An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

Philip Scheltens*, Niels Prins, Adriaan Lammertsma, Maqsood Yaqub, Alida Gouw, Alle Meije Wink, Hui May Chu, Bart N.M. van Berckel, John Alam

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Objective: The aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters. Methods: Sixteen patients with early AD received a highly selective p38α inhibitor (neflamapimod) for 84 days (12 weeks). To obtain a broad range of plasma drug exposures, subjects randomized to receive either 40 mg (n = 9) or 125 mg (n = 7) twice daily. Dynamic, 11C-PiB positron emission scans were performed at baseline and at Day 84 and quantitatively analyzed by reference parametric mapping. Episodic memory assessed as Wechsler Memory Scale (WMS) immediate and delayed recall composites. Result: In the 11C-PiB analyses there were no main group level effects, though in the prespecified responder analysis (>7% reduction in 11C-PiB signal) there were three responders in the 40 mg, and one in the 125 mg group. There were statistically significant increases from baseline in mean WMS immediate recall score and WMS delayed recall at both day 28 (P = 0.03 and P = 0.001) and day 84 (P = 0.001 and P < 0.001). Individual subject plasma drug concentration profiles were significantly positively correlated with the change in combined WMS immediate and delayed recall (P < 0.0001, r2= 0.70). Within-subject effect size was 0.59 for immediate recall and 0.67 for delayed recall. Interpretation: Selective p38α inhibition in patients with early AD may improve episodic memory and potentially impact β-amyloid production. These preliminary clinical findings support conduct of a longer duration placebo-controlled study, particularly to confirm the effects on episodic memory function.

Original languageEnglish
Pages (from-to)464-473
Number of pages10
JournalAnnals of Clinical and Translational Neurology
Issue number4
Publication statusPublished - 1 Apr 2018

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