On June 7, 2021 the FDA granted accelerated approval for aducanumab for the treatment of symptomatic Alzheimer disease. This decision was based on data from two unpublished phase III trials. In the approval release the FDA stated “accelerated approval can be based on a drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit for patients, with a required post-approval trial to verify that the drug the expected clinical benefit.”

The “amyloid cascade hypothesis” of Alzheimer disease posits that aggregated amyloid beta (Aβ) peptide causes injury to neurons in the brain. If true, then removal of this Aβ peptide should slow clinical progression or improve clinical deficits in patients with Alzheimer disease. To date this hypothesis has not been borne out in clinical trials of agents targeting Aβ, including monoclonal antibodies such as aducanumab.

Currently the only published clinical trials of aducanumab are phase 1 trials (primarily assessing safety, tolerability and pharmacokinetics) from 2016. In the first trial, 164 patients with mild dementia due to Alzheimer disease were treated with one of four fixed doses of aducanumab, ranging from one to 10 mg/kg of a single dose intravenously vs. placebo. The results of this small trial suggested adequate safety and tolerability of this medication in this dose range, setting the stage for more formal clinical trials. The second trial, with 53 patients, showed that doses up to 30 mg/kg may be safe but a dose of 60 mg/kg resulted serious amyloid related imaging abnormalities (ARIA).

Biogen subsequently undertook two similar 78-week phase III trials of aducanumab, EMERGE and ENGAGE, neither of which is published as of June 25, 2021. Data for this blog article comes from commentary articles reporting on a presentation of data in December 2019. Individuals with mild cognitive impairment or mild dementia with cerebral Aβ deposits seen on PET imaging (implying Alzheimer pathology) were included in these parallel group, double-blind placebo-controlled studies. The primary outcome was change in the Clinical Dementia Rating Scale® Sum-of-Boxes (CDR-SB), which is a commonly used scoring system in dementia trials. This is a clinical rating scale with a total score range from zero (no impairment) to 18 (severe impairment). Analysis of this scale suggested that a one to two-point increase in this score is indicative of a meaningful decline.

Because of concerns for ARIA-edema occurring in persons on high doses and in apolipoprotein E (APOE) epsilon 4 carriers, these studies were initially designed to test lower doses up to six mg/kg of aducanumab. However, these studies were modified partway through based on failure of lower dose trials in other agents and recognition of a relatively benign course in most ARIA-edema cases. Several protocol amendments were instituted by Biogen including raising the titrated dose to 10 mg/kg in the APOE epsilon 4 carrier group. Despite this, the timing of prespecified futility analysis was not shifted. In March 2019 Biogen announced that the trials were being halted based on the prespecified futility analysis (i.e. aducanumab was not effective).

In October 2019 Biogen issued a press release with a reanalysis of the aducanumab dataset including data collected after the futility analysis –– now reporting a clinical benefit of aducanumab in both trials. Selective data from this analysis was then presented at an international meeting in December of 2019 making efficacy claims for high-dose aducanumab (10 mg/kg) in both trials. A submission to the FDA was made by Biogen in July 2020.

In the reanalysis of the EMERGE trial, high-dose aducanumab showed benefits on the primary outcome (CDR-SB) and two secondary outcomes (Mini-Mental Status Examination and Alzheimer’s Disease Assessment Scale-Cognitive-13 item scale) but low-dose aducanumab did not.  In the reanalysis of the ENGAGE study, no clinical benefits were seen for either low- or high-dose aducanumab compared to placebo. Biogen engaged in extensive post hoc exploratory analyses to try to explain the discordance in clinical outcomes between the two studies. However, there is high risk of such analyses given the multiple variables involved. Reportedly, the trials differed in the number of patients and the number of doses of high-dose aducanumab administered –– a difference that Biogen has used to justify the discordance between the two studies. Both studies reported differences for CDR-SB for high-dose aducanumab were in the range of 0.26–1.02, being at best at the low end of a clinically important difference. Whether these results and confidence intervals will persist in final published reports is unknown.

In both trials, a dose-related reduction in brain amyloid beta was seen in amyloid PET imaging, leading the FDA to comment on this surrogate endpoint in their approval. However, it remains unclear whether clearing of amyloid burden from the brain translates into clinical improvement or stabilization of functional decline meaningful to patients and families.

At present we are left with two complex studies that are not concordant for outcomes and have been extensively reanalyzed in post hoc analysis. Further, they have not been reported in a form that enables wide-spread critical review.  Unpublished data by its nature is incomplete, not peer-reviewed, has a high risk of bias, and should be used for clinical decision-making only with great caution. Finally, even if we disregard these issues, the reported results are equivocal at best.

The FDA approval places clinicians in the difficult position of having to counsel distressed and desperate patients and families on the use of expensive medications with as yet uncertain clinical efficacy. The lack of guidance on who should receive the treatment (e.g., patients with very mild or mild dementia due to Alzheimer disease, or all patients with symptomatic Alzheimer disease), further complicates matters. Additional phase IV trials with high dose aducanumab and longer and more complete follow up are clearly required to guide management decisions and may affect the FDA ruling in the long run.