US-based Alzheon’s Alzheimer’s disease pill has failed in a Phase III trial, but the biopharma still holds hope for the drug after seeing signals in a subgroup of patients.
The company said that while valiltramiprosate did not meet the primary endpoint in the pivotal APOLLOE4 study, nominally statistically significant and clinically meaningful cognitive benefits were observed in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13), in a prespecified group of patients who could benefit from early intervention.
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ADAS-Cog13 is a 13-item version of a scale used to assess cognitive function in patients with Alzheimer’s disease, with higher scores indicating greater cognitive impairment.
The global APOLLOE4 study (NCT04770220) enrolled 325 patients with early Alzheimer’s disease who are homozygous for the ε4 allele of the apolipoprotein gene (APOE4/4). Patients were randomised to receive twice daily, oral valiltramiprosate or placebo over 78 weeks.
The trial’s primary endpoint was ADAS-Cog13, with key secondary endpoints being the Clinical Dementia Rating–Sum of Boxes (CDR-SB) and Amsterdam-Instrumental Activities of Daily Living (A-IADL). Investigators also measured hippocampal volume as the main imaging outcome and fluid biomarkers as additional outcomes.
In the overall population, the APOLLOE4 study did not meet the primary endpoint of slowing cognitive decline as assessed by ADAS-Cog13, with an 11% improvement in the treatment arm. However, a prespecified analysis in patients at the mild cognitive impairment stage of Alzheimer’s disease showed nominally statistically significant cognitive benefits of 52% as measured by ADAS-Cog13. The data also showed clinically meaningful functional effects of 102% as measured by CDR-SB and 96% benefit on the Disability Assessment for Dementia (DAD).
The company has not confirmed its regulatory plans for Alzheon’s Alzheimer’s drug based on the Phase III data.
GlobalData’s managing neurology analyst Pippa Salter comments: “Given the APOLLOE4 results, it remains to be seen whether Alzheon will pursue regulatory approval for early Alzheimer’s disease or if it will pivot to just the MCI patient population.
“There is also the potential for expansion as Alzheon plans to evaluate valiltramiprosate in additional patient populations, with prevention in APOE4 homozygotes a promising option since the results of the APOLLOE4 trial showed that valiltramiprosate was more effective the earlier in the disease it was administered.”
ARIA risk seemingly low
Regarding safety, the Phase III Alzheimer’s trial reported no increased risk of vasogenic brain oedema or microhaemorrhages described as amyloid-related imaging abnormalities (ARIA-E, ARIA-H) with Alzheon’s drug.
ARIA has been a safety issue associated with approved amyloid-targeting Alzheimer’s disease therapies. Both Eli Lilly’s Kisunla (donanemab) and Biogen and Eisai’s Leqembi (lecanemab) have reported ARIA incidents, with these both being points of contention with agencies ahead of their relative approvals.
Lilly’s drug was approved by the US Food and Drug Administration (FDA) in July 2024 for use in patients with mild cognitive impairment or dementia stage of disease. The drug carries a boxed warning about the risk of ARIA.
Meanwhile, the European Medicines Agency (EMA) has recommended the rejection of the drug for marketing authorisation in the EU due to the risk of ARIA events not being outweighed by the therapy’s benefit. Kisunla received approval in the UK in October 2024. On the same day of its UK approval, the National Institute for Health and Care Excellence (NICE) announced it would not be covering Kisunla for use in the UK’s National Health Service (NHS) due to the unfavourable risk-benefit profile and poor cost-effectiveness.
Biogen and Eisai’s drug made it to the market earlier, gaining FDA-accelerated approval in January 2023. After the Phase III readout, full approval was confirmed by the FDA in June 2023. In January 2025, the company submitted a new application to the agency seeking approval for a subcutaneous version of the drug. In November 2024, the EMA recommended the approval of Leqembi, three months after the UK granted the therapy’s approval. Again, NICE has not approved the drug for use on the NHS due to its benefit being too small to justify its cost.
Before Leqembi, Biogen and Eisai gained approval for another anti-amyloid Alzheimer’s therapy, Aduhelm (aducanumab). This has since been removed from the market due to Biogen wanting to focus on Leqembi.
GlobalData predicts the Alzheimer’s disease market will reach $19.3bn across the eight major markets (8MM: US, France, Germany, Italy, Spain, UK, Japan, and China) by 2033.
GlobalData is the parent company of Clinical Trials Arena.
