Weeks of controversy over the FDA’s approval last month of Aduhelm™ (aducanumab-avwa), the Alzheimer’s disease drug co-developed by Biogen and Eisai, culminated Friday in an unusual request by the agency’s acting commissioner to have a federal watchdog review the FDA’s dealings with Biogen.

Acting FDA Commissioner Janet Woodcock, MD, cited “concerns raised” about contact between representatives of Biogen and the FDA during the review process for Aduhelm, “including some that may have occurred outside of the formal correspondence process.”

“To the extent these concerns could undermine the public’s confidence in FDA’s decision, I believe it is critical that the events at issue be reviewed by an independent body such as the Office of Inspector General in order to determine whether any interactions that occurred between Biogen and FDA review staff were inconsistent with FDA policies and procedures,” Woodcock wrote in a letter to Christi A. Grimm, Acting Inspector General of the FDA’s parent agency, the U.S. Department of Health and Human Services (HHS).

Woodcock added: “Should such a review result in actionable items, you also have my commitment to addressing these issues and ensuring that FDA continues to earn the trust [that] the American public has placed in our regulatory processes and decision-making.”

“Another controversy”

Michael J. Yee, equity analyst with Jefferies, called the FDA’s review request a positive development.

“We would not expect the OIG [Office of Inspector General], or anyone else, to find any major issues, providing final affirmation that FDA had a scientific rationale on which to approve the drug,” Yee wrote. “While this is another controversy to deal with, we believe the info should show FDA had full authority to give an accelerated review, allowing markets to move on from this chapter.”

Yee cited in part a reassurance Woodcock offered in her letter: “I have tremendous confidence in the integrity of the staff and leadership of the Center for Drug Evaluation and Research involved in the aducanumab review and their commitment to unbiased and science-based decision-making.”

Biogen responded to Woodcock’s call for HHS inspector general review with a one-sentence statement: “We will, of course, cooperate with any inquiry in connection with a possible review of the regulatory process.”

Woodcock acted three days after Rep. Katie Porter (D-CA) called for a review by Grimm’s office. Porter sits on the U.S. House of Representatives Committee on Oversight and Reform, which is examining Aduhelm’s approval and list pricing—up to $56,000 annually. Biogen and Eisai have responded to criticism over the list price by committing to no price hikes for four years, and promoting various access programs.

In her letter to Grimm, Woodcock alluded to a reported “‘off-the-books’ meeting” in May 2019 between Biogen’s CSO, Alfred Sandrock Jr., MD, PhD, and Billy Dunn, MD, director of the FDA’s Office of Neuroscience.

The meeting between Dunn and Sandrock marked the start of efforts by Biogen to persuade the FDA to approve Aduhelm, two months after announcing the failure of two Phase III studies of the drug in March 2019—which led to a 30% drop in Biogen’s stock price that wiped out $16 billion of market value.

Biogen’s efforts succeeded on June 7, when the FDA granted accelerated approval subject to a new clinical trial for Aduhelm as the first novel therapy indicated for Alzheimer’s since 2003, despite limited and controversial efficacy data generated using a surrogate endpoint.

Denouncing the decision

In approving Aduhelm, the FDA took the unusual step of overriding concerns that prompted an advisory committee last year to recommend against approval of the drug—rejecting arguments by Biogen and Dunn, who sided with the company in recommending approval of Aduhelm.

Three members of the panel have since resigned in protest.

“The aducanumab decision by FDA administrators was probably the worst drug approval decision in recent U.S. history,” Aaron S. Kesselheim, MD, JD, of Harvard Medical School, director of the program on regulation, therapeutics, and law at Brigham and Women’s Hospital, declared in his resignation letter.

The other two panel members who resigned were David S. Knopman, MD, a clinical neurologist at the Mayo Clinic involved in research in late-life cognitive disorders, such as mild cognitive impairment and dementia; and Joel S. Perlmutter, MD, of Washington University in St. Louis, where he is the Elliot H. Stein Family chair in neurology.

Perlmutter, Knopman, and Kesselheim cited concerns ranging from the strength of the data, to the surrogate endpoint, and the FDA’s initial approval of a prescribing label that did not limit Aduhelm’s use by stage of Alzheimer’s disease or by genetic markers (APOE4 carrier status, for example).

On Thursday, Biogen and Eisai agreed to limit Aduhelm’s prescribing label from all Alzheimer’s patients to “patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials.”

“The new label should help narrow the patient population that seeks treatment and make it somewhat easier for physicians to “say no” to many patients that shouldn’t be candidates for usage in the first place. And the new label should help the payers for the same reason,” Marc Goodman, managing director, neuroscience, and a senior research analyst with SVB Leerink, wrote Thursday in a research note. “We don’t expect the new Aduhelm label to impact peak sales for this product.”

Goodman on June 10 raised his sales forecasts for Aduhelm:

  • From $50 million to $65 million for this year
  • From $500 million to $1.1 billion for 2022
  • From $2.8 billion to $5.7 billion for 2025

Colin Bristow, MD, managing director, biotechnology at UBS, has projected sales for Aduhelm more than twice as high as SVB’s best-case number, estimating about $13 billion in the United States alone. Bristow upgraded UBS’ rating on Biogen to Buy from Neutral with an increased $463 price target following the FDA’s approval of Aduhelm.

Latest about-face

The partial rewrite of the label was the latest about-face related to Aduhelm. In October 2019—five months after the Dunn-Sandrock meeting, which was first reported by STAT on June 29—Biogen surprised analysts by planning to file for FDA approval of aducanumab despite saying earlier that its Phase III trials had failed. The decision sparked a 40% surge in the price of Biogen shares.

Biogen and Eisai asserted that one of the Phase III trials, Study 301 or ENGAGE (NCT02484547), met its primary endpoint showing a significant reduction in clinical decline—a result the companies later said was supported by results from a subset of patients in the other halted Phase III trial, Study 302 or EMERGE (NCT02477800).

Aduhelm’s efficacy was assessed in three trials that recruited a total of 3,482 patients. In the three, Aduhelm showed a dose- and time-dependent effect on the lowering of amyloid beta plaques—by 59% in ENGAGE, 71% in EMERGE, and 61% in a Phase I proof of concept trial known as Study 103 or PRIME (NCT01677572).

The FDA’s accelerated approval pathway authorized Aduhelm based on the surrogate endpoint of reduction of amyloid beta plaque in the brain. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology.

Last year, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee acknowledged that Biogen presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology in PRIME in one of four votes related to Aduhelm.

But in its other three votes, the committee balked at endorsing the drug.

Paul Matteis, co-head of the biotechnology research team and a managing director with Stifel, dismissed the HHS review of FDA actions in a research note quoted by Seeking Alpha as “more noise and stress” for Biogen shareholders, whose effect on the stock would not be tangible.

“We think once the Aducanumab launch ramps,” Matteis observed, “the stock narrative will shift away from theoretical fears and towards actual fundamental drivers, like patients on therapy and revenues.”

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