight.
  • the dose, route of administration, and regime of cPG may be different for different diseases, disorders, and conditions. As an example, mild cognitive impairment may have a lower dose using the same or different route of administration than for Alzheimer’s disease.
  • a typical dosage for patient with mild cognitive impairment can be between about 0.2 mg to about 1 mg per day administered orally (for example, taking 1 capsule of 20 mg or 2 capsules per day per doctor prescription).
  • a more severe Alzheimer’s Disease or severe Traumatic Brain injury patent can be administered intravenously in a range from between about 50 mg to about 300 mg per day.
  • Pharmacology and Utility cPG can act as an anti-necrotic and anti-apoptotic in a process of cell death. Its anti- apoptotic and anti-necrotic activity in vivo can be measured by cell counts.
  • cPG can also be measured in vitro.
  • CNS damage may for example be measured clinically by the degree of permanent neurological deficit cognitive function, and''or propensity to seizure disorders.
  • compositions and Administration cPG itself as pail of the present invention can be used to prevent or treat cell damage and programmed death and the induction of myelin production. Usually this is effected through the direct administration of cGP to the patient. If desired, a combination of the cPG compounds and its analogues can be administered in a pharmaceutically acceptable composition.
  • the effective amount of cPG in the CNS can be increased by administration of a pro-drug from of cPG, which comprises cPG and a carrier, cPG and the carrier being joined by a linkage which is susceptible to cleavage or digested within the patient. Any suitable linkage can be employed which will be cleaved or digested to release cPG following administration.
  • Pro-drugs of cPG and its analogues can also be administered.
  • the pro-drug is metabolized or otherwise altered within the subject to form cPG.
  • cPG and its analogues such as but not limited to c(PG)3 and cyclic Glycyl-2-Ally 1 Proline, or cyclic Glycyl-Alkyl Proline or Cyclic Glycyl-2-Methyl-Prolime can be administered as part of a medicament or pharmaceutical preparation. This can involve combining cPG with any pharmaceutically appropriate carrier, adjuvant or excipient. The selection of the carrier, adjuvant or excipient will of course usually be dependent upon the route of administration to be employed.
  • the administration route can vary wddely and be any appropriate route of administration.
  • An advantage of cPG is that it can be administered peripherally. This means it need not be administered directly to the CNS of the patient in order to have effect in the CNS.
  • peripheral route can include but are not limited to parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion (using e.g., controlled release devices or minipumps such as osmotic pumps or skin patches), implant, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, oral, buccal, pulmonary, rectal or vaginal.
  • the compositions can be formulated for parenteral administration to humans or other mammals in therapeutically effective amounts (e.g., amounts which eliminate or reduce the patient's pathological condition) to provide therapy for the neurological diseases described above.
  • Two of the preferred administration routes will be by subcutaneous injection (such as but not limited to, dissolved in 0.9% sodium chloride) or orally (in a capsule).
  • cPG compounds may be directly administered to the CNS of the patient. Again, this can be achieved by any appropriate direct administration route. Examples include administration by lateral cerebroventricular injection or through a surgically inserted shunt into the lateral cerebroventricle of the brain of the patient.
  • Tire calculation of the effective amount of cPG compounds to be administered is within the skill of one of ordinary skill in the art, and will be routine to those persons skilled in the art. Needless to say, the final amount to be administered will be dependent upon the route of administration and upon the nature of tire neurological disorder or condition that is to be treated.
  • the cPG compound will be administered at between about 1 pg to 100 mg of cPG compound per per kilogram of body weight where the dose is administered centrally.
  • a suitable dosage for administration of cPG may be, for example, at between about 0.1 mg to about 10 mg per per kilogram of body weight, or at between about 1 mg to about 5 mg per per kilogram body weight.
  • the total pharmaceutically effective amount of the cPG compound administered parenterally per dose will be in a range that can be measured by a dose response curve.
  • the amount of cPG compound to be employed can be calculated on a molar basis based on these serum levels of cPG.
  • one method for determining appropriate dosing of the compound entails measuring cPG levels in a biological fluid such as a body or blood fluid. Measuring such levels can be done by any means, including RIA and ELISA. After measuring cPG levels, the fluid is contacted with the compound using single or multiple doses. After this contacting step, the cPG levels are re-measured in the fluid. If the fluid cPG levels have fallen by an amount sufficient to produce the desired efficacy for which the molecule is to be administered, then the dose of the molecule can be adjusted to produce maximal efficacy. This method can be carried out in vitro or in vivo.
  • this method is carried out in vivo, i.e., after the fluid is extracted from a mammal and the cPG levels measured, the compound herein is administered to the mammal using single or multiple doses (that is, the contacting step is achieved by administration to a mammal) and then the cPG levels are remeasured from fluid extracted from the mammal.
  • the compound may also be suitably administered by a sustained-release system.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include polylactides (U.S. Pat. No.
  • PEGylated peptides having a longer life can also be employed, based on, e.g., the conjugate technology described in WO 95/32003, published November 30, 1995.
  • the compound is formulated generally by mixing each at the desired concentration, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically, or parenterally, acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • a pharmaceutically, or parenterally, acceptable carrier i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the formulations are prepared by contacting the compound with liquid carriers or finely divided solid carriers or both. Then, if necessary', the product is shaped into the desired formulation.
  • the carrier is a parenteral carrier ⁇ more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution. Non- aqueous vehicles such as fixed oils and ethyl oleate may also be used.
  • the carrier may additionally contain additives such as substances that enhance isotonicity and chemical stability.
  • Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, trehalose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counter-ions such as sodium; non-ionic surfactants such as polysorbates, poloxamers, or polyethylene glycol (PEG);
  • the cPG compound is typically formulated in such vehicles at a pH of between about 5.5 to about 8.0.
  • Typical adjuvants which may be incorporated into tablets, capsules, and the like ar e a binder such as acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavoring agent such as peppermint, wintergreen, or cherry.
  • a liquid carrier such as a fatty oil.
  • a syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent, and a flavoring agent such as cherry.
  • a sweetener such as sucrose
  • preservatives like propyl paraben a coloring agent
  • a flavoring agent such as cherry.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants, and the like can be incorporated according to accepted pharmaceutical practice.
  • the compound to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes).
  • Therapeutic compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
  • the compound ordinarily will be stored in unit or multi-dose containers, for example, sealed glass ampules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution.
  • a lyophilized formulation 10-mL vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous solution of compound, and the resulting mixture is lyophilized.
  • the infusion solution is prepared by reconstituting the lyophilized compound using bacteriostatic Water-for-Injection.
  • Combination therapy with the cPG compound herein and one or more other appropriate reagents that increase total cPG in the blood or enhance the effect of the cPG is also contemplated. These reagents generally allow the cPG compound herein to release the generated cPG.
  • one aspect of the present invention includes using gene therapy for treating a mammal, using nucleic acid encoding the cPG compound, if it is a peptide.
  • gene therapy is used to increase (or overexpress) cPG levels in the mammal.
  • Nucleic acids, which encode the cPG peptide can be used for this purpose. Once the amino acid sequence is known, one can generate several nucleic acid molecules using the degeneracy of the genetic code, and select which to use for gene therapy.
  • nucleic acid (optionally contained in a vector) into the patient’s cells for purposes of gene therapy: in vivo and ex vivo.
  • in vivo delivery the nucleic acid is injected directly into the patient, usually at the site where the cPG compound is required.
  • ex vivo treatment the patient’s cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes which are implanted into the patient. See, for example, U.S. Pat. Nos. 4,892,538 and 5,283,187.
  • nucleic acids there are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. A commonly used vector for ex vivo delivery of the gene is a retrovirus.
  • the currently preferred in vivo nucleic acid transfer techniques include transfection with viral vectors (such as adenovirus, Herpes simplex I virus, or adeno-associated virus) and lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol, for example).
  • viral vectors such as adenovirus, Herpes simplex I virus, or adeno-associated virus
  • lipid-based systems useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol, for example.
  • an agent that targets the target cells such as an antibody specific for a cell-surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc.
  • proteins which bind to a cell-surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, and proteins that target intracellular localization and enhance intracellular half-life.
  • the technique of receptor-mediated endocytosis is described, for example, by Wu et al., 1987; Wagner el al., 1990).
  • Wu et al. 1987
  • Wagner el al. 1990
  • Kits are also contemplated for this invention.
  • a typical kit would comprise a container, preferably a vial, for the cPG compound formulation comprising cPG compound in a pharmaceutically acceptable buffer and instructions, such as a product insert or label, directing the user to utilize the pharmaceutical formulation.
  • Certain aspects of the present invention include the use of cPG in treatment of cognitive impairment associated with aging with neurodegenerative conditions or in situations in which cognitive impairment is found with no apparent neurodegeneration.
  • Such other agents can be selected from the non-limiting group of, for example, growth factors and associated derivatives, e.g,, insulin-like growth factor-I (IGF -I), insulin- like growth factor-II (IGF HI), growth hormone, nerve growth factor, growth hormone binding protein, and/or IGF-binding proteins.
  • growth factors and associated derivatives e.g, insulin-like growth factor-I (IGF -I), insulin- like growth factor-II (IGF HI), growth hormone, nerve growth factor, growth hormone binding protein, and/or IGF-binding proteins.
  • Lecanemab (previously BAN2401) is a humanized immunoglobulin G1 (IgGl) anti-amyloid beta (A(3) monoclonal antibody targeting aggregated forms of A[3. Extracellular deposits of A
  • IgGl immunoglobulin G1
  • A(3) monoclonal antibody targeting aggregated forms of A[3.
  • Accumulation of Ap in the brain has been proposed to be the primary driver of the disease process and precedes the accumulation of tau pathology and neural degeneration.
  • Lecanemab was approved by the FDA which was based on reduction in amyloid plaque burden measured by positron emission tomography (PET) imaging which is proposed to be reasonably likely to predict clinical benefit.
  • PET positron emission tomography
  • This FDA submission contains biomarker, efficacy, and safety data from Study 201, a multicenter, randomized, double- blind, placebo-controlled, parallel- group study in patients with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia.
  • compositions and methods of the present invention find use in the treatment of animals, such as human patients, suffering from cognitive impairment. Still more generally, the compositions and methods of the inventi on find use in the treatment of mammals, such as but not limited human patients and subjects, suffering from memory impairment, mild cognitive impairment, dementia, including dementia including dementias resulting from cerebral atrophy associated with Alzheimer's disease, Lewy-bodies disease, frontotemporal lobar degeneration, vascular dementia, head trauma; Huntington's disease, Parkinson's disease, or Down’s syndrome.
  • mammals such as but not limited human patients and subjects, suffering from memory impairment, mild cognitive impairment, dementia, including dementia including dementias resulting from cerebral atrophy associated with Alzheimer's disease, Lewy-bodies disease, frontotemporal lobar degeneration, vascular dementia, head trauma; Huntington's disease, Parkinson's disease, or Down’s syndrome.
  • Cyclic PG compounds can be administered as part of a medicament or pharmaceutical preparation. This can involve combining a compound of the invention with any pharmaceutically appropriate carrier, adjuvant or excipient. The selection of the carrier, adjuvant or excipient will of course usually be dependent upon the route of administration to be employed.
  • compounds of the present invention will be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination rvith other conventional therapeutic agents for the disease being treated.
  • a therapeutically effective amount may vary depending on the disease or injury, its severity, the age and relative health of the animal being treated, the potency of the compound(s), and other factors.
  • Therapeutically effective amounts of cyclic Prolyl Glycine can range from 0.01 to 10 milligrams per kilogram mass of the animal, with lower doses such as 0.01 to 0.1 mg/kg being appropriate for administration through the cerebrospinal fluid, such as by intracerebroventricular administration, and higher doses such as 0.1 to 10 mg/kg being appropriate for administration by methods such as oral, systemic (e.g.
  • transdermal transdermal
  • parenteral e.g. intravenous
  • a person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease or injury.
  • Cyclic Prolyl Glycine and cPG compound can be administered orally or peripherally via any peripheral route known in the art. These can include but are not limited to parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, intravenous infusion, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal or vaginal.
  • parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, intravenous infusion, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal or vaginal.
  • the cyclic Prolyl Glycine and cPG compounds can be administered orally.
  • the amount of a compound of this invention in the composition may vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary' skill in the art.
  • the final composition may comprise from 5 mg to 50 mg of cPG for a typical adult weighing 50 to 120 kg or 1 xlO' 3 percent to 3x 10' 4 by weight (% w) with the remainder being the excipient or excipients.
  • a compound can be injected directly into a site of neural damage.
  • the effective amount of compound in the CNS can be increased by administration of a pro-drug form of a compound, which comprises a compound of the invention and a carrier, where the carrier is joined to a compound of the invention by a linkage which is susceptible to cleavage or digestion within the patient. Any suitable linkage can be employed which will be cleaved or digested following administration.
  • restoring nerve function in an animal can include administering a therapeutic amount of cyclic Prolyl Glycine or cPG compounds in combination with another neuroprotective agent, selected from, for example, growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-11 (IGF-II), transforming growth factor-[31, activin, growth hormone, nerve growth factor, growth hormone binding protein, IGF-binding proteins, keratinocyte growth factor, androgen-induced growth factor.
  • growth factors and associated derivatives selected from, for example, growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-11 (IGF-II), transforming growth factor-[31, activin, growth hormone, nerve growth factor, growth hormone binding protein, IGF-binding proteins, keratinocyte growth factor, androgen-induced growth factor.
  • Additional members of the FGF family include, for example, fibroblast growth factor homologous factor- 1 (FHF-1 ), FHF-2, FHF-3 and FHF-4, karatinocyte growth factor 2, brain derived growth factor, neurotrophin 3, and neurotrophin 4.
  • FHF-1 fibroblast growth factor homologous factor- 1
  • FHF-2 FHF-2
  • FHF-3 FHF-4
  • karatinocyte growth factor 2 karatinocyte growth factor 2
  • brain derived growth factor derived growth factor
  • neurotrophin 3 neurotrophin 4.
  • neuroprotective therapeutic agents include clomethiazole, kynurenic acid, Semax, tacrolimus; glutamate agonist such as, NPS1506, GV1505260, MK-801, GV150526; AMPA ants such as 2,3-dihydroxy-6-nitro- 7-sulfamoylbenzo(f)quinoxaline (NBQX); anti-inflammatory agents directed against the addressin MAdCAM-1 and/or its integrin o.4 receptors (a4fH and 04(37), such as anti- MAdCAM-lmAb MECA-367 (ATCC accession no. HB-9478).
  • Cyclic Prolyl Glycine compounds can be suitably administered by a sustained- release system.
  • sustained-release compositions include semi- permeable polymer matrices in the form of shaped articles, for example, films, or microcapsules.
  • cyclic Prolyl Glcyine or cPG compounds is formulated generally by mixing each at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically, or parenterally, acceptable carrier, for example, one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
  • the formulations are prepared by contacting cyclic Prolyl Glycine or cPG compounds uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation.
  • the carrier is a parenteral carrier, ore preferably a solution that is isotonic with the blood of the recipient.
  • carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution.
  • Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein.
  • Cyclic Prolyl Glycine or cPG compounds are typically formulated in such vehicles at a pH of from or about 4.5 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of salts of the compound.
  • the final preparation may be a stable liquid or lyophilized solid.
  • Formulations of cyclic Prolyl Glycine or cPG compounds in pharmaceutical compositions can also include adjuvants.
  • Typical adjuvants which may be incorporated into tablets, capsules, and die like are a binder such as acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavouring agent such as peppermint, wintergreen, or cherry.
  • cyclic Prolyl Glycine or a cPG compounds and compositions can include binders and optionally, a smooth coating.
  • the dosage form When the dosage form is a capsule, in addition to tire above materials, it may also contain a liquid carrier such as a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit.
  • a syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent, and a flavoring agent such as cherry .
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired.
  • cyclic Prolyl Glycine or cPG compounds are preferably sterile. Sterility may be accomplished by any method known in the art, for example filtration through sterile filtration membranes (for example, 0.2-micron membranes).
  • Therapeutic compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper able to be pierced by a hypodermic injection needle.
  • the present invention provides a method for the treatment of mild cognitive impairment and related neurodegenerative disorders and psychological disorders using NA-831 and cPG analogues and cPG compounds, in combination with antibodies or active fragments thereof, such as the monoclonal antibody Lecanemab that specifically binds with.
  • the first aspect of the present invention includes a method for relieving or alleviating of Alzheimer’s Disease psychosis caused by a disease, injury, or condition in a mammal in need thereof, comprising: a) providing a mammal in need of relieving or alleviating of Alzheimer’s Disease psychosis caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic (tri (Prolyl Glycine) or cyclic Glycyl-2- Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to said mammal; wherein the disease is selected from the group consisting of Alzheimer's Disease psychosis.
  • cPG cyclic Prolyl Glycine
  • cPMeG
  • Another aspect of the present invention includes wherein the administration of cPG and Lecanemab is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
  • a further aspect of the present invention includes wherein the effective amount of cPG compound is from about Ipg to about 100 mg per kg of body weight.
  • An additional aspect of the present invention includes wherein the administration is in combination with artificial cerebrospinal fluid. Another aspect of the present invention includes wherein the administration is intravenous.
  • a further aspect of the present invention includes wherein the administration is combined with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin growth-like factor-II (IGF-II).
