Compositions and methods for treating dementia with lewy bodies

Abstract

The present invention provides methods and compositions for treating dementia with Lewy bodies.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of the parent application having the application date of July 12, 2020, the application number of 202080063520.0, and the invention title of “Compositions and methods for treating Lewy body dementia”. This application claims priority to U.S. Provisional Application No. 62 / 873,813, filed July 12, 2019, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] Dementia with Lewy bodies (DLB) is the second most common dementia after Alzheimer’s disease, but no approved therapies exist to address this progressive condition. SUMMARY

[0003] The present disclosure encompasses the discovery that selective p38a mitogen-activated protein kinase (MAPK) inhibitors can be used to prevent, reverse, or inhibit the loss of cholinergic neurons input to the hippocampus. In particular, it has been discovered that treatment with the selective p38a mitogen-activated protein kinase (MAPK) inhibitor neflamapimod can increase the survival rate of neurons, i.e., cholinergic neurons, in the medial septum, a brain region that is a potential post-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 p38a mitogen-activated protein kinase (MAPK) inhibitor.

[0005] In some embodiments, a method of reversing synapse dysfunction associated with alpha-synuclein in a subject is provided, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

[0006] In some embodiments, a method of treating a subject for a synucleinopathy is provided, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

[0007] In some embodiments, a method for inhibiting neuronal loss in the central nervous system of a subject is provided, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

[0008] In some embodiments, a method of reversing endosomal dysfunction in a subject having DLB is provided, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

[0009] In some embodiments, the selective p38a mitogen-activated protein kinase (MAPK) inhibitor is neflumamol.

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

[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 branch 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 DESCRIPTION OF DRAWINGS

[0013] FIG. 1 Crystal structure of neflumamol (VX-745) shown as a specific inhibitor of p38a kinase activity.

[0014] FIGS. 2A-2B Oral administration of neflumamol to Ts2 mice normalizes the number of ChAT positive neurons in the medial septum nucleus. Representative images of ChAT+ neurons from the medial septum nucleus and their stereological quantification are shown, n = 7-9 mice per condition, "+" indicates the mean value; one-way ANOVA, *** P<0.005 FIGS. 3A-3B Oral administration of neflumamol normalizes the morphology (size) in the medial septum nucleus (MSN). Representative images of ChAT+ neurons from the medial septum nucleus and their size quantification are shown, n > 99 ChAT+ neurons per condition, "+" indicates the mean value; one-way ANOVA, *** P<0.005 DEFINITIONS Vector The term "carrier" refers to any chemical entity that can be incorporated into a composition containing an active agent (e.g., a p38 MAPK a inhibitor, such as neflumamol) without significantly interfering with the stability and / or activity (e.g., the biological activity) of the agent. In certain embodiments, the term "carrier" refers to a pharmaceutically acceptable carrier.

[0015] FormulationAs used herein, the term "formulation" refers to a composition for administration to a patient that includes at least one active agent (e.g., a p38 MAPK alpha inhibitor, such as neflamisod) and one or more carriers, excipients, or other pharmaceutical additives. In general, the particular carrier, excipient, and / or other pharmaceutical additives are selected on the basis of the mode of administration being used and the dosage form being employed. The composition should suitably be adapted to provide the desired stability, release, distribution, and / or activity of the active agent, and should be suitable for the particular route of administration.

[0016] 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 can be used in the compositions of this application 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.

[0017] 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 that is sufficient to provide a therapeutic benefit, for example, to delay the onset or minimize (e.g., reduce the incidence and / or degree of) one or more symptoms associated with the disease, disorder, or condition to be treated, in the treatment, prevention, and / or management of the disease, disorder, or condition. In some embodiments, a composition can be said to contain a "therapeutically effective amount" of an agent if the amount contained by the composition is effective if administered in a single dose in the context of a treatment regimen. In some embodiments, a composition can be said to contain a "therapeutically effective amount" of an agent if the amount contained by the composition is effective if administered in more than one dose (e.g., two doses, three doses, or four or more doses) in the context of a treatment regimen. In some embodiments, a therapeutically effective amount is an amount that is statistically likely to delay or minimize (reduce the incidence and / or degree of) the onset of one or more symptoms or side effects of a disease, disorder, or condition when administered as part of a dosing regimen.

