The Food and Drug Administration on Monday approved the first new treatment for Alzheimer’s disease in nearly two decades, a landmark decision that has been eagerly awaited by millions of Americans diagnosed with the condition but that will be hotly contested by some in the scientific community who doubt the drug’s effectiveness.
While other drugs treat symptoms of Alzheimer’s, the new medicine, called Aduhelm, is the first to attack what some believe is an underlying cause of the disease and slow cognitive decline, albeit marginally. It does so by eliminating clumps of a toxic protein believed to destroy neurons and cause dementia. Aduhelm is not a cure for Alzheimer’s, and it doesn’t reverse the disease’s progression.
The drug — which just two years ago was declared a stunning failure — is now expected to generate billions of dollars in revenue for its maker, Biogen.
“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease,” Biogen CEO Michel Vounatsos said in a statement. “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.”
But the approval of Aduhelm, also known by its scientific name aducanumab, is all but sure to become one of the most controversial and disputed decisions on a drug application in recent years. The FDA granted marketing clearance to the drug over the strong objections of a panel of independent experts it convened in November. Those advisers reviewed Biogen’s clinical data and concluded overwhelmingly that there was insufficient evidence that the treatment had significant benefits for patients. They argued the drug should not be approved, as have many outside experts. Others saw enough evidence of efficacy — and a desperate need for new treatments.
Instead of judging Biogen’s treatment solely on its effects on cognition, the FDA granted a conditional approval based on Aduhelm’s ability to clear the toxic proteins, called beta-amyloid. In order to continue marketing the drug, Biogen will need to complete a large clinical trial to confirm that removing the plaque has cognitive benefits, the FDA said. If that study fails, the FDA has the authority to rescind its approval.
In approving the drug on a conditional basis, the agency departed from decades of regulatory precedent, setting a new bar for treatments with considerable potential but unproven benefits — a standard that could also be applied to other devastating diseases.
“I’m quite surprised. The most compelling argument for approval was the unmet need but that cannot, or should not, trump regulatory standards,” said Caleb Alexander, a Johns Hopkins epidemiologist who served on the FDA’s advisory panel and voted against the approval of Aduhelm. “It’s hard to find any scientist who thinks the data are persuasive. Unmet need is an important contextual factor but it’s not an evidentiary threshold.”
Aduhelm’s development has sharply divided Alzheimer’s experts. Now that Aduhelm is approved, they face a new challenge: prescribing the drug without overselling its effects.
“For patients who qualify, I’m hopeful for them,” said Ronald Petersen, a neurologist who leads the Mayo Clinic Alzheimer’s Disease Research Center. “Now we have a potential treatment for them that may modify the underlying disease course. But the largest responsibility for us is to educate patients and physicians as to what this means. This is not going to be penicillin for Alzheimer’s disease.”
To many patients and their caregivers, Aduhelm’s approval provides hope for a better life, despite the drug’s limitations. Alzheimer’s affects nearly 6 million people in the U.S. Current medicines for the disease have only short-term effects on symptoms and bring side effects that make them unusable for some patients.
Aduhelm offers the promise of treating the root cause of the disease.
“I know this medication isn’t going to save my life. I know it’s not a cure,” said Jeff Borghoff, who, at 57, has been living with the symptoms of Alzheimer’s for six years. Borghoff has been receiving Biogen’s drug on and off since 2018, first in a truncated Phase 3 trial and then in an extension study. He has seen improvements in his cognition and ability to focus, he said, which has been massively positive for his family.
“I just saw my middle daughter get married,” Borghoff said. “She’s talking about having kids now. I have two other kids talking about marriage. That’s what I want. I want more time to spend with my family so that I can create memories for myself and for them. Ultimately, I’ll lose those memories with this disease, but they won’t. Inside a healthy brain, proteins called beta amyloids are destroyed; in the brains of people with Alzheimer’s disease, they are not and accumulate to form sticky plaques.
Biogen said the yearly cost for a maintenance dose of Aduhelm, based on an average patient’s weight, would be $56,000. That’s a list price, not the net price or the price paid by patients with insurance. The out-of-pocket cost for patients with insurance will vary depending on their coverage. Analysts had expect it to cost between $10,000 and $25,000 per year, which would have already placed it among the most expensive medicines marketed to primary care physicians. The company expects to start shipping the drug in about two weeks.
