At Alzheon, we looked deeper at the data gathered from two pivotal studies of the active molecule tramiprosate in Alzheimer’s disease (AD), and assimilated this data with new insights into genetic markers and beta amyloid pathology in Alzheimer’s. By integrating this body of knowledge, we saw a new picture that led us to create ALZ-801, a prodrug of the active molecule tramiprosate.
From 2004 to 2008, tramiprosate was evaluated in more than 2,000 patients with AD in two Phase 3 studies: a North American study and a European study.
While the primary efficacy analysis of all subjects (i.e., the Intent-to-Treat population, ITT) in the North American Phase 3 study showed positive efficacy trends for tramiprosate in AD, it did not achieve statistical significance, due to misdiagnosis of the disease in approximately 30% of the subjects and other features of the study design. The North American study showed less-than-expected worsening in the placebo group (~30%, likely due to misdiagnosis) and, therefore, the study was underpowered for both primary endpoints. A second, European, Phase 3 study with tramiprosate was terminated early after the results of the North American study became known.
When these signs of efficacy of the active molecule tramiprosate were brought together with Alzheon’s insight into beta amyloid biology and an emerging understanding of the genetics of AD, we uncovered an opportunity to accelerate the development of new treatments for AD. New data from amyloid PET imaging studies suggest that APOE4 genotype confers a reliable diagnosis in patients with Alzheimer’s disease, in particular in subjects homozygous for APOE4 (APOE4/4), where the rate of misdiagnosis is < 5% (versus ~40% in APOE4 non-carriers).
As part of Alzheon’s clinical and regulatory development program, we conducted extensive clinical data analyses, working with three independent expert statistical groups and using industry standard methodologies, in order to evaluate tramiprosate efficacy in the APOE4/4 homozygous and APOE4 carrier subgroups in the tramiprosate Phase 3 studies. Our team found a clinically compelling and nominally significant improvement in cognition (as measured on the ADAS-cog scale) as well as function (as measured on the CDR-SB scale) that was sustained through 18 months of treatment (both p-values < 0.05). Importantly, the efficacy was demonstrated on top of the maximum standard of care symptomatic therapy currently used today (Abushakra et al., 2016).
ADAS-cog in Mild AD
CDR-SB in Mild AD
Similarly to the results from clinical studies with other disease modifying agents, the effect of tramiprosate in the APOE4/4 homozygous population was stronger in the Mild AD population than in the more advanced patients with Alzheimer’s. This is also consistent with the expected effect of an amyloid targeting agent, where an earlier intervention in the underlying pathology is more effective. Therefore, we will target the Mild AD population in our initial confirmatory studies with ALZ-801.
ADAS-cog in Mild to Moderate AD
CDR-SB in Mild to Moderate AD
Finally, the Phase 3 studies of tramiprosate demonstrated a favorable safety profile. Our subsequent studies have shown that the safety profile is further improved with the ALZ-801 prodrug.
In summary, this data support initiation of confirmatory clinical studies with ALZ-801 in APOE4/4 homozygous AD subjects, followed by evaluation of the molecule in all patients with Alzheimer’s disease or even at risk for the disease.