  • a neuroprotective agent insulin-like growth factor-I (IGF-I) or insulin growth-like factor-II (IGF-II).
  • a further aspect of the present invention includes wherein the administration is in the form of a pharmaceutical composition including pharmaceutically acceptable carrier thereof.
  • An additional aspect of the present invention includes wherein the administration is in combination with artificial cerebrospinal fluid.
  • Another aspect of the present invention includes wherein the administration is combined with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin growth-like factor-II (IGF-II).
  • IGF-I insulin-like growth factor-I
  • IGF-II insulin growth-like factor-II
  • a further aspect of the present invention includes herein the administration is combined with an anti-inflammatory agent.
  • a second aspect of the present invention includes a method for rel ieving or alleviating of cognitive impairment caused by a disease, injury, or condition in a mammal in need thereof, comprising: a) providing a mammal in need of relieving or alleviating of cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Gly cyl-2- Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to said mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease, Dementia, and multi-infarct dementia, memory loss, attention
  • Relieving cognitive impairment generally refers to methods that can relieve symptoms related to memory, thinking, language and other thought processes. In addition, they may also help with mood, agitation and other behavioral issues.
  • cyclic Prolyl Glycine or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Gly cyl-2 -Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with lecanemab thereof, includes an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.
  • a further aspect of the present invention includes wherein said cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri( Prolyl Glycine) or cyclic Glycyl-2 -Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, further includes one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule.
  • cPG cyclic Prolyl Glycine
  • cPMeG cyclic GlycPG compound
  • An additional aspect of the present invention includes wherein the disorder is a mild cognitive impairment, Alzheimer Disease, memory' loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerati ve origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • the disorder is a mild cognitive impairment, Alzheimer Disease, memory' loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerati ve origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alky 1 Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof, route of administration.
  • cPG cyclic Prolyl Glycine
  • cPMeG cyclic Prolyl Glycine
  • a further aspect of the present invention includes wherein the cognitive impairment is caused by cholinergic hypofunction.
  • An additional aspect of the present invention includes wherein the cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
  • CAI granular cell layer
  • Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination thereof, causes an increase in AMP A receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
  • CAI granular cell layer
  • An additional aspect of the present invention includes wherein the cerebral hypoxia/ischemia caused by traumatic brain injury.
  • Another aspect of the present invention includes wherein the cognitive impairment caused by multi-infarct dementia.
  • a further aspect of the present invention includes wherein tire cognitive impairment caused by coronary arterial bypass surgery (CABG).
  • CABG coronary arterial bypass surgery
  • An additional aspect of the present invention includes wherein the cognitive impairment caused by Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • a third aspect of the present invention includes a method of preventing the symptoms of a mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need thereof, including: a) providing a mammal in need of preventing cognitive impairment caused by a disease, injury, or condition; b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Proly 1 Glycine) or cyclic Glycyl-2-Ahyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease, Dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated
  • Preventing the symptoms of a mild cognitive impairment generally refers actions that would be performed to prevent the symptomatic phase and primarily to reduce the risk of disease.
  • prevention in dementia can be referred to as levels of prevention: primary, secondary and tertiary.
  • the secondary prevention stage can apply to the phase of mild cognitive impairment. At this point, symptoms are present but are not sufficiently severe to constitute dementia. Therefore, treatment of cPG compounds in combination with Lecanemab aimed at subjects with MCI could be considered secondary prevention studies.
  • a fifth aspect of the present invention includes a method for relieving or alleviating of cognitive impairment caused by a disease, injury’, or condition in a mammal in need thereof, including: a) providing a mammal in need of relieving or alleviating of cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-AIlyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease.
  • cPG cyclic Prolyl Glycine
  • cPMeG
  • Dementia, and multi-infarct dementia memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated wdth Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration;
  • the injury is selected from the group consisting of neurotoxic injury', cerebral hypoxia/ischemia, traumatic brain injury, coronary artery bypass surgery; where said condition is normal aging, age-related memory loss, memory impairment, cholinergic hypofunction, vascular narrowing or blockage in the brain, neuroinflammation, mild cognitive impairment, cerebral atrophy, frontotemporal lobar degeneration, Pick's disease, HIV infection, Down's syndrome, and loss of synaptic plasticity; further wherein said mammal is for relieved or alleviated of cognitive impairment caused by a disease, injury, or condition, including Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease
  • Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alky 1 Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof, route of administration.
  • cPG cyclic Prolyl Glycine
  • cPMeG cyclic Prolyl Glycine
  • a further aspect of the present invention includes wherein the pharmaceutically effective amount of cPG has a lower limit of about 0.001 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 100 mg/kg of said mammal.
  • a further aspect of the present invention includes wherein the pharmaceutically effective amount of Lecanemab has a lower limit of about 1.00 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 10.00 mg/kg of said mammal.
  • An additional aspect of the present invention includes wherein the cognitive impairment is caused by cholinergic hypofunction.
  • Another aspect of the present invention includes wherein the cholinergic hypofunction is caused by scopolamine.
  • An additional aspect of the present invention includes wherein the cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
  • CAI granular cell layer
  • Another aspect of the present invention includes wherein the cPG compound causes an increase in AMPA receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
  • CAI granular cell layer
  • a further aspect of the present in vention includes wherein tire cyclic Prolyl Glycine (cPG) or its analogues ( cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alky 1 Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, causes an increase in neuronal plasticity caused by said cPG compound in the granule cell layer (CAI) and the pyramidal cell layer (CA3) regions of said mammal's hippocampus.
  • cPG tire cyclic Prolyl Glycine
  • CAI granule cell layer
  • CA3 pyramidal cell layer
  • An additional aspect of the present invention includes wherein the cerebral hypoxia/ischemia caused by traumatic brain injury.
  • Another aspect of the present invention includes wherei n the cognitive impairm ent caused by multi-infarct dementia.
  • a further aspect of the present invention includes wherein the cognitive impairment caused by coronary arterial bypass surgery (CABG).
  • CABG coronary arterial bypass surgery
  • An additional aspect of the present invention includes wherein the cognitive impairment caused by Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin , pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
  • An sixth aspect of the present invention includes a method of preventing the symptoms of a mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need thereof, including: a) providing a mammal in need of preventing cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease.
  • cPG cyclic Prolyl Glycine
  • cPMeG cyclic Prolyl Glycine
  • a seventh aspect of the present inventi on includes a method of treating the symptoms of a mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need thereof, including: a) providing a mammal in need of treating of cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cynch(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease.
  • cPG cyclic Prolyl Glycine
  • Dementia and multi -infarct dementia, memory' loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson’s disease, progressive supranuclear palsy or cortical basal degeneration.
  • Cyclic Prolyl Glycine was available from commercial suppliers such as Bachem (Torrance, Calif.), and Sigma (St. Louis, Mo.).
  • Lecanemab and Donanemab are an IgGl anti-soluble aggregated amyloid beta (A
  • cPG administered to animals treated with scopolamine-induced cognitive dysfunction produces clinical improvement in those animals, similar to the therapeutic improvement observed in people suffering from cholinergic hypofunction.
  • Scopolamine is commonly used in animal models of cholinergic hypofunction associated with Alzheimer's disease.
  • the functional deficits observed after scopolamine treatment include those found in human patients with Alzheimer's disease.
  • scopolamine treatment is reasonably predictive of cognitive impairment found in human diseases.
  • scopolamine treatment mimics cognitive disfunctions in humans w'ho do not have neurodegenerative disorders.
  • the first part of the study involved acute testing of the cyclic Prolyl Glycine in the Morris Water Maze memory model.
  • the MWM test is one of the most frequently used tests for assessing spatial memory in rats and is well recognized to accurately predict effects of disease and treatment on spatial memory generally. Therefore, the MWM test reflects effects of disease and treatment in human subjects.
  • Scopolamine was administered hal f an hour before the probe test commenced.
  • cPG cyclic Prolyl Glycine
  • Cyclic Prolyl Glycine (10 mg/kg; daily) and cyclic Prolyl Glycine in combination with Lecanemab (5 mg/kg of cPG plus 5 mg of Lecanemab) and cyclic Prolyl Glycine in combination with Donanemab (5 mg/kg of cPG plus 5 mg of Donanemab) significantly reversed the cognitive impairment induced by scopolamine.
  • Lecanemab alone, or Donanemab alone did not significantly reverse the cognitive impairment induced by scopolamine.
  • Patients were evaluated at screening to ensure that all criteria for study participation are met. These evaluations will include specific measures of psychosis severity, delirium, dementia, cardiovascular condition, and pregnancy status. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all protocol-specified entry criteria).
  • Participants were excluded if they had received treatment with antipsychotics, medications that prolong the QT interval, centrally acting anticholinergic medications, mianserin, nefazodone, cyproheptadine, and fluvoxamine. Also excluded were those whose dose of antidepressant and anxiolytic drugs, if used, changed during the study. Those receiving an acetylcholinesterase inhibitor or memantine, or both, must have been on stable doses for 3 months before baseline and during the study.
  • Participants (1 :1) were randomly assigned to receive either NA-831 (60 mg per day orally ) or placebo (60 mg per day orally) , stratified by baseline Mini-Mental State Examination (MMSE)24 total score and NPI-NH psychosis score (four categories: MMSE ⁇ 10 and NPI-NH psychosis score ⁇ 12, MMSE ⁇ 10 and NPI-NH psychosis score ⁇ 12, MMSE ⁇ 10 and NPI-NH psychosis score ⁇ 12, and MMSE ⁇ 10 and NPI-NH psychosis score ⁇ 12).
  • MMSE Mini-Mental State Examination
  • NPI-NH psychosis score hallucinations + delusions
  • Prespecified sensitivity analyses for the primary outcome were responder analyses and different imputation models (pattern mixture model and last observation carried forward).
  • Correlation analysis at week 6 and week 12 (NPI-NH psychosis score, NPI-NH total score, NPI-NH agitation,' aggression, Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) total score, and the Cohen- Mansfield Agitation Inventory- Short Form (CMAI-SF) total score) was also done.
  • ADCS-CGIC Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change
  • ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily Living
  • CMAI-SF Cohen- Mansfield Agitation Inventory- Short Form
  • ADCS-CGIC assessed as the effect on all clinical domains including cognition and function to evaluate any global deterioration associated with treatment
  • NPI-NH agitation/ aggression and sleep and nighttime behavior disorders domains assessed as the effect on all clinical domains including cognition and function to evaluate any global deterioration associated with treatment
  • CMAI-SF total and subdomain scores as a measure of agitation.
  • Prespecified exploratory outcomes included the NPI-NH total score as an overall measure of neuropsychiatric sy mptoms and each of its remaini ng individual domains, NPI- NH psychosis score by subgroups, durability of response from weeks 6 to 12, NPI-NH occupational distress total score, ADCS-ADL (total, basic, and instrumental subdomain scores), and use of rescue medications for behavioral disturbances and sleep.
  • Subgroup analyses were also prespecified, focusing on baseline NP1-NH psychosis score ( ⁇ 12 or ⁇ 12), baseline MMSE ( ⁇ 10 or ⁇ 10), sex (men or women), age ( ⁇ 85 years or ⁇ 85 years), concomitant use of selective serotonin reuptake inhibitor, concomitant use of anti-dementia medication, and previous antipsychotic use. Additionally, cognitive impairment was assessed by the MMSE and extrapyramidal symptoms were measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) part III from baseline to week 12. Tthe 1987 UPDRS part III was used, as this version has been validated in people with dementia.
  • UPDRS Unified Parkinson’s Disease Rating Scale
  • Safety outcomes measured over 12 weeks, included reported adverse events, adverse events leading to study discontinuations, serious adverse events, and mortality, and included assessment by physical examinations, vital signs (ECGs were obtained at baseline, day 15, and day 85 or early termination to calculate corrected QT interval using Fridericia’s method [QTcF]), and clinical laboratory tests (hematology, clinical chemistry, and urinalysis).
  • Baseline demographic and clinical characteristics of parti cipants were generally well balanced between treatment groups, 23 of 93 (24.7%) of participants in the NA-831 group and 24 of 93 (25.8%) placebo group had more severe psychotic symptoms as documented by NPI-NH psychosis score of 12 or more, and 16 (17.2%) of 93 participants in the NA-831 group and 17 (18.3%) of 93 participants in the placebo group had an MMSE score of less than 10.
  • the adjusted mean change in the NPI-NH psychosis score at week 6 was -3.7 points (SE 0-58) for NA-831 and -2.2 points (0-66) for placebo.
  • the adjusted mean change in the NPI-NH psychosis score at week 12 was -4.2 points (SE 0-63) for NA-831 and -2.8 points (0-67) for placebo.
  • results of a phase clinical trial of NA-831 showed significant treatment benefits of NA-831 compared with placebo at the primary timepoint of week 6 and the secondary' timepoint of week 12, with an acceptable tolerability profile and without negative effect on cognition.

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Abstract

The present invention recognizes that there is an unmet need for the treatment of mild cognitive impairment. A first aspect of the present invention generally relates to a method of treating, relieving, or alleviating mild cognitive impairment in a subject. A second aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer's Disease in a subject. A third aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer's Disease Psychosis in a subject. A fourth aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer's Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject. A fifth aspect of the present invention generally relates to a method of treating, relieving, or alleviating Early Onset Alzheimer's Disease in a subject.

Description

THERAPEUTIC AGENT COMPOSITION AND METHOD OF USE OF COMBINATION THERAPY FOR TREATMENT
OF MILD COGNITIVE IMPAIRMENT
CROSS REFERENCE TO RELATED APPLICATIONS
The present application: claims benefit of priority to United States Provisional Patent Application Serial Number 63/526,195, filed July 12, 2023, now pending;
Each of which is incorporated by reference herein in their entirety' .
FIELD OF THE INA ENTION
The present invention generally relates to novel cyclic dipeptides compounds structurally related to diketopiperazines and methods for their therapeutic use. Particularly, the present invention generally relates to the use of cyclic prolyl glycine (“cyclic GP” or “cPG”) and cPG analogues and cPG compounds, pharmacologically effective analogues thereof, and pharmaceutical compositions thereof in combination with specific binding members such as antibodies, or active fragments thereof, such as but not limited to monoclonal antibody Lecanemab, in the treatment and prevention of progression of cognitive impairment and related neurodegenerative disorders and psychological disorders such as but not limited mild cognitive impairment such as but no limited to as related to Alzheimer’s Disease.
BACKGROUND
Mild cognitive impairment (“MCI”) is a syndrome defined as cognitive decline greater than expected for an individual's age and education level. Mild cognitive impairments are those involving impairments of memory and other cognition functi ons, beyond the age norm but not leading to the characteristic of dementia.
The prevalence of MCI varies by age. The prevalence of MCI among different age groups is as follows: 6.7% forages 60-64; 8.4% for ages 65-69, 10.1% for ages 70-74, 14.8% for ages 75-79, and 25.2% for ages 80-84. More than half progress of people with MCI progress to dementia within 5 years. (Petersen RC, Lopez 0, Armstrong MJ, Getchius T, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A (January 2018). "Practice guideline update summary: Mild cognitive impairment - Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology". Neurology. Special article. 90 (3): 1-10. .T0.1212/WNL.0000000000004826. https://en.wikipedia.org/wiki/TubMed_Identifier" \o "PubMed Identifier 29282327. )
Dementia is an overall term that describes a group of symptoms associated with a decline in memory or other thinking skills severe enough to reduce a person's ability to perform everyday activities. Alzheimer's disease accounts for 60 to 80 percent of these types of cases. Vascular dementia, which occurs after a stroke, is the second most common dementia type. But there are many other conditions that can cause symptoms of dementia, including some that are reversible, such as thyroid problems and vitamin deficiencies.
While symptoms of dementia can vary greatly, at least two of the following core mental functions are to be significantly impaired to be considered dementia: memory, communication and language, ability to focus and pay attention, reasoning and judgment, and visual perception.
Alzheimer's disease (AD) is a progressive disease of the brain that is characterized by impairment of memory and eventually by disturbances in reasoning, plaiming, language, and perception. There are more than 6 million people in the US and 50 million people worldwide that have Alzheimer’s disease in 2018. (Ref: Alzheimer’s Disease International’s World Alzheimer Report 2018). The growth in the prevalence of Alzheimer’s disease over the next few decades is anticipated to result in great pressure on the social and health-care systems of developed and developing economies alike. There is a long unmet need for therapies that halt, substantially slow, slow or otherwise ameliorate the progression, symptoms, or provide comfort or palli ative care of this disease and related diseases.
Currently approved AD treatments include the cholinesterase inhibitors donepezil rivastigmine, and galantamine, that are purported to address cholinergic deficits in AD by increasing acetylcholine levels in the central nervous system (CNS), and the N-methyl-D- aspartate antagonist memantine. Memantine was approved in 2003, and is the most recently approved novel medication for AD; it is postulated to work by binding preferentially to N- methyl-D-aspartate (NMDA) receptor-operated cation channels to block persistent activation by the excitatory amino acid glutamate. These drugs provide modest benefits to patients with AD, but it is unclear whether these drugs slow or prevent neurodegeneration in patients with AD. In 2021, Aducanumab, an anti-amyloid beta-directed antibody, was approved under that accelerated approval pathway for the treatment of treatment of Alzheimer's Disease, with use specifically recommended for patients with mild cognitive impairment or mild dementia stage: of disease. This approval was based, on a demonstration of reduction of brain amyloid-beta (AP) plaque on PET imaging, a surrogate endpoint that was determined to be reasonably likely to predict clinical benefit.