[0018] Treat / Treating. As used herein, the term "treatment" refers to the partial or complete alleviation, inhibition, delay of onset, reduction in incidence, prophylactic effect, amelioration, and / or reversal of a disorder, disease, or condition, or one or more symptoms or manifestations of the disorder, disease, or condition.

[0019] Unit dose . As used herein, the expression "unit dose" refers to a physically discrete unit of formulation suitable for administration to a subject to be treated (e.g., for a single dose); each unit contains a predetermined quantity of active agent(s) selected to produce the desired therapeutic effect in association with a pharmaceutical acceptable carrier, which can be present in a predetermined amount, optionally in association with a pharmaceutical acceptable carrier, which can be present in a predetermined amount. A unit dose can be, for example, a volume of liquid containing a predetermined quantity of one or more therapeutic agents (e.g., an acceptable carrier), a predetermined quantity 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 quantity of one or more therapeutic agents, etc. It will be appreciated that a unit dose can contain components other than therapeutic agents. For example, as described below, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc. can be included. It will be appreciated, however, that the total daily usage of the formulations of the present application will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject can depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular active compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration and the rate of excretion of the particular active compound employed; the duration of the treatment; drugs and / or other therapies used in combination or coincidentally with the specific compound employed; and like factors as are well known in the medical arts. In some embodiments, the unit dose of a p38 MAPKα inhibitor, such as 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. DETAILED DESCRIPTION

[0020] The present application provides, inter alia, compositions and methods for treating Lewy body dementia (DLB) and related pathologies by administering a composition comprising a selective p38 MAPKα inhibitor. In some embodiments, the selective p38 MAPKα inhibitor is neflamapimod.

[0021] In some embodiments, the present application provides compositions and methods for treating a subject susceptible to, or at risk of developing or progressing to, DLB.

[0022] Various aspects of the application are described in detail in the following sections. The use of sections is not meant to imply a limitation of the application. Each section can apply to any aspect of the application. In this application, the use of "or" means "and / or" unless otherwise stated.

[0023] Lewy body dementia There are currently no therapies available for DLB to reverse and / or slow disease progression. Therapeutic interventions targeting synapse dysfunction, such as naftifϊnne, have the potential to reverse existing synaptic deficits and further slow functional decline.

[0024] A core feature of DLB is progressive dementia, i.e., cognitive decline associated with functional deficits, characterized by deficits in attention and executive function, but can include memory deficits. Associated symptoms include fluctuations in attention, slowness of movement, rigidity, disruption of REM sleep, visual hallucinations, loss of smell, fluctuations in attention, depression, apathy, and autonomic nervous system dysregulation. DLB is associated with alpha-synuclein deposits in cells, which are referred to as Lewy bodies or Lewy neurites.

[0025] Hippocampal pathology is present in both DLB and AD, and memory impairment can be a prominent symptom of both disorders. However, the symptoms and pathology of DLB differ from AD in some important ways. For example, in DLB, Lewy-related neurites can be found in the CA2-CA3 region of the hippocampus, an area that is found to be relatively preserved in AD at autopsy (Fujishiro et al., Acta Neuropathol, 111:109-1114 (2006)).

[0026] The medial septum (also referred to as Chl) and vertical branches of the diagonal band (also referred to as Ch2) provide cholinergic innervation to the hippocampus. Loss of neurons in the medial septum and vertical branches of the diagonal band is a particular 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 the selective p38a MAPK inhibitor naftifϊnne.

