Methods for treating and preventing parkinson's disease

Abstract

Methods for treating and preventing Parkinson's disease have been developed wherein allopregnanolone is administered to a human in need thereof in an amount between about 2 mg and about 6 mg, preferably 4 mg per dose. The methods include administering a dosage of from 2 mg to 6 mg, preferably 4 mg, to the subject once within a 24 hour period. The dosing is repeated every seven days, or less frequently.

Description

[0001] Attorney Docket Ref: UA 25-148 PCT

[0002] METHODS FOR TREATING PARKINSON’S DISEASE CROSS-REFERENCE TO RELATED APPLICATION

[0003] This application claims the benefit of and priority to U.S. Provisional Application No.

[0004] 63 / 728,552, filed December 5, 2024, and U.S. Provisional Application No. 63 / 725,406, filed November 26, 2024, the contents of which are hereby incorporated by reference in their entirety.

[0005] STATEMENT REGARDING FEDERALLY

[0006] SPONSORED RESEARCH OR DEVELOPMENT

[0007] This invention was made with Government Support under National Institute on Aging grant numbers UF1AG046148, U01AG031115 and U01AG047222. The Government has certain rights in the invention.

[0008] FIELD OF THE INVENTION

[0009] This invention is in the field of a method of administering allopregnanolone pharmaceutical compositions for preventing and reversing neurological deficits associated with Parkinson’s disease.

[0010] BACKGROUND OF THE INVENTION

[0011] Parkinson’s disease is a brain disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. Symptoms usually begin gradually and worsen over time. As the disease progresses, people may have difficulty walking and talking. They may also have mental and behavioral changes, sleep problems, depression, memory difficulties, and fatigue.

[0012] Parkinson’s disease (PD) is a debilitating neurodeg enerative disease and growing source of disability and mortality among neurologic disorders and is the second most common neurodegenerative disease of aging.

[0013] Persons living with Parkinson’s:

[0014] Worldwide >10 million

[0015] United States >1 .2 million by 2030

[0016] Average age of diagnosis: 60

[0017] Life expectancy following diagnosis is 10-20 years.

[0018] While virtually anyone could be at risk for developing Parkinson’s, some research studies suggest this disease affects more men than women. One clear risk is age: Although most people with Parkinson’s first develop the disease after age 60, about 5% to 10% experience onset before the age of 50. Early-onset fomis of Parkinson’s are often, but not always, inherited, and some fomis have been linked to specific alterations in genes.

[0019] 1

[0020] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0021] The most prominent signs and symptoms of Parkinson’s disease occur when nerve cells in the basal ganglia, an area of the brain that controls movement, become impaired and / or die. Normally, these nerve cells, or neurons, produce an important brain chemical known as dopamine. When the neurons die or become impaired, they produce less dopamine, which causes the movement problems associated with the disease. Scientists still do not know what causes the neurons to die.

[0022] People with Parkinson’s disease also lose the nerve endings that produce norepinephrine, the main chemical messenger of the sympathetic nervous system, which controls many functions of the body, such as heart rate and blood pressure. The loss of norepinephrine might help explain some of the non-movement features of Parkinson’s, such as fatigue, irregular blood pressure, decreased movement of food through the digestive tract, and sudden drop in blood pressure when a person stands up from a sitting or lying position.

[0023] Many brain cells of people with Parkinson’s disease contain Lewy bodies, unusual clumps of the protein alpha-synuclein. Scientists are trying to better understand the normal and abnormal functions of alpha-synuclein and its relationship to genetic variants that impact Parkinson's and Lewy body dementia.

[0024] Some cases of Parkinson’s disease appear to be hereditary, and a few cases can be traced to specific genetic variants. While genetics is thought to play a role in Parkinson’s, in most cases the disease does not seem to run in families. Many researchers now believe that Parkinson’ s results from a combination of genetic and environmental factors, such as exposure to toxins.

[0025] Parkinson’s has four main symptoms: tremor in hands, arms, legs, jaw, or head; muscle stiffness, where muscle remains contracted for a long time; slowness of movement; impaired balance and coordination, sometimes leading to falls. Other symptoms may include: depression and other emotional changes, difficulty swallowing, chewing, and speaking, urinary problems or constipation, and skin problems.

