Biogen’s Controversial Alzheimer’s Drug Wins Historic FDA Approval

If there ever was a fantasy story where a drug almost got scraped, but returned to come up trumps against multiple hurdles, then this is it. After years of crisscrossing between hope and despair, Biogen’s Aduhelm (aducanumab) has finally snatched a controversial accelerated approval from the FDA to treat patients with Alzheimer’s disease (AD).

With this, the drug has become the first authorized AD treatment in nearly 20 years. In light of the approval, Biogen’s shares soared nearly 52% to $434.52 when trading resumed. US shares of its partner Eisai Co. shot 45%, to $107.75.

Alzheimer’s disease is an age-related neurodegenerative disorder that results in slow cognitive decline, affecting the victim’s memory, reasoning, and thinking abilities. The illness is characterized by amyloid plaques composed of amyloid beta (Aβ) proteins—one of the two major neuropathological hallmarks. Aduhelm is a monoclonal antibody that targets the Aβ protein.

Originally discovered by Neurimmune together with a team of researchers at the University of Zurich, Aduhelm was licensed by Biogen in 2007. By specifically targeting Aβ aggregation, aduhelm was shown to enter the brain and reduce soluble and insoluble Aβ in a dose-dependent manner in both mice models and patients with mild AD.

Things were looking up as the drug met the primary endpoints in two Phase 3 trials, EVOLVE, and EMERGE. But in March 2019, Biogen decided to end the trials following a futility analysis conducted by an independent data monitoring committee.

Regulatory Hurdles Following U-Turn

However, in October 2019, the drugmaker made a surprise turnaround by announcing plans to revive aduhelm and set it on its path to regulatory approval. Biogen said that new analyses of the EMERGE trial data showed that the drug impacted the pathophysiology of the disease and slowed the cognitive and functional decline in patients with mild AD. Besides, a subset of patients from the Phase 3 ENGAGE study who received higher exposure to the drug supported their findings from EMERGE.

But the road to approval was far from straightforward. In November 2020, just days after receiving promising comments from the FDA staff, an advisory panel voted 8-1 (2 uncertain), claiming that the EMERGE trial does not provide strong evidence supporting aduhelm’s effectiveness for AD treatment.

Although 5 members (6 uncertain) agreed that Biogen presented strong evidence of a pharmacodynamic effect of aduhelm on AD pathophysiology, 7 (4 uncertain) voted against the claim that Phase 3 PRIME trial data demonstrated the drug’s efficacy. Altogether, 10 out of 11 members disagreed that the EMERGE trial data can be used as primary evidence of the effectiveness of aduhelm.

Mixed Reactions to Historic Approval

The FDA approval of aduhelm was met with mixed reactions. In a statement, Dr. Patrizia Cavazzoni, Director, FDA Center for Drug Evaluation and Research, conveyed that the approval was “significant in many ways”. The statement pointed out that:

• Aduhelm is the first novel therapy approved for AD since 2003.
• Aduhelm is the first treatment directed at the underlying pathophysiology of AD, the presence of Aβ plaques in the brain.
• Clinical trials for Aduhelm were the first to show that a reduction in these plaques is expected to lead to a reduction in the clinical decline.

Michel Vounatsos, CEO of Biogen termed the regulatory win as a “historic moment”. In a press release, he said that the approval “is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease”.

Dr. Ronald Petersen, an Alzheimer’s disease expert at the Mayo Clinic, stated, “This is good news for patients with Alzheimer’s disease. We’ve not had a disease modifying therapy approved ever,” he said. However, he warned, “This is not a cure. It’s hoped that this will slow the progression of the disease.”

“I think this is a big day,” Dr. Peterson said. “But we can’t overpromise.”

Yet, some others like Dr. G. Caleb Alexander, a member of the FDA advisory committee, did not welcome the approval. Two days earlier, he had expressed that no solid evidence has been presented to suggest that aduhelm works and FDA approval would set a remarkably dangerous precedent for drug regulation in the US.

“The FDA gets the respect that it does because it has regulatory standards that are based on firm evidence. In this case, I think they gave the product a pass,” said Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of public health.

Today’s approval also gives a huge boost to the researchers who support the amyloid beta hypothesis. In addition to that, the decision has also eased the regulatory pathway for drugs that could potentially rival aduhelm — Eli Lilly’s donanemab and Roche’s gantenerumab. Nevertheless, today’s landmark approval marks a significant moment for AD patients and their families. One must wait to see if Biogen’s and most importantly, the FDA’s bet on aduhelm pays off.

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Author

Rajaneesh K. Gopinath