Michel VounatsosMichel Vounatsos
In a surprising reversal, Biogen has announced that it will bring its anti-amyloid drug aducanumab to the FDA for approval despite failing a previous futility analysis earlier this year.1

Aducanumab is a human monoclonal antibody that selectively targets aggregated forms of amyloid-beta, including both soluble oligomers and insoluble fibrils. Since 2017, Biogen and Eisai have collaborated on the development and commercialization of the agent, which was previously granted fast track designation by the FDA. The drug was examined in patients with early-stage Alzheimer disease, including mild cognitive impairment and mild Alzheimer dementia.

The decision to proceed with the regulatory process was made after Biogen analyzed an expanded dataset from the phase 3 EMERGE trial that included an additional 3 months of data on patients receiving high-dose aducanumab. They reported observing statistically significant changes on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, with P values of .010 or .031 based on cutoff dates. The high-dose group also hit several secondary endpoints, according to the company, leading them to definitively claim that “the result of the futility analysis was incorrect.”1

Notably, data from the identical phase 3 ENGAGE study did not show the same results, with the study drug performing worse than placebo on the primary end point as well as a test of cognitive function. Still, Biogen said that data from patients in the ENGAGE trial who achieved sufficient exposure to high-dose aducanumab support the findings from the EMERGE trial.

In a presentation, the company explained that the population included in the futility analysis had enrolled earlier in the studies and had a lower average exposure to the study drug. A protocol amendment later put in place allowed APOE e4 carriers originally randomized to a 6 mg dose to receive the higher 10 mg dose and for a longer duration.

“We did know that the protocol amendments could have had differential effects on the two studies due to the relative timing of enrollment, but we did not anticipate the magnitude of the effect this would have on the data,” the company wrote in a presentation.

Additional data on the primary end point in the EMERGE trial demonstrated a 23% reduction in clinical decline in the intent to treat population who received high-dose aducanumab (n = 547). The same reduction in clinical decline was observed in the opportunity to complete population.

“With such a devastating disease that affects tens of millions worldwide, today’s announcement is truly heartening in the fight against Alzheimer’s. This is the result of groundbreaking research and is a testament to Biogen’s steadfast determination to follow the science and do the right thing for patients,” Michel Vounatsos, Biogen’s chief executive, said in a statement.2 “We are hopeful about the prospect of offering patients the first therapy to reduce the clinical decline of Alzheimer’s disease and the potential implication of these results for similar approaches targeting amyloid beta.”
REFERENCE
1. Aducanumab Update. Biogen. October 22, 2019. investors.biogen.com/static-files/5a31a1e3-4fbb-4165-921a-f0ccb1d64b65. Accessed October 22, 2019.
2. Biogen Plans Regulatory Filing for Aducanumab in Alzheimer’s Disease Based on New Analysis of Larger Dataset from Phase 3 Studies [news release]. Cambridge, MA and Tokyo: Biogen and Eisai. October 22, 2019. biospace.com/article/releases/biogen-plans-regulatory-filing-for-aducanumab-in-alzheimer-s-disease-based-on-new-analysis-of-larger-dataset-from-phase-3-studies/. Accessed October 22, 2019.