Alam_2023_Neurology__

BACKGROUND AND OBJECTIVES: In a proportion of patients, dementia with Lewy bodies (DLB) is associated with Alzheimer's disease (AD) co-pathology, which is linked to accelerated cognitive decline and more extensive cortical atrophy. The objective herein was to evaluate the relationship between a biomarker of AD co-pathology, plasma tau phosphorylated at residue 181 (ptau181), and the treatment effects of the p38alpha kinase inhibitor neflamapimod, that 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), pre-treatment plasma ptau181 levels were determined and participants grouped based on a cut-off 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 40mg three-times-daily (TID; the higher, and more clinically active of two doses studied) were analyzed utilizing Mixed Models for Repeated Measures within each sub-group (baseline plasma ptau181 < and <=2.2 pg/mL). RESULTS: Pre-treatment plasma ptau181 levels determined in eight-five participants with mild-to-moderate DLB receiving cholinesterase inhibitors; with 45 participants below, and 40 above, the 2.2 pg/mL cut-off at baseline. In the 16-week treatment period, in the comparison of placebo with neflamapimod 40mg TID, for all endpoints evaluated, improvements with neflamapimod treatment were greater in participants below the cut-off, compared with that in those above the cut-off. In addition, participants below the ptau181 cut-off 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,-0.06, p=0.031, d=0.70), the Timed Up and Go test (-3.1 sec, 95%CI:-4.7,-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 DLB patient population that is more responsive to neflamapimod. More generally, plasma biomarkers of AD co-pathology at study entry should be considered as stratification variables in DLB clinical trials. NCT04001517 at clinicaltrials.gov.