Neflamapimod, an experimental, oral drug targeting neuroinflammation being developed by CervoMed, led to a significant reduction in a key blood biomarker of neurodegeneration, which correlated with a significant slowing of disease progression in dementia with Lewy bodies (DLB) in the phase 2b RewinD-LB trial.

Patients in the trial who reached target blood levels of the drug experienced less cognitive and functional decline compared with those receiving an older, less bioavailable batch of the drug, suggesting disease-modifying effects.

The findings were presented on December 4 at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference.

Rapid Progression

DLB is an area of “high unmet need with no currently approved therapies in the US or Europe. With neflamapimod, we’ve got a well-documented scientific rationale and clinically validated mechanism of action and we’re seeing a durable, clinically significant effect and a favorable, safety profile in patients with pure DLB,” John-Paul Taylor told conference attendees.

In an interview with Medscape Medical News, John Alam, MD, CervoMed CEO, noted that the average time from diagnosis of DLB to nursing home placement or requiring full-time assistance is only about 2 years.

“What our data with neflamapimod are showing is that globally, we are slowing, and to a great extent preventing, the progression of the dementia and the global dementia symptoms. This is fundamentally what patients are and caregivers are looking for,” said Alam.

DLB is a progressive alpha-synucleinopathy characterized by widespread cortical and subcortical Lewy bodies. In the early stages, a major driver of disease expression and progression is dysfunction and degeneration of the basal forebrain cholinergic neurons.

Neflamapimod is an oral p38-alpha kinase inhibitor that targets dysfunction and degeneration of acetylcholine-producing neurons. In the basal forebrain, there is accumulation of alpha-synuclein, which leads to neuroinflammation and hyperactivation of p38-alpha kinase, leading to pathologic sequelae, culminating in synaptic dysfunction, Taylor explained.

By inhibiting this kinase, neflamapimod aims to remediate this synaptic dysfunction and there is positive preclinical and phase 2a data to validate this drug target and support advancement to phase 2b, Taylor said.

The RewinD-LB phase 2b trial included 159 patients with DLB and had two parts: a 16-week, randomized, placebo-controlled phase trial where patients received neflamapimod 40 mg three times daily or matching placebo, and a 32-week open-label extension phase, where patients received neflamapimod 40 mg three times daily.

Neflamapimod capsules used in the initial phase (batch A) did not produce the expected and targeted plasma drug concentrations, resulting in no significant difference between placebo and neflamapimod on the primary endpoint of Clinical Dementia Rating Sum of Boxes (CDR-SB).

In the extension phase, a new formulation (batch B) did achieve the expected and targeted plasma concentrations of neflamapimod, allowing a clear assessment of the drug’s efficacy.

Achieving target concentrations of the drug in the extension phase led to a significant benefit on clinical progression — most prominently in the subgroup of patients with a low likelihood of having Alzheimer’s disease co-pathology (< 21 pg/mL ptau181, the “pure” DLB subgroup), Taylor told attendees.

Toward the First Approved DLB Med

At week 16 of the extension phase, the mean change (worsening) in CDR-SB was 52% lower with batch B than with batch A in all participants and 82% lower in pure DLB subgroup, he noted.

The clinical effect was durable at 32 weeks, with a 65% reduction in the mean CDR-SB change when targeted plasma drug concentrations were achieved in all participants and 89% reduction in the pure DLB subgroup.

The risk for clinical progression, defined as ≥ 1.5-point increase in CDR-SB, was reduced by 67% with batch B vs batch A (P < .001) and by 75% with batch B vs placebo (P < .001).

The median time to progression was 16 weeks with batch A and 24 weeks with batch B. In batch B, the median time to progression “could not be achieved in the duration of the trial; and indeed, projecting it out, assuming that neflamapimod has a sustained effect, it would only lead to progression at 1.5 years — giving about a year of clinical stability,” Taylor reported.

Neflamapimod also led to clinically meaningful improvements in Clinical Global Impression of Change and multiple secondary and exploratory measures, including mobility, cognitive fluctuations, and neuropsychological test performance.

Achieving target levels of neflamapimod with batch B was also associated with a significant reduction in plasma levels of glial fibrillary acidic protein, a biomarker of neurodegeneration, and these changes correlated with clinical treatment response, “further supporting that neflamapimod acts on the underlying disease process,” Taylor said.

The drug was generally well tolerated, with low rates of discontinuation over 48 weeks of treatment. During the placebo-controlled portion of the study, 2.5% of neflamapimod recipients discontinued for liver enzyme elevation during the placebo phase and 1.3% during the extension phase. All events of liver enzyme elevation were reversible; none were associated with bilirubin elevation.

“The results build on a growing body of preclinical and clinical evidence and give us renewed confidence that we are moving closer to the first approved treatment for patients and their families,” Taylor said in a news release.

The company plans to launch a global phase 3 randomized, placebo-controlled trial in the second half of 2026. The study will enroll about 300 patients, focusing on those with pure DLB. Patients will receive oral neflamapimod or placebo for 32 weeks, followed by a neflamapimod-only 48-week extension phase.

“We now have two different studies that have shown neflamapimod acts on CDR sum of boxes. We believe that phase 3 will truly confirm what we have already seen,” said Alam.

The RewinD-LB study was funded by a $21 million grant from the National Institute on Aging, with additional support from CervoMed. Alam is an employee of CervoMed, and Taylor has consulted for the company.