S. Abushakra, MD, A. Porsteinsson, MD, C. Sadowsky, MD, B. Vellas, MD, S. Gauthier, MD, A. Power, MD, L. Shen, PHD, P. Wang, PHD, J. Hey, PHD, M. Tolar, MD, PHD

Background:  ALZ-801 is in development as an oral AD treatment with disease modification potential. ALZ-801 is a pro-drug of tramiprosate that provides improved pharmacokinetics and GI tolerability. Tramiprosate, the active agent in ALZ-801, inhibits the aggregation of beta amyloid (Aβ) monomers into toxic, soluble Aβ oligomers through a recently reported enveloping molecular mechanism of action (Kocis et al. 2017). In transgenic CRND8 mice tramiprosate reduced amyloid plaque and soluble Aβ42 in brain (Gervais et al. 2007). In a 12-week study in AD patients, tramiprosate showed a dose-dependent decrease in soluble Aβ42 in CSF, with up to 70% reduction at 150mg BID (Aisen et al. 2006). On this basis, tramiprosate was evaluated in two global Phase 3 studies, one in North America (NA study), and the other in Western Europe (EU study). The NA study did not show efficacy in the overall Mild to Moderate AD study population, and therefore the EU study was terminated. Recent re-analyses of the NA dataset based on APOE4 genotype showed positive effects of tramiprosate in APOE4/4 homozygotes at 150mg BID (Abushakra et al. 2016), with larger effects in the Mild subgroup of patients (Abushakra et al. 2017). The NA study had a safety extension of up to an additional 52 weeks of treatment (Study 017). We evaluated efficacy and safety of tramiprosate in APOE4/4 homozygotes in the Extension Study.

Methods: The NA Study was a randomized, double-blind, placebo-controlled parallel-arm multi-center study of 78-weeks duration, and enrolled 1,053 AD patients (MMSE range 16-26) to either placebo, 100mg BID, or 150mg BID. The NA placebo-controlled study included 148 APOE4/4 subjects. ADAS-cog11 and CDR-SB were the co-primary efficacy outcomes. Subjects who completed this study were offered enrollment into the blinded extension study for up to 52 weeks of treatment, where all subjects received 150mg BID after a titration period. All subjects and sites remained blinded to treatment assignment in the placebo-controlled phase. Efficacy was analyzed in APOE4 subgroups as described previously for the placebo-controlled study (Abushakra et al. 2016). 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:  735 subjects completed the 78-week NA study and enrolled in the Extension Study. 104 subjects were APOE4/4 homozygotes: 43, 33 and 28 from the original placebo, low and high-dose groups respectively; and 27, 25, 18 completed a total of 130 weeks on study drug. The baseline demographics of the 3 dose arms were similar at the start of the Extension Study. Mean baseline MMSE were: 21.6, 21.3, and 21.0 for placebo, low and high dose arms respectively. The 150mg-150mg group showed significantly larger ADAS-cog benefits at both 104 and 130 weeks compared to the placebo-150mg group. On ADAS-cog, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 2.4 (p= 0.12), 3.3 (p=0.04), and 3.9 (p=0.03); the effects were smaller for the 100mg-150mg group. For CDR-SB, the differences in the change from baseline at Week 78, Week 104 and Week 130 were: 0.7 (p= 0.22), 0.9 (p=0.12), and 1.0 (p=0.09) for the 150mg-150mg group; the 100mg-150mg group showed no difference from the placebo-150mg group. For the 150mg-150mg group, ADAS-cog effect showed a trend to increase with time. In the Mild AD subgroup of APOE4/4 homozygotes (MMSE 22-26), the positive effects at the 150mg-150mg group were larger for both ADAS-cog and CDR-SB. Across all 735 patients, which included 471 who received active drug for up to 130 weeks, the most common TEAE were falls, nausea, urinary tract infection, diarrhea, and decreased weight. The safety profile in the 115 APOE4/4 homozygotes was similar.

Conclusions:  Reanalysis of two prior tramiprosate studies showed promising efficacy in the APOE4/4 homozygous patients with Mild and Moderate AD over 78 weeks. We further analyzed the efficacy analysis of the APOE4/4 homozygotes subgroup over an additional 52 weeks in the Extension Study. In APOE4/4 patients, tramiprosate 150mg BID exhibited sustained cognitive and functional benefits over 2.5 years, compared to the “delayed start” group who initially received placebo. The differences between the two treatment groups increased with time in the Extension Study. These results suggest potential disease modifying effects of tramiprosate, consistent with its molecular mechanism inhibiting formation of amyloid oligomers. The safety profile remained favorable with no new toxicities observed at exposures up to 2.5 years. This profile of sustained efficacy and favorable long-term safety supports further development of ALZ-801, an optimized prodrug of tramiprosate, in an upcoming confirmatory study in APOE4/4 homozygous AD patients.