WO2022099094A1 - Compositions and methods for treating depression - Google Patents

Abstract

The present invention provides methods and compositions for treatment of depression.

Description

COMPOSITIONS AND METHODS FOR TREATING DEPRESSION CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application No.63/110,914 filed November 6, 2020, the entire content of which is incorporated herein by reference. herein. BACKGROUND [0002] Depression is a leading cause of disability in the world with more than 260 million people suffering worldwide. SUMMARY [0003] The present disclosure encompasses the discovery that p38α mitogen activated protein kinase (MAPK) inhibitors can be used to inhibit or reverse effects or symptoms of depression and/or dysphoria. In particular, it has been found that administration of a p38α MAPK inhibitor can improve mean change in depression severity score when tested in human subjects. [0004] In some embodiments, the disclosure provides methods of treating a subject having depression or one or more symptoms of depression, comprising administering to the subject a p38 mitogen activated protein kinase (MAPK) inhibitor (e.g., a p38α, p38β, p38γ, or p38δ MAPK inhibitor). [0005] In some embodiments, the depression to be treated is depression is major depressive disorder (e.g., seasonal affective depression), persistent depressive disorder, manic depression, depressive psychosis, perinatal depression, premenstrual dysphoric disorder, situational depression, or atypical depression. In some embodiments, the depression to be treated is depression is major depressive disorder (e.g., seasonal affective depression). [0006] In some embodiments, one or more symptoms of depression are deep feelings of sadness, dysphoria, dark moods, angry outbursts or irritability, loss of interest, sleep disturbances, tiredness, reduced appetite, increased appetite, weight loss, weight gain, anxiety, restlessness, slowed thinking or body movements, feelings of worthlessness, trouble concentrating, suicidal thoughts, or unexplained physical symptoms. In some embodiments, one or more symptoms of depression is dysphoria. [0007] In some embodiments, the p38α mitogen activated protein kinase (MAPK) inhibitor has greater affinity for isoform p38α than for isoforms p38β, p38δ, or p38γ. In some embodiments, the p38α mitogen activated protein kinase (MAPK) inhibitor is selective for the p38α isoform of p38 MAPK. In some embodiments, the p38α MAPK inhibitor is neflamapimod. BRIEF DESCRIPTION OF THE DRAWINGS [0008] FIG.1 shows the effect of a selective p38α MAPK inhibitor, neflamapimod, on the mean change in depression/dysphoria severity score in human subjects treated over the course of 16 weeks with 40 mg neflamapimod or placebo, twice per day (BID) or three times per day (TID). [0009] FIG.2 shows the change from baseline in depression/dysphoria FxS score in human subjects treated over the course of 16 weeks with 40 mg neflamapimod or placebo, twice per day (BID) or three times per day (TID). DEFINITIONS [0010] Carrier: The term “carrier” refers to any chemical entity that can be incorporated into a composition containing an active agent (e.g., a p38α MAPK inhibitor) without significantly interfering with the stability and/or activity of the agent (e.g., with a biological activity of the agent). In certain embodiments, the term “carrier” refers to a pharmaceutically acceptable carrier. [0011] Formulation: The term “formulation” as used herein refers to a composition that includes at least one active agent (e.g., p38α MAPK inhibitor) together with one or more carriers, excipients or other pharmaceutical additives for administration to a patient. In general, particular carriers, excipients and/or other pharmaceutical additives are selected in accordance with knowledge in the art to achieve a desired stability, release, distribution and/or activity of active agent(s) and which are appropriate for the particular route of administration. [0012] Pharmaceutically acceptable carrier, adjuvant, or vehicle: The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. [0013] Therapeutically effective amount and effective amount: As used herein, and unless otherwise specified, the terms “therapeutically effective amount” and “effective amount” of an agent refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and/or management of a disease, disorder, or condition, e.g., to delay onset of or minimize (e.g., reduce the incidence and/or magnitude of) one or more symptoms associated with the disease, disorder or condition to be treated. In some embodiments, a composition may be said to contain a “therapeutically effective amount” of an agent if it contains an amount that is effective when administered as a single dose within the context of a therapeutic regimen. In some embodiments, a therapeutically effective amount is an amount that, when administered as part of a dosing regimen, is statistically likely to delay onset of or minimize (reduce the incidence and/or magnitude of) one or more symptoms or side effects of a disease, disorder or condition. [0014] Treat or Treating: The terms “treat” or “treating,” as used herein, refer to partially or completely alleviating, inhibiting, delaying onset of, reducing the incidence of, yielding prophylaxis of, ameliorating and/or relieving or reversing a