The magnitude of neflamapimod’s effect on several efficacy measures proved to be consistent with the mechanism of action and prior preclinical data, with p-tau181 data suggesting a stronger effect on nonmixed Lewy body pathology.
Patients with baseline plasma phospho-tau 181 (p-tau181) less than 2.2 mg/mL—indicating the presence of nonmixed, pure Lewy body dementia (LBD) pathology—showed significantly greater efficacy outcomes when treated with neflamapimod (EIP Pharma) than those with higher levels, according to data from a phase 2 study. These findings support the notion that neflamapimod has potent and specific activity against basal forebrain cholinergic dysfunction, the underlying disease processes of DLB.1,2
The AscenD-LB trial (NCT04001417) was a phase 2, double-blind, proof-of-concept study that randomized patients 1:1 to either 40-mg neflamapimod capsules or matching placebo. Dosing regimen was based on weight, with participants weighing less than 80 kg receiving capsules twice-daily (BID) and those weighing greater than or equal to 80 kg received capsules thrice daily (TID). At baseline, 53% (22 of 41) of placebo and 54% (22 of 42) of the neflamapimod participants in the efficacy population had plasma p-tau181 less than 2.2 pg/mL, which predicts a lack of AD copathology.
The data, presented at the 14th Clinical Trials on Alzheimer Disease Conference (CTAD), November 9-12, further demonstrate the clinically significant treatment effect of neflamapimod. When efficacy was analyzed using plasma p-tau181 status to identify patients with or without copathology, patients without copathology demonstrated better efficacy outcomes, with effect size ranging from 0.56 to 0.78 for major efficacy end points for the comparison of 40-mg TID vs placebo in patients.
"The final results of the AscenD-LB study are extremely exciting for patients with DLB, caregivers and clinicians as we may be looking at the first DLB treatment that modifies the underlying disease",James E. Galvin, MD, MPH, professor of neurology, and director, Lewy Body Dementia Research Center of Excellence, University of Miami Miller School of Medicine, said in a statement.2
Using a mixed model confined to patients with pure DLB, the magnitude of the treated population relative to placebo was substantial and clinically important. On cognition, investigators observed an effect size of 0.15 (P >.02) and 0.29 (P = .185) on Neuropsychological Test Battery (NTB) composite z-scores and Attention composite z-scores in all neflamapimod groups compared with placebo, respectively.
On Timed Up and Go Test, investigators observed effect sizes of 0.40 (P = .024) and 0.74 (P <.001) in the all neflamapimod and neflamapimod 40-mg TID groups vs placebo, respectively. Effect sizes were 0.58 (P = .0129) and 0.70 (P = .031) for those respective groups on Clinical Dementia Rating Scale.
Galvin added, "combined with the scientific studies that preceded the clinical study, the results suggest that neflamapimod has the potential to change the course of the disease and significantly improve function and quality of life in patients with DLB. In addition, AscenD-LB has also advanced the field by increasing our understanding of the disease and the tools we can use to measure drug treatment effects in clinical trials in dementia with Lewy bodies."
Neflamapimod remains the first treatment with potential impact on cognition, function, and motor function in patients with DLB. EIP Pharma previously announced that the study met its primary end point of demonstrating an improvement in cognition as assessed by the NTB (effect size d = 0.52; P = .015). Significant improvements (P <.05) or trends (P <.01) were evident on multiple secondary clinical end points as well.3
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