[0027] Neflamapimod Many extracellular stimuli, including proinflammatory cytokines and other inflammatory mediators, elicit specific cellular responses through the activation of mitogen-activated protein kinase (MAPK) signaling pathways. MAPKs are serine-threonine kinases that target proline, which transduce environmental stimuli to the nucleus. Once activated, MAPKs phosphorylate and activate other kinases or nuclear proteins, including potential transcription factors and substrates. The four isoforms of p38 MAP kinase (a, b, d, and g) constitute a specific MAPK family that mediates responses to cellular stress and inflammatory signals. Neflamapimod is a selective small molecule inhibitor of the a isoform of p38 MAPK. Neflamapimod (VX-745) Pharmaceutical composition In some embodiments, the provided methods comprise administering to a patient a pharmaceutical composition comprising neflamapimod with one or more therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present application provides a pharmaceutical composition comprising a dose of neflamapimod with one or more therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the dose of neflamapimod results in a mean 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 dose of neflamapimod results in a mean blood concentration of 8 ng / mL. Table 2 of WO 2017 / 185073 shows neflamapimod plasma concentration values by collection time interval post-dose, and is incorporated herein by reference.

[0028] It will also be appreciated that the 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 and susceptibility of the particular disease being treated. The amount of a compound of the present application in the composition will also depend on the particular compound in the composition.

[0029] Administering In some embodiments, the compositions are administered in a therapeutically effective amount and / or according to a dosing regimen associated with a particular desired outcome (e.g., treating a disease or reducing the risk of a disease).

[0030] In some embodiments, the provided compositions are administered in a therapeutically effective amount and / or according to a dosing regimen associated with a particular desired outcome (e.g., reducing, etc.).

[0031] Alternatively or additionally, in some embodiments, appropriate dosages or amounts are determined by using one or more in vitro or in vivo assays to help identify the desired or optimal dosage range or amount to be administered.

[0032] In various embodiments, the provided compositions are administered in a therapeutically effective amount. Generally, a therapeutically effective amount is sufficient to effectuate a meaningful benefit (e.g., treatment, modulation, cure, prevention, and / or amelioration of the underlying disease or condition) to the subject. In some embodiments, the method of treating a subject having DLB comprises administering a therapeutically effective amount of a selective p38a inhibitor. In some embodiments, the method of treating a subject having DLB comprises administering a therapeutically effective amount of neflamapimod.

[0033] In some embodiments, the compositions are provided in a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation is in an amount of or comprises a unit dose for administration according to a dosing regimen associated with achieving a reduction, containment, or slowing of the rate of functional decline caused by DLB in terms of DLB symptoms.

[0034] In some embodiments, the formulation comprising the provided compositions as described herein is administered in a single dose. In some embodiments, the formulation comprising the provided compositions as described herein is administered in two doses. In some embodiments, the formulation comprising the provided compositions as described herein is administered at regular intervals. As used herein, administration at "intervals" indicates that the therapeutically effective amount is administered periodically (as opposed to a one-time dose). The intervals can be determined by standard clinical techniques. In some embodiments, the formulation comprising the provided compositions as described herein is administered twice a week, three times a week, every other day, once a day, twice a day, or once every eight hours.

[0035] In some embodiments, the formulation comprising the provided compositions as described herein is administered twice a day. In some embodiments, the twice-a-day administration is separated by about 9 to 15 hours. In some embodiments, the twice-a-day administration is separated by about 12 hours. In some embodiments, the twice-a-day administration comprises a formulation comprising about 40 mg to about 250 mg of neflamapimod. In some embodiments, the administration is performed while the patient is in a fed state. In some embodiments, the administration is performed within 30 to 60 minutes after the subject has eaten. In some embodiments, the administration is performed while the patient is in a fasted state. The interval of administration for a single individual need not be a fixed interval, but can vary over time, depending on the needs of the individual.

[0036] In some embodiments, the formulation comprising the provided composition as described herein is administered at regular intervals. In some embodiments, the formulation comprising the provided composition as described herein is administered at regular intervals for a defined period of time. In some embodiments, the 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, the formulation comprising the provided composition as described herein is administered at regular intervals for 16 weeks.

