Presented at the Alzheimer’s Association International Conference (AAIC) 2016 in Toronto, Canada
ALZ-801, an oral amyloid aggregation inhibitor, which is being developed as a treatment for AD, is a pro-drug of tramiprosate with improved pharmacokinetic profile and GI tolerability. Tramiprosate, the active agent in ALZ-801, was previously evaluated in >2,000 patients in two Phase 3 studies in Mild to Moderate AD. The North American (NA) study efficacy results were not significant (Aisen, et al. 2011), and the European (EU) study was prematurely terminated. We present Phase 3 efficacy results in the subgroup of homozygous APOE4/4 patients, and pooled safety analyses of both studies that inform the design of an upcoming ALZ-801 Phase 3 study.
The two similarly designed RCTs were 78 weeks in duration with 3 parallel arms (placebo and 2 active doses), and enrolled patients with MMSE 16-26. In the EU study, most patients completed treatment through week 52 only. In both studies, approximately 60% of patients were carriers of the APOE4 allele, a prespecified covariate, and 15% of trial patients were APOE4/4 homozygotes.The APOE4 subgroup analyses were pre-specified, but originally not performed. Analyses used the mixed effects repeatedmeasures (MMRM) method.
The ITT population of the NA study included 147 APOE4/4 patients. The co-primary outcomes were the differences between treatment arms in the change from baseline on the ADAS-cog and CDR-SB. On the ADAS-cog (primary outcome) the 150mg BID dose showed significant benefit at Week 65 (delta 3.5, p = 0.007) and 78 (delta 2.6, p = 0.04). On the co-primary CDR-SB, the same dose showed the following effects: at Week 65 (0.8, p = 0.06) and at Week 78 (0.5, p = 0.21). These differences correspond to >30% efficacy benefit over placebo at Week 65. The EU study showed similar results at 52 weeks on observed case analysis. Pooled safety data included 2,025 patients overall, with 263 APOE4/4 patients, who showed a similar safety profile to overall population. The most common adverse events were mild to moderate gastrointestinal AEs, and only 5% led to withdrawal. There were no ARIA-E events in the MRI subset of patients treated with tramiprosate.
In the APOE4/4 population tramiprosate showed significant and clinically meaningful efficacy on cognition and a positive trend on function. The longterm safety and tolerability profile was favorable. A Phase 3 study of ALZ-801, at a dose equivalent to tramiprosate 150mg BID, is planned in this genetically homogenous population known to have a high prevalence and burden of amyloid pathology.