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WO2025163129A1 - Acétylleucine pour le traitement de la maladie de parkinson - Google Patents

Acétylleucine pour le traitement de la maladie de parkinson

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Publication number
WO2025163129A1
WO2025163129A1 PCT/EP2025/052506 EP2025052506W WO2025163129A1 WO 2025163129 A1 WO2025163129 A1 WO 2025163129A1 EP 2025052506 W EP2025052506 W EP 2025052506W WO 2025163129 A1 WO2025163129 A1 WO 2025163129A1
Authority
WO
WIPO (PCT)
Prior art keywords
leucine
acetyl
patient
disease
parkinson
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/052506
Other languages
English (en)
Inventor
Mallory Factor
Michael Strupp
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Intrabio Ltd
Original Assignee
Intrabio Ltd
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Filing date
Publication date
Application filed by Intrabio Ltd filed Critical Intrabio Ltd
Publication of WO2025163129A1 publication Critical patent/WO2025163129A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • Parkinson ⁇ s disease is the second-most common neurodegenerative disorder and characterized by neuronal loss in the substantia nigra, which causes striatal dopamine deficiency.
  • clinical diagnosis relies on the presence of bradykinesia and other motor defects, Parkinson ⁇ s disease is associated with many non-motor symptoms including mental deterioration.
  • Parkinson ⁇ s disease is a progressive disease that lacks any curative treatments.
  • therapeutic agents that are shown to be broadly neuroprotective are thought to be applicable to neurodegenerative diseases generally.
  • many neurodegenerative diseases are associated with lysosomal dysfunction.
  • acetyl- leucine e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof
  • PD Parkinson ⁇ s disease
  • PD may, but need not, be associated with lysosomal dysfunction.
  • acetyl-leucine e.g. acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof
  • a pharmaceutically acceptable salt thereof for use in a method of reducing the severity of, eliminate, delay or reverse the progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) in a subject in need thereof, said method comprising administering a therapeutically effective amount of acetyl-leucine (e.g.
  • acetyl-DL-leucine acetyl-L-leucine
  • acetyl-D-leucine acetyl-leucine
  • the present disclosure describes acetyl-leucine (e.g.
  • acetyl-leucine or a pharmaceutically acceptable salt thereof, is disclosed for use in a method of reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms associated with Parkinson ⁇ s disease (PD) over time, wherein the method comprises administering a therapeutically effective amount of the acetyl-leucine to the subject in need thereof for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.
  • acetyl-leucine or a pharmaceutically acceptable salt thereof, is disclosed for use in a method of improving in a subject in need thereof a biochemical marker of Parkinson ⁇ s disease (PD) over time, wherein the method comprises administering a therapeutically effective amount of the acetyl-leucine to the subject in need thereof for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.
  • PD Parkinson ⁇ s disease
  • the present disclosure includes acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of reducing the severity of Parkinson ⁇ s disease (PD) or reducing the severity of or eliminating one or more existing symptoms associated with Parkinson ⁇ s disease (PD) in a subject in need thereof.
  • the present disclosure includes acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of providing neuroprotection in a subject having Parkinson ⁇ s disease (PD), wherein the method comprises administering a therapeutically effective amount of the acetyl-leucine to the subject for a duration chosen from at least about 3 months, at least about 6 months, at least about 1 year, at least about 2 years, and at least about 5 years.
  • Additional embodiments of the present disclosure include, acetyl-leucine, or a pharmaceutically acceptable salt thereof, for use in a method of delaying progression of Parkinson ⁇ s disease (PD) or a lysosomal storage disorder (LSD) in a subject.
  • acetyl-leucine or a pharmaceutically acceptable salt thereof, for use in a method of providing neuroprotection in a subject having Parkinson ⁇ s disease (PD) or a LSD.
  • the acetyl-leucine is in racemate form, in an enantiomeric excess of the L- enantiomer or in an enantiomeric excess of the D-enantiomer.
  • the acetyl- leucine is in racemate form.
  • the acetyl-leucine is in an enantiomeric excess of the L-enantiomer.
  • the acetyl-leucine is in an enantiomeric excess of the D-enantiomer.
  • the methods further comprise administering the acetyl-leucine in a dose of between 1.5 g and 10 g per day.
  • the methods further comprise administering the acetyl-leucine, or a pharmaceutically acceptable salt thereof, in a therapeutically effective amount.
  • the therapeutically effective amount is ranges from 1 g to 15 g per day, from 1 g to 10 g per day, from 1.5 g to 7 g per day, from 4 g to 6 g per day, or from 4 g to 5 g per day.
  • the therapeutically effective amount is about 5 g per day.
  • acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in one dose, two doses, three doses, four doses or more per day.
  • the acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in two doses per day.
  • the acetyl-leucine, or a pharmaceutically acceptable salt thereof is administered in two doses per day with a total daily dosage of about 4g to 5g, preferably about 5g.
  • the methods further comprise administering the acetyl-leucine for a treatment duration of two weeks or more.
  • the methods comprise administering the acetyl-leucine, or a pharmaceutically acceptable salt thereof, before the onset of a symptom of the disease or disorder to be treated.
  • the methods further comprise administering another therapy or agent intended to prevent or treat the disease or disorder to be treated.
  • a kit for delaying progression of Parkinson ⁇ s disease (PD) or a LSD in a subject the kit comprising a means for diagnosing or prognosing Parkinson ⁇ s disease (PD) or a LSD, and acetyl-leucine or a pharmaceutically acceptable salt thereof.
  • the kit comprises a means for diagnosing or prognosing Parkinson ⁇ s disease (PD) or a LSD, and acetyl-leucine or a pharmaceutically acceptable salt thereof.
  • a means for diagnosing or prognosing Parkinson ⁇ s disease (PD) or a LSD and acetyl-leucine or a pharmaceutically acceptable salt thereof.
  • it provides for use of acetyl-leucine, or a pharmaceutically acceptable salt thereof, as a neuroprotective agent in a subject having Parkinson ⁇ s disease (PD) or a LSD.
  • acetyl-leucine, or a pharmaceutically acceptable salt thereof is disclosed for use in a method of reducing the severity of, eliminate, delay or reverse the progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD), wherein the administration of Acetyl-leucine, or a pharmaceutically acceptable salt thereof, improves the biochemical marker and/or the symptoms associated with PD over time.
  • the one or more symptoms of Parkinson ⁇ s disease comprises reducing one or more of the severity, frequency or occurrence of any one or more of the symptoms associated with PD compared to the severity, frequency or occurrence before treatment with acetyl-leucine, wherein the symptoms comprise hypokinesia, rigor, resting tremor, hyposmia, or vegetative dysfunction, cognitive deficits, optionally wherein the cognitive deficits comprise dementia, psychiatric symptoms, optionally wherein the psychiatric symptoms are behavioural disorders, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, gait deterioration, increased propensity to falls, speech deterioration associated with fronto-temporal dementia with parkinsonism, REM Sleep Behavior Disorder (RBD), restless-leg syndrome (RLS), neurological symptoms and/or decreased mood.
  • REM Sleep Behavior Disorder RBD
  • RLS restless-leg syndrome
  • Figure 1 shows photographs of treated ( Figure 1A) and untreated (Figure 1B) Npc1 ⁇ / ⁇ mice at nine weeks of age.
  • Figures 2A and 2B show weight data for Npc1 ⁇ / ⁇ mice compared to wild-type (Npc1 +/+ ) mice, with and without acetyl-DL-leucine treatment from weaning.
  • Figures 3A - 3G show gait analysis data for Npc1 ⁇ / ⁇ mice compared to wild-type (Npc1+/+) mice, with and without acetyl-DL-leucine treatment from weaning.
  • diagonal support, cadence and step sequence data are shown in Figures 3A - 3C, respectively.
  • Figures 3D and 3E show front paw (FP) data (stand mean and step cycle in panel D; duty cycle in panel E).
  • Figures 3F and 3G show hind paw (HP) data (stand mean and step cycle in panel F; duty cycle in panel G).
  • Figures 4A - 4H show motor function analysis data for Npc1 ⁇ / ⁇ mice compared to wild-type (Npc1+/+) mice, with and without acetyl-DL-leucine treatment from weaning. Centre rearing, activity, rearing and front to back (FR) count are shown in Figures 4A - 4D, respectively. Active time, mobile time, rearing time and total manual rearing count are shown in Figures 4E - 4H, respectively.
  • Figure 5 shows that treatment with acetyl-DL-leucine (0.1 g/kg from 3 weeks of age) is associated with a small but statistically significant increase in lifespan in the Npc1-/- mouse.
  • Figures 6A and 6B shows the reduction of lysosomal volume in non-neuronal NPC cells following treatment with acetyl-DL-leucine.
  • Figures 6C-6H show the effect of treatment with acetyl-DL-Leucine on lysosomal volume in NPA, MLII, MPS IIIB, Aspartylglucosaminuria, MLIIIA, and MPS VII patient fibroblasts, respectively.
  • Figure 7A shows a survival curve representing mortality in untreated or acetyl-leucine- treated wild-type and Sandhoff mice.
  • Figure 7B shows bar crossing scores for untreated and acetyl-leucine-treated Sandhoff model mice.
  • Figure 7C shows the step cycle time for untreated and acetyl-leucine-treated Sandhoff mice assessed at 12 weeks of age.
  • Figures 8A-8C show the effect of treatment with acetyl-DL-leucine on glycosphingolipid (GSL) levels in GM2 gangliosidoses patient fibroblasts (Tay-Sachs disease, Sandhoff disease, and AB variant of Tay-Sachs disease, respectively).
  • GSL glycosphingolipid
  • Figure 9 shows a gait analysis matrix for a 75 year-old male patient diagnosed with corticobasal-degeneration-syndrome before and during treatment with acetyl-leucine, wherein fewer pink areas in the matrix indicate improvement compared to before treatment.
  • Figures 10A and 10B show the effect of treatment with acetyl-DL-leucine over time on the overall clinical severity score (CSS) and overall annual severity increment score (ASIS), respectively, of ten NPC patients.
  • Figures 11A-11J show the effect of treatment with acetyl-DL-leucine over time on the CSS subscores for each of the ten NPC patients.
  • Figures 12A and 12B show the effect of treating wild type NPC1 -/- mice with acetyl-DL-leucine on levels of amyloid precursor protein C-terminal fragments (APP-CTFs) and levels of microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3-II), respectively.
  • Figures 13A-13C show that after treatment with acetyl-DL-leucine, a patient who had been diagnosed with downbeat nystagmus syndrome could partially suppress the nystagmus by visual fixation.
  • Figure 14 shows the reduction of lysosomal volume in NPC Chinese Hamster Ovary (CHO) cells following treatment with acetyl-DL-leucine, acetyl-D-leucine, acetyl-L-leucine, DL- leucine, D-leucine, and L-leucine, respectively.
  • Acetyl-leucine in racemate form (acetyl-DL-leucine) and salts of the same are effective in the treatment of vertigo of various origins, notably Meniere’s vertigo and vertigo of inflammatory (vestibular neuritis) or toxic origin.
  • acetyl-leucine is marketed by Pierre Fabre Medicament in racemate form as an anti-vertigo medicament under the name Tanganil ® .
  • Clinical results of Tanganil ® reported by various authors demonstrate an improvement in vertigo symptomology in more than 95% of cases, including the disappearance of vertigo attacks.
  • Acetyl-DL-leucine has been used in France to treat acute vertigo since 1957 and has an excellent safety profile, but its long-term safety in chronic use has not been determined.
  • hypotheses including stabilisation of membrane potential, its pharmacological and electrophysiological modes of action remain unclear.
  • acetyl-DL-leucine is not known to treat neurodegenerative diseases, which generally progress over the course of years to decades, such as Parkinson ⁇ s disease (PD).
  • PD Parkinson ⁇ s disease
  • acetyl-leucine or a pharmaceutically acceptable salt of the same, can be used in a method of treating Parkinson ⁇ s disease (PD) in a subject in need thereof, for example, by delaying or reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD), such as over long durations, as compared to typical disease progression.
