AC Immune Alzheimer’s Drug Reduces Cognitive Decline but Misses Functional Endpoints

AC Immune’s Phase II Lauriet study of investigational anti-Tau monoclonal antibody, semorinemab, in mild-to-moderate Alzheimer’s disease (AD), only met one endpoint.

One could be forgiven for thinking that AC Immune may get a stock market bump from Alzheimer’s data showing a statistically significant reduction in cognitive decline. But investors can be picky: they want both endpoints to be met in a trial.

AC Immune’s stock fell 9% on the news that its Phase II Lauriet study of investigational anti-Tau monoclonal antibody, semorinemab, in mild-to-moderate Alzheimer’s disease (AD), only met one. The data, presented by partner Genentech (Roche) at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference on Wednesday, demonstrated a 43.6% reduction in the rate of cognitive decline with semorinemab compared to placebo on the Alzheimer’s Disease Assessment Scale, Cognitive Subscale (ADAS-Cog11) at week 49. That was the good news.

The bad news: Semorinemab missed the second co-primary endpoint, Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). The drug also failed to measure up in the two secondary endpoints of Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB). The trial was assessing 272 adult participants with mild-to-moderate AD across 43 study centers globally.

“We are pleased that the data presented at CTAD confirm Lauriet’s remarkable findings, which provide the first evidence of therapeutic impact on cognition for an anti-Tau monoclonal antibody in mild-to-moderate AD, by showing a statistically significant slowing of the rate of cognitive decline,” stated AC Immune CEO Prof. Andrea Pfeifer, Ph.D. The co-founder and longtime chief executive added that the company was encouraged by the data, but is being “cautious about what it may mean for patients” due to the lack of effect in the functional endpoints. She said the company looks forward to learning more about the drug’s long-term effects in the ongoing open-label extension but did not mention anything about further development of semorinemab.

Cautious optimism despite a lack of functional improvement is becoming a trend after the landmark approval of Biogen’s Aduhelm – the first drug approved for Alzheimer’s in 18 years, despite missing functional endpoints during clinical trials. Aduhelm was approved on the basis that it did act on what is widely believed to be a key driver of AD, clearing the beta-amyloid protein clumps that form plaques in the brains of patients.

So, a drug that elicits a “statistically significant” decrease in cognitive decline could foreseeably have a future. Also important, said Chief Medical Officer Prof. Johannes Streffer, M.D., is that the data make the case for the use of a monoclonal anti-Tau antibody – and the Tau hypothesis in general – in treating Alzheimer’s disease.

“It is the first example of a monoclonal anti-Tau antibody slowing cognitive decline in mild-to-moderate AD, adding to an emerging dataset that provides a strong scientific rationale for Tau as a valid target in Alzheimer’s disease,” Streffer said in a statement.

Ultimately, trials such as this one call out the complexities inherent in developing an effective drug to treat Alzheimer’s disease. Besides semorinemab, AC Immune has an anti-p Tau vaccine also in Phase II development, partnered with Janssen (Johnson & Johnson), and a tau aggregation inhibitor for rare tauopathies in late preclinical development with Eli Lilly, among other assets.