OBJECTIVES: 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 a promising signal in patients homozygous for the ε4 allele of apolipoprotein E (APOE4/4 homozygotes). Tramiprosate efficacy was further analyzed in APOE4/4 patients with Mild versus Moderate AD.

METHODS: The 78-week Phase 3 North American study enrolled 1,052 AD patients (MMSE range 16- 26) on a 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 the overall population and the two Mild groups: MMSE (20-26) and (22-26) at baseline.

RESULTS: Analyses 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 Mild to Moderate AD group, early benefits were observed and sustained for 52, 65 and 78 weeks (ADAS-cog) or 52 weeks (CDR-SB). The largest and most significant effects occurred in the Milder subgroup (MMSE 22-26).

CONCLUSIONS: In the APOE4/4 AD population, tramiprosate showed the largest benefit with sustained cognitive and functional improvement above baseline in Milder (MMSE 22-26) patients. This preferential efficacy in Milder AD is consistent with the effects of other anti-amyloid agents. Surprisingly, Mild to 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 and Milder patients.