disorder, disease, or condition, or one or more symptoms or manifestations of the disorder, disease or condition. [0015] Unit Dose: The expression “unit dose” as used herein refers to a physically discrete unit of a formulation appropriate for a subject to be treated (e.g., for a single dose); each unit containing a predetermined quantity of an active agent selected to produce a desired therapeutic effect when administered according to a therapeutic regimen (it being understood that multiple doses may be required to achieve a desired or optimum effect), optionally together with a pharmaceutically acceptable carrier, which may be provided in a predetermined amount. The unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form (e.g., a tablet or capsule), a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may contain a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included. It will be understood, however, that the total daily usage of a formulation of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts. In some embodiments, a unit dose of a p38 MAPKα inhibitor is about 1 mg, 3 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60mg, 80 mg, 100 mg, 125 mg, or 250 mg. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS [0016] The present disclosure provides, among other things, compositions and methods for treating depression and/or associated symptoms thereof, by administering a composition comprising a p38α MAPK inhibitor. In some embodiments, the p38α MAPK inhibitor is a selective p38α MAPK inhibitor. In some embodiments, the p38α MAPK inhibitor is neflamapimod. [0017] In some embodiments, the disclosure provides compositions and methods for treating subjects susceptible to or at risk of developing depression (e.g., postpartum women who have suffered previously from postpartum depression). [0018] Various aspects of the disclosure are described in detail in the following sections. The use of sections is not meant to limit the disclosure. Each section can apply to any aspect of the disclosure. Depression [0019] Depression is a complex mental disorder that involves any of a multiple symptoms, e.g., feelings of sadness, dysphoria, dark moods, angry outbursts or irritability, loss of interest, sleep disturbances, tiredness, reduced appetite, increased appetite, weight loss, weight gain, anxiety, restlessness, slowed thinking or body movements, feelings of worthlessness, trouble concentrating, suicidal thoughts, or unexplained physical symptoms. The Diagnostic and Statistical Manual of Mental Disorders provides criteria for identifying a subject or patient suffering from depression. [0020] In some embodiments, depression can manifest as dysphoria. In some embodiments, dysphoria involves symptoms of depressed mood, anhedonia, guilt, suicide, fatigue, and anxiety (see e.g., Cassidy et al:PsycholMed 2000; 30:403-411). P38 MAPK [0021] Many extracellular stimuli, including pro-inflammatory cytokines and other inflammatory mediators, elicit specific cellular responses through the activation of mitogen- activated protein kinase (MAPK) signaling pathways. MAPKs are proline-targeted serine- threonine kinases that transduce environmental stimuli to the nucleus. Once activated, MAPKs activate other kinases or nuclear proteins through phosphorylation, including potential transcription factors and substrates. The four isoforms (a, b, d, and g) of p38 MAP kinase comprise one specific family of MAPKs in mammals that mediate responses to cellular stresses and inflammatory signals. [0022] Pharmacological inhibitors of p38 MAPK have been developed as potential therapeutics for a variety of disorders. These include compounds that inhibit α, β, γ, δ isoforms of p38 MAPK (pan inhibitors), such as SB239063, compounds that inhibit both α and β isoforms such as RWJ67657, and compounds that selectively inhibit the α isoform, such as neflamapimod (VX-745) and BMS582949 (for review, see Shahin et al., (2017) Future Sci OA, 3(4) FSO204). [0023] In some experimental paradigms, the pharmacological effects of pan inhibitors are distinguishable from those of isoform selective inhibitors. For example, in hippocampal cell culture, the pan p38 MAPK inhibitor SB239063 was found to be ineffective against amyloid β- derived diffusible ligand (ADDL) induced synaptotoxicity, whereas neflamapimod, a p38α selective MAPK inhibitor, showed positive effects (see Fang et al. PLoS (2018), 1-32, Amin et al., “Role of p38α MAP kinase in amyloid-β derived diffusible ligand (ADDL) induced dendritic spine loss in hippocampal neurons,” Alzheimer's Association International Conference, July 2019). However, in addition to inhibition of p38 MAPK, SB239063 has also been reported to inhibit casein kinase isoforms CKIδ and CKIε (Verkaar et al. (2011) Chem. & Biol.,18:485-494). [0024] Earlier studies in animal models of depression supported a p38 pathway as a target for treating inflammation-related depression (Zhao et al., Front Pharmacol.2018 May 15; 9:511). See also, Int. J. Mol. Sci. 2020, 21, 4833. However, clinical trials testing the effect of the p38 inhibitor, losmapimod, failed to show any efficacy for treating depression (Molecular Psychiatry (2020) 25:1275–1285; and J Psychopharmacol. 2014 Jun;28(6):570-81). Neflamapimod [0025] Neflamapimod is a selective small-molecule inhibitor of the alpha isoform of p38 MAPK.

