FDA picks accelerated approval path to decide in favor of Biogen Alzheimer’s drug

brain in hands

A closely watched Alzheimer’s disease drug developed by Biogen has won FDA approval, making it the first new treatment for the memory-robbing disease in decades. Approval of the drug also marks the first for a drug that addresses the way this disease progresses, specifically, the buildup of plaques of amyloid protein on the brains of Alzheimer’s patients.

Aducanumab’s approval is not without controversy. The precise role of amyloid in Alzheimer’s is still uncertain, and drugs developed to break up these protein plaques have produced a long series of late-stage clinical trial failures. Biogen CEO Michael acknowledges those failures. In a letter posted on the company’s website, he noted that at least 100 drug development programs have ended since 2003, when Forest Laboratories won the agency’s O.K. for memantine (Namenda) as a treatment for patients with moderate-to-severe disease. “What it tells us is that the path for innovation is not straightforward, especially for something as complex as Alzheimer’s research,” Vounatsos wrote.

The path zigzagged for Biogen, as well. The industry stumbles since Forest Labs’ approval include clinical a trial failure for aducanumab. These mixed clinical results led some clinicians to call for more testing of the drug to better understand if it works. They will get that trial, but perhaps not in the way they had expected. The Biogen drug, which will be marketed under the name “Aduhelm,” was granted marketing authorization under the FDA’s accelerated approval pathway. This quicker path to the market based on a thinner body of evidence requires companies to conduct additional post-marketing studies.

The causes of Alzheimer’s disease remain unknown but one of the telltale indicators of the disease is buildup of amyloid plaques. These plaques lead to a loss of neurons, which in turn affects memory and cognition. Aduhelm is an antibody drug designed to bind to amyloid plaques and clear them from the brain. Reducing that plaque buildup is hoped to slow the progression of Alzheimer’s.

Biogen advanced its Alzheimer’s drug to two Phase 3 studies. In 2019, the company halted both of them after an independent analysis concluded the studies were unlikely to succeed. But later that year, Biogen announced it would seek regulatory approval of the drug based on a new analysis of a larger dataset from the Phase 3 study. The company said that this new analysis, conducted in collaboration with the FDA, showed that one of the two Phase 3 tests of the drug met the main goal, which was to show the drug slowed cognitive impairment and function according to a scale used to assess dementia.

The FDA accepted Biogen’s drug application last August, granting it priority review. That status shaves about four months off of the standard 10-month review, but it does not change the scientific standards of approval or the quality of the evidence needed to support approval.

Last November, an independent advisory panel to the FDA held a hearing to evaluate aducanumab, weighing its risks and benefits. The panel voted nearly unanimously against recommending approval, citing in part the conflicting results of the two Phase 3 studies.

Billy Dunn, the director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research, explained the rationale for the FDA’s decision in a letter sent to the advisory committee on Monday. The agency weighed the uncertainty of the two conflicting Phase 3 clinical trial results. Internal discussions led to the consideration of the accelerated approval pathway—a route that was not discussed during the advisory committee hearing and was not sought by the company. This pathway is reserved for drugs treating serious diseases in which the new therapy may offer a “meaningful advantage” over available drugs even if uncertainty remains about how much benefit patients receive from the new drug. Such approvals are based on a surrogate endpoint, a sign that that a drug may be working. A drug doesn’t need to demonstrate clear clinical benefit, only that clinical benefit is reasonably likely.

In a prepared statement, CDER Director Patrizia Cavazzoni, said that currently available Alzheimer’s therapies only address symptoms. She acknowledged the two conflicting Phase 3 studies for Aduhelm, but she added that in all of its studies, the Biogen drug led to a reduction in amyloid.

“Although the Aduhelm data are complicated with respect to its clinical benefits, FDA has determined that there is substantial evidence that Aduhelm reduces amyloid beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients,” she said. “As a result of FDA’s approval of Aduhelm, patients with Alzheimer’s disease have an important and critical new treatment to help combat this disease.”

The accelerated approval pathway is frequently used to review drugs for cancers and rare diseases. In these instances, companies must conduct additional post-marketing clinical trials to verify that a drug is indeed benefiting patients. Now Biogen must do the same for Aduhelm. FDA documents do not specify whether these studies will be placebo controlled but large Alzheimer’s studies typically enroll thousands of patients. It could be years before a post-marketing study produces data confirming Aduhelm’s benefit. If these studies do not verify clinical benefit, the FDA can take steps to remove the Biogen drug from the market.

Aduhelm is dosed as a one-hour intravenous infusion given every four weeks. So far, the drug has been tested in more than 3,000 patients. The most frequently reported serious side effect was amyloid-related imaging abnormalities, or ARIA, which are abnormalities observed in the brain scans of patients. ARIA was observed in 41% of patients treated with the Biogen drug compared to 10% of those given a placebo. The most common symptom in patients with ARIA was a headache. Other symptoms include confusion and dizziness. Aduhelm’s dosing instructions say patients must have MRI scans done before the seventh and twelfth infusions to check for ARIA.

Biogen licensed aducanumab from Neurimmune. Upon the launch of the drug in the U.S., the licensing agreement entitles the Switzerland-based company to a $100 million milestone payment, according to Biogen’s annual report. Neurimmune will also earn royalties from the drug’s sales. Biogen developed the Alzheimer’s drug in collaboration with Japan-based pharmaceutical giant Eisai. According to the agreement, the two companies will promote the drug, splitting the profits based on particular regions. Biogen is taking the lead on ongoing development of the drug.

As of the end of last year, Biogen had about $93.8 million of pre-launch inventory of the Alzheimer’s drug, according to the company’s 2020 annual report. The drug is still under review by regulatory bodies in Europe and Japan.

Biogen will further discuss the Aduhelm approval during a June 8 webcast scheduled for 8 a.m. Eastern daylight time.

Photo: Matthew Horwood, Getty Images

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