  • PD Parkinson ⁇ s disease
  • PD Parkinson ⁇ s disease
  • PD Parkinson ⁇ s disease
  • PD Parkinson ⁇ s disease
  • PD Parkinson ⁇ s disease
  • neurodegenerative diseases including Parkinson ⁇ s disease
  • acetyl-leucine is acting as a neuroprotective agent and so inhibiting and/or reversing the neurodegeneration that would otherwise be expected to manifest.
  • many neurodegenerative diseases, including PD are associated with defects in lysosomal storage, and, lysosomal dysfunction, such as aberrantly high levels of lysosomal storage, may be a cause of neuronal dysfunction and death.
  • acetyl-leucine can improve cellular dysfunction (e.g., by reducing lysosomal volumes towards control values) and provide neuroprotection, e.g in patients suffering from PD (Example 23). Consequently, the present disclosure provides acetyl-leucine, or a pharmaceutically acceptable salt of the same, for use in a method of treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) in a subject in need thereof.
  • PD Parkinson ⁇ s disease
  • PD Parkinson ⁇ s disease
  • a “subject”, as used herein, may be a vertebrate, mammal or domestic animal.
  • compositions according to the disclosure may be used to treat any mammal, for example livestock (e.g. a horse, cow, sheep or pig), pets (e.g. a cat, dog, rabbit or guinea pig), a laboratory animal (e.g. a mouse or rat), or may be used in other veterinary applications.
  • livestock e.g. a horse, cow, sheep or pig
  • pets e.g. a cat, dog, rabbit or guinea pig
  • a laboratory animal e.g. a mouse or rat
  • the subject is a human being.
  • “Neurodegenerative disease”, as used herein, refers to any disorder that affects neurons and involves the progressive loss of neuronal structure, the progressive loss of neuronal function, or progressive neuron cell death.
  • the singular forms “a,” “an,” and “the” include plural reference.
  • administer refers to (1) providing, giving, dosing and/or prescribing by either a health practitioner or his authorized agent or under his direction a composition according to the disclosure, and (2) putting into, taking or consuming by the patient or person himself or herself, a composition according to the disclosure.
  • References to “acetyl-leucine” throughout include pharmaceutically acceptable salts of the same, even if not expressly stated.
  • the acetyl-leucine may be in racemic form, which means that the compound comprises about equal amounts of enantiomers. Alternatively, it may be present in an enantiomeric excess of either the L-enantiomer or the D-enantiomer.
  • the acetyl-leucine may be in a single enantiomeric form of either the L-enantiomer or the D-enantiomer.
  • the single enantiomeric form is the L-enantiomer.
  • the racemic and enantiomeric forms may be obtained in accordance with known procedures in the art.
  • a “pharmaceutically acceptable salt” as referred to herein, is any salt preparation that is appropriate for use in a pharmaceutical application.
  • salts include, but are not limited to, amine salts, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chloro- benzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine, tris(hydroxymethyl)aminomethane and the like; alkali metal salts, such as lithium, potassium, sodium and the like; alkali earth metal salts, such as barium, calcium, magnesium and the like; transition metal salts, such as zinc, aluminum and the like; other metal salts, such as sodium hydrogen phosphate, disodium phosphate and the like; mineral acids, such as hydrochlorides, sulfates and the like; and salts of organic acids, such as
  • the acetyl-leucine, or a pharmaceutically acceptable salt of the same may be formulated and administered to a subject in accordance with known teachings in the art.
  • the acetyl-leucine, or a pharmaceutically acceptable salt of the same may be formulated as a pharmaceutical composition.
  • the pharmaceutical composition may comprise acetyl-leucine, or a pharmaceutically acceptable salt of the same, and a pharmaceutically acceptable carrier.
  • Reference to the pharmaceutical composition encompasses the active agent alone or in the form of a pharmaceutical composition.
  • the pharmaceutical composition may take any of a number of different forms depending, in particular, on the manner in which it is to be used.
  • the pharmaceutically acceptable carrier is any known compound or combination of known compounds that are known to those skilled in the art to be useful in formulating pharmaceutical compositions. It will be appreciated that the carrier of the pharmaceutical composition should be one which is tolerated by the subject to whom it is given.
  • the pharmaceutically acceptable carrier may be a solid, and the composition may be in the form of a powder or tablet.
  • a solid pharmaceutically acceptable carrier may include, but is not limited to, one or more substances which may also act as flavouring agents, buffers, lubricants, stabilisers, solubilisers, suspending agents, wetting agents, emulsifiers, dyes, fillers, glidants, compression aids, inert binders, sweeteners, preservatives, dyes, coatings, or tablet-disintegrating agents.
  • the carrier may also be an encapsulating material.
  • the carrier may be a finely divided solid that is in admixture with the finely divided active agents according to the invention.
  • the active agent may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets may, for example, contain up to 99% of the active agents.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • the pharmaceutically acceptable carrier may be a gel and the composition may be in the form of a cream or the like.
  • the carrier may include, but is not limited to, one or more excipients or diluents.
  • the pharmaceutically acceptable carrier may be a liquid.
  • the pharmaceutical composition is in the form of a solution. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the acetyl-leucine may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier may contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators.
  • suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilizers or osmo-regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, such as sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurised compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, may be utilised by, for example, intramuscular, intrathecal, epidural, intraperitoneal, intravenous and particularly subcutaneous injection.
  • the active agent may be prepared as a sterile solid composition that may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • compositions may be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
  • bile salts for example, enough saline or glucose to make the solution isotonic
  • acacia gelatin
  • sorbitan monoleate sorbitan monoleate
  • polysorbate 80 oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
  • the compositions may also be administered orally either in liquid or solid composition form.
  • Compositions suitable for oral administration include solid forms, such as pills, capsules,
  • Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • Acetyl-leucine and compositions comprising the same may alternatively be administered by inhalation (e.g. intranasally).
  • Compositions may also be formulated for topical use. For instance, creams or ointments may be applied to the skin.
  • Acetyl-leucine may be incorporated within a slow- or delayed-release device. Such devices may, for example, be inserted on or under the skin, and the medicament may be released over weeks or even months. Such devices may be advantageous when long-term treatment with acetyl-leucine used according to the present disclosure is required and which would normally require frequent administration (e.g. at least daily administration).
  • a tablet may be formulated as is known in the art.
  • Tanganil ® for example, includes wheat starch, pregelatinised maize (corn) starch, calcium carbonate and magnesium stearate as excipients. The same, or similar, excipients, for example, may be employed with the present disclosure.
  • the composition of each 700 mg Tanganil ® tablet is as follows: 500 mg acetyl-DL-leucine, 88 mg wheat starch, 88 mg pregelatinised maize (corn) starch, 13 mg calcium carbonate and 11 mg magnesium stearate. The same tablets, for example, may be employed with the present disclosure.
  • the present disclosure describes acetyl-leucine, including compositions and methods thereof, for treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) in a subject in need thereof.
  • the subject in need thereof may have a genetic, biochemical, or other similar identifiable marker of Parkinson ⁇ s disease (PD).
  • the marker of Parkinson ⁇ s disease (PD) may be a cellular marker.
  • the subject in need thereof may have been diagnosed as having Parkinson ⁇ s disease (PD).
  • the subject may have been diagnosed with Parkinson ⁇ s disease (PD) according to a genetic, biochemical, or other similar identifiable marker or due to one or more symptoms associated with PD.
  • the subject in need thereof may be suspected of having PD.
  • the subject may have a genetic predisposition to Parkinson ⁇ s disease (PD) (e.g., the subject may have one or more family members with Parkinson ⁇ s disease (PD)).
  • the subject in need thereof is symptomatic (i.e., has one or more symptoms associated with Parkinson ⁇ s disease (PD)). It should be understood that the term “symptomatic” is used with reference to symptoms of Parkinson ⁇ s disease (PD).
  • Subjects who have a genetic, biochemical, or other similar identifiable marker of Parkinson ⁇ s disease such as subjects who have been diagnosed with Parkinson ⁇ s disease (PD) based on a genetic, biochemical, or other similar identifiable marker, but who have no further symptoms of the disease are asymptomatic, and thus not included within the scope of “symptomatic” for purposes of the present disclosure.
  • treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) refer to reducing the severity of Parkinson ⁇ s disease (PD) or reducing the severity of or eliminating one or more existing symptoms associated with Parkinson ⁇ s disease (PD), delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time as compared to typical disease progression, and/or reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time.
  • “Treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” may also refer to improving a biochemical marker of Parkinson ⁇ s disease (PD).
  • the subject having PD undergoes co-treatment with L-DOPA and acetyl-Leucine (e.g. acetyl-DL-Leucine).
  • L-DOPA may be administered separately from Acetyl-Leucine or together with Acetyl-Leucine.
  • “Treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” and the like may also refer to reducing or eliminating the need for L-DOPA, e.g., reducing the daily dosage of L-DOPA by at least 500 mg, at least 400 mg, at least 300 mg, at least 200 mg, or at least 100 mg.
  • co-treatment with L-DOPA and acetyl-leucine reduces the rate of typical disease progression of PD.
  • co-treatment with L-DOPA and acetyl-leucine stabilizes, delays or reverses the progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) compared to typical PD progression with L-DOPA monotherapy.
  • PD Parkinson ⁇ s disease
  • PD dementia ⁇ s disease
  • Typical or expected disease progression may be based, for example, on a known scale, index, rating, or score, or other suitable test, for assessing the progression of Parkinson ⁇ s disease (PD), one or more symptoms of Parkinson ⁇ s disease (PD), or a biochemical marker of Parkinson ⁇ s disease (PD), such as those described as examples herein.
  • the scale, index, rating, score, or other suitable test may correspond to the progression of the disease overall or to the progression of one or more symptoms associated with the disease.
  • typical or expected disease progression may be based on the typical or expected onset or severity of the PD or a symptom or collection of symptoms associated with PD.
  • the typical or expected disease progression may be determined on a subject-by-subject basis or may be based on what is typically observed for or experienced by a collection of subjects afflicted with PD, such as a population or subpopulation of subjects.
  • Subpopulations may include, for example, subpopulations of the same gender, of the same or similar age, of the same or similar timing for the onset of one or more symptoms, etc.
  • the disease progression, severity of the disease and/or delay or reduction of PD or the symptoms associated with PD may be monitored using any known scale, index, rating, or score, or other suitable test, for assessing the progression of Parkinson ⁇ s disease (PD), e.g., Unified Parkinson's Disease Rating Scale (UPDRS), which is an acknowledged standard in measuring disease progression and to measure the clinical improvement of FDA approved medications in clinical trials of PD.
  • UPD Unified Parkinson's Disease Rating Scale
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” refers to delaying onset of one or more symptoms of Parkinson ⁇ s disease (PD) that would otherwise be expected to manifest according to typical disease progression.
  • onset of one or more symptoms of Parkinson ⁇ s disease refers to increasing the time to, or preventing, onset of the PD or one or more symptoms of PD.
  • onset can be said to be delayed when the time to manifestation of one or more symptoms of Parkinson ⁇ s disease (PD) takes at least 5% longer than that observed according to typical disease progression.
  • an increase in time of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% is observed.
  • the subject in need of therapy or treatment with acetyl-leucine e.g.
  • acetyl-DL- leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof is a symptomatic subject.
  • the administration of acetyl-leucine may be initiated at the time the subject is symptomatic but to delay onset of further symptoms associated with Parkinson ⁇ s disease (PD) that would otherwise be expected to manifest according to typical disease progression
  • PD Parkinson ⁇ s disease
  • the subject in need thereof may continue to receive treatment with acetyl-leucine in accordance with the durations described herein.
  • the treatment prevents onset of one or more symptoms of PD in the subject having been diagnosed with PD, that would otherwise be expected to manifest according to typical disease progression.
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” refers to reducing the severity of Parkinson ⁇ s disease (PD) or reducing the severity of or eliminating one or more existing symptoms associated with Parkinson ⁇ s disease (PD).
