Treatment of Selected Populations of Patients with Dementia with Lewy Bodies

Abstract

The present invention provides methods and compositions for treating subjects with dementia with Lewy bodies (DLB) but without substantial tau pathology.Subjects with DLB but without substantial tau pathology are shown to be particularly responsive to treatment with selective p38α mitogen-activated protein kinase (MAPK) inhibitors compared to subjects with DLB with substantial tau pathology.In some embodiments, a method is provided for treating dementia with Lewy bodies (DLB) in subjects with DLB but without substantial tau pathology, comprising administering a selective p38α mitogen-activated protein kinase (MAPK) inhibitor to the subject.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 276,529, filed November 5, 2022, which is incorporated by reference in its entirety herein. [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 administration of the selective p38α MAPK inhibitor neflamapimod is effective in treating a selected patient population with dementia with Lewy bodies (DLB) but without substantial tau pathology. Specifically, neflamapimod was effective in treating DLB symptoms in patients without substantial tau pathology as characterized by biomarkers of tau pathology (e.g., plasma phosphorylated tau (ptau) levels). Elevated ptau levels in plasma are a surrogate measure of tau pathology in the brain, which is often associated with Alzheimer's disease pathology. It has been discovered herein that a subset of DLB ​​patients have tau pathology, while another subset of DLB ​​patients do not have substantial tau pathology, and that patients without substantial tau pathology respond differently to neflamapimod treatment. Provided herein is a method of treatment that includes administering neflamapimod to DLB patients without substantial tau pathology.

[0004] In some embodiments, a method is provided for treating dementia with Lewy bodies (DLB) in a subject who has DLB but does not have substantial tau pathology, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor.

[0005] In some embodiments, the p38α mitogen-activated protein kinase (MAPK) inhibitor is neflamapimod.

[0006] In some embodiments, the absence of substantial tau pathology in the subject is characterized by levels of ptau181 in plasma. In some embodiments, the absence of substantial tau pathology in the subject is characterized by levels of ptau217 in plasma. In some embodiments, the absence of substantial tau pathology in the subject is characterized by positron emission tomography (PET) of the brain.

[0007] In some embodiments, the absence of substantial tau pathology in a subject is associated with a lower level of amyloid beta (Aβ)42 in cerebrospinal fluid in the subject than in subjects diagnosed with Alzheimer's disease.

[0008] In some embodiments, the absence of substantial tau pathology in a subject is characterized by a level of plasma ptau that is lower than that of a subject with Alzheimer's disease or Alzheimer's disease-related pathology as measured in a Simoa ptau181 assay, or its equivalent in another assay methodology that measures plasma ptau.

[0009] In some embodiments, the absence of substantial tau pathology in a subject is characterized by ptau181 levels of less than 2.2 pg / mL in plasma. In some embodiments, the absence of substantial tau pathology in a subject is characterized by ptau181 levels of less than 2.2 pg / mL in plasma as assessed by a Simoa platform assay, or the equivalent thereof in another assay methodology.

[0010] In some embodiments, provided herein is a method of treating an alpha-synuclein associated degenerative disease in a subject who has DLB but does not have substantial tau pathology, the method comprising administering to the subject a selective p38alpha mitogen-activated protein kinase (MAPK) inhibitor.

[0011] In some embodiments, a method is provided for inhibiting neuronal loss in the central nervous system of a subject who has DLB but does not have substantial tau pathology, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor.

[0012] In some embodiments, a method is provided for reversing endosomal dysfunction in a subject with DLB but without substantial tau pathology, the method comprising administering to the subject a selective p38α mitogen-activated protein kinase (MAPK) inhibitor.

[0013] In some embodiments, the MAPK inhibitor is neflamapimod. In some embodiments, neflamapimod is administered at 40 mg TID.

[0014] In some embodiments, the subject has cholinergic neurodegeneration in the basal forebrain. In some embodiments, administration of neflamapimod results in a reduction in the symptomatic effects of cholinergic neurodegeneration in the basal forebrain of the subject.

[0015] In some embodiments, the subject has synaptic dysfunction in the medial septum, neuronal cell loss in the hippocampus, neuronal loss in the medial septum, or neuronal cell loss in the vertical limb of the diagonal band nucleus. In some embodiments, the neuronal cell loss in the hippocampus is in the CA2-3 region of the hippocampus.