[0026] The symptoms of Parkinson’s and the rate of progression differ among individuals. Early symptoms of this disease are subtle and occur gradually. For example, people may feel mild tremors or have difficulty getting out of a chair. They may notice that they speak too softly, or that their handwriting is slow and looks cramped or small. Friends or family members may be the first to notice changes in someone with early Parkinson’s. They may see that the person’s face lacks expression and animation, or that the person does not move an arm or leg normally.

[0027] People with Parkinson's disease often develop a parkinsonian gait that includes a tendency to lean forward; take small, quick steps; and reduce swinging their arms. They also may have trouble initiating or continuing movement. Symptoms often begin on one side of the body or even in one

[0028] 2

[0029] 45805241.1 Attorney Docket Ref: UA 25-148 PCT limb on one side of the body. As the disease progresses, it eventually affects both sides. However, the symptoms may still be more severe on one side than on the other.

[0030] Many people with Parkinson’ s disease note that prior to experiencing stiffness and tremor, they had sleep problems, constipation, loss of smell, and restless legs. Changes in cognition and Parkinson's disease

[0031] Some people with Parkinson’s may experience changes in their cognitive function, including problems with memory, attention, and the ability to plan and accomplish tasks. Stress, depression, and some medications may also contribute to these changes in cognition. Over time, as the disease progresses, some people may develop dementia and be diagnosed with Parkinson’s dementia, a type of Lewy body dementia. People with Parkinson’s dementia may have severe memory and thinking problems that affect daily living.

[0032] Medicines can help treat the symptoms of Parkinson’s by: increasing the level of dopamine in the brain; having an effect on other brain chemicals, such as neurotransmitters, which transfer information between brain cells, and helping control nonmovement symptoms. The main therapy for Parkinson’s is levodopa. Nerve cells use levodopa to make dopamine to replenish the brain’s dwindling supply. Usually, people take levodopa along with carbidopa, to prevent or reduce some of the side effects of levodopa therapy such as nausea, vomiting, low blood pressure, and restlessness and reduce the amount of levodopa needed to improve symptoms. Other medicines to treat Parkinson’s symptoms, including: dopamine agonists to stimulate the production of dopamine in the brain; enzyme inhibitors (e.g., MAO-B inhibitors, COMT inhibitors) to increase the amount of dopamine by slowing down the enzymes that break down dopamine in the brain; amantadine to help reduce involuntary movements; anticholinergic drugs to reduce tremors and muscle rigidity; and deep brain stimulation.

[0033] Dopaminergic therapies are the mainstay of pharmacologic treatment for Parkinson’s Disease (PD). Current therapies for PD are effective for treatment of some not all symptoms.

[0034] None modify progression or severity of underlying disease.

[0035] None restore brain health.

[0036] None regenerate the regions of the brain affected in Parkinson’s disease.

[0037] In spite of significant efforts, to date no satisfactory agents or treatment methods exist to treat Parkinson’s disease. Accordingly, there is a need for new treatment modalities directed to improving the adverse neurological conditions associated with Parkinson’ s disease.

[0038] Therefore, it is an object of the invention to provide method for the treatment or prevention of symptoms of Parkinson’s disease.

[0039] 3

[0040] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0041] SUMMARY OF THE INVENTION

[0042] Parkinson’s disease (PD) is a progressive neurodegenerative disease that currently affects ~1 million Americans with a projected yearly increase of 90,000. PD, while characterized by progressive loss of motor control, affects multiple neural systems including sleep, olfaction, taste and cognition. While considered a neurodegenerative disease of aging, idiopathic Parkinson’s often emerges early during aging, often in the 60' s with men at greater risk relative to women. Multiple neuronal populations in brain can degenerate during the course of disease and include, but not limited to, the dopamine neurons of the substantia nigra and olfactory nucleus. Therapeutics to prevent, delay and treat Parkinson’s disease (PD) remains to be achieved.

