Alzheon, Inc., a clinical-stage biopharmaceutical company advancing novel therapies and diagnostics for Alzheimer’s disease (AD) and other neurodegenerative disorders, announced the peer-reviewed publication of its pivotal APOLLOE4 Phase 3 trial results in Drugs, a leading scientific journal. The paper, titled “Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer’s Disease: Results of Phase 3, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial”, presents detailed findings on the investigational oral therapy valiltramiprosate (ALZ-801) in patients with early Alzheimer’s disease carrying two copies of the APOE4 gene. The full publication is available on Springer’s website here.
A Targeted Therapy for the Highest-Risk Alzheimer’s Patients
Valiltramiprosate (ALZ-801) is an oral, disease-modifying therapy designed to inhibit the formation of soluble neurotoxic amyloid oligomers, a critical upstream step in the amyloid cascade linked to Alzheimer’s pathology. The APOLLOE4 study, the first large-scale Phase 3 interventional trial focused exclusively on symptomatic APOE4/4 homozygotes, enrolled 325 participants across North America and Europe diagnosed with early Alzheimer’s disease — including both Mild Cognitive Impairment (MCI) and Mild AD dementia.
“Despite major advancements in Alzheimer’s research, there is still a critical unmet need for safe, effective, and accessible disease-modifying treatments,” said Dr. Susan Abushakra, Chief Medical Officer at Alzheon. “While the overall trial population did not achieve the primary endpoint, prespecified analyses showed clinically meaningful and statistically significant cognitive and functional improvements in patients at the MCI stage. These results represent real progress for an underserved population and highlight the importance of precision medicine in Alzheimer’s disease.”
Dr. Abushakra further emphasized that imaging results showed consistent and significant slowing of brain atrophy across several regions, alongside reduced water diffusivity — indicators of slowed neurodegeneration, one of the hallmarks of Alzheimer’s progression.
Demonstrated Efficacy in MCI and Strong Neuroprotection
The APOLLOE4 trial provided the most comprehensive dataset ever collected for APOE4/4 homozygotes, a group known for accelerated cognitive decline and higher risk of AD onset. The prespecified subgroup of MCI patients demonstrated nominally statistically significant benefits in both cognition and daily function. MRI data supported these findings with widespread reductions in brain atrophy, further suggesting a potential neuroprotective effect of valiltramiprosate.
“The findings from this trial are highly encouraging,” said Dr. Marwan Sabbagh, FAAN, a lead investigator for APOLLOE4. “The slowing of brain atrophy, coupled with meaningful cognitive and functional improvements in the MCI subgroup, provide compelling evidence of potential disease modification. Just as importantly, the absence of vasogenic edema or amyloid-related imaging abnormalities makes ALZ-801 a promising and safe oral option for high-risk patients.”
A Breakthrough in Safety for APOE4/4 Carriers
Safety remains a significant barrier for Alzheimer’s treatments targeting the amyloid pathway, as most existing anti-amyloid antibodies carry the risk of amyloid-related imaging abnormalities (ARIA), such as brain edema or microhemorrhage — risks that are especially high in APOE4/4 carriers. In contrast, valiltramiprosate demonstrated no increased risk of ARIA, with no symptomatic cases observed across the study.
Approximately 15% of Alzheimer’s patients globally are APOE4/4 homozygotes, yet few have safe treatment options capable of slowing disease progression. The APOLLOE4 results thus mark a pivotal advancement, showing that valiltramiprosate may offer a well-tolerated oral alternative capable of modifying disease progression without the serious safety liabilities seen in antibody-based therapies.
“APOLLOE4 represents the largest and most comprehensive clinical evaluation ever conducted in APOE4/4 homozygotes,” said Dr. Aidan Power, Chief Development Officer at Alzheon. “The benefits in the MCI population, combined with excellent safety, position valiltramiprosate as a potential first-in-class oral therapy that could slow Alzheimer’s pathology in genetically defined patients. Our goal is to continue advancing regulatory discussions and bringing this differentiated therapy to patients who urgently need it.”
A Study Designed for Inclusivity and Real-World Relevance
The 78-week randomized, double-blind, placebo-controlled trial was meticulously designed to reflect real-world patient diversity. Participants aged 50–80 years with early-stage Alzheimer’s (MCI or Mild AD dementia) were included based on established clinical criteria, cognitive assessments (MMSE ≥22, CDR-G 0.5 or 1), and memory performance benchmarks (RBANS-delayed memory ≤85).
To enhance inclusivity, Alzheon conducted targeted recruitment efforts to ensure the participation of underrepresented populations in the U.S., reflecting the company’s commitment to equitable access in Alzheimer’s research.
Importantly, the study allowed participants with pre-existing microbleeds and siderosis lesions on MRI — conditions typically excluded from anti-amyloid antibody trials due to ARIA risk. As a result, 31% of participants entered the trial with at least one microhemorrhage, with some showing over 160 microbleeds or up to five superficial siderosis lesions at baseline. Despite this, valiltramiprosate showed no increase in microbleed frequency or symptomatic events, reinforcing its strong safety profile even in patients predisposed to cerebrovascular fragility.