There have been several anti-Ap monoclonal antibodies studied in AD that have had negative studies in Phase 3 development; however, differences in enrollment criteria, study design, and trial endpoints make it difficult to compare them to the aducanumab program. There are also significant differences between anti-Ap monoclonal antibodies related to binding at different epitopes, and selectivity for different Ap variants (e.g., monomers, soluble oligomers, aggregated forms) (Linse et al. 2020). The degrees of amyloid reduction in these studies have been variable.
Monoclonal antibodies directed against aggregated forms of beta amyloid, such as Lecanemab, can cause amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and ARIA with hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.
ARIA was observed in 12% of participants treated with lecanemab 10 mg/kg biweekly (20 out of 161) compared to 5% participants on placebo (13 out of 245). In the Lecanemab 10 mg/kg biweeklv arm, ARIA-E was observed in 10% of treated participants compared to 1% of participants on placebo. Symptomatic AREA occurred in 3% (5 out of 161 ) of participants treated with lecanemab 10 mg/kg biweekly in Study 201 sponsored by Eisai and in none of the participants on placebo. The most common symptoms in participants treated with Lecanemab 10 mg/kg biweekly, that occurred in 2 or more participants who had an observation of ARIA, were headache, confusion/mental status changes, agitation and visual disturbance. Clinical symptoms resolved in 4 out of 5 participants during the period of observation.
(van Dyck CH et al.- Lecanemab in Early Alzheimer’s Disease- DOI:
10.1056/NEJMoa2212948N Engl J Med 2023;388:9-21. DOI: 10.1056/NEJMoa2212948) (The incidence of ARIA-E was higher in apolipoprotein E s4 (ApoE s4) homozygotes (5 out of 10) than in heterozygotes (2 out of 39) or in non-carriers (9 out of 112). There were 4 ApoE E4 homozygotes who had symptomatic ARIA, of whom 2 had severe symptoms. Due to protocol changes to reduce risk in the proposed dose arm during the conduct of Study 201, only 30 % of participants treated with lecanemab 10 mg/kg biweekly were ApoE c4 carriers compared to up to 60-70 % of individuals with AD in the general population. Therefore, interpretation of ARIA related analyses should consider the limitations of the small number of ApoE s4 carriers in the proposed dose. However, published topline results from Study 301 also suggest a higher incidence of ARIA overall and symptomatic ARIA in ApoE e4 homozygotes compared to heterozygotes and noncarriers.
The majority of ARIA -E radiographic events occurred within the first three months daring treatment, although ARIA can occur at any time. Of the 16 participants treated with lecanemab 10 mg/kg biweekly who had ARIA-E, the maximum radiographic severity was mild in 7, moderate in 7, and severe in 2. In the lecanemab 10 mg/kg biweekly arm, resolution occurred in 62 % of ARIA-E participants by 12 weeks, 81% by 21 weeks, and 94% overall after detection. There was no imbalance in isolated ARIA-H between lecanemab and placebo. Cerebral hemorrhage greater than 1 cm was reported in 1 participant on lecanemab 10 mg/kg biweekly and in no participants on placebo in Study 201 . Events of intracerebral hemorrhage greater than 1 cm in diameter in patients taking Lecanemab 10 mg/kg biweekly have also been reported in Study 301 and its extension study.
In the placebo-controlled period of Study 201, Lecanemab was to be discontinued if ARIA occurred. Limited data are available from the open label extension phase of Study 201 on the safety of continued dosing after ARIA-E with Lecanemab. Infusion-related reactions occurred in 20% of patients on lecanemab 10 mg/kg biweekly versus 3% in placebo. Infusion reactions were mild (56%) or moderate (44%) in severity, and 88% occurred at the time of the first infusion. Symptoms included fever and flu-like symptoms (chills, generalized aches, feeling shaky and joint pain). The most common adverse drug reactions with lecanemab are ARIA-E, infusion related reactions, and headache. All occurred in at least 10% of participants on the proposed dose of lecanemab 10 mg/kg biweekly and at least 2% more frequently than placebo in the controlled period of Study 201.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 generally illustrates time for rats to reach the platform-in Morris Water Maze (MWM) Model of Learning and Memory Used to Assess Effects of cyclic Prolyl Glycine (cPG), Lecanemab and Donanemab and the combination of cPG + Lecanemab and cPG + Donanemab
Figure 2 generally illustrates adjusted mean change from baseline to week 12 in the NPI-NH psychosis score (cPG vs. Placebo).
Figure 3 generally illustrates adjusted mean change from baseline to week 12 in the NPI-NH psychosis score (cPG, Lecanemab vs Placebo, and cPG + Lecanemab vs. Placebo).
SUMMARY OF THE IN VENTION
The present invention recognizes that there is a long felt need for the treatment of mild cognitive impairment. As a non- limiting introduction to the breath of the present invention, the present invention includes several general and useful aspects, including but not limited to:
A first aspect of the present invention generally relates to a method of treating, relieving, or alleviating mild cognitive impairment in a subject.
A second aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease in a subject.
A third aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject
A fourth aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject.
A fifth aspect of the present in venti on generally relates to a method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject.
These aspects of the present, invention, as well as others described herein, can be achieved by using the methods, articles of manufacture, and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the present invention.
The applicants do not wish to be bound by any proposed mechanisms of action that may be provided herein. The present invention is not limited to any specific mechanisms of action.
The neurotoxicity of amyloidogenic proteins was demonstrated to affect long-term potentiation, plasticity; synaptic signaling, dendritic morphology, and cognition in a preclinical study. Tran’s patent has reported that NA-831 induces hippocampal neurogenesis. (Ref. Lloyd Tran- US Patent 11,090,303 issued on August 17, 2021).
In the present invention, the combined treatment is believed to also induce neurogenesis and compared the effects of the combined treatment with NA-831 or LEQ alone. The administrations of combined treatment with NA-831 and LEQ led to increased survival of newly proliferating and differentiated neuronal cells compared with NA-831 or LEQ alone. Hippocampal neurogenesis plays a key role in long-term memory and cognitive function. In addition; brain-derived neurotrophic factor (BDNF) is reported to be one of the most important factors in inducing neurogenesis, and there is a report that NA-831 increases the expression level of BDNF.
Studies suggest that BDNF contributes to neurogenesis of dentate gyrus granule cells. This is a very important topic because neurogenesis of granule cells is thought to be relevant to learning, depression, and possibly other aspects of neurological and psychiatric function (Eisch, 2002; Jacobs et al., 2000). Furthermore, the results suggest that it might be possible to use BDNF in the future to increase granule cell numbers after neuronal loss. Especially promising is the fact that isolated administration of BDNF to one area of the hippocampus appeared to have widespread effects throughout both hippocampi. This could be favorable therapeutically.
Taken together, these results show that combined treatment enhances the survival of newborn cells, suggesting that I..EQ may potentially affect a part of the toxic microenvironment.
About 55 million people worldwide are living with Alzheimer’s disease Neuropsychiatric symptoms (NPS) are almost ubiquitous in people with dementia, with prevalence estimates as high as 97% (Steinberg, M. et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study, hit. J. Geriatr. Psychiatry 23, 170-177 (2008).
These non-cognitive symptoms are distressing not only for people with Alzheimer’s Disease (AD) or other dementias but also for their caregivers, and are associated with poor outcomes in terms of function, quality of life, disease course, mortality and economic cost.
These NPS include impairments in motivation, interest, social behavior and awareness, mood disorders, anxiety, agitation, impulsivity, and hallucinations and delusions, all of which often require clinical intervention. If untreated, psychotic symptoms tend to have an intermittent and variable course with a pattern of recovery and relapse, in which symptom severity can increase and decrease.
Psychotic symptoms, which consist of hallucinations and delusions, are among the most clinically relevant NPS, and are associated with hospitalization or institutionalization, cognitive and functional impairment, accelerated cognitive decline and mortality, as well as caregiver distress.
Although antipsychotics are commonly used to treat psychosis in patients with Alzheimer’s disease, no drug is approved for treating psychosis in Alzheimer’s disease.
Antipsychotic use in people with Alzheimer’s disease is associated with side- effects that include accelerated decline in cognition; increased serious medical adverse events, such as stroke, bronchopneumonia, and pulmonary embolism; and increased short- term mortality. Therefore, although psychosis has a major impact in people with Alzheimer’s disease, no safe or effective pharmacological treatment is approved, leaving a key unmet treatment need. (Ismail, Z., Creese, B., Aarsland, D. et al. Psychosis in Alzheimer disease — mechanisms, genetics and therapeutic opportunities. Nat Rev Neurol 18, 131—144 (2022). https://doi.org/10.1038/s41582-021-00597-3).
In the present invention, in a preferred and not-limiting example, the present invention provides a preferred embodiment of a combination therapy of NA-831 and a specific binding member or active fragment thereof, such as but not limited to the monoclonal antibody Lecanemab, to reduce the side effects of Lecanemab while enhancing the efficacy of both drugs for the treatment of Alzheimer’s Disease psychosis.
One aspect the invention provides cyclic Prolyl Glycine compounds suitable for the drug combination therapy with a specific binding member such as an antibody or active fragment thereof, such as a monoclonal antibody, such as Lecanemab, for treatment and prevention of disease and injury in animals and humans. The cyclic PG being preferably selected from the group that includes cPG, cPG analogues, cPG peptidomimetics and relating compounds which promote or cause the formation of cPG or cPG analogues in vivo.
A further aspect the invention relates to a method of restoring the myelination of axons in a mammal in need of restored myelination due to neural injury or disease, comprising administering a therapeutic amount of a cPG compound, where a cPG compound comprises cPG, a biologically active cPG analogue such as c(PG)3 and cGAL, a biologically active cPG peptidomimetic, a compound that increases the concentration of cPG, or a compound that increases the concentration of cPG analogues, effective to restore myelination of axons in a mammal, hi one aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound comprises stimulation of astrocytes to promote remyelination. In another aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound comprises stimulation of oligodendrocytes to produce myelin.
In yet another aspect of the invention, the method of restoring myelination of axons to a mammal in need of restored myelination further comprises administering a therapeutic amount of a cPG compound in combination with a compound selected from IGF-I or an interferon. In one aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of a cPG compound in combination with IGF-I or an interferon to stimulate astrocytes to promote remyelination. In another aspect of the invention, the method of restoring myelination of axons comprising administering a therapeutic amount of cPG in combination with IGF-I or an interferon to stimulate oligodendrocytes to produce myelin. In preferred embodiments, the interferon comprises interferon beta lb (Betaseron). In a further most preferred embodiment, the interferon comprises consensus interferon (Infergen®, interferon alfacon-1).
In still a further aspect of the invention, the methods to treat or prevent cell damage and death in response to injury and disease, comprises administration of a therapeutic amount of a cPG compound, preferably but not limited to an amount from between about 10 pg to about 150 mg of cPG per kg of body weight of the mammal. A suitable dosage for administration of cPG can be, for example, preferably but not limited to between about 0.1 mg to about 100 mg per kilogram of body weight, between about 1 mg to about 100 mg per kilogram of body weight, between about 5 mg and about 70 mg per kilogram of body weight, between about 10 mg to about 50 mg per kilogram of body weight, or between about 20 mg to about 40 mg per kilogram of body weight. The dose, route of administration, and regime of cPG may be different for different diseases, disorders, and conditions. As an example, mild cognitive impairment may have a lower dose using the same or different route of administration than for Alzheimer’s disease. For example: a typical dosage for patient with mild cognitive impairment may be between about 10 mg to about 50 mg per day administered orally (taking 1 capsule of 20 mg or 2 capsules per day per doctor prescription). Whereas a more severe Alzheimer’s Disease or severe Traumatic Brain injury patent may be administered intravenously in a range from between about 50 mg to about 300 mg per day. The particulars of the dose, route of administration, and regime for a particular disease, disorder, or condition can be evaluated in general or for a particular subject or patient.
In yet another aspect of the invention, the method of restoring myelination of axons to a mammal in need of restored myelination further comprises administering a therapeutic amount of a cPG compound in combination with IGF-1 from about 1 mg to about 10 mg of IGF-I per 1 Kg body weight of the mammal or an interferon from about 1.0 pg to about 10 pg of IGF-I per Kg of body weight of the mammal. In a preferred embodiment, the interferon is interferon beta. A suitable dosage for administration of cPG can be, for example, preferably but not limited to between about 0.1 mg to about 100 mg per kilogram of body weight, between about 1 mg to about 100 mg per kilogram of body weight, between about 5 nig and about 70 mg per kilogram of body weight, between about 10 mg to about 50 mg per kilogram of body weight, or between about 20 mg to about 40 mg per kilogram of body weight. The dose, route of administration, and regime of cPG may be different for different diseases, disorders, and conditions. As an example, mild cognitive impairment can have a lower dose using the same or different route of administration than for Alzheimer’s disease. For example: a typical dosage for patient with mild cognitive impairment can be between about 10 mg to about 40 mg per day administered orally (taking 1 capsule of 20 mg or 2 capsules per day per doctor prescription). Whereas, a more severe Alzheimer’s Disease or severe Traumatic Brain injury patent can be administered intravenously in a range from between about 50 mg to about 300 mg per day. The particulars of the dose, route of administration, and regime for a particular disease, disorder, or condition can be evaluated in general or for a particular subject or patient.
In a further preferred embodiment of the methods to treat or prevent cell damage and death in response to injury and disease, comprising administration of a cPG compound, the cPG compound is administered to the mammal through a shunt into a ventricle of the mammal.
In a further preferred embodiment of the methods to treat or prevent cell damage and death in response to injury and disease, comprising administration of a cPG compound, the cPG compound is administered to the mammal by peripheral administration. The present invention provides a method of treatment for stimulating mature astrocytes to promote myelin production after hypoxic-ischemic injury’ including the step of increasing the active concentration of cPG and/or the concentration of analogues of cPG in the CNS of mammals.
Most preferably, it is the effective amount of IGF-I itself that is increased within the CNS of the mammal. This can be effected by direct administration of a cPG compound such as cPG, c(PG)3 or cGAL or cGMeP and indeed this is preferred. However, the administration of compounds that indirectly increase the effective amount of IGF-I (for example a pro-drug which, within the patient is cleaved to release cPG) is in no way- excluded.
Tire active compound (IGF-I or its analogue or its mimetic) can be administered alone, or as is preferred, a part of a pharmaceutical composition.
The composition can be administered directly to the CNS. The latter route of administration can involve, for example, lateral cerebroventricular injection, focal injection or a surgically inserted shunt into the lateral cerebroventricle of the brain of the patient.
Conveniently, the stimulation and promotion of myelin production in oligodendrocytes and the support, stimulation and promotion of remyelination by mature astrocytes is promoted through the administration of cPG compounds in the prophylaxis or therapy of demyelinating diseases such as multiple sclerosis.
In still other aspects, present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of cyclic GP or its analogues with structural formulas given above to treat a disease, disorder, or condition, including but not limited to Alzheimer’s disease and its related conditions such an impairment of cognitive function.
In further aspects, the present invention provides methods of treating an animal having a cognitive impairment, comprising administration to that animal an effective amount of a composition comprising cyclic GP or its analogues. In yet further aspects, the animal to be treated is a human.
One aspect of the present invention is generally directed to therapeutic treatments of neurological diseases and injuries. The present invention is not limited to any specific mechanisms of action and may, in part be based on inducing neurogenesis, in particular. neural stern cell, or progenitor cell proliferation, the proliferation of neural stem cell. In accordance with one aspect of the present invention, cyclic Prolyl Glycine and it analogues f‘cPG compounds”) act as key neurogenesis modulating agents that facilitate and induce proliferation and'or differentiation in neural cells.
“Neurogenesis” is defined herein as proliferation, differentiation, migration, or survival of a neural cell in vivo or in vitro. In a preferred aspect of the present invention, the neural cell can be an adult, fetal, or embryonic neural stern cell or progenitor cell. Neurogenesis also refers to a net increase in cell number or a net increase in cell survival. As used herein, “neural stem cell (NSC)” would include, at least, all brain stem cells, all brain progenitor cells, and all brain precursor ceils.
It has been previously shown that increased levels of cAMP and/or Ca*r elicit the proliferation of adult neural stem cells. In some cases, this induction follows the activation of G-proteih coupled receptors (GPCRs). Increasing intracellular cAMP and/or Ca21 levels through GPC.R ligands can induce the increase of proliferation of adult neural stem cells.
G-protein -coupled receptors (GPCRs), also known G protein-linked receptors (GPLR), constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses.
The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins. GPCRs in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate. G protein-coupled receptors are involved in many diseases, and are also the target of approximately 34% of all modem medicinal drugs.
One aspect of the present invention includes, and not being limited by any proposed mechanisms, that cPG and its analogues can act as a neurogenesis modulating agents that modulate intracellular levels of cAMP and/or Ca2\ cPG has been shown chemically and biologically to be capable of increasing cAMP (e.g., by increasing synthesis or decreasing breakdown) and/or Ca2” (e.g., by increasing influx or decreasing efflux).
One aspect of the present invention describes a new method for promoting regeneration of damaged nerve tissue, compri sing administering an effective amoun t of cyclo Prolyl Glycine (cPG), and its analogues, which can reduce the rate of growth of glial cells to facilitate the growth of nerve tissue.