[0043] A regenerative medicine approach to restore neurons and neural networks affected in Parkinson’s is based on decades of fundamental mechanistic science, FDA-IND enabling translational research and clinical trials in Alzheimer’s disease. Building on this foundational knowledge, we are conducting an open-label clinical trial of the regenerative therapeutic, allopregnanolone (Allo), in person’s diagnosed with Parkinson’s disease (NCT06263010). Preliminary findings from brain imaging analyses indicate that after 3 months of Allo treatment, Parkinson’s participants exhibited increased MRI-based signal in two brain regions, the substantial nigra and red nucleus and increased dopamine signal in the striatum. Based on the safety profile of Allo, early indicators of functional recovery and participant interest, we sought and received FDA approval to extend the open label trial in the same participants.

[0044] Allopregnanolone targets endogenous neural stem cells and disease modifying mechanisms. Clinical data indicate a favorable safety and tolerability profile, and potential efficacy. Allopregnanolone (Allo) is a pleiotropic neurosteroid that preclinically promotes neurogenesis and restores cognitive function in AD. In addition to neurogenesis, Allo promotes myelin regeneration and promotes generation of human neural stem cells in vitro. Allo is a low molecular weight neurosteroid endogenous to the brain and blood brain barrier penetrant with abundant existing safety data in animals and humans.

[0045] Methods have been developed for administration of compositions for the treatment or prevention of symptoms associated with Parkinson’s disease. Compositions contain a-hydroxy-5oc- pregnan-20-one (also referred to as allopregnanolone, THP, Allo, or APa), a derivative, analogue or prodrug thereof, a pharmaceutically acceptable salt thereof, or combinations thereof. In some embodiments, the amount of Allo effective to alleviate one or more symptoms of PD is between about 2 mg and about 6 mg, preferably 4 mg per dose, as demonstrated by the clinical study described in the example. Suitable analogues or derivatives of THP include, but are not limited to, 3-beta- phenylethynyl derivatives of 3a-hydroxy-5a-pregnan-20-one; analogues or derivatives of

[0046] 4

[0047] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0048] 3a-hydroxy-5a-pregnan-20-one that exhibit substantially equivalent neuro-enhancing activity as 3a-hydroxy-5a-pregnan-20-one; progesterone: and progesterone-like molecules, which are either natural metabolites of progesterone or synthetic variants of progesterone, and exhibit substantially equivalent neuro-enhancing activity as 3a-hydroxy-5a-pregnan- 20-one.

[0049] The allopregnanolone can be administered in a single dose within a 24 hour period. Dosing is repeated after a refractory period of about 6 days, about 7 days, or about 8 days, for example, once every week, or less frequently (i.e., dosages are administered more than 6 days, more than 7 days, more than 8 days after the last previous dose). The effective administration periods depend on the particular neurological disease or defect being targeted. The compositions are typically administered in single administrations (orally, topically or by injection, with release of the drug into the patient being substantially complete within a 24 hour period) over an extended period of time, for example, at least about 10 weeks, preferably at least about 30 weeks, more preferably at least about 60 weeks, even more preferably at least about 72 weeks, and most preferably as long as the patient is receiving noticeable benefit from the treatment method. In one embodiment, the composition is administered once a week for at least 6 months. The formulation is significantly less effective in these patients if administered more frequently than less than six or seven days between administrations.

[0050] Compositions of Allo can be formulated for systemic delivery via enteral or parenteral administration. The compositions can further contain one or more pharmaceutically acceptable excipients, carriers, and / or additives. Administration by injection is preferred at this time.

[0051] BRIEF DESCRIPTION OF THE DRAWINGS

[0052] FIG. 1 and FIG. 2 show average percent change from baseline in DaTscan uptake data from two of four participants who completed 12 treatments with ALLO over three months.

[0053] FIG 3A are DaTscan images comparing baseline on left and after ALLO treatment on right, in two patients; mean percent change (n=4) in neuromelanin-sensitive contrast ratio in the substantia nigra and red nucleus (reference region: crus cerebri). FIG. 3B is a graph showing the average percent DaTScan change from baseline in regions of the brain in four subjects treated with a once a week infusion for a period of 12 weeks. N=4; Values reported as mean + / - SEM.

[0054] FIG. 4A is MRI evidence for regeneration and restoration in two brain regions affected in Parkinson's and in neural connectivity, the substantia nigra and red nucleus. The substantia nigra shows 12.05% increase, left; 1.22% increase, right; 6.64% increase overall. The red nucleus showed a 26.99% increase, left; 22.25% increase, right; 24.6% increase overall. FIG. 4B shows the white matter tracks of motor control having a 2% increase in baseline.

