WO2025224600A1 - Treatment of alpha-synucleinopathies and neuroprotection - Google Patents

Abstract

A method of treating an alpha-synucleinopathy in a patient in need thereof includes administering to the patient a therapeutically effective amount of a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I as described herein or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof. Also disclosed is a method of providing neuroprotection to the central or peripheral nervous system of a patient in need of such neuroprotection. The method includes administering to the patient the dual TYK2/JAK1 inhibitor.

Description

TREATMENT OF ALPHA-SYNUCLEINOPATHIES AND NEUROPROTECTION

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application Serial No. 63/636,819, filed on April 21, 2024, the content of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

[0001] The application generally relates to methods of treating alpha-synucleinopathies, as well as methods of providing neuroprotection.

BACKGROUND

[0002] Among neurodegenerative diseases, those involving abnormal accumulation of a- synuclein are referred to as alpha-synucleinopathies or simply synucleinopathies. There are three main types of synucleinopathies - Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). PD is the second most commonly observed neurodegenerative disease. DLB is a cause of the second most commonly observed dementia, after Alzheimer’s disease (AD). MSA is a rare disease but tends to progress more rapidly than PD, and most people with MSA will require an aid for walking, such as a cane or walker, within a few years after symptoms begin. Despite all the advances in recent years, an effective method for treating synucleinopathies is still needed.

[0003] Meanwhile, PD is a neurodegenerative disease that is pathologically manifested by a chronic and progressive loss of dopaminergic neurons in the substantia nigra (SN). The symptoms of PD, such as movement abnormalities, rigidity, and tremor may be alleviated by L-DOPA and other drugs (i.e., dopamine receptor agonists). However, it has been challenging to stop the progression of the disease. Therefore, there remains a need for new therapies that can provide neuroprotection to the central or peripheral nervous system for the treatment of neurodegenerative diseases such as PD.

SUMMARY

[0004] A method of treating an alpha-synucleinopathy in a patient in need thereof is disclosed. The method includes administering to the patient a therapeutically effective amount of a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof:

Formula I.

[0005] Also disclosed is a method of providing neuroprotection to the central or peripheral nervous system of a patient in need of such neuroprotection. The method includes administering to the patient a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I as described hereinabove, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which:

[0007] FIG. 1 shows the effects of the TYK2/JAK1 inhibitor used in the examples on the PD- related motor behavior based on the movement distance in open field (meter, m) in adeno- associated virus (AAV)-a-synuclein mouse model of Parkinson’s disease;

[0008] FIG. 2 shows the effects of the TYK2/JAK1 inhibitor on the PD-related motor behavior based on the time on the rotarod (second, s) in AAV-a-synuclein mouse model of Parkinson’s disease;

[0009] FIG. 3 shows the effects of the TYK2/JAK1 inhibitor on the PD-related motor behavior based on the peak grip (gripping force, gf) in AAV-a-synuclein mouse model of Parkinson’s disease;

[0010] FIG. 4 compares the number of tyrosine hydroxylase positive (TH+) cells in Sham group, Model group, and mice groups administered with 10 mpk or 30 mpk of the TYK2/JAK1 inhibitor in AAV-a-synuclein mouse model of Parkinson’s disease;

[0011] FIG. 5 compares the density of TH+ cells per section in Sham group, Model group, and mice groups administered with 10 mpk or 30 mpk of the TYK2/JAK1 inhibitor in AAV- a-synuclein mouse model of Parkinson’s disease; [0012] FIG. 6 compares the number of adaptor molecule 1 positive (Ibal+) cells in Sham group, Model group, and mice groups administered with 10 mpk or 30 mpk of the TYK2/JAK1 inhibitor in AAV-a-synuclein mouse model of Parkinson’s disease;

[0013] FIG. 7 compares the number of Ibal+ cells per section in Sham group, Model group, and mice groups administered with 10 mpk or 30 mpk of the TYK2/JAK1 inhibitor in AAV- a-synuclein mouse model of Parkinson’s disease;

[0014] FIG. 8 shows the effects of the TYK2/JAK1 inhibitor on Interleukin-6 (IL-6) concentration (picogram per milliliter, pg/mL) in AAV-a-synuclein mouse model of Parkinson’s disease;

