To evaluate safety of valiltramiprosate/ALZ-801 in APOE4/4 Early AD subjects.

Valiltramiprosate/ALZ-801, a valine-conjugated prodrug of tramiprosate that prevents toxic amyloid-oligomer formation, was evaluated in APOE4/4 homozygotes with Early AD (NCT04770220). APOE4 is a risk factor for both cerebral amlyloid angiopathy and ARIA. This is the first completed Phase 3 trial focused on APOE4/4 AD patients at highest ARIA risk with anti-amyloid antibodies.

325 homozygotes with MMSE ≥22 were randomized 1:1 (placebo:265mg BID), MRIs every 26 weeks were centrally evaluated for ARIA-E/H. Anti-platelets were allowed, anti-coagulants were exclusionary. Subjects with any number of baseline microhemorrhages (MH) and superificial siderosis lesions were allowed.

Population was 51% females, 89% Caucasian, mean age 69 years, MMSE 25.6; 298 with screening and 290 post-treatment MRI. At baseline, 32% had >1 MH (placebo, 32%, active, 31%); 11% of placebo and 8% active had siderosis (maximum 4 and 5 lesions, respectively); and 5% per/arm ≥ 10 MH. ARIA-E occurred in 5 subjects/arm (3%) and macrohemorrhages 2 subjects/arm. Increase in MH from low to high category (0, 1-4, 5-9, ≥10 MH) occurred in 14% placebo and 9% active. All ARIA-E were mild except 1 severe (placebo) and 1 moderate (active), all ARIA-E/H events were asymptomiatic. AEs incidence >5% and >2x placebo rate were nausea (26%), weight decrease (14%), decreased appetite and vomiting (10% each); with lower headache, falls and dizziness rates in active arm.

In this placebo-controlled trial, valiltramiprosate was well tolerated with favorable safety over 78-weeks. Gastrointestinal AEs were typically mild/moderate and transient, weight loss either resolved or stabilized. ARIA-E rates were similar between treatment arms (~3%), ARIA-H was lower with valiltramiprosate treatment, and no ARIA events were symptomatic. Coupled with promising efficacy in MCI, valiltramiprosate provides a favorable benefit-risk profile for APOE4/4 AD patients with unmet need for safe and effective disease-modifying treatments.