Advancing Alzheimer’s Research Through Precision Medicine
APOE4/4 homozygotes are 8–12 times more likely to develop Alzheimer’s and experience faster cognitive decline. Alzheon’s precision medicine approach directly targets the molecular and genetic mechanisms underlying this progression. By inhibiting toxic amyloid oligomer formation — a process occurring earlier in the amyloid cascade — valiltramiprosate intervenes upstream, offering a differentiated and potentially safer mechanism compared to late-stage amyloid clearance therapies.
“The APOLLOE4 trial results reaffirm our strategy to focus on genetically defined populations and early intervention,” said Dr. Abushakra. “By tailoring treatment to APOE4/4 carriers, we are not just developing another Alzheimer’s therapy — we are redefining how to approach the disease itself.”
Looking Ahead
With the APOLLOE4 publication, Alzheon strengthens its leadership in developing genetically targeted, orally administered therapies for Alzheimer’s disease. The company continues to advance its broader clinical program, including potential registrational studies, biomarker research, and collaborations with global regulatory agencies.
“The APOLLOE4 trial is a landmark moment in Alzheimer’s research,” concluded Dr. Power. “It brings us closer to a future where treatments are safer, more effective, and designed specifically for the patients who need them most.”
In summary, the APOLLOE4 study establishes valiltramiprosate (ALZ-801) as a safe, well-tolerated, and potentially disease-modifying oral therapy for APOE4/4 homozygotes at the earliest symptomatic stages of Alzheimer’s disease — a population that has long lacked viable therapeutic options. The findings mark a major step forward in precision medicine and underscore Alzheon’s commitment to delivering meaningful, accessible innovation for Alzheimer’s patients worldwide.
About Valiltramiprosate/ALZ-801
Valiltramiprosate/ALZ-801 is a potential first-in-class, investigational oral agent in Phase 3 development as a potentially disease-modifying treatment for AD.2-6,8,11 Valiltramiprosate is designed to block the formation of neurotoxic soluble beta amyloid oligomers implicated in cognitive decline in Alzheimer’s patients.2-6,8,13 In preclinical mechanism of action studies, ALZ-801 has fully inhibited the formation of neurotoxic soluble beta amyloid oligomers at the Phase 3 clinical trial dose.2,8,11,13 Valiltramiprosate is designed to act through a novel enveloping molecular mechanism of action to block formation of neurotoxic soluble amyloid oligomers in the human brain13 associated with the onset and progression of cognitive decline in AD patients.2,3,6,8,9 Valiltramiprosate received Fast Track designation from the U.S. Food and Drug Administration in 2017 for Alzheimer’s disease. In clinical trials, valiltramiprosate has shown potential for robust clinical efficacy and favorable safety results with no increased risk of brain vasogenic edema.4-9,12,14 The initial Phase 3 program for valiltramiprosate is focusing on Early AD patients with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), with potential future program expansion to AD treatment and prevention in patients carrying one copy of the APOE4 gene and noncarriers.
Valiltramiprosate APOLLOE4 Phase 3 Trial
An Efficacy and Safety Study of Valiltramiprosate in APOE4/4 Early Alzheimer’s Disease Subjects (NCT04770220): This trial was designed to evaluate the efficacy, safety, biomarker and imaging effects of 265 mg twice daily oral dose of valiltramiprosate in Early AD subjects with two copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), who constitute approximately 15% of Alzheimer’s patients. This double-blind, randomized trial compared oral valiltramiprosate to placebo treatment over 78 weeks. The APOLLOE4 trial was supported by a grant from the National Institute on Aging to Alzheon, with Susan Abushakra as the principal investigator.
Valiltramiprosate APOLLOE4 Long Term Extension Trial (Phase 3 LTE)
An ongoing long-term extension of the trial, APOLLOE4-LTE evaluates valiltramiprosate in subjects who complete the core APOLLOE4 study for an additional 104 weeks of treatment for a total of 182 weeks or 3.5 years over the core and LTE study. This LTE study is currently ongoing in the US, UK and Canada (NCT06304883).
Valiltramiprosate Phase 2 Biomarker Trial
Biomarker Effects of Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s Disease (NCT04693520): This trial was designed to evaluate the effects of 265 mg twice daily oral dose of valiltramiprosate on biomarkers of AD pathology in subjects with Early AD, who have either the APOE4/4 or APOE3/4 genotype and constitute 65-70% of Alzheimer’s patients. The primary outcome was the change from baseline in plasma p-tau181. The trial also included evaluation of clinical efficacy, safety, tolerability, and pharmacokinetic profile of valiltramiprosate over 104 weeks of treatment. An ongoing long-term extension of the trial evaluates the same dose of valiltramiprosate for an additional 104 weeks of treatment for a total of 208 weeks.
