Despite high expectations and pleas from patients, caregivers, and advocacy groups, a US Food and Drug Administration (FDA) advisory panel has declined to recommend approval of aducanumab, an amyloid-clearing Alzheimer's drug.
Members of the Peripheral and Central Nervous System Drugs Advisory Committee determined that results from Biogen's one large positive trial did not provide strong enough evidence of efficacy for the treatment of Alzheimer's disease (AD).
Committee members acknowledged the urgent need for new AD therapies and praised Biogen and the FDA for their hard work in preparing background information on the drug application.
However, the panel raised red flags about the strength of the evidence presented. In addition, some committee members noted that approving a drug without rigorous scientific evidence could hinder future clinical research.
With such an important application, "we have to get it right," said G. Caleb Alexander, MD, professor of epidemiology and medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Aducanumab is a recombinant human monoclonal antibody targeting β-amyloid (Aβ). If approved, it would be the first disease-modifying treatment for AD.
Early trials of aducanumab were promising, showing that the drug engaged and cleared amyloid plaques. This led to two multisite phase 3 trials. Each trial had more than 1600 patients, most of whom were in their 70s, with mild cognitive impairment (MCI) or mild dementia and elevated Aβ levels on positron-emission tomography.
However, in March 2019, Biogen announced discontinuation of these trials after an interim analysis showed that the drug was not likely to produce meaningful benefit.
However, a further analysis that included an additional 3 months of data showed that one of the trials ― Study 302 (EMERGE) ― met its primary endpoint of a significant reduction in clinical decline. Additional analysis suggested that a subset of patients from the second trial ― Study 301 (ENGAGE) ― supports these positive findings.
The company maintained that another randomized controlled trial ― the phase 1b Study 103 (PRIME) ― also supported these findings.
Biogen formally submitted a new drug application to the FDA earlier this year.
However, there have been vocal critics of pursuing approval of aducanumab with currently available data, among them David S. Knopman, MD, from the Mayo Clinic, Rochester, Minnesota, who is an expert in late-life cognitive disorders. He was reportedly recused from the advisory committee meeting because of his involvement in conducting clinical trials of aducanumab.
Medscape Medical News reached out to Knopman for an interview, but he declined to comment.
In an article in Alzheimer's and Dementia, Knopman and colleagues argue that although post hoc analyses of EMERGE and ENGAGE showed that biomarker data were consistent with target engagement, no evidence was presented to correlate biomarker changes to cognitive benefits.
"Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes," they note.
Need for Another Phase 3 Study
Knopman is calling for another phase 3 trial that is adequately powered and designed to prove efficacy.
In the presentations to the advisory committee, Biogen and the FDA maintained that Study 302 provided "persuasive" evidence that high-dose (10 mg/kg) aducanumab significantly slowed AD progression.
Compared to placebo, the benefit on the primary outcome, the Clinical Dementia Rating Scale Sum of Boxes, was –22% (P = .012) for high-dose aducanumab.
On the other four clinical measures, high-dose aducanumab yielded a consistent, statistically significant reduction in cognitive decline in comparison with placebo. Treatment differences ranged from –18% on the Mini–Mental State Examination to –87% on the Neuropsychiatric Inventory–10. The study results also showed substantial effects on objective measures of underlying AD pathophysiology, including tau tangles and amyloid.
Although Study 301 failed to meet its primary and secondary objectives, Biogen and the FDA jointly concluded that it does not represent evidence that aducanumab is ineffective.
During the meeting, Billy Dunn, MD, director, Office of Neuroscience, Office of New Drugs, Center for Drug Evaluation and Research, FDA, said the discordant results of Study 301 can be explained. Using multiple methods, participants in Study 301 who received 10 mg/kg had clinical outcomes similar to those in Study 302, he said.
Dunn also noted that in this study's high-dose group, clinical outcomes were substantially affected by an imbalance in a very small number of "rapidly progressing" participants.
Committee members learned that high-dose aducanumab had an acceptable safety profile. Amyloid-related imaging abnormalities (ARIA) were the most common adverse event, but these were mostly asymptomatic and transient.
However, in the end, the advisory panel was unconvinced and thought the evidence of efficacy from Study 302 wasn't strong enough. Of 11 committee members, one voted in favor of recommending the drug for approval, eight voted no, and two were uncertain.
Panel members voiced numerous concerns about Study 302. These included the change in the study's protocol, the fact that not all participants completed the study, and potential unblinding of patients with ARIA, inasmuch as ARIA requires additional imaging. Some also questioned the statistical conclusions and consistency of the evidence.
In Study 103, safety and tolerability were primary outcomes, and it also had two efficacy endpoints. This study was relatively small and was conducted only in the United States. Results from this trial showed the high dose yielded a statistically significant clinical benefit, as well as dose- and time-dependent effects on brain amyloid plaque levels. These results support the high-dose results from Study 302, said Dunn.
Despite this, none of the panel members agreed that Study 103 provided supportive evidence for aducanumab in AD. None voted in favor, and four members were uncertain.
"Since I don't think study 302 provides solid evidence of the effectiveness of the drug, it's challenging for me to think that study 103 provides supportive evidence," said Aaron S. Kesselheim, MD, associate professor of medicine, Harvard Medical School, Boston, Massachusetts.
He and others noted that Study 103 was not powered to determine efficacy. Some committee members said they didn't view this study as adequate or well controlled and that it was certainly not confirmatory.
Effect on Tau "Murky"
Alexander noted that effectiveness lost statistical significance after patients who were taking other AD medications were excluded and that there was a lack of a "strong dose-response relationship."
Regarding the strength of evidence of the pharmacodynamic effect of aducanumab on AD pathophysiology, five panel members agreed that the presented evidence was strong. Six were uncertain.
Most members acknowledged that the drug engages amyloid, but many felt the impact on tau was more difficult to understand.
"While I think the biomarker profile in terms of amyloid is very elegant and compelling, it becomes a little bit murky in terms of tau," said Madhay Thambisetty, MD, PhD, senior investigator and chief, Clinical and Translational Neuroscience Section, National Institute on Aging, and adjunct professor of neurology, Johns Hopkins University School of Medicine
When asked to vote on the strength of the evidence as a whole, the committee members believed there was not enough evidence to support approval of aducanumab as an AD treatment.
The FDA is expected to make a final decision on aducanumab's approval by March 7, 2021.
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Cite this: Aducanumab's Road to Approval Blocked - Medscape - Nov 09, 2020.