Neflamapimod Receives Orphan Drug Designation by FDA for Frontotemporal Dementia

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Most recently reported topline data from the RewinD-LB phase 2b trial in patients with dementia with Lewy bodies showed that neflamapimod failed to meet its primary end point and secondary end points.

John Alam, MD

(Credit: CervoMed)

In recent news, the FDA has granted orphan drug designation to CervoMed’s oral investigational drug neflamapimod for the treatment of patients with frontotemporal dementia (FTD). The company noted that it is actively collaborating with clinical experts to plan a proof-of-concept study in FTD but is pausing all preparations for its previously planned phase 3 trial of neflamapimod in early-stage dementia with Lewy bodies (DLB) until the full analysis is complete.^1,2

“We are pleased to have received Orphan Drug Designation as it implicitly recognizes the scientific rationale and potential for neflamapimod to treat this debilitating condition. Patients diagnosed with frontotemporal dementia have no available treatment options, and this rare condition is extremely burdensome to patients and caregivers alike,” John Alam, MD, Chief Executive Officer of CervoMed, said in a statement.¹ “Within this year, there have been multiple scientific presentations and publications that indicate neflamapimod targets specific pathogenic mechanisms associated with FTD.”

A couple of weeks later, the company reported new topline data from the company's RewinD-LB phase 2b trial (NCT05869669) of neflamapimod for DLB revealed that the study did not meet its primary end point of change in the Clinical Dementia Rating Sum of Boxes (CDR-SB) or any of its key secondary end points including change from baseline in Timed Up and Go test, change from baseline in a Neuropsychological Test Battery, and the Clinician’s Global Impression of Change. In the initial analysis, the target plasma drug concentrations were not achieved in the double-blind phase of the study which the company noted may have adversely impacted trial results.

“Obviously, we are disappointed with these results, particularly given our prior clinical experience with neflamapimod in patients with early-stage DLB and we are investigating the reasons for the lower-than-expected plasma drug concentrations. We continue to believe neflamapimod may have potential as a treatment for DLB, and we will thoroughly analyze the clinical and pharmacokinetic data from the trial to better understand its outcome and potential future development paths for the drug,” Alam said in a statement at the time.²

RewinD-LB was similar in design to the phase 2a AscenD-LB trial (NCT04001417); however, in that study, treatment with neflamapimod met its primary end point of improvement in cognition using the neuropsychological test battery. In RewinD-LB, 160 patients with DLB were randomized 1:1 to 40 mg neflamapimod or placebo for a 16-week treatment period, followed by a 32-week open-label extension phase. Participants in the trial were in the early stage of their disease, demonstrated by CDR scale scores of less than 1, and had a normal plasma phosphorylated-tau (p-tau)181 levels.

Neflamapimod is designed to inhibit p38MAP kinase alpha (p38a), which is expressed in neurons under conditions of stress and disease, and has been thought to play a role in inflammation-induced synaptic toxicity, leading to synaptic dysfunction. In the RewinD-LB phase 2b trial, neflamapimod displayed a favorable safety and tolerability profile that was consistent with prior clinical studies, with no new safety signals observed.

CervoMed also noted that the full data set from the double-blind phase of the RewinD-LB trial assessing neflamapimod is anticipated to be available to the company in January 2025 and the data from the first 16 weeks of the open label extension portion of the trial are expected to be available in the late second quarter of 2025. The company also plans to announce the timing of any presentation of additional data from the trial at a later date upon completion of the first 16 weeks of the open label extension portion of the trial and its analysis of all the data.

“We are grateful to the entire DLB community, including trial participants, their caregivers and families, and all of our investigators, sites and coordinators,” Kelly Blackburn, senior vice president of clinical development at CervoMed, said in a statement.²

REFERENCES
1. CervoMed Announces Orphan Drug Designation Granted to Neflamapimod by U.S. Food and Drug Administration for the Treatment of Frontotemporal Dementia. News Release. CervoMed. Published November 27, 2024. Accessed December 13, 2024. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-orphan-drug-designation-granted-neflamapimod
2. CervoMed Announces Topline Data from RewinD-LB Phase 2b Clinical Trial in Patients with Dementia with Lewy Bodies. News Release. CervoMed. Published December 10, 2024. Accessed December 13, 2024. https://ir.cervomed.com/news-releases/news-release-details/cervomed-announces-topline-data-rewind-lb-phase-2b-clinical
3. Prins ND, Gardner A, Chu HM, et al. A phase 2b clinical trial of neflamapimod in dementia with Lewy bodies designed to confirm the efficacy results from phase 2a. Presented at: 2023 CTAD annual meeting; October 24-27; Boston, MA. POSTER OC08