The FDA on Monday granted accelerated approval to Biogen and Eisai's anti-amyloid antibody Aduhelm (aducanumab) for the treatment of Alzheimer's disease, capping a controversial and at times contentious review process that saw the agency's panel of outside experts coming out overwhelmingly against clearing the drug based on the available evidence. With the approval, Aduhelm becomes the first novel therapy cleared for Alzheimer's disease since 2003 and the first directed at the underlying pathophysiology of the condition. Biogen's stock gained as much as 60% on the news, while Eisai's US shares traded up 45%.
"We understand that Aduhelm has garnered the attention of the press, the Alzheimer's patient community, our elected officials and other interested stakeholders," stated Patrizia Cavazzoni, director of the FDA's Center for Drug Evaluation and Research. She acknowledged that the data submitted by Biogen and Eisai "were highly complex and left residual uncertainties regarding clinical benefit," but the agency went over the clinical trial findings "with a fine-tooth comb," solicited input from its advisory committee (AdCom) and also "listened to the perspectives of the patient community," before deciding that the accelerated approval pathway would be the way to go.
According to the FDA, approval of Aduhelm is based on the surrogate endpoint of reduction of amyloid plaque in the brain, which it said "is reasonably likely to result in clinical benefit." The agency also noted that the trials for Aduhelm were the first to show that reducing these plaques is expected to lead to a reduction in clinical decline. That, plus the unmet need in Alzheimer's disease, made Aduhelm eligible for the accelerated approval pathway, the regulator added.
Current Alzheimer's disease treatments approved in the US, including AbbVie's Namenda (memantine) and Pfizer's Aricept (donepezil), are intended to ease symptoms of the disease. Biogen and Eisai, who sought approval for their treatment last year, will be required to conduct confirmatory studies to verify the anticipated clinical benefit of Aduhelm. According to the FDA approval letter, Biogen must submit a draft protocol by October indicating an "appropriate control" and an "acceptable endpoint" for the confirmatory trial. A final protocol must be ready by August 2022, with the deadline for trial reporting in 2030.
Biogen CEO Michel Vounatsos, who called the decision a "historic moment," said "we believe this first-in-class medicine will transform the treatment of people living with Alzheimer's disease and spark continuous innovation in the years to come." The company has set the wholesale acquisition cost of Aduhelm, which is given intravenously every four weeks, at $4312 per infusion on average, based on weight. For the maintenance dose of 10 mg/kg, this works out to $56,000 per year, although the cost during the first year will be lower due to the titration period.
Vounatsos suggested the cost was "fair" and a reflection of "two decades of no innovation," but nevertheless vowed not to increase the price for the next four years. However, he said it was time to "invest" in treatment given the financial toll of the disease and other forms of dementia on patients and on the US as a whole.
The prospects for Aduhelm were dim when in 2019, the companies stopped two Phase III trials, EMERGE and ENGAGE, early after a futility analysis suggested the drug would not work. Both studies assessed change from baseline at week 78 on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) scale in patients with early Alzheimer's disease. However, Biogen and Eisai later claimed that re-analysis involving a larger dataset showed a modest 22% reduction on CDR-SB compared to placebo for high-dose (10 mg/kg) Aduhelm in EMERGE. On the other hand, ENGAGE still did not show statistical significance on the CDR-SB scale for high-dose patients – in fact there was a worsening on that measure compared to placebo – but the companies considered that a subset of data from ENGAGE supported the EMERGE findings. They said the discrepancy between the two trials was driven mainly by greater exposure to high-dose Aduhelm in EMERGE and a higher number of "rapid progressors" in ENGAGE.
On Monday, the FDA explained that while the AdCom did not agree that it was reasonable to consider the clinical benefit of one successful trial as the primary evidence, given conflicting data from the second trial, the option of accelerated approval had not been discussed by the panel. The agency said that "treatment with Aduhelm was clearly shown in all trials to substantially reduce amyloid beta plaques," and that its review concluded that the benefits of the drug outweigh its risks. In their joint statement Monday, Biogen and Eisai said the drug "consistently showed a dose- and time-dependent effect on the lowering of amyloid beta plaques…a defining pathology of the disease," including a reduction of 59% in ENGAGE and of 71% in EMERGE, at 18 months of treatment.
