Alzheon Initiates Open-Label Extensions for Phase 2 and 3 Studies of Alzheimer Agent ALZ-801


Phase 2 biomarker trial participants who completed 156 weeks of treatment were offered enrollment into another 52-week extension to continue to observe safety, assessments of plasma biomarkers, and cognitive effects, among others.

Aidan Power, MSc, MRCPsych, chief development officer at Alzheon

Aidan Power, MSc, MRCPsych

Alzheon, the drug manufacturers of ALZ-801, an investigational oral disease-modifying therapy in development for early-stage Alzheimer disease (AD), has announced patient dosing in an open-label extension of its pivotal phase 3 APOLLOE4 trial (NCT04770220). The trial, a follow-up to a successful phase 2 biomarker study (NCT04693520), is fully enrolled with topline data expected in the third quarter of 2024.1

APOLLOE4, a double-blind, randomized trial, is designed to evaluate the efficacy, safety, biomarker, and imaging effects of 265 mg twice daily oral dose of ALZ-801 in 325 patients with early AD who have 2 copies of the apolipoprotein ε4 allele (APOE4/4 homozygotes), who make up approximately 15% of patients with AD. Supported by a $51 million grant from the National Institute on Aging, the 78-week study will primarily assess effects on cognition, determined using the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog) as the primary end point.

The phase 3 study also includes several notable secondary end points that evaluate aspects of function, activities of daily living, and neuropsychiatric symptoms. In addition, investigators will also observe treatment effects on fluid and imaging biomarkers, similar to the previously completed phase 2 study. Following the completion of 78 weeks, patients may be eligible to enter an open-label extension, where they will be treated with ALZ-801 for 52 weeks, followed by a 4-week safety visit after their final dose.

"We look forward to the topline data from the 78-week, randomized, placebo-controlled portion of the APOLLOE4 Phase 3 trial in the second half of this year. We have designed this confirmatory study in an unprecedented way by applying a precision-medicine approach, focusing initially on the high-risk patients with the APOE4/4 genotype, and incorporating state-of-the-art fluid and imaging biomarkers,” Aidan Power, MSc, MRCPsych, chief development officer at Alzheon, said in a statement.1 "Following the completion of the trial, participants who choose to continue into the long-term extension where all subjects receive active treatment, will help us evaluate long-term effects of ALZ-801/valiltramiprosate on the progression of Alzheimer’s disease, as well as generate additional safety and tolerability data."

In its update, Alzheon also announced an additional 52-week extension for the phase 2 trial, the second extension so far for the study. In addition to safety, the extension will assess plasma biomarkers, hippocampal volume, cortical thickness, and cognitive effects at weeks 156 and 208.

In the phase 2 trial, ALZ-801 met its primary end point, demonstrating a statistically significant 31% reduction of plasma phosphorylated tau (p-tau)181 at 104 weeks. The study originally enrolled 84 individuals who had an average age of 69 years and an average Mini-Mental State Exam score of 26.0. Comprised of mostly those with mild cognitive impairment (MCI; 70%), patients were tested on plasma and clinical outcomes every 13 weeks, with MRI conducted every 52 weeks.

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Two-year data from the study, announced in September 2023 and later presented at the 2024 American Academy of Neurology Annual Meeting, showed that ALZ-801 had a significant impact on several relevant AD biomarkers, including amyloid-ß (Aß). Throughout weeks 52-104, investigators observed a reduction of 4% in Aß42 levels with treatment of ALZ-801. In addition to changes in p-tau and Aß42, patients on the therapy reported 3.6% hippocampus atrophy, which was around 28% less than those from the Alzheimer Disease Neuroimaging Initiative (ADNI-1) study, an external control.2,3

John Hey, PhD, chief scientific officer at Alzheon

John Hey, PhD

After 104 weeks, there were no reported cases of amyloid-related imaging abnormalities (ARIA) for patients treated with ALZ-801. Among safety concerns, the most commonly observed adverse events included COVID-19 infection, nausea, and decreased appetite. In total, 50% and 33% of patients with MCI and mild AD, respectively, maintained their Clinical Dementia Rating stage throughout treatment.

"The Phase 2 biomarker trial generated compelling data demonstrating that treatment with oral ALZ-801 leads to a sustained reduction in p-tau181, a key measure of brain neurodegeneration, as well as slowing of hippocampal atrophy compared to a matched external control arm, and stabilization of cognition for two years." John Hey, PhD, chief scientific officer at Alzheon, said in a statement.1 "Given these encouraging results, we are compelled to extend the trial for an additional year, bringing the treatment period to four years for these patients. We believe this extension phase will offer meaningful insights into the correlation of fluid and imaging biomarkers with the progression of Alzheimer’s disease, help evaluate disease-modifying effects of ALZ-801 tablet and provide further evidence for expanding our treatment to APOE4 carriers representing 65-70% of Alzheimer’s patients in a planned Phase 3 trial."

Additional findings from the phase 2 study showed that patients treated with ALZ-801 had consistent improvements in Rey Auditory Learning Test (RAVLT) and Digit Symbol Substitution Test (DSST), 2 cognitive scales, after 26 weeks. These improvements remained stable and above baseline through the 104-week treatment period. In comparison with matched ADNI individuals, treated patients showed a statistically significant 24% improvement (P <.0001) on RAVLT Total Score, which combines effects on immediate and delayed recall tests.

1. Alzheon announces first patient dosed in long-term extension of APOLLOE4 phase 3 trial of oral ALZ-801/valiltramiprosate and launches 52-week extension of phase 2 biomarker trial in patients with early Alzheimer’s disease. News release. Alzheon. April 30, 2024. Accessed April 30, 2024.
2. Alzheon reports industry-leading biomarker, brain preservation and clinical benefits following 24 months of treatment in phase 2 trial of oral ALZ-801 (valiltramiprosate) in patients with early Alzheimer’s disease. News release. Alzheon. September 13, 2023. Accessed April 30, 2024.
3. Alzheon to present baseline imaging characteristics from ongoing APOLLOE4 phase 3 trial of oral tablet ALZ-801 (Valiltramiprosate) and results of phase 2 biomarker study at American Academy of Neurology Conference in Boston. News release. Alzheon. April 18, 2023. Accessed April 30, 2024.
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