Safety and Efficacy of Mevidalen in Lewy Body Dementia: A Phase 2, Randomized, Placebo-Controlled Trial

Background Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype. Objective To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD). Methods PRESENCE was a phase 2, 12-week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog(13)), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Numerous safety measures were collected. Results Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose-dependent improvements of MDS-UPDRS total score (sum of Parts I-III, 10 mg P < 0.05, 30 mg P < 0.05, 75 mg P < 0.01, compared to placebo). The 30 mg and 75 mg mevidalen doses significantly improved ADCS-CGIC scores compared to placebo (minimal or better improvement: 30 mg P < 0.01, 75 mg P < 0.01; moderate or better improvement: 30 mg P < 0.05, 75 mg P < 0.001). Increases in blood pressure, adverse events, and cardiovascular serious adverse events were most pronounced at the 75 mg dose. Conclusions Mevidalen harnesses a novel mechanism of action that improves motor symptoms associated with LBD on top of standard of care while improving or not worsening non-motor symptoms associated with traditional dopaminergic therapy. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society