Tramiprosate, an oral amyloid anti-aggregation agent, shows robust cognitive efficacy in APOE4/4 homozygous AD patients: efficacy and safety analyses from two Phase 3 trials

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

¹Susan Abushakra, ²Bruno Vellas, ³Jeffrey Cummings, ⁴Jakub Hort, ⁵Anton Porsteinsson, ¹John A. Hey, ¹Aidan Power, ¹Martin Tolar

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:
ALZ-801 is a novel, orally bioavailable pro-drug of tramiprosate with improved pharmacokinetic characteristics, which is being developed as a potential disease modifying treatment for Alzheimer’s disease (AD). Tramiprosate, the active moiety of ALZ-801, is an amyloid anti-aggregation agent that reduces amyloid oligomer toxicity in preclinical studies. In a Phase 2 study, tramiprosate was associated with ~70% decrease in CSF at the highest 150mg BID dose, thus showing target engagement (Aisen et al. 2006). In two completed Phase 3 studies in over 2000 patients with Mild to Moderate AD, tramiprosate showed a favorable safety profile over 78 weeks of treatment. These studies showed numerical improvements but did not achieve statistical significance in the overall study population (Aisen et al. 2011). Since these studies were completed, our understanding of AD pathology has markedly advanced. It is now known that cortical amyloid burden and APOE4 carrier status play a critical role in progression of AD, including loss of cognitive function. In addition, APOE4 carrier status is associated with increased vulnerability to some amyloid targeting drugs, with APOE4 carriers being more susceptible to vasogenic edema. Therefore, the tramiprosate Phase 3 studies were analyzed based on number of APOE4 alleles (homozygous and heterozygous groups).

Methods:
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) were previously published (Aisen et al. 2011, Gauthier et al. 2009). This study was placebo controlled, double blind, 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.  APOE4/4 homozygotes accounted for ~25% of the APOE4 carrier patients, and for 10-15% of overall AD patients in population samples.  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 was a total of 146 APOE4/4 homozygous patients (age up to 85 years, placebo 58, low dose 48, high dose 40). Their mean age was 71 years, MMSE = 20.9 ± 3.3 (~60% Mild, 40% Moderate), 100% were on AChEI and 48% on memantine. In the EU study, the APOE4/4 patients (n= 100) had similar demographics. In the combined APOE4/4 group there was a total of 257 patients (placebo 96, low dose 86, high dose 75). The high dose showed robust and significant cognitive drug effects on ADAS-cog at 52, 65, and 78 weeks in the combined groups: 2.85 (p = 0.02); 4.18 (p < 0.001); and 4.56 (p < 0.001). The drug effect on ADAS-cog showed a positive trend (delta ~ 1.7, p = 0.14) starting at 26 weeks and increased over time. The CDR-SB results with the high dose at 52, 65, and 78 weeks in the combined groups were: 0.64 (p = 0.054); 0.86 (p < 0.02); and 0.60 (p = 0.1). The CDR-SB was significant at 26 weeks (delta = 0.71, p = 0.02). In contrast, APOE4 non-carriers showed no benefit on ADAS or CDR-SB. In the merged data sets, the incidence of adverse events was similar between the ApoE4/4 homozygotes (n = 263) and non-carriers (n = 713). In the NA study, the incidence of diarrhea and falls in APOE4/4 patients was lower than the non-carriers. There were no reports of vasogenic edema in these studies.

Conclusion:
APOE4/4 subjects comprise a genetically well-defined population at highest risk of developing amyloid pathology, and of developing progressive AD symptoms before 70 years of age. A recent meta-analysis of imaging studies report rates of amyloid positivity ~90-95% in APOE 4/4 with AD dementia (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 shows robust cognitive efficacy (ADAS-cog ~4.6 points at 78 weeks), supported by a consistent and positive trend on function, with a favorable safety profile. Of note, higher efficacy of tramiprosate in the APOE4/4 homozygous group compared to the heterozygotes (see Tolar et al. presentation at this conference) suggests a gene dose effect of APOE4, potentially due to larger amyloid burden in APOE4/4 homozygotes. In both APOE4 carrier populations, the optimal benefit risk profile of tramiprosate supports the development of ALZ-801 (the tramiprosate prodrug) for APOE4 homozygous and heterozygous AD patients. ALZ-801 has promise to be a safe and effective oral treatment for symptomatic AD in patients already receiving maximal standard of care.