Biogen’s new drug to treat Alzheimer’s disease is heading to market blessed by regulators but dogged by controversy that there’s no conclusive evidence that it works — and a fair amount of evidence that it doesn’t.
A polarizing decision by the Food and Drug Administration last month has only intensified a yearslong fight over the treatment: The Cambridge company and some doctors hail the medicine as a pivotal step forward in the fight against Alzheimer’s, the fifth-leading cause of death among Americans over 65. Critics say the FDA should never have allowed Biogen to seek approval based on a less rigorous standard of efficacy, after the drug produced muddled results in two late-stage clinical trials.
The fallout from this medical maelstrom is extensive, complicating Biogen’s financial outlook, denting the FDA’s reputation, and leaving many of the 6 million Americans with Alzheimer’s wondering if they should take the intravenous drug, marketed under the name Aduhelm. It’s also raises hard questions for Medicare, which must decide whether to cover the cost of the drug for most patients, a potentially staggering bill.
Greater Boston, arguably the hub of the life sciences and medical universe, has a lot riding on what happens next.
“This will spur innovation,” said Peter Hecht, chief executive of Cyclerion Therapeutics, a Cambridge startup that’s working on ways to treat diseases of the central nervous system, including Alzheimer’s. “There is a clearer path to approval.”
The FDA’s decision to greenlight the first new Alzheimer’s treatment since 2003 has stirred up the long-running debate over what’s known as accelerated approval: authorizing a treatment targeting a debilitating or deadly disease without direct evidence it will make a difference for patients. That’s how Aduhelm eventually got the OK.
Hecht said the FDA faced a difficult decision on Aduhelm given its poor clinical trial results, but he makes a case for how the use of accelerated approval might boost the quest for an Alzheimer’s cure — and treatments for other deadly diseases.
“It’s unreasonable to expect that the first drug for such a complicated disease is going to be a cure or even have dramatic effect,” he said. “This history of the drug industry is to have some meaningful improvement and then build on it.”
Hecht, who previously co-founded and was CEO of Ironwood Pharmaceuticals in Boston, noted that many early cancer drugs were also expensive and only partially effective, but provided a base off which better treatments were developed.
The Aduhelm controversy has been fueled by the unusual route the drug — called aducanumab during its clinical trials — took through the FDA, as well as by what news site STAT reported was the agency’s “extraordinarily proactive role” in helping Biogen could win approval.
Seven months after pulling the plug on aducanumab in March 2019 because of poor clinical trial results, Biogen reversed course, saying a deeper dive into the data showed that a high dose of the drug did provide a modest boost to memory and other cognitive functions in one of the trials. But there was a second roadblock: Last November, all but one of the 11 members of an FDA panel of outside experts voted that Biogen had failed to offer enough evidence that aducanumab was effective.
Although the panel’s recommendation was nonbinding, FDA staffers came up with a new strategy, according to STAT: the accelerated approval program. Biogen, guided by agency staffers, then sought approval of aducanumab based on a different measure: its ability to chip away at the buildup of the beta-amyloid protein that some scientists think may cause Alzheimer’s, which the FDA found was “reasonably likely” to lead to cognitive improvement.
The FDA gave final approval on June 7, a rare instance when it has ignored a near-unanimous recommendation of its independent experts. The uproar from some Alzheimer’s researchers, doctors, and even patient groups was immediate.
“The process was problematic and the outcome was problematic,” said Aaron S. Kesselheim, a professor at Harvard Medical School and one of three advisory group experts who quit in protest. “At the 11th hour,” he said, “the FDA switched the basis for decision-making.”
“It is important to recognize that collaboration between industry and regulatory agencies is common, appropriate, and beneficial,” said Alfred Sandrock, Biogen’s head of research and development. He said that Aduhelm had been the focus of “extensive misinformation and misunderstanding.”
Michel Vounatsos, the company’s chief executive, said that accelerated approval was an important program for taking on very difficult diseases. “Progress has to be made by the first step,” he said.
