Compositions and methods for treating Lewy body dementia

Abstract

The present invention provides methods and compositions for the treatment of dementia with Lewy bodies. The present disclosure encompasses the discovery that selective p38α mitogen-activated protein kinase (MAPK) inhibitors can be used to prevent, restore, or inhibit the loss of cholinergic neuronal input to the hippocampus. In particular, it has been found that treatment with the selective p38α mitogen-activated protein kinase (MAPK) inhibitor neflamapimod can improve the survival of cholinergic neurons in the medial septum, a brain region underlying the pathological sequelae of dementia with Lewy bodies (DLB).

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 873,813, filed Jul. 12, 2019, the entire content of which is incorporated herein by reference.

Background Art

[0002] Background Lewy body dementia (DLB) is the second most common dementia after Alzheimer's disease, and there is still no approved treatment to address this progressive disorder.

Summary of the Invention

Means for Solving the Problems

[0003] Summary This disclosure encompasses the discovery that selective p38α mitogen - activated protein kinase (MAPK) inhibitors can be used to prevent, reverse, or inhibit the loss of cholinergic neuronal input to the hippocampus. In particular, treatment with nepicastat, a selective p38α mitogen - activated protein kinase (MAPK) inhibitor, has been found to improve the survival of cholinergic neurons in the medial septum, a brain region underlying the pathological sequelae of Lewy body dementia (DLB).

[0004] In some embodiments, a method of treating a subject having Lewy body dementia (DLB) is provided, the method comprising administering to the subject a selective p38α mitogen - activated protein kinase (MAPK) inhibitor.

[0005] In some embodiments, a method of reversing synapse dysfunction associated with α - synuclein in a subject is provided, the method comprising administering to the subject a selective p38α mitogen - activated protein kinase (MAPK) inhibitor.

[0006] In some embodiments, a method of treating an α-synuclein-related neurodegenerative disorder in a subject, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor is provided.

[0007] In some embodiments, a method for inhibiting neuronal loss in the central nervous system of a subject, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor is provided.

[0008] In some embodiments, a method for reversing endosomal dysfunction in a subject having DLB, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor is provided.

[0009] In some embodiments, the selective p38α mitogen-activated protein kinase (MAPK) inhibitor is nepicastat.

[0010] In some embodiments, the synaptic dysfunction includes dysfunction in the medial septum.

[0011] In some embodiments, the neuronal cell loss is in the hippocampus. In some embodiments, the neuronal cell loss is in the CA2-3 region of the hippocampus. In some embodiments, the neuronal cell loss is in the medial septum. In some embodiments, the neuronal cell loss is in the vertical limb of the diagonal band of Broca. In some embodiments, the neuronal cells are cholinergic neurons.

[0012] In some embodiments, the subject to be treated has α-synuclein deposits in the hippocampus.

Brief Description of the Drawings

[0013] Brief Description of the Drawings

Figure 1

[0014]

Figure 2-1

Figure 2-2

[0015]

Figure 3-1

Figure 3-2

Best Mode for Carrying Out the Invention

[0016] Definition Carrier: As used herein, the term "carrier" refers to any chemical entity that can be incorporated into a composition containing an active agent (e.g., a p38 MAPKα inhibitor (e.g., nepamapimod)) without significantly interfering with the stability and / or activity of the agent (e.g., the biological activity of the agent). In certain embodiments, the term "carrier" refers to a pharmaceutically acceptable carrier.

[0017] Formulation). As used herein, the term "formulation" refers to a composition containing at least one active agent (e.g., a p38 MAPKα inhibitor (e.g., nepamapimod)) together with one or more carriers, excipients, or other pharmaceutical additives for administration to a patient. Generally, specific carriers, excipients, and / or other pharmaceutical additives are selected according to the knowledge in the art to achieve the desired stability, release, distribution, and / or activity of the active agent, which is appropriate for a particular route of administration.

[0018] A 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 formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0019] Therapeutically effective amount and effective amount. As used herein and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of an agent mean 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 the onset of the disease, disorder or condition to be treated or to minimize one or more symptoms associated therewith (e.g., reduce its incidence and / or magnitude). In some embodiments, a composition can 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 treatment regimen. In some embodiments, a composition can be said to contain a "therapeutically effective amount" of an agent if it contains an amount that is effective when administered as more than one dose (e.g., 2 doses, 3 doses, or 4 or more doses) within the context of a treatment regimen. In some embodiments, a therapeutically effective amount is an amount that, when administered as part of a dosing regimen, has the potential, statistically, to delay the onset of a disease, disorder or condition or to minimize one or more symptoms or side effects thereof (reduce its incidence and / or magnitude).

