Neurology | September 1, 2023

Alam JJ, Maruff P, Doctrow SR, Chu HM, Conway J, Gomperts SN, Teunissen C.

Neurology. 2023

https://doi.org/10.1212/WNL.0000000000207755

Abstract

Background and Objectives In a proportion of patients, dementia with Lewy bodies (DLB) is associated with Alzheimer disease (AD) copathology, which is linked to accelerated cognitive decline and more extensive cortical atrophy. The objective was to evaluate the relationship between a biomarker of AD copathology, plasma tau phosphorylated at residue 181 (ptau181), and the treatment effects of the p38α kinase inhibitor neflamapimod, which targets the cholinergic degenerative process in DLB.

Methods The AscenD-LB study was a phase 2a, randomized (1:1), 16-week, placebo-controlled clinical trial of neflamapimod in DLB, the main results of which have been published. After the study was completed (i.e., post hoc), pretreatment plasma ptau181 levels were determined and participants were grouped based on a cutoff for AD pathology of 2.2 pg/mL (established in a separate cohort to identify AD from healthy controls). Clinical outcomes for the comparison of placebo with neflamapimod 40 mg three times daily (TID; the higher and more clinically active of 2 doses studied) were analyzed using mixed models for repeated measures within each subgroup (baseline plasma ptau181 < and ≥2.2 pg/mL).

Results Pretreatment plasma ptau181 levels were determined in eighty-five participants with mild-to-moderate DLB receiving cholinesterase inhibitors, with 45 participants below and 40 above the 2.2 pg/mL cutoff at baseline. In the 16-week treatment period, in the comparison of placebo with neflamapimod 40 mg TID, for all end points evaluated, improvements with neflamapimod treatment were greater in participants below the cutoff, compared with those above the cutoff. In addition, participants below the ptau181 cutoff at baseline showed significant improvement over placebo in an attention composite measure (+0.42, 95% CI 0.07–0.78, p = 0.023, d = 0.78), the Clinical Dementia Rating Scale Sum of Boxes (−0.60, 95% CI −1.04 to −0.06, p = 0.031, d = 0.70), the Timed Up and Go test (−3.1 seconds, 95% CI −4.7 to −1.6, p < 0.001, d = 0.74), and International Shopping List Test-Recognition (+1.4, 95% CI 0.2–2.5, p = 0.024, d = 1.00).

Discussion Exclusion of patients with elevated plasma ptau181, potentially through excluding patients with extensive cortical neurodegeneration, enriches for a patient with DLB population that is more responsive to neflamapimod. More generally, plasma biomarkers of AD copathology at study entry should be considered as stratification variables in DLB clinical trials.