FDA, in Reversal, Limits Aduhelm’s Use to People With Mild Disease

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Aduhelm and FDA label change


The U.S. Food and Drug Administration (FDA) has pulled back the controversial and sweeping approval recently given to Aduhelm (aducanumab), updating the treatment’s label at its manufacturer’s request so that it is prescribed to early-stage Alzheimer’s patients only rather than all with this disease.

Whereas the FDA’s original June approval indicated simply that Aduhelm could be used “for the treatment of Alzheimer’s disease,” the updated label is more restrictive.

“Treatment with Aduhelm should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials,” it now reads.

Aduhelm, by Biogen and Eisai, was approved under the FDA’s accelerated approval pathway, based on data from clinical trials showing that the medication could reduce levels of beta-amyloid plaques — the protein clumps in the brain that are characteristic of Alzheimer’s.

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Its development has been tumultuous, and its approval contentious. Following positive results in early clinical studies, Biogen launched two Phase 3 clinical trials, ENGAGE (NCT02477800) and EMERGE (NCT02484547), which collectively enrolled nearly 3,300 people with mild cognitive impairment (MCI) or early Alzheimer’s.

Biogen then halted work on Aduhelm in March 2019, after an interim analysis of these trials suggested it was unlikely to benefit patients. But the company reversed course later that year, after more trial data from were available and analyzed. These data showed that one trial (EMERGE) — but not the other — had met its primary goal, with Aduhelm significantly slowing patients’ decline in cognition and function, relative to a placebo.

The FDA’s accelerated approval of Aduhelm was based on the earlier clinical data concerning beta-amyloid plaques, and mandates that additional trials be conducted to clarify the medication’s effect on cognition and function.

This decision also led to three members of an FDA advisory committee — which voted overwhelmingly against approval — to resign.

The controversy is continuing, even with Aduhelm’s more restrictive new label.

Janet Woodcock, the FDA’s acting commissioner, asked the Health and Human Services inspector general on July 9 to open an independent review and assessment of interactions between Biogen and FDA officials during the agency’s review process, to “determine whether any of those interactions were inconsistent with FDA policies and procedures.”

This request follows concerns raised that some such interactions “may have occurred outside of the formal correspondence process” that accompanies the review process, Woodcock wrote.

Aduhelm’s initial approval label, which guides doctors in prescribing a medication, applied to a much broader Alzheimer’s population than that evaluated in the treatment’s clinical trials in patients, sparking confusion and debate.

“Based on our ongoing conversations with prescribing physicians, FDA and patient advocates, we submitted this label update with the goal to further clarify the patient population that was studied across the three Aduhelm clinical trials that supported approval,” Alfred Sandrock, Jr., MD, PhD, head of research and development at Biogen, said in a July 8 company press release.

The updated label was welcomed by the Alzheimer’s Association, a patient advocacy organization that had pushed for the FDA to approve Aduhelm  — the disease’s first new treatment in 18 years.

“Today’s announcement is consistent with the Alzheimer’s Association position that Aduhelm should be made available specifically to the population represented in the clinical trials where there was evidence of clinical benefit,” Maria C. Carrillo, PhD, the association’s chief science officer, said in a webpage release.

“We appreciate the FDA’s thoughtful consideration and response to the Alzheimer’s Association and others in the community including physicians, researchers and patients to ensure this treatment is prescribed only to those who may see benefit,” Carrillo added.

Another controversial aspect of Aduhelm’s approval is its cost — the medication carries a U.S. list price of about $56,000 a year, which the Alzheimer’s Association has said is “simply unacceptable.” Experts also raised concerns that its price could strain Medicare, the U.S. government program that provides health insurance to elderly people.

report released June 30 by the Institute for Clinical and Economic Review (ICER) — an independent U.S. group that evaluates prices given new drugs relative to likely benefit — estimated that Aduhelm might be cost-effective at annual prices ranging from $2,950 to $8,360.

But its report also determined that the available evidence, based on trial data, “is insufficient to conclude that the clinical benefits of aducanumab [Aduhelm] outweigh its harms or, indeed, that it reduces progression of AD [Alzheimer’s disease] in patients with MCI [mild cognitive impairment] and mild AD.”

ICER’s report also highlighted safety concerns associated with the medication. Over a third of patients treated with Aduhelm in its clinical trials experienced ARIA, a type of fluid accumulation in the brain. Some people with ARIA won’t experience any overt symptoms, but in others, symptoms can be severe.

“The need for disease-modifying treatment for patients with AD is great, however, it is unclear that treatment with aducanumab provides net health benefits,” ICER stated. “Given the certainty that harms can occur … and uncertainty about benefits, we rate the evidence to be insufficient to determine the net health benefit of aducanumab” in people with mild Alzheimer’s and cognitive impairment.

ICER is holding a public meeting on July 15, beginning at noon EST, at which representatives of Biogen, the Alzheimer’s Association, and a former FDA chief, among others, will discuss Aduhelm and the report. Registration is required to follow the webinar.