ALZ-801 is an oral pro-drug of tramiprosate being developed as a disease-modifying agent for Alzheimer’s disease (AD). Tramiprosate inhibits formation of Aβ oligomers and neurotoxicity. In a Phase 3 study in Mild/Moderate AD, tramiprosate did not demonstrate efficacy in the overall population but subgroup analyses showed promising signal in patients homozygous for e4 allele of apolipoprotein E (APOE4/4 homozygotes). Tramiprosate efficacy was further analyzed in APOE4/4 patients with Mild versus Moderate AD. Method
The 78-week Phase 3 North American study enrolled 1,053 AD patients (MMSE range 16-26) on background of stable symptomatic AD drugs in 3 parallel arms: placebo, 100 mg BID, 150 mg BID. ADAS-cog and CDR-SB co-primary outcomes were analyzed using MMRM in Moderate (18-21) and Mild (22-26) subgroups.Results
RESULTSAnalyses included 147 APOE4/4 homozygous AD patients. In the Mild AD subgroup (~65%), tramiprosate showed early and progressive trends for cognitive and functional benefit (nominally significant at Weeks 52-78). In the Moderate AD sub-group, early benefits were observed and sustained for 65 weeks (ADAS-cog) or 52 weeks (CDR-SB).Conclusion
In APOE4/4 AD population, tramiprosate showed largest benefit with sustained cognitive and functional improvement above baseline in Mild patients. This preferential efficacy in Mild AD is consistent with effects of other anti-amyloid agents. Surprisingly, Moderate AD patients also showed efficacy, lasting for ~65 weeks. This data suggests that ALZ-801, the optimized pro-drug of tramiprosate in preparation for Phase 3 studies, may provide benefit in both Mild and Moderate APOE4/4 patients, but with stronger effects in Mild patients.