The treatment, administered intravenously once a month, is approved for all patients with Alzheimer’s disease. Clinical trials tested it only in patients with early-stage Alzheimer’s who have had a PET scan confirming the presence of amyloid in their brains.
For decades, scientists who study Alzheimer’s have focused much of their research on amyloid. A succession of companies including Eli Lilly, Pfizer, Roche, and Merck have attempted to treat Alzheimer’s with various types of antibody drugs that work by targeting and eliminating beta-amyloid — all without success.
Biogen believed it could succeed where the others failed; it designed Aduhelm to be more potent and therefore better able to eliminate amyloid plaques than earlier drugs. The company also focused on administering Aduhelm to people with mild cognitive impairment or the earliest signs of Alzheimer’s, before brain cells were too damaged to stem the tide of the disease.
Biogen tested Aduhelm in two identically designed, Phase 3 randomized, placebo-controlled clinical trials called Engage and Emerge. In March 2019, both studies were halted after independent monitors, looking at data during an interim analysis, concluded that Aduhelm was unlikely to benefit patients. In scientific parlance, the drug was deemed to be “futile” — and appeared to join the long list of failed Alzheimer’s treatments.
But then in October 2019, Biogen announced a new analysis based on previously unavailable data that showed Aduhelm slowed cognitive decline in Alzheimer’s patients in one of the studies. It was a success in Emerge, achieving the primary goal with statistical significance. But the benefit, measured by tests of cognition and function, was small: The difference between Aduhelm and placebo was a fraction of a point on an 18-point scale. Biogen performed the new analysis on the Engage study as well, but here, Aduhelm still failed.
While Aduhelm’s effect on cognition was debatable, both studies found that the drug was markedly effective at removing amyloid from patients’ brains. Over 78 weeks, patients who received the approved dose of Aduhelm saw roughly 30% reductions in amyloid, as measured by PET scan, compared to those on placebo. About 40% of clinical trial patients who got the approved dose of Aduhelm developed painful brain swelling.
Biogen submitted both studies — one positive, the other negative — to the FDA in July 2020. The company’s decision to seek approval of the drug based on studies that were first halted, then reopened, and reanalyzed with mixed results, generated significant controversy, as did the FDA’s extended review.
During an advisory panel meeting in November 2020, Billy Dunn, the top FDA official in charge of the Aduhelm review, acknowledged working closely with Biogen on its reanalysis of the Phase 3 clinical trials. Dunn also expressed support for Aduhelm and favored its approval.
However, 10 of the 11 outside experts invited by the FDA to review the same Aduhelm data at the November meeting determined that a single positive study was insufficient to show convincing proof that the treatment was slowing cognitive decline in people with Alzheimer’s. The other panelist voted “uncertain.” Some of the outside experts went further, criticizing Dunn and the FDA for the way they worked alongside Biogen, which they said threatened the agency’s status as an independent arbiter of drug efficacy and safety.
The approval of Aduhelm will be a boon to Biogen’s bottom line and its stock price, although how much is still an open question. Demand from patients and their caregivers is expected to be sky high, but Biogen’s ability to treat them — and generate revenue — could be slowed by reimbursement barriers established by insurers.
Last month, the Institute for Clinical and Economic Review, a nonprofit that measures the value of new medicines, said Aduhelm would be cost-effective if it is priced between $2,500 and $8,300 a year due to “insufficient” evidence that the drug works, according to a preliminary analysis. That assessment could give insurers more reasons to hold back on the treatment.
The logistics of receiving Aduhelm will also be a challenge. Patients will have to undergo expensive brain scans to determine eligibility for Aduhelm, and then the drug must be administered monthly via an intravenous infusion at a doctor’s office or similar health care facility.
Even with challenges to the price and logistics, Aduhelm has the potential to generate U.S. sales in the range of $5 billion to $6 billion per year for Biogen, said Umer Raffat, an analyst at Evercore ISI, who uses a $10,000 per year price tag.
Brian Abrahams, an analyst at RBC Capital, models peak sales of the drug reaching $5 billion in the U.S. at a slightly lower $9,600 per year cost. Abrahams assumes 18% of patients with mild or moderate Alzheimer’s will receive Aduhelm.