[0055] 5

[0056] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0057] DETAILED DESCRIPTION OF THE INVENTION

[0058] I. Definitions

[0059] The term “analogue”, refers to a chemical compound with a structure similar to that of another (reference compound) but differing from it in respect to a particular component, functional group, atom, etc.

[0060] The term “derivative”, refers to compounds which are formed from a parent compound by one or more chemical reaction(s).

[0061] The term “prodrug”, refers to an active drug chemically transformed into a per se inactive derivative which, by virtue of chemical or enzymatic attack, is converted to the parent drug within the body before or after reaching the site of action. Prodrugs are frequently (though not necessarily) pharmacologically inactive until converted to the parent drug. Methods for converting to drugs to prodmgs are known in the art. Suitable examples of prodrugs include, but are not limited to, ester and amide prodmgs; polyethylene glycol prodmgs with or without a linker; carbonate prodmgs; and dihydroxypropyl prodmgs. “Pharmaceutically acceptable salt”, refers to the modification of the parent compound by making the acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts. The pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," P. Heinrich Stahl and Camille G. Wermuth, Eds., Wiley-VCH, Weinheim, 2002.

[0062] 6

[0063] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0064] The term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0065] II. Compositions

[0066] A. 3a-hydroxy-5a-pregnan-20-one (APa)

[0067] In a preferred embodiment, the compositions contains a naturally occurring metabolite of progesterone, 3 a-hydroxy-5a-pregnan- 20-one ( referred to herein as Allo; APa), also known as tetrahydroprogesterone (THP), as well as the pharmaceutically acceptable salts and hydrates thereof. 3a-hydroxy-5a-pregnan-20-one (THP) is generally classified as a neurosteroid as it is produced in the central nervous system and previously has been found to be an allosteric modulator of GABA receptors.

[0068] Other suitable analogs and derivatives include variant molecules of 3a-hydroxy-5a- pregnan-20-one or substituted derivatives of 3a-hydroxy-5a-pregnan- 20-one, such as 3a-oxy derivatives, 3a-alkyl derivatives, 3a-alkenyl derivatives, 3a-ester derivatives, 3a-ether derivatives; 3ss-phenylethynyl derivatives of 3a-hydroxy-5a-pregnan- 20-one, and 3p-phenylethynyl derivatives of 3a-hydroxy-5a-pregnan-20-one, as described in Hawkinson, et al. J. Pharmacology & Experimental Therapeutics 287: 198-207 (1998); as well as steroids derivatives of the 5a pregnan- 20-one series such as those described in U. S. Patent Nos. 5,925,630; 6,143,736; and 6, 277, 838.

[0069] Analogs or derivatives of 3a-hydroxy-5a-pregnan-20-one include progesterone-like molecules that are either natural precursors or metabolites of progesterone or synthetic variants of progesterone that exhibit substantially equivalent neurogenic activity as 3 -hydroxy-5 -pregnan- 20-one. Substantially equivalent neuro-enhancing activity is defined as approximately 30% to approximately 300% of the neuro-enhancing activity of 3a-hydroxy-5a-pregnan- 20-one.

[0070] The compounds may have one or more chiral centers and thus exist as one or more stereoisomers. Such stereoisomers can exist as a single enantiomer, a mixture of diastereomers or a racemic mixture. As used herein, the term "stereoisomers" refers to compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomers" refers to two stereoisomers which are non-superimposable mirror images of one another. As used herein, the term "optical isomer" is equivalent to the term "enantiomer". As used herein the term "diastereomer" refers to two stereoisomers which are not mirror images but also not superimposable. The terms "racemate", "racemic mixture" or "racemic

[0071] 7

[0072] 45805241.1 Attorney Docket Ref: UA 25-148 PCT modification" refer to a mixture of equal parts of enantiomers. The term "chiral center" refers to a carbon atom to which four different groups are attached. Choice of the appropriate chiral column, eluent, and conditions necessary to effect separation of the pair of enantiomers is well known to one of ordinary skill in the art using standard techniques (see e.g. Jacques, J. et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc. 1981).