[0016] In some embodiments, the subject is (a) Deficits in attention, verbal fluency, and episodic memory as measured by the Attention Composite z-score; (b) Deficits in motility as measured by Timed Up and Go (TUG); (c) Deficits in memory, orientation, judgment and problem solving, community affairs, home and hobbies performance, and personal care as measured by the Clinical Dementia Rating Scale (CDR-SB); and / or (d) deficits in neuropsychological activity as measured by the Neuropsychological Test Battery (NTB); has.

[0017] In some embodiments, the subject has alpha-synuclein deposits in the hippocampus.

[0018] In some embodiments, the subject does not have Alzheimer's disease.

[0019] In some embodiments, neflamapimod is administered to a subject with DLB and a plasma ptau181 level of less than 3 pg / mL.

[0020] In some embodiments, neflamapimod is administered to a subject with DLB and a plasma ptau181 level of less than 2.5 pg / mL.

[0021] In some embodiments, neflamapimod is administered to a subject with DLB and a plasma ptau181 level of less than 2 pg / mL.

[0022] In some embodiments, neflamapimod is administered to a subject with DLB and a plasma ptau181 level of less than 1 pg / mL.

[0023] In some embodiments, the subject is also receiving a cholinesterase inhibitor.

[0024] In some embodiments, the daily dose of neflamapimod administered is equivalent to a dose of 40 mg TID.

[0025] In some embodiments, the subject receiving neflamapimod is also receiving cholinesterase inhibitor therapy. In some embodiments, the subject having a plasma ptau level of less than 2.2 pg / mL and receiving cholinesterase therapy is administered neflamapimod at a dose of at least 40 mg TID. [Brief description of the drawings]

[0026] [Figure 1] Figure 1 shows the results of a clinical trial in subjects receiving neflamapimod for attention composite z-scores of tests within a neuropsychological test panel (NTB) that evaluates information processing speed. Data are presented as output (mean, 95% CI) of analysis change from baseline using a Mixed Model for Repeated Measures (MMRM). Improvement is reflected as an increase in NTB and attention composite z-scores.

[0027] [Diagram 2]FIG. 2A shows the clinical trial results in subjects receiving neflamapimod on the Clinical Dementia Rating Scale (CDR-SB). Data are presented as output (mean, 95% CI) of analysis change from baseline using a mixed model for repeated measures (MMRM). Improvement is reflected as a decrease in CDR-SB scores. 40 mg TID vs. placebo is plotted.

[0028] FIG. 2B shows clinical trial results in subjects receiving neflamapimod for the Timed Up and Go (TUG) study. Data are presented as output (mean, 95% CI) of analysis change from baseline using a mixed model for repeated measures (MMRM). Improvement is reflected as a reduction in time to complete the TUG study. 40 mg TID vs. placebo is plotted.

[0029] [Diagram 3] Figure 3 shows the clinical trial results in subjects receiving neflamapimod on the International Shopping List Test (ISLT). Data are presented as output (mean, 95% CI) of analysis change from baseline using a mixed model for repeated measures (MMRM). Improvement is reflected as an increase in ISLT score. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] 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 MAPK alpha 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 pharma- ceutically acceptable carrier.

[0031] Formulation: The term "formulation" as used herein refers to a composition that includes 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. In general, 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, which is appropriate for the particular route of administration.

[0032] Pharmaceutically acceptable carrier, adjuvant, or vehicle. The term "pharmaceutical 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. The pharmaceutical acceptable carrier, adjuvant, or vehicle that can be used in the composition of the present invention includes, but is not limited to, ion exchanger, alumina, aluminum stearate, lecithin, serum protein (e.g., human serum albumin), buffering substance (e.g., phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and wool fat.

[0033] 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, for example, 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 to be treated. In some embodiments, a composition may be said to contain a "therapeutically effective amount" of an agent if it contains an amount that is effective when administered as a single dose within the context of a treatment 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 treatment 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 or minimize (reducing the incidence and / or magnitude of) one or more symptoms or side effects of a disease, disorder, or condition.

[0034] 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 relieving or reversing a disorder, disease or condition, or one or more symptoms or manifestations of said disorder, disease or condition.