[0020] Treat or treating. The term "treat" or "treating" as used herein means to partially or completely alleviate, inhibit, delay the onset of, reduce the incidence of, prevent the occurrence of, ameliorate and / or reduce or reverse a disorder, disease, or condition or one or more symptoms or manifestations of the foregoing disorder, disease, or condition.

[0021] Unit dosage. As used herein, the term "unit dosage" refers to physically discrete units of a formulation suitable for the subject to be treated (e.g., for a single dosage); each unit contains a predetermined amount of the active agent selected to produce the desired therapeutic effect when administered according to a treatment regimen (it is understood that multiple dosages may be required to achieve the desired or optimal effect), together with a pharmaceutically acceptable carrier, if necessary, which may be provided in a predetermined amount. The unit dosage may be, for example, the volume of a liquid (e.g., an acceptable carrier) containing a predetermined amount of one or more therapeutic agents, a solid form containing a predetermined amount of one or more therapeutic agents (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 is recognized that the unit dosage may contain various components in addition to the therapeutic agent. For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffering agents, preservatives, etc. may be included as follows. However, it is understood that the total daily use of the formulations of the present invention is determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular subject may depend on a variety of factors including: the disorder being treated and the severity of the disorder; the activity of the specific active compound being used; the specific composition being used; the age, weight, general health, gender and diet of the subject; the time of administration, and the rate of excretion of the specific active compound being used; the duration of treatment; drugs and / or additional therapies used in combination with or simultaneously with the specific compound being used, as well as similar factors well known in the medical arts. In some embodiments, the unit dosage of a p38 MAPKα inhibitor (e.g., nepamipimod) 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, 100 mg, 125 mg, or 250 mg.

[0022] Detailed description of certain embodiments The present invention provides, inter alia, compositions and methods for treating dementia with Lewy bodies (DLB) and related pathologies by administering a composition comprising a selective p38 MAPKα inhibitor. In some embodiments, the selective p38 MAPKα inhibitor is nepicastat.

[0023] In some embodiments, the present invention provides compositions and methods for treating a subject suspected of having or at risk of developing or progressing DLB.

[0024] Various aspects of the present invention are described in detail in the following sections. The use of the sections is not meant to limit the invention. Each section can apply to any aspect of the invention. In this application, the use of "or" means "and / or" unless stated otherwise.

[0025] Dementia with Lewy bodies Currently, there are no treatments available for DLB to reverse and / or slow disease progression. Therapeutic interventions that target synaptic dysfunction (e.g., nepicastat) have the potential to reverse existing synaptic deficits and slow further decline.

[0026] The central feature of DLB is a progressive dementia, i.e., a decline in cognitive function associated with a functional impairment that may include memory impairment, characterized by a decrease in attention and executive function. Associated symptoms include fluctuations in attention, bradykinesia, rigidity, REM sleep disorder, visual hallucinations, anosmia, fluctuations in attention, depression, apathy, and autonomic dysfunction. DLB is associated with the deposition of α-synuclein in cells (known as Lewy bodies or Lewy neurites).

[0027] Hippocampal pathology exists in both DLB and AD, and memory impairment can be a prominent symptom of both disorders. However, the symptoms and pathology of DLB are different from AD in important respects. For example, in DLB, Lewy body-related neurites can be found in the CA2-CA3 region of the hippocampus, an area that has been found to be relatively preserved anatomically in AD (Fujishiro et al., Acta Neuropathol, 111:109-1114 (2006).

[0028] The medial septum (also known as Ch1) and the vertical limb of the diagonal band (also known as Ch2) provide cholinergic innervation to the hippocampus. Loss of neurons in the medial septal nucleus and the vertical limb of the diagonal band is a specific feature of DLB that distinguishes it from AD (Fujishiro et al., Acta Neuropathol, 111:109-1114 (2006). It has been discovered herein that loss of cholinergic neurons in the medial septum can be inhibited by administration of nepamipimod, a selective p38α MAPK inhibitor.