[0037] Examples The following examples are provided for illustrative purposes and are not intended to limit the scope of the present application.

[0038] Example 1 Wild-type (WT) mice or Ts2 mice were treated with vehicle (1% Pluronic F108) or 3 mg / kg naftifϊnide in vehicle twice daily for 28 days (n = 8-10 per group; 1:1 female / male). Treatment was initiated at 4.7-6.4 months of age, when cholinergic neuron loss is present in Ts2 mice. Cortical Rab5+ endosome number and size, and medial septal nucleus (MSN) choline acetyltransferase (ChAT)+ neurons were quantified.

[0039] Naftifϊnide treatment has been shown to improve cholinergic neuron attenuation normalization in the medial septal nucleus of Ts2 mice.

[0040] Example 2 Naftifϊnide treatment of human subjects with Lewy body dementia (DLB) A Phase 2, multicenter, randomized, double-blind, placebo-controlled study of neflamapod versus matched placebo (1 : 1 randomization) with food administration of neflamapod and placebo to subjects with DLB for 16 weeks is conducted. The primary objective is to assess the effect of neflamapod on cognitive function as assessed in the study-specific COGSTATE Neuropsychological 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 a potential biomarker for DLB.

[0041] Oral administration of 40 mg neflamapod capsules with food BID or TID for 16 weeks; if subject weight < 80 kg, then the BID regimen will be followed, or if weight > 80 kg, then the TID regimen will be followed. The placebo comparator is 40 mg orally administered matched placebo capsules with food BID or TID for 16 weeks; if subject weight < 80 kg, then the BID regimen will be followed, or if weight > 80 kg, then the TID regimen will be followed.

[0042] The primary outcome measure is the composite score of the study-specific COGSTATE Neuropsychological Battery (NTB) at 16 weeks, including the COGSTATE Letter Fluency Test and Category Fluency Test. Using a mixed model repeated measures (MMRM) analysis method, the change from baseline to Week 16 in the composite score of the study-specific Cog-state Neuropsychological Battery (NTB) including assessment of attention, executive function, and visual spatial function in subjects treated with neflamapod compared to subjects treated with placebo is analyzed. The following six tests are included in the composite score: (1) COGSTATE Detection Test (DET), (2) COGSTATE Identification Test (IDN), (3) COGSTATE One Card Learning Test (OCL), (4) COGSTATE One Back Test (ONB), (5) Letter Fluency Test, (6) Category Fluency Test (CFT). Each score of the individual tests will be converted to a z-score and subsequently a total z-score will be calculated with equal weight for each test. The change in total z-score for neflamapod recipients versus placebo recipients is analyzed. Since the analysis is based on z-scores, there is no minimum or maximum.

[0043] A secondary outcome measure was the change in Clinical Dementia Rating-Box Sum of Boxes (CDR-SB) score based on semi-quantitative ratings of each domain (box) assessing cognitive impairment in both the milder and more progressive forms of dementia in subjects treated with neflamapimod compared to placebo recipients. Box scores were calculated for the sum of box scores. Secondary efficacy indicators utilized the same analysis methods and models as the primary indicator.

[0044] Another secondary outcome measure was the change in Mini-Mental State Examination (MMSE) in orientation, memory, concentration, language, and practicality (scores range from 0 to 30, with lower scores indicating greater cognitive impairment) in subjects treated with neflamapimod compared to placebo recipients. Secondary efficacy indicators utilized the same analysis methods and models as the primary indicator.

[0045] Another secondary outcome measure was the change in International Shopping List Test (ISLT) immediate and delayed recall and recognition, which is used to assess episodic memory, in subjects treated with neflamapimod compared to placebo recipients. Secondary efficacy indicators utilized the same analysis methods as the primary indicator.

[0046] Another secondary outcome measure was the change in Timed Up and Go Test (TUG), which is used to assess mobility, in subjects treated with neflamapimod compared to placebo recipients (scores > 15 seconds indicate an increased risk of falls in the subject). Secondary efficacy indicators utilized the same analysis methods and models as the primary indicator.

