Questions linger about Biogen's aducanumab following new study details on resurrected Alzheimer's disease drug

Biogen on Thursday unveiled more details from the Phase III EMERGE and ENGAGE trials of aducanumab, with some analysts saying the lack of any new negatives in the latest report indicates the company will probably take the data on the once-discontinued Alzheimer's disease drug to the FDA for review. However, Stifel's Paul Matteis said he saw aspects of the data update that were both "incrementally better and worse than expected," and he puts the probability of the drug winning approval at less than 50%.

Earlier this year, Biogen and partner Eisai discontinued studies of the experimental anti-amyloid beta antibody following a failed futility analysis, but in October revived the drug based on findings from a larger dataset from EMERGE and ENGAGE (for related analysis, see ViewPoints: Biogen's aducanumab about-face – stunning resurrection or Hail Mary?). The two identically-designed trials showed mixed results in that analysis, with EMERGE meeting its primary endpoint, showing a significant reduction in clinical decline at the highest dose of aducanumab, while ENGAGE was still considered a failure. However, the companies said at the time that a subset of patients in the ENGAGE trial "who received sufficient exposure to high-dose aducanumab support the findings from EMERGE."

The companies have said they intend to file aducanumab for FDA approval early next year, and while some analysts have been skeptical about the drug's chances, CEO Michel Vounatsos has claimed he is "reasonably confident" the US regulator would eventually approve it.

In the latest analysis presented Thursday at the Clinical Trials on Alzheimer's Disease (CTAD) conference, Biogen said patients on aducanumab in EMERGE saw their rate of decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale slow by 14% or 23% depending on whether they were on the low or high dose of the drug. However, only the high dose was statistically significant. In the ENGAGE study, the rate of decline was slowed by 12% in the low-dose group, but actually accelerated 2% in the high-dose arm.

According to Biogen, the difference can be explained by a protocol amendment implemented during the trial that led to more patients being given high-dose aducanumab. Moreover, the ENGAGE trial had enrolled about 200 more patients than EMERGE at the time of the change, affecting how many patients in each study ultimately received the higher dose. Once more patients were given the higher dose, Biogen said EMERGE shows a 24% reduction in the rate of decline among patients on low-dose aducanumab, and a 30% reduction in the high-dose group. The corresponding ENGAGE trial results showed reductions of 20% and 27%, respectively. Benefit was also only statistically significant for the high-dose group.

Ronald Petersen, an Alzheimer's expert from Mayo Clinic who moderated the CTAD panel, commented that while the EMERGE data were "overwhelmingly positive," ENGAGE was not, but "overall, I think it's more positive than negative." He was also not very worried about the rates of cerebral oedema, which occurred in 34% to 35.5% of patients in the high-dose groups of EMERGE and ENGAGE, respectively, saying "the side effects are there....they're to be expected, but I think they're manageable." Biogen reported that rates of cerebral microhaemorrhages were 18.6% and 17.6%, respectively.

Meanwhile, the company stated that it is also "finalising the details of a re-dosing study with the aim to offer access to aducanumab to eligible patients previously enrolled in the aducanumab clinical studies."

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