Neurons are closely surrounded by glial cells or astrocytes. One of the difficulties in achieving regeneration of neurons after they have been damaged or severed is that the glial cells proliferate and form a barrier to the regenerating neurons. The result is that the further movement of the neurons toward anticipated attachment sites is blocked and regeneration of structure and function ceases. It has been observed that formation of astrocytic and connective tissue scars and progressive necrosis have negative impact on the regeneration of neuronal functions.
Accordingly, one aspect of the present invention is a method for promoting regeneration of damaged nerve tissue in a mammal (such as a human), comprising administering an effective amount of cPG compounds (cPG and its analogues) to the damage site.
Some objectives of the experiments provided herein is to provide enablement for a method of regenerating neurons and gl ial cells or a method of repairing damaged neurons and glial cells as claimed.
One aspect of the invention includes, that cyclic Prolyl Glycine (cPG) and its pharmaceutically active analogues act as a neuronal modulating agents in order to treat depression and other psychological disorders. The A-methyl- aspartate receptor (“NMDA receptor'’), is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three types of ionotropic glutamate receptors, the others being the AMP A and kainate receptors. The NMDA receptor is activated when glutamate and glycine bind to it. and when activated it allows positively charged ions to flow through the cell membrane. (Furukawa, Hiroyasu; Singh, Satinder K; Mancussol, Romina; Gouaux, Eric (November 2005). "Subunit arrangement and function in NMDA. receptors". Nature. 438 (7065): 185 92. doi:10.1038/nature04089. PMID 16281028).
The NMDA receptor channels play an important role in synaptic plasticity and synapse formation underlying memory, learning and formation of neural networks during development in the central nervous system (CNS). Over activation of the receptor, causing excessive influx of Ca2 b can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.
The NMDA receptor is an ion channel protein receptor that is activated when glycine and glutamate bind to it. The receptor is a heteromeric complex that interacts with multiple intracellular proteins by three different subunits: NR1, NR2 and NR3. NR1 has eight different subunits generated by alternative splicing from a single gene. There are four different NR2 subunits (A-D), and NR3A and NR3B subunits have been reported. Six separate genes encode for NR2 and NR3. [Loftis J. M., Janowsky A. (2003). ''The N- methyl-D-aspartate receptor subunit NR2B: localization, functional properties, regulation, and clinical implications” (Pharmacol Ther. 97 (1): 55-85. doi: 10.1016/s0163- 7258(02)00302-9).
Agonists or allosteric modulators of NMDA receptors, in particular NR2B subunit- containing channels, have been investigated as therapeutic agents for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437). The NR2B subunit has been involved in modulating activity such as learning, memory, processing and feeding behaviors, as well as being implicated in number of human derangement. The basic structure and functions associated with the NMDA receptor can be attributed to the NR2B subunit.
An allosteric, non-competitive binding site has also been identified in the N- terminal domain of NR2B. The NR2 subunit acts as the binding site for glutamate, one of the predominant excitatory neurotransmitter receptors in the mammalian brain. [Yoshimura Y, Ohmura T, Komatsu Y (July 2003). "Two forms of synaptic plasticity with distinct dependence on age, experience, and NMDA receptor subtype in rat visual cortex" (The Journal ofNeuroscience. 23 (16): 6557-66. PMID 12878697).
NR2B has been associated with age- and visual-experience-dependent plasticity’ in the neocortex of rats, where an increased NR2B/NR2A ratio correlates directly with the stronger excitatory LTP in young animals. This is thought to contribute to experience- dependent refinement of developing cortical circuits.
The role of NR2B subunit of the NMDA receptor has been demonstrated in the action of different antidepressant agents. [Poleszak E, Wlaz P, Szewczyk B, Wlaz A, Kasperek R, Wrobel A, Nowak G (2011) A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice. J Neural Transm 118: 1535-1546],
G-protein-coupled receptors (GPCRs), also known G protein- Linked receptors (GPLR), constitute a large protein family of receptors that detect molecules outside the cell and activate internal signal transduction pathways and, ultimately, cellular responses.
GPCRs in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate. G protein-coupled receptors are involved in many diseases and are also the target of approximately 34% of all modern medicinal drugs.
One aspect of the invention includes, that cyclic Prolyl Glycine (cPG) and its pharmaceutically active analogues act as a neuronal modulating agents in order to treat depression and other psychological disorders. One possible mechanism, though expressly not being limited to any mechanism, is the modulation of intracellular levels ofcAMP and/or Ca2+. Herein, cPG has been shown chemically and biologically to be capable of increasing cAMP (e.g., by increasing synthesis or decreasing breakdown) and/or Ca2'’’ (e.g., by increasing influx or decreasing efflux).
In addition, cyclic Prolyl Glycine and its pharmaceutically active analogues have been shown to selectively bind the N-terminal domain of NR2B, which might sustain an antidepressant response in human.
The present in vention provides technical advantages of cyclic Prolyl Glycine (“cPG”) and its pharmaceutically active analogues, together is known as cPG compounds, which are ligands for the NR2B receptor and can be useful for the treatment of various disorders of the central nervous system. In addition, the cPG compounds provide advantages for pharmaceutical uses, for example, wdth regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
In carrying out the method of the invention, patients are given the combination of substances at pharmaceutically effective dosage levels using appropriate routes of administration and regime. The substances can be administered in the form of a single dosage unit in which the active ingredients are combined with a suitable carrier; or they may be given in separate dosage units in which the active materials are individually combined with a suitable carrier. When administered separately, the administration may be simultaneous or at selected time intervals.
The administration is preferably orally and the carrier or carriers are selected with this in mind. While this is the case, other modes of administration of both substances as well as mixed modes with the individual materials is considered part of the present invention.
The dosage levels of the materials will vary with the particular material being used and the severity of the condition of the patient being treated. The cyclic Prolyl Glycine (cPG) is used in amounts ranging from about 0.1 mg to about 10 mg per kg of body weight. It is recommended to administer orally with a dose of about 20 mg to about 80 mg per day and can be up to about 100 mg per day for some severe cases per physician’s prescription order.
The pharmaceutical compositions of the present invention are prepared by utilizing the active ingredients in association with the pharmaceutical carriers conventionally employed wi th such materials. The compositions of the present invention are in general contemplated for administration orally to achieve an antidepressant effect. This may be in any of the dosage forms such as tablets, capsules, powders, suspensions, solutions, syrups and the like, including sustained release preparations. The term dosage form as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosage, each unit containing a predetermined quantity of active material in association with the required diluent, carrier or vehicle. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units.
While the present invention contemplates, primarily, oral administration, other modes are certainly not excluded. Ampules for parenteral application can be prepared and preferably contain water soluble salts of the active substances and possible buffer substances in aqueous solution. In liquid compositions, whether designed for oral or parenteral administration in which the active substances are combined, care must be taken to insure stability of the active materials.
In cases where the active materials are to be administered separately, individual compositions are prepared in the manner indicated above. These individual compositions can then be administered as such or combined into a single-dosage unit while maintaining the separate identity, as for example in a multilayer tablet or single capsule containing both components in a plurality of discrete particles.
The present invention is described with reference to specific embodiments thereof. Other aspects of this invention can be appreciated with reference to the drawings. Drawings have been provided in the above text and attached drawings as well, and are further provided below and their description provided at that location.
DETAILED DESCRIPTION OF THE INVENTION
The present invention recognizes that there is a long felt need for the treatment of mild cognitive impairment.
As a non-limiting introduction to the breath of the present invention, the present invention includes several general and useful aspects, including but not limited to:
A first aspect of the present invention generally relates to a method of treating, relieving, or alleviating mild cognitive impairment in a subject.
A second aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease in a subject.
A third aspect of the present invention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject
A fourth aspect of the presen t i nvention generally relates to a method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject
A fifth aspect of the present invention generally relates to a method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject
These aspects of the presen t invention, as well as others described herein, can be achieved by using the methods, articles of manufacture, and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the present invention. I. METHOD OF TREATING, RELIEVING, OR ALLEVIATING MILD CONGNITIVE IMPAIRMENT
A first aspect of the present invention includes a method of treating, relieving, or alleviating mild cognitive impairment in a subject, including: a) providing a subject in need of treating, relieving, or alleviating mild cognitive impairment; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the mild cognitive impairment; further wherein the subject is treated for the mild cognitive impairment.
A. MILD CONGNITIVE IMPAIRMENT
An aspect of the present invention includes wherein the mild cogniti ve impairment is related to Alzheimer’s Disease.
B. cPG COMPOUND
Another aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is from about 1 pg to about 100 mg per kg of bodyweight.
A further aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is administered at an amount from about 0.1 mg to about 10 mg/kg per day, from about 0.5 mg to about 20 mg/kg per day, from about 0.2 mg to about 40 mg/kg per day, from about 5 mg to about 50 mg/kg per day, or from about 10 micrograms to about 100 mg/kg per day. An additional aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound has a lower limit of about 0.1 milligrams per kilogram mass (mg, kg) of the mammal and an upper limit of about 10 mg/kg of the subject.
An aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is from about 20 mg and about 80 mg per day, or from about 20 mg and about 100 mg per day.
Another aspect of the present invention includes wherei n the administeri ng of the pharmaceutically effective amount of the cPG compound is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
A further aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is in combination with artificial cerebrospinal fluid.
An additional aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is intravenous.
An aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is combined with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF-II), or a combination thereof.
Another aspect of the present in vention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is combined with the administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof
A further aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the cPG compound is combined with administration of an anti-inflammatory agent.
An additional aspect of the present invention includes wherein the cPG compound is provided in aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.
An aspect of the present invention includes wherein the cPG compound includes one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or a combination thereof. Another aspect of the present invention includes wherein the pharmaceutically effective amount of the cPG compound is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.
A further aspect of the present invention includes wherein the cPG compound is in the form of a tablet, capsule, or a combination thereof.
C. SPECIFIC BINDING MEMBER THAT SPECIFICALLY AND OPERABLY BINDS WITH AB SOLUBLE PROTOFIBRILS
An additional aspect of the present invention includes wherein the specific binding member includes a receptor, receptor agonist, polypeptide, ligand, antibody, polyclonal antibody, monoclonal antibody, humanized antibody, an active fragment thereof, or a combination thereof.
These terms are used herein in their ordinary meaning and usage as they are known in the art.
An aspect of the present invention includes wherein the specific binding member includes Lecanemab, Aducanumab, Donanemab, Crenezumab, Semorinemab, Gantenerumab an active fragment thereof, or a combination thereof.
These compounds and related compositions are as they are known in the art and commercially available. The particular characteristics may not be publicly available at this point in time.
Another aspect of the present invention includes wherein the specific binding is biding with Amyloid p soluble protofibrils.
A further aspect of the present invention includes wherein the specific binding is binding with Amyloid P (Ap42) soluble protofibrils.
An additional aspect of the present invention includes wherein the operably binds is binding with Amyloid p soluble protofibrils to modulate at least one activity thereof. The modulation of an activity relates to the ability to provide a desired effect, such as but not limited to a pharmaceutical effect, such as but not limited to a pharmaceutical effect as described or demonstrated herein.
An aspect of the present invention includes wherein the operably binds is binding with Amyloid [3 (A|342) soluble protofibrils to modulate at least one activity thereof.
Another aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is from about Ipg to about 100 mg per kg of body weight.
A further aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is administered at an amount from about 0.1 mg to about 10 mg/kg per day, from about 0.5 mg to about 20 mg/kg per day, from about 0.2 mg to about 40 mg/kg per day, from about 5 mg to about 50 mg/kg per day, or from about 10 micrograms to about 100 mg/kg per day.
An additional aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member has a lower limit of about 0.1 milligrams per kilogram mass (mg/kg) of the mammal and an upper limit of about 100 mg/kg of the subject.
An aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is from about 20 mg and about 80 mg per day, or from about 20 mg and about 100 per day.
Another aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
A further aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is in combination with artificial cerebrospinal fluid.
An additional aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is intravenous.
An aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is combined with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF -II), or a combination thereof.
Another aspect of the present invention includes wherein the administering of the pharmaceutically effective amoun t of the specific binding member is combined with the administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof.
A further additional aspect of the present invention includes wherein the administering of the pharmaceutically effective amount of the specific binding member is combined with administration of an anti-inflammatory agent.
An additional aspect of the present invention includes wherein the administering of the pharmaceutically effecti ve amount of the specific binding member Lecanemab (Leqembi®) at a dose of 10 mg/kg, once every two weeks, in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier, such as 0.9% sodium chloride injection.
An aspect of the present invention includes wherein the specific binding member is provided in aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.
Another aspect of the present invention includes wherein the specific binding member includes one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or a combination thereof.
A further aspect of the present invention includes wherein the pharmaceutically effective amount of the specific binding member is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracisternal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.
An additional aspect of the present invention includes wherein the specific binding member is in the form of a tablet, capsule, nasal spray, injectable, intravenous infusion, or a combination thereof. D. SUBJECT
An aspect of the present invention includes wherein the subject is a mammal.
Another aspect of the present invention includes wherein the subject is a subject is human.
E. EFFECTIVE AMOUNT THAT TOGETHER TREAT SAID SUBJECT FOR MILD COGNITIVE IMPAIRMENT
A further aspect of the present invention includes wherein the effective amount that together treat the subject for mild cognitive impairment is from about 0.1 mg/kg to about 20 mg/kg body weight of cPG in combination with from about 1 gg to about 100 mg per kg of body weight of a specific binding member.
F. TREATING, RELIEVEING, OR ALLEVIATING
An additional aspect of the present in vention includes wherein the treating, relieving, or alleviating is treating.
To treat a condition means to heal the disease, disorder, or condition, so that the patient recovers completely and no longer has the symptoms of the disease, disorder, or condition. To treat can include mitigation, delay the onset of the disease, relieve the disease, alleviate the symptoms of the disease, or a combination thereof. These are distinct from the concept of cure, which relates to the end of the disease from a subject, or as the term is known in the art, particularly in the medical field.
An aspect of the present invention includes wherein the treating, relieving, or alleviating is relieving.
To relieve means to become less severe or serious of the above problems and symptoms.
Another aspect of the present invention includes wherein the treating, relieving, or alleviating is alleviating. To alleviate means to make it less severe or serious and more bearable of the above problems and symptoms.
II. METHOD OF TREATING, RELIEVING, OR ALLEVIATING ALZHEIMER’S DISEASE
A second aspect of the present invention includes a method of treating, relieving, or alleviating Alzheimer’s Disease in a subject, includes: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the Alzheimer’s Disease; further wherein the subject is treated for the Alzheimer’s Disease.
III. METHOD OF TREATING, RELIEVING, OR ALLEVIATING ALZHEIMER’S DISEASE PSYCHOSIS
A third aspect of the present invention includes a method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject, including: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease Psychosis; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2 -Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the Alzheimer’s Disease Psychosis; further wherein the subject is treated for tire Alzheimer’s Disease Psychosis.
IV. METHOD OF TRE ATING, RELIEVING, OR ALLEVIATING ALZHEIMER’S DISEASE BEHAVIOR, AGRESSION, AGITATION, ANGER, APATHY
A fourth aspect of the present invention includes a method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject, including: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease behaviours, aggression, agitation, anger, apathy, or a combination thereof; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPGj or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl- Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with A$ soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof; further wherein the subject is treated for tire Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof.
V. METHOD OF TREATING, RELIEVING, OR ALLEVIATING EARLY ONSET ALZHEIMER’S DISE ASE
A fifth aspect of the present invention includes a method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject, including: a) providing a subject in need of treating, relieving, or alleviating Early Onset Alzheimer’s Disease; b) administering to the subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Metliyl-Proline (cPMeG), or a combination thereof, col lectively called a cPG compound; c) administering to the subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein the cPG compound and the specific binding member are administered to the subject each in an effective amount that together treat the subject for the Early Onset Alzheimer’s Disease; further wherein the subject is treated for tire Early Onset Alzheimer’s Disease. cPG Compounds
As generally described hi U.S. Published patent application US20100247483A1 expressly incorporated herein fully by reference, cyclic Prolyl Glycine (“cyclic PG5’ or “cPG”) has the following structure;
Figure imgf000028_0001
Structure T. cyclic Prolyl Glycine
(This structure and compound are also known as NA-831 and those terminologies are used interchangeably herein).
The present invention includes novel diketopiperazines that are structurally related to cPG.
One aspect of this invention provides novel cyclic compounds having the structural formula and substituents described below.
Figure imgf000029_0001
Structure 2: cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline refered herein as “cGAL”
Where R can be an Alkyl” which refers to a saturated branched, straight chain or cyclic hydrocarbon radical. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopiopyimethyl, hexyl and the like.
Where R can be an Ally, which refer to a group is a substituent with the structural formula I hC CH Cl IJL where R is the rest of the molecule.
With R is a methyl, an aspect of the present invention that includes Cyclic Glycyl- 2- Alkyl Proline is (8aS)-Methyl-hexahydropyrrolo[l,2-a]pyrazine- 1,4-dione, which is referred to as Cyclic Glycyl-2-Methyl-Pro!ime or cyclicGMeP or cGMeP.
Figure imgf000029_0002
Structure 3:Cvdic G-2MeP (which is available for purchase from polypeptide suppliers such as Bachem Americas, Inc. (Torrance, California, USA).
