S. Abushakra, C. Sadowsky, A. Porsteinsson, S. Gauthier, B. Vellas, A. Power, L. Shen, P. Wang, J. Hey, M. Tolar
Background: ALZ-801 which is in development as an oral treatment for AD, is a pro-drug of tramiprosate that provides improved pharmacokinetics and GI tolerability. Tramiprosate, the active agent in ALZ-801, inhibits the formation of toxic amyloid oligomers and amyloid aggrgation and was previously evaluated in two Phase 3 studies of Mild to Moderate AD. In the completed North American Phase 3 study, patients homozygous for ε4 allele of apolipoprotein E (APOE4/4 subgroup) showed significant efficacy over 78 weeks. Results for APOE4/4 patients who enrolled in an extension study for an additional 52 weeks are presented.
Methods: The NA Study enrolled 1,053 AD patients (MMSE range 16-26) including 148 APOE4/4 homozygotes to either placebo, 100mg BID, or 150mg BID. A total of 735 patients who completed this 78-week study enrolled in extension study, all at tramiprosate 150mg BID, but assignment during the controlled phase remained blinded. Changes in ADAS-cog and CDR-SB from original baseline up to 130 weeks were analyzed using a mixed effects model with repeated measures (MMRM).
Results: Of 735 patients enrolled in extension study, 104 were APOE4/4 homozygotes: 43, 33 and 28 from the original placebo, low and high-dose groups respectively; and 27, 25, 18 completed 130 weeks. The 150mg-150mg group showed larger ADAS-cog benefits at both 104 and 130 weeks than the placebo-150mg group (Δ = 3.9, p-value < 0.05), and a positive trend on CDR-SB (Δ = 1.0, p-value < 0.1). The ADAS-cog effect showed a trend to increase with time. The most common TEAE across all 735 patients were urinary tract infection and falls (>10%), while incidence of nausea and vomiting (< 10%) was lower than in controlled phase.
Conclusions: In APOE4/4 patients with Mild to Moderate AD, tramiprosate exhibited sustained cognitive and functional benefits over 2.5 years, compared to “delayed start” group who initially received placebo. These results suggest potential disease modifying effects, consistent with amyloid anti-aggregation mechanism. The profile of sustained efficacy and favorable long-term safety supports further development of ALZ-801 in APOE4/4 homozygous AD patients.