Adieu to Aduhelm: Biogen Stops Marketing Antibody
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Biogen has thrown in the towel on its controversial anti-amyloid antibody aducanumab. The company announced January 31 that it would stop all development of the drug, and halt the post-market, confirmatory Envision trial.
Biogen said it made this decision to free up resources to commercialize Leqembi, which it jointly markets with Eisai, as well as for developing new Alzheimer’s therapeutics, such as its tau antisense oligonucleotide BIIB080 (Apr 2023 news).
Aducanumab was originally licensed from Swiss company Neurimmune, and the rights will revert to it. Biogen’s announcement was covered in the popular press, including CNN and The New York Times.
Alzheimer’s researchers were unsurprised, and said the decision would have little effect, because very few patients were taking aducanumab. “I don’t think this drug ever had a future after Medicare and insurers declined to provide coverage,” Ian Grant at Northwestern University in Chicago wrote to Alzforum. James Noble at Columbia University in New York noted that lecanemab simply out-competed aducanumab, with more convincing data showing it was effective and safe.
Aducanumab’s path to market became fraught when its Phase 3 trials were stopped early for futility before the drug was suddenly resurrected (Mar 2019 news; Oct 2019 news). The U.S. Food and Drug Administration greenlit aducanumab under its accelerated approval pathway after its advisory committee had rejected the drug; regulators in other countries rejected it (Nov 2020 community news; Jun 2021 news).
The resulting controversy led to resignations, congressional investigations, and a negative coverage decision by the Centers for Medicare and Medicaid Services (Jun 2021 news; Jan 2022 news; Jan 2023 community news).
Doubts over the drug meant many neurologists and clinics never prescribed it. “As an institution, we did not feel that Aduhelm had demonstrated compelling clinical or biomarker data, and did not add it to our formulary,” Brendan Kelley at the University of Texas Southwestern Medical Center, Dallas, wrote to Alzforum. Irina Skylar-Scott and others at Stanford University did not prescribe it. “Our clinicians did not think the benefits outweighed the risks for our patients,” she wrote to Alzforum.
Where aducanumab was prescribed, few patients were on it. Many of those have become amyloid-negative and stopped taking it. At Kansas University Medical Center, Kansas City, 10 patients took aducanumab, most completing an 18-month course. “At this point, we would not introduce another monoclonal antibody [in those patients], absent a demonstrable re-emergence of plaques,” Russell Swerdlow at Kansas wrote to Alzforum.
On the trials front, open-label extensions of the aducanumab trials ended last year, and few people had enrolled in Envision, noted Lon Schneider at the University of Southern California, Los Angeles.
Biogen will continue to supply the drug to patients in the U.S. until November 1, when the license reverts to Neurimmune. Envision will stop in May. The confirmatory trial was a requirement for aducanumab’s accelerated approval, and the FDA has not indicated whether it will now rescind that approval.
Despite aducanumab’s ignominious end, researchers said it helped stimulate renewed hope and investment in AD (Aug 2021 conference news). “The drug paved the way for other important efforts for treatments for AD, and while it will no longer be used, it served an important purpose,” Zoe Arvanitakis at Rush University, Chicago, wrote to Alzforum.
Meanwhile, Neurimmune said it plans to develop a subcutaneous aducanumab formulation for early intervention studies (Endpoints story). This drug has been left for dead before. Time will tell if it can stage another comeback.—Madolyn Bowman Rogers
References
Therapeutics Citations
News Citations
- Paper Alert: Tau Antisense Oligonucleotide BIIB080 Hits Its Target
- Biogen/Eisai Halt Phase 3 Aducanumab Trials
- ‘Reports of My Death Are Greatly Exaggerated.’ Signed, Aducanumab
- FDA Advisory Committee Throws Cold Water on Aducanumab Filing
- Aducanumab Approved to Treat Alzheimer’s Disease
- Aducanumab Approval Sparks Backlash
- CMS Plans to Limit Aduhelm Coverage to Clinical Trials
- U.S. House Scolds FDA Over Aduhelm Approval
- Aduhelm Approval Reverberates Through Research
External Citations
Further Reading
News
- Exposure, Exposure, Exposure? At CTAD, Aducanumab Scientists Make a Case
- Advisory Committee Again Urges FDA to Vote No on Aducanumab
- Flurry of Investigations Besets Aducanumab
- European Regulators Turn Down Aduhelm; Price Drops
- On Aduhelm, Medicare Agency Gets Pressure From All Sides
- Drilling Down into the CMS Aduhelm Decision—A Primer
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Comments
University of Southern California Keck School of Medicine
Cancelling Aduhelm is an uncontroversial decision. Aducanemab was the vehicle on which FDA established its approval standards for amyloid antibodies: (1) plaque lowering buys accelerated approval, and (2) a touch of statistical significance on a composite clinical rating buys regular approval. The FDA interpreted plaque reduction as evidence for likely future clinical benefit and effectively established plaque lowering as a surrogate marker for clinical outcome for regulatory purposes.
Following the aducanumab experience, lecanemab was first given accelerated approval based on plaque lowering in Phase 2; then attained regular approval based on a statistically significant primary outcome of −0.45 CDR-SB points difference in Phase 3, nearly the same as aducanumab’s −0.39-point difference.
That Biogen would end their 1,500-patient ENVISION trial, discontinue marketing support, and turn aducanumab back to Neuroimmune means they (1) couldn’t wait threee more years for ENVISION to finish and for regular approval; (2) are not very confident in a positive outcome; (3) don’t think aducanumab can be competitive or gain commercial success. Importantly, a negative result from ENVISION would reflect poorly on the perception of the effectiveness of Leqembi and other amyloid-targeting antibodies in general. Biogen, for now, has a bird in hand, and is picking up prescriptions. Why market two very similar treatments?
A remaining question is whether Neuroimmune will share aducanumab’s Phase 3 databases with independent investigators so that we may learn a bit more about these antibodies. This is something Biogen staunchly refused to do. The MRI brain volume losses at least deserve a further look, as well as claims that plaque lowering is responsible for clinical improvement.
Abington Neurological
It is not true that only a "few people had enrolled in Envision." Over half the study population was enrolled, with the first subject enrolled about a year and a half ago, so it was perhaps on pace to complete enrollment this year.
Adu's tragedy wasn't biologic or medical. It polarized the community and payers (CMS). Non-coverage was to the detriment of patients. Many from those days progressed into moderate stages and now are looking at the natural history of a fatal disease with zero hope. I see them almost daily.
Adu was the first DMT approval in Alzheimer's disease, and as the front-runner it took a lot of arrows. The decision to approve via biomarker was prescient. The prediction came true as later trials supported amyloid removal and clinical benefit—lec and don—as compared with gant. We should learn from this.
Pour a drink for adu. It was first, but thankfully won't be last. Let's focus on finishing it up safely and with attention to any data we can use to build upon, like switching therapies. Best to all those trial subjects and personnel moving forward.
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