Alzheon's amyloid inhibitor advances

LEXINGTON, Mass.—The 12^th International Conference on Alzheimer's and Parkinson’s Diseases saw biopharmaceutical company Alzheon Inc. present Phase 1 for its lead candidate, ALZ-801. ALZ-801 is an optimized prodrug of tramiprosate, and is a first-in-class small molecule inhibitor of amyloid formation and neurotoxicity for the treatment of Alzheimer’s disease. Alzheon also presented expanded post-hoc analyses of Phase 3 data with tramiprosate, which engendered sustained efficacy on cognition and function in Alzheimer's patients that tested positive for the ε4 gene variant of apolipoprotein E (ApoE4), which is associated with an increased risk of Alzheimer’s.

ApoE4 positive patients, Alzheon notes on its website, “present with a 10 to 30 years earlier onset of the disease, as well as faster progressing, more severe course,” and make up 50 to 60 percent of Alzheimer's disease patients. Homozygous ApoE4 subjects, who present with two ε4 allele of the Apolipoprotein E gene, represent 10 to 14 percent of Alzheimer's patients, and the detrimental effect is even more noticeable in this population.

“These findings on ALZ-801 and its parent molecule, tramiprosate, advance promising observations in the field of Alzheimer’s disease,” said Dr. Jeffrey Cummings, ScD, director of Cleveland Clinic Lou Ruvo Center for Brain Health and the Camille and Larry Ruvo Chair for Brain Health and member of Alzheon's scientific advisory board. “First, they build valuable new drug development insights based on the observed clinical effect with tramiprosate in ApoE4 population and second, they leverage the evidence that ApoE4 is an important risk factor for Alzheimer’s disease.”

Alzheon's Phase 1 study was a single ascending dose study in 67 healthy elderly adults. ALZ-801 saw superior therapeutic attributes compared to tramiprosate, particularly in reducing the inter-subject pharmacokinetic variability that hampered tramiprosate's efficacy signal in previous Phase 3 studies. The compound demonstrated an extended half-life of 14.9 hours—extended bioavailability that could allow for once-daily dosing—as well as improved gastrointestinal tolerability, as seen in a reduction in cases of nausea and vomiting.

In the company's post-hoc analyses of its North American Phase 3 trial of tramiprosate, Alzheon reported that treating patients who were homozygous ApoE4-positive with a twice-daily administration of 150 mg of tramiprosate resulted in a greater than four-point improvement in the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) subscale at 78 weeks compared to the placebo group. In all-comers ApoE4-positive patients (both homozygous and heterozygous), tramiprosate administration resulted in sustained improvement in ADAS-cog of up to two points over 78 weeks. The participants consisted of 599 Alzheimer's disease patients from the Phase 3 trial who presented with the heterozygous or homozygous ApoE4 genotype.

“These data leverage the extensive safety and clinical efficacy dataset with an established drug molecule, tramiprosate, and extend it to bring new clinical advancements for the prodrug ALZ-801 with the potential to offer a novel medicine for Alzheimer’s disease where new treatments are desperately needed,” Dr. Miia Kivipelto, director of Research and Education at the Geriatric Clinic and Head of the Unit of Clinical Trials at Karolinska University Hospital in Stockholm, said in a press release. Kivipelto is also a member of Alzheon's scientific advisory board, and co-authored the posted on ALZ-801 with Cummings.

“With ALZ-801, Alzheon has an exciting new molecule with compelling clinical rationale as a late-stage drug candidate for Alzheimer’s disease,” added Dr. John Hey, chief scientific officer of Alzheon. “We are highly encouraged by the Phase 1 data, which met our criteria for demonstrating optimized drug properties of ALZ-801 over tramiprosate, as well as strong therapeutic profile. Additionally, our extensive analyses of the previous Phase 3 dataset of tramiprosate further clarify and focus our clinical plan as we advance ALZ-801 toward a Phase 2/3 pivotal study later this year.”