Findings from the phase 2a AscenD-LB, a study of neflamapimod in patients with mild-to-moderate Alzheimer disease, served as supportive data to guide the phase 2b study.
At the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, investigators presented an outline of the phase 2b RewinD-LB study (NCT05869669), a new trial powered to confirm the clinical efficacy of neflamapimod (EIP Pharma), an agent in development for patients with dementia with Lewy bodies (DLB).1
The study is similar in design to the phase 2a AscenD-LB trial (NCT04001417), where treatment with the therapy met its primafy end point of improvement in cognition using the neuropsychological test battery (NTB). In RewinD-LB, 160 patients with DLB will be randomized 1:1 to 40 mg neflamapimod or placebo for a 16-week treatment period, followed by a 32-week open-label extension phase.
To be included, patients must be in the early stage of their disease, demonstrated by Clinical Dementia Rating scale scores of less than 1, and must have normal plasma phosphorylated-tau (p-tau)181 levels. Led by Niels Prins, MD, director of the Brain Research Center in Amsterdam, the Netherlands, the trial’s primary end point will look at change in CDR-Sum of Boxes score, while other secondary end points include change in Timed Up and Go (TUG), NTB, and the Alzheimer’s Disease Cooperative Scale-Clinical Global Impression of Change.
In sample size calculations based on simple t-test at week 16, assuming the effect size in patients with normal baseline plasma ptau181, with 80 patients per arm and alpha of 0.05, the statistical power was around 85% with the NTB, 95% with TUG, and greater than 95% with CDR-SB. Based on these, investigators concluded that the new phase 2b study has high statistical power to confirm the efficacy results seen in AscenD-LB, and has the potential to demonstrate effects on pathologic disease progression in the basal forebrain.
EIP Pharma originally announced the results of AscenD-LB in late 2020, with the treatment meeting its primary end point of improvement in cognition based on NTB in a cohort of patients with mild-to-moderate DLB. The data showed that patients who received neflamapimod 3 times daily demonstrated significant improvement on the NTB compared with those who received neflamapimod twice daily or placebo (effect size d = 0.52; P = .015). No patients discontinued the study because of drug-related adverse events.2
Earlier this year, an additional prespecified analysis of the study showed that patients with DLB without elevated ptau181 levels were much more responsive to neflamapimod. During the 16-week treatment period, improvements in all end points were higher among neflamapimod-treated patients who were below the 2.2 pg/mL of ptau181 cutoff at baseline (below cutoff, n = 45; above cutoff, n = 40), compared with those above it. Participants below the cutoff showed significant improvement compared with placebo in an Attention Composite measure (+0.42; 95% CI, 0.07–0.78; P = .023, Cohen's d effect size = .78), the CDR-SB (-0.60; 95% CI, -1.04 to -0.06; P = .031, d = .74), the TUG test (-3.1 sec; 95%CI, -4.7 to -1.6; P <.001, d = .74), and International Shopping List Test-Recognition (+1.4; 95% CI, 0.2–2.5, P = .024, d = 1.00).3
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. It received FDA fast track designation for the treatment of DLB in November 2019.