EMERGE study analysis shows Aduhelm slows decline in early Alzheimer’s disease
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Aduhelm demonstrated a consistent treatment effect for slowing decline in cognitive, functional and behavioral domains among patients with early Alzheimer’s disease in item-level analysis of the phase 3 EMERGE study.
Results from this analysis demonstrated consistency with results from the primary analysis of clinical endpoints for Aduhelm (aducanumab, Biogen/Eisai), according to the study results. Researchers presented results from the item-level analysis at the Alzheimer’s Association International Conference.
“This research was prompted by an interest in exploring the clinical benefit of the individual items and domains that comprise the clinical scales used in the phase 3 [Aduhelm] EMERGE study,” Sharon Cohen, MD, FRCPC, medical director of the Toronto Memory Program, told Healio Neurology. “This item-level analysis was descriptive in nature and performed on the [intention to treat] population.”
Earlier this year, a piece published in the Ideas and Opinions section of Annals of Internal Medicine called the approval of Aduhelm as one of the FDA’s “most controversial [approvals] ever.” The authors cited concerns about the use of the accelerated approval pathway for Aduhelm, in which the FDA approves a drug based on its effect on a surrogate marker of disease, and the impact Aduhelm could have on drug development. Specifically, the authors criticized the FDA’s willingness to accept amyloid as a surrogate marker, which could prompt Biogen and other companies “to seek approval for other drugs that reduce levels of amyloid or other biomarkers but have unclear clinical benefits.”
Questions about the efficacy and safety of Aduhelm first arose late last year, when an FDA advisory committee decided not to recommend approval for the agent, and continued when the drug was approved earlier this year, with questions still unanswered about the drug’s safety and efficacy. The FDA has also called for a federal investigation into the approval of Aduhelm, citing concerns about contacts between representatives from Biogen and FDA during the review process, including some that may have occurred outside the formal correspondence process.
Results demonstrate ‘consistency of benefit’
In the findings presented at the Alzheimer's Association International Conference, Cohen and colleagues aimed to analyze the treatment benefit of high-dose Aduhelm across individual items and domains outlined for the primary, secondary and tertiary clinical endpoints in the EMERGE trial. The EMERGE trial included 1,643 individuals aged 50 to 85 years with confirmed presence of amyloid pathology as well as mild cognitive impairment or mild dementia consistent with stage 3 and stage 4 of AD.
Participants received Aduhelm or placebo via IV infusion every 4 weeks over 76 weeks, for 20 doses in all. The researchers randomly assigned participants to receive high doses or low doses of Aduhelm or placebo. Changes from baseline to week 78 in the Clinical Dementia Rating (CDR) Sum of Boxes score served as the primary outcome. Secondary outcomes included scores for the Mini-Mental State Examination, the AD Assessment Scale, cognitive subscale of 13 items (ADAS-Cog13), and the AD Cooperative Study-Activities of Daily Living-Mild Cognitive Impairment (ADCS-ADL-MCI). The 10-item Neuropsychiatric Inventory Questionnaire (NPI-10) served as a tertiary clinical outcome measure.
The trial included 547 patients who received high-dose Aduhelm and 548 patients who received placebo. Study results showed consistency between the two groups regarding age (mean, 70.6 years in the Aduhelm group vs. 70.8 years in the placebo group), sex (women, 52% in the Aduhelm group vs. 53% in the placebo group) and race (white, 77% in the Aduhelm group vs. 79% in the placebo group; Asian, 8% in the Aduhelm group vs. 9% in the placebo group).
At week 78, study results showed evidence of treatment effects across all six domains of the CDR score. This evidence included a decrease in decline on the ADAS-Cog13 items “that are sensitive to change in early symptomatic [AD],” such as word recognition, orientation, immediate and delayed word recall and number cancellation, according to the study results. The researchers observed the clinical benefit of Aduhelm in preserving daily function across “a broad range” of items on the ADCS-ADL-MCI.
Treatment with Aduhelm also correlated with a decrease in behavioral and psychiatric symptoms of AD as measured by the NPI-10.
“This consistency of benefit was present across all clinical aspects of AD (ie, cognition, function and neuropsychiatric symptoms), with no one particular domain or limited group of items, and no one source of information (direct patient testing, caregiver interview or expert clinician judgement) driving the benefit,” Cohen said.
Analysis addresses questions about Aduhelm
The findings are relevant to questions that remain about Aduhelm following the drug’s approval, according to Cohen.
“The FDA accelerated approval of [Aduhelm] focuses attention on [its] ability to lower beta-amyloid, a key pathology in [AD]. Clinical benefit was not addressed in this approval, despite [Aduhelm] having met its primary, secondary and tertiary clinical endpoints in one of its two phase 3 studies (EMERGE),” she said. “There has been speculation that with one positive phase 3 trial and one negative phase 3 trial, there is insufficient evidence for clinical benefit.”
Findings from the item-level analysis of the EMERGE trial address some of these concerns, she continued.
“In this item-level analysis, the high degree of consistency of the treatment effect across clinical items and domains not only provide support for the primary analysis of the clinical endpoints but also provide increased confidence for clinicians that, regardless of the scale used, or the heterogeneity of symptoms in early AD, disease slowing can be expected on a broad range of items relevant to this patient population and their caregivers,” Cohen said. “This is particularly relevant given that clinicians often rely on different scales in day-to-day practice than those used in clinical trials.”
Further clinical study of Aduhelm, including the collection of real-world data and a forthcoming confirmatory trial, “is expected to provide additional support” regarding the clinical impact of high-dose Aduhelm in patients with early symptomatic AD, according to Cohen.
Editor’s note: This article was updated July 28, 2021, to include mention of the controversies surrounding the FDA approval of Aduhelm, for context.
Perspective
Back to TopRebecca M. Edelmayer, PhD
This presentation focused on how to test the different clinical symptoms, behaviors and experiences in patients who were in the clinical trials. The researchers looked at cognitive and behavioral changes in people living with early AD dementia and at the perspective of their caregivers as well.
This disease has an impact on an individual’s activities of daily living, their behaviors and their lifestyle. There is not one single test that will tell anyone that they have AD or not. There are many cognitive and functional tests administered in a clinical trial or even in a thorough examination. Also, the medication may have a slightly different effect in one person compared with another. Everyone has a slightly different experience with AD. In the clinical trial setting, and in an exam, it is important to look at multiple factors that might capture the experience of someone living with dementia and the effects that the medication might be having on their experience.
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Cohen S, et al. Item-level analysis of clinical measures in patients with early symptomatic Alzheimer’s disease following treatment with high-dose aducanumab in the phase 3 study EMERGE. Presented at: Alzheimer’s Association International Conference; July 26-30 (virtual meeting).
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