Neflamapimod (VX-745) Pharmaceutical Compositions [0026] In some embodiments, a provided method comprises administering to a patient a pharmaceutical composition comprising a p38α MAPK inhibitor, such as neflamapimod, together with one or more therapeutic agents and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides a pharmaceutical composition comprising a dose of p38α MAPK inhibitor together with one or more therapeutic agents and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the dose of p38α MAPK inhibitor results in an average blood concentration of from about 1 ng/mL to about 15 ng/mL, from about 1 ng/mL to about 10 ng/mL, from about 5 ng/mL to about 15 ng/mL, or from about 5 ng/mL to about 10 ng/mL. [0027] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition. Dosing [0028] In some embodiments, compositions are administered in a therapeutically effective amount and/or according to a dosing regimen that is correlated with a particular desired outcome (e.g., with treating or reducing risk for disease). [0029] In some embodiments, provided compositions are administered in a therapeutically effective amount and/or according to a dosing regimen that is correlated with a particular desired outcome (e.g., reduction in symptoms of depression, etc.). [0030] Alternatively or additionally, in some embodiments, an appropriate dose or amount is determined through use of one or more in vitro or in vivo assays to help identify desirable or optimal dosage ranges or amounts to be administered. [0031] In various embodiments, provided compositions are administered at a therapeutically effective amount. As used herein, the term “therapeutically effective amount” or “therapeutically effective dosage amount” is largely determined based on the total amount of the therapeutic agent contained in the pharmaceutical compositions of the present invention. Generally, a therapeutically effective amount is sufficient to achieve a meaningful benefit to the subject (e.g., treating, modulating, curing, preventing and/or ameliorating the underlying disease or condition). [0032] In some embodiments, a composition is provided as a pharmaceutical formulation. In some embodiments, a pharmaceutical formulation is or comprises a unit dose amount for administration in accordance with a dosing regimen correlated with achievement of disease reduction in symptoms of prion disease, arrest or decrease in rate of decline of function due to prion disease. [0033] In some embodiments, a formulation comprising provided compositions as described herein is administered as a single dose. In some embodiments, a formulation comprising provided compositions as described herein is administered as two doses. In some embodiments, a formulation comprising provided compositions as described herein is administered as three doses. In some embodiments, a formulation comprising provided compositions as described herein is administered at regular intervals. Administration at an “interval,” as used herein, indicates that the therapeutically effective amount is administered periodically (as distinguished from a one-time dose). The interval can be determined by standard clinical techniques. In some embodiments, a formulation comprising provided compositions as described herein is administered twice weekly, thrice weekly, every other day, daily, twice daily, thrice daily, or every eight hours. [0034] In some embodiments, a formulation comprising provided compositions as described herein is administered once daily. In some embodiments, a formulation comprising provided compositions as described herein is administered twice daily. In some embodiments, the twice daily administering occurs from about 9 to 15 hours apart. In some embodiments the twice daily administering occurs about 12 hours apart. In some embodiments, a formulation comprising provided compositions as described herein is administered thrice daily. In some embodiments, the three times daily administering occurs from about 4 to 8 hours apart. In some embodiments, the thrice daily administering occurs from about 6 to 12 hours apart. In some embodiments the thrice daily administering occurs about 8 hours apart. In some embodiments, a formulation comprising from about 20 mg to about 250 mg of neflamapimod is administered twice daily. In some embodiments, a formulation comprising from about 20 mg to about 250 mg of neflamapimod is administered thrice daily. In some embodiments, a formulation comprising from about 40 mg to about 250 mg of neflamapimod is administered twice daily. In some embodiments, a formulation comprising from about 40 mg to about 250 mg of neflamapimod is administered thrice daily. In some embodiments, the administering occurs when the patient is in a fed state. In some embodiments, the administering occurs within 30 to 60 minutes after the subject has consumed food. In some embodiments, the administering occurs when the patient is in a fasted state. The administration interval for a single individual need not be a fixed interval, but can be varied over time, depending on the needs of the individual. [0035] In some embodiments, a formulation comprising provided compositions as described herein is administered at regular intervals. In some embodiments, a formulation comprising provided compositions as described herein is administered at regular intervals for a defined period. In some embodiments, a formulation comprising provided compositions as described herein is administered at regular intervals for 2 years, 1 year, 11 months, 10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4 months, 3 months, 2 months, a month, 3 weeks, 2, weeks, a week, 6 days, 5 days, 4 days, 3 days, 2 days or a day. In some embodiments, a formulation comprising provided compositions as described herein is administered at regular intervals for 16 weeks. [0036] In some embodiments, a p38α inhibitor is administered to a subject to provide acute treatment of depression (e.g., major depressive disorder). In some embodiments, a p38α inhibitor is administered to a subject to maintain an antidepressant response. EXEMPLIFICATION [0037] The following examples are provided for illustrative purposes and are not intended to limit the scope of the invention. Example 1 [0038] This example demonstrates the effects of a p38 MAPK inhibitor, neflamapimod, on depression in human subjects. Study design [0039] A double-blind placebo-controlled, 16-week, treatment with neflamapimod was conducted in parallel groups at 22 centers in the US and 2 centers in the Netherlands. [0040] Inclusion criteria included Mild-to-moderate (MMSE 15-28) probable dementia with Lewy bodies by consensus criteria (McKeith et al, Neurology, 2017; 89:88–100), a positive reading of DaTscan^TM, and have to have been currently receiving cholinesterase inhibitor therapy (> 3 months and stable dose > 6 weeks). If DaTscan^TM was negative, subjects could also be enrolled with history of polysomnography-confirmed REM sleep disorder (6 study participants so enrolled). The study was randomized 1:1 to 40 mg neflamapimod or matching-placebo capsules. Dosing regimen was based on weight: subjects weighing <80 kg received capsules twice-daily (BID) and those weighing ≥80 kg received capsules three-times-a-day (TID). [0041] Table 1 provides baseline characteristics of the patient or subject population. Table 1