[0035] Unit dose. The expression "unit dose" as used herein refers to a physically discrete unit (e.g., for a single dose) of a formulation suitable for a subject to be treated; each unit contains a predetermined amount of an active agent selected to produce a desired therapeutic effect when administered according to a treatment regimen (it is understood that multiple doses may be required to achieve a desired or optimal effect), optionally together with a pharma- ceutically 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, and the like. 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 pharma-ceutically acceptable carrier), a diluent, a stabilizer, a buffer, a preservative, and the like may be included as described below. However, it is understood that the total daily use of the formulation of the present invention is determined by the attending physician within the scope of sound medical judgment.The specific effective dose level of any particular subject may depend on various factors, including: the disorder being treated and the severity of said disorder; the activity of the specific active compound used; the specific composition used; the age, weight, general health, sex and diet of said 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 MAPKα inhibitor (e.g., neflamapimod) is about 1mg, 3mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 100mg, 125mg or 250mg.

[0036] DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present invention provides, inter alia, compositions and methods for treating subjects with dementia with Lewy bodies (DLB) and related pathology, but without substantial tau pathology, by administering a composition comprising a selective p38 MAPKα inhibitor (e.g., neflamapimod). Tau pathology can be characterized by measuring circulating (e.g., blood or plasma) levels of phospho-tau (ptau).

[0037] In some embodiments, plasma ptau181 levels below 2.2 pg / mL indicate the absence of substantial tau pathology, and plasma ptau181 levels equal to or greater than 2.2 pg / mL indicate the presence of tau pathology in the brain.

[0038] In some embodiments, tau pathology in a subject is characterized by levels of ptau217 in plasma, positron emission tomography (PET) in the brain, and / or levels of amyloid beta (Aβ)42 in cerebrospinal fluid.

[0039] Thus, in some embodiments, methods of treating DLB in subjects without substantial tau pathology (or Alzheimer's disease-like pathology) are provided herein. In some embodiments, the ptau measured to determine tau pathology is ptau181. In some embodiments, the ptau measured to determine tau pathology is ptau217. In some embodiments, the ptau measured to determine tau pathology is ptau231. For exemplary ptau assays and comparable results, see, for example, Bayoumi et al., Alzheimer's Research & Therapy, 13:198 (2021).

[0040] Methods for identifying or diagnosing AD-like pathology are known. For example, AD pathology can be determined by measuring the level of β-amyloid, precursors, or fragments thereof in the blood, plasma, CSF, or brain of a subject.

[0041] In some embodiments, plasma ptau181 is used as a marker of tau pathology and the threshold for determining whether a subject has tau pathology is 2.2 pg / mL. In some embodiments, the threshold for ptau181 is at least 1.5 pg / mL. In some embodiments, the threshold for ptau181 is at least or greater than 1 pg / mL, 1.6 pg / mL, 1.7 pg / mL, 1.8 pg / mL, 1.9 pg / mL, 2 pg / mL, 2.1 pg / mL, 2.2 pg / mL, 2.3 pg / mL, 2.4 pg / mL, 2.5 pg / mL, 2.6 pg / mL, 2.7 pg / mL, 2.8 pg / mL, 2.9 pg / mL, or 3 pg / mL.

[0042] In some embodiments, the present invention provides compositions and methods for treating subjects suspected of or at risk for developing or progressing to DLB.

[0043] Various aspects of the present invention are described in detail in the following clauses. The use of clauses is not meant to limit the present 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.

[0044] Lewy body dementia 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.

[0045] The central feature of DLB ​​is progressive dementia, i.e., cognitive decline associated with impairment characterized by the decline of attention and executive function, but may include memory impairment.In addition, associated symptoms include attention fluctuation, slow movement, rigidity, REM sleep disorder, visual hallucinations, anosmia, attention fluctuation, depression, apathy, and autonomic nervous system dysfunction.DLB is associated with the deposition of α-synuclein in cells (known as Lewy body or Lewy neurite).

[0046] 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.

[0047] Nephramapimod 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 one 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. Neflamapimod is also known as VX-745 and has the chemical name 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one. [ka] Pharmaceutical Compositions

[0048] In some embodiments, the methods provided include administering to a patient a pharmaceutical composition comprising neflamapimod together with one or more therapeutic agents and a pharma- ceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, a pharmaceutical composition is provided comprising a dose of neflamapimod together with one or more therapeutic agents and a pharma- ceutically acceptable carrier, adjuvant, or vehicle, wherein the dose of neflamapimod produces 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 produces a mean blood concentration of 8 ng / ml. Table 2 of WO 2017 / 185073 illustrates neflamapimod plasma concentration values ​​by post-administration collection time interval and is incorporated herein by reference.

[0049] 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 present invention in the composition will also depend on the particular compound in the composition.

