Compositions and methods for treating dementia with lewy bodies

Abstract

To provide compositions and methods for treatment of Dementia with Lewy Bodies.SOLUTION: The present invention provides methods and compositions for treatment of Dementia with Lewy Bodies. The present disclosure encompasses the discovery that a selective p38α mitogen activated protein kinase (MAPK) inhibitor can be used to prevent, reverse, or inhibit loss of cholinergic neuron 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 neurons cholinergic neurons in the medial septum, a brain region underlying the pathological sequelae of Dementia with Lewy Bodies (DLB).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 873,813, filed July 12, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Dementia with Lewy bodies (DLB) is the second most common dementia after Alzheimer's disease, and there are currently no approved treatments to address this progressive disorder. Summary of the Invention [Means for solving the problem]

[0003] Abstract 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 cholinergic neuron survival in neurons in the medial septum, a brain region that underlies the pathological sequelae of dementia with Lewy bodies (DLB).

[0004] In some embodiments, a method of treating a subject having dementia with Lewy bodies (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 is provided for reversing synaptic dysfunction associated with alpha-synuclein in a subject, 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 alpha-synuclein-associated degenerative disease in a subject is provided, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor.

[0007] In some embodiments, a method is provided 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.

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

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

[0010] In some embodiments, the synaptic dysfunction comprises 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 nucleus. In some embodiments, the neuronal cells are cholinergic neurons.

[0012] In some embodiments, the subject to be treated has alpha-synuclein deposits in the hippocampus. [Brief explanation of the drawings]

[0013] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 shows the crystal structure of neflamapimod (VX-745), a specific inhibitor of p38α kinase activity.

[0014] [Figure 2-1] Figures 2A-2B show that oral administration of neflamapimod to Ts2 mice normalizes the number of ChAT-positive neurons in the medial septal nucleus. Representative images of ChAT+ neurons in the medial septal nucleus and their stereological quantification are shown (n = 7-9 mice for each condition; "+" indicates means; one-way ANOVA, *** P < 0.005). [Figure 2-2] Figures 2A-2B show that oral administration of neflamapimod to Ts2 mice normalizes the number of ChAT-positive neurons in the medial septal nucleus. Representative images of ChAT+ neurons in the medial septal nucleus and their stereological quantification are shown (n = 7-9 mice for each condition; "+" indicates means; one-way ANOVA, *** P < 0.005).

[0015] [Figure 3-1] Figures 3A-3B show that oral administration of neflamapimod normalizes morphology (size) in the medial septal nucleus (MSN). Representative images of ChAT+ neurons in the medial septal nucleus and their size quantification are shown (n>99 ChAT+ neurons for each condition, "+" indicates means; one-way ANOVA, *** P<0.005). [Figure 3-2] Figures 3A-3B show that oral administration of neflamapimod normalizes morphology (size) in the medial septal nucleus (MSN). Representative images of ChAT+ neurons in the medial septal nucleus and their size quantification are shown (n>99 ChAT+ neurons for each condition, "+" indicates means; one-way ANOVA, *** P<0.005). DETAILED DESCRIPTION OF THE INVENTION

[0016] definition Carrier: 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., neflamapimod)) 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 comprising at least one active agent (e.g., a p38 MAPKα inhibitor (e.g., neflamapimod)) together with one or more carriers, excipients, or other pharmaceutical additives for administration to a patient. Generally, a particular carrier, excipient, and / or other pharmaceutical additive will be selected according to knowledge in the art to achieve the desired stability, release, distribution, and / or activity of the active agent, and will be appropriate for a particular route of administration.

[0018] 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 carrier, adjuvant, or vehicle that can be used in the compositions of the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate), 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 carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat.

[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 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 the onset of or minimize (e.g., reduce the incidence and / or magnitude of) one or more symptoms associated with the disease, disorder, or condition being 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 composition may 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., two doses, three doses, or four or more doses) 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 the onset of a disease, disorder, or condition or minimize (reduce the incidence and / or magnitude of) one or more symptoms or side effects thereof.

[0020] Treat or Treating. The term "treat" or "treating," as used herein, refers to partially or completely alleviating, inhibiting, delaying the onset of, reducing the incidence of, causing prevention of, ameliorating, and / or alleviating or reversing a disorder, disease, or condition, or one or more symptoms or manifestations of said disorder, disease, or condition.

