Association of Plasma Phosphorylated Tau With the Response to Neflamapimod Treatment in Patients With Dementia With Lewy Bodies

Abstract

Background and ObjectivesIn 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 p38α kinase inhibitor neflamapimod, that targets the cholinergic degenerative process in DLB.MethodsThe 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).ResultsPre-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).DiscussionExclusion 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.NCT04001517at clinicaltrials.gov.

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies

“…In order to further define the optimal patient population to study in future studies, as pre-specified in the AscenD-LB protocol the AscenD-LB data were re-analyzed on a post-hoc basis following stratification of the sample according to the presence of Alzheimer’s disease (AD) co-pathology at baseline, as classified by pre-treatment levels of plasma ptau181. The motivation for that analysis, which was recently published ( 11 ), was a report published after the primary study was completed that showed that plasma ptau181 can be assessed in patients with DLB to identify patients with AD related co-pathology ( 18 ), which is associated with more advanced disease, including greater levels of neurodegeneration ( 19 ). That stratified analysis showed that the beneficial effects of neflamapimod compared to placebo over 16 weeks treatment were greater in those patients with normal pre-treatment levels of plasma ptau181, with treatment effect sizes of 0.7 or higher, for each of CDR-SB, TUG, attention, and ISLT-recognition.…”

“…That stratified analysis showed that the beneficial effects of neflamapimod compared to placebo over 16 weeks treatment were greater in those patients with normal pre-treatment levels of plasma ptau181, with treatment effect sizes of 0.7 or higher, for each of CDR-SB, TUG, attention, and ISLT-recognition. In Table 2 , we have extracted the results from both the primary publication ( 8 ) and the publication with the stratified results ( 11 ), and show the results in the neflamapimod 40mg TID patients compared to placebo in the Ascend-LB study for the overall patient population that includes a mixed population with respect to AD co-pathology (46% with, 54% without), and for those patients without AD co-pathology (i.e., excluding patients with plasma ptau 181 greater than the cut-off). With exclusion of patients with AD co-pathology, the magnitude of the level of improvement compared to placebo with neflamapimod treatment, assessed by Cohen’s d effect size, is substantially higher for all the parameters.…”

“…The clinical outcomes for patients given placebo and those treated with neflamapimod 40mg TID (the more clinically active of the two doses studied) within each sub-group (baseline plasma ptau181 < and ≥2.2 pg/mL). The results of this stratified analysis have been published recently ( 11 ) and separately from the primary publication.…”

“…In addition, at the highest dose studied (40mg three-times-daily, TID; 40mg twice-a-day, BID, was also evaluated in the study), neflamapimod improved outcomes in a six-test cognitive test battery, with the greatest benefits observed for tests of attention. Further analyses of the AscenD-LB study, specifically results stratified by pretreatment levels of phosphorylated tau as a marker of Alzheimer’s disease (AD) related co-pathology that showed the effects of neflamapimod are most prominent in the patients with pure DLB (i.e., patients without AD co-pathology), have also been recently reported ( 11 ). As an exploratory study, the AscenD-LB study did not have a primary hypothesis, and therefore definitive conclusions regarding efficacy could not be made.…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…Alam et al. ( 354 ) explored the correlation between plasma phosphorylated tau at residue 181 (ptau181) and the response to Neflamapimod treatment in patients with Dementia with Lewy Bodies (DLB). The study aimed to assess the impact of the p38α kinase inhibitor Neflamapimod, targeting the cholinergic degenerative process in DLB, on individuals with different baseline levels of pretreatment plasma ptau181.…”