Clinical Benefits of Oral Tramiprosate in APOE4/4 Homozygotes with Mild Alzheimer’s Disease (AD): Responder Analyses from the Phase 3 North American Trial

S. Abushakra,  A. Porsteinsson, C. Sadowsky, S. Gauthier, B. Vellas, A. Power, L. Shen, T. Lin, J. Hey, M. Tolar

Abstract

Background:
ALZ-801, an oral pro-drug of tramiporsate, received Fast Track designation for development as a disease modifying treatment for AD. ALZ-801 provides consistent plasma levels of the active agent tramiprosate with improved PK and GI tolerability (Hey et al. 2018). Tramiprosate inhibits formation of toxic soluble amyloid oligomers (Kocis et al. 2017) and was evaluated in Mild to Moderate AD patients. In the North American Phase 3 trial, patients homozygous for apolipoprotein e4 allele (APOE4/4) showed meaningful benefits in Mild AD patients (Abushakra et al. 2016 & 2017). We analyzed individual responses and response rates on the clinical outcomes.

Methods:
The 78-week NA trial enrolled 1,053 AD patients (MMSE16-26) to either placebo, tramiprosate 100mg BID, or 150mg BID; including 148 APOE4/4 homozygotes. At 150mg BID, APOE 4/4 homozygous patients with Mild AD showed significant and/or meaningful benefits on ADAS-cog and CDR-SB (co-primary endpoints) and DAD (disability assessment). For APOE4/4 Mild subgroups, individual changes from baseline were plotted for placebo and high dose (waterfall analysis). Responders were defined by changes on ADAS-cog ≤0 and CDR-SB ≤0 (no worsening); and DAD worsening ≤4 points. Responder analyses were conducted using Fisher’s exact test.

Results:
The APOE4/4 Mild subgroups in the high dose and placebo arms included n=65 (MMSE ³20) and n=50 (MMSE ³22). In MMSE ³20 group, responder proportions were: ADAS-cog 57% vs. 21% (p= 0.011), CDR-SB 35% vs. 25% (NS), and DAD 46% vs 18% (p= 0.039). In MMSE ³22 group, they were: ADAS-cog 67% vs. 24% (p= 0.011), CDR-SB 44% vs. 29% (NS), and DAD 56% vs. 20% (p= 0.024). Safety in the APOE4/4 subgroup was favorable, and the most common dose-dependent TEAE were nausea, vomiting, and weight loss (Abushakra et al. 2017).

Conclusion:
The responder analyses show that tramiprosate/ALZ-801 provides significant and meaningful benefits in APOE4/4 patients with Mild or Early AD. At the 150mg BID dose, approximately 57-67% of patients remained cognitively stable, and 46-56% had minimal or no functional decline over 1.5 years. These results will inform cut-off points for responder analyses in confirmatory ALZ-801 efficacy trials in this genetically defined AD population with high amyloid burden.