[0029] Nepamipimod Many extracellular stimuli (including pro-inflammatory cytokines and other inflammatory mediators) induce specific cellular responses through activation of the mitogen-activated protein kinase (MAPK) signaling pathway. MAPK is a proline-directed serine-threonine kinase that transmits environmental stimuli to the nucleus. Once activated, MAPK activates other kinases or nuclear proteins (including potential transcription factors and substrates) through phosphorylation. Four isoforms of p38 MAP kinase (α, β, δ, and γ) comprise a specific family of MAPKs that mediate responses to cellular stress and inflammatory signals. Nepamipimod is a selective small molecule inhibitor of the α isoform of p38 MAPK.

Chemical formula

[0030] Pharmaceutical composition In some embodiments, the provided method comprises administering to a patient a pharmaceutical composition comprising nepicastat together with one or more therapeutic agents and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the invention provides a pharmaceutical composition comprising a dosage of nepicastat together with one or more therapeutic agents and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the dosage of nepicastat results in an average blood concentration of about 1 ng / mL to about 15 ng / mL, about 1 ng / mL to about 10 ng / mL, about 5 ng / mL to about 15 ng / mL, or about 5 ng / mL to about 10 ng / mL. In some embodiments, the dosage of nepicastat results in an average blood concentration of 8 ng / ml. Table 2 of WO 2017 / 185073 illustrates nepicastat plasma concentration values by post-administration collection time intervals and is incorporated herein by reference.

[0031] It should also be understood that the specific dosage and treatment regimen for any particular patient depends on a variety of factors including the activity of the specific compound being used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of the compound of the invention in the composition also depends on the specific compound in the composition.

[0032] Administration In some embodiments, the composition is administered in a therapeutically effective amount and / or according to an administration regimen that correlates with a particular desired outcome (e.g., treating a disease or reducing the risk of a disease).

[0033] In some embodiments, the provided composition is administered in a therapeutically effective amount and / or according to an administration regimen that correlates with a particular desired outcome (e.g., reduction, etc.).

[0034] Alternatively or additionally, in some embodiments, an appropriate dosage or amount is determined through the use of one or more in vitro or in vivo assays to help identify the desired or optimal dosage range or amount to be administered.

[0035] In various embodiments, the compositions provided are administered in a therapeutically effective amount. Generally, a therapeutically effective amount is sufficient to achieve a meaningful benefit (e.g., treating, modulating, curing, preventing, and / or ameliorating an underlying disease or condition) to the subject. In some embodiments, a method of treating a subject having DLB includes administering a therapeutically effective amount of a selective p38α inhibitor. In some embodiments, a method of treating a subject having DLB includes administering a therapeutically effective amount of nepicastat.

[0036] In some embodiments, the composition is provided as a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation is a unit dosage or contains a unit dosage for administration according to an administration regimen correlated with achieving disease reduction in the symptoms of DLB, halting or reducing the rate of functional decline due to DLB.

[0037] In some embodiments, a formulation comprising the composition provided as described herein is administered as a single dose. In some embodiments, a formulation comprising the composition provided as described herein is administered as two doses. In some embodiments, a formulation comprising the composition provided as described herein is administered at regular intervals. Administration "at intervals," as used herein, indicates that a therapeutically effective amount is administered periodically (as distinguished from a single dose). The intervals can be determined by standard clinical techniques. In some embodiments, a formulation comprising the composition provided as described herein is administered twice a week, three times a week, once every two days, daily, twice a day, or every eight hours.

[0038] In some embodiments, a formulation comprising the provided composition as described herein is administered twice a day. In some embodiments, the twice-daily administration occurs about 9 to 15 hours apart. In some embodiments, the twice-daily administration occurs about 12 hours apart. In some embodiments, a formulation comprising about 40 mg to about 250 mg of neflamapimod is administered twice a day. In some embodiments, the administration occurs when the patient is in a fed state. In some embodiments, the administration occurs within 30 to 60 minutes after the subject has ingested food. In some embodiments, the administration occurs when the patient is in a fasting state. The dosing interval for an individual need not be a fixed interval, but can vary over time depending on the needs of the individual.

