Sixteen years after tramiprosate flunked a phase 3 trial, Alzheon’s prodrug form of the molecule has joined the lengthy list of pivotal Alzheimer’s disease failures.
The biotech picked tramiprosate off the scrap heap after identifying shortcomings with the failed phase 3 study and seeing signs of efficacy in patients with copies of the APOE4 gene. After public investors rebuffed its IPO plans twice in nine months, Alzheon rounded up $150 million across two private rounds and started a phase 3 trial of its valiltramiprosate prodrug formulation.
Valiltramiprosate was no better than placebo at slowing cognitive decline, as assessed by ADAS-Cog13, in the latest phase 3 trial, causing the study of 325 people with early Alzheimer’s to miss its primary endpoint. The result favored valiltramiprosate numerically, but the difference fell short of statistical significance.
That story repeated across the secondary endpoints. The study drug was numerically but not statistically better than placebo on cognition and function scale CDR-SB, cognitive impairment test MMSE and disability scale DAD. Scores on the daily living scale A-IADL favored placebo.
Following an age-old playbook for failed Alzheimer’s trials, Alzheon looked to a subgroup of patients with the earliest symptomatic stage of the disease for signs of efficacy. The prespecified analysis revealed a nominally statistically significant improvement in cognition versus placebo, as measured by ADAS-Cog13. Valiltramiprosate’s numeric advantage over placebo on other measures widened in the subgroup.
Alzheon saw the signs of efficacy in a subpopulation of patients who are poorly served by existing drugs. The study enrolled people with two copies of the APOE4 gene. People with the genes are more likely to develop amyloid-related imaging abnormalities than other patients when taking drugs such as Eisai and Biogen’s Leqembi and Eli Lilly’s Kisunla, a fact the FDA communicated in boxed warnings.
Susan Abushakra, M.D., chief medical officer of Alzheon, said in a statement that “a precision medicine approach is key to addressing the needs of Alzheimer’s patients who have the APOE4/4 genotype, and we are committed to this patient population.”