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.
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.
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.
Photo: Yuichiro ChinoImage, Getty Images
