Experimental Alzheimer’s Drug to Be Submitted for FDA Approval

“In a shocking reversal, Biogen (BIIB) on Tuesday [October 22] said that it would resurrect an Alzheimer’s drug that the company previously said had failed and will ask the Food and Drug Administration to approve it. The company said a ‘new analysis of a larger dataset’ showed that the drug, aducanumab, reduced clinical decline in patients with early Alzheimer’s disease on multiple measures of the drug’s effectiveness. That directly contradicts a decision in March to halt studies of the therapy based on the recommendations of an independent monitoring board that was charged with protecting patients in the study.

“Aducanumab’s failure sent shock waves far beyond Biogen. It was thought to be the last of a series of drugs — the previous ones, from many different drug companies, all failed — that targeted a protein in the brain called beta amyloid. After Biogen’s announcement in March, most researchers and biotechnology executives saw little hope for a drug that would help patients with Alzheimer’s disease even as cases mount.

“Biogen said that it conducted a new analysis in consultation with the FDA of a larger data set from the discontinued studies. The new analysis includes additional data that became available after the previous analysis showed the studies were ‘futile’ — that it had no chance of succeeding. Biogen said that the new data show aducanumab is ‘pharmacologically and clinically active’ and that it reduced patients’ clinical decline based on the results of a survey called Clinical Dementia Rating-Sum of Boxes (CDR-SB), which was the main goal of both studies.

“‘With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,’ Michel Vounatsos, Biogen’s chief executive, said in a statement. ‘We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.’

“Al Sandrock, Biogen’s head of research and development and chief medical officer, said in his first interview about the new results that his team could only find one previous instance where a trial was stopped for futility and then it turned out to be positive.

“‘I have to pinch myself because I almost don’t believe it yet,’ Sandrock said. ‘It’s so amazing to have this change from March. But I’m also very, very happy because … I know people with mild cognitive impairment and I felt like I had let them all down.’

“By June, as Biogen analyzed the full data set, researchers started to realize that a different picture was emerging of aducanumab, Sandrock said. The reason was because of changes that Biogen had made to the study late in the game. Initially, the company worried about a potential side effect — brain swelling — and limited the dosage of the drug. But later patients were allowed to receive higher doses of the medicine. ‘In retrospect, the results of the futility analysis were incorrect,’ Sandrock said. ‘That’s because it was from a smaller dataset that looked at patients with less exposure to high dose aducanumab.’

“In essence, Sandrock said, the futility analysis had happened too soon. It had looked at data based on last December. But the trials were actually stopped in March. Biogen had run two studies. One, was positive in its own right for the high dose. A second still failed, but shows signs of benefit in those patients who received the higher dose of aducanumab.

“The situation is highly unusual, and Sandrock said it will be up to the FDA to decide whether to approve the drug based on a single positive trial. But he said Biogen has met with the FDA twice to discuss its decision, first in June and then again on Monday. He said that the FDA had provided preliminary written comments that led Biogen to file for approval, and that Biogen moved forward with an announcement without waiting for meeting minutes because there were no surprises during the meeting.

“Sandrock has also been quietly sharing the data with outside experts. ‘People do have an initial skepticism,’ he said. ‘Rightly so. But then when we start to show them the data and take them through it, most of them get very excited because now they see there is a prospect that the drug could be approved.’

“Biogen presented new data from its Alzheimer’s trial on a conference call with Wall Street analysts, who grappled with the company’s about-face and with complex and somewhat contradictory information.

“Umer Raffat, an analyst at the investment bank Evercore/ISI, first asked if the departure of Michael Ehlers, Biogen’s previous research and development chief, had anything to do with disagreements over the Alzheimer’s dataset. Vounatsos, the Biogen CEO, said that Ehlers’ departure was personal, implying that disagreement over data did not play a role.

Raffat also asked whether, in a way, one trial was successful and another had failed. The data in the low-dose groups were consistent across trials. Why should there be confidence in a result that only occurred in one study?

“In one study, called Emerge, patients on the high-dose aducanumab had a 23% reduction in their rate of decline compared to those on placebo; those who were on the low dose were 11% lower than placebo, but that result was not statistically significant. But in the second trial, Engage, the decrease was only 2% in patients on the high dose. Biogen said that the patients in Emerge received higher doses due to changes made late in the studies. 

“But Biogen disclosed data in patients who completed the study, as well as in all patients. Raffat noted that the patients who did not complete seemed to show benefit as well. He called this ‘confusing’ in a note to investors following the conversation.

“In his note, Raffat still seemed skeptical. Given the one positive result, Raffat wrote that it is ‘not inconceivable that FDA is open to this filing.’ However, whether an FDA approval would translate into commercial success is ‘a whole different debate,’ he wrote.

“Both investors and researchers will spend the next several months struggling with the results. In the meantime, Biogen will make the drug available to patients who were previously enrolled in its clinical trials” (In Shocking Reversal, Biogen to Submit Experimental Alzheimer’s Drug for Approval by Matthew Herper).