In general, c(PG)3 and cGAL can be prepared by methods such as are already well- known to persons of ordinary skill in the art of peptide and modified peptide synthesis. See for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer- Verlag 1993. Synthesis of the diketopiperazine compounds of this invention may be by solution-phase synthesis as discussed in the Examples or via the solid-phase synthesis method exemplified by Merrifield et al. 1963 J. Amer. Chem. Soc.: 85, 2149-2156. Specific examples of diketopiperazme synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and references therein. A person of ordinary skill in the art will have no difficulty, taking account of that skill and the knowledge available, and of this disclosure, in developing one or more suitable synthetic methods for compounds of this invention.
In the present application, notably but not limited to this section where compound names and structures and abbreviations are provided, the various compounds can all be used in all aspects of the present invention included herein. For example, should cPG be indicted in the specification, then all other compounds of tliis section (and the application as a whole) that are cPG compounds and related derivatives such as but not limited to cGAL are included in that and other descriptions, notably but not limited to methods of treatment of a variety of conditions described herein.
Figure imgf000030_0001
Structure 4: one possible structure for cyclic (glvcyl-L-prolylglvcyl-L-prolylglvcyl- L-prolyl).
The chemical synthesis of cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-proIyl) was carried out as published in Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp, 15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences- by Charles M. Deber and Elkan R. Blout.
Synthesis of Cyc/o(glycyl-L -prolyl-glycyl-L -prolyl-glycyl-L -prolyl)
A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethyl -formamide (DMF) (20 ml, dried over sodium sulfate) was added dropwise with stirring over 6 hours to 500 ml of reagent-grade pyridine, at room temperature. The bright yellow mixture was constantly stirred over 48 hours at room temperature. Solvents were removed by rotary- evaporator-high vacuum pump system at 45°. The residue was washed with 20 ml of acetone which dissolved the p-nitrophenol and pyridine hydrochloride, but left the peptidic fraction insoluble. The insoluble materials and acetone were transferred to a flask and allow acetone to evaporate at 45°. The material was then dissolved in a minimum of DMF. The white microcrystalline precipitate was shown to be Cyc/o(glycyl-L -prolyl-glycyl-L - prolyl-glycyl-L -prolyl) (155 mg, with 28% yield), formed complexed with DMF. Crystallization from methanol-ether of 100 mg of this material gave crystalline cyclo(Pro- Gly)s (55 mg) free of DMF.
Chemical analysis: Calculated for CziHsoNeOdTO : C, 52.49; H, 6.71; N, 17.49. Elemental analysis found C, 52.60; H, 6.81 ; N, 17.38.
One example of cPG analogues is cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L- prolyl) or being abbreviated as cyclic(tri(Pro-Gly)) or referred herein as c(PG)3.
Another example of the cPG analogues is cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline referred herein as “cGAL.”
Collectively the cPG, c(PG)3, cGAL, and Cyclic Glycyl-2-Methyl-Proline, and their pharmaceutically acceptable salts, are referred herein collectively as the “cPG compounds.”
Also, Cyclic Glycyl-2-Methyl-Proline is a compound belong to the cyclic Glycyl- 2 -Alkyl Proline) group of compounds.
Furthermore, any of the cPG compounds, derivatives thereof, analogs thereof, and the like as disclosed herein or otherwise known in the art can be provided in the form of a pharmaceutically acceptable salt.
Preferably the cPG compounds are administered in a pharmaceutically acceptable composition such as a pharmaceutically acceptable carrier.
More preferably the composition additional!}' includes a therapeutic amount of a cPG compound in combination with a compound selected from growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-11 (IGF-II), GPE, transforming growth factor-ill, activin, growth hormone, nerve growth factor, growth hormone binding protein, JQF-binding proteins (especially JGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor, the hst/Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-1 (FHF-1) FHF-2 FHF-3 and FHF-4, karatinocyte growth factor 2, glial-activating factor, FGF- 10 and FGF- 16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin 3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial-cell line derived neurotrophic factor, activity -dependant neurotrophic factor, cytokine leukaemia inhibiting factor, oncostatin M, interleukin), P,a,x or consensus interferon, TNF- a; clomethiazole; kynurenic acid, Semax, FK506 [tacrolimus], L-threo-l-pheyl-2- decanoylamino-3 -morpholino- 1 -propanol, andrenocorticotropin-(4-9_ analogue [ORG2766] and dizolcipine [MK-801], selegiline; glutamate ants such as, NPS15O6, GV1505260, MK-801 , GV150526; AMPA ants such as 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo (f)quinoxaline (NBQX), LY3O3O7O and LY300164; anti-inflammatory agents directed against the addressin MAdCAM-1 and/or it integrin a4 receptors (a4f>l and a 4p7), such as anti-MAdCAM-lhnAb MECA-367 (ATCC accession no. (HB-9478), interferons including interferon beta lb and interferon alfacon-1.
Specific Binding Members and Active Fragments Thereof Such as the Monoclonal Antibody Lecanemab
Lecanemab or BAN2401 is the humanized Immunoglobulin G (IgG 1) version of the mouse monoclonal antibody mAb'l 58, which selectively binds to large, soluble A[3 protofibrils. This therapeutic antibody grew out of the discovery of the “Arctic” mutation in amyloid precursor protein (APP), which leads to a form of clinically typical Alzheimer's disease that is marked by particularly high levels of Ap protofibrils and relative absence of amyloid plaques (see Nilsberth et al., 2001). mAbl58 was originally developed at Uppsala University, Sweden. Lecanemab targets soluble Ap aggregates (oligomers and protofibrils) with high selectivity.
Lecanemab showed a high selectivity' for protofibrils versus monomers with an about 2300- and about 14,300-fold stronger binding to protofibrils (small and large, respectively) than to monomers when analyzed by SPR. Oligomerization of the amyloid P-protein (Ap) is believed to be a critical event in the development of Alzheimer’s Disease (AD). Ap is found primarily as either a 40- or 42- amino acid peptide, differing only in the addition of two hydrophobic residues (141 and A42) to the C -terminus of the former. This small difference in primary structure translates into large differences in the oligomerization patterns of Ap40 and Ap42.
Tire apparent importance of the C-terminus in the assembly of AP42 and the particularly strong link of A$42 to AD suggest that the C -terminus of Ap42 is a good target for developing inhibitors that disrupt Ap42 oligomerization as a means of preventing and treating AD. Recent experiments have shown that C -terminal fragments (CTFs) of AP42 were capable of disrupting the oligomerization and inhibiting the neurotoxicity of foil- length Ap42. Of the CTFs (AP(x-42), x=28-39) tested, three fragments showed particularly strong inhibitory effects: Ap(31-42), Ap(30-42) and AP(39-42), the shortest CTF tested. In particular, Ap(31-42), Ap(30-42) and Ap(39-42) inhibited 100%, 80% and 80% of Ap- induced toxicity, respectively. Although both AP(31-42) and AP(39-42) formed non-toxic heterooligomers with Ap42 monomers, tire mechanism was different: Ap(31-42) was a stronger inhibitor of intermolecular interactions among Ap42 monomers, whereas AP(39- 42) was a stronger inhibitor of intramolecular interactions within Ap42 monomers. (Wu C, Murray MM, Bernstein SL, Condron MM, Bitan G, Shea JE, Bowers MT. The structure of Abeta42 C-terminal fragments probed by a combined experimental and theoretical study. J Mol Biol. 2009 Mai- 27;387(2):492-501. doi: 10.1016/j .jmb.2009.01.029. Epub 2009 Jan 23. PMID: 19356595; PMCID: PMC2712569.).
Ap is a proteolytic product of amyloid precursor protein by p- and y-secretases. The imprecise cleavage of y-secretase at C-terminus of Ap sequence results in two major Ap isofomis: Ap42 (42 residues long) and Ap40 (40 residues long). The only difference between Ap42 and Ap40 is that Ap42 has two extra residues at the C-terminus. The concentration of Ap40 in cerebral spinal fluid has been found to be several-fold more than that of Ap42. However, Ap42 is the major component of amyloid plaques in AD brains. (Gu L, Guo Z. Alzheimer's Ap42 and Ap40 peptides form interlaced amyloid fibrils. J Neurochem. 2013 Aug;126(3):305-I 1. doi: 10.1111/jnc.12202. Epub 2013 Mar 12. PMID: 23406382; PMCID: PMC3716832 ). Lecanemab targets AP’s N-terminus (residues 1-16'), overlapping with fibrinogen’s binding site on Ap. Lecanemab blocked Ap42 binding to fibrinogen in a dose-dependent manner, while human IgG had no effect. The Ap42 preparation used was comprised of curvy linear aggregates (small protofibrils) 30-90 nm in length. ([Singh PK, Pires ENS, Chen ZL, Torrente D, Calvano M, Sharma A, Strickland S, Norris EH. Lecanemab Blocks the Effects of the Ap/Fibrinogen Complex on Blood Clots and Synapse Toxicity in Organotypic Culture. bioRxiv [Preprint]. 2024 Jan 21:2024.01.20.576458. doi: 10.1101/2024.01.20.576458. Update in: Proc Natl Acad Sei U S A. 2024 Apr 23;121(17):e2314450121. doi: 10.1073/pnas.2314450121. PMID: 38293058; PMCID: PMC 10827200.).
Tire extracellular accumulation of Ap in neuritic plaques and the binding of Ap to a variety of receptors appear to be the characteristic hal lmarks of Alzheimer's disease. The binding of Ap to a variety of receptors has been proposed as a cause for the neuronal toxicity: Ap oligomers were proposed to induce mitochondrial dysfunction and oxidative stress in AD neurons, resulting in a massive calcium influx and toxicity in neurons. Furthermore, soluble oligomeric Ap was proposed to be toxic through binding to a variety of receptors, including lipids, proteoglycans, and proteins, such as the Ap-binding p75 neurotrophin receptor (P75NRT), the low-density lipoprotein receptor-related protein (LRP), cellular prion protein (PrPc), metabotropic glutamate receptors (mGluR5), a subunit containing nicotinic acetylcholine receptor («7nAChR), N-methyl-D-aspartic acid receptor (NMDAR), P-adrenergic receptor (P-AR), erythropoietin-producing hepatoma cell line receptor (EphR), and paired immunoglobulin-like receptor B (PirB)97. The Ap/Ap receptor interactions are proposed to generate and transduce neurotoxic signals into neurons, causing cellular defects such as mitochondrial dysfunction and the ER stress response. In addition, some Ap receptors are most likely to internalize Ap into neurons to display distinct cellular defects. (Chen GF, Xu TH, Yan Y, Zhou YR, Jiang Y, Melcher K, Xu HE. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017 Sep;38(9):1205-1235. doi: 10. 1038/aps.2017.28. Epub 2017 Jul 17. PMID: 28713158; PMCID: PMC5589967.) Taken together, based on the unique structure of cPG, it is postulated that cPG binds to the C-tenninus in the assembly of AJ342, thus inhibiting the neurotoxicity of full- length Ap42.
A potential binding of IGF- 1 and its analogue, NA-831 with Lecanemab would potentially provide advantages over monotherapy of Lecanemab or NA-831 alone.
See for example: Sehlin D, Englund H, Simu B, Karlsson M, Ingelsson M, Nikolajeff F, et al. Large aggregates are the major soluble Abeta species in AD brain fractionated with density gradient ultracentrifugation. PLoS ONE, 2012;7(2):e32014. doi: 10.1371/joumalpone,0032014 ; Magnusson K, Sehlin D, Syvanen S, Svedberg MM, Philipson 0, Soderberg L, et al. Specific uptake of an amyloid-beta protofibril-binding antibody-tracer in AbetaPP transgenic mouse brain. J Alzheimers Dis. 2013;37(l):29— 40. doi: 10.3233/JAD-l 30029; Soderberg L, Johannesson M, Nygren P, Landon H, Eriksson F, Osswald G, Moller C. Lannfelt L. Lecanemab, Aducanumab, and Gantenerumab - Binding Profiles to Different Forms of Amyloid-Beta Might Explain Efficacy and Side Effects in Clinical Trials for Alzheimer’s Disease. Neurotherapeutics. 2023 Jah;20(l): 195-206. doi: 10. 1007/sl331 1-022-01308-6. Epub 2022 Oct 1". PMID: 36253511 ; PMCID: PMC10119362.
Data from late phase clinical trials indicates that Ap immunotherapy can have positive effects. However, amyloid -related imaging abnormalities, mainly with edema (ARIA-E), have been observed. The main risk factors identified for developing ARIA-E have been antibody dose and the presence of the apolipoprotein E4 (ApoE4 ) allele. The exact mechanism for the occurrence of ARIA-E has not been elucidated, but probable explanations involve direct binding of Ap antibodies to cerebral amyloid angiopathy (CAA). CAA is a pathology consisting of fibrillar Ap, mainly Ap 1 -40 deposited in the blood vessel walls and is a common occurrence in AD.
Lecaneniab-irmb is a recombinant human immunoglobulin gamma 1 (IgG 1 ) monoclonalantibody targeting aggregated soluble and insoluble forms of amyloid beta. It is expressed in a Chinese hamster ovary (CHO) cell line. Lecanemab-irmb inj ection is a preservative-free, sterile, clear to opalescent, and colorless to yellow solution for intravenous infusion after dilution. It is supplied in single-dose vials available in concentrations of 500 mg/5.0 mL (100 mg/mL) or 200 mg/2 mL (100 mg/mL). Lecanemab, a humanized IgG I monoclonal antibody that binds with high affinity to Ap soluble protofibrils, has been tested in persons with early Alzheimer’s disease. A multicenter, double-blind, phase 3 trial was conducted over 18 months involving 1795 participants 50 to 90 years of age with early Alzheimer’s disease. The primary end point was the change from baseline at 18 months in the score on the Clinical Dementia Rating- Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater impairment). The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least- squares mean change from baseline at 18 months was 1.21 with lecaneniab and 1.66 with placebo (difference, -0.45; 95% confidence interval [CI], -0.67 to -0.23; P<0.001). Lecaneniab resulted in infusion-related reactions in 26.4% of the participants and amyloid- related imaging abnormalities with edema or effusions in 12.6%. (Ref: Lecanemab in Early Alzheimer’s Disease. Christopher H. van Dyck, et al. January 5, 2023- N Engl J Med 2023; 388:9-21- DOI:10.1056/NEJMoa2212948).
It. is noted that the CDR-SB scores increased from a baseline of 3.2 to 4.41 in the lecanemab group, a change of 1.21 ; and increased to 4.86 in the placebo group, a change of 1.65. The -0.45 difference (4.41 -4.86) between the groups is often represented as 27% less cognitive decline (0.45/1.65), indicating the clinical benefit of Lecanemab treatment. This percentage is mis-leading and an erroneous conclusion based on the use of the wrong denominator. The actual CDR-SB scores give lecanemab a clinical benefit of 9.3% (0.45/4.86), and not 27%. This smaller value is unlikely to make any difference for people living w id1, early AD
It was concluded that Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events. However, Lecanemab was approved by the FDA on July 6, 2023, even though it was recommended that longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.
The FDA approved Lecanemab (trade name Leqembi it . herein is abbreviated as “LEQ”) for the treatment of early onset of Alzheimer’s disease (AD) based on an evaluation of effects of the drug in clinical stages. However, at a high dose of LEQ (about 10 mg /kg) resulted in infusion-related reactions in 26.4% of the participants and amyloid- related imaging abnormalities with edema or effusions in 12.6%. Patients who were treated with 10 mg/kg of LEQ experienced ARIA-E with headache, confusion, dizziness and nausea; microhemonhage; and superficial siderosis in clinical phase 3. Therefore, delivering a reduced dose of LEQ may be a key point for safety, however, this would render the drug less effective in the treatment of early onset of AD.
In the present invention, a combination therapy includes LEQ at reduced dose at 5 mg/kg administered intravenously, in addition to cPG administered orally at reduced dose of about 0.5 mg/kg. In a typical combination therapy, a patient is administered about 5 mg/ kg of Lecanemab intravenously biweekly, in addition to take between about 30 to about 60 mg of cPG orally per day.
This is a proposed clinical protocol of a combination therapy in which the dose of Lecanemab will be reduced from 10 mg/kg to a half at 5 mg/ kg to reduce the ARIA adverse effect, while the patient takes cPG at a half dose of 0.5 mg/kg
Notably, the combined treatment resulted in a marked improvement in. cognitive impairment after a 12-month treatment.
Although the effects of cPG are believed to be based on the facilitation of neurogenesis and may have different mechanisms and different biological relevance to AD treatment, the effects of the NA-831 were found to be synergistic as to the believed mechanism LEQ, being as human monoclonal antibodies that target the A|3 pathology in AD. Multiple clinical trials aiming at disease modifying therapies (DMT) to target the primary pathogenic proteins implicated in AD pathogenesis, such as A|3 and Tan, have failed to halt AD progression. This occurrence can be attributed to the current limitations in the knowledge of how to effectively overcome the blood-brain barrier (BBB) when developing novel treatments for central nervous system (CNS) disorders. Therefore, multi- target drugs that can address multiple pathologies simultaneously may be preferable. The development of multi-target drugs for dementia treatment aligns with the concept of repositioning anti-diabetic drugs for dementia, as the insulin/IGF-1 signaling pathway has been implicated in many dementia subtypes. From a molecular viewpoint, repositioning anti-diabetic drags such as IGF-1 for disease modifying therapies (DMT) against multiple subtypes of dementia appears to be a reasonable approach. As a metabolite of 1GF-I, cPG can cross the blood brain barrier and has been shown to exhibit neuroprotection and neurogenesis properties.
