No love for aducanumab from FDA advisors

The FDA Advisory Board has overwhelmingly voted against the data presented on the controversial Alzheimer’s disease candidate aducanumab Friday.

The authorities’ Peripheral and Central Nervous System (PCNS) Drug Advisory Board said that the positive results seen in one of two identical Phase III trials of biogen anti-amyloid drugs could not be considered alone. I can’t, but said I had to take it with the twins, who were clearly negative.

Therefore, even if the data from the previous Phase Ib trial were added to the equation, the positive trial was not evidence of the efficacy of aducanumab, the Commission said in a 10-0 vote, with one member abstaining. did.

“This analysis appears to be influenced by the Texas sharpshooter fallacy,” said Scott Emerson, MD, a panelist and biostatistician at the University of Washington, Seattle. ..

The PCNS Committee reviewed data from three studies: two identical Phase III trials, Engage (Negative results, called Study 301 at the conference) and EMERGE A Phase Ib safety and tolerability study known as Study 103 (showing a positive result called Study 302), which was further provided as supporting evidence of the efficacy of aducanumab.

ENGAGE and EMERGE ended in March 2019. Waste analysis The determined aducanumab was determined to be unlikely to outperform placebo upon completion. In October 2019, drug developer Biogen I reversed the positionA review of previously unavailable data stated that the drug actually reduced EMERGE’s cognitive decline, but not with ENGAGE.

On Friday, the Commission voted on four questions about evidence of the effectiveness of aducanumab.

• Whether EMERGE (Study 302) was viewed independently and without considering ENGAGE (Study 301) provided strong evidence to support the effectiveness of aducanumab as a treatment for Alzheimer’s disease. Johns Hopkins Graduate School of Public Health Panelist, G. Caleb Alexander, MD, said:
• Whether the Phase Ib trial (Study 103) provided evidence to support the efficacy of the drug: 7 voted negative, no voted in favor, 4 were uncertain, Emerson said “All Phase II trials are highly biased in their therapeutic efficacy.”
• Whether Biogen showed strong evidence of its pharmacodynamic effects on Alzheimer’s pathophysiology: 6 panelists were uncertain, 5 voted in favor and no voted against. Many “yes” voters agreed that it had an effect on amyloid pathology, but some pointed out that the data on other biomarkers, including tau, were “ambiguous.”
• Whether Phase Ib data and pharmacodynamic effects, in addition to the exploratory analysis of Phase III trials, make it reasonable to consider EMERGE data as the primary evidence of aducanumab efficacy: 10 panelists Voted against, no one voted for, and one was uncertain.

PCNS panelists expressed strong concern about the composition of the FDA’s presentation and whether they could see the results of one of the two identical studies individually, especially regarding the questions they were asked to vote for. Did. According to Emerson, the FDA’s interpretation of the data.

Others have pointed out that the wording of some questions limits their ability to express their views on the evidence presented.

At the conference, Biogen Senior Vice President Samantha Budd Haeberlein, PhD, sought to explain the difference between EMERGE and ENGAGE. This suggests that failure in one test does not compromise the results of the other. Billy Dunn, MD, Director of Neuroscience, FDA’s Center for Drug Evaluation and Research, generally agreed. Presented in FDA briefing document Released Wednesday, it highlighted the “urgent” need for treatment of Alzheimer’s disease.

However, throughout the meeting, advisory board members reiterated the contradictions clarified by FDA statisticians Tristan Massie, PhD. “There is a study 301 of the same size and designed in the same way, but this is in direct conflict with the 302. If there are two [studies] And you do your best and pretend to be the only one. Your quote may be biased like publication bias. “

The vote on Friday is non-binding and serves as a recommendation to the FDA. I decided to bring a girl By March 7, 2021. If approved, aducanumab will be the first new drug for Alzheimer’s disease since 2004 and the first disease modifier for this condition.