[0050] 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).

[0051] In some embodiments, provided compositions are administered in therapeutically effective amounts and / or according to a dosing regimen that correlates with (e.g., reduction of) a particular desired outcome (e.g., reduction of symptoms).

[0052] 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.

[0053] 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 to the subject (e.g., treat, regulate, cure, prevent, and / or ameliorate the underlying disease or condition). In some embodiments, the method of treating a subject with DLB comprises administering a therapeutically effective amount of a selective p38α inhibitor. In some embodiments, the method of treating a subject with DLB comprises administering a therapeutically effective amount of neflamapimod.

[0054] In some embodiments, the composition is provided as a pharmaceutical preparation.In some embodiments, the pharmaceutical preparation is a unit dose or comprises a unit dose for administration according to a dosage regimen that is correlated with achieving disease reduction in DLB symptoms, stopping or reducing the rate of functional decline caused by DLB.

[0055] In some embodiments, the formulation comprising the provided compositions as described herein is administered as a single dose. In some embodiments, the formulation comprising the provided compositions as described herein is administered as two doses. In some embodiments, the formulation comprising the provided compositions 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, the formulation comprising the provided compositions as described herein is administered twice a week, three times a week, once every two days, daily, twice a day, or every 8 hours.

[0056] In some embodiments, a formulation comprising a composition as described herein is administered once a day. In some embodiments, a formulation comprising a composition provided as described herein is administered twice a day. In some embodiments, the twice a day administration occurs about 9-15 hours apart. In some embodiments, the twice a day 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, a formulation comprising a composition as described herein is administered three times a day. In some embodiments, the administration occurs when the patient is in a fed state. In some embodiments, the administration occurs within 30-60 minutes after the subject ingests food. In some embodiments, the administration occurs when 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.

[0057] 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.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. EXAMPLES

[0058] Example The following examples are provided for illustrative purposes and are not intended to limit the scope of the present invention.

[0059] Example 1 This example clearly demonstrates that neflamapimod is particularly effective for the treatment of subjects with DLB without substantial tau pathology.

[0060] The treatment effect of neflamapimod in a population of mild-to-moderate DLB patients receiving cholinesterase inhibitor therapy was evaluated in a 16-week, placebo-controlled Phase 2 study (the "AscenD-LB Study") of 91 patients with mild-to-moderate DLB, where neflamapimod demonstrated significant improvements versus placebo in cognition (assessed by the DLB-specific Neuropsychological Test Panel (NTB)), motor function (assessed by the Timed-Up-and-Go (TUG) test), and cognitive function (assessed by the Clinical Dementia Rating Scale sum-of-boxes (CDR-SB)).

[0061] Up to half of patients with DLB have tau pathology, i.e., "AD copathology" (van der Lee et al., 2021), and such copathology can affect response to cholinesterase inhibitors (Graff-Radford et al., 2012). In patients with DLB, plasma phospho-tau (either ptau217 or ptau181) correlates with tau-PET signal in the temporal cortex and predicts abnormal tau-PET and CSF β-amyloid status (Hall et al., 2021). Thus, plasma ptau181 levels were assessed in plasma samples obtained during the screening phase of AscenD-LB. Results regarding the association of tau pathology with treatment outcomes in AscenD-LB are described below.

[0062] Dosing regimen With the goal of uniformly achieving a target mean plasma drug concentration of 20 nM in patients, the dosing regimen following randomization to neflamapimod or placebo was based on body weight: Body weight <80kg: 40mg neflamapimod capsule or matching placebo capsule BID Body weight ≥ 80 kg: 40 mg neflamapimod capsule or matching placebo capsule TID However, in the above study, 40 mg TID achieved target plasma drug concentrations; however, 40 mg BID did not, resulting in a deficit of approximately 30-40%. Trough plasma drug concentrations were 50% lower at 40 mg BID versus 40 mg TID.

[0063] As a result, efficacy analyses compared (1) all neflamapimod (i.e., including 40 mg BID and 40 mg TID) versus placebo; (2) 40 mg TID versus placebo (dose groups that achieved target concentrations); and (3) 40 mg TID versus placebo TID.

[0064] To assess treatment effects, repeated measures linear mixed effects models (LMMRM) were utilized to compare outcomes of NFMD 40 mg TID, the dose group that achieved therapeutic plasma drug levels and demonstrated efficacy in the primary analysis previously reported, with (1) all placebo recipients, and (2) matched higher weight placebo recipients (placebo TID). Plasma ptau181 levels were determined by the SIMOA pTau181 Assay (Quanterix) at VU Medical Center, where an in-house defined cutoff for tau pathology was set at 2.2 pg / mL.