Combination of cPG and Specific Binding Member
Preferably the combination therapy of cPG compounds and Lecanemab can be used in the treatment or prevention of cell damage or cell death in response to diseases and injury resulting from septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, allograft rejection, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye disease, corneal ulcer, keratitis, cataract, retinal disorders, age-related macular degeneration, optic neuritis ileitis, inflammation induced by overproduction of inflammatory cytokines, hemorrhagic shock, anaphylactic shock, burn, infection leading to the overproduction of inflammatory cytokines induced by bacteria, virus, fungus, and parasites, hemodialysis, chronic fatigue syndrome, stroke, cancers, cardiovascular diseases associated with overproduction of inflammatory cytokines, heart disease, cardiopulmonary bypass, ischemic/r eperfusion injury, ischemic/reperfusion associated with overproduction of inflammatory cytokines, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune disorders, eczema, psoriasis, heart failure, dermatitis, urticaria, cerebral ischemia, systemic lupus erythematosis, AIDS, AIDS dementia, chronic neurodegenerative disease, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, Huntington's disease, epilepsy, gastrointestinal motility disorders, obesity, hyperphagia, neuroblastoma, malaria, hematologic cancers, myelofibrosis, lung injury, graft-versus-host disease, head injury, CNS trauma, hepatitis, renal failure, chronic hepatitis C, paraquat poisoning, transplant rejection and preservation, fertility enhancement, bacterial translocation, circulatory shock, traumatic shock, hemodialysis, hangover, and combinations of two or more thereof. Preferably the combination therapy of cPG compounds and Lecanemab can be used in the restoration of myelination of axons in mammals where myelin depleted due to neural injury or disease.
Preferably cPG compound can be used in the restoration of myelination where depletion due to trauma, toxin exposure, asphyxia or hypoxia-ischemia, perinatal hypoxic- ischemic injury, injury to or disease of the w'hite matter of the CNS, acute brain injury, chronic neurodegenerative disease including multiple sclerosis, and demyelinating diseases and disorders including acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, Devic's disease, the leucodystrophies; non-inflammatory involvement: progressive multifocal leukoencephalopathy, and central pontine myelinolysis.
Preferably, the cPG compound can be administered at between about 1 ug to about 150 mg per kilogram of bodyweight. A suitable dosage for administration of cPG can be, for example, preferably but not limited to between about 0. ling to about 100 mg per kilogram of body weight, between about 1 mg to about 100 mg per kilogram of body weight, between about 5 mg and about 70 mg per kilogram of body weight, between about 10 mg to about 50 mg per kilogram of body weight, or between about 20 mg to about 40 mg per kilogram of bodyweight. The dose, route of administration, and regime of cPG may be different for different diseases, disorders, and conditions. As an example, mild cognitive impairment may have a lower dose using the same or different route of administration than for Alzheimer’s disease.
For example: a typical dosage for patient with mild cognitive impairment can be between about 0.2 mg to about 1 mg per day administered orally (for example, taking 1 capsule of 20 mg or 2 capsules per day per doctor prescription). Whereas, a more severe Alzheimer’s Disease or severe Traumatic Brain injury patent can be administered intravenously in a range from between about 50 mg to about 300 mg per day. The particulars of the dose, route of administration, and regime for a particular disease, disorder, or condition can be evaluated in general or for a particular subject or patient. Pharmacology and Utility cPG can act as an anti-necrotic and anti-apoptotic in a process of cell death. Its anti- apoptotic and anti-necrotic activity in vivo can be measured by cell counts. cPG can also be measured in vitro. (Gudasheva T. A. et al. FEBS Letters, Vol. 391, Issues 1-2, 5 August 1996, pp. 149-152). CNS damage may for example be measured clinically by the degree of permanent neurological deficit cognitive function, and''or propensity to seizure disorders. (Rakic L.J et al, in Rakic L.J et al Peptide and Amino Acid Transport Mechanisms in The Central Nervous System, 1988, The MacMillan Press Ltd. (London) pp.167-181).
Pharmaceutical Compositions and Administration cPG itself as pail of the present invention can be used to prevent or treat cell damage and programmed death and the induction of myelin production. Usually this is effected through the direct administration of cGP to the patient. If desired, a combination of the cPG compounds and its analogues can be administered in a pharmaceutically acceptable composition.
Those skilled in the art will appreciate there is no intention on the part of the applicants to exclude administration of other forms of cPG and its analogues. By way of example, the effective amount of cPG in the CNS can be increased by administration of a pro-drug from of cPG, which comprises cPG and a carrier, cPG and the carrier being joined by a linkage which is susceptible to cleavage or digested within the patient. Any suitable linkage can be employed which will be cleaved or digested to release cPG following administration.
In addition, it is envisaged cPG levels may be increased through an implant that includes a cell line capable of expressing cPG in an active from within the CNS of the patient.
Pro-drugs of cPG and its analogues can also be administered. In that instance, the pro-drug is metabolized or otherwise altered within the subject to form cPG. cPG and its analogues, such as but not limited to c(PG)3 and cyclic Glycyl-2-Ally 1 Proline, or cyclic Glycyl-Alkyl Proline or Cyclic Glycyl-2-Methyl-Prolime can be administered as part of a medicament or pharmaceutical preparation. This can involve combining cPG with any pharmaceutically appropriate carrier, adjuvant or excipient. The selection of the carrier, adjuvant or excipient will of course usually be dependent upon the route of administration to be employed.
The administration route can vary wddely and be any appropriate route of administration. An advantage of cPG is that it can be administered peripherally. This means it need not be administered directly to the CNS of the patient in order to have effect in the CNS.
Any peripheral route known in the art can be employed. These can include but are not limited to parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion (using e.g., controlled release devices or minipumps such as osmotic pumps or skin patches), implant, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, oral, buccal, pulmonary, rectal or vaginal. The compositions can be formulated for parenteral administration to humans or other mammals in therapeutically effective amounts (e.g., amounts which eliminate or reduce the patient's pathological condition) to provide therapy for the neurological diseases described above.
Two of the preferred administration routes will be by subcutaneous injection (such as but not limited to, dissolved in 0.9% sodium chloride) or orally (in a capsule).
It will also be appreciated that on occasion it may desirable to directly administer cPG compounds to the CNS of the patient. Again, this can be achieved by any appropriate direct administration route. Examples include administration by lateral cerebroventricular injection or through a surgically inserted shunt into the lateral cerebroventricle of the brain of the patient.
Tire calculation of the effective amount of cPG compounds to be administered is within the skill of one of ordinary skill in the art, and will be routine to those persons skilled in the art. Needless to say, the final amount to be administered will be dependent upon the route of administration and upon the nature of tire neurological disorder or condition that is to be treated. Preferably the cPG compound will be administered at between about 1 pg to 100 mg of cPG compound per per kilogram of body weight where the dose is administered centrally. A suitable dosage for administration of cPG may be, for example, at between about 0.1 mg to about 10 mg per per kilogram of body weight, or at between about 1 mg to about 5 mg per per kilogram body weight.
For inclusion in a medicament, cPG compounds can be obtained from a suitable commercial source such as Bachem AG of Bubendorf, Switzerland. Alternatively, cPG can be directly synthesized by conventional methods such as the stepwise solid phase synthesis method of Merrifield et al. 1963 J. Amer. Chem. Soc.: 85, 2149-2156. Alternatively synthesis can involve in the use of commercially available peptide synthesizers such as the Applied Biosystems model 430A. cGAL can be prepared by methods such as are well-known to those of ordinary skill in the art of the synthesis of peptides and analogues. Example: “Principles of Peptide Synthesis” by Bodanzsky, published by Springer- Ver lag 1993. c(PG)3 can be prepared by the method published in the Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp. 15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences- by Charles M. Deber and Elkan R. Blout.pu.
As a general proposition, the total pharmaceutically effective amount of the cPG compound administered parenterally per dose will be in a range that can be measured by a dose response curve. One can administer increasing amounts of the cPG compound to the patient and check the serum levels of the pa tient for cPG. The amount of cPG compound to be employed can be calculated on a molar basis based on these serum levels of cPG.
Specifically, one method for determining appropriate dosing of the compound entails measuring cPG levels in a biological fluid such as a body or blood fluid. Measuring such levels can be done by any means, including RIA and ELISA. After measuring cPG levels, the fluid is contacted with the compound using single or multiple doses. After this contacting step, the cPG levels are re-measured in the fluid. If the fluid cPG levels have fallen by an amount sufficient to produce the desired efficacy for which the molecule is to be administered, then the dose of the molecule can be adjusted to produce maximal efficacy. This method can be carried out in vitro or in vivo. Preferably, this method is carried out in vivo, i.e., after the fluid is extracted from a mammal and the cPG levels measured, the compound herein is administered to the mammal using single or multiple doses (that is, the contacting step is achieved by administration to a mammal) and then the cPG levels are remeasured from fluid extracted from the mammal.
The compound may also be suitably administered by a sustained-release system. Suitable examples of sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919; EP 58,481), copolymers of L- glutamic acid and gamma-ethyl-L-glutamate (Sidman et al., 1983), poly(2-hydroxyethyl methacrylate) (Langer et al, 1981), ethylene vinyl acetate (Langer et al., supra), or poly-D- (-)-3 -hydroxybutyric acid (EP 133,988).
Sustained-release compositions also include a liposomally entrapped compound. Liposomes containing the compound are prepared by methods known per se: DE Patent 3,218,121; Epstein et al., 1985; Hwang et al., 1980; EP Patent 52,322; EP Patent 36,676; EP Patent 88,046; EP Patent 143,949; EP Patent 142,641 ; Japanese Pat. Appln. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (from or about 200 to 800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the most efficacious therapy.
PEGylated peptides having a longer life can also be employed, based on, e.g., the conjugate technology described in WO 95/32003, published November 30, 1995.
If parenteral administration is preferred, the compound is formulated generally by mixing each at the desired concentration, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically, or parenterally, acceptable carrier, i.e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
Generally, the formulations are prepared by contacting the compound with liquid carriers or finely divided solid carriers or both. Then, if necessary', the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier^ more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution. Non- aqueous vehicles such as fixed oils and ethyl oleate may also be used. The carrier may additionally contain additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e.g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose, trehalose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counter-ions such as sodium; non-ionic surfactants such as polysorbates, poloxamers, or polyethylene glycol (PEG); and/or neutral salts, e.g., NaCl, KC1, MgCh CaCh etc.
The cPG compound is typically formulated in such vehicles at a pH of between about 5.5 to about 8.0. Typical adjuvants which may be incorporated into tablets, capsules, and the like ar e a binder such as acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavoring agent such as peppermint, wintergreen, or cherry. When the dosage form is a capsule, in addition to the above materials, it may also contain a liquid carrier such as a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. A syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent, and a flavoring agent such as cherry. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. Buffers, preservatives, antioxidants, and the like can be incorporated according to accepted pharmaceutical practice.
The compound to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e.g., 0.2 micron membranes). Therapeutic compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
The compound ordinarily will be stored in unit or multi-dose containers, for example, sealed glass ampules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-mL vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous solution of compound, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized compound using bacteriostatic Water-for-Injection.
Combination therapy with the cPG compound herein and one or more other appropriate reagents that increase total cPG in the blood or enhance the effect of the cPG is also contemplated. These reagents generally allow the cPG compound herein to release the generated cPG.
In addition, one aspect of the present invention includes using gene therapy for treating a mammal, using nucleic acid encoding the cPG compound, if it is a peptide. Generally, gene therapy is used to increase (or overexpress) cPG levels in the mammal. Nucleic acids, which encode the cPG peptide can be used for this purpose. Once the amino acid sequence is known, one can generate several nucleic acid molecules using the degeneracy of the genetic code, and select which to use for gene therapy.
There are two major approaches to getting the nucleic acid (optionally contained in a vector) into the patient’s cells for purposes of gene therapy: in vivo and ex vivo. For in vivo delivery, the nucleic acid is injected directly into the patient, usually at the site where the cPG compound is required. For ex vivo treatment, the patient’s cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient either directly or, for example, encapsulated within porous membranes which are implanted into the patient. See, for example, U.S. Pat. Nos. 4,892,538 and 5,283,187.
There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. A commonly used vector for ex vivo delivery of the gene is a retrovirus.
The currently preferred in vivo nucleic acid transfer techniques include transfection with viral vectors (such as adenovirus, Herpes simplex I virus, or adeno-associated virus) and lipid-based systems (useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPE and DC-Chol, for example). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell-surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell-surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g., capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, and proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., 1987; Wagner el al., 1990). For review of the currently known gene marking and gene therapy protocols, see Anderson 1992. See also WO 93/25673 and the references cited therein.
Kits are also contemplated for this invention. A typical kit would comprise a container, preferably a vial, for the cPG compound formulation comprising cPG compound in a pharmaceutically acceptable buffer and instructions, such as a product insert or label, directing the user to utilize the pharmaceutical formulation.
Certain aspects of the present invention include the use of cPG in treatment of cognitive impairment associated with aging with neurodegenerative conditions or in situations in which cognitive impairment is found with no apparent neurodegeneration.
Such other agents can be selected from the non-limiting group of, for example, growth factors and associated derivatives, e.g,, insulin-like growth factor-I (IGF -I), insulin- like growth factor-II (IGF HI), growth hormone, nerve growth factor, growth hormone binding protein, and/or IGF-binding proteins. Lecanemab
Lecanemab (previously BAN2401) is a humanized immunoglobulin G1 (IgGl) anti-amyloid beta (A(3) monoclonal antibody targeting aggregated forms of A[3. Extracellular deposits of A|3, referred to as amyloid plaques. Accumulation of Ap in the brain has been proposed to be the primary driver of the disease process and precedes the accumulation of tau pathology and neural degeneration.
Lecanemab was approved by the FDA which was based on reduction in amyloid plaque burden measured by positron emission tomography (PET) imaging which is proposed to be reasonably likely to predict clinical benefit. This FDA submission contains biomarker, efficacy, and safety data from Study 201, a multicenter, randomized, double- blind, placebo-controlled, parallel- group study in patients with MCI due to Alzheimer’s disease or mild Alzheimer’s disease dementia.
Therapeutic Applications
Compositions and methods of the present invention find use in the treatment of animals, such as human patients, suffering from cognitive impairment. Still more generally, the compositions and methods of the inventi on find use in the treatment of mammals, such as but not limited human patients and subjects, suffering from memory impairment, mild cognitive impairment, dementia, including dementia including dementias resulting from cerebral atrophy associated with Alzheimer's disease, Lewy-bodies disease, frontotemporal lobar degeneration, vascular dementia, head trauma; Huntington's disease, Parkinson's disease, or Down’s syndrome.
Pharmaceutical Compositions and Administration
Cyclic PG compounds can be administered as part of a medicament or pharmaceutical preparation. This can involve combining a compound of the invention with any pharmaceutically appropriate carrier, adjuvant or excipient. The selection of the carrier, adjuvant or excipient will of course usually be dependent upon the route of administration to be employed.
In general, compounds of the present invention will be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination rvith other conventional therapeutic agents for the disease being treated. A therapeutically effective amount may vary depending on the disease or injury, its severity, the age and relative health of the animal being treated, the potency of the compound(s), and other factors. Therapeutically effective amounts of cyclic Prolyl Glycine can range from 0.01 to 10 milligrams per kilogram mass of the animal, with lower doses such as 0.01 to 0.1 mg/kg being appropriate for administration through the cerebrospinal fluid, such as by intracerebroventricular administration, and higher doses such as 0.1 to 10 mg/kg being appropriate for administration by methods such as oral, systemic (e.g. transdermal), or parenteral (e.g. intravenous) administration. A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease or injury.
Cyclic Prolyl Glycine and cPG compound can be administered orally or peripherally via any peripheral route known in the art. These can include but are not limited to parenteral routes for example injection into the peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, intravenous infusion, aerosol, inhalation, scarification, intraperitoneal, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal or vaginal.
For the convenience to the patients, the cyclic Prolyl Glycine and cPG compounds can be administered orally. The amount of a compound of this invention in the composition may vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary' skill in the art. In general, the final composition may comprise from 5 mg to 50 mg of cPG for a typical adult weighing 50 to 120 kg or 1 xlO'3 percent to 3x 10'4 by weight (% w) with the remainder being the excipient or excipients.
Other convenient administration routes include subcutaneous injection or intravenous infusion (for example the active cPG is dissolved in a physiologically compatible carrier such as 0.9% sodium chloride or dextrose) or direct administration to tire CNS. Using stereotactic devices and accurate maps of an animals' CNS, a compound can be injected directly into a site of neural damage.
The effective amount of compound in the CNS can be increased by administration of a pro-drug form of a compound, which comprises a compound of the invention and a carrier, where the carrier is joined to a compound of the invention by a linkage which is susceptible to cleavage or digestion within the patient. Any suitable linkage can be employed which will be cleaved or digested following administration.
