On Jan. 31, pharmaceutical company Biogen announced it was discontinuing its controversial, amyloid-busting drug aducanumab (Aduhelm). This news did not come as much of a surprise to Alzheimer’s experts. It’s a cautionary tale of overpromising, under-delivering, and an inside look at FDA sausage-making.
The drug, which targets amyloid plaque in the brain, had iffy at best clinical data to prove efficacy, yet received fast-track FDA approval in July 2021. Patients were also required to enroll in the ENVISION Phase 4 trial as a condition of accelerated approval. And, Aduhelm came with a hefty price tag — $56,000 annually — causing Medicare premiums to rise in 2022 in anticipation of the financial outlay. Medicare also required physicians to participate in a registry with an appropriate clinical team and follow-up care to help track any ongoing safety concerns.
In a statement posted on its website, Biogen said the company will discontinue the development and commercialization of Aduhelm and will terminate the ENVISION clinical study. They said this decision was not related to any safety or efficacy concerns, but without published data, this statement cannot be independently confirmed. ENVISION is the Phase 4 confirmation trial required by FDA for full approval.
“As a pioneer in Alzheimer’s disease, Biogen is reprioritizing resources to build a leading franchise to address the multiple pathologies of the disease and patient needs. We plan to further advance the launch of LEQEMBI, together with Eisai, and continue to bolster innovation with the development of the other assets in our pipeline,” said Christopher A. Viehbacher, president and CEO of Biogen. “When searching for new medicines, one breakthrough can be the foundation that triggers future medicines to be developed. Aduhelm was that ground-breaking discovery that paved the way for a new class of drugs and reinvigorated investments in the field.”
An expected decision
“What took them so long?” said Lon Schnieder, M.D., director of the USC California Alzheimer’s Disease Research Center and professor of psychiatry, neurology, and gerontology at the USC Keck School of Medicine.
Schneider said it was clear Biogen would abandon Aduhelm once its other drug, LEQEMBI (lecanemab), received full FDA approval in July 2023. “It also points out Biogen’s high degree of uncertainty in whether their current ENVISON trial is going to be positive,” he added.
Biogen partnered with Eisai on LEQEMBI, which acts in a similar manner to clear the brain of amyloid plaque, with slightly better clinical safety and efficacy results. It received full FDA approval in July 2023.
AHCJ’s July 2023 Q&A on LEQEMBI with Judith Heidebrink, M.D., a neurologist and clinical core co-lead of the Michigan Alzheimer’s Disease Center, explains how the drug works and what side effects it has.
LEQEMBI is not without its own controversy. Independent journalist Kerry Dooley Young, a former AHCJ Health Beat Leader, and I wrote this tip sheet to help reporters better understand the study data.
“I think it’s just a business decision, as Biogen also is involved with LEQEMBI. With LEQEMBI already out and donanemab on the way, reviving aducanumab probably did not make business sense,” said Erik Musiek, M.D., Ph.D., an assistant professor of neurology at Washington University in St. Louis.
What happens now?
Over 6 million older Americans are believed to have Alzheimer’s disease, and this prevalence is expected to rise to 14 million by 2060, barring effective interventions. Finding a safe, effective drug to delay or even reverse Alzheimer’s has been a research goal for decades. Aduhelm was the first approved drug offering a small subset of people a bit of hope.
What about the patients who were enrolled in these Aduhelm follow-up studies?
“In theory, patients who are on aducanumab could switch to LEQEMBI,” Musiek wrote in an email. However, if their condition has declined substantially since starting aducanumab, they may not be eligible, he added.
“Switching is a bit complex and would require discussion with a neurologist and further testing to see where they stand in terms of cognitive function and amyloid pathology,” Musiek said. “However, we have no data to guide us with this switch, and do not know how it will impact the outcomes.”
Where is the FDA in all of this?
There was a tremendous amount of pushback when the FDA fast-tracked Aduhelm for approval in 2021. So much so that several members of its advisory panel resigned and members of Congress looked into the FDA’s review process and Biogen’s relationship with the agency. I reached out to the FDA for comment about what happens next for patients currently being treated with this drug and whether they would do it differently if they could go back.
The Center for Drug Evaluation and Review said in an emailed statement:
“Patients can continue treatment with Aduhelm until November 1, 2024. Patients taking Aduhelm should contact their health care provider to discuss treatment options.The FDA is generally unable to discuss existing or potential applications. That is confidential commercial information. What we can say is that all drugs must undergo a rigorous evaluation of safety, quality, and effectiveness before they are approved and can be sold. These standards exist to make sure that approved drugs have a high chance of helping those who use them. Medicines ultimately must lead to overall improvements in how patients feel, function or survive. The FDA’s drug review process is recognized worldwide as the gold standard.”
Aduhelm served as the vehicle on which FDA set up its standards, then LEQEMBI met it, Schneider said in a phone interview. Newer, possibly more effective and less risky treatments are in the pipeline, including Eli Lilly’s donanemab. But final approval of that drug is still pending,
Schneider wonders why it’s taking so long, since approval was expected in December.
“Delays may very well be about the adverse events and they and FDA might have some greater concerns about adverse events here than they do with LEQEMBI,” he said. “And [Eli Lilly] might not like what the labeling is looking like, or that FDA may have rejected Lilly’s proposed labeling, and this might be what they’re discussing,” he said.
Full FDA approval for donanemab is now expected sometime in the first quarter of 2024, FiercePharma reports.
The Aduhelm saga is a cautionary tale for health journalists reporting on any novel or breakthrough drug, especially one with accelerated approval, noted Dooley Young, who co-authored several AHCJ stories about this drug.
Any journalist writing about Alzheimer’s drugs should read Medicare’s 2022 explanation of its decision to limit Aduhelm coverage, she said. This document can help journalists develop smart questions about other experimental drugs being developed for Alzheimer’s disease.
“The Medicare decision is not as wonky as people might fear and the background section is very easy to read and provides a good overview of the challenges in trying to develop drugs for Alzheimer’s disease,” she said.
Resources
- CMS National Coverage Decision on aducanumab, 2022, CMS.
- Towards a future where Alzheimer’s disease pathology is stopped before the onset of dementia, 2023, Nature Aging.
- USC Alzheimer’s disease research center.
- Musiek Lab at Washington University, St. Louis.
- Alzheimer’s Disease Facts and Figures, 2022, Alzheimer’s Association.