[0021] Unit Dose. As used herein, the expression "unit dose" refers to a physically discrete unit (e.g., for a single dose) of a formulation appropriate for a subject to be treated; each unit contains a predetermined amount of an active agent selected to produce the desired therapeutic effect when administered according to a treatment regimen (it being understood that multiple doses may be required to achieve the desired or optimal 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 amount 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 is recognized that a unit dose may contain various components in addition to the therapeutic agents. For example, an acceptable carrier (e.g., a pharmaceutically acceptable carrier), a diluent, a stabilizer, a buffer, a preservative, etc., as described below, may be included. However, it is understood that the total daily use of the formulation of the present invention will be determined by the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular subject may depend on various factors, including: the disorder being treated and the severity of the disorder; the activity of the specific active compound used; the specific composition used; the age, weight, general health, sex and diet of the subject; the administration time and the excretion rate of the specific active compound used; the duration of treatment; the drugs and / or additional treatments used in combination with or simultaneously with the specific compound used, and similar factors well known in the medical field.In some embodiments, the unit dose of p38 MAPK alpha inhibitor (e.g., neflamapimod) 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 MAPK α inhibitor. In some embodiments, the selective p38 MAPK α inhibitor is neflamapimod.

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

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

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

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

[0027] Hippocampal pathology is present in DLB and AD, and memory impairment can be a prominent symptom of both disorders. However, the symptoms and pathology of DLB differ from those of AD in important ways. For example, in DLB, Lewy body-associated neurites can be found in the CA2-CA3 region of the hippocampus, a region that has been found to be relatively preserved in AD at autopsy (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 neflamapimod, a selective p38α MAPK inhibitor.

[0029] Neflamapimod Many extracellular stimuli, including proinflammatory cytokines and other inflammatory mediators, induce specific cellular responses through activation of the mitogen-activated protein kinase (MAPK) signaling pathway. MAPKs are proline-targeted serine-threonine kinases that transduce environmental stimuli to the nucleus. Once activated, MAPKs activate other kinases or nuclear proteins, including potential transcription factors and substrates, through phosphorylation. The 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. Neflamapimod is a selective small-molecule inhibitor of the α isoform of p38 MAPK. [ka]

[0030] Pharmaceutical Compositions In some embodiments, provided methods include administering to a patient a pharmaceutical composition comprising neflamapimod together with one or more therapeutic agents and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present invention provides pharmaceutical compositions comprising a dose of neflamapimod together with one or more therapeutic agents and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the dose of neflamapimod produces an average blood level 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 dose of neflamapimod produces an average blood level of 8 ng / mL. Table 2 of 2017 / 185073 illustrates neflamapimod plasma concentration values by post-dose collection time interval and is incorporated herein by reference.

[0031] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body 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 a compound of the invention in the composition will also depend on the particular compound in the composition.

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

[0033] In some embodiments, provided compositions are administered in a therapeutically effective amount and / or according to a dosing regimen that correlates with a particular desired outcome (eg, reduction, etc.).

[0034] Alternatively or additionally, in some embodiments, appropriate doses or amounts are determined through the use of one or more in vitro or in vivo assays to help identify desired or optimal dosage ranges or amounts to be administered.

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

[0036] In some embodiments, the composition is provided as a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation is a unit dose or comprises a unit dose for administration according to a dosing regimen that is correlated with achieving disease reduction in DLB symptoms, stopping or reducing the rate of functional decline caused by DLB.

[0037] In some embodiments, a formulation comprising a provided composition as described herein is administered as a single dose. In some embodiments, a formulation comprising a provided composition as described herein is administered as two doses. In some embodiments, a formulation comprising a provided composition 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 a provided composition as described herein is administered twice a week, three times a week, every other day, daily, twice a day, or every 8 hours.

[0038] In some embodiments, a formulation comprising a provided composition as described herein is administered twice daily. 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 daily. In some embodiments, the administration occurs while the patient is in a fed state. In some embodiments, the administration occurs within 30 to 60 minutes after the subject ingests food. In some embodiments, the administration occurs while the patient is in a fasted state. The administration interval for a single individual need not be a fixed interval, but can vary over time depending on the needs of the individual.

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

[0040] Example The following examples are provided for illustrative purposes and are not intended to limit the scope of the present 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 neflamapimod in vehicle (n = 8-10 / group; 1:1 female / male). Treatment began at 4.7-6.4 months of age, when cholinergic neuronal loss had occurred in Ts2 mice. Cortical Rab5+ endosome number and size, as well as medial septal nucleus (MSN) choline acetyltransferase (ChAT)+ neurons, were quantified.

