Tramiprosate

Alzheon saw signs of efficacy in patients with the earliest symptomatic stage of the disease. \n 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.”

Alzheon’s controversial, decade-long bet that a failed Alzheimer’s drug could offer bigger benefits to a subset of patients at the highest risk for the disease has ended in another disappointment. On Thursday, the Framingham, MA-based startup announced that its daily pill valiltramiprosate, also known as ALZ-801, failed to slow cognitive decline, the Phase 3 study’s primary endpoint. Valiltramiprosate is a reformulated version of tramiprosate, a molecule Alzheon licensed from Canadian drugmaker Bellus Health (formerly Neurochem) in 2013. Tramiprosate failed a major study in 2007, but Alzheon’s founders were convinced by a post-hoc analysis that the drug moved the needle for Alzheimer’s patients who carry two copies of the dreaded APOE4 gene, which dramatically increases the chance of developing Alzheimer’s. The new study enrolled 325 people with early Alzheimer’s and who had two copies of APOE4. According to the company’s press release, valiltramiprosate slowed cognitive decline by 11% on one scale (ADAS-Cog13, p=0.607) and 23% on another common scale (CDR-SB, p=0.309) compared with placebo. But both results were far from statistically significant. The results looked more promising in a prespecified subset of 125 people with mild cognitive impairment — the earliest symptomatic form of Alzheimer’s. Alzheon said the drug slowed cognitive decline in these patients by 52% on one scale (ADAS-Cog13, p=0.041) and appeared to practically stop decline on another scale (CDR-SB, p=0.053). But the first result was barely statistically significant and the second was insignificant. Alzheon had previously said that it expected to share the results and file for approval in 2024. And according to clinicaltrials.gov , the company finished the study in July 2024. That same month, the company raised a $100 million Series E financing to support regulatory filings and potential commercialization in 2025. Alzheon tried to go public twice but scrapped plans in 2018 and 2019 for an IPO . A lifeline came from a $47 million five-year grant from the National Institutes of Health in 2020, which expanded to more than $51 million by 2024 for its recently completed clinical trial. The company didn’t immediately respond to questions about its next steps, its plans for valiltramiprosate and its financial status. In the past few years, Alzheon had pitched its pill as a potentially safer alternative to antibody infusions developed by Biogen, Eisai and Lilly, whose trials have shown slow cognitive decline by about 30%. Those antibodies remove amyloid plaques from the brain, but in doing so can cause potentially lethal side effects of brain bleeding and swelling known as ARIA. The risk of ARIA is heightened for people with one copy of the APOE4 gene and dramatically enhanced for people with two copies of the gene. Alzheon’s pill, had it worked, would have provided a much-needed alternative for these patients. Alzheon says its small molecule blocks the misfolding and aggregation of amyloid monomers, potentially preventing or stalling the buildup of plaques. By avoiding direct plaque removal, it hoped the approach would be safer. That theory bore out in the study, with no increased risk of ARIA among drug recipients. The most common side effects were decreased appetite, loss of weight, nausea and vomiting. But the safety benefits were mooted by the lack of efficacy. The study may add fuel to an ongoing debate among neurologists about whether plaque removal is necessary for efficacy, and whether it is possible to disentangle the serious risks of amyloid-removing drugs from their benefits.