[0015] FIG. 9 is a graph of mean plasma concentration (nanogram per milliliter, ng/mL) of the TYK2/JAK1 inhibitor versus time (hour, h) after administration of the inhibitor at dose levels of 10 mg, 20 mg, or 30 mg;

[0016] FIG. 10 is a graph of mean plasma concentration (ng/mL) of TYK2/JAK1 inhibitor versus time (h) after administration of the inhibitor at dose levels of 6 mg, 10 mg, or 20 mg, and shows the steady-state PK of the inhibitor in plasma at Day 14;

[0017] FIG. 11 shows inhibitor concentrations (ng/mL) in plasma and cerebrospinal fluid (CSF) 6 hours or 24 hours after administration of the TYK2/JAK1 inhibitor;

[0018] FIG. 12 is a graph of inhibitor concentrations in plasma, spinal CSF, total brain, and unbound brain versus time (h) after administration of the TYK2/JAK1 inhibitor;

[0019] FIG. 13 shows the mean percent change of interferon beta (IFN-P) from baseline 14 days or 15 days after administration of various doses of the TYK2/JAK1 inhibitor or a placebo (PBO);

[0020] FIG. 14 shows the mean percent change of high-sensitivity C-reactive protein (hsCRP) from baseline 14 or 15 days after administration of various doses of the TYK2/JAK1 inhibitor or a placebo (PBO); and

[0021] FIG. 15 shows the mean percent change of interferon-gamma-induced protein 10 (IP- 10) from baseline 14 or 15 days after administration of various doses of the TYK2/JAK1 inhibitor or a placebo (PBO).

[0022] The above descriptions should not be considered limiting in any way.

DETAILED DESCRIPTION

[0023] The following detailed description is provided to aid those skilled in the art in practicing the present invention. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure.

Terminology

[0024] Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this application belongs. However, if a term in the present application contradicts or conflicts with a term in the incorporated reference, the term from the present application takes precedence over the conflicting term from the incorporated reference.

[0025] All ranges disclosed herein are inclusive of the endpoints, and the endpoints are independently combinable with each other.

[0026] The terms "a" and "an" and "the" do not denote a limitation of quantity and are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0027] "Or” means "and/or" unless clearly stated otherwise.

[0028] A "combination thereof' is open and includes any combination comprising at least one of the listed components or conditions optionally together with a like or equivalent component or condition not listed.

[0029] Unless otherwise indicated, any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, solvates, and hydrates, etc.

[0030] If stereochemistry is not indicated, a name or structural representation includes any stereoisomer or any mixture of stereoisomers.

[0031] "JAK" stands for to Janus kinase, which is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely, JAK1, JAK2, JAK3, and TYK2. A "dual JAK1/TYK2 inhibitor" refers to a compound that can inhibit the activity of both JAK1 (Janus Kinase 1) and TYK2 (Tyrosine kinase 2).

[0032] "Pharmaceutically acceptable salt" includes derivatives of the disclosed compounds wherein the parent compound is modified by making salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines. For example, acid salts can include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; as well as those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxylmaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2- acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, H00C-(CH2)_n- COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in G. Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors. Wiley-VCH, 2002.

[0033] The term "solvate" refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Suitable solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The dual TYK2/JAK1 inhibitor described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates.

Representative solvates include hydrates, ethanolates, and methanolates.

[0034] The term "hydrate" refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R XH2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R O.5H2O) ), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R 2 H2O) and hexahydrates (R 6H2O)).

[0035] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. Suitable polymorphs of the TYK2/JAK1 inhibitor include those described in WO 2020/244349 Al, the content of which is incorporated herein by reference in its entirety.

[0036] The term "carrier" applied to pharmaceutical compositions of the disclosure refers to an excipient, diluent, or vehicle with which an active compound (e.g., dual TYK2/JAK1 inhibitor) is provided. A "pharmaceutically acceptable carrier" means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier" includes both one and more than one such carrier.

[0037] A "patient" or a "subject" is a human or non-human animal. The term "non-human animal" includes, for example, vertebrates such as non-human primates, horses, livestock such as sheep and cows, pets such as dogs and cats, and rodents such as mice, rats and guinea pigs. In some embodiments, the patient or the subject is a human.

[0038] "Treatment" or "treating" means alleviating, inhibiting, ameliorating, relieving, reducing, and/or slowing a condition or a disease in a subject.