[0073] B. Additional active agents

[0074] The compositions can further contain one or more additional active agents. An example includes L-DOPA (levodopa) and carbidopa. L-Dopa is a dopamine replacement agent. Levodopa crosses the blood-brain barrier (BBB) and gets converted to dopamine in your central nervous system and peripheral nervous system. In some forms, the additional active agent is a dopamine agonist. Examples include, but are not limited to Pramipexole, Ropinirole and Rotigotine. Other useful active agents include, but are not limited to MAO-B inhibitors and COMT inhibitors. Examples of MAO-B inhibitor medications are selegiline and rasagiline. These slow down the activity of the enzyme that metabolizes dopamine. COMT ((catechol-O-methyltransferase) inhibitors include entacapone, tolcapone and opicapone. Providers typically prescribe them to extend the duration of the effect of levodopa. Amantadine, benserazide, or anticholinergic agents such as Benztropine mesylate, and Trihexyphenidyl, and Adenosine A2A antagonists (non- dopamingergic) such as istradefylline are additional examples of useful active agents.

[0075] C. Formulations

[0076] Formulations containing one or more of the compounds may be prepared using a pharmaceutically acceptable carrier composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions, preferably by injection although other routes may be utilized such as transdemial and intranasal or oral. The carrier is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. As generally used herein “carrier” includes, but is not limited to, diluents, binders, lubricants, disintegrators, fillers, pH modifying agents, preservatives, antioxidants, solubility enhancers, and coating compositions.

[0077] III. Methods of Use

[0078] Methods for reducing, preventing, or reversing symptoms in a subject suffering from Parkinson’s disease are provided. The methods include administering an effective amount of the composition of 3a-hydroxy-5a-pregnan-20-one, or a derivative or analog, or pharmaceutically acceptable salt thereof to the subject in an amount between about 2 mg and about 6 mg, preferably 4 mg. The methods include repeating the administration once every 7 days, or less frequently. Typically, a single dose of from 2 mg to 6 mg Allo is administered once within a 24 hour period,

[0079] 8

[0080] 45805241.1 Attorney Docket Ref: UA 25-148 PCT and the dosing is repeated once a week, or less frequently. In some embodiments, a single dose of from 2 mg to 6 mg Allo is administered repeatedly. Typically, the dose is administered once within 7 days, or less frequently, for a period of between one month and one year. In some embodiments, the composition is repeatedly administered once per week or less frequently for a period of three months, six months, 9 months, one year, or more than one year.

[0081] Methods including administering Allo in an amount of from 2 mg to 6 mg to the subject for a period of time effective to reduce the amount of 0-amyloid protein in the brain of the subject are provided. The amount of in the Allo administered in a single dose within a single 7 day period is between about 2 mg and about 6 mg, preferably between about 3 and about 5 mg, more preferably about 4 mg.

[0082] In an exemplary embodiment, a dosage of 4 mg Allo is administered via systemic route, such as by intravenous or intramuscular administration, in a manner such that the entire dosage of 4 mg is administered to the subject within a period of 1-2 hours. Administration of the same dosage of Allo is repeated once or more times to the same subject after a period of at least 6 days, such as after 7 days, after 8 days, after 9 days, or after more than 9 days. In some embodiments a dosage regimen “cycle” includes administering a first dose of an amount of Allo between about 2 mg and about 6 mg, preferably 4 mg on day 1, then no dose on day 2, no dose on day 3, no dose on day 4, no dose on day 5, no dose on day 6, no dose on day 7. A second cycle includes administering a second dose of Allo between about 2 mg and about 6 mg on day 8, then no dose on day 9, no dose on day 10, no dose on day 11, no dose on day 12, no dose on day 13, and no dose on day 14. This regimen is repeated for as many cycles as is deemed effective to treat one or more symptoms of AD, or to prevent or delay the onset of one or more symptoms of AD.

[0083] As used in this context, an "effective amount" of one or more neuro-enhancing agents is an amount that is effective to improve or ameliorate one or more symptoms associated with Parkinson’s disease. Such a therapeutic effect is generally observed within about 12 to about 24 weeks of initiating administration of a composition containing an effective amount of one or more neuro-enhancing agents, although the therapeutic effect may be observed in less than 12 weeks or greater than 24 weeks.

