ALZ-801 Safe, Tolerable in Patients With Early Alzheimer Disease Carrying APOE4

ALZ-801 (valiltramiprosate) is a potentially safer and more tolerable alternative to anti-amyloid antibodies in patients with Alzheimer disease (AD) who are apolipoprotein E4 (APOE4) carriers, according to study results presented at the 2024 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) and related neurological disorders, held from March 5 to 9, 2024, in Lisbon, Portugal.

Researchers conducted an ongoing phase 3, double-blind, placebo-controlled multicenter study (APOLLOE4; ClinicalTrials.gov Identifier: NCT04770220) to evaluate the cognitive, functional, and volumetric magnetic resonance imaging (MRI) effects of ALZ-801 265 mg twice daily in patients who were APOE4 homozygotes with early AD.

Patients with early AD aged between 50 and 80 with a Mini-Mental State Examination (MMSE) score of 22 and greater and a Global Clinical Dementia Rating (CDR-G) of 0.5 or 1 were included in the study. Patients with cerebral amyloid angiopathy (4 and greater microhemorrhages, any sclerosis, any macrohemorrhage) were compared with the remainder of the sample population. The primary endpoint was an estimated 2.5 placebo-adjusted Alzheimer Disease Assessment Scale-Cognitive Subscale version 13 (ADAS-cog13) effect at 78 weeks, while secondary outcomes included hippocampal volume and functional outcomes.

A total of 325 patients (women, 51%: mean age, 69; White, 82%; baseline MMSE, 26; on cholinesterase inhibitors, 35%) were enrolled in this study. At baseline, 65% of patients had mild cognitive impairment (MCI), while 35% had mild AD. The average ADAS-cog13 was 24, CDR sum of boxes (CDR-SB) was 3.0, and CDR global was 0.6. 

Of the 313 patients who had baseline MRIs, 32% had microhemorrhages, 9% had more than 4 microhemorrhages, 9% had siderosis, and 90% had mild or moderate white matter disease. 

Compared with the remainder of the sample population, the cerebral amyloid angiopathy group (n=47; 15%) had primarily men (70% vs 45%), were older (71 vs 68 years; P =.004), had more advanced disease (MMSE, 25 vs 26 [P =.018]; ADAS-cog, 27 vs 23 [P =.002]), and had more severe deep white matter disease (P =.015). 

While both groups had a comparable prevalence of hypertension, diabetes, obesity, hyperlipidemia, and statin use, patients in the cerebral amyloid angiopathy group reported a significantly greater prevalence of coronary artery disease (17% vs 8%; P =.049) and antiplatelet use (38% vs 22%; P =.026).

To date, there has not been an increased risk for amyloid-related imaging abnormalities representing vasogenic edema and related extravasated fluid detected.

One study limitation was the small sample size. 

“ALZ-801, an oral potentially disease-modifying agent, shows favorable safety and tolerability in ongoing APOE4 carrier studies, including homozygotes at highest risk for ARIA [amyloid-related imaging abnormalities], and may become a safe, convenient alternative to anti-amyloid antibodies in APOE4 carrier AD patients,” the researchers concluded.