A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease

Abstract

Background: In preclinical studies, p38⍺ kinase is implicated in Alzheimer's disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.

Methods: The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score ≥0.5, and Mini-Mental State Examination (MMSE) 20-28. The primary endpoint was the improvement in episodic memory, assessed by combined change in Z-scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau181), Aβ1-40, Aβ1-42, neurogranin, and neurofilament light chain].

Results: At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): -18.8 (-35.8, -1.8); P=0.031] and p-tau181 [-2.0 (-3.6, -0.5); P=0.012], with a trend for neurogranin [-21.0 (-43.6, 1.6); P=0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.

Conclusions and relevance: A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK-PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.

Trial registration: ClinicalTrials.gov identifier: NCT03402659 . Registered on January 18, 2018.

Keywords: Alzheimer’s; CSF biomarkers; Clinical trial; Episodic memory; Synaptic dysfunction; p38 MAPK.

Conflict of interest statement

NDP is a consultant to Boehringer Ingelheim. He serves on the DSMB of Abbvie’s M15-566 trial. He is the CEO and co-owner of the Brain Research Center, The Netherlands.

JEH reports receipt of personal fees in the past 2 years from AlzeCure, Aptinyx, Astra Zeneca, Athira Therapeutics, Axon Neuroscience, Axovant, Biogen Idec, BlackThornRx, Boehringer Ingelheim, Cerecin, Cognition Therapeutics, Compass Pathways, CRF Health, Curasen, EIP Pharma, Eisai, Eli Lilly, FSV7, G4X Discovery, GfHEU, Heptares, Lundbeck, Lysosome Therapeutics, MyCognition, Neurocentria, Neurocog, Neurodyn Inc, Neurotrack, Novartis, Nutricia, Probiodrug, Regeneron, Rodin Therapeutics, Samumed, Sanofi, Servier, Signant, Syndesi Therapeutics, Takeda, Vivoryon Therapeutics, vTv Therapeutics, and Winterlight Labs. Additionally, he holds stock options in Neurotrack Inc. and is a joint holder of patents with My Cognition Ltd.

H-MC has no conflicts to declare. JJA is the founder and CEO and Ms. Kelly Blackburn is an employee of the sponsor of the trial, EIP Pharma Inc.

PS reports receipt of fees (to the university) in the past 2 years from Axon Neuroscience, Cognition Therapeutics, EIP Pharma, Green Valley, GemVax, Novartis, Vivoryon (Probiodrug AG), FUJI Film/Toyama, Rodin Therapeutics, and Medavante. He is a paid medical advisor to the Brain Research Center and serves on the supervisory board.

Figures

Fig. 1

CONSORT flow diagram

Fig. 2

Results of CSF biomarkers of neurodegeneration and synaptic dysfunction. Mean (s.e.m.) absolute (pg/mL) change from baseline to week 24 CSF sampling is shown. The difference between neflamapimod treatment and placebo was significant for T-tau [difference (95% CI): −18.8 (−35.8, −1.8); P=0.031] and p-tau181 [−2.0 (−3.6, −0.5); P=0.012], with a trend for neurogranin [−21.0 (−43.6, 1.6); P=0.068.  N=68 for placebo and N=62 for neflamapimod for A, B, E and F.  N=70 for placebo and N=63 for neflmapimod for C and D.]

Fig. 3

Relationship between Ctrough and episodic memory measures. Plasma trough drug concentration in neflamapimod versus change from baseline to week 24. a HVLT-R combined total and delayed recall Z-score (i.e., primary endpoint), and b WMS combined immediate and delayed recall composite is shown in circles (open for treatment-naïve subjects, closed for those on background AD therapy). For comparison, placebo subjects are shown in triangles (open for treatment-naïve subjects, closed for those on background AD therapy) on the left side of the figure