Joined by a site investigator, both note long road ahead to determine efficacy for Alzheimer’s disease

Fallout from the recent approval of aducaumab, the first new treatment for Alzheimer’s disease in 18 years, continues with an editorial in the Annals of Internal Medicine that outlines the problem with the monocloncal antibody’s approval.

G. Caleb Alexander, MD, MS, from the Johns Hopkins Bloomberg School of Public Health and Johns Hopkins School of Medicine in Baltimore, Maryland, and Jason Karlawish, MD, from the University of Pennsylvania, Philadelphia, penned the “Ideas and Opinions” piece to outline what—in their view—are the “implications for clinical research and patient care” that this decision has wrought. They intimated that the road is long before the actual clinical benefit is known.

Alexander served on the FDA advisory committee that, in November 2020, told the FDA that aducanumab should not be approved due to lack of evidence. Alexander and Karlawish, who was a site investigator for the drug, noted that the advisory committee was assured that the drug was not being considered for accelerated approval.

They noted that aducanumab was granted accelerated approval based on its effect on brain β-amyloid levels, a surrogate biomarker for the disease, and not clinical outcomes.

“As Biogen sells Aduhelm [its brand name], it is required to conduct a randomized controlled clinical trial to confirm its clinical benefits,” Alexander and Karlawish wrote. “Biogen’s chief executive officer, Michel Vounatsos, has stated that the study will be completed by 2030. With the stakes so high, nine years is an unacceptably long time to wait. Moreover, such confirmatory studies, even when completed, may fail to identify true clinical benefit.”

They explained that accelerated approvals are usually reserved for “products expected to provide a meaningful advantage over available therapies for a serious disease but for which there is uncertainty about clinical benefit.” But aducanumab’s approval appears to turn this on its head.

“Elevated measures of β-amyloid, together with τ protein, are diagnostic of pathologic Alzheimer’s disease,” they wrote. “Aducanumab’s phase I study indicates the drug reduces β-amyloid levels. Whether β-amyloid alone is a valid surrogate for treatment of Alzheimer’s disease is unclear and was, until the morning of 7 June 2021, a topic of ongoing and important study. Now, treatment of an amyloid level is suddenly clinical practice.”

They pointed out that evidence from aducanumab’s phase III trials fail to show a cause-and-effect relationship between reducing β-amyloid and improved cognitive functions. They also pointed out dozens of other trials that failed to support the “amyloid cascade hypothesis.”

Additionally, the effect on Alzheimer’s patients and clinical research may be in peril with more companies seeking approval of other amyloid reducing drugs or other biomarkers, but again without evidence of clinical benefit. Alzheimer’s patients may opt to try aducanumab instead of remaining in clinical trials.

Insurance companies will weigh in on who should receive the drug and how much will be reimbursed. The drug is costly at $56K per year, per patient. “This price is in stark contrast to a value-based price estimated by the nonprofit Institute for Clinical and Economic Review of between $2,500 and $8,300.

“We can only imagine—aducanumab’s clinical benefits have not been validated. In reality, as desperate patients understandably take it and possibly other amyloid-reducing drugs, the pace and progress of demonstrating safe and effective treatments for Alzheimer’s disease will slow,” they continued.

The uncertainty about aducanumab’s efficacy, as well as its side effects, leave many questions unanswered that clinicians will have to address as patients clamor for this drug. And, as Alexander and Karlawish concluded: “We all must wait for evidence of whether this in fact benefits patients.”

Candace Hoffmann, Managing Editor, BreakingMED™

Cat ID: 33

Topic ID: 82,33,282,485,730,33,925