However, there is no intention on the part of the applicants to exclude other forms of administrati on. In other embodiments of the present invention, restoring nerve function in an animal can include administering a therapeutic amount of cyclic Prolyl Glycine or cPG compounds in combination with another neuroprotective agent, selected from, for example, growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-11 (IGF-II), transforming growth factor-[31, activin, growth hormone, nerve growth factor, growth hormone binding protein, IGF-binding proteins, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, fibroblast growth factor homologous factor- 1 (FHF-1 ), FHF-2, FHF-3 and FHF-4, karatinocyte growth factor 2, brain derived growth factor, neurotrophin 3, and neurotrophin 4. Other forms of neuroprotective therapeutic agents include clomethiazole, kynurenic acid, Semax, tacrolimus; glutamate agonist such as, NPS1506, GV1505260, MK-801, GV150526; AMPA ants such as 2,3-dihydroxy-6-nitro- 7-sulfamoylbenzo(f)quinoxaline (NBQX); anti-inflammatory agents directed against the addressin MAdCAM-1 and/or its integrin o.4 receptors (a4fH and 04(37), such as anti- MAdCAM-lmAb MECA-367 (ATCC accession no. HB-9478).
Cyclic Prolyl Glycine compounds can be suitably administered by a sustained- release system. Suitable examples of sustained-release compositions include semi- permeable polymer matrices in the form of shaped articles, for example, films, or microcapsules.
For parenteral administration, in one embodiment cyclic Prolyl Glcyine or cPG compounds is formulated generally by mixing each at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically, or parenterally, acceptable carrier, for example, one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.
Generally, the formulations are prepared by contacting cyclic Prolyl Glycine or cPG compounds uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, ore preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, a buffered solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein.
Cyclic Prolyl Glycine or cPG compounds are typically formulated in such vehicles at a pH of from or about 4.5 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of salts of the compound. The final preparation may be a stable liquid or lyophilized solid.
Formulations of cyclic Prolyl Glycine or cPG compounds in pharmaceutical compositions can also include adjuvants. Typical adjuvants which may be incorporated into tablets, capsules, and die like are a binder such as acacia, corn starch, or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent like corn starch or alginic acid; a lubricant such as magnesium stearate; a sweetening agent such as sucrose or lactose; a flavouring agent such as peppermint, wintergreen, or cherry. When dosage forms are tablets, cyclic Prolyl Glycine or a cPG compounds and compositions can include binders and optionally, a smooth coating. When the dosage form is a capsule, in addition to tire above materials, it may also contain a liquid carrier such as a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. A syrup or elixir may contain the active compound, a sweetener such as sucrose, preservatives like propyl paraben, a coloring agent, and a flavoring agent such as cherry . Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired. For injection, intraventricular administration and other invasive routes of administration, cyclic Prolyl Glycine or cPG compounds are preferably sterile. Sterility may be accomplished by any method known in the art, for example filtration through sterile filtration membranes (for example, 0.2-micron membranes). Therapeutic compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper able to be pierced by a hypodermic injection needle.
Preferred Aspects of the Present Invention
The present invention provides a method for the treatment of mild cognitive impairment and related neurodegenerative disorders and psychological disorders using NA-831 and cPG analogues and cPG compounds, in combination with antibodies or active fragments thereof, such as the monoclonal antibody Lecanemab that specifically binds with.
The first aspect of the present invention includes a method for relieving or alleviating of Alzheimer’s Disease psychosis caused by a disease, injury, or condition in a mammal in need thereof, comprising: a) providing a mammal in need of relieving or alleviating of Alzheimer’s Disease psychosis caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic (tri (Prolyl Glycine) or cyclic Glycyl-2- Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to said mammal; wherein the disease is selected from the group consisting of Alzheimer's Disease psychosis.
Another aspect of the present invention includes wherein the administration of cPG and Lecanemab is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
A further aspect of the present invention includes wherein the effective amount of cPG compound is from about Ipg to about 100 mg per kg of body weight.
An additional aspect of the present invention includes wherein the administration is in combination with artificial cerebrospinal fluid. Another aspect of the present invention includes wherein the administration is intravenous.
A further aspect of the present invention includes wherein the administration is combined with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin growth-like factor-II (IGF-II).
A further aspect of the present invention includes wherein the administration is in the form of a pharmaceutical composition including pharmaceutically acceptable carrier thereof.
An additional aspect of the present invention includes wherein the administration is in combination with artificial cerebrospinal fluid.
Another aspect of the present invention includes wherein the administration is combined with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin growth-like factor-II (IGF-II).
A further aspect of the present invention includes herein the administration is combined with an anti-inflammatory agent.
A second aspect of the present invention includes a method for rel ieving or alleviating of cognitive impairment caused by a disease, injury, or condition in a mammal in need thereof, comprising: a) providing a mammal in need of relieving or alleviating of cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Gly cyl-2- Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to said mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease, Dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia^ senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration; further wherein the injury is selected from the group consisting of neurotoxic injury, cerebral hypoxia/ischemia, traumatic brain injury, coronary artery bypass surgery, w'here said condition is normal aging, age-related memory loss, memory impairment, cholinergic hypo function, vascular narrowing or blockage in the brain, neuroinflammation, mild cognitive impairment, cerebral atrophy, frontotemporal lobar degeneration, Pick's disease, HIV infection, Down’s syndrome, and loss of synaptic plasticity; further wherein said mammal is for relieved or alleviated of cognitive impairment caused by a disease, injury, or condition, including Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Relieving cognitive impairment generally refers to methods that can relieve symptoms related to memory, thinking, language and other thought processes. In addition, they may also help with mood, agitation and other behavioral issues.
Another aspect of the present invention includes wherein said cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Gly cyl-2 -Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with lecanemab thereof, includes an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.
A further aspect of the present invention includes wherein said cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri( Prolyl Glycine) or cyclic Glycyl-2 -Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, further includes one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule.
An additional aspect of the present invention includes wherein the disorder is a mild cognitive impairment, Alzheimer Disease, memory' loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerati ve origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alky 1 Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof, route of administration.
Another aspect of the present invention includes wherei n the pharmac eutical ly effective amount has a lower limit of about 0.001 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 100 mg/kg of said mammal.
A further aspect of the present invention includes wherein the cognitive impairment is caused by cholinergic hypofunction.
An additional aspect of the present invention includes wherein the cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination thereof, causes an increase in AMP A receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
A further aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, causes an increase in neuronal plasticity caused by said cPG compound in the granule cell layer (CAI) and the pyramidal cell layer (CA3) regions of said mammal's hippocampus.
An additional aspect of the present invention includes wherein the cerebral hypoxia/ischemia caused by traumatic brain injury.
Another aspect of the present invention includes wherein the cognitive impairment caused by multi-infarct dementia.
A further aspect of the present invention includes wherein tire cognitive impairment caused by coronary arterial bypass surgery (CABG). An additional aspect of the present invention includes wherein the cognitive impairment caused by Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
A third aspect of the present invention includes a method of preventing the symptoms of a mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need thereof, including: a) providing a mammal in need of preventing cognitive impairment caused by a disease, injury, or condition; b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Proly 1 Glycine) or cyclic Glycyl-2-Ahyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease, Dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Preventing the symptoms of a mild cognitive impairment generally refers actions that would be performed to prevent the symptomatic phase and primarily to reduce the risk of disease. Typically, prevention in dementia can be referred to as levels of prevention: primary, secondary and tertiary.
In degenerative dementias, the secondary prevention stage can apply to the phase of mild cognitive impairment. At this point, symptoms are present but are not sufficiently severe to constitute dementia. Therefore, treatment of cPG compounds in combination with Lecanemab aimed at subjects with MCI could be considered secondary prevention studies.
Tertiary prevention refers to a treatment designed to halt the progression of the disease once it has been established. The goal is to reduce the disability and improve the long-term prognosis for individuals with the mild cognitive impairment. A fourth aspect of the present invention includes a method of treating the symptoms of a mild cognitive impairment caused by or associated with a disease, injury’, or condition in a mammal in need thereof, including: a) providing a mammal in need of treating of cognitive impairment caused by a disease, injury, or condition; b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease, Dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Treating the symptoms of a mild cognitive impairment generally refers to treating cognitive function, or the process of thought, includes but is not limited to abilities such as learning, reading, speaking and writing. Patients with mild cognitive impairment (MCI) retain these important cognitive skills, necessary’ to manage their everyday activities, but have difficulty remembering recent events or recently acquired information.
A fifth aspect of the present invention includes a method for relieving or alleviating of cognitive impairment caused by a disease, injury’, or condition in a mammal in need thereof, including: a) providing a mammal in need of relieving or alleviating of cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-AIlyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease. Dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated wdth Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration; further wherein the injury is selected from the group consisting of neurotoxic injury', cerebral hypoxia/ischemia, traumatic brain injury, coronary artery bypass surgery; where said condition is normal aging, age-related memory loss, memory impairment, cholinergic hypofunction, vascular narrowing or blockage in the brain, neuroinflammation, mild cognitive impairment, cerebral atrophy, frontotemporal lobar degeneration, Pick's disease, HIV infection, Down's syndrome, and loss of synaptic plasticity; further wherein said mammal is for relieved or alleviated of cognitive impairment caused by a disease, injury, or condition, including Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy' or cortical basal degeneration.
Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl -2 -Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, comprises an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers or adjuvants.
A further aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, further comprises one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule.
An additional aspect of the present invention includes wherein the disorder is a mild cognitive impairment, Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia^ senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
Another aspect of the present invention includes wherein the cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alky 1 Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof, route of administration.
A further aspect of the present invention includes wherein the pharmaceutically effective amount of cPG has a lower limit of about 0.001 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 100 mg/kg of said mammal.
A further aspect of the present invention includes wherein the pharmaceutically effective amount of Lecanemab has a lower limit of about 1.00 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 10.00 mg/kg of said mammal.
An additional aspect of the present invention includes wherein the cognitive impairment is caused by cholinergic hypofunction.
Another aspect of the present invention includes wherein the cholinergic hypofunction is caused by scopolamine.
A further aspect of the present invention includes wherein the cogniti ve impairment is age-related memory loss, cognitive impairment, MCI ("mild cognitive impairment"), Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
An additional aspect of the present invention includes wherein the cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
Another aspect of the present invention includes wherein the cPG compound causes an increase in AMPA receptors in the granular cell layer (CAI) of the hippocampus of said mammal.
A further aspect of the present in vention includes wherein tire cyclic Prolyl Glycine (cPG) or its analogues ( cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alky 1 Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, causes an increase in neuronal plasticity caused by said cPG compound in the granule cell layer (CAI) and the pyramidal cell layer (CA3) regions of said mammal's hippocampus.
An additional aspect of the present invention includes wherein the cerebral hypoxia/ischemia caused by traumatic brain injury.
Another aspect of the present invention includes wherei n the cognitive impairm ent caused by multi-infarct dementia.
A further aspect of the present invention includes wherein the cognitive impairment caused by coronary arterial bypass surgery (CABG).
An additional aspect of the present invention includes wherein the cognitive impairment caused by Alzheimer Disease, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin , pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration.
An sixth aspect of the present invention includes a method of preventing the symptoms of a mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need thereof, including: a) providing a mammal in need of preventing cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease. Huntington’s disease, Lewy Body disease, Dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortical basal degeneration. A seventh aspect of the present inventi on includes a method of treating the symptoms of a mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need thereof, including: a) providing a mammal in need of treating of cognitive impairment caused by a disease, injury, or condition; and b) administering a pharmaceutically effective amount of cyclic Prolyl Glycine (cPG) or its analogues (cy clic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl- Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), collectively called a cPG compound, or a combination with Lecanemab thereof, to the mammal; wherein the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy Body disease. Dementia, and multi -infarct dementia, memory' loss, attention deficit symptoms associated with Alzheimer disease, neurodegeneration associated with Alzheimer disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson’s disease, progressive supranuclear palsy or cortical basal degeneration.
EXAMPLES
The following in vitro and in-vivo studies demonstrate efficacy of cyclic Prolyl Glycine in combination with Lecanemab in reducing cognitive impairment. They are not intended to be limiting, and other compositions and methods of this invention can be developed without undue experimentation. All the following experiments were carried out using protocols developed under guidelines approved by the Animal Ethics Committee and Institutional Review Board.
Cyclic Prolyl Glycine was available from commercial suppliers such as Bachem (Torrance, Calif.), and Sigma (St. Louis, Mo.). Lecanemab and Donanemab (are an IgGl anti-soluble aggregated amyloid beta (A|3) monoclonal antibody, in humanized form, were supplied by Med Chem Express (Monmouth Junction, NJ 08852). Experiment 1
Morris Water Maze (MWM) Model of Learning and Memory Used to Assess Effects of cyclic Prolyl Glycine and Lecanemab on Cognitive Function. cPG administered to animals treated with scopolamine-induced cognitive dysfunction produces clinical improvement in those animals, similar to the therapeutic improvement observed in people suffering from cholinergic hypofunction. Scopolamine is commonly used in animal models of cholinergic hypofunction associated with Alzheimer's disease. The functional deficits observed after scopolamine treatment include those found in human patients with Alzheimer's disease. Thus, scopolamine treatment is reasonably predictive of cognitive impairment found in human diseases. Additionally, scopolamine treatment mimics cognitive disfunctions in humans w'ho do not have neurodegenerative disorders.
Tire purpose of the study was to investigate cyclic Prolyl Glycine to evaluate its impact cognitive deficit and affective state (anxiety).
Methods
The first part of the study involved acute testing of the cyclic Prolyl Glycine in the Morris Water Maze memory model. The MWM test is one of the most frequently used tests for assessing spatial memory in rats and is well recognized to accurately predict effects of disease and treatment on spatial memory generally. Therefore, the MWM test reflects effects of disease and treatment in human subjects.
The standard procedure for MWM was followed. A circular swimming pool (80 cm depth x 150 cm diameter) was filled with opaque water, with the temperature maintained at 20°C. A platform was hidden 1 cm below the water surface, with a white flag (10 cmx 10 cm) located either 20 cm above the platform for the visual cue and at 3 o'clock position in rel ation to the starting location for a spatial cue. On days 1-4 of the experiment rats underwent memory acquisition trials with 6 trials (60 seconds each) in each day of testing (habituation phase). Latency to reach the platform was recorded and the daily reduction of average latency wras used to measure the capability to learn wfiere the hidden platform was. On day 5 of the experiment normal , non-aged Wistar rats were sp lit into groups to receive either saline (N=12) or scopolamine (0.5 mg/kg, i.p. , N=12) to induce memory defici t . Scopolamine was administered hal f an hour before the probe test commenced.
10 min following the scopolamine treatment, the cyclic Prolyl Glycine (cPG) was administered intraperitoneal injection (i.p.) alone, and in combination with Lecanemab (i.p) , or in combination with Donanemab (i.p.) at the dosage given in Table 1. The vehicle- treated animals administered the diluent by oral gavage using an identical treatment protocol (n=15).
TABLE 1:
Animals Used to Test Effects of cPG and in combination with Lecanemab and Donanemab on Memory
Figure imgf000062_0001
Acute effects of cPG, cPG plus Lecanemab, and cPG plus Donanemab were then tested in animals with scopolamine-induced memory' impairment and in age-matched control animals with no memory impairment to determine any direct pharmacological effect on memory processing. Experimental groups are detailed in the Table 1 below.
On day 5, the probe MWM test was performed with the platform removed. There were 6 trials, each of maximum duration of 60 s, at least 5 min rest between trials). The amount of time the rats spend swimming near the platform provided a measure of how much they relied on visual and spatial cue to locate the platform, as opposed to using a non-spatial strategy. Data was collected and analyzed using Any-maze (v4.2) software. The data generated from behavioral tests was analyzed using one-way ANOVA for determining the difference between the aged-groups. Two-way ANOVA was used for examining the progress of behavioral results with the time points treated as dependent factors. GraphPad Prism version 3.02 was used for data analysis.
Results
The results are given in Figure 1. Treatment with scopolamine significantly impaired acquisition of spatial memory in treated animals.
Cyclic Prolyl Glycine, (10 mg/kg; daily) and cyclic Prolyl Glycine in combination with Lecanemab (5 mg/kg of cPG plus 5 mg of Lecanemab) and cyclic Prolyl Glycine in combination with Donanemab (5 mg/kg of cPG plus 5 mg of Donanemab) significantly reversed the cognitive impairment induced by scopolamine. However, Lecanemab alone, or Donanemab alone did not significantly reverse the cognitive impairment induced by scopolamine.
These results confirmed the presence of choline-positive effect in cPG (also known as NA-831) and cPG in combination with Lecanemab, or Donanemab on retrieval of learned skill of finding a submerged platform (spatial memory). Combination therapy of cPG and Lecanemab as well as cPG and Donanemab can be potentially effective for patients with mild cognitive impairment.
Experiment 2;
Phase 2 randomized, placebo-controlled, double-blind study to evaluation of the safety, tolerability, and efficacy of NA-831 and Lecanemab versus placebo in patients with Alzheimer’s disease psychosis
Methods
The study was conducted at research centers and nursing homes in Australia and New Zealand
The nursing homes were granted site-specific exemption by the research ethics committee; hence, all study procedures were done at the nursing home sites by the clinical investigator team Nursing home staff were not part of the study team. This study was done in accordance to guidance from the Declaration of Helsinki, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines, and the US Code of Federal Regulations.
Patients were evaluated at screening to ensure that all criteria for study participation are met. These evaluations will include specific measures of psychosis severity, delirium, dementia, cardiovascular condition, and pregnancy status. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all protocol-specified entry criteria).
The baseline demographic and clinical characteristics of participants is given in Table 2.
Tabic 2 : Basebae demographic aad dialed characteristics
Figure imgf000065_0001
Inclusion:
Participants of either sex who were aged 50 years or older with possible or probable
Alzheimer’s disease as defined by the National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer’s Disease and Related Disorders
Association and who met the criteria for psychosis of Alzheimer’s disease developed by Dilip Jeste and Sand}' Finkel (Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome (Am J Geriatr Psychiatry. 2000 Winter;8(I):29-34.)