  • the severity of Parkinson ⁇ s disease (PD) or of the existing symptom(s) may be assessed using a known scale, index, rating, or score, such as those described as examples herein, or another suitable test for assessing severity), e.g., Unified Parkinson's Disease Rating Scale (UPDRS).
  • UPD Unified Parkinson's Disease Rating Scale
  • the scale, index, rating, score, or other suitable test may correspond to the severity of the disease overall or to the severity of one or more symptoms associated with the disease.
  • the treatment improves such an assessment from a value or degree characteristic of a symptomatic patient to a value or degree characteristic of a non-symptomatic patient.
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” refers to delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms associated with Parkinson ⁇ s disease (PD) over time as compared to typical disease progression, or reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms associated with Parkinson ⁇ s disease (PD) over time.
  • the time over which the treatment delays or reverses progression may coincide with the duration of treatment as described herein.
  • the treatment may delay or reverse progression over a duration of, for example, about seven days or more, about two weeks or more, about three weeks or more, about one month or more, about six weeks or more, about seven weeks or more or about two months or more.
  • the treatment may delay or reverse progression over a duration of, for example, about three months or more, about four months or more, about five months or more or about six months or more. It may delay or reverse progression over a duration of, for example, about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more.
  • the treatment may delay or reverse progression of PD or one or more symptoms associated with PD over the lifetime of the patient.
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” refers to delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time as compared to typical disease progression.
  • “delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms associated with Parkinson ⁇ s disease (PD) over time” and the like refer to slowing and/or stopping progression of the disease or one or more symptoms of the disease (e.g., slowing and/or stopping the worsening or increasing severity of the disease or one or more symptoms of the disease) over time.
  • Disease progression may be determined, for example, using a known scale, index, rating, or score, such as those described as examples herein, or another suitable test for assessing progression.
  • the scale, index, rating, score, or other suitable test may correspond to the progression of the disease overall or to the progression of one or more symptoms associated with the disease.
  • “delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms associated with Parkinson ⁇ s disease (PD)” means that a subject’s disease severity value (e.g., overall severity or severity of one or more symptoms) determined by a known scale, index, rating, score, etc., or other suitable test for evaluating severity, does not meaningfully increase (e.g., at least remains substantially constant).
  • “delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” means preventing the subject from reaching, or increasing the time taken for a subject to reach (e.g., decreasing the rate of change of increasing severity), a severity value according to a known scale, index, rating, score, etc., or other suitable test, for assessing progression compared to a value corresponding to typical disease progression. For example, progression can be said to be delayed when the time to reach a severity value takes at least 5% longer than that observed according to typical disease progression.
  • an increase in time of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 100% is observed.
  • the time over which the treatment delays progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) may coincide with the duration of treatment as described herein.
  • the treatment delays progression for at least about three months, at least about four months, at least about five months, or at least about six months.
  • the treatment may delay progression for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years.
  • the treatment may delay progression over the lifetime of the patient.
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” refers to reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time.
  • “reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time” and the like refer to stopping progression and reducing the severity of the disease or one or more symptoms of the disease over time. Disease progression and severity may be determined, for example, using a known scale, index, rating, or score, such as those described as examples herein, or another suitable test for assessing progression and severity.
  • the scale, index, rating, score, or other suitable test may correspond to the progression and severity of the disease overall or to the progression and severity of one or more symptoms associated with the disease.
  • “reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time” means that a subject’s disease severity value (e.g., overall severity or severity of one or more symptoms) determined by a known scale, index, rating, score, etc., or another suitable test, for evaluating severity, improves over time (i.e., shows a reduction in severity over time).
  • the time over which the treatment reverses progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) may coincide with the duration of treatment as described herein.
  • the treatment reverses progression for at least about three months, at least about four months, at least about five months, or at least about six months.
  • the treatment reverses progression for at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, or at least about 10 years.
  • the treatment may reverse progression over the lifetime of the patient.
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” refers to improving in the subject a biochemical marker of Parkinson ⁇ s disease (PD) (e.g., increased levels of the storage metabolite(s) or secondary biochemical changes resulting from the primary storage).
  • a biochemical marker is a signal of disease activity and may provide ongoing indications of disease severity and progression over time.
  • the biochemical marker is improved in view of a control value.
  • the biochemical marker is chosen from increased lysosomal volume, increased glycosphingolipid (GSL) levels, increased microtubule-associated protein 1A/1B- light chain 3-phosphatidylethanolamine conjugate (LC3-II) levels, and increased amyloid precursor protein C-terminal fragment (APP-CTF) levels.
  • the biochemical marker is increased lysosomal volume and the treatment reduces lysosomal volume in the subject.
  • the biochemical marker is increased glycosphingolipid (GSL) levels and the treatment reduces GSL levels in the subject.
  • the biochemical marker is increased microtubule-associated protein 1A/1B- light chain 3-phosphatidylethanolamine conjugate (LC3-II) levels and the treatment reduces LC3-II levels in the subject.
  • the biochemical marker is increased amyloid precursor protein C-terminal fragment (APP-CTF) levels and the treatment reduces APP-CTF levels in the subject.
  • the treatment improves a biochemical marker over time.
  • improving a biochemical marker over time means that the treatment improves a biochemical marker over time toward a control value, prevents the progression of a biochemical marker over time, and/or delays the progression of the biochemical marker over time as compared to typical disease progression.
  • Symptoms as described herein include, but are not limited to, neurological symptoms and psychiatric symptoms.
  • neurological symptoms include ataxia, other movement disorders such as hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade/gaze palsy and neuropsychological deficits such as dementia.
  • psychiatric symptoms include depression, behavioural disorders or psychosis. Onset of symptoms may range from birth to adulthood.
  • the symptoms of Parkinson’s Disease may comprise one or more of hypokinesia, rigor, resting tremor, hyposmia, vegetative dysfunction and during the course of the disease cognitive deficits which can lead to dementia as well as psychiatric symptoms such as behavioural disorders, rigidity, tremor, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, decreased cognitive function and decreased mood.
  • the symptoms include hypokinesia, rigor, resting tremor, hyposmia, vegetative dysfunction and cognitive deficits (e.g. dementia).
  • the symptoms include psychiatric symptoms such as behavioural disorders. Onset of symptoms may range from early to late adulthood.
  • the symptoms of PD may further comprise gait deterioration, increased propensity to falls, and/or speech deterioration associated with fronto-temporal dementia with parkinsonism.
  • Neurological symptoms may include ataxia, hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade/gaze palsy and neuropsychological deficits such as dementia.
  • PD symptoms may be accompanied by REM Sleep Behavior Disorder (RBD), and restless leg syndrome (RLS). Progression of Parkinson ⁇ s disease (PD) over time or through treatment can be monitored, for example, using one or more known tests at two or more time points and comparing the results.
  • RBD REM Sleep Behavior Disorder
  • RLS restless leg syndrome
  • Unified Parkinson's Disease Rating Scale UPDRS or MDS-UPDRS
  • MDS-UPDRS Movement Disorder Society- sponsored revision of the Unified Parkinson's Disease Rating Scale
  • Disease progression and/or severity can be assessed, for example, using the Scale for the Assessment and Rating of Ataxia (SARA), Spinocerebellar Ataxia Functional Index (SCAFI), the International Cooperative Ataxia Rating Scale (ICARS), the brief ataxia rating scale (BARS), the modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L (EQ- 5D-5L), the visual analogue scale (VAS), neuropsychological tests, such as Wechsler Adult Intelligence Scale-Revised (WAIS-R), Wechsler Intelligence Scale for Children-IV (WISC-IV), Montreal Cognitive Assessment (MoCA), as well as scales used in movement disorders, such as the Unified Parkinson’s Rating Scale (UPRS) or the Unified Multiple System Atrophy Rating Scale (UMSARS), or other suitable tests.
  • SARA Scale for the Assessment and Rating of Ataxia
  • SCAFI Spinocerebellar Ataxia Functional Index
  • ICARS International Cooperative Ataxia Rating Scal
  • CCS clinical severity score
  • ASIS annual severity increment score
  • mDRS score modified 6-Domain NP-C disability Scale
  • the ASIS quantifies the annual rate of change in the CSS, calculated by dividing the CSS by the patient’s age.
  • certain scores in these tests are characteristic of symptomatic neurodegenerative disease patients (e.g. PD patients) and evidence disease progression and/or severity.
  • “treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)”, for example, may be equated to achieving an improved assessment, such as those described herein, of a UPDRS or MDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D- 5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA score, or result of another test suitable for characterising Parkinson ⁇ s disease (PD) patient.
  • an improved assessment such as those described herein, of a UPDRS or MDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D- 5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA score, or result of another test suitable for characterising Parkinson ⁇ s disease (PD) patient.
  • reducing the severity of Parkinson ⁇ s disease (PD) or reducing the severity of or eliminating one or more existing symptoms of Parkinson ⁇ s disease (PD) means improving a UPDRS or MDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS,UMSARS, and/or MoCA score, or a result of another suitable test, for evaluating severity, such as improving the score or result from a severity value characteristic of a symptomatic subject to a value characteristic of a non-symptomatic subject.
  • “delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD)” means that a subject’s UPDRS or MDS- UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA score, or a result of another suitable test for evaluating progression, does not meaningfully increase (e.g., at least remains substantially constant).
  • “delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms associated with Parkinson ⁇ s disease (PD)” means preventing a subject’s UPDRS or MDS-UPDRS, SARA, SCAFI, ICARS, BARS, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS, UPRS, UMSARS, and/or MoCA score, or a result of another suitable test for evaluating progression, from reaching, or increasing the time taken to reach, a value compared to that of typical disease progression.
  • “reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time” means that a subject’s UPDRS or MDS-UPDRS, SARA, SCAFI, mDRS, EQ-5D-5L, VAS, WAIS-R, WISC-IV, CSS and/or MoCA score, or a result of another suitable test for evaluating progression, improves over time (i.e., shows a reduction in severity over time).
  • the biochemical marker for Parkinson’s disease is identified by a fluorodeoxyglucose-positron emission tomography (FDG-PET) scan, a dopamine transporter (DAT) density as measured by a single photon emission computed tomography (SPECT) scan, or a combination of both.
  • FDG-PET fluorodeoxyglucose-positron emission tomography
  • DAT dopamine transporter
  • SPECT single photon emission computed tomography
  • the biochemical marker for Parkinson’s disease is identified by a EuroQol-5 Dimension-5 Levels (5Q-5D-5L) score, a Montreal Cognitive Assessment (MoCA) score, or a combination thereof.
  • mDRS a four-domain scale (ambulation, manipulation, language and swallowing), may be applied.
  • Cerebellar function may be evaluated using SARA, an eight-item clinical rating scale (gait, stance, sitting, speech, fine motor function and taxis; range 0–40, where 0 is the best neurological status and 40 the worst), and SCAFI, comprising the 8-m-Walking-Time (8MW; performed by having patients walking twice as quickly as possible from one line to another excluding turning), 9-Hole-Peg- Test (9HPT) and the number of “PATA” repetitions over 10 s. Subjective impairment and quality of life may be evaluated using the EQ-5D-5L questionnaire and VAS.
  • 3-dimensional videooculography may be used to measure the peak velocity of saccades, gain of smooth pursuit, peak slow phase velocity of gaze-evoked nystagmus (gaze-holding function), peak slow phase velocity of optokinetic nystagmus, and gain of horizontal vestibulo-ocular reflex.
  • WAIS-R or WISC- IV, and MoCA assessing different cognitive domains, including attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation with a maximum of 30 points and a cut-off score of 26, may be used. The skilled person will know how to perform these and other such tests.
  • the acetyl-leucine e.g.
  • acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof), or a pharmaceutically acceptable salt of the same may be administered, for example, at a dose ranging from about 500 mg to about 15 g per day or ranging from about 500 mg to about 10 g per day, from about 1.5 g to about 10 g, from about 1 g to about 15 g per day, from about 1 g to about 10 g per day, from about 1.5 g to about 7 g per day, from about 4 g to about 6 g per day, or from about 4 g to about 5 g per day.
