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Background: Tramiprosate is an oral amyloid anti-aggregation agent that reduces amyloid oligomer toxicity in preclinical studies and was evaluated in two 78-week trials in North America and Western Europe that enrolled 2,025 patients with Mild to Moderate Alzheimer’s Disease. The completed North American study did not achieve its efficacy objectives, but a pre-specified subgroup analysis suggested potential efficacy in apolipoprotein E4 (APOE4) carriers. To further explore this observation, we analyzed tramiprosate Phase 3 clinical data based on the number of APOE4 alleles. Objectives: To analyze tramiprosate efficacy, safety, and occurrence of vasogenic edema in the three APOE4 subgroups: homozygous, heterozygous and non-carriers. Design: Randomized, double-blind, placebo-controlled parallel-arm multi-center studies. Setting: Academic Alzheimer’s disease &amp; dementia centers, community-based dementia and memory clinics, and neuropsychiatric clinical research sites. Participants: Subjects included 2,025 patients, 50 years of age or older, with approximately 60% having APOE4 carrier status (10-15% homozygotes and 45-50% heterozygotes), and mild to moderate disease. All subjects were on stable symptomatic drugs. Intervention: Randomized subjects received placebo, 100 mg BID, or 150 mg BID of tramiprosate. Measurements: Co-primary outcomes in both studies were change from baseline in the ADAS-cog11 and CDR-SB assessment scales. Results: Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID of tramiprosate, showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit. In 426 patients with MRI scans, no cases of treatment-emergent vasogenic edema were observed. In the three subgroups, the most common adverse events were nausea, vomiting, and decreased weight. Conclusions: The “APOE4 Gene-Dose effect” is likely explained by the high prevalence of amyloid pathology in symptomatic APOE4 carriers. In APOE4/4 Alzheimer’s disease patients, the high dose of tramiprosate showed favorable safety and clinically meaningful efficacy in addition to standard of care.

CLINICAL BENEFITS OF TRAMIPROSATE IN ALZHEIMER’S DISEASE ARE ASSOCIATED WITH HIGHER NUMBER OF APOE4 ALLELES: THE “APOE4 GENE-DOSE EFFECT”