Biogen now has 10 years to confirm approved Alzheimer's drug works

 Biogen will have until the end of the decade to complete another clinical trial confirming its newly approved Alzheimer's treatment can actually benefit patients. 

The Food and Drug Administration mandated the follow-up study as a requirement of the conditional clearance it granted Biogen's drug, called Aduhelm, on Monday. According to an approval letter from the regulator, the biotech company has until next August to finalize a plan for the study, until 2029 to finish testing and until 2030 to submit a final report to regulators. 

If Biogen fails to complete the study, or results are negative, FDA officials said the agency would pull Aduhelm from market. In the meantime, however, Biogen will be able to sell the drug widely, potentially generating tens of billions of dollars in revenue without convincing proof of clinical effectiveness. 

"We believe that the data supports accelerated approval while holding the company accountable for conducting an additional study to confirm the benefits observed in one of the trials, which we fully intend to do," Patrizia Cavazzoni, head of the FDA's main drug review office, told reporters Monday. "We acknowledge that it will take some time to conduct a confirmatory trial." 

The agency hopes to accelerate testing, however, by incorporating "opportunities" for earlier study results while the overall trial continues, an FDA spokesperson told BioPharma Dive in a statement after this story was published.

"We consider the nine-year timeline a conservative estimate, which is an appropriate starting point for development of the draft protocol from the sponsor for its global confirmatory study," the spokesperson wrote in an email. STAT News previously reported the FDA viewed the trial timeline as conservative, citing an unnamed official. 

Yet, in a Monday interview with CNBC, Biogen CEO Michel Vounatsos emphasized that nine-year timeline, although he acknowledged the specific trial plans were not yet set. 

As things stand now, Aduhelm is backed by two nearly identical Phase 3 studies as well as an earlier Phase 1 trial. But the results are highly controversial, as data from those two late-stage studies were conflicting. In one, treatment appeared to modestly slow cognitive and functional decline among patients given a high dose of Aduhelm. In the other, treatment had no effect. Patients on the high dose even seemed to decline slightly faster than those given placebo. 

The discordant data has stirred significant doubts among experts whether Aduhelm truly slows disease progression, and whether data from the one successful trial was a false positive. Both questions are made more complicated by Biogen's March 2019 decision to halt the trials early, thinking then that the drug was unlikely to succeed. The company's subsequent reversal was highly unorthodox and muddied the statistics used to determine treatment benefit. 

Accordingly, in the run-up to Monday's decision, many experts had urged the FDA to reject Aduhelm and ask Biogen to complete a third large, well-controlled study before granting approval. 

"No number of post hoc analyses of these two trials can substitute for the value that could be generated by a new trial," said Caleb Alexander, a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, in an April interview. Alexander was a member of an FDA advisory committee that rejected Biogen and the agency's case for Aduhelm in a contentious November meeting. 

The FDA dismissed the committee's advice, choosing after a long review a middle-ground approach that it hadn't discussed at the meeting. Even though Biogen requested a full approval for Aduhelm, based on the signs of clinical benefit in the one trial, the agency instead granted an accelerated approval, based on the drug's effect in reducing a toxic plaque found in the brains of Alzheimer's patients. 

Aduhelm does that very well, but it's not clear whether plaque reductions directly correlate to slower cognitive and functional declines. At the November meeting, even the head of the FDA's neuroscience division said the agency was not using amyloid reduction as a surrogate of efficacy — a position the regulator seemingly reversed. 

Unlike full approvals, accelerated approvals require a confirmatory study, which Biogen will now have to complete in order to keep its drug on the market. But the long timeline allowed by the FDA gives the company more than eight years to do so, even if opportunities for interim results are built in. Aduhelm's two Phase 3 trials ran for about four years to complete, although they were stopped early.

"We expect the sponsor to commit all resources needed to move this trial forward as effectively as possible, with the aim of completing the trial as soon as is feasible, while assuring the quality of the data and the robustness of the results," the FDA spokesperson told BioPharma Dive. 

In its letter, the agency didn't specify whether the study must use a placebo as a comparison, asking instead for "an appropriate control for the treatment of Alzheimer's disease." 

Experts previously questioned whether an approval of Aduhelm would make other clinical trials testing Alzheimer's drugs much harder, as patients would be less willing to receive a placebo. 

https://www.biopharmadive.com/news/biogen-aduhelm-confirmatory-study-fda-approval/601422/