[0039] In some embodiments, a formulation comprising the provided composition as described herein is administered at regular intervals. In some embodiments, a formulation comprising the provided composition as described herein is administered at regular intervals over a defined period. In some embodiments, a formulation comprising the provided composition 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, 1 month, 3 weeks, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, a formulation comprising the provided composition as described herein is administered at regular intervals for 16 weeks.

Example

[0040] Illustration The following examples are provided for illustrative purposes and are not intended to limit the scope of the invention.

[0041] Example 1 Wild-type (WT) or Ts2 mice were treated twice daily for 28 days with vehicle (1% Pluronic F108) or 3 mg / kg nepicastat in vehicle (n = 8 - 10 / group; 1:1 female / male). Treatment was initiated at 4.7 - 6.4 months of age when cholinergic neuron loss is occurring in Ts2 mice. Cortical Rab5+ endosome number and size, and medial septal nucleus (MSN) choline acetyltransferase (ChAT)+ neurons were quantified.

[0042] Nepicastat treatment was shown to normalize and improve cholinergic neuron degeneration in the medial septal nucleus of Ts2 mice.

[0043] Example 2 Treatment of Human Subjects with Dementia with Lewy Bodies (DLB) A phase 2 multi-site randomized double-blind placebo-controlled trial is the implementation of administering nepicastat vs. a matching placebo (randomized 1:1) with food to subjects with DLB for 16 weeks. The primary objective is to evaluate the effect of nepicastat on cognitive function as assessed in the test-specific COGSTATE neuropsychological test battery (NTB). Secondary endpoints include the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI-10), Timed Up and Go Test, and electroencephalogram (EEG) as potential biomarkers of DLB.

[0044] Administer 40 mg capsules of neflamapimod orally with food BID or TID for 16 weeks; subjects follow the BID regimen if their weight < 80 kg or the TID regimen if their weight ≥ 80 kg. The placebo comparator is a 40 mg comparable placebo capsule administered orally with food BID or TID for 16 weeks; subjects follow the BID regimen if their weight < 80 kg or the TID regimen if their weight ≥ 80 kg.

[0045] The primary outcome measure is the composite score of the test-specific COGSTATE neuropsychological test battery (NTB) that includes the COGSTATE Language Fluency test and the Category Fluency test at 16 weeks. Analyze the change from baseline to week 16 in the composite score of the test-specific Cog-state neuropsychological test battery (NTB) that includes the assessment of attention, executive function, and visuospatial function in subjects treated with neflamapimod compared to placebo-treated subjects using the repeated measures mixed model (MMRM) analysis method. Include the following six tests in the composite: (1) COGSTATE Detection test (DET), (2) COGSTATE Identification test (IDN), (3) COGSTATE One Card Learning test (OCL), (4) COGSTATE One Back test (ONB), (5) Language Fluency test, (6) Category Fluency test (CFT). Convert each score for an individual test to a z-score and then calculate the total z-score. Here each test is equally weighted. Analyze the change in the total z-score in neflamapimod vs placebo recipients. Since the analysis is based on z-scores, there is no minimum or maximum value.

[0046] The secondary outcome measure is the change in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score based on semi-quantitative scoring of each domain (box), which assesses cognitive dysfunction in dementia in milder and more progressive forms in subjects treated with nepicastat compared to placebo recipients. The domain (box) scores are calculated with respect to the Sum of Boxes score. The secondary efficacy endpoint uses the same analysis method and model as the primary endpoint.

[0047] Another secondary outcome measure is the change in the Mini-Mental State Examination (MMSE) regarding orientation, memory, concentration, language, and execution (scores range from 0 to 30, and lower scores indicate greater cognitive dysfunction) in subjects treated with nepicastat compared to placebo recipients. The secondary efficacy endpoint uses the same analysis method and model as the primary endpoint.

[0048] Another secondary outcome measure is the change in immediate and delayed memory and recognition on the International Shopping List Test (ISLT). This is used to evaluate episodic memory in subjects treated with nepicastat compared to placebo recipients. The secondary efficacy endpoint uses the same analysis method as the primary endpoint.

[0049] Another secondary outcome measure is the change in the Timed Up and Go Test (TUG), which assesses mobility in subjects treated with nepicastat compared to placebo recipients (>15 seconds score indicates the subject has an increased risk of falls). The secondary efficacy endpoint uses the same analysis method and model as the primary endpoint.

