- Neflamapimod demonstrates that it reverses the neurodegenerative process in the basal forebrain cholinergic system in animal models.
- Phase 2a data in Dementia with Lewy Bodies show positive effects of neflamapimod on clinical endpoints associated with cholinergic neuronal function.
- EIP Pharma plans initiation of confirmatory Phase 2b clinical trial for DLB.
A private clinical stage biopharmaceutical company focused on developing investigative therapies for CNS diseases with significant unmet patient need, EIP Pharma Inc., today (September 21) announced the publication of an article in Nature Communications showing translational results from preclinical animal models to an exploratory, placebo-controlled clinical trial of neflamapimod in patients with mild to moderate Dementia with Lewy Bodies (DLB). The findings in “Preclinical and Randomized Clinical Evaluation of the p38a Kinase Inhibitor Neflamapimod for Basal Forebrain Cholinergic Degeneration” demonstrate that neflamapimod’s unique mechanism of action has the potential to improve cognitive and motor function in patients with neurodegenerative diseases affecting the basal forebrain cholinergic system, such as DLB.
Neflamapimod, which has been granted Fast Track status as a treatment for DLB by the U.S. Food and Drug Administration (FDA), is an oral, brain-penetrating small molecule that selectively targets and inhibits within the neuron the enzyme p38 MAP kinase alpha (p38a), which is known to regulate Rab5, a key protein implicated in the underlying disease process of neural degeneration in the basal forebrain. The animal studies in the publication show that neflamapimod reduces Rab5 activity and reverses the neurodegenerative process in the basal forebrain. The pre-clinical data were translated into the clinic in an exploratory Phase 2a clinical trial in DLB patients in which neflamapimod was shown to be generally safe and well tolerated, and improved versus placebo the dementia, as assessed by the gold standard dementia rating scale, and motor function. These combined pre-clinical and clinical results provide a foundation for a confirmatory, hypothesis-testing Phase 2b clinical study evaluating neflamapimod for DLB.
Ralph A Nixon, MD, PhD, Director of the Center for Dementia Research at the Nathan S. Kline Institute for Psychiatric Research in Orangeburg NY and senior author on the publication, commented, “We are pleased to report on the finding of a major translational step forward towards a therapy that treats cholinergic degeneration in the basal forebrain. We hypothesized that neflamapimod would achieve this therapeutic objective because it inhibits p38a kinase, an enzyme known to regulate activity of a central player in the pathogenic process underlying cholinergic degeneration, the endosome-associated protein Rab5. Indeed, in an animal model, neflamapimod reduced Rab5 activity and reversed the neurodegenerative process in the basal forebrain.
“Furthermore, in the placebo-controlled clinical trial of neflamapimod in DLB patients, the beneficial effects on cognition and motor function are consistent with neflamapimod treating the cholinergic deficit that underlies the clinical presentation of DLB. Taken together, the findings indicate that neflamapimod appears to represent a scientific breakthrough towards treating degeneration of the basal forebrain cholinergic system, a long-standing objective of drug development for a range of neurodegenerative diseases.”
The basal forebrain is the primary source of cholinergic neural stimulation in the brain, and its degeneration occurs in aging and neurodegenerative disease-related cognitive disorders, including Dementia with Lewy Bodies (DLB), the second most common form of neurodegenerative dementia. In DLB, dysfunction in the basal forebrain cholinergic neuron (BFCN) is an important driver of disease expression and progression. Recent studies have also demonstrated that BFCN loss underpins gait dysfunction in Parkinson’s Disease. Correcting the functional deficit in the cholinergic system amplifies the release of acetylcholine and has the potential to alter the course of the neurodegeneration that drives a number of devastating brain diseases.
“With this unique mechanism that treats cholinergic neuronal degeneration, in vivo preclinically and clinically in DLB patients, we strongly believe in neflamapimod’s potential to play an important role in the treatment of neurodegenerative diseases, especially in DLB where cholinergic dysfunction contributes to both the cognitive deficits and gait dysfunction that together make this a particularly debilitating disease,” said John Alam, MD, scientific founder, and Chief Executive Officer of EIP Pharma.
“The cholinergic system has long been known to be critical in the pathogenesis of dementia, and neflamapimod’s profile is well suited to become a foundational treatment in a disease like DLB, where there are no approved therapies. The data published today provide us confidence to progress neflamapimod into a confirmatory Phase 2b clinical trial in Dementia with Lewy Bodies.”
