BACKGROUND: Tramiprosate is an oral amyloid antiaggregation 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 & 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.