In a phase 2 trial (NCT04001517), participants with mild-to-moderate dementia with Lewy bodies (DLB) neflamapimod (VX-745; EIP Pharma, Boston, MA) had statistically significant and clinically meaningful improvements in cognition compared with participants treated with placebo. Additionally, a dose-response effect was seen when comparing those treated with 120 mg/day in 3 doses vs 80 mg/day in 2 doses. Benefits were seen as early as 4 weeks and were maintained throughout the 16-week study.
Cognitive improvement was assessed with a neuropsychologic test batter (NTB) that included 6 tests from the Cogstate battery (Detection, Identification, One Card Learning, One Back, Letter Fluency, and Category Fluency). Individual tests were equally weighted with a goal of evaluating attention and executive function. Statistically significant positive effects on motor symptoms, measured with the Timed Up and Go Test were also observed. Improvements on the 10-item Neuropsychiatric Inventory (NPI-10), particularly with respect to hallucinations, and on the Clinical Dementia Rating Sum of Boxes (CDR-SB) with neflamapimod vs placebo were observed but did not reach statistical significance in this phase 2 study.
"It is exciting to see efficacy of potential new drugs for Lewy Body Dementia," said Marwan Sabbagh, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health. "It is a huge area of unmet need."
"The demonstrated positive effects on the AscenD-LB study's primary endpoint, cognition, and on a number of secondary endpoints, establishes proof-of-concept for neflamapimod as a possible treatment for patients with DLB. If these findings are confirmed in phase 3 clinical studies, neflamapimod could potentially become the first approved therapy for this devastating disease," said Stephen Gomperts, MD, PhD, director of the Lewy Body Dementia Unit and assistant professor of Neurology at Massachusetts General Hospital, and an investigator in the AscenD-LB study. "DLB is not only the second most common neurodegenerative dementia but is also associated with substantial reduction of patient quality of life and high caregiver burden."
The trial enrolled 91 participants age 55 or more who took 40 mg neflamapimod or placebo (1:1 random assignment) orally 2 or 3 per day for 16 weeks. All participants had been diagnosed with mild to moderate cognitive deficits associated with DLB and were on a stable dose of cholinesterase inhibitors.
Neflamapimod was well tolerated with no discontinuation related to adverse events. Related treatment-emergent adverse events reported by more than 1 participant included headache, diarrhea, and nausea. In the groups treated with placebo or 80 mg neflamipimod, there were 10 discontinuations due to intercurrent medical illness (2 in placebo, 2 in 80-mg group) or withdrawal of consent/disease worsening (2 in placebo, 4 in 80-mg group).
Neflamapimod is an inhibitor of p38 MAP kinase alpha (p38α), which is expressed in neurons under conditions of stress and disease and plays a role in inflammation-induced synaptic degeneration. In earlier studies in people with Alzheimer disease, neflamapimod reduced tau levels in cerebrospinal fluid.
Ganesh M. Babulal, PhD, OTD, and Catherine M. Roe, PhD
Adam M. Staffaroni, PhD; Elena Tsoy, PhD; Jack Taylor, BS; Adam L. Boxer, MD, PhD; and Katherine L. Possin, PhD
Nupur Ghoshal, MD, PhD