AdCom panelists had also expressed concern about amyloid-related imaging abnormalities, including cerebral oedema (ARIA-E) and microhaemorrhages (ARIA-H). These events occurred at a rate of 41% in patients treated with high-dose Aduhelm, compared to 10% for placebo, although the cases were mostly asymptomatic. The FDA noted Monday that while Biogen and Eisai proposed a risk evaluation and mitigation strategy (REMS) for the drug, the agency determined that it would not be necessary at this time.
Alfred Sandrock, head of research at Biogen, said the company found out about a month ago that the FDA was considering an accelerated approval for Aduhelm, which led to labeling discussions. Sandrock added that discussions with the agency are continuing on details of the required confirmatory trial and would provide details soon.
While the decision was hailed in some quarters, particularly by patient groups, the Institute for Clinical and Economic Review (ICER) issued a scathing rebuke of the FDA, saying the agency had "failed in its responsibility to protect patients...from unproven treatments with known harms." ICER recently calculated that the drug would have to be priced between $2500 and $8300 per patient per year in order to be cost-effective.
Rather than requiring the companies to conduct a third trial, ICER said the agency instead chose to "move the goalposts" to allow approval based on the surrogate endpoint of amyloid plaque removal, and not "the patient-centred outcome of clinical benefit, which has been required of all previous emerging treatments for Alzheimer's disease." The FDA's decision is "all the more puzzling," given that "many other drugs have been shown to remove amyloid from the brain, yet have failed to help patients," ICER stated.
It added that the approval now raises some key questions, such as how will patients be diagnosed, how insurers will cover the drug, and how patients will be screened for possible side effects, while "questions about the design of the confirmatory trial now also take centre stage." Meanwhile, Cigna's chief clinical officer Steve Miller said the insurer will likely cover Aduhelm for patients with early-stage Alzheimer's disease and amyloid buildup in their brains, a population Biogen and Eisai estimate to be about 1.5 million in the US, although the drug's label states it is indicated for all patients with Alzheimer's disease, with no mention of potential limitations such as amyloid positivity via PET scan, disease severity or ApoE4 status, for example.
Vounatsos remarked that by giving Aduhelm a broad label, "the FDA is basically empowering the physician to make the decision" about who it is most appropriate for.
Biogen has been laying the groundwork to launch Aduhelm immediately upon approval, with Vounatsos noting that over 900 infusion sites are prepared to handle the "very large" anticipated influx of patients. "We know that the availability of specialists and diagnosis capabilities are a bottleneck, so we had to prepare the sites of care," the executive said. He added the company is also working closely with Medicare as well as private insurers.
Guggenheim analyst Yatin Suneja predicted Aduhelm has the potential to generate at least $10 billion in peak sales, and that a successful launch could "completely change" the profile for Biogen. The drug is seen as critical to Biogen's revenue growth prospects as competition has hurt sales of its mainstay multiple sclerosis drug Tecfidera (dimethyl fumarate), as well as its spinal muscular atrophy treatment Spinraza (nusinersen).
Other companies developing Alzheimer's disease treatments saw shares gains on Monday as well. Eli Lilly, which is developing a modified β-amyloid-targeting antibody called donanemab as a potential treatment for Alzheimer's disease, rose a record 13%. Smaller firms working on treatments for the disease also saw their stock value jump, including Cassava Sciences and Annovis Bio, which posted gains of 19% and 31%, respectively.
For related analysis, see ViewPoints: Projecting the fallout from FDA’s divisive Aduhelm approval, and ViewPoints: Barn door swings wide open in Alzheimer’s and beyond. Also read, Physician Views Preview: A new hope in Alzheimer’s disease…
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