[0039] The term "therapeutically effective amount" is the amount sufficient to effect treatment, as defined herein, when administered to a patient or a subject in need of such treatment.

[0040] "Administering" or "administration" means giving, providing, applying, or dispensing by any suitable route.

Treatment of alpha-synucleinopathies and neuroprotection

[0041] Alpha-synucleinopathies are neurodegenerative diseases that are pathologically manifested by a chronic and progressive loss of dopaminergic neurons in the brain. Neuroinflammation is considered a significant mechanism contributing to the development and progression of alpha-synucleinopathies.

[0042] The inventors hereof have found that a dual TYK2/JAK1 inhibitor as disclosed herein can be used to treat alpha-synucleinopathies. In particular, the dual TYK2/JAK1 inhibitor can be efficacious in alleviating symptoms of alpha-synucleinopathies, decreasing neuroinflammation response and reversing neuron cell death.

[0043] The dual TYK2/JAK1 inhibitor can also provide neuroprotection to the central or peripheral nervous system of a patient. Neuroprotection can protect or rescue neurons vulnerable to the neurodegenerative process, potentially slowing or halting progression of a neurodegenerative disease such as PD.

[0044] The dual TYK2/JAK1 inhibitor has effective brain penetration. The PK data supports once-daily oral dosing. In the clinic, the dual TYK2/JAK1 inhibitor has generally been safe and well tolerated. The dual TYK2/JAK1 inhibitor is also highly selective, and can avoid the safety liabilities of JAK2/3 inhibition.

[0045] Accordingly, in an aspect, the disclosure is directed to a method of treating an alpha- synucleinopathy in a patient in need thereof. The method comprises administering a therapeutically effective amount of a dual TYK2/JAK1 inhibitor optionally at a dose of 5 milligrams (mg) to 90 mg once per day.

[0046] In another aspect, the disclosure is directed to a method of providing neuroprotection to the central or peripheral nervous system of a patient in need of such neuroprotection. The method comprises administering to the patient a dual TYK2/JAK1 inhibitor.

[0047] The dual TYK2/JAK1 inhibitor used in the methods of treating synucleinopathies and providing neuroprotection is a compound of Formula I, or a salt, solvate, hydrate, or polymorph thereof:

Formula I.

[0048] A preferred dose or therapeutically effective amount of the TYK2 and JAK1 dual inhibitor can be in the range from about 5 mg to 90 mg, 10 mg to 50 mg, 10 to 30 mg, or 20 mg once per day.

[0049] The dual TYK2/JAK1 inhibitor can be administered to the patient in a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the dual TYK2/JAK1 inhibitor.

[0050] Examples of the carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the disclosure of which is incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers are those that are compatible with the dual TYK2/JAK1 inhibitor and other active ingredients, if present, in the formulation and are biologically acceptable.

[0051] Pharmaceutically acceptable carriers or excipients used in the manufacture of the pharmaceutical composition include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0052] The pharmaceutical composition may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, among others. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the dual TYK2/JAK1 inhibitor and the pharmaceutical composition are administered orally.

[0053] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the dual the TYK2/JAK1 inhibitor described herein are mixed with solubilizing agents such as alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0054] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1, 3 -butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0055] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) release control polymers such as various grades of hydroxypropyl methylcellulose (HPMC), (h) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (i) absorbents such as kaolin and bentonite clay, (j) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0056] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.

[0057] The pharmaceutical composition can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0058] Preferably, the pharmaceutical composition is formulated to contain between 5 mg to 90 mg, from 10 to 50 mg, from 10 to 30 mg, or 20 mg of the dual TYK2/JAK1 inhibitor, alone or in combination with at least one additional compound which may be used to treat the synucleinopathies or to provide neuroprotection. [0059] The dual TYK2/TAK1 inhibitor is effective to treat synucleinopathies. The synucleinopathies which may be treated in accordance with the present invention include Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, or a combination thereof. In some embodiments, a patient suffering from an alpha-synucleinopathy can be treated by administering to the patient a therapeutic effective amount of the dual TYK2/JAK1 inhibitor as disclosed herein once daily optionally in pharmaceutically acceptable carriers or diluents, and optionally in combination with other known pharmaceutical agents, preferably agents which can assist in treating synucleinopathies, or ameliorating the secondary effects and/or symptoms associated with these diseases. This treatment can also be administered in conjunction with other conventional therapies, such as radiation treatment or surgery for cancer.

