Aduhelm Pros and Cons Debated at ICER Meeting

Biogen officials defended Aduhelm (aducanumab) and criticized the Institute for Clinical and Economic Review’s (ICER) cost-effectiveness assessment of its recently approved Alzheimer’s disease during an occasionally emotional and tense daylong meeting today of an ICER advisory committee. But the 15-member committee ultimately cast a series of negative votes on Aduhelm, including a unanimous vote that evidence of the drug having a health benefit is inadequate and a majority vote that it would have a major negative effect on efforts to reduce health inequities.

Patient advocates, committee members and ICER President Steve Pearson, M.D., M.Sc., spoke movingly about the decline of loved ones with Alzheimer’s and the wrenching experience of caring for them (both of Pearson’s parents were affected by the disease).

But the committee members and some outside experts asked questions and made statements that cast doubt on whether Aduhelm produces a clinically meaningful difference in slowing the worsening of Alzheimer’ disease while raising concerns about the harm it might cause.

“We need something that does more, but I don’t think this is it,” said Victor W. Henderson, M.D., M.S., a Stanford professor and director of its Alzheimer’s Disease Research Center who participated in the meeting as a clinical expert.

Today’s meeting came after ICER published a report on June 30 that said the evidence for Aduhelm having a net health benefit is insufficient. ICER’s cost-effectiveness analysis said the drug should be priced between about $3,000 per year and $8,400, which is far less than Biogen’s price of $56,000. 

A wide range of issues were discussed at the meeting. People on anticoagulants were excluded from the two phase 3 trials that produced the data that Biogen used to gain approval for Aduhelm. Ralph G. Brindis, M.D., M.PH., a clinical professor of medicine at University of California, San Francisco, and a member of the ICER advisory committee, expressed concern that patients with atrial fibrillation and other conditions treated with anticoagulants would stop taking the medications so they could start taking Aduhelm and therefore run the risk of having a stroke or other condition caused by blood clots.

The FDA’s approval of Aduhelm was in category called accelerated approval that allows drugmarkers to use lab values or imaging results as stand-ins for evidence of clinical benefit. For Aduhelm, the stand-in, or “surrogate marker,” was a reduction in the beta-amyloid plaques in the brain that are believed by many to have a causative role in the disease. But one line of discussion in the meeting raised questions about how strength of the correlation between amyloid plaques and the cognitive deficits that characterize Alzheimer’s disease.

Chris Leibman, Pharm.D., M.S. head of value and access at Biogen, and Maha Radhakrishnan, M.D., the company’s chief medical officer, defended the Aduhelm and the company’s positive interpretation of the two phase 3 trials of Aduhelm, one called ENGAGE and the other, EMERGE. They also criticized ICER’s cost-effectiveness assessment of the drug as being too limited.

“Assessing the first treatment for Alzheimer’s disease is a complex matter that requires innovative thinking and new methodology framework,” said Radhakrishnan. “We regret that ICER assessment missed the mark on this. The central problem surrounding this assessment is that it applies a surprisingly narrow framework to the burden of Alzheimer’s disease and the value of Alzheimer’s disease treatments.”

Leibman argued that “willingness to pay” standards used in cost-effectiveness analysis should be higher for Alzheimer’s disease ICER used $50,000 to $200,000 per quality-adjusted life year (QALY) gained; Leibman it could be five times as much, but Biogen has advocated for $250,00 per QALY gained for Alzheimer’s disease.

The results from the ENGAGE trial did not show Aduhelm as having any benefit, but Biogen did an analysis of the EMERGE results that showed that people in a high-dose group experienced a slower worsening of Alzheimer’s disease as measured by a cognitive test called the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). Biogen’s analysis and explanation for the disparate results of the two trials has been controversial. David Rind, M.D., M.Sc., ICER’s chief medical officer, said at the meeting today that applying Biogen’s reasoning for the ENGAGE trial results to those from EMERGE causes the EMERGE results “to just look ridiculous — they don’t make any sense at all. Why should we believe that analysis?”

One of the arguments for approving Aduhelm on an accelerated basis is that it will stimulate research and development of other Alzheimer’s disease drugs. Radhakrishnan compared the current state of Alzheimer’s disease drug development to drug development for multiple sclerosis 20 year ago. But Annette Langer-Gould, M.D., Ph.D., a member of the committee and multiple sclerosis specialist at Kaiser Permanente, disputed the analogy between Aduhelm and early MS drug because, she said, there was evidence of clinical benefit for the MS drugs.

The Alzheimer’s Association has steered a middle course on Aduhelm, praising the FDA for approving the drug while criticizing Biogen for pricing it at $56,000 a year. Matthew Baumgart, the group’s vice president of health policy, mentioned price when talking about the importance of access at today’s meeting: “Access means a drug price that is not unacceptably high and the price set by Biogen is unacceptably.” But Baumgart also criticized ICER’s cost-effectiveness report for not capturing the “the full and true value of the drug.” Aduhelm fills a huge need for Alzheimer’s patients whose disease lacks effective treatments, he said. “They have no other alternatives,” said Baumgart. “Having one, finally one, even one that falls short of perfect, adds value.”