What is aducanumab? FDA advisory panel rejects Biogen’s experimental drug for treating Alzheimer’s patients
The agency is expected to decide whether or not to approve the drug by March 2021
The future of aducanumab, Biogen’s experimental treatment for Alzheimer’s disease, remains uncertain. This comes after an independent advisory panel concluded that there was insufficient evidence to demonstrate that the drug was effective in slowing cognitive decline in patients with Alzheimer’s. When asked whether a clinical study provided strong evidence that the drug effectively treated Alzheimer’s, eight of 11 experts voted 'No'. The panel also rejected the merits of a second study of the drug, with seven voting 'No' and four 'Uncertain'.
The peripheral and central nervous system drugs advisory committee met on November 6 at the behest of the US Food and Drug Administration (FDA). Finally, the committee voted 0 'Yes', 10 'No' and 1 'Uncertain' on the question, “In light of the understanding provided by the exploratory analyses of Study 301 and Study 302, along with the results of Study 103 and evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology, it is reasonable to consider Study 302 as primary evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s disease?”
“There are literally a dozen different red threads that suggest concerns about the consistency of evidence,” said one member, Dr Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, reports The New York Times. He added that he “could not understand how the FDA could conclude that there is substantial evidence of effectiveness.”
“Alzheimer’s treatment is a huge, urgent, unmet need. But if we approve something with data that is not strong we have the risk of delaying good, effective treatments,” another panelist Dr Joel Perlmutter, Washington University School of Medicine, told NBC News.
Alzheimer’s disease is a progressive neurodegenerative disorder that slowly destroys memory and thinking skills, and subsequently the ability to perform daily activities. Over 5.5 million Americans are living with the disease. There are currently no approved drugs that can reverse the mental decline from Alzheimer’s. The FDA has approved Alzheimer’s drugs aimed at helping symptoms.
What is aducanumab?
It is an investigational human monoclonal antibody studied for the treatment of Alzheimer’s disease. The drug does not cure or reverse Alzheimer’s. According to Biogen, it has “the potential to impact underlying disease pathophysiology, slow cognitive and functional decline and provide benefits on patients’ ability to perform activities of daily living, including conducting personal finances, performing household chores, such as cleaning, shopping and doing laundry, and independently traveling out of the home.”
Aducanumab targets a compound in the brain known as beta-amyloid, which is thought to play a role in the devastating disease. Since October 2017 Biogen and Eisai have collaborated on the development and commercialization of aducanumab globally.
In March 2019, Biogen halted Phase 3 trials of the drug after an independent data monitoring committee found that the medicine was unlikely to work. However, Biogen subsequently announced that it was seeking regulatory approval for aducanumab. The company said that later results showed one study was positive, and one was negative. It added that an independent study provided “consistent evidence.” “Consistent exposure to 10 mg/kg aducanumab is effective at reducing the clinical decline in patients with early symptomatic Alzheimer’s disease,” the company stated.
What did FDA say?
Before the meeting, a 343-page FDA document said the results from Biogen’s late-stage trial were “robust,” “highly persuasive,” and the study was “capable of providing the primary contribution to a demonstration of substantial evidence of effectiveness” of aducanumab.
The report also explained that aducanumab has an “acceptable safety profile” that would support use in individuals with Alzheimer’s disease. “Based on the considerations above, the applicant has provided substantial evidence of effectiveness to support approval,” the agency added.
However, not every FDA reviewer was convinced. Buried in the FDA document, one expert stated that the single positive trial of aducanumab cannot outshine the negative one, writing that “the second (negative) study directly conflicts with the negative study.” “There is no compelling, substantial evidence of treatment effect or disease slowing and that another study is needed to confirm or deny the positive study and the negative study,” the reviewer concluded.
Ahead of the meeting, the Alzheimer’s Association submitted a letter, stating that there is a “dire and drastic need” to offer relief and support to the millions of Americans impacted each day by the “crushing realities of Alzheimer’s.”
Dr David Knopman, who sits on the advisory panel but was recused from the hearing because he was a site investigator at one of the aducanumab trials, submitted a comment before the hearing, stating that “perfection may be the enemy of the good, but for aducanumab, the evidence doesn’t even rise to good.” “Contrary to the hope that aducanumab will help Alzheimer’s patients, the evidence shows it will offer improvement to none, it will harm some of those exposed, and it will consume enormous resources,” he cautioned.
Dr Knopman, a professor of neurology at Mayo Clinic, advised that the solution is that Biogen should conduct another trial with high dose aducanumab. “If the drug's benefits are truly substantial, such a trial could recruit quickly and only several hundred patients would need to be randomized,” he suggested.
What happens now?
The FDA is not bound to follow the recommendations of the guidance committee, though it has historically done so. If approved, the drug will become the first new Alzheimer’s therapy in nearly two decades. The FDA is expected to decide by March 2021.
Commenting on the panel’s decision, Michel Vounatsos, chief executive officer at Biogen, said, “Biogen thanks the many patients and advocates who shared their personal thoughts and experience at today’s advisory committee meeting, reflecting the significant unmet need for a treatment for Alzheimer’s. We appreciated the opportunity to share our data with the Advisory Committee, and we will continue to work with the FDA as it completes its review of our application.”