[0060] Optionally, the additional pharmaceutical agent can be an anti-CNS disorder agent. Examples include antipsychotics selected from butyrophenone, phenothiazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthene, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, a dopamine partial agonist, lamotrigine, memantine, tetrabenazine, cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate, and tetrabenazine; antidepressant or mood stabilizer selected from fluoxetine , paroxetine, escitalopram, citalopram, seriraline, fluvoxamine, venlafaxine, milnacipram, duloxetine, mirtazapine, mianserin, reboxetine, bupropion, amitriptyline, nortriptiline, protriptyline, desipramine, trimipramine, amoxapine, bupropion, bupropion sr, s-citalopram, clomipramine, desipramine, doxepin, isocarboxazid, velafaxine xr, tranylcypromine, trazodone, nefazodone, pheneizine, lamatrogine, lithium, topiramate, gabapentin, carbamazepine, oxacarbazepine, valporate, maprotiline, mirtazapine, brofaromine, gepirone, moclobemide, isoniazid, and iproniazid; or medication for improving cognition and/or inhibiting neurodegeneration selected from aricept, donepezil, tacrine, rivastigmine, memantine, physostigmine, nicotine, arecoline, huperzine alpha, selegiline, riluzole, vitamin C, vitamin E, carotenoids, Ginkgo biloba. Any anti-CNS disorder agent known in the art can be co-used with the dual TYK2/JAK1 inhibitor to treat synucleinopathies or to provide neuroprotection.

[0061] The dual TYK2/TAK1 inhibitor is also effective to provide neuroprotection. Neuroprotective therapies can slow or halt the progress of a neurodegenerative disease such as PD, rather than just managing symptoms. In one embodiment, providing neuroprotection can comprise treating a neurodegenerative disease such as Parkinson’s disease.

[0062] The invention also provides kits for use in the instant methods. Kits can include at least one container that includes the TYK2/JAK1 inhibitor or a pharmaceutical composition comprising the same, and instructions for use in accordance with any of the method described herein. Generally, these instructions comprise a description of administration of the TYK2/JAK1 inhibitor to treat alpha-synucleinopathies, or to provide neuroprotection, according to any of the method described herein. The kit may, for example, comprise a description of selecting an individual suitable for treatment based on identifying whether that individual has alpha-synucleinopathies or may be benefited from neuroprotection. The instructions are typically provided in the form of a package insert, or label, in accordance with the requirements of the regulatory having authority over the jurisdiction where the pharmaceutical composition is to be provided to patients.

[0063] Compound of Formula (I) may also be useful to treat other CNS conditions such as neurotoxicity and/or neurotrauma, including but not limited to acute neuronal injury (e.g., traumatic brain injury (TBI) , stroke, epilepsy) or a chronic neurodegenerative disorder (e.g., multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease).

[0064] The invention is further illustrated by the following non-limiting examples.

EXAMPLES

TYK2/JAK1 inhibitor

[0065] The TYK2/JAK1 inhibitor used in the examples is the compound of Formula I as disclosed herein. Preparation of the TYK2/JAK1 inhibitor has been described in WO 2023/035913, the content of which is incorporated herein by reference in its entirety.

EXAMPLE 1

Objective

[0066] The object of the example is to evaluate the therapeutic effect of the TYK2/JAK1 inhibitor in a mouse model of Parkinson' s disease induced by AAV-hm-A53T-a-Syn injection.

The Establishment of an a-Syn Overexpressing Mouse Model [0067] The PD mouse model was established by stereotactic unilateral injection of AAV-hm- a-Syn into the SN brain regions of C57BL/6J male mice. Animals were orally dosed for 39 consecutive days starting on Day 3 post AAV-hm-a-Syn injection.

Behavioral Testing (Day 42, n=10)

[0068] Behavioral tests (open field, rotarod, grip strength) were performed 6 weeks post AAV-hm-A53T-a-Syn injection.

Open Field

[0069] Prior to test, the mice were placed in the test room for 30 min for adaption. Then the mice were placed in the middle of the open field, and data were collected using ANY-Maze software for 10 min. Total movement distance of each mouse was recorded.

