After all the expectation, Biogen and Eisai’s Alzheimer’s drug BAN2401 was shown to reduce disease progression by a third at the highest dose in a phase 2 trial – but shares in the companies still declined.
Both companies dipped around 10% in after-hour trading after the data was presented at the Alzheimer’s Association International Conference in Chicago, revealing that the high dose of BAN2401 hit the mark on two outcome measures but missed another in early-stage Alzheimer’s patients.
There was also concern that patients on lower doses of the amyloid-targeting drug seemed to decline more quickly than those on placebo, and while the companies suggest this could be because of an imbalance between the groups at enrolment in patients with a genetic predisposition for rapid progression (APOE4+), the lack of a clear dose response on clinical endpoints raised eyebrows.
Using the Alzheimer’s Disease Composite Score (AD-COMS) – a catch-all of commonly-used disease endpoints – the highest dose of BAN2401 (10mg/kg biweekly injections) slowed progression by 30% compared to placebo, while on the more widely-used ADAS-Cog rating it did even better, with a 47% reduction versus placebo. That begged the questions why the ADAS-Cog data looks so much better than AD-COMS, and the investigators said this could be because cognitive declines are more important in early-stage disease.
Meanwhile, on a third measure – the Clinical Dementia Rating (CDR) – the difference at the highest dose was 26%, which did not reach statistical significance. That could have a knock-on effect for Biogen’s other Alzheimer’s drug aducanumab, which also targets soluble amyloid and also showed some activity in a clinical trial, as CDR is the primary endpoint in aducanumab trials due to read out in 2020.
All those results came against a backdrop of a very high level of clearance of the amyloid plaques in the brain that characterise Alzheimer’s disease, with the anti-amyloid beta protofibril antibody clearing 93% of them at the highest dose tested, showing that the drug was working as expected. On this measure a dose-response with the drug was apparent.
Despite the data dissection that will no doubt run and run, Eisai and Biogen are happy with the data, saying that the study is further evidence that targeting amyloid can be an effective disease-modifying treatment strategy in Alzheimer’s and is robust enough to head to regulatory authorities and discuss how to take the programme forward.
Showing an impact on progression is in itself remarkable given the host of amyloid-targeting drugs have failed in trials, but with the trial posing more questions than it has answered, it would be premature to get too excited about BAN2401’s potential in Alzheimer’s disease.
The AAIC’s official release on the study reads: “This is the second Alzheimer’s clinical trial that has demonstrated both clearance of amyloid from the brain and cognitive benefits – again, the studies were not large enough to definitely demonstrate cognitive efficacy and the BAN2401 study did not meet its primary endpoint”, referring to the 12-month data reported last year.
“That said, these two studies indicate that amyloid remains an important therapeutic target to pursue in Alzheimer’s disease,” it adds.