  • the therapeutically effective amount is about 5 g per day.
  • the administration may be by solid oral or liquid oral route.
  • the acetyl-leucine, or a pharmaceutically acceptable salt of the same may be administered, for example, in a dose according to that of Tanganil ® , which is prescribed to adults in a dose of 1.5 g to 2 g per day, 3-4 tablets in two doses, morning and evening. If one enantiomer is administered, the doses may be reduced accordingly.
  • the dose may range from about 250 mg to about 15 g per day, range from about 250 mg to about 10 g per day, or range from about 250 mg to about 5 g per day, such as from about 0.75 g to about 5 g per day.
  • Acetyl-leucine as used herein may refer to acetyl-DL leucine.
  • Acetyl-leucine as used herein may refer to acetyl-L-leucine, acetyl-D-leucine or a combination thereof.
  • the administered dose ranges from about 1 g to about 15 g per day, from about 1 g to about 10 g per day, or from about 1.5 g to about 7 g per day. It may be from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 g to about 15 g per day. It may be from about 2, 3, 4, 5, 6, 7, 8 or 9 g to about 10 g per day. It may be more than about 1.5 g per day, but less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6 or 5 g per day. In one embodiment, the dose ranges from about 4 g to about 6 g per day. In one embodiment, the dose ranges from about 4 g to about 5 g per day. In one embodiment, the dose is about 4.5 g per day.
  • the dose is about 5 g per day. In one embodiment, these doses are administered in a solid oral dosage form, notably tablets. In another embodiment, these doses are for acetyl-leucine when in its racemic form. Doses for acetyl-leucine when an enantiomeric excess is present may be lower than those recited here, for example, around 50% lower. The above recited dose-ranges when halved are thus also explicitly encompassed by the present disclosure. In one embodiment, acetyl-DL-leucine is administered in a dose of about 5 g per day. In one embodiment, acetyl-DL-leucine is administered in a dose of about less than 5 g per day.
  • acetyl-DL-leucine is administered in a dose of about 4 to 6 g per day. In one embodiment, acetyl-L-leucine is administered in a dose of about 5 g per day. In one embodiment, acetyl-L-leucine is administered in a dose of about less than 5 g per day. In one embodiment, acetyl-L-leucine is administered in a dose of about 4 to 6 g per day. In one embodiment, acetyl-D-leucine is administered in a dose of about 5 g per day. In one embodiment, acetyl-D-leucine is administered in a dose of about less than 5 g per day.
  • acetyl-D-leucine is administered in a dose of about 4 to 6 g per day.
  • the total daily dose may be spread across multiple administrations, i.e. administration may occur two or more times a day to achieve the total daily dose.
  • the required number of tablets to provide the total daily dose of acetyl-leucine may be split across two administrations (for example, in the morning and evening) or three administrations (for example, in the morning, noon and evening). Each dose may be suitably administered with or without food.
  • acetyl-leucine may be dosed by about 1 or about 2 hours before meals, such as at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, or at least about 1 hour before meals, or may be dosed by about 1, about 2, or about 3 hours after meals, such as waiting at least about 20 minutes, at least about 30 minutes, at least about 1 hour, at least about 1.5 hours, at least about 2 hours, or at least about 2.5 hours after meals.
  • a total daily dose of 4.5 g acetyl-DL-leucine may be administered as three Tanganil ® (or equivalent) tablets before, with, or after breakfast, three further tablets before, with, or after lunch and three further tablets before, with, or after dinner.
  • the symptoms of Parkinson’s Disease may comprise one or more of hypokinesia, rigor, resting tremor, hyposmia, or vegetative dysfunction, cognitive deficits, optionally wherein the cognitive deficits comprise dementia, psychiatric symptoms, optionally wherein the psychiatric symptoms are behavioural disorders, slow movement, decreased fluidity of limb movements, instable gait and mobility, constipation, gait deterioration, increased propensity to falls, speech deterioration associated with fronto-temporal dementia with parkinsonism, REM Sleep Behavior Disorder (RBD), restless-leg syndrome (RLS), neurological symptoms and/or decreased mood.
  • REM Sleep Behavior Disorder RBD
  • RLS restless-leg syndrome
  • Neurological symptoms may include one or more of ataxia, hypokinesia, rigor, tremor or dystonia, central ocular motor disorders such as vertical and horizontal supranuclear saccade/gaze palsy and neuropsychological deficits such as dementia.
  • an advantage of treatment with acetyl-leucine is that acetyl-leucine (e.g.
  • acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, or a combination thereof may be administered over a long duration of time to, for example, delay or even reverse progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) in a subject as compared to typical disease progression.
  • Treatment duration may be, for example, about seven days or more, about two weeks or more, about three weeks or more, about one month or more, about six weeks or more, about seven weeks or more, or about two months or more. In one embodiment, it is about three months or more, about four months or more, about five months or more or about six months or more.
  • the treatment duration may be about 1 year or more, about 2 years or more, about 4 years or more, about 5 years or more, or about 10 years or more.
  • the treatment duration may be the life-time of the patient. Any and all combinations of dosage form, dose amount, dosing schedule and treatment duration are envisaged and encompassed by the invention.
  • the dose is from about 4 g to about 10 g per day, taken across one, two, or three administrations per day, for a treatment duration of about two months or more.
  • the dose is more than 4 g but no more than 5 g per day, taken across one, two, or three administrations per day, for a treatment duration of about six months or more.
  • the dosage form may be a solid oral dosage form, notably tablets.
  • the pharmaceutical composition may be used as a monotherapy (e.g., use of the active agent alone) for treating Parkinson ⁇ s disease (PD) in a subject.
  • the pharmaceutical composition may be used as an adjunct to, or in combination with, other known therapies, e.g., for treating Parkinson ⁇ s disease (PD) in a subject.
  • Parkinson ⁇ s disease (PD) may, but need not, be associated with lysosomal dysfunction (e.g., lysosomal storage defect).
  • Major symptoms of Parkinson's Disease (PD) include rigidity, tremor, and slow movement. There are other diseases in which these symptoms are prevalent. These diseases, and PD itself, fall under the umbrella term Parkinsonism.
  • PD can be referred to as Primary Parkinsonism.
  • Parkinsonisms include: Multiple System Atrophy; Progressive Supranuclear Palsy; Normal pressure hydrocephalus; and Vascular or arteriosclerotic parkinsonism.
  • Parkinson-Plus Syndromes Unlike PD patients, individuals with Parkinson-Plus Syndromes do not respond to L-Dopa.
  • the term “parkinsonism” as used herein may refer to a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability.
  • Parkinsonian syndromes can be divided into four subtypes, according to their origin: primary or idiopathic; secondary or acquired; hereditary parkinsonism; and Parkinson plus syndromes or multiple system degeneration.
  • the parkinsonism is a Parkinson plus syndrome or multiple system degeneration.
  • the parkinsonism is vascular (arteriosclerotic) Parkinsonism, lower- body Parkinsonism, Multiple System Atrophy with predominant parkinsonism (MSA-P), Multiple System Atrophy with cerebellar features (MSA-C; Sporadic olivopontocerebellar atrophy (OPCA)), Shy–Drager syndrome, Progressive Supranuclear Palsy (Steele- Richardson-Olszewski syndrome), Lewy body dementia, Pick's disease, or frontotemporal dementia and parkinsonism linked to chromosome 17.
  • the acetyl-leucine e.g.
  • acetyl-DL-leucine, acetyl-L-leucine, acetyl-D- leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof treats gait deterioration, increased propensity to falls, and/or speech deterioration associated with fronto-temporal dementia with parkinsonism.
  • the acetyl-leucine, or a pharmaceutically acceptable salt thereof may reduce the severity of or eliminate, or delay or reverse the progression of gait deterioration, increased propensity to falls, and/or speech deterioration associated with fronto-temporal dementia with parkinsonism.
  • the acetyl-leucine e.g.
  • acetyl-DL-leucine, acetyl-L-leucine, acetyl-D- leucine, or a combination thereof), or a pharmaceutically acceptable salt thereof treats increased propensity to falls and/or gait deterioration associated with corticobasal- degeneration-syndrome.
  • the acetyl-leucine, or a pharmaceutically acceptable salt thereof may reduce the severity of or eliminate, or delay or reverse the progression of increased propensity to falls and/or gait deterioration associated with corticobasal- degeneration-syndrome.
  • a method of treating Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) in a subject in need thereof comprising administering a therapeutically effective amount of acetyl-leucine, or a pharmaceutically acceptable salt thereof, to the subject.
  • a “therapeutically effective amount” of an agent is any amount which, when administered to a subject, is the amount of agent that is needed to produce the desired effect, which, for the present disclosure, a therapeutic effect.
  • the dose may be determined according to various parameters, such as the specific form of acetyl-leucine used; the age, weight and condition of the patient to be treated; the type of the disease; the route of administration; and the required regimen.
  • a daily dose may be from about 10 to about 225 mg per kg, from about 10 to about 150 mg per kg, or from about 10 to about 100 mg per kg of body weight.
  • a kit for treating Parkinson ⁇ s disease (PD) in a subject comprising a means for diagnosing or prognosing the disease/disorder, and acetyl-leucine or a pharmaceutically acceptable salt thereof.
  • the means for diagnosing or prognosing Parkinson ⁇ s disease may include a specific binding agent, probe, primer, pair or combination of primers, an enzyme or antibody, including an antibody fragment, which is capable of detecting or aiding in the detection of Parkinson ⁇ s disease (PD), as defined herein.
  • the kit may comprise LysoTracker ® , which is a fluorescent marker and is commercially-available from both Invitrogen and also Lonza. The LysoTracker ® may be blue, blue-white, yellow, green or red.
  • the kit also comprises acetyl-leucine or a pharmaceutically acceptable salt thereof, as defined herein.
  • the kit may further comprise buffers or aqueous solutions.
  • the kit may further comprise instructions for using the acetyl-leucine or a pharmaceutically acceptable salt thereof in a method of the invention.
  • acetyl-leucine e.g. acetyl-DL-leucine, acetyl-L- leucine, acetyl-D-leucine, or a combination thereof
  • a pharmaceutically acceptable salt thereof for use in a method of providing neuroprotection in a subject in need thereof (e.g., a subject having Parkinson ⁇ s disease (PD)).
  • Neuronal refers to prevention, a slowing in, and/or a reversed progression of neurodegeneration, including, but not limited to, progressive loss of neuronal structure, progressive loss of neuronal function, and/or progressive neuronal death.
  • Providing neuroprotection may result in reducing the severity of Parkinson ⁇ s disease (PD) or reducing the severity of or eliminating one or more existing symptoms associated with Parkinson ⁇ s disease (PD), delaying progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time as compared to typical disease progression, and/or reversing progression of Parkinson ⁇ s disease (PD) or one or more symptoms of Parkinson ⁇ s disease (PD) over time.
  • the time over which neuroprotection is provided may coincide with the duration of treatment as described herein.
  • the treatment may provide neuroprotection over a duration of, for example, about seven days or more, about two weeks or more, about three weeks or more, about one month or more, about six weeks or more, about seven weeks or more or about two months or more.
  • the treatment may provide neuroprotection over a duration of, for example, about three months or more, about four months or more, about five months or more or about six months or more. It may provide neuroprotection over a duration of, for example, about 1 year or more, about 2 years or more, about 3 years or more, about 4 years or more, about 5 years or more, or about 10 years or more.
  • the treatment may provide neuroprotection over the lifetime of the patient.
  • a method of providing neuroprotection in a subject in need thereof comprises administering a therapeutically effective amount of acetyl-leucine, or a pharmaceutically acceptable salt thereof, to the subject.
  • a kit for providing neuroprotection in a subject in need thereof e.g., a subject having PD
  • the kit comprising a means for diagnosing or prognosing the disease/disorder, and acetyl-leucine or a pharmaceutically acceptable salt thereof.