[0084] Symptoms associated with Parkinson’s disease which may be decreased, include, but are nor limited to decreased tremor, recovery of heal to toe walking (alleviation of dystonic pseudo foot drop), recovery of smell, improved grip and muscle strength, improved ability to conduct fine motor tasks such as buttoning a shirt, improved sleep, improved or cessation of episodes of REM Sleep Disorder, reduced rigidity, decreased fatigue and increased energy (in some forms, evidenced by increased capacity to work).

[0085] 9

[0086] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0087] The individual is a mammal suffering from Parksons, such as a canine, or a primate, and is preferably an adult human, and more preferably the human is over the age of 30, who has lost some amount of neurological function as a result of Parkinson’s disease. In some forms, the subject does not have / has not been diagnosed with Alzheimer’s disease. Generally neural loss implies any neural loss at the cellular level, including loss in neurites, neural organization or neural networks. The compositions can be administered weekly, or less frequently in an amount to provide a therapeutically effective increase in the blood level of the one or more neuro-enhancing agents. For example, the total daily dosage will be about 3-5 mg and more preferably about 4 mg when administered systemically within a 24 hour period.

[0088] In a preferred embodiment, the dosage of allopregnanolone is 4 mg administered once within a week. Therefore, a balance between optimal neurogenesis and optimal anti-amyloidogenic effects is predicted to be achievable with a once per week dosing schedule. The compositions are typically repeatedly administered for an extended period of time, for example, administered a total of 5-10 times over about 10 about weeks, a total of about 15-30 times over about 30 weeks, a total of 30-60 times over about 60 weeks, etc., and most preferably, administered regularly once per week or less frequently for as long as the patient is receiving noticeable benefit from the treatment method.

[0089] In a preferred embodiment, the composition containing one or more neuro-enhancing agents is administered to an individual as a single 4 mg dose, repeated once per week or less frequently for a period effective to produce an improvement in at least one criterion set forth as indicative of an improvement in one or more symptoms of Parkinson’s disease. Improvements include an improvement in cognitive abilities, memory, motor skills, learning or the like, preferably an improvement is observed in at least two such criteria.

[0090] The disclosed methods can be further understood in view of the following non-limiting paragraphs and examples.

[0091] 1 . A method of treating a subject with Parkinson’s disease, comprising administering in a dosing regimen of no more frequently than a period of 24 hours or less, systemic levels over a period of more than six days, a compound selected from the group consisting of 3a-hydroxy-5a- pregnan-20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof, in an amount between about 2 mg and about 6 mg, inclusive

[0092] 2 The method of paragraph 1, wherein the compound is administered at a dosage of about 4 mg.

[0093] 3. The method of paragraph 1 or 2, wherein the compound is 3a-hydroxy-5a-pregnan-20-one.

[0094] 10

[0095] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0096] 4. The method of any one of paragraphs 1-3, wherein the compound is formulated for injection.

[0097] 5. The method of any one of paragraphs 1-4, wherein the dosage of the agent is between 0.01 mg / kg to about 0.08 mg / kg body weight of a normal adult human having an average weight of 60- 70 kg.

[0098] 6. The method of any one of paragraphs 1-5 wherein the composition is administered once within a 24 hour period, and wherein the dosing is repeated once every 7 days, 8 days, 9 day, or a longer period of time.

[0099] 7. The method of paragraph 6, wherein the dosing is repeated once every 7 days.

[0100] 8. The method of paragraph 6, wherein the dosing is repeated once every 8 days.

[0101] 9. The method of paragraph 6, wherein the dosing is repeated once every 9 days.

[0102] 10. The method of any one of paragraphs 1-9, wherein 3a-hydroxy-5a-pregnan-20-one is administered in a dosage of 4 mg.

[0103] 11. The method of any one of paragraphs 1-10, wherein the subject is a human subject.

[0104] 12. The method of any one of paragraphs 1-11, wherein the compound is a derivative of 3a- hydroxy-5a-pregnan-20-one selected from the group comprising a 3a-oxy derivative, 3a-alkyl derivative, 3a-alkenyl derivative, 3a-ester derivative, 3a-ether derivative; 3ss-phenylethynyl derivative, and 3p-phenylethynyl derivative.

