The investigational agent developed by Biogen and Eisai is now expected to receive regulatory review by June 7, 2021.
Biogen and Eisai have announced that the FDA today extended the review period for the duo’s biologic license application (BLA) for the investigational Alzheimer disease treatment, aducanumab. The extension moves the Prescription Drug User Fee Act (PDUFA) action date from March 7, 2021, 3 months later in the year to June 7, 2021.1
As part of the process with the regulatory agency, Biogen submitted a response to an information request which consisted of additional clinical data and analyses. This was deemed a Major Amendment to the BLA, which resulted in the need for additional review time. The BLA was originally submitted in July 2020 and was first accepted for review the following month.
“We are committed to working with the FDA as it completes its review of the aducanumab application. We want to thank the FDA for its continued diligence during the review,” said Michel Vounatsos, chief executive officer, Biogen, in a statement.
Aducanumab has been the subject of much conversation in the Alzheimer and dementia space since late 2019, when Eisai and Biogen announced and then presented new data at the 12th Annual Clinical Trials in Alzheimer Disease (CTAD) conference suggesting that the therapy produced statistically significant changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with P values of .010 or .031 based on cutoff dates.2
Prior to that announcement, many had written off the anti-amyloid agent as another failure in the space, particularly after its developers discontinued the pair of phase 3 clinical trials, EMERGE (NCT02484547) and ENGAGE (NCT02477800) as well as its phase 2 safety study, EVOLVE (NCT03639987), that were assessing the therapy, for reasons of futility. Shortly after the CTAD presentation, in January 2020, the FDA approved a phase 3b redosing clinical trial (NCT04241068) in order to demonstrate long-term safety and tolerability in a targeted enrollment of 2400 patients from 4 previous clinical trial programs in the aducanumab development program.
In December 2020, aducanumab trial investigator Marwan Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, noted to NeurologyLive that the BLA’s supporting data from the clinical development program are extremely complex, but are also contextually driven.
“It's not like the EMERGE data is by itself. It comes built on the shoulders of PRIME, [the phase 1b trial,] and there is clearly a dose-related effect and it is clearly driven at the highest dose,” Sabbagh said. “Every time you see the FDA come out with a position statement, it keeps lowering the bar. At the last iteration, [in 2019], EMERGE data hit the target of what the FDA has said is the threshold it will consider [for approval]. I think it hits that, so I disagree with the negative voices.”
The decision for the therapy ultimately lies in the hands of the FDA, of course, but worth noting is that in early November 2020, the agency’s Peripheral and Central Nervous System Drugs Advisory Committee voted not to recommend regulatory approval of aducanumab.3
In the final vote, which assessed whether or not the findings from the EMERGE trial (Study 302)—in the context of information from Studies 301, 302, 103, and pharmacodynamic data—could serve as primary evidence for the effectiveness of aducanumab in Alzheimer disease, the committee voted 10–0 (10 no; 0 yes; 1 uncertain) that the trial did not provide such evidence.
The committee voted 8–1 (8 no; 1 yes; 2 uncertain) that the phase 3 EMERGE study (NCT02484547) in patients with mild Alzheimer disease was enough to demonstrate efficacy. Additionally, the group voted 7–0 (7 no; 0 yes; 4 uncertain) that the prior phase 1 study, PRIME (NCT01677572), demonstrated supporting evidence of efficacy. As for the presence of strong evidence of the therapy’s pharmacodynamic effect on Alzheimer, the committee voted 5–0 (0 no; 5 yes; 6 uncertain).
For more on aducanumab’s journey from development to the FDA, check out NeurologyLive’s 3-part series: Support, Skepticism, and Statistics: The Aducanumab Saga.