  • the present disclosure further includes the use of acetyl-leucine, or a pharmaceutically acceptable salt thereof, as a neuroprotective agent in a subject in need thereof (e.g., a subject having Parkinson ⁇ s disease (PD)).
  • a subject in need thereof e.g., a subject having Parkinson ⁇ s disease (PD)
  • the subject has been diagnosed with PD.
  • All of the features described herein including any accompanying claims, abstract and drawings), and/or all of the steps of any method so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Examples
  • the invention will now be explained in further detail in the following Examples, which demonstrate the utility of acetyl-leucine in treating Parkinson ⁇ s disease (PD) in a subject and providing neuroprotection in said subject.
  • mice have been undertaken at the whole animal, cellular, and molecular levels (Baudry, 2003; Smith, 2009; Cologna, 2014; Cologna, 2012). It is the most intensively studied animal model of NPC. Prior to about 4–5 weeks of age Npc1 ⁇ / ⁇ mice have no discernible behavioural indication of disease that distinguishes them from wild-type littermates. First indications of behavioural deficits, such as tremor and ataxic gait, appear by weeks 5–6; by weeks 7–8 defects in motor coordination become more apparent, and by 9–10 weeks ataxia is advanced and accompanied by increased loss in weight and poor coat condition as feeding and drinking becomes difficult (humane end point applied) (Smith, 2009).
  • behavioural deficits such as tremor and ataxic gait
  • Wild-type (Npc1 +/+ ) littermates were used as a control.
  • Treatment Protocol A group of Npc1 ⁇ / ⁇ mice and a group of Npc1+/+ mice were treated with 0.1 g/kg acetyl-DL- leucine, provided mixed in the mouse chow, from weaning (three weeks of age). Separate groups of Npc1 ⁇ / ⁇ and Npc1 +/+ mice were left untreated, as controls.
  • Coat Condition The coat condition of Npc1 ⁇ / ⁇ mice, with and without acetyl-DL-leucine treatment, was compared by simple observation of the mice at nine weeks of age. Weight Data Animals were weighed twice a week.
  • Motor Function Analysis Motor function analysis was performed on mice at eight and nine weeks of age using an Open Field Activity Monitor according to manufacturer’s instructions (Linton Instruments, Amlogger Software). Each mouse was placed in a plastic cage with bedding and analysed for five minutes. Rears were counted manually. Motor function parameters measured were: 1 . Centre Rearing: mice rearing on hind legs unsupported; 2.
  • Weight Data As can be seen in Figure 2A, wild-type (Npc1 +/+ ) mice progressively put on weight for the duration of the study, i.e. from three weeks to 10 weeks of age.
  • Treatment with acetyl-DL-leucine had no significant effect on this weight gain.
  • Npc1 ⁇ / ⁇ mice initially put on weight, largely in the same manner as Npc1 +/+ controls. However, the Npc1 ⁇ / ⁇ mice then began to lose weight from six weeks of age.
  • Diagonal support, cadence and step sequence data are shown in Figures 3A - 3C, respectively.
  • Figures 3D and 3E show front paw (FP) data (stand mean and step cycle in Figure 3D; duty cycle in Figure 3E).
  • Figures 3F and 3G show hind paw (HP) data (stand mean and step cycle in Figure 3F; duty cycle in Figure 3G).
  • the first bar in each graph shows the gait properties of wild-type (Npc1 +/+ ) mice.
  • the second bar in each graph shows the gait properties of wild-type (Npc1 +/+ ) mice treated with acetyl-DL-leucine. There was no significant difference in gait properties between these mice and their untreated littermates.
  • the third bar in each graph shows the gait properties of an Npc1 ⁇ / ⁇ mouse. On the whole, this mouse showed poor gait compared to Npc1 +/+ mice.
  • the fourth bar in each graph shows the gait properties of Npc1 ⁇ / ⁇ mice treated with acetyl- DL-leucine. These mice demonstrated significantly improved gait compared to their untreated littermates. In fact, they showed similar gait properties to Npc1 +/+ mice.
  • Motor Function Analysis Analysis at eight weeks of age revealed no difference in motor function properties between Npc1 ⁇ / ⁇ and wild-type (Npc1 +/+ ) mice (data not shown). By nine weeks of age, however, defects in motor coordination had become apparent. The results of the motor function analysis at nine weeks are shown in Figure 4. Centre rearing, activity, rearing and front to back (FR) count are shown in Figures 4A - 4D, respectively.
  • the third bar in each graph shows the motor function properties of an Npc1 ⁇ / ⁇ mouse. On the whole, this mouse showed poor motor function compared to Npc1 +/+ mice. The mouse spent extremely little time, if any, rearing (panel H), particularly on its hind legs unsupported (panel A).
  • the fourth bar in each graph shows the motor function properties of Npc1 ⁇ / ⁇ mice treated with acetyl-DL-leucine. These mice demonstrated significantly improved motor function compared to their untreated littermates. In fact, they showed similar motor function properties to Npc1 +/+ mice.
  • Npc1 ⁇ / ⁇ mice with acetyl-DL-leucine delayed onset and progression of NPC symptoms and showed evidence of neuroprotection. It is reasonable to expect that, as acetyl-DL-leucine provided general neuroprotection, that the results observed in NPC will also be observed in other neurodegenerative disorders, and neurodegenerative disorders that are associated with defects in lysosomal storage.
  • Example 2 Methods A fibroblast cell line from an NPC patient was treated for 3 days with N-acetyl-DL-leucine (1 mM) and relative lysosomal volume was quantified via LysoTracker, a fluorescent dye that accumulates in acidic organelles.
  • Increased LysoTracker fluorescence is indicative of an increase in lysosomal size and/or number, and is a hallmark of NPC cells.
  • fibroblasts derived from Niemann-Pick A (NPA), Mucolipidosis Type II (MLII), Mucopolysaccharidosis Type IIIB (MPS IIIB), Aspartylglucosaminuria, Mucolipidosis Type IIIA (MLIIIA), and Mucopolysaccharidosis Type VII (MPS VII) patients were treated with acetyl-DL-Leucine (1 mM) for 6 days and lysosomal volume was quantified via LysoTracker.
  • N-acetyl-DL-leucine treatment was associated with the rectification of disturbed lysosomal storage by reducing lysosomal volume and thus acetyl-leucine directly corrected a phenotype of these lysosomal storage disorders.
  • These diseases represent different classes of LSDs, and thus these results further support utility of acetyl-leucine’s effect against a broad range of lysosomal storage disorders.
  • Example 3 Sandhoff disease is a disorder which may result from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the beta-subunit of beta-hexosaminidase.
  • GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS).
  • CNS central nervous system
  • acetyl-leucine-treated mice were treated with 0.1 g/kg acetyl-leucine from 3 weeks of age.
  • Bar crossing test is a method for assessing motor function in mice in which the mouse is placed hanging from the centre of a horizontal bar by its front limbs.
  • a wild-type mouse with normal motor function will be able to engage its hind limbs and thereby move to one of the platforms at either end of the bar, and in doing so complete the test.
  • An untreated Sandhoff mouse is able to complete the test up until around 11 weeks of age. After this point motor function and hind-limb mobility/engagement have deteriorated to the point to which the mouse cannot complete the test, and will drop from the bar onto the padded surface below.
  • Step cycle Step cycle is the length of time taken during locomotion by a limb from the time it leaves the ground until it leaves the ground on the next occasion. Step cycle time was assessed at 12 weeks of age in untreated and acetyl-leucine treated Sandhoff model mice.
  • Acetyl-leucine treatment constituted 0.1g/kg body weight acetyl- leucine from 3 weeks of age.
  • Treatment of the Sandhoff mouse model with acetyl-leucine was associated with significantly faster front step cycle times (p ⁇ 0.05 vs untreated SH mouse), significantly faster hind step cycle times (p ⁇ 0.01 vs untreated SH mouse) and significantly faster average step cycle times (p ⁇ 0.001 vs untreated SH mouse) (Figure 7C).
  • FIG. 7 C Acetyl-leucine treatment of 0.1 g/kg body weight was provided from 3 weeks of age.
  • Front step cycle refers to the mouse’s front limbs, hind step cycle to the mouse’s rear limbs, and average step cycle takes into account all of the mouse’s limbs.
  • the asterisks (*/**/***) indicate p-values of ⁇ 0.05/0.01/0.001 versus untreated Sandhoff mouse. Data shown is mean ⁇ Stdev.
  • acetyl-leucine treatment was associated with a faster step cycle in the Sandhoff mouse model, which may indicate improvement in motor function.
  • GM2 gangliosidoses are a group of lysosomal storage disorders arising from defects in ⁇ - hexosaminidase activity. The group encompasses Tay-Sachs disease, Sandhoff disease, and the AB variant of Tay-Sachs disease.
  • the patient was not able to stand or walk, could do single steps with strong support, and had distinct postural instability, ocular movement disorder, dysphagia and dysarthria, and mild cognitive function disorder.
  • First symptoms were observed at the age of 16 years. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 21.6 s MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 48.3 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 44.9 s MW PATA Word Test: 20 Montreal Cognitive Assessment (MoCA): 18/30 Video of the patient was also recorded for later comparison. The day following this examination, the patient was started on therapy with acetyl-leucine, at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.
  • SCAFI Spinocerebellar Ataxia Functional Index
  • Patient 2 The patient in this case study was a 32 year-old female who was genetically diagnosed with Tay-Sachs disease and who exhibited ataxia of stance and gait, fine motor impairment, paraparesis of lower extremities, and muscle atrophies. In particular, walking was not possible without support, and the patient suffered from dysphagia and speech disorder, ocular movement disorder, and mild cognitive function disorder. First symptoms were observed at the age of 7 years. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 10.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • results from the patient’s Spinocerebellar Ataxia Functional Index (SCAFI) analysis were: Mean 8-meters Walking Test (8MW): 12.5 s MW 9-Hole Pegboard Test Dominant (9HPTD) (right): 21.5 s MW 9-Hole Pegboard Test Non-Dominant (9HPTND): 35.5 s MW PATA Word Test: 18 Montreal Cognitive Assessment (MoCA): 21/30 Video of the patient was also recorded for later comparison. The day of the examination, the patient was started on therapy with acetyl-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.
  • SCAFI Spinocerebellar Ataxia Functional Index
  • Patient Evaluation Parameters Patient 3 The patient in this case study was an 8 year-old male who was genetically diagnosed with Tay-Sachs disease and who had epileptic cramps (tonic-clonic, about 10 seconds, self- limiting) almost every day before falling asleep, ocular movement disorder, anarthria, distinct problems in cognitive function and concentration (neurological examination was not possible), was not able to stand or walk by himself, and was very limited in daily activities (eating, washing or dressing himself was not possible). First symptoms were observed at the age of 9 months.
  • Example 6 The patient in this case study was a 13 year-old male who was genetically diagnosed with GM1 Gangliosidosis and who was not able to stand or walk by himself, was very limited in daily activities (eating, washing, dressing himself was not possible), and had ocular movement disorder, anarthria, and distinct problems in cognitive function and concentration (neurological examination was not possible). First symptoms were observed at the age of 2 years. Before treatment was commenced, examination of the patient indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 35/40, a mRDS score of 15, and a EQ-5D- 5L visual scale of 50.
  • SARA Scale for Assessment and Rating of Ataxia
  • Example 7 Patient 1
  • the patient in this case study was a 73 year-old male who had previously been diagnosed with amyotrophic lateral sclerosis (ALS).
  • the patient’s symptomatology was characterised by progredient dysarthria (nasal and slurred speech) and weakness of the right dorsiflexor with consequent foot drop over the course of the previous three years.
  • the patient showed bulbar speech, a 3/5 paresis of the right foot-dorsiflexors and big toe-lift, generalised exaggerated reflexes and spastic tone increase of the right lower limb.
  • EMG showed spontaneous activity and cMRT did not show any pathology.
