NOVEL ALZHEIMER'S PILL MAY SLOW DECLINE IN SOME HIGH-RISK PATIENTS
A phase III trial of investigational valiltramiprosate (ALZ-801) did not meet its primary endpoint in people with early symptomatic Alzheimer's disease, but the drug did show benefits in a prespecified population with mild cognitive impairment who carried two copies of APOE4.
In the overall efficacy population of APOE4 homozygotes with early Alzheimer's disease, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) scores were not significantly different between those who were treated with oral valiltramiprosate versus placebo at 78 weeks (P=0.67), with similar results for other clinical outcomes.
Hippocampal atrophy did slow by 18% (P=0.017) with valiltramiprosate in this population, reported Susan Abushakra, MD, of Alzheon in Framingham, Massachusetts, at the Clinical Trials on Alzheimer's Disease (CTAD) annual meeting.
Differences between the valiltramiprosate and placebo groups were not significant in the subgroup of participants with mild dementia. Among participants with mild cognitive impairment, however, clinical outcomes favored valiltramiprosate: ADAS-Cog13 scores were 2.14 points lower (P=0.042). Disability Assessment for Dementia scores improved by 6.1 points (P=0.016) versus placebo, and Clinical Dementia Rating-Sum of Boxes scores were 0.65 points lower and trended toward significance (P=0.053).
In this subgroup with mild cognitive impairment, hippocampal atrophy was 26% slower in the valiltramiprosate group compared with the placebo group (P=0.004), Abushakra said.
The most common treatment-emergent adverse events in the overall population were nausea, weight loss, appetite change, and vomiting. The incidence of amyloid-related imaging abnormalities with edema (ARIA-E) was the same with valiltramiprosate as with placebo, affecting five patients in each arm. There were no reports of symptomatic ARIA-E or ARIA with hemosiderin (ARIA-H), and no deaths in the study.
Valiltramiprosate is a brain-penetrant small molecule that blocks amyloid from aggregating into toxic oligomers, which are precursors to amyloid plaque. It's a prodrug of tramiprosate (homotaurine), a compound marketed as a nutritional supplement.
Valiltramiprosate was developed to improve the pharmacokinetic variability and gastrointestinal tolerability of tramiprosate. Tramiprosate did not show efficacy in two phase III studies of mild to moderate Alzheimer's disease, but a subsequent analysis suggested it had a possible positive effect in APOE4 homozygotes with mild Alzheimer's.
The strongest genetic risk factor for sporadic Alzheimer's disease is APOE4. In a study of APOE4 homozygotes, nearly all had abnormal cerebrospinal fluid amyloid levels by age 65, and 75% had positive amyloid scans. The prevalence of these markers increased with age.
People with two copies of APOE4 are at high risk of ARIA, which can occur with anti-amyloid immunotherapies like lecanemab (Leqembi) and donanemab (Kisunla). Both drugs carry a boxed warning about ARIA risks for APOE4 homozygotes.
Main findings from the APOLLOE4 study were published earlier this year in Drugs. The trial assessed 325 APOE4 homozygotes with early Alzheimer's disease who had Mini-Mental State Examination (MMSE) scores of 22 to 30. This included people with mild cognitive impairment (MMSE scores above 26) or mild dementia (MMSE scores of 22 to 26). All participants had a Clinical Dementia Rating global score of 0.5 or 1.0.
Participants were randomized to 265 mg of valiltramiprosate twice a day or placebo for 78 weeks. The subgroup with mild cognitive impairment included 125 participants: 67 who received valiltramiprosate and 60 who received placebo. Nausea was the main adverse event in this subgroup, affecting 34.3% of those who received valiltramiprosate.
Starting valiltramiprosate at the mild cognitive impairment stage may be important for the drug to show positive clinical results, Abushakra observed. "The overall phase III trial did not achieve significance on the primary cognitive endpoint of ADAS-Cog13; that was driven by the more advanced dementia subjects not showing benefit," she told MedPage Today.
Other valiltramiprosate research presented at CTAD reported significant correlations between clinical and brain volume effects in APOE4 homozygotes with mild cognitive impairment.
"Our plans are to start a phase III study in APOE4/4 [homozygote] mild cognitive impairment patients and to keep engaging FDA about our data," Abushakra said.
This study was sponsored by Alzheon.
Abushakra is an Alzheon employee and holds stock or stock options in the company.