Rotarod Test

[0070] Mice were placed in the test room for 30 min before testing. Each test animal was placed on the rotarod for adaptive training for 5 min. Mice were placed on the rotarod in batches for testing. The rotation speed was 20 rpm/min, and the test time was 5 min. The mean time on the rotarod was calculated.

Grip strength

[0071] Mice were placed on a platform with both forelimbs on a grasping rod. Grasp the mouse tail and pull straight backward. Animals instinctively grasp anything to stop receding when they move backwards unintentionally until the pull exceeds their grip. After the animal loses grip force, the preamplifier automatically records the maximum value of the pulling force and displays it on the LCD screen. After the measurement was completed, the mean value of the maximum pulling force of each animal was calculated. The test was conducted 3 times for each animal.

Histopathology

[0072] Immunofluorescence staining for tyrosine hydroxylase (TH) positive neurons and ionized calcium binding adaptor molecule 1 (Ibal) positive microglia were performed in the substantia nigra (SN) and striatum (Str) of mouse brain. Interleukin-6 (IL-6) level was assessed from tissues of the substantia nigra and striatum regions. Pharmacokinetics of the TYK2/JAK1 inhibitor was determined. Results

Behavioral tests

[0073] The results of the behavioral tests are illustrated in FIGS. 1-3. In the figures, *, **, and *** mean p < 0.05, p < 0.01, orp < 0.001 versus Model.

[0074] Compared to the Sham group, the total movement distance, the time on the rotarod, and the peak grip strength were significantly decreased (P < 0.001) in the Model group, demonstrating the successful establishment of the disease model.

[0075] Behavioral tests (grip strength, open field, rotarod test) showed that compromised behavior was manifested in mice 6 weeks after AAV-hm-A53T-a-Syn injection, and the TYK2/JAK1 inhibitor showed inhibitory effects on hm-A53T-a-Syn induced behavioral abnormalities. Compared to the Model group, administration of Compound 1 at 10 mg/kg, 30 mg/kg, and 90 mg/kg twice-daily increased the movement distance in open field by 36.8%, 61.4%, and 65.4%, the time on the rotarod by 14.8%, 64.4%, and 31.7%, and the maximal force in grip strength test by 48.5%, 47.5%, and 53.2% respectively.

[0076] Results from this study demonstrate the therapeutic efficacy of the TYK2/JAK1 inhibitor in inhibiting the behavioral abnormalities in PD model mice induced by AAV-hm- A53T-a-Syn injection.

TH staining in Str and SN regions

[0077] The results are shown in FIG. 4 and FIG. 5.

[0078] Compared to the Model group, the number of TH+ cells in the SN brain region of mice in the TYK2/JAK1 inhibitor 10 mpk and 30 mpk groups was significantly increased, and the difference was substantially significant (P < 0.001); the fluorescence intensity of TH+ neurons in the nerve endings of Str region was also significantly increased, and the difference was substantially significant (P < 0.001).

[0079] The results indicate that the TYK2/JAK1 inhibitor treatment can reverse neuron death, as indicated by increased TH+ dopaminergic neurons in SN region, and decreased nerve ending damage of dopaminergic neurons in Str region.

Ibal staining in Str and SN regions

[0080] The results are summarized in FIG. 6 and FIG. 7. [0081] Compared to the Model group, the number of Ibal+ cells in the Str and SN brain regions of mice in the TYK2/JAK1 inhibitor 10 mpk and 30 mpk groups significantly reduced, and the difference was highly significant (P < 0.001).

[0082] The results demonstrate the inhibitory effects on neuroinflammatory signatures, including microglia activation. The TYK2/JAK1 inhibitor treatment can mitigate microglia activation represented by reduced numbers of Ibal+ microglia in SN and Str.

IL-6 level in Str and SN tissues

[0083] The results are illustrated in FIG. 8. IL-6 levels in Str and SN tissues were significantly lower in mice treated with the TYK2/JAK1 inhibitor (10 mpk and 30 mpk), compared to the Model group (P < 0.01). Accordingly, the TYK2/JAK1 inhibitor treatment alleviated inflammation response in brain as exemplified by decreased expression of pro- inflammatory cytokine IL-6 compared to the Model Group.

Conclusion

[0084] The TYK2/JAK1 inhibitor is a highly selective, brain-penetrant TYK2/JAK1 inhibitor. The TYK2/JAK1 inhibitor is efficacious in an a-Syn overexpressing PD mouse model, represented by reduced PD-related motor behavior, decreased neuroinflammation response and reversed neuron cell death.

