Trials and tribulations in Biogen’s Alzheimer’s drug reviews

Regulatory reviews of Biogen’s Alzheimer’s drug aducanumab are now ongoing on both sides of the Atlantic, but debate is still ongoing about whether the data behind the drug is strong enough to support approval.

The EMA has just kicked off its review of the anti-amyloid therapy, following in the footsteps of the FDA in the US which has been looking at the drug since August, but a new analysis of the mixed phase 3 data for aducanumab argues that an additional trial should be carried out.

The paper in the journal Alzheimer’s & Dementia, led by Mayo Clinic neurologist David Knopman, says that efficacy of aducanumab “as a treatment for the cognitive dysfunction in Alzheimer’s disease cannot be proven by clinical trials with divergent outcomes.”

Meanwhile, the paper also notes that Knopman has been excluded from an FDA advisory committee meeting due to discuss the data on Friday, ahead of a decision on the marketing application due in March.

The expert – who was an investigator in the phase 3 trials of Biogen’s drug – told Reuters he was recused from the panel because of his involvement in conducting clinical trials of aducanumab.

Aducanumab – which Biogen is developing with Japanese drugmaker Eisai – was all but abandoned in 2019 after the partners decided that two phase 3 trials of the drug were unlikely to show an effect on cognitive decline in Alzheimer’s.

Shares in Biogen were hit hard, as investors lost hope that aducanumab might be rescue the almost defunct amyloid hypothesis of Alzheimer’s disease, which holds that blocking the formation of amyloid plaques in the brain could delay the onset of dementia.

Just a few months later however they said a fresh look at the results of the EMERGE and ENGAGE studies had revealed that the initial futility analysis was “incorrect.” In fact, the drug reduced clinical decline in patients with early, a chance was put down to more exposure to a higher dose in additional patient follow-up.

Some patients showed statistically significant improvements on symptoms like memory, orientation, and language, as well as being able to carry out day-to-day tasks more easily.

There’s a lot riding on the FDA and EMA reviews. If approved, aducanumab will become the first therapy to reduce the clinical decline of Alzheimer’s and to change the course of the disease, says Biogen. It would also be the first amyloid-targeting drug to reach the market, after dozens of others have failed in clinical development.

Meanwhile, aducanumab is the big hope in Biogen’s late-stage pipeline, which otherwise is looking fairly thin, at a time when the biotech is facing the loss of patent protection for its blockbuster multiple sclerosis therapy Tecfidera (dimethyl fumarate).

Knopman and fellow authors argue in the Alzheimer’s & Dementia paper that Biogen’s interpretation of data in the two trials might not be correct.

They write that they have found alternative explanations for the apparent drug benefits unrelated to the treatment, and say that while there is evidence that aducanumab was working on amyloid and other biomarkers like tau protein as expected, “no evidence was presented to correlate biomarker changes to cognitive benefits.”

They also say there were differences in the placebo responses between the two studies, which could have contributed to the divergent results.

“Our analysis supports the conduct of a third, definitive phase 3 trial with high‐dose aducanumab [that is] optimally designed and adequately powered to prove efficacy,” they conclude.

The FDA has not commented on the reasons for Knopman’s exclusion from the advisory committee meeting publicly, but in these cases there is usually a conflict of interest.

Along with his involvement in EMERGE and ENGAGE, Knopman also serves on a data safety monitoring board for a tau drug for Alzheimer’s developed by Biogen, and is an investigator in a trial sponsored by Eli Lilly and the University of Southern California.

He also performs unpaid consultancy work for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences, according to the paper’s conflict of interest statement.

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