Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration

Ying Jiang, John J. Alam (), Stephen N. Gomperts, Paul Maruff, Afina W. Lemstra, Ursula A. Germann, Philip H. Stavrides, Sandipkumar Darji, Sandeep Malampati, James Peddy, Cynthia Bleiwas, Monika Pawlik, Anna Pensalfini, Dun-Sheng Yang, Shivakumar Subbanna, Balapal S. Basavarajappa, John F. Smiley, Amanda Gardner, Kelly Blackburn, Hui-May Chu, Niels D. Prins, Charlotte E. Teunissen, John E. Harrison, Philip Scheltens and Ralph A. Nixon ()
Additional contact information
Ying Jiang: Nathan S. Kline Institute for Psychiatric Research
John J. Alam: EIP Pharma Inc
Stephen N. Gomperts: Massachusetts Alzheimer’s Disease Research Center
Paul Maruff: Cogstate Ltd, Runway East Borough Market
Afina W. Lemstra: Amsterdam Neuroscience - Neurodegeneration
Ursula A. Germann: EIP Pharma Inc
Philip H. Stavrides: Nathan S. Kline Institute for Psychiatric Research
Sandipkumar Darji: Nathan S. Kline Institute for Psychiatric Research
Sandeep Malampati: Nathan S. Kline Institute for Psychiatric Research
James Peddy: Nathan S. Kline Institute for Psychiatric Research
Cynthia Bleiwas: Nathan S. Kline Institute for Psychiatric Research
Monika Pawlik: Nathan S. Kline Institute for Psychiatric Research
Anna Pensalfini: Nathan S. Kline Institute for Psychiatric Research
Dun-Sheng Yang: Nathan S. Kline Institute for Psychiatric Research
Shivakumar Subbanna: Nathan S. Kline Institute for Psychiatric Research
Balapal S. Basavarajappa: Nathan S. Kline Institute for Psychiatric Research
John F. Smiley: Nathan S. Kline Institute for Psychiatric Research
Amanda Gardner: EIP Pharma Inc
Kelly Blackburn: EIP Pharma Inc
Hui-May Chu: Anoixis Corporation
Niels D. Prins: Brain Research Center
Charlotte E. Teunissen: Amsterdam Neuroscience - Neurodegeneration
John E. Harrison: Amsterdam Neuroscience - Neurodegeneration
Philip Scheltens: Amsterdam Neuroscience - Neurodegeneration
Ralph A. Nixon: Nathan S. Kline Institute for Psychiatric Research

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight 80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.

Date: 2022
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DOI: 10.1038/s41467-022-32944-3

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