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

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 or thrice-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.

Dementia with Lewy Bodies Drug Therapies in Clinical Trials: Systematic Review up to 2022

“…We identified four instruments for assessing clinical outcome measures specific for DLB: the Dementia Cognitive Fluctuation Scale (DCFS) evaluating cognitive fluctuations to distinguish Lewy body dementias from AD and vascular dementia [28] used in the CST-103/CST-107 trial and various composite scores used in clinical trials of neflamapimod, ATH-1017 (fosgonimeton), and mevidalen. The composite scores were different across trials and included measures designed to capture attention, executive function, and visual learning impairments specific to DLB [29,30].…”

Clinical trials in dementia with Lewy bodies: the evolving concept of co-pathologies, patient selection and biomarkers

“…The use of AD biomarkers as predictive biomarkers to stratify treatment response is increasing in clinical trials for DLB and have been included in recent trials for irsenotrine, neflamapimod and ambroxol [127–129,130 ▪ ] (Table 2). For irsenotrine no differential treatment outcomes were found according to amyloid status [127] but in the phase 2 clinical trial for neflamapimod a greater magnitude of effect was found in patients with DLB without evidence of AD co-pathology [130 ▪ ,131]. These early applications are promising and the use of biomarkers to stratify clinical trials is likely to continue in the future.…”

Listening session with the US Food and Drug Administration, Lewy Body Dementia Association, and an expert panel

“…Primary outcome measures were mainly focused on cognitive measures, such as the Alzheimer's Disease Assessment Scale, and global measures, such as the Clinical Dementia Rating (CDR) scale and the Clinical Global Impression of Change scale. Mevidalen was associated with improvement of motor symptoms as measured by the Unified Parkinson's Disease Rating Scale, and neflamapimod was associated with improved performance on the CDR–Sum of Boxes and the Timed Up and Go Test compared to placebo 19 . Most studies did not report statistically significant results favoring treatment for their respective primary cognitive endpoints.…”

“…Although rivastigmine is approved to treat PDD in the United States, there have been relatively few studies on it specifically directed at DLB. Trials to date have included HEADWAY‐DLB (which assessed intepirdine), 17 PRESENCE (which assessed mevidalen), 18 and AscenD‐LB (which assessed neflamapimod) 19 . All three DLB studies included cognitive and motor symptoms, but inclusion and exclusion criteria differed among the studies, with some including participants with PDD.…”

“…Trials to date have included HEADWAY-DLB (which assessed intepirdine), 17 PRESENCE (which assessed mevidalen), 18 and AscenD-LB (which assessed neflamapimod). 19 All three DLB studies included cognitive and motor symptoms, but inclusion and exclusion criteria differed among the studies, with some including participants with PDD. The is not yet fully studied.…”