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

[0043] Example 2 Neflamapimod Treatment of Human Subjects with Dementia with Lewy Bodies (DLB) This Phase 2, multicenter, randomized, double-blind, placebo-controlled study will evaluate neflamapimod versus a matching placebo (randomized 1:1) administered with food for 16 weeks in subjects with DLB. The primary objective is to evaluate the effect of neflamapimod on cognitive function, as assessed by the study-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] Neflamapimod 40 mg capsules will be administered orally with food BID or TID for 16 weeks; subjects will follow the BID regimen if they weigh <80 kg or the TID regimen if they weigh ≥80 kg. The placebo comparator will be a 40 mg matched placebo capsule administered orally with food BID or TID for 16 weeks; subjects will follow the BID regimen if they weigh <80 kg or the TID regimen if they weigh ≥80 kg.

[0045] The primary outcome measure is the study-specific COGSTATE neuropsychological test battery (NTB) composite score, which includes the COGSTATE Verbal Fluency Test and Category Fluency Test, at Week 16. Changes from baseline to Week 16 in the study-specific Cog-state neuropsychological test battery (NTB) composite score, which includes assessments of attention, executive function, and visuospatial function, in neflamapimod-treated subjects compared with placebo-treated subjects will be analyzed using a repeated measures mixed model (MMRM) analysis. The following six tests will be included in the composite: (1) the COGSTATE Detection Test (DET), (2) the COGSTATE Validation Test (IDN), (3) the COGSTATE One Card Learning test (OCL), (4) the COGSTATE One Back test (ONB), (5) the Verbal Fluency Test, and (6) the Category Fluency Test (CFT). Each score on each individual test will be converted to a z-score, and then a total z-score will be calculated, with each test given equal weight. The change in total z-score in neflamapimod vs. placebo recipients will be analyzed. Because 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, which is based on semiquantitative scoring of each domain (box), assessing cognitive impairment in milder and more progressive forms of dementia in neflamapimod-treated subjects compared to placebo recipients. Domain (box) scores are calculated in terms of the Sum of Boxes score. The secondary efficacy endpoints utilize the same analytical methods and models as the primary endpoint.

[0047] Another secondary outcome measure is the change in the Mini-Mental State Examination (MMSE) for orientation, memory, concentration, language, and performance (scores range from 0 to 30, with lower scores indicating greater cognitive impairment) in neflamapimod-treated subjects compared to placebo recipients. The secondary efficacy endpoints utilize the same analytical methods and models as the primary endpoint.

[0048] Another secondary outcome measure is change in immediate and delayed memory and cognition on the International Shopping List Test (ISLT), which will be used to assess episodic memory in neflamapimod-treated subjects compared to placebo recipients. Secondary efficacy endpoints will utilize the same analytical methods as the primary endpoint.

[0049] Another secondary outcome measure is the change in the Timed Up and Go Test (TUG), which assesses mobility, in neflamapimod-treated subjects compared to placebo recipients (a score of >15 seconds indicates the subject is at increased risk of falling). Secondary efficacy endpoints utilize the same analytical methods and models 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 (focusing on all waveforms, particularly relative alpha and theta wave power), which are evaluated as potential biomarkers of DLB. Slowing of dominant frequency bands by qEEG over the posterior aspect of the brain has been recognized as prominent in DLB, and various identified patterns may distinguish DLB from AD.

[0051] Subject Inclusion criteria included: Men and women ≥ 55 years of age 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), probable DLB and identified cognitive impairment, specifically one core clinical feature and a positive DaTscan, are required. Subjects are also eligible if their DaTscan is negative but they have previously had PSG-verified RBD. MMSE score of 15–28 (inclusive) during screening. Currently receiving cholinesterase inhibitor therapy and have been receiving such therapy for more than 3 months and at least 6 weeks at a stable dose at the time of randomization. The dose of the cholinesterase inhibitor may not be changed during the study, except to reduce the dose for tolerability reasons. Have normal or corrected-to-normal vision and hearing sufficient to perform all aspects of the cognitive and functional assessment. They have no history of learning disabilities that may interfere with their ability to complete cognitive testing. There must be a trusted informant or caregiver.

[0052] Exclusion criteria included: A diagnosis of any other ongoing 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). Suicidality, defined as suicidal ideation within 6 months prior to screening or at baseline, answering yes to items 4 and 5 on the C-SSRS, or a history of a suicide attempt in the past 2 years, or being at serious risk for suicide in the investigator's opinion. Ongoing major and active psychiatric disorder and / or other concomitant medical condition that, in the opinion of the investigator, may compromise safety and / or compliance with study requirements. Diagnosis of alcohol or drug abuse within the past two years. Poorly controlled clinically significant medical conditions (e.g., hypertension (blood pressure >180 mmHg) systolic or 100mmHg diastolic); myocardial infarction within 6 months; decompensated congestive heart failure or other significant cardiovascular, pulmonary, renal, hepatic, infectious, immune, or metabolic / endocrine disorder or other disease that would prevent evaluation 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 human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection. Participation in a study of an investigational drug for less than 3 months or 5 half-lives of the investigational drug, whichever is longer, prior to enrollment in this study. History of previous brain neurosurgery. For men with female partners of childbearing potential, unwilling or unable to comply with the contraceptive requirements specified in the protocol. Women who had not reached menopause or had not undergone hysterectomy or bilateral oophorectomy / salpingo-oophorectomy >1 year prior, had a positive pregnancy test result during screening, and / or were unwilling or unable to comply with the contraceptive requirements specified in the protocol.