  • the patient was started on medication with Riluzol around the time of ALS diagnosis. However, the clinical symptomatology remained unchanged. The patient was then started on therapy with acetyl-DL-leucine, at a dose of 3 gram per day for the first week, then a dose of 5 gram per day for the second week onwards. The results were documented by video. After 15 days of treatment, a medical examination was conducted in which the patient reported significant improvement of speech. The patient was able to speak more fluently and was able to modulate his voice better compared to pre-medication (which was documented by video). After a further 20 days, a further medical examination was conducted in which the patient reported further improvement of speech. In addition, the patient reported improvement of gait.
  • the patient’s symptomatology was characterised by progredient dysarthria (nasal and slurred speech) and concomitant dysphagia, and weakness while walking for over a year, and a paresis of the left upper limb for approximately four months.
  • EMG had shown generalised polyphasic activity and chronic neurogenic impairment in the bulbar, cervical and lumbar segment.
  • Clinical examination of the patient showed severe dysarthria, hypomotility of the tongue, 2/5-3/5 paresis of the left arm with impairment of fine motor skills, generalised exaggerated reflexes and fasciculations. Medication with Riluzol had been started one month earlier.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then a dose of 5 g per day for the second week onwards. After approximately 2 months, the patient was re-examined and he reported progredient deterioration of the motor function of the left hand, but a discrete improvement of walking. In addition, swallowing functions have remained stable.
  • Patient 3 The patient in this case study was a 66 year old male who had been previously diagnosed with ALS. The patient’s symptomatology was characterized by progredient weakness and atrophy of both proximal upper extremities, slight impairment of fine motor skills, and generalized fasciculations and cramps.
  • EMG had shown pathologic spontaneous activity and chronic neurogenic change, MRT of the brain and cervical column did not show any pathology .
  • Medication with Riluzol was started. About two months later, a clinical examination showed a 3/5 to 4/5 paresis of both shoulders and proximal arms and a slowing of fine motor scills, generalized fasciculations, and normal reflexes.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then a dose of 5 g per day for the second week onwards. After one month, the patient did not report improvement of symptomatology, with no improvement of muscle force of upper limbs.
  • Medication with acetyl-DL-leucine was suspended and the patient was asked to report worsening of symptomatology.
  • Patient 4 The patient in this case study was a 66 year old male who had been diagnosed with ALS. The patient’s symptomatology was characterized by progressive weakness and atrophy of both proximal upper extremities, slight impairment of fine motor skills, and generalized fasciculations and cramps. EMG showed pathologic spontaneous activity and chronic neurogenic change. MRT of the brain and cervical column did not show any pathology. Treatment with riluzole was started.
  • a clinical examination showed a 3/5 to 4/5 paresis of both shoulders and proximal arms, a slowing of fine motor scills, generalized fasciculations, and normal reflexes, and an ALS-FRS score of 44/48.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then a dose of 5 g per day for the second week onwards. After about one month, the patient reported subjective improvement of dysphagia and less hypersalivation. His relatives reported improved and more vital facial expression. Weakness of limbs was unchanged.
  • Clinical examination of the patient revealed central cerebellar ocular motor signs, moderate dysarthrophonia, mild limb ataxia, and moderate ataxia of stance and gait. Furthermore, a MRI of the patient showed atrophy of the cerebellum and the brainstem, in particular of the pons and mesencephalon. The patient was accordingly diagnosed as having MSA-C. The patient was started on treatment with acetyl-DL-leucine, at a dose of 5 g per day (2 g upon waking, 1.5 g prior to lunch and 1.5 g prior to the evening meal). After one week of treatment the patient already showed a significant improvement in speech. Patient 2 The patient in this case study was a 77 year-old male who had been diagnosed with MSA-C.
  • the patient’s symptomatology was characterised by progressive difficulties of walking and insecure gait with a tendency to fall (the patient fell approximately 10 times a month).
  • the patient exhibited dizziness, hypokinetic-rigid syndrome, saccadic eye movements, dysmetria in the coordination test, and autonomic dysfunction, for example erectile dysfunction, orthostatic hypotension and incomplete bladder emptying over the course of the last four years.
  • the patient’s symptoms remained unchanged over at least a three-month period.
  • the patient was started on treatment with acetyl-DL-leucine at a dose of 3 gram per day for the first week, followed by a dose of up to 5 gram per day. After 3 weeks of treatment, a further examination was carried out.
  • the patient confirmed progressive deterioration of gait and dizziness two days after stopping the treatment, and a very strong tendency to fall 5 days after stopping the treatment.
  • Patient 3 The patient in this case study was a 76 year-old male who had been diagnosed with oligosymptomatic MSA-C.
  • the patient’s symptomatology was characterised by progressive difficulties in walking and insecure gait (without falls), as well as dizziness. Clinically, the patient showed saccadic eye movement and dysmetria in the coordination tests. cMRI showed an atrophy of the mesencephalon, and FDG-PET of the brain showed a reduced metabolism of the striatum and cerebellum.
  • the patient’s posturography test results were pathological with a high tendency to fall. Before treatment was commenced, the patient’s clinical symptomatology remained unchanged over at least a one-year period.
  • Gait analysis was performed, which showed atactic gait, and reduced speed and increased track width compared to the normal range, and fluctuations of gait.
  • the patient was then started on treatment with acetyl-DL-leucine at a dose of 3 gram per day for the first week, followed by a dose of 5 gram per day for the second week onwards. After one month of treatment, a further examination was carried out. Gait analysis showed an improvement of gait speed, and reductions of track width and gait fluctuations. Shortly after After 27 days Normal range ( ⁇ commencing of treatment SD) treatment S peed (cm/sec) 72 106 110.81 (18.33) Max.
  • Gait analysis showed an increased gait width comparable to pre-therapy status: After 20 days of re-suspending treatment S peed (cm/sec) 106 Max. speed (cm/sec) 197 Cadence (steps/minute) 112 Track width (cm) 17.5 Step cycle length (cm) 115 Double stance (%) 27.1 Coefficient of variation (temporal) 2.5 Functional Gait Assessment 22/30 Table 6. Gait analysis parameters.
  • Example 9 The patient in this case study was a 59 year-old male with progredient personality change characterised by apathy, lethargy and indifference.
  • the patient showed a mainly left-side hypokinetic-rigid syndrome with impairment of fine motor skills and reduced resonation of left arm. Furthermore, the patient showed generalised bradykinesia and gait disorder with small steps and 2-3 falls per month. The patient also shows slurred speech and cognitive deficits concerning psychomotoric slowing and reduced semantic word fluency. The patient was diagnosed with frontotemporal dementia with parkinsonism and Datscan revealed a reduction of dopamine receptors supporting the diagnosis. FDG-PET of the brain showed a mainly frontal reduced metabolism. The patient exhibited little improvement during treatment with L-Dopa and Ropinirol.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 gram per day for one week, then a dose of 5 gram per day for 4 weeks. After approximately one month of acetyl-leucine treatment, medication was stopped and the patient was re-examined 13 days later. The patient and his wife and daughter reported a significant improvement of gait under therapy with acetyl-leucine and in addition the patient’s falls stopped. The patient also exhibited an improvement of speech, which was less slurred, more comprehensible and subjectively much more controlled. After suspension of treatment the symptoms worsened.
  • Example 10 The patient in this case study was a 75 year-old male with progressive insecure gait disorder and dizziness leading to backward falls.
  • the patient presented a mainly left-sided hypokinetic-rigid syndrome with apraxia and alien-limb phenomenon.
  • the patient was diagnosed with corticobasal syndrome.
  • a Datscan revealed a reduction of dopamine-receptors and an MRI showed an atrophic motorcortex of the right hemisphere supporting the diagnosis.
  • the patient exhibited no improvement during treatment with L-Dopa.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced. After 20 days of acetyl-leucine treatment, the patient was re-examined.
  • the patient was re-examined about two months later and reported a stable symptomatology of underlying progressive supranuclear palsy; there was no clinical progression.
  • the PSPRS Score remained stable, and the reduction of dizziness was still significant.
  • Patient 2 The patient in this case study was a 66 year-old female with symmetric hypokinetic-rigid syndrome, gait disorder with insecure and small steps (strong tendency to fall) and vertical gaze palsy with impairment of fine motor skills.
  • the patient was diagnosed with progressive supranuclear palsy. Datscan revealed a reduction of dopamine-receptors and FDG-PET of the brain showed a mainly frontal reduced metabolism, supporting the diagnosis. There was no levodopa response.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced. After 17 days of treatment, medication was stopped and the patient was re-examined 4 days later. The patient reported no significant improvement of gait or hypokinetic rigid syndrome. - Before After 17 days of Normal values ( ⁇ SD) treatment treatment s peed (cm/ sec) 51 68 119.12 (17.27) Max.
  • Patient 3 The patient in this case study was a 56 year-old male with symmetric hypokinetic-rigid syndrome, insecure and history of falls and vertical gaze palsy with impairment of fine motor skills. The patient was diagnosed with progressive supranuclear palsy. Datscan revealed a reduction of dopamine-receptors and FDG-PET of the brain showed a frontomesial and parietotemporal reduced metabolism, supporting the diagnosis. There was no levodopa response. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced.
  • Patient 4 The patient in this case study was a 76 year-old male with progredient gait disorder, insecure and small steps (strong tendency to fall), camptocormia, slow and hypometric saccades, blepharospasmus and impairment of fine motor skills. The patient was diagnosed with progressive supranuclear palsy. MRI showed discreet atrophy of the mid brain (Mickey Mouse sign). There was a slight levodopa response. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. Gait analysis was performed before treatment commenced. After three weeks of treatment, medication was stopped and the patient was re-examined.
  • the patient was diagnosed with downbeat nystagmus: the patient was severely impaired by blurred vision (oscillopsia) due to the nystagmus, and experienced difficulties while reading and writing.
  • the patient’s visual acuity was: right 0.75, left 0.67, binocular 0.83, and the downbeat nystagmus was documented by video-oculography.
  • the patient also exhibited increased body sway, which was documented by posturography.
  • Treatment with 4-aminopyridine (Fampyra, 10 mg twice daily) for four weeks did not give rise to any benefit.
  • the patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day (1 g upon waking, 1 g prior to lunch and 1 g prior to the evening meal) for one week, then a dose of 5 gram per day (2 g upon waking, 1.5 g prior to lunch and 1.5 g prior to the evening meal). After 10 days, the patient reported significant benefit and that the effect developed slowly. The patient continued with this treatment dosage, and no side-effects resulted. A temporary suspension of the medication led to a considerable deterioration. The patient was re-examined approximately 14 weeks after starting acetyl-leucine treatment, during which the patient reported to be very happy with the benefit.
  • the patient did not benefit from Fampyra®.
  • the patient began taking acetyl-DL-leucine (3 g/day for the first week; 5 g/day thereafter) and subsequently showed improvement of gait, with the ability to walk much longer distances (one hour), and improved alertness.
  • the patient s downbeat nystagmus also improved (documented by video-oculography).
  • the patient could partially suppress the nystagmus by visual fixation, as evaluated using a target center (dot presented in the center of a display for 30 seconds, Figure 13A) and in complete darkness using goggles covered with special glasses for 45 seconds (Figure 13B).
  • Gait analysis showed a decrease of self-chosen velocity from 85 to 72 cm/sec and maximal gait velocity from 155 to 113 cm/sec.
  • Example 13 Patient 1 The patient in this case study was a 70 year-old female with mainly right sided hypokinetic- rigid syndrome and tremor, antecollis, frequent falls, orthostatic dysfunction and urge incontinence. The patient was diagnosed with with multiple system atrophy Parkinson type (MSA-P). Datscan revealed a mainly left sided reduction of dopamine-receptors and FDG-PET of the brain showed a mainly parieto-occipital reduced metabolism. There was a discreet Levodopa response (100/25mg 3 x daily).
  • the patient began taking acetyl-DL-leucine (3 g/day for the first week; 5 g/day thereafter). After 3 weeks on acetyl-DL-leucine, the patient was evaluated and reported no significant improvement of gait, reduction of falls or improved hypokinetic rigid-syndrome. Medication was stopped. 6 weeks later the patient did not report deterioration of symptoms after stopping medication.
