On 1 April, at the AD/PD 2025 International Conference on Alzheimer’s and Parkinson’s Diseases, during a symposium sponsored by Alzheon, the company presented data from its Phase III APOLLOE4 (NCT04770220) trial of ALZ-801 (valiltramiprosate) for the treatment of early Alzheimer’s disease—mild cognitive impairment (MCI) and mild Alzheimer’s —in patients who are homozygous for the APOE4 gene. Valiltramirosate is an oral small molecule that inhibits the formation of neurotoxic amyloid beta (Aβ) oligomers.
The APOLLOE4 trial did not meet its primary endpoint, change from baseline in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13). However, when evaluating just the prespecified MCI patient population, which accounted for 39% of the overall trial population, treatment with valiltramiprosate was found to be significantly effective over 78 weeks. Compared with placebo, treatment with valiltramiprosate resulted in a 52% benefit on the ADAS-Cog13 scale, with differences between the treatment group and placebo group seen from 13 weeks. In the MCI population, valiltramiprosate treatment also resulted in significant improvements in Disability Assessment for Dementia (DAD) score, and, while not statistically significant, clinically meaningful effects of valiltramiprosate were also seen across the Clinical Dementia Rating – Sum of Boxes (CDR-SB) scores, mini-mental state examination (MMSE) scores, and Amsterdam – Instrumental Activities of Daily Living (A-IADL) scores.
Go deeper with GlobalData
Alzheon also presented brain volume results from the APOLLOE4 trial. In the overall patient population, significant positive effects on all measures of brain volume were seen, including significant slowing of hippocampal volume (HV) atrophy, with the size of the positive effects increasing when only the prespecified MCI population was evaluated. Additionally, the HV positive effects were correlated with both ADAS-Cog13 and CDR-SB clinical effects. Based on the results from the APOLLOE4 trial, as well as data from trials of anti-Aβ monoclonal antibodies (mAbs) in MCI and mild Alzheimer’s patients, it was suggested during the symposium that HV effects could be used to predict clinical effects and could be used as an additional biomarker to demonstrate the efficacy of a drug for early Alzheimer’s.
Despite missing the primary endpoint, the results presented from the APOLLOE4 trial, especially in MCI patients, are promising, particularly as Alzheon is targeting a subset of Alzheimer’s patients where there is a high unmet need. APOE4-homozygous Alzheimer’s patients typically have an earlier onset of the disease that is also more likely to progress quickly, resulting in more rapid clinical decline, and they have a higher risk of developing amyloid-related imaging abnormalities (ARIAs). The current disease-modifying therapies (DMTs) approved for the treatment of early AD—Eisai/Biogen’s Leqembi (lecanemab) and Eli
Lilly’s Kisunla (donanemab)—are associated with the risk of ARIA. As such, their use is limited in APOE4 homozygotes, with some regulators only approving these drugs for patients with one copy or no copy of the APOE4 gene, such as the EMA’s approval of Leqembi. In contrast to the mAbs, data presented during the symposium showed that valiltramiprosate resulted in no increased risk of ARIA when compared with placebo, and there were no incidences of symptomatic ARIA during the 78-week APOLLOE4 trial. Thus, Alzheon will be able to position valiltramiprosate as a safe and effective treatment option for a patient population with a high unmet need. Furthermore, the majority of treatment-emergent adverse events (TEAEs) in the APOLLOE4 trial were mild, with the most common TEAEs being nausea and weight loss. Overall, the drug was well tolerated, and a high percentage of trial participants opted to continue taking the drug in the long-term extension study. The fact that valiltramiprosate is orally administered gives it a further competitive advantage over the anti-Aβ mAbs in terms of ease of administration for patients.
Given the APOLLOE4 results, it remains to be seen whether Alzheon will pursue regulatory approval for early Alzheimer’s or if it will pivot to just the MCI patient population. There is also the potential for expansion as Alzheon is planning to evaluate valiltramiprosate in additional patient populations, with prevention in APOE4 homozygotes as a promising option since the results of the APOLLOE4 trial showed that valiltramiprosate was more effective earlier in the disease it was administered. GlobalData forecasts that valiltramiprosate will generate US sales of approximately $663.3m in the MCI patient populations in 2033, accounting for 82% of the potential total early Alzheimer’s sales.
