How Biogen Salvaged Alzheimer’s Drug After a Costly Failure
How Biogen Salvaged Its Alzheimer’s Drug After a Costly Failure
(Bloomberg) -- It was one of the most surprising and puzzling reversals in drug-industry history. Biogen Inc. said an Alzheimer’s treatment it had left for dead earlier this year may work after all.
The revival of the experimental therapy, called aducanumab, whipsawed the medical world on Tuesday. Before the company had pulled the plug on the therapy in March, aducanumab was seen as one of the most promising drugs of its kind. Doctors, patients and Biogen researchers were stunned when the trials were halted after an analysis suggested that the drug would fall short of its targets.
At the University College London, the decision to end the trial jolted researchers who were studying the drug. Word came down so abruptly that three patients were in the middle of getting infusions at the time, said Catherine Mummery, a consulting neurologist there and a principal investigator for one of the trials.
Mummery had to rush down to the clinic to tell the patients their treatments needed to be stopped immediately.
After that, there were few details from Biogen for months, until she got an urgent call from a project manager late Monday night. One of the trials had succeeded after all, she was told, and the company planned to submit the drug for approval. Now, Mummery is racing to set up a call with patients to explain the sudden change.
“It was totally gob-smacking,” said Mummery. “I am still coming to terms with it. I want to believe it.”
When Biogen slammed on the brakes, the company lost a quarter of its market value and was faced with questions about its future. That all changed on Tuesday, when the company said a deeper dive into a larger trove of aducanumab trial data had produced hope the treatment could clear away the sticky clumps of amyloid that cloud the brains of Alzheimer’s sufferers.
Biogen shares surged 26% to $281.87 on Tuesday, the biggest single-day gain for the stock in more than 20 years. Shares of its partner on the drug, Eisai Co., jumped 18%, the most in 15 months, in trading in Japan on Wednesday.
The drugmaker now stands on the precipice of submitting the first disease-modifying therapy for Alzheimer’s to the U.S. Food and Drug Administration for approval. That could draw other pharmaceutical companies back into an area that has burned them badly in the past.
“It has been a long dry spell for the Alzheimer’s field,” said Zaven Khachaturian, editor-in-chief of the medical journal Alzheimer’s & Dementia. “In 40 years, this is the first really good news.”
Statistical Riddle
The about-face left many researchers scratching their heads over how a set of trials that had been declared futile in the spring could be found to give convincing support for the company to seek approval for aducanumab just months later.
“It’s an extremely unusual situation. It’s a remarkable situation,” said Biogen Chief Medical Officer Al Sandrock, who added that the company could find only one comparable episode in the published medical literature.
The fate of millions of patients and billions of dollars hangs in the balance, after failure upon failure by numerous drugmakers to come up with a treatment. If aducanumab gets approval, it could reap more than $10 billion in annual sales, said Yatin Suneja, an analyst at Guggenheim Securities, in a note to clients. It could also fundamentally reshape Biogen, Suneja said.
When the company’s researchers analyzed the full results, which included three months more of treatment data than were available when the trials were halted, one of two trials turned out to be clearly positive, at least at the higher of two doses.
The second trial still failed to show an effect. But Biogen now believes that may be because there wasn’t a sufficient number of patients who got sustained treatment at the highest dose of the medication. That took months for researchers to understand.
‘Devastating Feeling’
When Biogen decided to halt its trials, the surprise and disappointment rippled through the company, baffling scientists who’d seen encouraging results in the earliest trials. It also dealt a blow to patients. Biogen studied aducanumab at over 350 trial sites with more than 3,000 patients. Each needed to be told that it had failed.
“There was a devastating feeling that the studies hadn’t worked,” said Samantha Budd Haeberlein, head of clinical development for Alzheimer’s disease at Biogen. “My brain was screaming at me: Something has gone wrong. The phase 1 was perfect. What the hell happened?”
After the futility analysis, Biogen told 20 of its scientists to comb the trial data for answers. The team eventually expanded to 49. “I thought we must have been missing something,” said Sandrock. He said he pressed his team to keep looking for what went wrong.
Depressingly, initial analysis appeared to confirm the decision to halt the trials. But then more data rolled in, and that changed the picture for one of the studies. By June, one of the studies turned positive. The other study was still negative, for unclear reasons.
Biogen met with the FDA in June to discuss what it had found, and officials there were encouraging. “They granted us a meeting unusually quickly,” Sandrock said. “The most clear thing we got in that first meeting was that they didn’t think the drug was inactive.”
The FDA also suggested several new analyses Biogen could perform. That gave Biogen fuel to keep going. By summer, Haeberlein says her team was regularly working 15-hour days and sometimes weekends. As they pored over the data, a picture emerged that seemed to explain the discordant results.
Two Trials
Biogen changed the plan for the trials twice: once to temporarily suspend treatment for patients who experienced side effects, and once to allow patients with a common genetic variant to get a higher dose.
But the changes affected the two trials unequally. One had already enrolled many more patients. Fewer got the higher, more potent dose for extended periods of time. The second trial started later, with more patients getting consistent, high-dose treatment.
It was the second trial where aducanumab clearly slowed the disease, while the first one, with fewer patients on the highest dose, failed to show an effect.
The way forward became clear to the company only Monday afternoon, after a two-hour meeting at FDA headquarters in Maryland. A 15-person contingent from Biogen traveled down to discuss the results with regulators. The agency, said Sandrock, told them it was reasonable to submit the data package for possible approval.
Given the mixed results, what lies ahead is uncertain. With few drugs on the market, the FDA might be pressured to approve Biogen’s therapy on the basis of one positive trial, if it appears to be safe, researchers said.
Kostas Lyketsos, director of the Alzheimer’s and Memory Center at Johns Hopkins University, emphasized that the benefits are modest at best.
“The data I have seen suggests there is relative benefit over placebo,” he said, “but the overall trajectory is for steady decline even though amyloid is being cleared from the brain.”
Given the controversy generated by Biogen’s reversal, the FDA is likely to call on a committee of outside advisers to review the data, said Samuel Gandy, the associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York.
“It will be up to the people on the advisory committee, those who make a recommendation on whether to approve it,” Gandy said. “They have to be positive and enthusiastic. If the advisory panel gives a very negative opinion, it would be hard, in the face of all this failure, to approve it. That would carry the day.”
To contact the reporters on this story: Robert Langreth in New York at rlangreth@bloomberg.net;Michelle Fay Cortez in Minneapolis at mcortez@bloomberg.net;Riley Griffin in New York at rgriffin42@bloomberg.net
To contact the editors responsible for this story: Drew Armstrong at darmstrong17@bloomberg.net, Timothy Annett
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