[0065] Baseline disease characteristics At baseline, in the efficacy analysis population (baseline and on-treatment data for at least one efficacy endpoint), 22 of 41 placebo participants (53%) and 22 of 42 neflamapimod participants (54%) had plasma ptau181 <2.2 pg / mL (i.e., those predicted to have no tau pathology). See Table 1. Table 1. Baseline characteristics by plasma ptau181 status [Table 1-1] [Table 1-2] * Cognitive fluctuations, visual hallucinations, REM sleep disorder, or parkinsonism Means (SD) except when presented as percentages Note: For ISLT (latency) and ISLT (recognition), data are missing in 1 NFMD participant with baseline ptau<2.2pg / mL and 1 placebo participant with ptau>2.2pg / mL. TUG data are also missing in 1 participant with baseline ptau181 ≥2.2pg / mL.

[0066] result For all four endpoints that showed significant treatment effects in the primary analyses (NTB z-score, attention z-score, TUG, CDR-SB), descriptive assessment of results by baseline ptau181 status revealed that the positive treatment effects were for patients who were below the threshold for having tau pathology (2.2 pg / mL), with no discernible treatment effect (positive or negative) associated with baseline plasma ptau181 levels above the threshold, i.e., those with tau pathology.

[0067] When the LMMRM analysis was restricted to patients with ptau181 <2.2 pg / mL at baseline, for both comparisons, a significant positive treatment advantage in favor of NFMD 40 mg TID was observed for attention composite z-score (p=0.021 vs placebo, difference=0.42 95% CI: 0.07, 0.78; p=0.034 vs placebo TID, difference=0.46 z-score, 95% CI: 0.04, 0.88). See Figure 1.

[0068] When the LMMRM analysis was restricted to patients with ptau181<2.2 pg / mL at baseline, for both comparisons, a significant positive treatment advantage in favor of NFMD 40 mg TID was observed relative to TUG (p<0.001 vs. placebo, difference=-3.1, 95% CI: -4.7,-1.6; p=0.010 vs. placebo TID, difference=-3.5 s, 95% CI: -6.1,-0.9). See Figure 2B.

[0069] When the LMMRM analysis was restricted to patients with ptau181 <2.2 pg / mL at baseline, for both comparisons, a significant positive treatment advantage in favor of NFMD 40 mg TID was observed for CDR-SB (p=0.031 vs. placebo, difference=-0.60, 95% CI: -1.14, -0.06; p=0.009 vs. placebo TID, difference=-0.93 points, 95% CI: -1.61, -0.25). See Figure 2A.

[0070] When the LMMRM analysis was restricted to patients with ptau181 < 2.2 pg / mL at baseline, a significant positive treatment advantage in favor of NFMD 40 mg TID for both comparisons was observed for NTB z-score, but numerically favored NFMD 40 mg TID treatment (difference vs placebo = 0.21, 95% CI: -0.07, 0.49; difference vs placebo TID = 0.25, 95% CI: -0.07, 0.57). When the sample size was restricted, the difference was not significant (p = 0.13 vs placebo, p = 0.12 vs placebo TID). However, a significant PK-PD relationship was revealed for NTB (p = 0.035, r = 0.46 for estimated trough plasma nephromapimod drug concentration vs NTB z-score).

[0071] When the LMMRM analysis was restricted to patients with ptau181<2.2 pg / mL at baseline, for both comparisons, a significant positive trend in favor of NFMD 40 mg TID was observed for ISLD immediate recall (p=0.053 vs. placebo, difference=2.1 words, 95% CI: -0.0, 4.2; p-0.063 vs. placebo TID, difference=2.3 words, 95% CI: -0.1, 4.7) and a significant positive improvement in favor of NFMD 40 mg TID for ISLD recognition (p=0.024 vs. placebo, difference=1.4 words, 95% CI: 0.2, 2.5; p=0.035 vs. placebo TID, difference=0.9 words, 95% CI: 0.1, 1.7). See Figure 3. The positive effects on ISLD awareness are consistent with the effects on working memory.