EXAMPLE 2

Objective

[0085] The objective of the example is to use the data from Study 1 and Study 2 to evaluate safety and tolerability, plasma pharmacokinetics, cerebrospinal fluid (CSF), and pharmacodynamics of the TYK2/JAK1 inhibitor.

Methods

[0086] Study 1 and Study 2 are each a single-center, phase 1, double-blind, placebo- controlled study conducted in healthy adult males and females aged 18-55 years.

[0087] In Study 1 single ascending dose (SAD) phase: 8 participants randomized 3: 1 received one dose of either the TYK2/JAK1 inhibitor (10, 20, or 30 mg) or placebo. In Study 1 multiple ascending dose (MAD) phase, 8 participants randomized 3 : 1 received either the TYK2/JAK1 inhibitor (6, 10, or 20 mg) or placebo by mouth once daily for 14 days. Plasma PK samples were collected up to 72 hours post-dosing in the SAD and MAD phases. Inflammatory biomarkers were collected pre-dosing (Days 1 and 14) and 24 hours postdosing (Day 15).

[0088] In Study 2, 10 participants randomized 3:1 received the TYK2/JAK1 inhibitor (20 mg) or placebo by mouth once daily for 7 days. CSF PK samples were collected at 6 hours (Day 6) and 24 hours (Day 8) post-dosing.

[0089] All PK data were analyzed with a validated liquid chromatography/mass spectrometry assay, and PK parameters were calculated using noncompartmental methods.

[0090] Evaluations of safety included adverse event (AE) monitoring, clinical laboratory tests, vital signs, electrocardiograms (ECGs), physical examinations, and the Columbia Suicide Severity Rating Scale.

Results

Safety

[0091] The results indicate that the TYK2/JAK1 inhibitor has generally been safe and well tolerated, with rates of adverse events (AEs) comparable to placebo, no serious AEs, and no dose-limiting changes in laboratory parameters, vital signs, or ECG findings.

Pharmacokinetics

Overall Summary of PK

[0092] Median Tmax ranged from 4 to 6 hours. The geometric mean half-life for Compound 1 ranged from 11 to 14 hours. Low to moderate PK variability was observed.

Single-Dose Plasma PK

[0093] As shown in FIG. 9, increasing the dose of the TYK2/JAK1 inhibitor resulted in a general trend of increased drug exposure. The TYK2/JAK1 inhibitor demonstrated sustained concentrations over time, supporting once-daily dosing.

Multiple-Dose Plasma and CSF PK

[0094] The accumulation ratio at steady state for AUC and Cmax was ~1.8-fold across the MAD cohorts as shown in FIG. 10 and the table below.

[0095] Mean exposures in the CSF remained above the target half-maximal inhibitory concentration through 24 hours post-dose in the MAD study arm as show in FIG. 11 and FIG. 12. The results show that brain PK sustained above EC50 for 24 hours at 20 mg QD.

Table Compound 1 Steady-State Plasma Cmax and AUC

Pharmacodynamics

Serum PD Biomarkers

[0096] As shown in FIGS. 13-15, there were greater reductions from baseline in IFN-y- inducible protein 10 kDa (IP-10), high-sensitivity C-reactive protein (hsCRP), and IFN-B in each the TYK2/JAK1 inhibitor cohort versus placebo. The results indicate that the TYK2/JAK1 inhibitor effectively reduces inflammatory biomarker levels.

Conclusion

[0097] The TYK2/JAK1 inhibitor is a first-in-class inhibitor with the potential to interrupt peripheral and central hyperactive immune responses that drive progression of neurodegenerative disorders. In the clinic, Compound 1 has generally been safe and well tolerated. The PK data show effective brain penetration and support once-daily oral dosing. [0098] Set forth below are various aspects of the disclosure.

[0099] Aspect 1. A method of treating an alpha-synucleinopathy in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof. [0100] Aspect 2. The method of aspect 1, wherein the alpha-synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy, or a combination thereof. [0101] Aspect 3. The method of aspect 1, wherein the alpha-synucleinopathy is Parkinson’s disease.

[0102] Aspect 4. The method of any of aspects 1 to 3, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 90 mg once per day.