In a statement to the Globe, the FDA said “companies and the FDA have taken great strides to make the drug development process more efficient, without compromising FDA’s gold standard for evaluating drug safety, efficacy and quality.”
One immediate impact of Aduhelm’s approval was a surge in Biogen’s stock price. The shares jumped 38 percent on the day the FDA gave its official nod, adding more than $16 billion to the company’s market capitalization.
That’s a good indication of how much value investors place on Aduhelm.
But after all the twists and turns in the Aduhelm story, Biogen’s stock price is trading up just 1.6 percent since the day before it pulled the plug on the drug’s trials in 2019. Meanwhile, the Nasdaq Biotech Index has climbed 46 percent.
Investors are concerned that doctors won’t prescribe Aduhelm without more proof that it works, and that Medicare, which would cover a large majority of Aduhelm users in the country, will balk at paying $56,000 a year for a treatment that has yet to demonstrate its worth.
Estimates for the cost to the government-funded program range anywhere from $29 billion a year to more than $330 billion, depending on how many people take the medication. But the estimates don’t factor in any potential savings from better patient care that Aduhelm may make possible.
The Centers for Medicare & Medicaid Services has said it will take up to 6 months to propose a decision and 9 months to make a final call.
Point32Health, the second-biggest health insurer in Massachusetts, said Friday that in its view Aduhelm is “experimental and investigational,” and thus it would not cover treatment. The company, formed by the recent merger of Tufts Health Plan and Harvard Pilgrim Health Care, is the first insurer here to take such as stand.
Although $56,000 a year is a steep cost for a drug, “The pricing would be reasonable, if it stopped the progression of Alzheimer’s,” said Brian Skorney, a senior biotech research analyst at investment firm Robert W. Baird & Co. “But it doesn’t.”
Nonetheless, Skorney expects Medicare to reimburse at least some portion of Aduhelm’s cost and estimates that sales will hit a peak of $7.5 billion in 2025. Biogen had revenue of more than $13 billion in 2020, making it the state’s largest biotech by sales, but it is counting on Aduhelm to help offset declining sales of its MS drugs.
Medical ethicist Arthur L. Caplan sees Aduhelm as the latest in a series of drugs approved by an FDA willing to place more importance on speed over safety when patients have few or no options in life or death situations.
First came emergency approval for Ebola treatments amid a 2014 outbreak of the deadly virus, said Caplan, the founding head of the division of medical ethics at NYU School of Medicine. Then, in 2016, the agency approved Exondys 51, a drug for Duchenne muscular dystrophy, a rare muscle-wasting disease that typically strikes young boys and kills them in their 20s. Sarepta Pharmaceuticals of Cambridge had tested Exondys 51 on just 12 patients.
The FDA gave the Sarepta drug the green light despite a negative recommendation by an advisory panel and a split within the agency over its efficacy. The company rallied patient advocates, who argued that the FDA should not require the same level of data generated in large-scale clinical trials of more common diseases.
Up next, Caplan said, may be drugs for amyotrophic lateral sclerosis, or ALS.
“My prediction is that we are going to have an enormous debate over speed and patients’ right to choose versus safety and cost to society,” Caplan said.
Meanwhile, Alzheimer’s patients and their doctors face a difficult question: With its high cost and side effects, is Aduhelm worth taking?
Harvard’s Kesselheim said he’ll try to convince his Alzheimer’s patients seeking Aduhelm outside of a clinical trial that it isn’t the answer they’ve been searching for.
“People don’t want empty hope,” he said. “They want hope that something actually works.”
Jay Reinstein, a North Carolina resident who retired three years ago after being diagnosed with early-stage Alzheimer’s, sees it differently.
“I do understand the controversy, and it does worry me,” said Reinstein, 60, who has tracked the ups and downs of Aduhelm for more than two years and has discussed the drug with his neurologist.
He took part in a “listening session” with the FDA, along with other Alzheimer’s patients, prior to the agency’s final decision. “I think that helped them understand that there is such a level of desperation out there.”
“I want hope,” said Reinstein. “This drug gave me hope.”
Jonathan Saltzman of the Globe staff contributed to this story.