Susan Abushakra MD*, Bruno Vellas MD, Serge Gauthier MD, Anton Porsteinsson MD, Carl Sadowsky MD, Aidan Power MD, Larry Shen PhD, Lu Wang MS, Tim Lin MS, John Hey PhD, Martin Tolar MD PhD
ALZ-801 is being developed as an oral disease modifying treatment for AD and has received Fast Track designation from the U.S. FDA. ALZ-801 is a pro-drug of tramiprosate which was designed to improve the oral bioavailability of the active agent tramiprosate. ALZ-801 provides consistent plasma levels of tramiprosate with improved GI tolerability (Hey et al. 2018). Tramiprosate which inhibits the formation of toxic soluble amyloid oligomers (Kocis et al. 2017) without binding to amyloid plaques, was previously evaluated in Mild to Moderate AD patients. Subgroup analyses of the completed North American (NA) Phase 3 trial, showed that patients homozygous for ε4 allele of apolipoprotein E (APOE4/4) showed meaningful benefits in Mild AD patients (Abushakra et al. 2016 & 2017). In this subgroup of APOE4/4 homozygous patients with Mild AD, we analyzed individual responses and response rates on cognitive and functional outcomes.
The 78-week NA trial enrolled 1,052 AD patients with Mild to Moderate AD (MMSE16-26) to either placebo, tramiprosate 100mg BID, or 150mg BID; and included 152 APOE4/4 homozygotes across the three dose arms. At 150mg BID, APOE4/4 homozygous patients with Mild AD (two Mild AD groups: MMSE 20 or greater; MMSE 22 and greater) showed significant and/or meaningful benefits on ADAS-cog and CDR-SB (co-primary endpoints) and DAD (disability assessment). For these two APOE4/4 Mild subgroups, individual changes from baseline were plotted for patients in the placebo and high dose arms (waterfall analysis). Responders were defined by changes on ADAS-cog ≤0 and CDR-SB ≤0 (no worsening); and DAD worsening ≤4 points, respectively. Responder analyses were performed on the Week 78 completer dataset using summary statistics and treatments groups were compared with Fisher’s exact test. The responder analyses were also performed on subjects who completed 52 weeks, 65 weeks, and 78 weeks, using repeated measure logistic regression analysis via generalized estimating equations (GEE) to account for the effect of missing data.
The APOE4/4 Mild subgroups in the high dose and placebo arms included n=65 (MMSE ³20) and n=50 (MMSE ³22), respectively. 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, the responder proportions were: ADAS-cog 67% vs. 24% (p=0.011), CDR-SB 44% vs. 29% (NS), and DAD 56% vs. 20% (p=0.024). Responder results using the repeated measure analyses showed similar results on the 3 outcomes. The safety database of tramiprosate across all APOE genotypes includes approximately 1,600 patients exposed to active drug for up to 1.5 years, and approximately 400 patients exposed for up to 2.5 years. Safety in the APOE4/4 subgroup at the high dose was also favorable, and the most common dose-dependent treatment emergent adverse events were nausea, vomiting, and weight loss (Abushakra et al. 2017). There were no events of vasogenic edema in the subset of patients who underwent MRI analyses, including the APOE4 carriers (Abushakra et al. 2016).
In APOE4/4 patients, these responder analyses suggest that tramiprosate/ALZ-801 can provide significant and meaningful benefits in patients with Early/Mild 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 response definition, and for responder analyses in confirmatory efficacy trials with ALZ-801, which are planned in APOE4/4 homozygotes with Early/Mild AD. Considering the favorable long-term safety and the promising efficacy signals in APOE4/4 homozygotes, ALZ-801 has the potential to become a meaningful treatment for this genetically defined high-risk AD population with substantial amyloid burden and aggressive disease course.