Damaged Nerve Cell
[Source: Sciepro/Science Photo Library / Getty Images]

When researchers at the Cleveland Clinic studied the success rate of clinical trials for Alzheimer’s disease drug candidates nearly a decade ago, the results were discouraging: A 99.6% failure rate and high attrition rates, with 72% of agents failing in Phase I, 92% failing in Phase II, and 98% failing in Phase III.

The FDA has defended its review of Aduhelm and accelerated approval: “The Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy.”

Those findings, published in 2014, plus a sizeable patient population, illustrate the unmet medical need cited by the FDA in June when it granted accelerated approval subject to a new clinical trial for Aduhelm (aducanumab-avwa) as the first novel therapy indicated for Alzheimer’s since 2003, despite limited and controversial efficacy data generated using a surrogate endpoint.

In approving Aduhelm, co-developed by Biogen and Eisai, the FDA took the unusual step of setting aside concerns that prompted an advisory committee last year to recommend against approval of the drug. Three members of the panel have since resigned in protest.

“The FDA’s decision and backlash after the decision has raised doubts in the minds of the public about the agency’s motivations and credibility,” Supriya Munshaw, a senior lecturer in the Practice Track at Johns Hopkins Carey Business School, told Clinical OMICs. “I think this is particularly harmful to the FDA’s image, especially since this follows several controversies around emergency use authorizations of COVID-19 treatments early in the pandemic.

Supriya Munshaw
Supriya Munshaw, senior lecturer, Johns Hopkins Carey Business School

“As for drug developers, this opens opportunities to apply for approval based on incomplete trials based on surrogate endpoints. If the treatment is for an area of high unmet need, it lowers the bar for approval,” Munshaw added.

That potentially lower bar could facilitate dozens of additional approvals. A study published in May tallied 126 Alzheimer’s candidates under evaluation in 152 clinical trials. Twenty-eight treatments were in Phase III trials, 74 in Phase II, and 24 in Phase I, according to the study by a team headed by Jeffrey L. Cummings, M.D., Sc.D., director of the Chambers-Grundy Center for Transformative Neuroscience and a research professor at University of Nevada, Las Vegas.

Moving the goalposts

“The recent approval of Aduhelm moves the goalposts for FDA drug approval, which could lead to an increase in approvals for drugs to manage neurological conditions,” Mark Dallas, an associate professor at the University of Reading in the U.K., told Clinical OMICs. “We may see a renaissance in the neuroscience R&D world as companies seek approval based on these new criteria, but the likelihood of medicines transforming a patient’s life being approved remains relatively small.”

Approval of Aduhelm “undoubtedly has harmed the reputation of the FDA and confidence in its decision-making processes,” Dallas said. “For the Alzheimer’s field there are candidate molecules that could now be put forward for approval even through the clinical trials were ended because of no clear benefit to individuals living with Alzheimer’s.”

Patrizia Cavazzoni
Patrizia Cavazzoni, director, FDA Center for Drug Evaluation and Research

The FDA has defended its review and accelerated approval of Aduhelm. “The Agency concluded that the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy,” Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research, stated on the agency’s website.

“The data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit,” Cavazzoni contended.

In a June 23 statement, Biogen and Eisai estimated an “appropriate” patient population for Aduhelm of up to one-third of the 6.2 million Americans with Alzheimer’s dementia estimated by the Alzheimer’s Association, which said it “enthusiastically welcomes” Aduhelm’s FDA approval.

Biogen and Eisai say Aduhelm is suitable for between 1 and 2 million patients. On July 8, the companies limited 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.”

While Biogen has emphasized its close relationship with patients and other Alzheimer’s stakeholders, the company also cultivated ties with the FDA through an effort that began with a May 2019 “‘off-the-books’ meeting” between Billy Dunn, director of the FDA’s Office of Neuroscience—who later sided with Biogen and Aduhelm against the advisory committee consensus—and Biogen’s Chief Scientific Officer Alfred Sandrock, Jr., accord to a report published in STAT.

United States Rep. Katie Porter (D-CA) has since requested HHS’ inspector general investigate the FDA’s dealings with Biogen. Porter sits on the U.S. House of Representatives Committee on Oversight and Reform, which is examining Aduhelm’s approval and pricing—up to $56,000 annually. Biogen and Eisai have committed to no price hikes for four years and are promoting various access programs.

Surprising filing

In October 2019, five months after the meeting with Dunn, Biogen surprised analysts by announcing its plans to file for FDA approval of aducanumab despite halting two failed Phase III studies of the drug seven months earlier, which led to a 30% drop in Biogen’s stock price—roughly $16 billion of market value. Biogen and Eisai asserted that one of those 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.

“The big issue here is the use of a surrogate endpoint to approve Aduhelm and putting faith in this being a true predictor of patient benefit,” Dallas said. “In addition, not choosing to give all the evidence equal weighting undermines the essence of evidence-based medicine.

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee acknowledged in November 2020 that aducanumab’s U.S. sponsor Biogen presented strong evidence of a pharmacodynamic effect on Alzheimer’s disease pathophysiology in PRIME, in a 5–0 vote with six members uncertain.

But in three other votes, the committee balked at endorsing aducanumab:

By an 8–1 vote (two members uncertain), the panel agreed that EMERGE, viewed independently from ENGAGE, did not provide strong evidence supporting the effectiveness of aducanumab for the treatment of Alzheimer’s disease.

a 10-0 vote (with one member uncertain), the committee also voted that it was not “reasonable to consider EMERGE as primary evidence of effectiveness of aducanumab for Alzheimer’s.”

The panel also concurred 7–0 (with four uncertain) that the PRIME trial failed to provide evidence supporting the effectiveness of aducanumab as an Alzheimer’s treatment.

Decrying the decision

“Accelerated Approval is not supposed to be the backup that you use when your clinical trial data are not good enough for regular approval,” Aaron S. Kesselheim, of Harvard Medical School, and director of the Program on Regulation, Therapeutics, And Law at Brigham and Women’s Hospital, tweeted minutes after the FDA’s approval.

Three days later, Kesselheim became one of three members who resigned from the advisory panel, declaring in his resignation letter: “The aducanumab decision by FDA administrators was probably the worst drug approval decision in recent U.S. history.”

Also resigning from the advisory committee:

David S. Knopman, M.D., 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, M.D., of Washington University in St. Louis, where he is Elliot H. Stein Family Chair in Neurology.

Critics of the FDA approval have also cited Aduhelm’s safety data. The most frequently reported adverse event was radiographic detection of events termed Amyloid Related Imaging Abnormalities (ARIA). ARIA -E and/or -H was seen in 41% of patients treated with Aduhelm 10 mg/kg compared to 10% of patients on placebo.

Clinical symptoms were seen in 24% of patients treated with Aduhelm 10 mg/kg who had an observation of ARIA -E and/or -H, compared to 5% of placebo patients. Aduhelm’s label includes a warning for ARIA.

What effect will Aduhelm’s approval have on the FDA’s drug approval process?

“In terms of changes to the process, I think that while the decision does not need to align with the advisory committee every time, it should strongly reconsider a more robust and transparent process when there is so much disagreement internally and externally,” Munshaw said.

Dallas added: “Time will tell with respect to Aduhelm and I hope for those living with Alzheimer’s that it does pan out to make a difference, but I fear not.

“The decision to approve leads the FDA down a slippery slope and sets a precedent for other Alzheimer’s drugs to follow.”

Also of Interest