[0047] Another secondary outcome measure was the change in quantitative electroencephalogram (qEEG) parameters (all waveforms, with a particular focus on relative alpha and theta power) in subjects while awake according to the 10-20 International System of Electrode placement, which is being evaluated as a potential biomarker for DLB. Slowing of the dominant frequency band in the posterior regions of the brain is considered prominent in DLB, and various defined patterns can distinguish DLB from AD.

[0048] Subject Inclusion criteria included the following: Males and females > 55 years of age.

[0049] The subject or the subject's legally authorized representative was willing and able to provide written informed consent.

[0050] DLB probable and established cognitive impairment according to current consensus criteria (McKeith et al., 2017), with exactly one core clinical feature and a positive DaTscan. If the DaTscan is negative, but the subject has a history of RBD confirmed by PSG, then the subject is also eligible.

[0051] MMSE score of 15-28, inclusive, during screening.

[0052] At randomization, currently receiving cholinesterase inhibitor therapy, have received the therapy for more than 3 months, and are taking a stable dose for at least 6 weeks. The dose of cholinesterase inhibitor must not be changed during the study, except for reduction for tolerability reasons.

[0053] Have normal or corrected visual acuity and hearing sufficient to perform all aspects of cognitive and functional assessment.

[0054] Have no history of learning difficulties that would interfere with their ability to complete cognitive testing.

[0055] Must have a reliable informant or caregiver.

[0056] Exclusion criteria include the following: Have a diagnosis of any other ongoing central nervous system (CNS) condition, including but not limited to post-stroke dementia, vascular dementia, Alzheimer’s disease (AD), or Parkinson’s disease (PD), in addition to DLB.

[0057] Have suicidal ideation, defined as having active suicidal ideation within 6 months prior to screening or at baseline, defined as a response of “yes” to C-SSRS item 4 or 5, or a history of suicide attempt within the past 2 years, or in the opinion of the investigator, a serious risk of suicide.

[0058] Have a persistent major and active psychiatric disorder and / or other concurrent medical conditions that, in the opinion of the investigator, can compromise safety and / or compliance with study requirements.

[0059] Diagnosed with alcohol or drug abuse within the past 2 years.

[0060] Have clinically significant medical illnesses that are poorly controlled, such as hypertension (blood pressure > 180 mmHg (systolic) or 100 mmHg (diastolic)); myocardial infarction within 6 months; decompensated congestive heart failure or other significant cardiovascular disease, pulmonary disease, renal disease, liver disease, infectious disease, immune disorder, or metabolic / endocrine disorder, or other illness that would interfere with the assessment of drug safety.

[0061] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN), total bilirubin >1.5 x ULN, and / or international normalized ratio (INR) >1.5.

[0062] Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.

[0063] Participation in a study of an investigational drug less than 3 months or 5 half-lives of the investigational drug, whichever is longer, prior to enrollment in this study.

[0064] Prior history of neurosurgical procedures on the brain.

[0065] If male and in a relationship with a female partner of childbearing potential, unwilling or unable to comply with the contraception requirements specified in the protocol.

[0066] If female, not postmenopausal for >1 year, not undergone hysterectomy or bilateral ovariectomy / tube-ovarian resection, pregnancy test result positive during screening, and / or unwilling or unable to comply with the contraception requirements specified in the protocol.

[0067] Outcome A total of 91 patients with mild or moderate Lewy body dementia were enrolled and randomized between October 2019 and March 2020, 45 received 40 mg of naftifϊnide capsules and 46 received, on a blinded basis, matching placebo capsules. Based on body weight, patients were assigned to either a twice daily (BID) or a thrice daily (TID) dosing regimen (BID if <80 kg and TID if >80 kg).

