According to an analysis published in the journal Alzheimer's & Dementia, Biogen and Eisai's anti-amyloid beta drug candidate aducanumab, which is set to be discussed at an FDA advisory panel meeting on November 6, should undergo a third Phase III study to determine its potential benefit to patients with Alzheimer's disease. Aducanumab is currently being assessed by the FDA under a priority review based on a controversial post-hoc evaluation of the arrested Phase III EMERGE and ENGAGE trials.
However, the authors of the latest analysis, led by David Knopman, said the drug's "efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes." Knopman, who is a site investigator in the Biogen trials, and also a member of the FDA's Peripheral and Central Nervous System Drugs advisory committee, has been recused from the upcoming meeting.
Biogen and Eisai had discontinued the two identically-designed EMERGE and ENGAGE trials in March last year after a failed futility analysis. At the time, EMERGE was "trending positive," while ENGAGE was "unlikely to meet its primary endpoints" in patients with mild cognitive impairment or mild dementia. However, they later reversed course and revived plans to seek US approval, claiming a new analysis showed that subsets of patients receiving sufficiently high doses of aducanumab demonstrated benefits in both trials.
In the dataset from March 2019, high‐dose aducanumab in EMERGE had shown benefits on the primary outcome of Clinical Dementia Rating Scale - Sum of Boxes (CDR‐SB), and on some secondary outcomes, while no benefits were seen for the drug in ENGAGE. Knopman and colleagues, which focused their review on clinical trial design and analysis, noted that "in a disease with high person‐to‐person heterogeneity in progression, obtaining two positive studies is more convincing than just one…Logically, the negative outcome in ENGAGE is as likely to be giving the true message as is the positive result in EMERGE."
Meanwhile, Knopman and colleagues also pointed out that although they had identical designs, EMERGE and ENGAGE still differed in that there were "inevitable variations in execution that introduced heterogeneity," one being duration of exposure to high‐dose aducanumab. In the post-hoc analysis, Biogen said high-dose aducanumab significantly slowed cognitive decline in EMERGE, and although there was still no benefit in ENGAGE, the company attributed the difference to mid-study protocol changes that had raised dosing and disproportionately benefitted EMERGE participants.
Knopman and colleagues said the post hoc analysis also highlighted another important difference between EMERGE and ENGAGE, namely that the placebo groups in the two studies performed differently, with less progression occurring in the placebo group of ENGAGE compared to EMERGE. The co-authors described this finding as "perplexing," but they believe that "most likely, it represents random variation, which in turn arose due to the inevitable heterogeneity of the [Alzheimer's disease] biological phenotype in mildly symptomatic disease." They suggested that the "larger decline in the placebo group in EMERGE is an alternative explanation for statistically significant benefits for high‐dose aducanumab in that trial."
Further, they pointed to evidence from tau positron emission tomography (PET) studies performed in a small number of participants, including 11 placebo, 14 low‐dose, and 11 high‐dose participants, as potentially being relevant to the efficacy claim. "While a dose‐related reduction in tau by PET is intriguing and is further support for target engagement, the small sample size coupled with the enormous heterogeneity in cognitive outcomes makes it difficult to know whether this biomarker can be a surrogate for cognition," they said.
The authors concluded that the data from EMERGE and ENGAGE as they have so far been presented by Biogen "do not support the [claim] that aducanumab has clinical benefits." Further, while post-hoc analyses suggest there may be a benefit, the data are "unreliable, but are a legitimate rationale for undertaking a definitive, third Phase III trial optimally designed and adequately powered to prove efficacy," they said.
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