Masupirdine in combination with donepezil and memantine in patients with moderate Alzheimer's disease: Subgroup analyses of memantine regimen, plasma concentrations and duration of treatment

Background Masupirdine (SUVN‐502), a selective 5‐hydroxytryptamine‐6 (5‐HT6) receptor antagonist has demonstrated efficacy in animal models of cognitive impairment. To assess its clinical utility, a randomized, double blind, placebo controlled 26 week phase 2 study was conducted in moderate Alzheimer’s disease (AD) patients who were on stable treatments with donepezil and memantine. Method In the phase 2 study, a total of 564 moderate AD patients with MMSE scores between 12 and 20 were randomized to receive either 50 mg or 100 mg of masupirdine or placebo once daily for 26 weeks. All patients were treated with donepezil 10 mg + memantine 10 mg BID or Namenda XR 28 mg QD; or Namzaric (donepezil 10 mg + 28 mg Namenda XR). The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog11). In subgroup analyses, impact of memantine regimen, memantine plasma concentrations and memantine treatment duration on the efficacy of masupirdine in moderate AD patients was analysed. Result In participants whose memantine plasma concentrations were ≤100 ng/mL at Week 26, there was lesser decline in ADAS‐Cog 11 scores in participants taking masupirdine than in those on placebo. In participants taking the higher masupirdine study dose of 100 mg daily, there were also congruent signals for less decline on MMSE and CDR‐SB. Additionally, in participants whose memantine plasma concentrations were ≤100 ng/mL at Week 26, masurpirdine treatment was associated with Week 26 response rates on the ADAS‐Cog 11, for improved or stable scores compared to baseline, that were twice that of placebo. In participants on background memantine treatment for > 4 years, masupirdine treatment (versus placebo) was associated with lesser decline in ADAS‐Cog 11 scores. Conclusion Subgroup analyses of the masupirdine Phase 2 POC study to assess potential effects of memantine regimen, memantine plasma concentrations and duration of treatment on primary and secondary study outcomes revealed several potential signals for differential effects favoring masupirdine treatment. These observations merit better understanding and further possible investigations of masupirdine as a potential treatment for AD dementia.