English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  In preclinical studies, p38⍺ kinase is implicated in Alzheimer’s disease (AD) pathogenesis. In animal models, it mediates impaired synaptic dysfunction in the hippocampus, causing memory deficits, and is involved in amyloid-beta (Aβ) production and tau pathology.    Methods  The REVERSE-SD (synaptic dysfunction) study was a multi-center phase 2, randomized, double-blind, placebo-controlled trial of the p38⍺ kinase inhibitor neflamapimod; conducted December 29, 2017, to June 17, 2019; 464 participants screened, and 161 randomized to either 40 mg neflamapimod (78 study participants) or matching placebo (83 study participants), orally twice daily for 24 weeks. Study participants are as follows: CSF AD-biomarker confirmed, Clinical Dementia Rating (CDR)-global score 0.5 or 1.0, CDR-memory score  ≥ 0.5, and Mini-Mental State Examination (MMSE) 20–28. The primary endpoint was the improvement in episodic memory, assessed by combined change in  Z -scores of Hopkins Verbal Learning Test-Revised (HVLT-R) Total and Delayed Recall. Secondary endpoints included change in Wechsler Memory Scale-IV (WMS) Immediate and Delayed Recall composites, CDR-SB, MMSE, and CSF biomarkers [total and phosphorylated tau (T-tau and p-tau 181 ), Aβ 1-40 , Aβ 1-42 , neurogranin, and neurofilament light chain].    Results  At randomization, the mean age is 72, 50% female, 77% with CDR-global score 0.5, and mean MMSE score 23.8. The incidence of discontinuation for adverse events and serious adverse events (all considered unrelated) was 3% each. No significant differences between treatment groups were observed in the primary or secondary clinical endpoints. Significantly reduced CSF levels with neflamapimod treatment, relative to placebo, were evident for T-tau [difference (95% CI): −18.8 (−35.8, −1.8);  P =0.031] and p-tau 181  [−2.0 (−3.6, −0.5);  P =0.012], with a trend for neurogranin [−21.0 (−43.6, 1.6);  P =0.068]. In pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, subjects in the highest quartile of trough plasma neflamapimod levels demonstrated positive trends, compared with placebo, in HLVT-R and WMS.    Conclusions and relevance  A 24-week treatment with 40 mg neflamapimod twice daily did not improve episodic memory in patients with mild AD. However, neflamapimod treatment lowered CSF biomarkers of synaptic dysfunction. Combined with PK–PD findings, the results indicate that a longer duration study of neflamapimod at a higher dose level to assess effects on AD progression is warranted.    Trial registration   ClinicalTrials.gov  identifier:  NCT03402659 . Registered on January 18, 2018    Supplementary Information  The online version contains supplementary material available at 10.1186/s13195-021-00843-2.

A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer’s disease