[0050] Another secondary outcome measure is the change in quantitative electroencephalogram (qEEG) parameters in awake subjects according to the 10-20 International System of Electrode placement, which is evaluated as a potential biomarker for DLB (focusing on the full waveform, particularly the relative alpha and theta wave outputs). The slowing of the dominant frequency band by qEEG over the posterior aspect of the brain is recognized as prominent in DLB, and various identified patterns can distinguish DLB from AD.

[0051] Subject Inclusion criteria include the following: Men and women aged ≥ 55 years The subject or the subject's legal representative is willing and able to provide written informed consent. According to current consensus criteria (McKeith et al., 2017), the possibility of DLB and the identified cognitive impairment, specifically one major clinical feature and DaTscan positivity. If the subject is DaTscan negative but has a past history of PSG-verified RBD, that subject is also eligible. During screening, a MMSE score of 15 - 28 (inclusive). Currently receiving cholinesterase inhibitor treatment and, when randomizing, having received such treatment for more than 3 months and at a stable dose for at least 6 weeks. The dose of cholinesterase inhibitor may not be changed during the trial, except for reducing the dose for reasons of tolerance. Normal or corrected vision and hearing sufficient to perform all aspects of cognitive and functional assessment. No history of learning disability that could interfere with their ability to complete cognitive testing. Must have a reliable informant or caregiver.

[0052] Exclusion criteria include the following: Diagnosis of any other existing central nervous system (CNS) condition other than DLB (including, but not limited to, post-stroke dementia, vascular dementia, Alzheimer's disease (AD), or Parkinson's disease (PD)). Suicidal tendency, defined as suicidal thoughts within 6 months prior to screening or at baseline, answering "yes" to items 4 and 5 on the C-SSRS, or having a history of attempted suicide in the past 2 years, or being defined by the opinion of the study investigator as having a serious risk of suicide. An active and major psychiatric disorder during the onset and / or other concomitant medical conditions that, in the opinion of the study investigator, may endanger safety and / or compliance with the study requirements. Diagnosis of alcohol or drug abuse within the past 2 years. Inadequate management of clinically significant medical illnesses (e.g., hypertension (blood pressure >180 mmHg systolic or >100 mmHg diastolic); myocardial infarction within 6 months; decompensated congestive heart failure or other major cardiovascular, pulmonary, renal, hepatic, infectious diseases, immune disorders, or metabolic / endocrine disorders or other diseases that may interfere with the assessment of drug safety). Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 × upper limit of normal (ULN), total bilirubin >1.5 × ULN, and / or international normalized ratio (INR) >1.5. Known infection with human immunodeficiency virus, hepatitis B, or hepatitis C virus. Participation in a trial of a test drug for less than 3 months or 5 half-lives of the test drug, whichever is longer, prior to enrollment in this trial. History of previous neurosurgical procedures on the brain. In the case of a male with a female partner who may be pregnant, not wishing or being unable to comply with the contraceptive requirements specified in the protocol. A female who has not reached menopause more than 1 year ago or has not undergone hysterectomy or bilateral oophorectomy / salpingo-oophorectomy, has a positive pregnancy test result during screening, and / or does not wish or is unable to comply with the contraceptive requirements specified in the protocol.

[0053] Results A total of 91 patients with mild or moderate Lewy body dementia were enrolled and randomized between October 2019 and March 2020 to receive 45 patients with 40 mg of nepicastat capsules on a blinded basis and 46 patients to receive a comparable placebo capsule. Patients were assigned to a twice-daily (BID) or three-times-daily (TID) dosing regimen based on body weight (BID if <80 kg and TID if ≥80 kg).

[0054] The COVID-19 pandemic had a major impact on the conduct of the trial from March to June 2020, as many of the sites were unable to see patients in person at their respective clinics; instead, patients were monitored remotely via telephone or video chat. With this approach, it was not possible to obtain the neuropsychological test battery (NTB; consisting of six cognitive function tests) in approximately half of the in-person visits during this approximate time period. A final analysis using a repeated measures mixed model (MMRM) could be used to account for the effects of these remote visits, whether or not there was imputation of missing data points.