[0103] Aspect 5. The method of any of aspects 1 to 4, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 50 mg once per day.

[0104] Aspect 6. The method of any of aspects 1 to 4, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 30 mg once per day.

[0105] Aspect 7. The method of any of aspects 1 to 6, wherein the dual TYK2/JAK1 inhibitor is administered to the patient in a pharmaceutical composition comprising a carrier and the dual TYK2/JAK1 inhibitor. [0106] Aspect 8. The method of any of aspects 1 to 7, wherein the dual TYK2/JAK1 inhibitor is administered to the patient orally.

[0107] Aspect 9. A method of providing neuroprotection to the central or peripheral nervous system of a patient in need of such neuroprotection, the method comprising administering to the patient a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof.

[0108] Aspect 10. The method of aspect 9, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 90 mg per day.

[0109] Aspect 11. The method of any of aspects 9 to 10, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 50 mg per day.

[0110] Aspect 12. The method of any of aspects 9 to 11, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 30 mg per day.

[0111] Aspect 13. The method of any of aspects 9 to 12, wherein the dual TYK2/JAK1 inhibitor is administered to the patient once a day.

[0112] Aspect 14. The method of any of aspects 9 to 13, wherein the dual TYK2/JAK1 inhibitor is administered to the patient in a pharmaceutical composition comprising a carrier and the dual TYK2/JAK1 inhibitor.

[0113] Aspect 15. The method of any of aspects 9 to 14, wherein the dual TYK2/JAK1 inhibitor is administered to the patient orally.

[0114] Aspect 16. The method of any of aspects 9 to 15, wherein providing neuroprotection treats a neurodegenerative disease.

[0115] Aspect 17. The method of aspect 16, wherein the neurodegenerative disease is Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy.

[0116] Aspect 18. The method of aspect 16, wherein the neurodegenerative disease is Parkinson’s disease.

[0117] The composition and method can alternatively comprise, consist of, or consist essentially of, any appropriate materials or steps herein disclosed. The composition and method can additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any materials (or species), or steps, which are otherwise not necessary to the achievement of the function or objectives of the composition and method.

[0118] All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. [0119] While particular embodiments have been described, alternatives, modifications, variations, improvements, and substantial equivalents that are or may be presently unforeseen may arise to applicants or others skilled in the art.

Claims

CLAIMS What is claimed is:

1. A method of treating an alpha-synucleinopathy in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof:

Formula I.

2. The method of claim 1, wherein the alpha-synucleinopathy is Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy, or a combination thereof.

3. The method of claim 1, wherein the alpha-synucleinopathy is Parkinson’s disease.

4. The method of any of claims 1 to 3, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 90 mg once per day.

5. The method of any of claims 1 to 4, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 50 mg once per day.

6. The method of any of claims 1 to 4, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 30 mg once per day.

7. The method of any of claims 1 to 6, wherein the dual TYK2/JAK1 inhibitor is administered to the patient in a pharmaceutical composition comprising a carrier and the dual TYK2/JAK1 inhibitor.

8. The method of any of claims 1 to 7, wherein the dual TYK2/JAK1 inhibitor is administered to the patient orally.

9. A method of providing neuroprotection to the central or peripheral nervous system of a patient in need of such neuroprotection, the method comprising administering to the patient a dual TYK2/JAK1 inhibitor, wherein the dual TYK2/JAK1 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof:

Formula I.

10. The method of claim 9, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 90 mg per day.

11. The method of any of claims 9 to 10, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 50 mg per day.

12. The method of any of claims 9 to 11, wherein the dual TYK2/JAK1 inhibitor is administered to the patient at a dose of 10 mg to 30 mg per day.

13. The method of any of claims 9 to 12, wherein the dual TYK2/JAK1 inhibitor is administered to the patient once a day.

14. The method of any of claims 9 to 13, wherein the dual TYK2/JAK1 inhibitor is administered to the patient in a pharmaceutical composition comprising a carrier and the dual TYK2/JAK1 inhibitor.

15. The method of any of claims 9 to 14, wherein the dual TYK2/JAK1 inhibitor is administered to the patient orally.

16. The method of any of claims 9 to 15, wherein providing neuroprotection treats a neurodegenerative disease.

17. The method of claim 16, wherein the neurodegenerative disease is Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy.

18. The method of claim 16, wherein the neurodegenerative disease is Parkinson’s disease.