  • Patient 2 The patient in this case study was a 78 year-old male diagnosed with multiple system atrophy Parkinson type (MSA-P). The patient’s symptomatology was characterized by a progressive hypokinetic-rigid syndrome, orthostatic dysfunction and consecutive dizziness and balance disorder. The patient showed saccadic eye movement and symmetric rigor of both upper limbs.
  • Gait analysis was performed. After one month without medication, the patient reported stable symptomatology. No worsening of dizziness or insecurity of gait was reported. Gait analysis was performed. After two months without medication, a gait analysis was performed and showed reduction of velocity of gait, reduction of step length and worsening of FGA-Score. The patient reported a worsening of general symptomatology, including progressive weakness of legs and increased insecureness of gait. After 1 month After 1 month After 2 Normal values of treatment without months ( ⁇ SD) treatment without treatment s peed (cm/ sec) 109 114 94 110.81 (18.33) Max.
  • the patient’s symptomatology was characterized by progressive hypokinetic-rigid syndrome, urinary incontinence, incipient cognitive dysfunction, and gait disorder with small steps and 2-3 falls per month. Cognitive deficits were characterized by psychomotoric slowing and intermittent mental confusion. Datscan revealed a reduction of dopamine-receptors, which supported the diagnosis. FDG-PET of the brain showed a mainly striatal reduced metabolism. Levodopa therapy was suspended due to side effects. The patient was started on treatment with acetyl-DL-leucine, at a dose of 3 g per day for the first week, then 5 g per day. The patient evaluated after one month on acetyl-DL-leucine.
  • Example 14 The patient in this case study was a 45-year-old male diagnosed with spinocerebellar ataxia 28 (SCA 28). Genetic testing showed a known pathogenic variant in AFG3L2. The patient’s symptomatology was characterized by progressive cerebellar syndrome since the age of 30, characterized by slurred speech, unstable gait, balance disorder and dizziness. The patient’s father and grandmother suffered from a similar symptomatology.
  • the patient showed saccadic eye movements and dysmetria in the coordination tests, ataxic gait, slurred speech, exaggerated reflexes of the lower limbs, spasticity of the lower limbs and a positive Babinski sign on the left.
  • cMRI showed a marked atrophy of the cerebellum.
  • the patient was started on treatment with acetyl-DL-leucine at a dose of 5 g per day. A gait analysis was performed before treatment commenced. After about one month of treatment, medication was stopped and the patient was evaluated. The patient reported an improvement of the symptomatology, in particular reduced dizziness (almost vanished), and a more stable gait.
  • Example 15 Patients 1 & 2
  • the patients in this case study were 2 female siblings, 24 (Patient 1) and 19 (Patient 2) years old, respectively.
  • the patients suffer from ataxia telangiectasia.
  • Patient 1 showed delayed developmental milestones.
  • the patient did not walk until 2 years of age and had progression of cerebellar ataxia signs and symptoms, seizures, together with generalized, distal pronounced hypertonia and telangiectasias on the eyes, ears, and chest. Diagnosis was established at the age of 9 years.
  • Patient 1 ocular motor function showed downbeat-nystagmus with gaze straight-ahead and in the gaze to the left greater than right, gaze-holding nystagmus upward, vertical and horizontal saccadic smooth pursuit, and hypometric saccades horizontally and vertically, with restricted motility upward.
  • SARA Scale for Assessment and Rating of Ataxia
  • Patient 1 began treatment with acetyl-DL-leucine (5 g/day) following examination. After one month of treatment, the patient was re-evaluated. Caregivers reported an improvement of speech and gait. The patient herself did not perceive any change. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 15.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • Patient 1 SARA and SCAFI subsets improved after treatment, and video-oculography showed significant improvement of fixation stability and decrease of intensity of downbeat- nystagmus.
  • Patient 2 showed delayed developmental milestones, seizure at the age of 1, generalized hypotonia, contractures of low extremities with pes equinovarus bilaterally, areflexia, acute lymphoblastic leukemia at the age of 3 years, slightly enlarged spleen, hypercholesterolemia, hypochromatic microcytic anemia, pigmental naevi, and vitiligo. First symptoms were noticed by the patient’s parents at the age of 15 months.
  • Patient 2 began treatment with acetyl-DL-leucine (5 g/day) following examination. After one month of treatment, the patient was re-evaluated. Caregivers reported an improvement of fine motor function, hand tremor, and speech. The patient herself did not perceive any benefit. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 23.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • Video-oculography showed improvement of fixation stability and significant improvement of downbeat-nystagmus intensity in Patient 2.
  • Patient 3 The patient in this case study was a 19 year old female suffering from ataxia telangiectasia from early childhood, having: -Delayed motor development, cerebellar ataxia signs and symptoms, pronounced axial hypotonia with acral hypertonia, severe contractures of feet with orthopedic deformities pes equinus et transversoplanus bilaterally and was thus confined to wheelchair, dysdiadochokinesis, and areflexia of low extremities with decreased proprioceptive perception; and -Non-Hodgkin lymphoma, polymorphism MTHFR (C677T), lymphangioma of the lower lip, cholecystolithiasis, dilated cardiomyopathy, pigmental naevi, thoraco- lumbar kyphoscoliosis, and scleral teleangiectasia
  • the patient’s ocular motor function showed gaze-holding nystagmus to the right and to the left, saccadic eye movements, slow saccades to all directions, especially horizontally, pathological vestibulo-ocular reflex with corrective catch-up saccades, and pathological visual-fixation suppression of the vestibulo-ocular reflex.
  • SARA Scale for Assessment and Rating of Ataxia
  • the patient began treatment with acetyl-DL-leucine (5 g/day) about six months after the examination. After slightly over 7 months of treatment, the patient was re-evaluated. Caregivers and patient reported general improvement of well-being, without clearer specification. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 21.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • the patient showed slight improvement of SARA and SCAFI subset 9HPT, and significant improvement of fixation stability and decrease of intensity of gaze-holding nystagmus at all positions.
  • Patient 4 The patient in this case study was a 15 year-old female suffering from ataxia telangiectasia from 4-years of age. From 7-years of age, the patient showed severe cerebellar ataxia signs and symptoms, fine motor impairment, muscular hypotonia with areflexia, muscular atrophy, and plantar flexion with discrete contractures. The patient was confined to a wheelchair, but was able to walk with constant support.
  • the patient had severe hemolytic anemia, hypogammaglobulinemia, telangiectasias on the scleras and chest, Secondary Cushing syndrome due to corticosteroid intake, and was suspected of having CNS Non- Hodgkin lymphoma.
  • the patient’s ocular motor function showed slow deviation of the eyes upward, left beating nystagmus in the central position, gaze-holding nystagmus in all directions, horizontally with downbeating component, startle with sudden head movement.
  • SARA Scale for Assessment and Rating of Ataxia
  • the patient began treatment with acetyl-DL-leucine (5 g/day) following the examination. After slightly over 1 month of treatment, the patient was re-evaluated. The patient and her mother reported improvement in handwriting, especially due to decreased hand tremor and fine motor function. The patient also reported that drinking was easier and no longer needed a straw. Family members described improvement of gait, with increased stability and needing less support. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 18.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • the patient showed improvement of SARA and SCAFI subset 9HPT of the dominant hand.
  • Video-oculography showed general improvement of fixation stability and decrease of intensity of spontaneous and gaze-holding nystagmus at all positions.
  • Patient 5 The patient in this case study was a 10 year-old boy suffering from ataxia telangiectasia from his early childhood, having: - Delayed psychomotor development, instable walking at 14 months with increased incidence of falls, severe cerebellar ataxia signs and symptoms, dysarthria and dyslalia, fine motor impairment, infrequent head tremor, slow psychomotor tempo, hypotonia with muscular atrophy and hyporeflexia, anteflexia of the head with kyphosis in the thoracal area, pedes transversoplani, scapullae allatae, parasomnia with pavor nocturnus, and autism; and -Significant immunosuppression, telangiectasias on the soft palate, scleras,
  • the patient was confined to a wheelchair but was able to perform a few steps with strong constant support.
  • the patient’s ocular motor function showed oculomotor apraxia with pronounced head anteflexia, head and eye movement “en bloc” when looking to the right and left, vertical gaze palsy with slow vertical saccades and saccadic smooth pursuit, slow horizontal saccades to the left, saccade palsy to the right, restricted eye motility, especially vertically, and fixation instability in all positions.
  • SARA Scale for Assessment and Rating of Ataxia
  • the patient began treatment with acetyl-DL-leucine (5 g/day) following examination. After about 1 month of treatment, the patient was re-evaluated. The patient’s mother described a significant improvement of stability of the gait; prior to the therapy, he was constantly falling backward and had to be partially “transported”. On medication, he was able to walk with only holding the caregiver ⁇ s hand. Fine motor function, the intensity of hand tremor, and body holding improved. Improvement of fine motor function was reflected in daily activities, such as eating and drinking independently. The patient gained 1.5 kg and had a better appetite. Examination indicated a Scale for Assessment and Rating of Ataxia (SARA) score of 20.5/40.
  • SARA Scale for Assessment and Rating of Ataxia
  • Patient 6 The patient in this case study was a 10 year-old female suffering from ataxia telangiectasia who had ataxic gait and stance, fine motor function disorder with hand tremor, dysphagia and speech disorder, ocular movement disorder, and problems with cognitive function and concentration. First symptoms were observed at the age of one year. After baseline examination, the patient started acetyl-DL-leucine treatment at 1.5 g/day for the first week and at 3 g/day for the second week onwards. The patient was evaluated after one month and six months of treatment, respectively. After one month of treatment, the patient showed increased fine motor skills with reduced hand tremor, improved postural stability and gait, increased enunciation, and increased self-confidence.
  • Example 16 The patient in this case study was a female in her early 60s who was genetically diagnosed with Spinocerebellar Ataxia (SCA) 1. Before treatment, the patient had severe problems with speaking and swallowing, tremor of both arms, spasticity and moderate ataxia of stance and gait. The patient also had problems sleeping. Three weeks on medication with acetyl-DL-leucine (5 g/day), all symptoms significantly improved, as further demonstrated by clinical examination, including spasticity and impairment of ocular motor function. Three months later the medication was stopped. After two weeks, the intensity of the signs and symptoms were the same as before therapy. Treatment was started again, and the patient has remained, and continues, on the treatment after over two years, on the same dosage without any side-effects.
  • SCA Spinocerebellar Ataxia
  • Example 17 The patient in this case study was a 70 year-old female with insecure gait and frequent falls, visual hallucinations at night, REM-sleep disorder. The patient had symmetric hypokinetic- rigid syndrome with impairment of fine motor skills and fluctuations in attention and awareness. The patient was diagnosed with Lewy Body dementia. FDG-PET of the brain showed a synaptic dysfunction in the parietal and occipital lobe and DATscan showed a degeneration of presynaptic dopamine transporter, supporting the diagnosis.
  • the patient started taking acetyl-leucine (3 g/day for one week; 5 g/day thereafter) and was evaluated after four weeks. The patient reported increased fatigue and a deterioration of balance and speech. Medication was reduced to 3 g/day, and the patient was instructed to stop medication about two weeks later. The patient was re-evaluated about one month after ceasing medication and did not report improvement of symptomatology with the decreased dose and no deterioration of symptoms after stopping medication.
  • Example 18 In this case study, four patients (male siblings) suffered from, and were later diagnosed with, ataxia with oculomotor apraxia type 4. The older three siblings were 12, 11, and 10 years of age, respectively, at the time of disease onset. Prior to commencing treatment with acetyl- DL-leucine, by the age of 15/16 years, the three older siblings walked with an expedient, as reported by the patients’ mother. The older siblings began treatment with acetyl-leucine at 25, 23, and 19 years of age, respectively, and have been on the treatment for approximately four years. No long-term clinical data is available for these three patients. The youngest sibling was 11 years old at the time of onset. He began treatment with acetyl- DL-leucine at the age of 13.
