Confusing Alzheimer’s Data Leaves Big Decision in FDA Hands

(Bloomberg) -- Biogen Inc. unveiled the most detailed data yet on the Alzheimer’s drug that it shelved and then brought back in one of the most head-spinning episodes in biotechnology history.

Now, the U.S. Food and Drug Administration could be facing a momentous decision: Approve the therapy based on what numerous scientists believe is an inconclusive or even contradictory record, or force Biogen to carry out another costly clinical trial that could take years to complete.

The data presented by the company to a packed session at the Clinical Trials on Alzheimer’s Disease conference in San Diego on Thursday provided fuel for both sides. One trial suggested the drug, called aducanumab, may be the first-ever to slow the progression of Alzheimer’s. But a second, essentially identical trial showed no effect on the disease at all.

Choosing a course of action is shaping up as one of the most consequential drug-approval decisions that the FDA has made in years. Biogen has said it plans to submit aducanumab to the agency in early 2020. At stake are the fates of millions of Alzheimer’s patients, along with billions of dollars in sales and stock-price gains for Biogen and its Japanese partner Eisai Co.

A hopeful but wary reception to Biogen’s disclosures was on display not just in the crowded conference ballroom where it was presented, but also among the field’s brightest researchers and investment analysts who want to see even more data.

Eisai gained 6.6% in Tokyo, while Biogen shares advanced 0.2% in premarket trading on Friday.

“This will soon be under review at regulatory authorities,” said Al Sandrock, Biogen’s chief medical officer, on a late Thursday conference call with analysts. “For that reason, we are very sensitive about what we want to present now. We have nothing to hide but there is a time and a place for everything.”

In the tightly packed room in San Diego, Biogen produced reams of data laid out in 60 slides styled with colorful graphics. An audience of researchers and doctors hung on every word. But after the presentation, many said none of what they saw resolved the essential conundrum: what to believe.

“They need a tiebreaker,” said Suzanne Craft, an Alzheimer’s researcher at Wake Forest School of Medicine, shortly after the presentation, expressing a widely held sentiment among the attendees. “We all want it to be real, but the evidence is not sufficient to justify declaring this a ready-for-prime-time treatment.”

Plaque Fighter

Aducanumab is intended to combat the amyloid plaque that fills the brains of patients, the primary hallmark of the disease long-believed to be responsible for the mental decline that comes with it.

In fact, amyloid was one area in which there was no controversy. Patients were screened for the plaque build-up before being allowed into the trial, and the drug clearly removed it. Whether its dispersal led to any benefit, however, remained a topic of heated debate among researchers.

“It’s inconclusive right now,” said Mayo Clinic neurologist David Knopman, in an interview the night before the meeting. “I think most of my colleagues explicitly or in their hearts believe another study has to be done. I don’t see any other choice.”

Knopman, who was the Mayo Clinic’s lead investigator for one of the studies, said that approving aducanumab now would mean that doctors and patients would never get a definitive answer about its benefits. After the presentation, he said the Biogen talk contained some helpful details but nothing that fundamentally changed his views.

The information presented by Biogen in some cases raised more questions because of some aspects of how the study was done. The company had to estimate results for some patients who didn’t finish the trial, and it didn’t say how patients fared in different geographic areas. The company also didn’t say how patients with a genetic predisposition to developing the disease responded to the drug, a key issue.

Analysts who track the biotechnology industry were generally more skeptical.

Sam Fazeli, a senior pharmaceutical analyst at Bloomberg Intelligence, said the presentation raised more questions and added to the uncertainty around the drug’s potential for approval.

“While we’d love to see a drug benefit millions of people, this remains a subgroup analysis of post-hoc data,” he wrote. “In a normal world, this isn’t sufficient for approval.”

If approved, the drug is likely to be costly for the health-care system. In addition to the price of the medication itself, patients will need to go to their doctor’s office to have it infused and submit to regular imaging scans of their brains. There are also potential side effects. More than 40% of people who took high doses developed brain swelling or small brain hemorrhages; most of the time those incidents were seen on brain scans and didn’t produce symptoms.

While the safety issues would be acceptable if the drug was unequivocally effective, the lingering questions and potential complications are likely to tip the scales in favor of the FDA requiring additional studies, according to Brian Skorney, an analyst at Robert W. Baird & Co.

“Aducanumab’s profile is not benign,” said Skorney, who has been skeptical about the drug’s future. “We expect that the FDA will view the potential for aducanumab to induce brain bleeds as a key risk factor during the review.”

Hope & Skepticism

At an opening reception the night before the Biogen presentation, doctors and researchers from around the world buzzed with anticipation as they ate sushi and listened to jazz standards in the conference hotel overlooking San Diego’s harbor. In the past, the annual conference had frequently been a sedate affair, in which one failure after another was agonized over.

This time, there was the prospect of at least a partially positive result.

Nonetheless, doubt hovered over the gathering. Attendees were discussing a skeptical editorial in The Lancet Neurology by Lon Schneider, the director of the University of Southern California’s Alzheimer’s Disease Center. In technical detail, Schneider pointed out several statistical questions hovering over the Biogen data.

Among other issues, he said that because some patients stopped taking the therapy due to drug-related imaging abnormalities but then started again, doctors treating the patients, who were supposed to be in the dark, now knew that those patients were on the experimental medicine.

Because the successful trial was stopped before 40% of patients were able to complete it, “treatment effects are likely exaggerated” and “could be random,” Schneider wrote. It’s possible that if the trial had continued to its planned end, instead of being stopped short, the apparent effect would have dissipated, he said.

Costs of Delay

A new trial examining the higher, more effective dose could take three years or more to complete and cost as much as $1 billion, significantly deferring access to a potentially helpful treatment, doctors said. Some Alzheimer’s patients who took part in the trials and were monitoring the presentation remotely said they hoped the FDA approves the drug now.

Jeff Borghoff, a 55-year-old former software developer with Alzheimer’s from Forked River, New Jersey, was in one of the aducanumab trials and said he “was crushed” when they were ended in March. He thinks the drug helped him.

“There is no solution out there or medication out there to slow the progession of this disease,” he said. “We need something and I would like to see this move forward.“

Biogen itself has gone back and forth on what to make of its data. It halted the two trials early in March, declaring that a futility analysis had shown they were unlikely to work. Then it changed its mind in October after analyzing more data, declaring it thought the drug worked after all. That reversal jolted investors and excited patients.

But the decision to halt the studies, combined with several mid-course modifications Biogen made to the trials, have made the results all the more difficult to interpret. It’s impossible to tell now what would have happened, and whether the results would have been more clear, had the studies been continued to the end.

Biogen research executive Samantha Budd Haeberlein argued in her presentation Thursday that the study that failed may have failed because it had fewer patients who were exposed to higher, more effective doses. She said that a subgroup of patients in the failed trial who received consistently high doses may have benefited.

“It is unfortunate that we terminated the studies,” Haeberlein said.

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

To contact the editors responsible for this story: Drew Armstrong at darmstrong17@bloomberg.net, Timothy Annett

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