Update: Outcomes from Friday's FDA advisory committee meeting on aducanumab are reported in a follow-up story.
The controversial Alzheimer's drug candidate aducanumab received positive remarks from FDA reviewers ahead of an to be held Friday.
Aducanumab, Biogen's investigational monoclonal antibody targeting beta-amyloid protein, goes before the Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee.
The 343-page reviewed several aducanumab studies, including two parallel phase III trials, and , which were terminated in March 2019 when a futility analysis determined aducanumab was unlikely to outperform placebo at completion.
In October 2019, Biogen reversed its position, saying a review of previously unavailable data showed the drug actually reduced cognitive decline in EMERGE, but not in ENGAGE, and announced plans to seek regulatory approval.
At a presentation last December, the company suggested different enrollment periods and a midstream protocol amendment accounted for differences in the EMERGE and ENGAGE data. Biogen pointed to a subgroup of patients who received 14 treatments of the highest dose (10 mg/kg) of aducanumab who reaped the most benefit.
In its report prepared for PCNS panel members to review before Friday's meeting, FDA reviewers largely agreed.
While one trial is a "negative study and does not contribute to the evidence of effectiveness of aducanumab," the effect of aducanumab in the other trial "is robust and exceptionally persuasive on several of the instruments used to evaluate efficacy," they wrote.
In the EMERGE study, "the treatment effect for the high dose arm is supported by consistently favorable results across subgroups of interest," the reviewers added.
In the high-dose group, patients had roughly a 40% incidence of ARIA-E (brain edema) or ARIA-H (cerebral microhemorrhage, macrohemorrhage, or superficial siderosis). ARIA-E episodes generally resolved in 4 to 16 weeks and most patients with ARIA continued in the trial. (ARIA is an acronym for amyloid-related imaging abnormalities, generally considered adverse.)
The FDA reviewers noted that, if efficacy is demonstrated, "appropriate labeling language will address adverse reactions of concern," and that prescriber and patient education about ARIA was important. They also pointed out that while some degree of functional unblinding caused by ARIA was inevitable, the Biogen analyses "do not indicate a systematic bias introduced by ARIA."
Not every agency reviewer agreed with the tenor of the report. In an extensive appendix, FDA statistician Tristan Massie, PhD, found "no compelling substantial evidence of treatment effect or disease slowing" and said another study is needed. "The absence of a significant impact of data collected after ARIA events" doesn't necessarily imply there's no bias, Massie pointed out.
But, overall, the review team maintained there is "an urgent and unmet medical need for effective treatments" for Alzheimer's, and "a particular unmet need for effective treatments to delay, halt, or reverse the pathophysiological processes that ultimately lead to the clinical deficits of Alzheimer's disease."
On Friday, the PCNS panel will vote on:
- Whether EMERGE, viewed independently and without regard for ENGAGE, provides strong evidence supporting aducanumab's effectiveness as an Alzheimer's treatment
- Whether a randomized, double-blind, placebo-controlled phase Ib safety and tolerability study provides supportive evidence of the drug's effectiveness
- Whether Biogen has presented strong evidence of a pharmacodynamic effect on Alzheimer's pathophysiology
- And whether, considering ENGAGE and EMERGE findings including exploratory analyses, plus phase Ib data and pharmacodynamic effects, it's reasonable to consider EMERGE data as primary evidence of aducanumab's effectiveness
The Friday votes are nonbinding and will serve as recommendations to the FDA, which is scheduled to on or by March 7, 2021. If approved, aducanumab will be the first novel medication for Alzheimer's disease since 2004 and the first disease-modifying drug for the condition ever.