A recently published critique of aducanumab's trial results calls for a third and definitive phase 3 study of the investigational agent, which is awaiting a decision from the FDA.
David S. Knopman, MD
A perspective piece recently published in Alzheimer’s & Dementia is calling for a third and definitive phase 3 trial of aducanumab, the investigational—and somewhat controversial—anti-amyloid agent developed by Biogen and Eisai for the treatment of Alzheimer disease, suggesting that the proposed efficacy of the therapy based on available data from a pair of phase 3 trials is unclear.1
The drug’s future is 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.2
The commentary, authored by David S. Knopman, MD, professor of neurology, Mayo Clinic; David T. Jones, MD, assistant professor of neurology and radiology, Mayo Clinic; and Michael D. Greicius, MD, MPH, associate professor of neurology and neurological sciences, Stanford Hospital and Clinics, posits that although biomarker data from the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) clinical trials were consistent with target engagement, no evidence has been presented to correlate biomarker changes to cognitive benefits.
Although it is possible that the therapy offers cognitive benefits, the existing data are “clearly insufficient to support a claim of efficacy,” the authors wrote, noting that even when looking past the distortions brought on by the premature termination of the trials, the finding of 1 positive and 1 negative result from the 2 trials “is a statement of inconclusiveness.”
Knopman, who is a site investigator in the aducanumab trials, and colleagues noted that the placebo groups in the 2 trials performed differently, with less disease progression occurring in the ENGAGE group compared with those in EMERGE, a fact they called “perplexing, but obviously” not associated with active treatment. Additionally, the greater proportion of placebo patients in ENGAGE (60.9%) who completed the full 78-week treatment period compared with those who completed the period in EMERGE (52.6%) does not allow for a greater duration of observation to account for EMERGE’s greater placebo decline. This, they wrote, most likely “represents random variation.”
“The key point is this: The larger decline in the placebo group in EMERGE is an alternative explanation for statistically significant benefits for high‐dose aducanumab in that trial,” Knopman et al. wrote. “Similarly, in the ENGAGE analyses limited to participants exposed to the full 14 sets of infusions for those randomized to the high dose, it was the larger placebo group decline (–1.79 vs –1.55 [Clinical Dementia Rating-Sum of Boxes (CDR-SB)] points) that contributed to the larger point estimate together with a larger confidence interval for the high‐dose aducanumab versus placebo difference compared to the ENGAGE intention-to-treat analysis.”
In addition, Knopman et al. noted that although biomarker data of amyloid-beta levels did show a clear dose-related lowering of those levels as measured by positron emission tomography (PET), the larger decline observed in the EMERGE high‐dose group—which the authors noted may have had a beneficial effect on cognition—was not observed in the ENGAGE high‐dose group. They conceded that this could be due to a nonlinear effect in this reduction, though this hypothesis remains unsupported independently.
As well, the authors wrote that the dose-response relationship observed in medial temporal tau accumulation, which was measured with tracer MK6240 in 36 participants (placebo, n = 11; low-dose, n = 14; high-dose, n = 11), also was not noted alongside any data correlating it with cognitive performance.
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“As clinicians, we experienced the disappointment firsthand—though not as directly as did the patients and families we care for—when Biogen halted the aducanumab trials in March 2019,” Knopman et al. wrote, referencing the decisions made based on a futility analysis that were later reversed when the trial sponsors announced results from an expanded analysis in October 2019. “However, our analysis of the data presented subsequently by Biogen leaves us uncertain whether aducanumab has efficacy for treating Alzheimer disease. The pending FDA decision will be monumental for our field. The stakes for offering genuine benefit for our current patients, for future health economics, and for future clinical trials in Alzheimer disease, could not be higher.”