[0053] result A total of 91 patients with mild or moderate dementia with Lewy bodies were enrolled and randomized on a blinded basis between October 2019 and March 2020: 45 to receive 40 mg neflamapimod capsules and 46 to receive matching placebo capsules. 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 significantly impacted the conduct of the study, as many of the sites were unable to see patients on-site at their respective clinics between March and June 2020; instead, patients were monitored remotely via telephone or video chat. This approach made it impossible to obtain the neuropsychological test battery (NTB; consisting of six cognitive tests) during approximately half of the visits during this estimated time. Final analyses using mixed models for repeated measures (MMRM), with or without imputation of missing data points, can be used to account for the impact of these remote visits.

[0055] Preliminary evaluation revealed a strong data set for evaluating efficacy at week 4. Data availability decreased significantly beyond that time point. At week 4, statistically significant positive neflamapimod treatment effects compared with placebo were observed for the COGSTATE Detection Test (DET) and Verbal Fluency Test (LFT), measures of attention and executive function, respectively. For the DET, where a decrease indicates improvement, the mean change from baseline to week 4 was +0.024 in the placebo group vs. -0.024 in the neflamapimod group (p = 0.031 for difference, Wilcoxson rank sum test) (Table 1). For the LFT, where an increase indicates improvement, the mean change from baseline to week 4 was -1.7 in the placebo group vs. +3.0 in the neflamapimod group (p = 0.027 for 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 vs. placebo, p=0.02 for detection and p=0.01 for LFTs).

[0056] Positive cognitive effects of neflamapimod in the TID dosing regimen were also observed for the Mini-Mental State Examination (MMSE) at week 8, the first treatment time point at which the MMSE was administered. 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 neflamapimod TID patients (p=0.033 for the difference) (Table 2). There was also a dose-response for the MMSE at week 8, and dose-trend analysis revealed a significant dosing regimen-dependent treatment effect (p=0.041 by Jonckheere-Terpstra statistical test). Table 1. Mean changes (SD) from baseline to week 4 in cognitive function measures by treatment group [Table 1] Table 2. Mean changes (SD) from baseline to week 8 in cognitive function measures by treatment group [Table 2]

[0057] The combined results, particularly when a dose response is demonstrated, indicate that neflamapimod has a significant beneficial effect on cognitive function in patients with dementia with Lewy bodies.

[0058] Equivalents and Scope 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. It is not intended that the scope of the present invention be limited to the above detailed description, but rather is as set forth in the claims that follow. The present invention provides, for example, the following items. (Item 1) 1. A method of 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 of reversing synaptic dysfunction associated with alpha-synuclein in a subject, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 3) A method of treating an alpha-synuclein-associated degenerative disease in a subject, the method comprising administering to the subject a selective p38alpha mitogen-activated protein kinase (MAPK) inhibitor. (Item 4) A method for inhibiting neuronal loss in the central nervous system of a subject, said method comprising administering to said subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 5) A method of reversing endosomal dysfunction in a subject with DLB, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor. (Item 6) 6. The method according to any one of items 1 to 5, wherein the selective p38α mitogen-activated protein kinase (MAPK) inhibitor is neflamapimod. (Item 7) 3. The method of claim 2, wherein the synaptic dysfunction comprises dysfunction in the medial septum. (Item 8) 5. The method of claim 4, wherein the neuronal cell loss is in the hippocampus. (Item 9) 5. The method of item 4, wherein the neuronal cell loss is in the CA2-3 region of the hippocampus. (Item 10) 5. The method of claim 4, wherein the neuronal cell loss is in the medial septum. (Item 11) 5. The method of claim 4, wherein the neuronal cell loss is in the vertical limb of the diagonal band nucleus. (Item 12) 5. The method of claim 4, wherein the neuronal cell is a cholinergic neuron. (Item 13) The method of any of the preceding items, wherein the subject has alpha-synuclein deposits in the hippocampus.

Claims

[Claim 1] The invention described in the specification.

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