Biogen’s investigational Alzheimer disease treatment is currently under review with a Prescription Drug User Fee Act target action date of March 7, 2021, if not earlier.
The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted not to recommend regulatory approval of Biogen's aducanumab, in one of the most anticipated advisory committee decisions of the year.1
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).
In the final slide of the statistical review of aducanumab, the committee summarized that “at best, the evidence in this application is from [EMERGE] only and there exists compellingly conflicting phase 3 evidence,” noting that the approval of aducanumab could present challenges for other candidate therapies with regard to noninferiority, as well as issues with recruitment and retention for ongoing trials.
They did acknowledge Biogen for its design of the clinical trials and its inclusion of biomarker-based data, as well as its subsequent effort to get the data on track for approval, calling for more collaboration between sponsors and the FDA in these processes.
“Biogen thanks the many patients and advocates who shared their personal thoughts and experience at today’s Advisory Committee meeting, reflecting the significant unmet need for a treatment for Alzheimer’s,” said Michel Vounatsos, chief executive officer, Biogen, in a statement.2 “We appreciated the opportunity to share our data with the Advisory Committee, and we will continue to work with the FDA as it completes its review of our application.”
Aducanumab’s ultimate fate remains in the hands of the FDA, as Biogen’s biologics license application (BLA) is currently under review with a Prescription Drug User Fee Act target action date of March 7, 2021, if not sooner.3 It's important to remember that although the opinions presented in these committee meetings can influence the agency's final approval decision, the FDA can—and has—approved drug therapies that were not previously recommended during these exercises.
POLL: Do you feel that the FDA Advisory Committee's assessment of aducanumab for Alzheimer disease was fair?
This result adds to the ongoing contentiousness surrounding the interpretation of the data from EMERGE and ENGAGE. Thomas Wisniewski, MD, professor of neurology, and director, Pearl I. Barlow Center for Memory Evaluation and Treatment, NYU Langone Health, who was not affiliated with the studies, told NeurologyLive that he believes the evidence is clear.
“There were clear cognitive benefits on a number of end point measures, which [is] unprecedented in a phase 3 Alzheimer disease trial, and furthermore, there was a very clear indication of target engagement, as measured by a dose-dependent reduction in amyloid plaques on amyloid PET,” he explained. “As well, very significantly, there were reductions in phosphorylated-tau in the subset of patients that had cerebrospinal fluid examinations—again, in a dose-dependent manner.”
Wisniewski added that the potential of aducanumab is “game-changing” and that even though the effect size is not necessarily enormous, “it does look like it's disease-modifying and of cognitive benefit.”
In late October, Howard Fillit, MD, founding executive director and chief science officer, Alzheimer’s Drug Discovery Foundation, who was also not part of the clinical trials, told NeurologyLive that, in the least, the trials represent progress in the Alzheimer space. “I think the incremental work that aducanumab represents is really a step forward. Will it be the cure? It won’t be a cure. We’re going to need combination therapy; we’re going to have to hit multiple targets, just like other diseases of aging. From the perspective of history, it’s a very exciting time in Alzheimer research,” he said.
Earlier this week, a perspective piece published in Alzheimer’s & Dementia called for a third and definitive phase 3 trial of aducanumab, suggesting that the proposed efficacy of the therapy based on available data from a pair of phase 3 trials is unclear.4 That article was followed by a response from 2 of the drug’s key investigators, Marwan N. Sabbagh, MD, and Jeffrey S. Cummings, MD, ScD.5 Ultimately, they explained that the data warrant approval with accompanying phase 4 surveillance, a stance that has been endorsed by the Alzheimer's Association.
Aducanumab‘s journey to the FDA has been full of ups and downs. After a futility analysis published in March 2019 showed that the therapy missed its primary end point—change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score in patients with mild cognitive impairment (MCI) due to Alzheimer disease and mild Alzheimer dementia—October 2019 brought a change in course with the reports of an additional analysis of the EMERGE dataset which showed statistically significant changes on the CDR-SB score, with P values of .010 or .031 based on cutoff dates.6
Notably, by the 78-week cutoff in EMERGE's intent to treat population—who received high-dose aducanumab—there was a 22% reduction in clinical decline observed. The opportunity to complete population reported similar results. As well, a consistent reduction in clinical decline was observed in the secondary end points, measured by the Mini-Mental State Exam (18% vs placebo; P = .05), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (27% vs placebo; P = .01), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (40% vs placebo; P = .001). Imaging data suggested that both doses of therapy were associated with a reduction in amyloid plaque deposit burden at both weeks 26 and 78 when compared with placebo (P <.001).
That October report also included an additional 3 months of data from the subjects who received a high dose of the drug. At the time, Biogen noted that although ENGAGE failed to meet its end points, data from patients in that trial who achieved sufficient exposure to high-dose aducanumab supported the findings from the EMERGE trial.
In January this year, the FDA gave the go-ahead for a phase 3b redosing clinical trial of aducanumab (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.