FDA Grants Accelerated Approval to Aducanumab for Alzheimer’s Disease, Explains its Decision
June 7, 2021

The US Food and Drug Administration (FDA) has granted accelerated approval to aducanumab (Aduhelm) for the treatment of Alzheimer’s disease -- the first novel therapy approved for Alzheimer’s disease since 2003.

Accelerated approval can be based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, with a required post-approval trial to verify that the drug provides the expected clinical benefit.

“We are well-aware of the attention surrounding this approval” said Patrizia Cavazzoni, MD, FDA’s Center for Drug Evaluation and Research, Rockville, Maryland. “...the data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit. There has been considerable public debate on whether aducanumab should be approved. As is often the case when it comes to interpreting scientific data, the expert community has offered differing perspectives.”

“At the end of the day, we followed our usual course of action when making regulatory decisions in situations where the data are not straightforward,” she continued. “We examined the clinical trial findings with a fine-tooth comb, we solicited input from the Peripheral and Central Nervous System Drugs Advisory Committee, we listened to the perspectives of the patient community, and we reviewed all relevant data. We ultimately decided to use the Accelerated Approval pathway -- a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit. In determining that the application met the requirements for Accelerated Approval, the Agency concluded that the benefits of aducanumab for patients with Alzheimer’s disease outweighed the risks of the therapy.”

Aducanumab is the first treatment directed at the underlying pathophysiology of Alzheimer’s disease -- the reduction of amyloid beta plaques in the brain. The late-stage development program for aducanumab consisted of 2 phase 3 clinical trials. One study met the primary endpoint, showing reduction in clinical decline. The second trial did not meet the primary endpoint. In all studies in which it was evaluated, however, aducanumab consistently and very convincingly reduced the level of amyloid plaques in the brain in a dose- and time-dependent fashion. It is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.

“We know that the Peripheral and Central Nervous System Drugs Advisory Committee, which convened in November 2020 to review the clinical trial data and discuss the evidence supporting the aducanumab application, did not agree that it was reasonable to consider the clinical benefit of the one successful trial as the primary evidence supporting approval,” said Dr. Cavazzoni. “The option of Accelerated Approval was not discussed by the Advisory Committee. As mentioned above, treatment with aducanumab was clearly shown in all trials to substantially reduce amyloid beta plaques. This reduction in plaques is reasonably likely to result in clinical benefit. After the Advisory Committee provided its feedback, our review and deliberations continued, and we decided that the evidence presented in the aducanumab application met the standard for Accelerated Approval. We thank the Advisory Committee for its independent review of the data and valuable advice.”

As part of the Accelerated Approval, drug companies are required to conduct post-approval studies to verify the anticipated clinical benefit. These studies are known as phase 4 confirmatory trials. If the confirmatory trial does not verify the drug’s anticipated clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.

The FDA will continue to monitor aducanumab as it reaches the market and ultimately the patient’s bedside and Biogen is required to conduct a post-approval clinical trial to verify the drug’s clinical benefit.

“If the drug does not work as intended, we can take steps to remove it from the market,” said Dr. Cavazzoni. “But hopefully, we will see further evidence of benefit in the clinical trial and as greater numbers of people receive aducanumab. As an agency, we will also continue to work to foster drug development for this catastrophic disease.

The prescribing information for aducanumab includes a warning for amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain that usually resolves over time and does not cause symptoms, though some people may have symptoms such as headache, confusion, dizziness, vision changes, or nausea. Another warning for aducanumab is for a risk of hypersensitivity reactions, including angioedema and urticaria. The most common side effects of aducanumab in clinical trials were ARIA, headache, fall, diarrhoea, and confusion/delirium/altered mental status/disorientation.

References: https://www.fda.gov/news-events/press-announcements/fda-grants-accelerat... and https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-...

SOURCE: US Food and Drug Administration