Investigational Oral Agent ALZ-801 Slows Brain Atrophy and Cognitive Decline in APOE4 Homozygotes with Early AD

The investigational oral amyloid-targeting agent valiltramiprosate (ALZ-801) significantly slowed brain atrophy and cognitive decline in people carrying 2 copies of the APOE ε4 allele, the strongest genetic risk factor for Alzheimer disease (AD).1 The findings, from the phase 3 APOLLOE4 clinical trial, were recently published in the journal Drugs, according to valiltramiprosate developer Alzheon.2

In the 78-week trial, participants with mild cognitive impairment (MCI) due to AD who received valiltramiprosate showed 52% slower cognitive decline and nearly complete preservation of functional ability compared with participants who were treated with placebo. Imaging results supported these findings, with hippocampal atrophy slowed by 26% in the MCI group and 18% in the overall population.1

“Despite the progress in approved therapies for [Alzheimer] disease, there remains a major unmet need for treatments that combine safety, efficacy, and access,” Susan Abushakra, MD, Alzheon chief medical officer and principal investigator of the trial, said in a statement.2 “Prespecified analyses demonstrated clinically meaningful benefits at the MCI stage, along with large and consistent slowing of brain atrophy—key indicators of neuroprotection.”2

Precision-Medicine Approach

The apolipoprotein E ε4 (APOE ε4) allele, the strongest genetic risk factor for AD, is found in approximately 15% of people with the disease, and confers an 8- to 12-fold higher lifetime risk for AD and accelerates progression.3,4 Individuals who are homozygous for the gene accumulate high levels of soluble beta-amyloid (Aβ) oligomers, recognized as the most neurotoxic amyloid species, long before plaque formation.3,4

Current antiamyloid antibodies (AAA) target plaques but carry amyloid-related imaging abnormality (ARIA) rates of approximately 33% to 41% in APOE ε4 homozygotes; treatment frequently requires extensive MRI safety monitoring and infusion centers.5,6 Valiltramiprosate, by contrast, is an oral, brain-penetrant small molecule that blocks Aβ monomers from aggregating into oligomers, acting upstream in the amyloid cascade.1

“Our goal was to neutralize the earliest toxic Aβ assemblies before irreversible neuronal injury occurs,” Abushakra said. “The APOLLOE4 trial provides the most comprehensive dataset to date on APOE ε4 homozygotes, underscoring our precision-medicine approach to addressing the needs of patients most at risk for Alzheimer’s disease.”2

The APOLLOE4 Phase 3 Trial

The double-blind, placebo-controlled trial enrolled 325 APOE ε4 carriers aged 50–80 years in North America and Europe, all with early symptomatic AD (mild cognitive impairment [MCI] or mild dementia). Participants received valiltramiprosate 265 mg twice daily or placebo for 78 weeks. The authors noted that the early AD population in APPOLLOE4 was similar to the cohorts in the pivotal trials of the anti-amyloid antibodies.5,6

Although Abushakra and colleagues reported that the primary endpoint—change in ADAS-Cog13 score in the overall population, did not reach statistical significance, prespecified subgroup analysis of participants with MCI revealed marked benefits1:

• 52% slower decline on ADAS-Cog13 (p=0.041)
• 96% slower decline in daily function on the Disability Assessment for Dementia (P =.016)
• >100% slower functional decline on CDR-Sum of Boxes (trend, P =.053)

The magnitude of cognitive effect, the authors said, exceeded the commonly accepted 30% threshold for clinical meaningfulness, suggesting stabilization of function for roughly 18 months.

MRI and diffusion tensor imaging further demonstrated broad neuroprotective effects, including 35% less cortical thinning and 22% less whole-brain atrophy, with tissue integrity preserved across gray and white matter regions.1

“The slowing of brain atrophy across multiple regions, combined with meaningful cognitive and functional effects in MCI patients, provides compelling evidence of neuroprotection,” APOLLOE4 investigator Marwan Sabbagh, MD, said in the statement.2

Safety, Practicality

Valiltramiprosate demonstrated a favorable safety profile throughout 78 weeks of treatment. The most common adverse effects (AEs) were mild or transient, nausea, decreased appetite, weight loss. Fewer than 5% of participants discontinued treatment as a result of any AEs.1

Most importantly, the study team observed no increase in vasogenic brain edema or microhemorrhage. Incidence of ARIA-E was identical between treatment and placebo groups (3.4%), and new microhemorrhages occurred less often with valiltramiprosate.1

“The favorable safety profile differentiates valiltramiprosate from other anti-amyloid approaches, especially in APOE ε4 homozygotes, who are most susceptible to serious side effects such as ARIA,” Aidan Power, MB, BCh, MRCPsych, Alzheon chief development officer, said.2

He added that the results “reinforce valiltramiprosate’s potential to become the first oral agent capable of slowing [Alzheimer] pathology in these genetically distinct patients.”2

Next steps

APOLLOE4 is the largest clinical trial ever conducted in symptomatic APOE ε4 patients, according to Alzheon. Its consistent cognitive, functional, and imaging findings—together with the absence of vascular safety issues—support early therapeutic intervention targeting soluble amyloid species, the company said.2

Among the study's limitations the authors acknowledged its limited ethnic diversity (89% White) and a smaller-than-planned MCI subgroup (125 participants), but the converging clinical and imaging data suggest a robust treatment signal.1

Alzheon has launched an ongoing long-term extension study (APOLLOE4-LTE) to evaluate valiltramiprosate over 3.5 years, as well as a separate phase 2 biomarker trial assessing its effects on phosphorylated tau and other Alzheimer biomarkers.2

The results reinforce valiltramiprosate’s potential to become the first oral agent capable of slowing Alzheimer pathology in APOE ε4 carriers, a population at high genetic risk and with limited safe treatment options.2

References

1. Abushakra S, Power A, Watson D, et al. Clinical efficacy, safety and imaging effects of oral valiltramiprosate in APOEε4/ε4 homozygotes with early Alzheimer’s disease: results of the Phase III, randomized, double‑blind, placebo‑controlled, 78‑week APOLLOE4 trial. Drugs. Published online September 28, 2025. doi:10.1007/s40265-025-02250-5
2. Alzheon announces peer-reviewed scientific publication of results from pivotal APOLLOE4 Phase 3 trial of oral valiltramiprosate/ALZ-801 in APOE4/4 homozygous individuals with early Alzheimer’s disease. News release. October 14, 2025. Accessed October 28, 2025. https://alzheon.com/alzheon-announces-peer-reviewed-scientific-publication-of-results-from-pivotal-apolloe4-phase-3-trial-of-oral-valiltramiprosate-alz-801-in-apoe4-4-homozygous-individuals-with-early-alzheimers/
3. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1467–72. doi:10.1212/wnl.43.8.1467.
4. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3. doi:10.1126/science.8346443
5. Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. doi:10.1056/NEJMoa2212948.
6. 32. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330:512–27. doi:10.1001/jama.2023.13239