  • CCS clinical severity score
  • an untreated patient In an untreated patient, one can typically predict how the CSS will change over time in an individual, as disease progression appears to be linear. For example, if Patient A moves from a CSS of 8 to a CSS of 12 between month 0 and month 12, it can be predicted that by month 36, the patient will have a CSS of 20.
  • the annual severity increment score (ASIS) quantities the annual rate of change in the CSS, calculated by dividing the CSS of a patient by the patient’s age. For example, if untreated Patient B had a CSS of 8 at two years of age, the patient’s ASIS would be 4. Each year, the patient would be expected to progress by 4 CSS points, such that at 4 years of age, the patient’s CSS would be 16.
  • ASIS score was determined at baseline, and at various time points, for eye movement, ambulation, speech, swallow, fine motor skills, cognition, memory, and seizures.
  • An overall CSS was calculated at baseline and at each such time point by adding the individual CSS values for each parameter (eye movement, ambulation, etc.). The number of days post-initiation of therapy at which CSS was assessed was different for each patient, as shown in Table 25.
  • Clinical Severity Score P atient I.D Baseline Time Point 2 Time Point 3 Time Point 4 1 0 0 0 2 4 4 4 4 3 2 2 2 2 5 2 2 2 2 6 3 3 3 3 7 3 3 3 8 2 2 2 9 3 3 3 10 2 2 Table 30. CSS swallow.
  • Clinical Severity Score P atient I.D Baseline Time Point 2 Time Point 3 Time Point 4 1 1 1 1 2 5 5 5 5 3 2 1 1 4 1 1 1 5 1 1 1 1 6 4 4 4 4 7 2 2 2 8 2 1 1 9 4 4 10 1 1 Table 31. CSS fine motor skills.
  • Clinical Severity Score P atient I.D Baseline Time Point 2 Time Point 3 Time Point 4 1 3 3 3 2 5 5 5 5 5 3 3 3 3 4 3 3 3 5 3 3 3 3 6 4 4 4 4 4 7 4 4 4 8 3 3 3 9 4 4 4 10 3 2 Table 32. CSS cognition. Clinical Severity Score (CSS) P atient I.D Baseline Time Point 2 Time Point 3 Time Point 4 1 1 1 1 2 4 4 4 4 3 1 1 0 4 1 1 0 5 1 1 1 1 6 3 3 3 3 3 7 4 4 4 8 1 1 1 9 4 4 3 10 2 0 Table 33. CSS memory.
  • Example 20 The Niemann-Pick Disease Type C (NPC) mouse model shares a number of pathological features with Alzheimer’s disease (AD) as described herein.
  • Wild type NPC1 -/- mice were treated with acetyl-dl-leucine (0.1 g/kg body weight daily) from 3 weeks of age. Mice were sacrificed at 8 weeks of age.
  • Levels of amyloid precursor protein C-terminal fragments (APP- CTFs) were evaluated relative to total amyloid precursor protein (APP) levels in the cerebellum for wild type, untreated wild type NPC1 -/- mice, and AL-treated wild type NPC1 -/- mice.
  • LC3-II microtubule-associated protein 1A/1B-light chain 3- phosphatidylethanolamine conjugate
  • Example 21 NPC Chinese Hamster Ovary (CHO) cells were treated in vitro for 72 hours with 1 mM of acetyl-DL-leucine, acetyl-L-leucine, acetyl-D-leucine, DL-leucine, L-leucine, and D-leucine, respectively. Relative lysosomal volume was quantified via LysoTracker.
  • the NPC CHO cells were observed to have elevated LysoTracker fluorescence levels relative to wild-type controls, which is indicative of increased lysosomal volume of the diseased phenotype.
  • Treatment of the NPC CHO cells with each of acetyl-DL-leucine, acetyl-L-leucine, acetyl-D- leucine, DL-leucine, L-leucine, and D-leucine significantly reduced lysosomal volume in the cells.
  • Data presented in Figure 14 show the results for each treatment, with lysosomal volume expressed as fold change relative to untreated wild-type fibroblasts.
  • Example 22 Patient 1 The patient in this case study was a 55-year-old female showing proximal weakness of the lower limb. She had a flexor paresis of the head slowly progressive since age 42 and had been diagnosed (genetically confirmed) with myotonic dystrophy type 2.
  • the patient was started on therapy with acetyl-DL-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.
  • the IRLS dropped to 26, and after another 5 weeks, the IRLS declined to 9.
  • Interruption of 4 weeks of the treatment after week 12 of the treatment increased the IRLS to 28.
  • Re-introduction of the treatment re-declined the score to 8 after 2 weeks.
  • Continuation of treatment over more than 22 weeks stabilized the IRLS score at 8.
  • Patient 2 The patient in this case study was a 72-year-old female showing proximal weakness of the lower limb.
  • the patient was started on therapy with acetyl-DL-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.
  • the IRLS dropped to 22, and after another 5 weeks, the IRLS declined to 7.
  • Continuation of treatment over more than 28 weeks stabilized the IRLS score at 8.
  • Patient 3 The patient in this case study was a 73-year-old male showing mild proximal weakness of the upper and lower limbs slowly progressive since age 50.
  • the patient had been diagnosed (genetically confirmed) with McArdle myopathy about 16 years ago.
  • the patient was started on therapy with acetyl-DL-leucine at a dose of 3 g per day for the first week, followed by a dose of 5 g per day for the second week onwards.
  • the IRLS dropped to 20, and after another 10 weeks, the IRLS declined to 10.
  • Continuation of treatment over more than 30 weeks stabilized the IRLS score at 10.
  • the patient s fatigue declined (Fatigue Severit Scale: 9 (minimum) to 63 (maximum)) from 53 to 28.
  • Example 23 The patient in this case study was a male 79 year-old subject, who suffered from REM Sleep Behavior Disorder (RBD), hypokinetic type with intestinal hypokinetic disorder and Restless Legs Syndrome (RLS). The patient was diagnosed with Parkinson’s disease. Patient suffered from the RBD in combination with the RLS since 2003, which was severe and considered to be a 10 on a scale from 1 – 10 before treatment with Acetyl-DL-leucine (AL). The patient began treatment with AL in March 2021, and received AL at a dosage of 1500 mg at noon, and 3500 mg at night, resulting in a total daily dosage of 5 g AL. Within 2-3 weeks, significant and dramatic improvements could be detected.
  • RBD REM Sleep Behavior Disorder
  • RLS Restless Legs Syndrome
  • PD Parkinson’s disease
  • the evaluated and observed improvements after 6 weeks treatment with acetyl-leucine included patient ⁇ s gait and mobility, fluidity of patient ⁇ s arm movements, constipation (as a symptom of Parkinson’s disease), cognitive function, alertness and mood.
  • the severity of PD symptoms can be measured with any suitable known scale, e.g.
  • Example 24 The patient in this case study was a male 83 year-old subject, who was diagnosed with early Parkinson ⁇ s disease one year prior to starting therapy with acetyl-DL-leucine (AL) at a total daily dosage of 5 g AL. After 4 weeks, the subject noticed an improvement of his constipation. Constipation frequently occurs in PD patients due to improper functioning of the autonomic nervous system, and is a nonmotor symptom in the early stages of PD. Conclusion Acetyl-leucine treatment was associated with a improvement in early PD symptoms.
  • A acetyl-DL-leucine
  • Example 25 The patient in this case study was a 63 year-old female subject, who was diagnosed with Parkinson ⁇ s disease (PD) and under treatment regimen of 300 mg/day L-DOPA. After none year of the diagnosis and L-DOPA treatment, the patient was started on a therapy with acetyl-DL-leucine (AL) at a total daily dosage of 5 g AL per day. Patient suffered mainly from hypomimia, bradykinesia and rigor more on left, slight tremor more on the left. During treatment with acetyl-leucine, PD symptoms were stable for 22 months and treatment is ongoing. There was also no need to increase the dosage of L-Dopa over this period of time. Acetyl-leucine was well tolerated.
  • AL acetyl-DL-leucine
  • Acetyl-leucine treatment was associated with an improvement in PD symptoms.
  • Example 26 The patient in this case study was a 69 year-old male subject, who was diagnosed with Parkinson ⁇ s disease in 2019, with the main symptoms being hypokinesia and rigor bilaterally, more pronounced on the left, moderate tremor.
  • Patient was treated with L-DOPA since 2022 and due to increasing severity of PD symptoms, the dosage of L-DOPA was increased to 1000 mg L-DOPA per day.
  • Treatment with acetyl-DL-leucine (AL) at a total daily dosage of 5 g AL per day began at the beginning of 2024. After six weeks of treatment the dosage of L-Dopa could be reduced to 600 mg per day because of the symptomatic effects.
  • AL acetyl-DL-leucine
  • Acetyl-DL-leucine After the initiation of the treatment with Acetyl-DL-leucine his mobility, hypokinesia of arms and legs, gait impairment and mobility increased, according to the patient by 50%. The patient is much more active, and his sleeping problems improved. Further, his depression – one of the leading symptoms during the course of the disease – also improved. Patient ⁇ s quality of life improved.
  • Acetyl-leucine was well tolerated. Patient under continuous treatment. Conclusion Acetyl-leucine treatment was associated with drastic improvements in PD symptoms, including mobility, sleep problems and depression.
  • Example 28 The patient in this case study was a 85 year-old male subject, who was diagnosed with Parkinson ⁇ s disease in 2023 and suffered mainly from tremor dominating, right side. Patient received 400 mg/d L-DOPA after the diagnosis was made. Treatment with Acetyl-leucine (5 g/d) commenced in summer 2024. Since then, his condition is stable (further deterioration was prevented) and his tremor improved. Acetyl- leucine was well tolerated. Patient under continuous treatment. Conclusion Acetyl-leucine treatment was associated with drastic improvements in PD symptoms.
  • Example 29 The patient in this case study was a 83 year-old male subject, who was diagnosed with Parkinson ⁇ s disease in July 2024. Symptoms began in 2023 on the left side with reduced arm movements and slight tremor. Patient received 300 mg/d L-DOPA to treat his tremor dominating on the right side. Co-therapy with acetyl-DL-leucine (AL) was started in November 2024 at a total daily dosage of 5 g AL. As of January 2025, patient reported general improvement of his movement disorder, including improvement in arm movements, hypokinesia, tremor and sleep quality, resulting in an overall improvement of quality of life. Acetyl-leucine has been well tolerated. Patient under continuous treatment.
  • Acetyl-leucine treatment was associated with drastic improvements in PD symptoms.
  • Example 30 The patient in this case study was a 85 year-old male subject, whose symptoms of hypokinesia and gait disorder began at the beginning of 2023, and were slowly progressive. He was diagnosed with Parkinson ⁇ s disease in November 2024. Since then, the patient received L-Dopa at a dosage of 300 mg per day plus Acetyl-Leucine 4 g/day (Acetyl-L- Leucine; Aqneursa, individual off-label use). After two months of treatment, a significant improvement of all symptoms, including improved coordination of the arms, improved walking and general mood, were reported. Patient was very satisfied with state of conditions. Acetyl-leucine has been well tolerated. Patient under continuous treatment. Conclusion Acetyl-leucine treatment was associated with drastic improvements in PD symptoms.

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Abstract

La présente divulgation concerne un traitement de la maladie de Parkinson (MP) comprenant l'administration d'acétylleucine ou d'un sel pharmaceutiquement acceptable de celle-ci à un sujet en ayant besoin.
PCT/EP2025/052506 2024-02-01 2025-01-31 Acétylleucine pour le traitement de la maladie de parkinson Pending WO2025163129A1 (fr)

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WO2018029658A1 (fr) * 2016-08-11 2018-02-15 Intrabio Limited Agents thérapeutiques pour maladies neurodégénératives
WO2019079536A1 (fr) * 2017-10-18 2019-04-25 Intrabio Ltd Agents thérapeutiques pour mobilité et fonction cognitive améliorées et pour le traitement de maladies neurodégénératives et de troubles de stockage lysosomal
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