Reference: “Preclinical and Randomized Clinical Evaluation of the p38a Kinase Inhibitor Neflamapimod for Basal Forebrain Cholinergic Degeneration” by Jiang, Y., Alam, J.J., Gomperts S.N. et al., 21 September 2022, Nature Communications.
Neflamapimod is an investigational oral, brain-penetrating small molecule drug that inhibits the intra-cellular enzyme p38MAP kinase alpha (p38a), which is expressed in neurons under conditions of stress and disease. P38a plays a major role in inflammation-induced synaptic toxicity, leading to impaired synaptic function. In pre-clinical studies, neflamapimod reverses synaptic dysfunction, including within the part of the brain most affected by Dementia with Lewy bodies (DLB) – the basal forebrain cholinergic system. Results from the AscenD-LB Phase 2a clinical study demonstrated neflamapimod significantly improved cognition and function as measured by the gold standard dementia rating test, the Clinical Dementia Rating Sum-of-Boxes (CDR-SB), and also showed significant impact on motor function as measured by the Timed Up and Go test (TUG). In addition, at 40mg TID, the higher of two doses in the study, neflamapimod improved outcomes on a cognitive test battery (“Neuropsychological Test Battery”, NTB) designed to evaluate the cognitive domains most prominently impacted in DLB, attention and executive function. Neflamapimod is the first treatment that shows potential impact on cognition, function and motor function in patients with DLB. The combined pre-clinical and clinical data are consistent with neflamapimod treating the underlying disease process and having the potential to be the first disease-modifying treatment for DLB.
About EIP Pharma
EIP Pharma, Inc. is a private, clinical-stage biotechnology company advancing CNS-focused therapeutics to benefit patients with a range of debilitating neurodegenerative diseases with significant unmet patient need. The Company is focused on the potential of neflamapimod, an investigational compound being evaluated for its potential to treat synaptic dysfunction, the reversible aspect of the underlying neurodegenerative processes that cause disease in Dementia with Lewy Bodies and certain other major neurological disorders.
J.J.A, A.G., and K.B. are employees of EIP Pharma, the sponsor of the clinical study. J.J.A. is also founder of and has stock ownership in EIP Pharma. U.A.G. receives compensation as a scientific consultant to EIP Pharma. S.N.G. has served on Advisory Boards of Jannsen, Acadia, and Sanofi, has received consulting fees from EIP Pharma, and has received funding from the NIH, the DOD CDMRP, the Michael J. Fox Foundation, the FFFPRI, and the Lewy Body Dementia Association. N.D.P. is CEO and co-owner of Brain Research Center. P.M. is a full-time employee at Cogstate Ltd. J.E.H. reports receipt of personal fees in the past 2 years from Actinogen, AlzeCure, Aptinyx, Astra Zeneca, Athira Therapeutics, Axon Neuroscience, Axovant, Bial Biotech, Biogen Idec, BlackThornRx, Boehringer Ingelheim, Brands2life, Cerecin, Cognito, Cognition Therapeutics, Compass Pathways, Corlieve, Curasen, EIP Pharma, Eisai, G4X Discovery, GfHEU, Heptares, Ki Elements, Lundbeck, Lysosome Therapeutics, MyCognition, Neurocentria, Neurocog, Neurodyn Inc, Neurotrack, the NHS, Novartis, Novo Nordisk, Nutricia, Probiodrug, Prothena, Recognify, Regeneron, reMYND, Rodin Therapeutics, Samumed, Sanofi, Signant, Syndesi Therapeutics, Takeda, Vivoryon Therapeutics and Winterlight Labs. In addition, he holds stock options in Neurotrack Inc. and is a joint holder of patents with My Cognition Ltd. C.E.T. has a collaboration contracts with ADx Neurosciences, Quanterix and Eli Lilly; performed contract research or received grants from AC-Immune, Axon Neurosciences, Bioconnect, Bioorchestra, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Grifols, Novo Nordisk, PeopleBio, Roche, Toyama, and Vivoryon; and has had speaker contracts for Roche, Grifols, and Novo Nordisk. P.S. has received consultancy fees (paid to the institution) from AC Immune, Brainstorm Cell, EIP Pharma, ImmunoBrain Checkpoint, Genentech, Novartis, Novo Nordisk. P.S. is also principal investigator of studies with AC Immune, FUJI-film/Toyama, UCB, and Vivoryon; and is an employee of EQT Life Sciences (formerly LSP). The remaining authors declare no competing interests.