[0105] 13. The method of paragraph 10, wherein a dosage of 4 mg 3a-hydroxy-5a-pregnan- 20-one is administered via systemic route, in a manner such that the entire dosage of 4 mg is administered to the subject within a period of 1-2 hours.

[0106] 14. The method of any one of paragraphs 1-13, wherein the compound is administered by intravenous or intramuscular administration.

[0107] 15. fhe method of any one of paragraphs 1-14, wherein the compound is administered in a repeating regimen cycle comprising administering a first dose of an effective amount of the compound on day 1, then no dose on day 2, no dose on day 3, no dose on day 4, no dose on day 5, no dose on day 6, no dose on day 7, a second dose on day 8 then no dose on day 9, no dose on day 10, no dose on day 11, no dose on day 12, no dose on day 13, and no dose on day 14.

[0108] 16. The method of any one of paragraphs 1-15, further comprising administered at least one additional active agent to the subject.

[0109] 17. The method of paragraph 16, wherein the additional active agent is selected from the group consisting of levodopa, carbidiopa, entacapone, amantadine and benserazide.

[0110] 18. The method of paragraph 16 or 17, comprising administering one agent selected from the group consisting of a dopamine agonist, a monoamine oxidase B inhibitor, a catechol-O-

[0111] 1 1

[0112] 45805241.1 Attorney Docket Ref: UA 25-148 PCT mcthyltransfcrasc inhibitor, an anticholinergic agent and a Adenosine A2A antagonist, optionally, in an effective amount to reduce one or more symptoms of Parkinson’s disease.

[0113] Examples

[0114] Example 1: Allopregnanolone Regenerative Therapeutic For Parkinson’s Disease: Openlabel clinical trial preliminary Imaging Outcomes

[0115] Objectives:

[0116] To assess early signals of efficacy of allopregnanolone, a neurosteroid, in Parkinson’s disease (PD).

[0117] Previous preclinical data demonstrated that once-per-week treatment with allopregnanolone restored the number of tyrosine hydroxylase immunoreactive neurons and total cell counts in the nigrostriatal tract of MPTP-lesioned mice and increased BrdU-positive-cells in the substantia nigra pars compacta. In mouse models of Alzheimer’s disease (AD), it induced neurogenesis, correlated with restoration of learning and memory function, and reduced microglial activation. Previous clinical trial in AD demonstrated safety, tolerability, maximal-tolerated-dose, and feasibility for evaluation of efficacy indicators.

[0118] Methods:

[0119] A total of 10 participants have been recruited to the open-label trial (NCT06263010). Participants are males or females, age 40-80 years, with a history of idiopathic-sporadic PD or prodromal PD. Allopregnanolone 4mg was administered once-per-week via an intravenous infusion of 30-minute duration. Primary objectives are safety, tolerability, and feasibility over 12 weeks of treatment. Exploratory objectives included potential indicators of efficacy using neuroimaging measures over 12 weeks.

[0120] Neuroimaging was conducted at baseline and post-treatment. The imaging battery included high-resolution T1 and T2-weighted images, neuromelanin-sensitive 2D T1 -weighted magnetization transfer sequence, multiband / multishell diffusion-weighted sequence, and DaT- SPECT imaging. Treatment related changes were evaluated per-participant.

[0121] Results:

[0122] Five of 10 participants have completed the 12- week allopregnanolone treatment regimen. DaT-SPECT imaging outcomes indicated increased striatal dopamine transporter uptake. MRI analysis indicated increased neuromelanin signal in the substantia nigra pars compacta and red nucleus in 3 participants. One participant exhibited a substantial increase in segmented left olfactory bulb volume consistent with improved olfaction. All participants exhibited an increase in fractional anisotropy in multiple PD-relevant regions of the brain.

[0123] 12

[0124] 45805241.1 Attorney Docket Ref: UA 25-148 PCT

[0125] The results arc shown in the Figures.

[0126] FIG. 1 and 2 show average percent change from baseline in DaTscan uptake data from two of four participants who completed 12 treatments with ALLO over three months.

[0127] FIG 3A are DaTscan images comparing baseline on left and after ALLO treatment on right, in two patients. FIG. 3B is a graph showing the percent DaTScan change from baseline in regions of the brain in four subjects treated with a once a week infusion for a period of 12 weeks. ALLO Treatment: 1 / Week Infusion for 12 weeks. The data was obtained by calculating average percent change from Baseline in DaTscan uptake in 4 participants treated with ALLO. Values reported as mean + / - SEM.

