Talk turned skeptical well before lunchtime in the meeting of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee to consider Biogen Inc.’s aducanumab for Alzheimer’s disease (AD), and it stayed that way until the end, when panelists voted thumbs down.
Aducanumab, the anti-amyloid beta monoclonal antibody partnered by Cambridge, Mass.-based Biogen with Eisai Co. Ltd., of Tokyo, was the subject of buoyant briefing documents that took many off guard, given the mixed data, but the FDA’s biostatistics analysis painted a gloomy, practically opposite picture of the overall clinical program. Panelists had a hard time squaring the two.
This summer, the FDA accepted the BLA related for aducanumab in AD and assigned it priority review. Biogen and Eisai about a year ago restarted the clinical program with aducanumab, which had failed a futility analysis, after ransacking a larger dataset to find post hoc that the drug may have activity in AD.
Guggenheim analyst Yatin Suneja was optimistic ahead of the adcom, noting that the briefing docs focus mainly on two positive studies deemed positive, 103 (called Prime) and 302 (Emerge) and not so much on the negative 301 (Engage) experiment, with 302 considered primary and 103 supportive. The meeting went smoothly at first, with the FDA’s presentation seeming almost as positive as Biogen’s own. Aducanumab hit rough water when panelist Scott Emerson – not surprisingly, a biostatistician himself – from the University of Washington in Seattle, came out sharply critical. Emerson called the FDA’s offering “terrifically one-sided.” Caleb Alexander, epidemiologist at Johns Hopkins Bloomberg School of Public Health in Baltimore, didn’t sound happy, either.
On the question, “Does study 302, viewed independently and without regard for study 301, provide strong evidence that supports the effectiveness of aducanumab for the treatment of AD?,” the vote was 1 yes, 8 no, and 2 uncertain.
Concerns about consistency of evidence
“The bottom line is that I find the materials that the FDA has provided strikingly incongruent,” Alexander said. “I have a very hard time understanding – after carefully reviewing what I thought was a very well done and well-articulated biostatistical review, which convincingly argued the evidence was ‘at best compellingly conflicted’ – how the FDA could conclude that there is substantial evidence of effectiveness, and in particular that study 302 provides a ‘robust and exceptionally persuasive study.’ It just feels to me like the audio and the video on the TV are out of sync. There are literally a dozen different red threads that suggest concerns about the consistency of evidence. A dozen. I mean, for every point that you can find suggesting support, there is another point or two that raises concerns.” Patient representative Richard Hoffmann, a retired pharmacist in Hernando, Fla., voted uncertain. “I don’t really think the question was a reasonable request of us,” he said. “I really can’t view 302 in isolation knowing about the existence of 301.”
On the question, “Does study 103 provide supportive evidence of the effectiveness of aducanumab for the treatment of AD?,” the vote was 0 yes, 7 no, 4 uncertain.
The panel did throw Biogen a bone of sorts. On the question, “Has the applicant presented strong evidence of a pharmacodynamic effect on AD pathophysiology?,” the vote was 5 yes, 0 no, 6 uncertain.
On the question, “In light of the understanding provided by the exploratory analyses of study 301 and study 302, along with the results of study 103 and evidence of a pharmacodynamic effect on AD pathophysiology, is it reasonable to consider study 302 as primary evidence of effectiveness of aducanumab for the treatment of AD?,” the vote was 0 yes, 10 no, 1 uncertain.
Agency ‘politics on full display’
Analysts tried to guess the outcome ahead of the meeting and in the process gained potential clues about aducanumab’s longer future. SVB Leerink’s Marc Goodman hosted a call with a key opinion leader in AD, who said the briefing docs “clearly underscore the FDA’s unusually positive opinion about aducanumab’s treatment effect in early AD,” and agreed strongly that the phase III Emerge study plus the supporting phase Ib Prime experiment, “and even parts of the [phase III] Engage study, provide substantial evidence to support the approval of aducanumab in this population.” He predicted a split or negative vote just the same, since committee members “tend to be more cautionary by default.” Regulators will probably approve the drug anyway, in his view.
J.P. Morgan’s Cory Kasimov conducted a survey that included 26 respondents treating an average of 246 AD patients per year. About two-thirds (62%) are from an academic setting; the remaining 38% work in community centers/practices. Most (88%, n=23) reviewed the FDA briefing docs prior to taking the survey. “The bottom line for aducanumab is that it is indeed looking pretty good,” he said. “The physicians voted in favor of the drug in every question (only a minority against), except the fourth and final voting question – arguably the money question.”
Evercore ISI’s Umer Raffat said the makeup of the roster signaled that a decision in Biogen’s favor was likely not “as much of a layup as the FDA’s conclusion reads” in the briefing docs. He pointed out that the agency’s questions to the panel “are worded a certain way” – that is, suggesting that the committee members consider the positive phase III without taking into consideration the negative one. “FDA politics are [on] full display, and it appears that aducanumab has buy-in” from the agency, he said in an email to investors. Raffat, too, predicted the drug still will win marketing approval.
Trading in Biogen shares (NASDAQ:BIIB) were halted while the adcom deliberated.