[0055] From the preliminary evaluation, a strong dataset for evaluating efficacy became apparent at the 4-week time point. Beyond that time point, the availability of data decreased significantly. At the 4-week time point, a statistically significant positive treatment effect of nefampimod compared to placebo was observed for the COGSTATE Detection Test (DET) and the Language Fluency Test (LFT) (measures of attention and executive function, respectively). For the DET where a decrease represents improvement, the mean change from baseline to week 4 was +0.024 in the placebo group versus -0.024 in the nefampimod group (p = 0.031 for the difference, Wilcoxon rank sum test) (Table 1). For the LFT where an increase represents improvement, the mean change from baseline to week 4 was -1.7 in the placebo group versus +3.0 in the nefampimod group (p = 0.027 for the difference) (Table 1). For both measures, there was a dose-response where the effect was more pronounced in patients receiving the TID dosing regimen (TID versus placebo, p = 0.02 for DET and p = 0.01 for LFT).

[0056] The positive cognitive function effect of nefampimod in the TID dosing regimen was also observed for the Mini-Mental State Examination (MMSE) at week 8, which was the time point at the first treatment when the MMSE was performed. The mean change from baseline to week 8 in the MMSE where an increase represents improvement was -0.43 in the placebo group and +1.07 in the nefampimod TID patients (p = 0.033 for the difference) (Table 2). There was also a dose-response for the MMSE at week 8, and from the dose trend analysis, a significant treatment effect dependent on the dosing regimen was revealed (p = 0.041 by the Jonckheere-Terpstra statistical test). Table 1. Mean change (SD) from baseline to week 4 in cognitive function measures by treatment group

Table 1

Table 2

[0057] Combining the results, particularly when a dose response is shown, it is shown that nepicastat has a significantly beneficial effect on cognitive function in patients with Lewy body dementia.

[0058] Equivalents and ranges One of ordinary skill in the art can recognize or confirm many equivalents to the specific embodiments of the invention described herein using only routine experimentation. The scope of the present invention is not intended to be limited to the above detailed description, but rather is as set forth in the following claims. The present invention provides, for example, the following items. (Item 1) A method for treating a subject having dementia with Lewy bodies (DLB), the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 2) A method for reversing synapse dysfunction associated with α-synuclein in a subject, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 3) A method for treating an α-synuclein-related neurodegenerative disease in a subject, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 4) A method for inhibiting neuronal loss in the central nervous system of a subject, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 5) A method for reversing endosomal dysfunction in a subject having DLB, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 6) The method according to any one of Items 1 to 5, wherein the selective p38α mitogen-activated protein kinase (MAPK) inhibitor is nepicastat. (Item 7) The method according to Item 2, wherein the synapse dysfunction includes dysfunction in the medial septum. (Item 8) The method according to Item 4, wherein the neuronal cell loss is in the hippocampus. (Item 9) The method according to Item 4, wherein the neuronal cell loss is in the CA2-3 region of the hippocampus. (Item 10) The method according to Item 4, wherein the neuronal cell loss is in the medial septum. (Item 11) The method according to Item 4, wherein the neuronal cell loss is in the vertical limb of the diagonal band nucleus. (Item 12) The method according to Item 4, wherein the neuronal cells are cholinergic neurons. (Item 13) The method according to any one of the preceding items, wherein the subject has α-synuclein deposition in the hippocampus.

Claims

1. A composition for treating a subject having Lewy body dementia (DLB), comprising a selective p38α mitogen-activated protein kinase (MAPK) inhibitor, wherein the selective p38α mitogen-activated protein kinase (MAPK) inhibitor is nepicastat, and the treatment comprises inhibiting neuronal loss.

2. A composition for inhibiting neuronal loss in the central nervous system of a subject having Lewy body dementia (DLB), comprising a selective p38α mitogen-activated protein kinase (MAPK) inhibitor, wherein the selective p38α mitogen-activated protein kinase (MAPK) inhibitor is nepicastat.

3. The composition according to claim 2, wherein the neuronal loss is in the hippocampus.

4. The composition according to claim 2, wherein the neuronal loss is in the CA2-3 region of the hippocampus.

5. The composition according to claim 2, wherein the neuronal loss is in the medial septum.

6. The composition according to claim 2, wherein the neuronal loss is in the vertical limb of the nucleus of the diagonal band.

7. The composition according to claim 2, wherein the neuronal loss is in cholinergic neurons.

8. The composition according to any one of claims 1 to 7, wherein the subject has α-synuclein deposition in the hippocampus.

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