In response to Knopman and colleagues’ article, 2 of the drug’s key investigators, Marwan N. Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, and Jeffrey L. Cummings, MD, ScD, director emeritus, Cleveland Clinic Lou Ruvo Center for Brain Health and vice-chair, department of brain health, University of Nevada–Las Vegas, published their own take in the journal.3 Ultimately, they wrote that the data warrant approval with accompanying phase 4 surveillance, a stance that has been endorsed by the Alzheimer's Association.4
The pair also pointed out that “the results of the aducanumab studies have not been published in peer‐reviewed form and both the analysis presented by Dr. Knopman and collaborators and this perspective are based on data presented in 2019 at the Clinical Trials in AD (CTAD) meeting; both discussions must be seen as tentative until full data are available.”
Sabbagh and Cummings elucidated their point further, noting that the analysis of EMERGE and ENGAGE is complex, and pointed to the small dose-related decreases in cerebrospinal fluid (CSF) tau and the significant dose- and time‐related reductions in amyloid PET as suggesting that “engaging and removing insoluble amyloid plaques and amyloid oligomers is followed by ‘downstream’ effects on markers of p‐tau and tau PET associated with neurofibrillary tangles. The biomarkers support a disease‐modifying effect of aducanumab.”
As well, Sabbagh and Cummings noted that the clinical effects may be secondary to additional actions extending past amyloid removal, such as reductions in tau, inflammation, and improved milieu health, among others.
In their perspective, Knopman et al. wrote with regard to the CSF data that “except by association with one trial versus the other, there was no direct evidence presented that showed that CSF tau levels correlated with cognitive outcomes.” In light of these inconsistencies and a missing link to cognitive outcomes, the claim of efficacy is unsupported, and the claim of target engagement is supported on uncertain terms.
Sabbagh and Cummings concluded their response article with the larger point that aducanumab’s approval could “represent the beginning of the modern treatment era for Alzheimer [disease],” comparing the possibility to the approvals of statins and early HIV treatments.
“This is not a cure but the first incremental step in transforming the disease from an untreatable terminal illness to a manageable chronic disease. Advancing aducanumab forward toward approval could pave the way for other monoclonal antibodies and therapeutic interventions,” they wrote, adding that no approval would be a devastating moment for patients, advocates, and the larger Alzheimer disease community—denying access to any benefit from aducanumab. They added that a potential denial “will have a chilling effect on investment in Alzheimer disease research and development.”
This sentiment was echoed to NeurologyLive in a recent conversation with Howard Fillit, MD, founding executive director and chief science officer, Alzheimer’s Drug Discovery Foundation, who was not part of the clinical trials. Fillit noted that the work with aducanumab, in the end, represents progress—something he welcomes for the treatment of Alzheimer disease after years and years of failures in the 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,” Fillit told NeurologyLive.
Aducanumab has undergone a rather turbulent journey on its road to regulatory review. After a futility analysis published in March 2019 showed that the therapy missed its primary end point—change in the CDR-SB score in patients with mild cognitive impairment (MCI) due to Alzheimer disease and mild Alzheimer dementia—an about-face came in October 2019 when an additional analysis of the EMERGE dataset reportedly showed statistically significant changes on the CDR-SB score, with P values of .010 or .031 based on cutoff dates.5 That analysis 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 2020, 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.
“The protocol of the re-dosing study that aims at offering access to aducanumab to all eligible patients who were actively enrolled in the aducanumab studies in March 2019 has been successfully submitted to the FDA,” Biogen said in a statement to NeurologyLive at the time. “We are now working with US trial sites to initiate this open-label clinical trial, which does not include a placebo-controlled arm. In the US, we expect the first patients to be re-dosed starting in March of this year.”
An FDA Advisory Committee meeting is scheduled to take place Friday, November 6, 2020, where members will review data and hear statements from the clinical community and the public, ultimately culminating in a vote for or against recommendation for approval. Stay with NeurologyLive for coverage of the meeting and the latest updates on aducanumab’s journey.
In August 2020, Sabbagh spoke with NeurologyLive about the potential impact of aducanumab on clinical trials in Alzheimer disease. Watch him offer his insight below.