[0072] Efficacy analysis of the primary endpoint shows that responses in patients with baseline plasma ptau181 < 2.2 pg / mL (i.e., those without substantial tau pathology) appear to be better than responses in patients with baseline plasma ptau181 levels ≧ ​​2.2 pg / mL (i.e., those with tau pathology in the brain and, potentially, mixed AD-related pathology).

[0073] When protocol-specified efficacy analyses (repeated measures mixed models) were restricted to patients without substantial tau pathology, the magnitude of neflamapimod treatment effect versus placebo was substantial and clinically important. See Table 2. Table 2: Summary of Neflamapimod Efficacy in a DLB Patient Population Without Tau Pathology (Baseline Plasma ptau181 < 2.2 pg / mL) [Table 2] When compared with results in the entire population, the magnitude of the effect of neflamapimod treatment versus placebo for individual endpoints was 1.5-2.0-fold greater in the population with plasma ptau181 <2.2 pg / mL at baseline.

[0074] 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.

Claims

1. 1. A composition for treating a subject having dementia with Lewy bodies (DLB) but without substantial tau pathology, the composition comprising a selective p38α mitogen-activated protein kinase (MAPK) inhibitor, wherein the composition is administered to the subject.

2. 2. The composition of claim 1, wherein the p38α mitogen-activated protein kinase (MAPK) inhibitor is neflamapimod.

3. The composition of any of claims 1-2, wherein the absence of substantial tau pathology in the subject is characterized by a level of ptau181 in plasma.

4. The composition of any of claims 1-2, wherein the absence of substantial tau pathology in the subject is characterized by a level of ptau217 in plasma.

5. The composition of any of claims 1-2, wherein the absence of substantial tau pathology in the subject is characterized by positron emission tomography (PET) of the brain.

6. 3. The composition of any of claims 1-2, wherein the absence of substantial tau pathology in a subject is associated with a lower level of amyloid beta (Aβ)42 in the cerebrospinal fluid of the subject than that of a subject diagnosed with Alzheimer's disease.

7. 6. The composition of claim 5, wherein the absence of substantial tau pathology in the subject is characterized by a level of plasma ptau that is lower than that of a subject with Alzheimer's disease or Alzheimer's disease-related pathology, as measured in a Simoa ptau 181 assay.

8. 1. A composition for treating an α-synuclein-associated degenerative disease in a subject having DLB but not substantial tau pathology, the composition comprising a selective p38α mitogen-activated protein kinase (MAPK) inhibitor, wherein the composition is administered to the subject.

9. 1. A composition for inhibiting neuronal loss in the central nervous system of a subject having DLB but not substantial tau pathology, the composition comprising a selective p38α mitogen-activated protein kinase (MAPK) inhibitor, wherein the composition is administered to the subject.

10. A composition for reversing endosomal dysfunction in a subject having DLB but not substantial tau pathology, the composition comprising a selective p38α mitogen-activated protein kinase (MAPK) inhibitor, wherein the composition is administered to the subject.

11. The composition of any one of claims 8 to 10, wherein the MAPK inhibitor is neflamapimod.

12. 12. The composition of claim 11, wherein the neflamapimod is administered at 40 mg TID.

13. The composition of any one of claims 1 and 8 to 10, wherein the subject has cholinergic neurodegeneration in the basal forebrain.

14. 14. The composition of claim 13, wherein said administration results in a reduction in the symptomatic effects of cholinergic neurodegeneration in the basal forebrain of said subject.

15. 11. The composition of any of claims 1 and 8-10, wherein the subject has synaptic dysfunction in the medial septum, neuronal cell loss in the hippocampus, neuronal loss in the medial septum, or neuronal cell loss in the vertical limb of the diagonal band nucleus.

16. The composition of claim 15, wherein the neuronal cell loss in the hippocampus is in the CA2-3 region of the hippocampus.

17. The subject is (a) Deficits in attention, verbal fluency, and episodic memory as measured by the attention composite z-score; (b) deficits in motility as measured by Timed Up and Go (TUG); (c) Deficits in memory, orientation, judgment and problem-solving, community tasks, home life and hobby performance, and personal care as measured by the Clinical Dementia Rating Scale (CDR-SB); and / or (d) deficits in neuropsychological activity as measured by the Neuropsychological Test Battery (NTB); The composition of any one of claims 1 and 8 to 10, wherein

18. The composition of any of claims 1 and 8-10, wherein the subject has alpha-synuclein deposits in the hippocampus.

19. The composition of any of claims 1 and 8-10, wherein the subject does not have Alzheimer's disease.

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