Tramiprosate

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.

An experimental Alzheimer’s disease therapy designed by Alzheon to reduce depositions of amyloid plaque in the brain failed to beat a placebo in a Phase 3 study, the latest blow to a drug whose history is marked by clinical trial shortfalls. The twice-daily pill, valiltramiprosate, did not meet the main clinical trial goal of slowing cognitive decline measured at 78 weeks, Alzheon announced Thursday. Nevertheless, the Framingham, Massachusetts-based company pointed to measures of brain volume showing a slowing of brain atrophy, which it said suggest potential neuroprotective benefits of the drug. Alzheon also noted nominally statistically significant cognitive benefits and clinically meaningful functional effects in a prespecified subgroup — patients at the earliest stages of the disease. That’s a subgroup of the genetically defined patient subgroup Alzheon had hoped would benefit from drug. Sponsored Post Understanding EGPA: The Role of Eosinophils and Advancements in Treatment Options FASENRA® (benralizumab) injection, for subcutaneous use, 30 mg is indicated for the treatment of adult patients with eosinophilic granulomatosis with polyangiitis (EGPA). FASENRA provides a treatment option for HCPs to consider when managing this challenging disease. By FASENRA, Sponsored Content The Alzheon drug, known in earlier stages of development as ALZ-801, was licensed from Quebec-based Bellus Health in 2013. That biotech’s small molecule, called tramiprosate, was designed to bind to beta amyloid. The hope was this approach could prevent the aggregation of amyloid plaque in the brains of Alzheimer’s patients. But results from two Phase 3 studies conducted by the Canadian company showed the drug did not lead to statistically significant improvement in cognitive function. Alzheon’s analysis of the tramiprosate data found variability in blood levels of the drug in study participants. Valiltramiprosate is a prodrug of tramiprosate, which means it converts to tramiprosate in the body. Alzheon’s changes to the Bellus drug include improvement in how the compound is absorbed in the body with a goal of reducing the variability observed in previous tests. Alzheon’s analysis of the previous trial data also found signs of improvement in patients who carry the ApoE4 gene, a variant that increases the risk of developing Alzheimer’s. Alzheon’s Phase 3 test enrolled 325 patients who carry two copies of ApoE4. The new Alzheimer’s medications approved by the FDA in the past two years, Leqembi from Eisai and Kisunla from Eli Lilly, are antibodies, large molecule drugs administered by infusion. Alzheon hoped its oral drug would offer patients the advantage of an easier dosing formulation. There was also potential for a safety edge. The anti-amyloid antibody drugs introduce the risk of brain inflammation and bleeding called amyloid-related imaging abnormalities (ARIA). ApoE4 carriers have a substantially higher risk of developing ARIA, so Alzheimer’s patients who carry this genetic variant could benefit from a drug offering a different approach. While Leqembi and Kisunla may be used to treat such patients under their FDA approvals, the labels of these products carry black box warnings that flag this higher complication risk. This risk has also been a sticking point for efforts to secure regulatory approvals in Europe and Australia. Sponsored Post Changes in Nurse Staffing Answer Clinician Demands The ongoing nursing shortage facilitates high turnover rates since nurses know they won’t have difficulties finding new jobs. In order to retain and attract staff, it’s in a facility’s best interest to understand what nurses want. By Tomasz Rezik Alzheon reported no serious adverse reactions and no deaths in the Phase 3 test of valiltramiprosate. The company also said there was no increased risk of ARIA. Alzheon plans to publish more detailed Phase 3 results in a peer-reviewed publication. Despite missing the main goal of the pivotal test, Alzheon is not abandoning the drug. In the company’s announcement of the study’s preliminary results, Chief Medical Officer Susan Abushakra said patients who have two copies of ApoE4 “have a desperate need for additional treatment options.” “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,” she said. A long-term extension study is continuing to evaluate patients who completed the Phase 3 test of valiltramiprosate. This study, ongoing in the U.S., U.K., and Canada, is following patients for an additional 52 weeks. Last June, privately held Alzheon raised $100 million in Series E financing to support completion of the pivotal study and prepare for potential commercialization of its Alzheimer’s drug. The Phase 3 program is also supported by $51 million in grant funding from the National Institutes of Health’s National Institute on Aging.