The FDA has delayed its decision on Biogen's Alzheimer's drug. What was once heralded as the biggest break in Alzheimer's research is falling apart upon closer scrutiny. Why did the FDA decide that additional analyses and clinical data were needed, and what did Biogen actually provide?
On November 6, 2020 an advisory committee to the Food and Drug Administration (FDA) assembled to analyze Biogen’s clinical trial data for aducanumab, the company’s experimental treatment for Alzheimer’s disease. Aducanumab, a monoclonal antibody that targets the classic beta-amyloid plaques that are found in the brains of people with Alzheimer’s, began what was to become an epic journey to regulatory approval in March of 2015. Despite a canceled Phase 3 study in March 2019 due to unconvincing data, Biogen remained true to their mission and sought regulatory approval a few months later following reanalysis of the data and a second pivotal study. The FDA’s internal clinical review team deemed Biogen’s second set of supporting data as strong enough to justify approval in November 2020, however an independent panel of 11 experts came to the opposite conclusion. It wasn’t even close. Ten out of the eleven panelists voted that Biogen did not sufficiently prove aducanumab’s efficacy. How could these two groups arrive at such differing conclusions?
The legacy of aducanumab began in 2007, when Biogen in-licensed the worldwide rights to the drug from Neurimmune Holding AG, placing the fate of the drug and the future of Alzheimer's treatment in the hands of Biogen's team. The company began it's first Phase 1a study (a single dose of the drug administered) in Alzheimer's patients, titled "SAD", in 2011. The SAD study was a placebo-controlled trial in 53 patients with mild-to-moderate Alzheimer's disease with the goal of establishing the safety and pharmacokinetics Encouraged by the results, Biogen initiated a Phase 1b study (multiple doses are given to each patient) entitled "Prime" in 2013, followed by 2 other Phase 1 studies in different patient populations. The results were published in 2015 and 2016 and prompted the initiation of 2 Phase 3 studies entitled "Engage" (2015) and "Emerge" (2016). Both Phase 3 studies had identical designs, were placebo controlled, and had~1,650 participants each. "Engage" failed to meet its primary endpoint, but patients enrolled in "Emerge" who received high doses of aducanumab experienced improvement in cognitive function. The results were promising and it was determined that treatment with a high dose of aducanumab significantly reduced the cognitive decline of patients compared to placebo based on the primary and secondary efficacy endpoints. These findings were further substantiated by biomarker results.
Currently, Biogen has an ongoing open-label trial called "Embark". The goal of the trial is to determine the long-term safety and efficacy of aducanumab dosing with the highest dose tested in the prior Phase 3 trials, and measure the changes in clinical and biomarker measures during the treatment window. Biogen is attempting to enroll 2,400 patients and conduct follow-up analyses for up to 2 years after treatment. As of an update provided in November 2020, Biogen had enrolled only 531 patients who received infusions of a high dose of aducanumab and subjected to regular safety screenings and cognitive tests. Interestingly, the study has no placebo group, and the primary goal of the study is to qualify the safety of the drug; the efficacy of aducanumab is an afterthought, and with no placebo group to compare it to it will be very difficult to draw meaningful conclusions (unless the effect size is enormous, in which case it will be astonishingly successful). Biogen will have to rely on comparing an individual patient's cognitive scores before and after treatment. Biogen submitted the results from more than 500 "Embark" patients collected after 26 weeks of treatment to the FDA. It will be interesting to see how the FDA responds to this new information.
Why is the Biogen data so controversial within the FDA? Two big names are at the heart of this battle: Billy Dunn, director of the FDA's Office of Neuroscience, and Tristan Massie, a biostatistician employed by the FDA's Division of Biometrics. Dunn is bullish on the original Phase 3 data while Massie has argued against its approval. The FDA's advisory panel ultimately sided with Massie during their original meeting in 2020. The Agency is also facing outside influence from the Alzheimer's Association who spoke with FDA officials. The absence of a FDA commissioner may also play a role in the Agency's hesitation to approve aducanumab. Biden's top candidates for the role, Janet Woodcock (senior FDA official serving as acting commissioner )and Josha Sharfstein (Johns Hopkins University professor of health policy), have opposing views on regulatory flexibility. Ms. Woodcock is in favor of bringing more drugs to market to increase the pool of available treatments to patients with dire conditions, while Mr. Sharfstein advocates for more rigid standards for drug approval.
There have been several occurrences of FDA approval of drugs that received negative recommendations from independent advisory panels. However, there is a precedent for mandating extended reviews and additional data before a final decision can be made. For Biogen, their ongoing "Embark" study may or may not provide enough information. Only time will tell.
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