Early Results Disappoint, but Subgroup Data Offer Hope
In April, the outlook for valiltramiprosate (ALZ-801), an experimental Alzheimer’s drug, appeared grim after topline results showed no significant benefit over placebo in a study of more than 300 genetically at-risk adults aged 50 and older. But a deeper analysis released in September has revived optimism. Researchers discovered that a subgroup of 125 participants with only mild cognitive impairment (MCI) at the study’s start demonstrated substantial benefits from the treatment.
According to Dr. Susan Abushakra, chief medical officer of Alzheon, “those participants showed very meaningful responses.” In this group, ALZ-801 slowed cognitive decline by 52%, a result comparable to the efficacy of the leading Alzheimer’s drugs lecanemab and donanemab. However, scientists caution that the findings are based on a small sample and need confirmation through larger trials.
Brain Imaging Suggests Reduced Atrophy
Beyond cognitive measures, the study revealed notable effects on brain structure. Participants receiving ALZ-801 experienced about 18% less hippocampal atrophy than those on placebo. The hippocampus, a region central to memory and learning, is one of the first areas affected by Alzheimer’s. The findings, published in the journal Drugs and supported by a $47 million NIH grant, suggest that the treatment could slow the physical degeneration associated with the disease.
A Different Approach from Current Therapies
Unlike the monoclonal antibody drugs currently approved for Alzheimer’s, which require regular intravenous infusions, ALZ-801 is an oral pill taken twice daily at home. The drug’s mechanism also differs: rather than breaking down existing amyloid plaques, it aims to prevent the plaques from forming in the first place by stopping amyloid proteins from clumping.
This approach could make ALZ-801 safer for patients, as monoclonal antibody therapies are known to sometimes cause brain swelling and microbleeding. The drug’s lower risk profile could be particularly advantageous for people with certain genetic vulnerabilities, researchers say.
Promise for High-Risk APOE4 Carriers
ALZ-801 may hold special potential for individuals carrying two copies of the APOE4 gene, which increases Alzheimer’s risk by roughly tenfold. Although APOE4/4 carriers account for only 2% of the general population, they represent about 15% of Alzheimer’s cases. These patients are also more prone to severe side effects from antibody-based treatments.
“This group is at higher risk for inflammation in the brain that can be quite serious,” said Jessica Langbaum, a researcher at Banner Health in Phoenix. She believes monoclonal antibodies can still be used safely at lower doses or earlier stages, but others argue that a safer oral therapy like ALZ-801 would be a welcome alternative.
Encouraging Long-Term Results
Dr. David Watson, a scientist with two APOE4 copies and a co-author of the study, believes ALZ-801 is showing promise in maintaining neuronal health. “We’re really making a difference in keeping neurons alive,” he said, noting that participants who continued taking ALZ-801 after the initial 18-month study period have maintained stable cognition well into their 60s and 70s.
While experts stress that more research is needed before FDA approval, the latest data point to ALZ-801 as a potentially safer, more accessible option in the fight against Alzheimer’s disease—especially for genetically high-risk individuals who have few alternatives today.