Presented at the 14th Annual International Athens/Springfield Symposium on Advances in Alzheimer Therapies Conference in Athens Greece

1Martin Tolar, 2Bruno Vellas, 3Jeffrey Cummings, 4Anton Porsteinsson, 1Susan Abushakra, 1Aidan Power, 1Jeremy Yu, 1John A. Hey
1Alzheon Inc., Framingham, MA, USA; 2University of Toulouse, Toulouse, France; 3Cleveland Clinic and Lou Ruvo AD Center, Las Vegas, NV, USA; 4Charles University, Prague, Czech Republic, 5 University of Rochester, Rochester, NY, USA

Background:
Tramiprosate is an oral inhibitor of amyloid aggregation that demonstrated a decrease in soluble and insoluble amyloid aggregation, deposition and neurotoxicity in preclinical studies. ALZ-801 is a novel, oral, small molecule pro-drug of tramiprosate with improved pharmacokinetic properties, and enhanced gastrointestinal tolerability, allowing more consistent plasma exposures to the active moiety, tramiprosate. Tramiprosate showed evidence of amyloid target engagement in a Phase 2 study in AD subjects, with up to 70% reduction in CSF Abeta 42. On this basis, tramiprosate was evaluated in two global Phase 3 studies of 78 weeks duration in North America (NA) and several EU countries. These studies enrolled approximately 2,000 patients with Mild and Moderate AD (NA study: Aisen et al. 2011), and approximately 55% were carriers of the APOE4 gene. Subgroup analyses of subjects with at least one ε4 allele of APOE gene (APOE4 carriers, N = 1,099 in both studies) were previously reported (Hey et al. ADPD 2015), and showed significant efficacy on cognitive and functional outcomes. We herein report the results of the combined dataset of patients with a single ε4 allele of APOE gene (APOE4 heterozygotes).

Methods:
The tramiprosate Phase 3 program included two similarly designed global studies of 78 weeks duration in North America (NA) and several EU countries. The two studies enrolled approximately 2,000 patients with Mild and Moderate AD. The design and results of the NA study (Alphase study) was previously published (Aisen et al. 2011, and Gauthier et al. 2009). This study was placebo controlled, double blinded, 3-arm study (placebo, 100mg BID, 150mg BID), of 78 weeks duration, and enrolled patients with mild and moderate AD, MMSE 16-26. The study allowed stable doses of acetylcholinesterase inhibitors (AChEI) and/or memantine. The EU study was of similar design, but did not allow use of memantine. The co-primary outcome measures in both studies were ADAS-cog and CDR-SB at 78 weeks. Approximately 55% of the study populations were APOE4 carriers. APOE4 heterozygotes accounted for ~75% of the APOE4 carrier patients, and for ~40-45% of overall AD patients in these two Phase 3 studies. Efficacy outcomes were analyzed using a mixed model repeated measure analysis.

Results:
The baseline demographics of overall population in each study were similar, except for the use of memantine background therapy (NA study ~50%, EU study none). Since the initial NA study did not achieve its primary objectives in the overall population, the EU study was terminated early, but most patients had completed at least 52 weeks of treatment, and the study remained blinded until the database lock. In the NA study, there were a total of 434 APOE4 heterozygous patients (age up to 85 years, placebo 145, low dose 140, high dose 149). Mean age was ~71 years, MMSE was ~21 (~60% Mild, 40% Moderate), 100% were on AChEI and ~50% on memantine. In the EU study, the APOE4 heterozygotes (n = 436) had similar demographics. In the combined APOE4 heterozygous subgroups there were a total of 870 patients (placebo 299, low dose 284, high dose 287). In the NA study, the low dose showed significant cognitive drug effects on ADAS-cog at 52, 65, and 78 weeks: 3.19 (p = 0.0003); 1.93 (p = 0.03); and 2.38 (p = 0.008). In the combined datasets, the same dose also showed significant cognitive drug effects on ADAS-cog at 52, 65, and 78 weeks: 2.08 (p = 0.001); 1.62 (p = 0.016); and 1.85 (p = 0.009). The CDR-SB results in the NA study with the low dose at 52, 65, and 78 weeks were: 0.65 (p = 0.04); 0.82 (p = 0.01); and 0.86 (p = 0.008). At the high dose, the CDR results at 52-78 weeks showed a consistent positive trend: delta of 0.59-0.56, (p < 0.1). In the combined datasets, the CDR results with the low dose at 52, 65, and 78 weeks were: 0.37 (p = 0.06); 0.63 (p = 0.003); and 0.70 (p = 0.001); and at the high dose were significant at 78 weeks: 0.6, (p = 0.007). In contrast, APOE4 non-carriers showed no benefit on ADAS or CDR-SB. In the merged data sets, the overall incidence of adverse events was similar across the 3 treatment groups, and between the ApoE4 heterozygotes (n = 915) and non-carriers (n = 713). The incidence of nausea was lower in APOE4 heterozygotes compared to non-carriers. There were no reports of vasogenic edema in these studies.

Conclusion:
APOE4 heterozygous subjects comprise approximately 50-60% of all AD patients, and are at high risk of developing amyloid pathology and AD symptoms (~4x more risk than non-carriers). They also have high rates of amyloid positivity in imaging studies (~70-80%), with more advanced patients having higher rates than earlier AD patients (Ossenkoppele et al. 2015). This population is also at high risk of developing vasogenic edema (ARIA-E) with emerging anti-amyloid immunotherapies. Based on data from the two Phase 3 studies, tramiprosate seems to provide cognitive efficacy at the low dose (ADAS-cog up to 2-2.4 points) with positive effect on function at 78 weeks (at both doses). Both doses showed a comparable favorable safety profile in this population, who may be at risk of vasogenic edema with emerging anti-amyloid antibodies. This positive benefit risk profile in APOE4 heterozygotes supports the future development of oral ALZ-801 (the tramiprosate pro-drug) for this large population of AD patients. Of note, larger clinical efficacy of tramiprosate in homozygous (see Abushakra et al presentation at this conference) versus heterozygous population suggests a gene dose effect of APOE4, potentially due to larger amyloid burden in homozygous APOE4 subjects. In both populations, ALZ-801 has promise to provide a safe, effective, and oral treatment in AD patients already receiving maximal standard of care, thus fulfilling an unmet need for this large segment of the AD population.