Participants were eligible if they had psychotic symptoms including visual or auditory hallucinations, delusions, or both, that developed after the diagnosis was established. Participants must also have been a nursing home resident for 4 weeks or more before randomisation, not bedridden, and expected to remain in the facility throughout the study. Additionally, they must have actively experienced and verbally communicated psychotic symptoms during the month before screening, at least once per week during the previous 2 weeks before baseline and required treatment for symptoms of psychosis in Alzheimer’s disease. Participants were required to have symptoms at screening and baseline severe enough to warrant treatment with an antipsychotic agent, and to have a score of 4 or more on the hallucinations.
Exclusion:
Participants were excluded if they had received treatment with antipsychotics, medications that prolong the QT interval, centrally acting anticholinergic medications, mianserin, nefazodone, cyproheptadine, and fluvoxamine. Also excluded were those whose dose of antidepressant and anxiolytic drugs, if used, changed during the study. Those receiving an acetylcholinesterase inhibitor or memantine, or both, must have been on stable doses for 3 months before baseline and during the study. Additionally, participants were excluded if they were unable to communicate verbally and had a history of significant psychotic disorders before or concomitantly with the diagnosis of Alzheimer’s disease, including but not limited to schizophrenia or bipolar disorder, as well as any medical condition or surgical procedure that could interfere with the conduct of the study. Written informed consent were obtained from participants or their legally authorized representative before initiation of the study procedures.
Randomization and masking
Participants (1 :1) were randomly assigned to receive either NA-831 (60 mg per day orally ) or placebo (60 mg per day orally) , stratified by baseline Mini-Mental State Examination (MMSE)24 total score and NPI-NH psychosis score (four categories: MMSE <10 and NPI-NH psychosis score <12, MMSE ≥10 and NPI-NH psychosis score <12, MMSE <10 and NPI-NH psychosis score ≥12, and MMSE ≥10 and NPI-NH psychosis score ≥12). An independent statistician without any other involvement in the study generated the randomisation sequence with use of permuted block sizes of four, which was implemented using Trident software (version 1.2).
Participants, caregivers, the study sponsor, and study personnel were masked at the clinic site to treatment assignment. The masking of active treatment and placebo were achieved by using identical-appearing tablets. The study was unmasked after all participants had completed the study and following database lock. See Table 3.
Table 3: Treatment Intervention
Figure imgf000067_0001
Figure imgf000068_0001
Outcomes
Primary outcome was the efficacy of NA-831 versus placebo, defined as change from baseline to week 6 in the NPI-NH psychosis score (hallucinations + delusions). Prespecified sensitivity analyses for the primary outcome were responder analyses and different imputation models (pattern mixture model and last observation carried forward). Correlation analysis at week 6 and week 12 (NPI-NH psychosis score, NPI-NH total score, NPI-NH agitation,' aggression, Alzheimer’s Disease Cooperative Study- Clinical Global Impression of Change (ADCS-CGIC), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) total score, and the Cohen- Mansfield Agitation Inventory- Short Form (CMAI-SF) total score) was also done.
Secondary outcomes were the assessment of behavioral symptoms at 6 and 12 weeks with use of ADCS-CGIC (measured as the effect on all clinical domains including cognition and function to evaluate any global deterioration associated with treatment), NPI-NH agitation/ aggression and sleep and nighttime behavior disorders domains, and CMAI-SF total and subdomain scores as a measure of agitation.
Prespecified exploratory outcomes included the NPI-NH total score as an overall measure of neuropsychiatric sy mptoms and each of its remaini ng individual domains, NPI- NH psychosis score by subgroups, durability of response from weeks 6 to 12, NPI-NH occupational distress total score, ADCS-ADL (total, basic, and instrumental subdomain scores), and use of rescue medications for behavioral disturbances and sleep. Subgroup analyses were also prespecified, focusing on baseline NP1-NH psychosis score (<12 or ≥12), baseline MMSE (<10 or ≥10), sex (men or women), age (<85 years or ≥85 years), concomitant use of selective serotonin reuptake inhibitor, concomitant use of anti-dementia medication, and previous antipsychotic use. Additionally, cognitive impairment was assessed by the MMSE and extrapyramidal symptoms were measured with the Unified Parkinson’s Disease Rating Scale (UPDRS) part III from baseline to week 12. Tthe 1987 UPDRS part III was used, as this version has been validated in people with dementia.
All participants who were randomly assigned and received the study intervention were included in the safety analysis. Safety outcomes, measured over 12 weeks, included reported adverse events, adverse events leading to study discontinuations, serious adverse events, and mortality, and included assessment by physical examinations, vital signs (ECGs were obtained at baseline, day 15, and day 85 or early termination to calculate corrected QT interval using Fridericia’s method [QTcF]), and clinical laboratory tests (hematology, clinical chemistry, and urinalysis).
Statistical analysis
For the purpose of sample size calculation, an effect size of 0.4— 0.5 SD was assumed between active treatment and placebo would be clinically meaningfol. Assuming the true difference in the mean change of the NPI-NH psychosis score from baseline to week 6 was 3 points between NA-831 and placebo, and the common SD was 6 points. All statistical analyses were done with use of SAS (version 9.3).
Results
A total of 287 people were screened, 101 people were excluded. 186 participants were selected and assigned. Amongst 186 participants, ninety-three (93) participants were randomly assigned taking 60 mg of NA-831 orally daily. Ninety-three (93) participants were randomly assigned with the placebo, including in the modified intention-to-treat population. Amongst 186 participants, a cohort of 34 participants were set aside to evaluate the potential treatment of NA-831 in combination with Lecanemab for the treatment of Alzheimer’s Disease psychosis. Amongst 93 participants on drug treatment, 17 participants were randomly assigned to receive NA-831 at 30 mg per day orally, while they were also on intravenous infusion of Lecanemab bi-weekly of 5 mg/ kg of Lecanemab over the 12 week period of study. Amongst 93 participants on placebo, 17 participants were randomly- assigned to receive the placebo of NA-831 per day orally, while they were on intravenous infusion of a placebo bi-weekly over the 12-week period of study
The baseline demographic and clinical characteristics of participants is given in Table 1.
Rescue medications for behavioral or sleep disturbances were used by 6 (6.5%) of 93 participants in the NA-831 group and 8 (8.6%) of 93 participants in the placebo group.
Baseline demographic and clinical characteristics of parti cipants were generally well balanced between treatment groups, 23 of 93 (24.7%) of participants in the NA-831 group and 24 of 93 (25.8%) placebo group had more severe psychotic symptoms as documented by NPI-NH psychosis score of 12 or more, and 16 (17.2%) of 93 participants in the NA-831 group and 17 (18.3%) of 93 participants in the placebo group had an MMSE score of less than 10.
For the primary outcome, the adjusted mean change in the NPI-NH psychosis score at week 6 was -3.7 points (SE 0-58) for NA-831 and -2.2 points (0-66) for placebo. The adjusted mean change in the NPI-NH psychosis score at week 12 was -4.2 points (SE 0-63) for NA-831 and -2.8 points (0-67) for placebo.
On average, participants in the NA-831 group had a 42.7 % reduction in their NPI- NFI psychosis score at week 12 compared with 18.7% reduction in the placebo group.
The cohort of patients on Lecanemab did not show any significant difference as compared with placebo.
However, the cohort of patients on combination therapy of N A-831 and Lecanemab showed significant improvement at week 12 as compared with the participants on NA-831 at week 12.
Figure 2: shows Adjusted mean change from baseline to week 12 in the NPI-NH psychosis score of NA-831. Figure 3: shows Adjusted mean change from baseline to week 12 in the NPI-NH psychosis score of NA-831 in combination with Lecanemab.
Response, defined as ≥30% improvement, was observed in 52 (55.9%) for NA-831 versus 32 (34.4%) for placebo (p=0.012).
Three adverse events (3.2%) of 93 participants reported in the NA-831 group as compared with (2.1%) of 93 in the placebo group.
No notable differences between treatment groups were observed for physical examination, vital signs, or clinical laboratory tests. At week 12, mean change in body weight was of an average of-4 kg (SE 0.66) with NA-831 and -0.3kg (SE 0.28) with placebo. Categorical analysis showed 18% of participants in the NA-831 group who had diabetes experienced weight loss of 10% of their body weight over 12 weeks (17 or 18.3% of 93) for NA-831, as compared with (3 or 2.9% of 93) for placebo.
Cardiac adverse event considered related to the study treatment occurred in 6 (6.4%) of 93 participants in the NA-831 group versus 17 (18.3%) of 93 in the placebo group.
Conclusion:
The results of a phase clinical trial of NA-831 showed significant treatment benefits of NA-831 compared with placebo at the primary timepoint of week 6 and the secondary' timepoint of week 12, with an acceptable tolerability profile and without negative effect on cognition.
The results showed no significant treatment benefits of Lecanemab compared with placebo at the primary timepoint of week 6 and the secondary timepoint of week 12.
It is noted that a combination of NA-931 and Lecanemab showed significant improvement at week 12 as compared with the participants on NA-831 alone at week 12.
All publication, including patent documents and scientific articles, referred to in this application, including any bibliography, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified. As used herein, “about” or other similar terminology, refers to plus or minus 10% of the indicated value.
When a range is included and refers to “between” or “fiom” both ar e intended to include the referenced value in the range rather than the range being not inclusive of the reference value.

Claims

CLAIMS What is claimed is:
1. A method of treating, relieving, or alleviating mild cognitive impairment in a subject, comprising: a) providing a subject in need of treating, relieving, or alleviating mild cognitive impairment b) administering to said subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyc!ic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic GlycyI-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to said subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein said cPG compound and said specific binding member are administered to said subject each in an effective amount that together treat said subject for said mild cognitive impairment; further wherein said subject is treated for said mild cognitive impairment.
2. The method of claim 1 , wherein said mild cognitive impairment is related to Alzheimer’s Disease.
3. The method of claim 1 , wherein said pharmaceutically effective amount of said cPG compound is from about 1 pg to about 100 mg per kg of body weight.
4. The method of claim 1 , wherein said pharmaceutically effective amount of said cPG compound is administered at an amount from about 0.1 mg to about 10 mg/kg per day, from about 0.5 mg to about 20 mg/kg per day, from about 0.2 mg to about 40 mg/kg per day, from about 5 mg to about 50 mg/kg per day, or from about 10 micrograms to about 100 mg/kg per day.
5. The method of claim 1, wherein said pharmaceutically effective amount of said cPG compound has a lower limit of about 0.1 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 10 mg/kg of said subject.
6. The method of claim 1, wherein said pharmaceutically effective amount of said cPG compound is from about 20 mg and about 80 mg per day, or from about 20 mg and about 100 mg per day.
7. The method of claim 1, wherein said administering of said pharmaceutically effective amount of said cPG compound is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
8. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said cPG compound is in combination with artificial cerebrospinal fluid.
9. The method of claim 1, wherein said administering of said pharmaceutically effective amount of said cPG compound is intravenous.
10. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said cPG compound is combined with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF-II), or a combination thereof.
11. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said cPG compound is combined with the administration of an anti-inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof
12 The method of claim 1, wherein said administering of said pharmaceutically effective amount of said cPG compound is combined with administration of an anti-inflammatory agent.
13. The method of claim 1 , wherein said cPG compound is provided in aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.
14. The method of claim 1, wherein said cPG compound comprises one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or a combination thereof.
15. The method of claim 1 , wherein said pharmaceutically effective amount of said cPG compound is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracistemal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.
16. The method of claim 1, wherein said cPG compound is in the form of a tablet, capsule, or a combination thereof.
17. The method of claim 1, wherein said specific binding member comprises a receptor, receptor agonist, polypeptide, ligand, antibody, polyclonal antibody, monoclonal antibody, humanized antibody, an active fragment thereof, or a combination thereof.
18. The method of claim 1, wherein said specific binding member comprises Lecanemab, Aducanumab, Donanemab, Crenezumab, Semorinemab, Gantenerumab an active fragment thereof, or a combination thereof.
19. The method of claim 1 , wherein said specific binding is biding with Amyloid P soluble protofibrils.
20. The method of claim 1, wherein said specific binding is binding with Amyloid P (Ap42) soluble protofibrils.
21. The method of claim 1 , wherein said operably binds is binding with Amyloid P soluble protofibrils to modulate at least one activity thereof.
22. The method of claim 1 , wherein said operably binds is binding with Amyloid P (Ap42) soluble protofibrils to modulate at least one activity thereof.
23. The method of claim 1, wherein said pharmaceutically effective amount of said specific binding member is from about 1 pg to about 100 mg per kg of body weight.
24. The method of claim 1, wherein said pharmaceutically effective amount of said specific binding member is administered at an amount from about 0.1 mg to about 10 mg/kg per day, from about 0.5 mg to about 20 mg/kg per day, from about 0.2 mg to about 40 mg/kg per day, from about 5 mg to about 50 mg/kg per day, or from about 10 micrograms to about 100 mg/kg per day.
25. The method of claim 1, wherein said pharmaceutically effective amount of said specific binding member has a lower limit of about 0.1 milligrams per kilogram mass (mg/kg) of said mammal and an upper limit of about 100 mg/kg of said subject.
26. The method of claim 1, wherein said pharmaceutically effective amount of said specific binding member is from about 20 mg and about 80 mg per day, or from about 20 mg and about 100 per day.
27. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said specific binding member is in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier.
28. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said specific binding member is in combination with artificial cerebrospinal fluid.
29. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said specific binding member is intravenous.
30. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said specific binding member is combined with the administration of a neuroprotective agent, insulin-like growth factor-I (IGF-I) insulin growth-like factor-II (IGF-II), or a combination thereof.
31. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said specific binding member is combined with the administration of an anti- inflammatory agent, an anti-integrin alpha 4 subunit agent, or a combination thereof.
32. The method of claim 1, wherein said administering of said pharmaceutically effective amount of said specific binding member is combined with administration of an anti-inflammatory agent.
33. The method of claim 1 , wherein said administering of said pharmaceutically effective amount of said specific binding member Lecanemab (Leqembi®) at a dose of 10 mg/kg, once every two weeks, in the form of a pharmaceutical composition including a pharmaceutically acceptable carrier, such as 0.9% sodium chloride injection.
34. The method of claim 1, wherein said specific binding member is provided in aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, adjuvants, or a combination thereof.
35. The method of claim 1, wherein said specific binding member comprises one or more pharmaceutically acceptable excipients, carriers, additives, adjuvants, binders, or a combination thereof.
36. The method of claim 1 , wherein said pharmaceutically effective amount of said specific binding member is administered via an oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, ophthalmic, intraspinal, intracisternal, topical, infusion, implant, aerosol, inhalation, scarification, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.
37. The method of claim 1, wherein said specific binding member is in the form of a table, capsule, nasal spray, injectable, intravenous infusion, or a combination thereof.
38. The method of claim 1, wherein said subject is a mammal.
39. The method of claim 1 , wherein said subject is a subject is human.
40. The method of claim 1, wherein said effective amount that together treat said subject for mild cognitive impairment is from about 0.1 mg/kg to about 20 mg/kg body weight of cPG in combination with from about 1 pg to about 100 mg per kg of body weight of a specific binding member.
41. The method of claim 1 , wherein said treating, relieving, or alleviating is treating.
42. The method of claim 1, wherein said treating, relieving, or alleviating is relieving.
43. The method of claim 1, wherein said treating, relieving, or alleviating is alleviating.
44. A method of treating, relieving, or alleviating Alzheimer’s Disease in a subject, comprising: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease; b) administering to said subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to said subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein said cPG compound and said specific binding member are administered to said subject each in an effective amount that together treat said subject for said Alzheimer’s Disease; further wherein said subject is treated for said Alzheimer’s Disease.
45. A method of treating, relieving, or alleviating Alzheimer’s Disease Psychosis in a subject, comprising: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease Psychosis; b) administering to said subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyc!ic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to said subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein said cPG compound and said specific binding member are administered to said subject each in an effective amount that together treat said subject for said Alzheimer’s Disease Psychosis; further wherein said subject is treated for said Alzheimer’s Disease Psychosis.
46. A method of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof, in a subject, comprising: a) providing a subject in need of treating, relieving, or alleviating Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof; b) administering to said subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2- Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to said subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein said cPG compound and said specific binding member are administered to said subject each in an effective amount that together treat said subject for said Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof; further wherein said subject is treated for said Alzheimer’s Disease behaviors, aggression, agitation, anger, apathy, or a combination thereof.
47. A method of treating, relieving, or alleviating Early Onset Alzheimer’s Disease in a subject, comprising: a) providing a subject in need of treating, relieving, or alleviating Early Onset Alzheimer’s Disease; b) administering to said subject a pharmaceutically effective amount of at least one cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2 -Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic GlycyI-2-Methyl-Proline (cPMeG), or a combination thereof, collectively called a cPG compound; c) administering to said subject a pharmaceutically effective amount of at least one specific binding member that specifically and/or operably binds with Ap soluble protofibrils; wherein said cPG compound and said specific binding member are administered to said subject each in an effective amount that together treat said subject for said Early Onset Alzheimer’s Disease; further wherein said subject is treated for said Early Onset Alzheimer’s Disease.
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