[0128] FIG. 4A is MRI evidence for regeneration and restoration in two brain regions affected in Parkinson’s and in neural connectivity, the substantia nigra and red nucleus. The substantia nigra shows 12.05% increase, left; 1.22% increase, right: 6.64% increase overall. The red nucleus showed a 26.99% increase, left; 22.25% increase, right; 24.6% increase overall. FIG. 4B shows the white matter tracks of motor control having a 2% increase from baseline.

[0129] Conclusion:

[0130] Neuroimaging data indicate early signals of efficacy of allopregnanolone as a regenerative therapeutic in PD.

[0131] All patent and non-patent references cited in this specification are herein incorporated by reference as if each individual patent or non-patent reference were specifically and individually indicated to be incorporated by reference.

[0132] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

[0133] 13

[0134] 45805241.1

Claims

1. Attorney Docket Ref: UA 25-148 PCTWe claim:I. A method of treating a subject with Parkinson’s disease, comprising administering in a dosing regimen of no more frequently than a period of 24 hours or less, systemic levels over a period of more than six days, a composition comprising a compound selected from the group consisting of 3a-hydroxy-5a-pregnan- 20-one, a derivative or analog thereof, or a pharmaceutically acceptable salt thereof, in an amount between about 2 mg and about 6 mg, inclusive2 The method of claim 1, wherein the compound is administered at a dosage of about 4 mg.

3. The method of claim 1, wherein the compound is 3a-hydroxy-5a-pregnan-20-one.

4. The method of claim 1, wherein the composition is formulated for injection.

5. The method of claim 1, wherein the dosage of the agent is between 0.01 mg / kg to about 0.08 mg / kg body weight of a normal adult human having an average weight of 60-70 kg.

6. The method of claim 1, wherein the composition is administered once within a 24 hour period, and wherein the dosing is repeated once every 7 days, 8 days, 9 day, or a longer period of time.

7. The method of claim 6, wherein the dosing is repeated once every 7 days.

8. The method of claim 6, wherein the dosing is repeated once every 8 days.

9. The method of claim 6, wherein the dosing is repeated once every 9 days.

10. The method of claim 3, wherein 3a-hydroxy-5a-pregnan- 20-one is administered in a dosage of 4 mg.I I . The method of claim 1, wherein the subject is a human subject.

12. The method of claim 1, wherein the compound is a derivative of 3a-hydroxy-5a-pregnan- 20-one selected from the group comprising a 3a-oxy derivative, 3a-alkyl derivative, 3a-alkenyl derivative, 3a-ester derivative, 3a-ether derivative; 3ss-phenylethynyl derivative, and 3p- phenylethynyl derivative.

13. The method of claim 10, wherein a dosage of 4 mg 3a-hydroxy-5a-pregnan- 20-one is administered via systemic route, in a manner such that the entire dosage of 4 mg is administered to the subject within a period of 1-2 hours.

14. The method of claim 1, wherein the compound is administered by intravenous or intramuscular administration.

15. The method of claim 10, wherein the compound is administered in a repeating regimen cycle comprising administering a first dose of an effective amount of the compound on day 1, then no dose on day 2, no dose on day 3, no dose on day 4, no dose on day 5, no dose on day 6, no dose1445805241.1Attorney Docket Ref: UA 25-148 PCT on day 7, a second dose on day 8 then no dose on day 9, no dose on day 10, no dose on day 11, no dose on day 12, no dose on day 13, and no dose on day 14.

16. The method of claim 1, further comprising administered at least one additional active agent to the subject.

17. The method of claim 16, wherein the additional active agent is selected from the group consisting of levodopa, carbidiopa, entacapone, amantadine and benserazide.

18. The method of claim 16, comprising administering one agent selected from the group consisting of a dopamine agonist, a monoamine oxidase B inhibitor, a catechol-O-methyltransferase inhibitor, an anticholinergic agent and a Adenosine A2A antagonist, optionally, in an effective amount to reduce one or more symptoms of Parkinson’s disease.1545805241.1

Images