[0068] The Covid-19 crisis had a significant impact on the conduct of the study, as between March and June 2020, many of the study sites were unable to see patients on-site at their respective clinical centers; instead, patients were monitored remotely via phone or video chat, a method that did not allow for the collection of neuropsychological battery (NTB; consisting of six cognitive tests) results during approximately half of the visits during this time frame. The final analysis, using a mixed model for repeated measures (MMRM), allowed for the impact of these remote visits to be taken into account, with and without imputation of missing data points.

[0069] Preliminary assessments showed that the dataset assessing efficacy was robust at the Week 4 timepoint, outside of which data availability dropped significantly. At the Week 4 timepoint, statistically significant positive effects of neflamapmod treatment were seen on the COGSTATE Detection Test (DET) and the Letter Fluency Test (LFT), which measure attention and executive function, respectively, compared to placebo. For the DET, where a decrease represents improvement, the mean change from baseline to Week 4 for the placebo group was +0.024, whereas for the neflamapmod group, the mean change was -0.024 (for difference, p = 0.031, Wilcoxson rank sum test) (Table 1). For the LFT, where an increase represents improvement, the mean change from baseline to Week 4 for the placebo group was -1.7, whereas for the neflamapmod group, the mean change was +3.0 (for difference, p = 0.027) (Table 1). For both measures, there was a dose response, with effects more pronounced in patients receiving the TID dosing regimen (TID vs. placebo, p = 0.02 for DET, and p = 0.01 for LFT).

[0070] At Week 8, the first timepoint at which the MMSE was administered in the treatment, a positive cognitive effect of neflamapmod in the TID dosing regimen was also seen on the Mini Mental State Examination (MMSE). In the MMSE, where an increase represents improvement, the mean change from baseline to Week 8 for the placebo group was -0.43, whereas for the neflamapmod TID patients, the mean change was +1.07 (for difference, p = 0.033) (Table 2). For the MMSE, there was also a dose response at Week 8, with a dose trend analysis showing a significant dosing regimen dependent treatment effect (p = 0.041, Jonckheere-Terpstra statistical test).

[0071] Table 1. Mean change (SD) from baseline to Week 4 in cognitive measures by treatment group. Test Placebo NFMD Detect +0.024 -0.024 Letter fluency test -1.7 +3.0 Table 2. Mean change (SD) from baseline to Week 8 in cognitive measures by treatment group. Test Placebo NFMD MMSE -0.43 +1.07 The overall results, particularly taking into account the dose response, indicate a clear beneficial effect of neflamapmod on cognition in patients with Lewy body dementia.

[0072] Equivalents and ranges Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation numerous equivalents to the specific embodiments of the application described herein. The scope of the application is not intended to be limited to the above description but is instead to be accorded the full scope consistent with the claims attached hereto.

Claims

1. A method of treating a subject having Lewy body dementia (DLB), the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

2. A method of reversing synapse dysfunction associated with alpha-synuclein in a subject, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

3. A method of treating an alpha-synuclein-related degenerative disease in a subject, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

4. A method for inhibiting neuronal loss in the central nervous system in a subject, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

5. A method of reversing endosome dysfunction in a subject having DLB, the method comprising administering to the subject a selective p38a mitogen-activated protein kinase (MAPK) inhibitor.

6. The method of any one of claims 1 to 5, wherein the selective p38a mitogen-activated protein kinase (MAPK) inhibitor is neflumamol.

7. The method of claim 2, wherein the synapse dysfunction comprises medial septum dysfunction.

8. The method of claim 4, wherein the neuronal cell loss is in the hippocampus.

9. The method of claim 4, wherein the neuronal cell loss is in the CA2-3 region of the hippocampus.

10. The method of claim 4, wherein the neuronal cell loss is in the medial septum.

11. The method of claim 4, wherein the neuronal cell loss is in the vertical branch of the diagonal band nucleus.

12. The method of claim 4, wherein the neuronal cell is a cholinergic neuron.

13. The method of any one of the preceding claims, wherein the subject has alpha synuclein deposits in the hippocampus.

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