Biogen Inc. took a colossal risk in late 2019. It revived a drug for Alzheimer’s disease it had left for dead earlier that year after the medication appeared to fail two large clinical trials.

The company wasn’t ready to take no for an answer. Biogen, along with its Tokyo-based partner Eisai Co. Ltd., had poured years of effort into developing the therapy, then called aducanumab, and was counting on it as its next big therapeutic advance.

After months of controversy, Biogen’s bet paid off in spectacular fashion Monday when the U.S. Food and Drug Administration granted the treatment its approval, making it the first new Alzheimer’s drug in almost 20 years and first to attack an underlying process of the disease.

The potential that the drug will generate billions of dollars in annual sales sent Biogen’s stock soaring, and boosted the shares of rival drugmakers working on similar therapies.

Alzheimer’s patients and their families, some of whom have been waiting years for such a moment, also celebrated.

“Today is a huge day for us in the Alzheimer’s community,” said Jeffrey Borghoff, 57, an early Alzheimer’s sufferer in Forked River, New Jersey. “I was elated.” Borghoff, who was diagnosed when he was 51, has been getting aducanumab as part of a clinical trial.

Regulators granted Biogen practically everything they could have asked for: They cleared the drug, branded Aduhelm, for Alzheimer’s patients broadly, not just for the early-stage sufferers Biogen had focused on in its clinical studies. And they essentially left it up to doctors and insurance companies to decide who qualifies for it. The FDA has “shifted the responsibility of defining the patients to the payer community,” said Steve Miller, chief clinical officer at insurer Cigna Corp.

The approval appears to signal a fundamental shift in the way the agency thinks about Alzheimer’s disease, one that could have lasting ramifications for other drugs in the pipeline at Eli Lilly & Co., Roche Holding AG and elsewhere.

Aduhelm is also under review in Japan, Europe, Canada, Australia and Brazil, according to a company statement. Biogen said it is prepared to supply the drug in those markets should it win approval.

Elusive proof

For years, regulators have been looking for proof that new Alzheimer’s drugs slow the inexorable decline of cognitive or daily functioning. That proof has been hard to come by, with numerous clinical trials failing or producing murky results. Biogen’s studies were no less confusing. One trial failed to show effectiveness overall, and in the other, the drug slowed patients’ decline by a very modest 22%, when the drug was used at high doses.

But in an unexpected shift, the FDA decided proof that the drug slowed cognitive decline could wait. It found that aducanumab’s ability to remove a protein called amyloid, thought to trigger a cascade of events eventually leading to brain-cell death, was sufficient for an accelerated approval, contingent on results from a future study.

The role that amyloid plays in Alzheimer’s has been debated for years, however, and some health experts remain wary.

“The overwhelming demand and magnitude of unmet medical need pushed this product across the line,” said Caleb Alexander, an epidemiologist at Johns Hopkins Bloomberg School of Public Health, who was on a panel of agency advisers that voted against recommending the drug’s approval in November. “It certainly wasn’t approved based on the persuasiveness of the evidence.”

The FDA acknowledged, in classic regulatory understatement, “residual uncertainties regarding clinical benefit” of Aduhelm. Even in the best-case scenario, the drug “is hardly a panacea,” Alexander said.

In the run-up to the decision, researchers and patients debated whether Biogen had proven that the drug works. Patient groups lobbied hard for approval: The Alzheimer’s Association conducted an advertising and social-media campaign this May, and brought patients and the families in front of the FDA for a listening session earlier this year.

However, an approval based on such disputed evidence isn’t likely to end the long dispute over the value of removing amyloid from Alzheimer’s patients’ brains.

“This is not going to make the nonamyloid believers change their minds,” said John Hardy, a geneticist at University College London, who was one of the first researchers to propose that accumulation of amyloid was behind the brain-wasting disease. “It was a close decision for a perfectly good reason.”

Still, many doctors said it was a start.

The drug gives patients hope that “we can do something in a disease-modifying sense, as long as they understand this is not a cure,”Ronald Petersen, a neurologist at the Mayo Clinic who has consulted for Biogen in the past, said. “There was probably sufficient evidence that some people will benefit from this.”

Expensive scans

The drug’s lofty cost is likely to provoke pushback. Biogen set the price at $56,000 a year, far higher than analysts were expecting. Patients will also need expensive brain scans to check for side effects such as brain swelling. And there will be significant charges to administer the infusions as well as for scans or other tests to confirm patients have amyloid build-up.

Biogen’s price was “far above where we believe most investors had speculated,” RBC Capital Markets analyst Brian Abrahams wrote in a research note. That type of pricing is more in line with specialty medications for diseases that affect hundreds of thousands of patients per year, not common diseases like Alzheimer’s, he said.

The price “is likely to generate additional controversy and debate, as well as access hurdles,” Abrahams wrote.

Biogen isn’t entirely home-free. Since its trials produced such conflicting results, the FDA said Biogen will have to conduct another randomized, controlled trial to confirm that the drug does indeed slow cognitive decline. Biogen promised Monday to share details on that trial soon, pending completion of talks about it with the FDA. But the trial will likely take several years to complete, and in the meantime, Biogen will be able sell the drug widely into a market it practically has to itself.

The Aduhelm verdict suggests the FDA is looking at Alzheimer’s medicines much as it does advanced cancer drugs. Those are often approved based on tumor shrinkage seen in scans, on the assumption this will lengthen life or slow progression of the disease. But while tumor shrinkage is a widely agreed upon marker of likely treatment benefit, the relationship between amyloid lowering and cognitive decline is at the core of the debate over aducanumab.

Over the years numerous amyloid-lowering drugs have failed to show benefit in large trials amid controversy over whether amyloid is a major cause of the disease or just a minor contributor. Biogen’s drug initially looked like it would join this long list of failures.

Early setbacks

After an early trial showed promising results in 2015, Biogen started two final-stage trials that eventually enrolled more than 3,200 people with early Alzheimer’s. The company halted the trials in March 2019 after a statistical analysis showed the medicine was unlikely to work. But as more data rolled in from patient follow-up visits, one of the trials turned positive.

In October 2019, after consulting with the FDA, Biogen reversed course, declared one of the trials a success, and revived the drug. Some Alzheimer’s researchers were still skeptical, believing a third big trial was needed as a tiebreaker.

Biogen applied for approval in July 2020. Its shares surged on Nov. 4 when, in an unusual move, FDA staff released a joint report with the company, in which the agency called the evidence behind the drug “exceptionally persuasive.” But two days later, a panel of independent FDA advisers reviewing the evidence took a much dimmer view. It voted 8 to 1, with two undecided, that the one successful trial was insufficient to prove the drug works.

That put the FDA in an awkward position. While the advisory panel vote isn’t binding, the FDA has rarely gone against such a lopsided vote. The accelerated approval gave the FDA a way to solve the dilemma. It essentially didn’t rule on whether the drug slows cognitive decline or not, but just said that the ability to remove amyloid made the drug reasonably likely to do so.

The results “shows the FDA is willing to accept imperfect data,” says Dennis Selkoe, co-director of the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, and a long-time proponent of the amyloid hypothesis. In the long run, the approval “makes it easier” for the development of other Alzheimer’s drugs that may have more robust benefits.

In the meantime, doctors will soon be in a position to give patients and their families the very good news that there’s now a drug that just may slow the course of the disease.

“Even if it helps 15% to 20% of patients, and I believe it will be more,” Selkoe said, “that will be huge.”

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