[0042] Secondary clinical endpoints included the following: (a) International Shopping List Test (ISLT); (b) Times Up and Go Test (TUG), Ten item Neuropsychiatric Inventory (NPI- 10); and (d) Clinical Dementia Rating scale Sum-of-Boxes (CDR-SB). FIG.1 shows results of Mean Change in Depression/Dysphoria Severity Score. [0043] FIGs.1 and 2 show effect of neflamapimod on the depression/dysphoria component within the NPI-10 test. EQUIVALENTS AND SCOPE [0044] 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. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims:

Claims

CLAIMS What is claimed is: 1. A method of treating a subject having depression or one or more symptoms of depression, the method comprising administering to the subject neflamapimod. 2. The method of claim 1, wherein the depression is major depressive disorder, persistent depressive disorder, manic depression, depressive psychosis, perinatal depression, premenstrual dysphoric disorder, situational depression, or atypical depression. 3. The method of claim 2, wherein the subject has major depressive disorder. 4. The method of claim 1, wherein the one or more symptoms of depression are deep feelings of sadness, dysphoria, dark moods, angry outbursts or irritability, loss of interest, sleep disturbances, tiredness, reduced appetite, increased appetite, weight loss, weight gain, anxiety, restlessness, slowed thinking or body movements, feelings of worthlessness, trouble concentrating, suicidal thoughts, or unexplained physical symptoms. 5. The method of claim 4, wherein the one or more symptoms of depression is dysphoria. 6. The method of claim 1, wherein the daily amount of neflamapimod administered is equivalent to a dose of 40 mg (TID). 7. The method of claim 1, wherein neflamapimod is administered at a dose of 40 mg more than once per day. 8. The method of claim 7, wherein the neflamapimod is administered three times per day.