Controversial Alzheimer Disease Drug Aducanumab Is Approaching a Decision From the FDA: Here’s What You Need to Know

Author: Matthew Schrag, MD, PhD
Vanderbilt Memory and Alzheimer’s Center
Vanderbilt Brain Institute
Vanderbilt University Medical Center Department of Neurology
Nashville, Tennessee
www.SchragLAB.com

For over two decades, numerous pharmacologic programs for Alzheimer disease (AD) have developed approaches to immunologically remove β-amyloid plaques from the brain. Initial efforts to vaccinate patients against β-amyloid were promising and innovative, but ultimately too toxic to be a viable clinical strategy.

Since then, so-called “passive immunization,” or administration of specific antibodies against β-amyloid, has been the leading strategy. Several of these antibodies showed promising early results and several have markedly lowered β-amyloid levels in the brain as measured by positron emission tomography (PET) imaging, but all, so far, have failed to convincingly improve cognition.

There also remain some safety concerns, as many of the candidate antibodies cause a meningoencephalitis in a significant minority of patients. Biogen’s aducanumab is the first of these antibodies to make a credible case to the US Food and Drug Administration (FDA) that it may improve cognition which, if true, would be a historic breakthrough. It would be the first FDA-approved drug for AD since 2003 and the first ever disease-modifying drug for AD. Unfortunately, the development of aducanumab has been plagued by complexities and controversies which jeopardize its approval. A final decision is expected in June 2021.

Aducanumab binds to aggregated clumps of β-amyloid and was discovered from a lymphocyte library developed from elderly people with excellent memory. After a dose-finding study, Biogen initiated a phase 2 trial called PRIME in 2012 which convincingly showed target engagement by lowering β-amyloid levels on amyloid-PET scans.¹ Two phase 3 trials were initiated, named EMERGE and ENGAGE, each of which initially planned to enroll 1350 patients with mild cognitive impairment and positive amyloid-PET scans. The study enrollment was later increased to more than 1600 patients each.

Prior to announcements of the results of both phase 3 trials, Biogen announced promising results from a phase 2 trial of another anti-amyloid antibody in their portfolio, BAN2401 (now called lecanumab). The results were initially greeted with great optimism, but once detailed results were released, it became clear that patients with an apolipoprotein E ε4 allele, a genetic risk factor predisposing them a more-aggressive course of AD, were preferentially placed in control and low-dose groups due to regulatory requirements, biasing the study toward a favorable outcome. This embroiled Biogen in controversy shortly before initial results from the phase 3 trials of aducanumab were reported.² At the interim analysis, both trials were halted for futility—a decision that was made because, while EMERGE was trending favorably, ENGAGE was not, and the pre-specified requirement for continuation was that both were trending positively.

On later reevaluation, Biogen announced the premature termination was an incorrect decision and that in the final analysis, there was a positive result for EMERGE. While ENGAGE did not meet primary efficacy endpoints, Biogen felt there was enough evidence in subgroup analyses to build an argument for efficacy based on the patients in the highest dose group who had received the longest duration of therapy.³ This subgroup contained 288 patients, which comprised roughly half of the intention-to-treat group. Both studies demonstrated significant reduction in β-amyloid levels on amyloid-PET scans, so differences in target engagement do not appear to explain the heterogenous results. Numerous voices have raised concerns that the heterogeneity of this result is insufficient to prove the efficacy for aducanumab,⁴ and the FDA’s scientific advisory committee concurred with this concern in a November 2020 vote.  

Importantly, a remarkable 35% of treated patients developed cerebral edema called Alzheimer-Related Imaging Abnormality-Edema (ARIA-E), and about 18% had bleeding associated with the swelling. The concerns around this adverse effect have been widely downplayed, but the long-term risk of vascular cognitive impairment and/or intracerebral hemorrhage among patients who experience ARIA-E is not well understood and could be substantial.

In my opinion, the equivocal results of the aducanumab trials should not be interpreted blind to the failures of similar antibodies: Ponezumab, bapineuzumab, solanezumab, crenezumab, and gantenerumab. These antibodies all failed to slow progression among patients with AD. In response to repeated failed clinical trials, treatment at increasingly earlier timepoints was attempted, but continued to fail.

Finally, the ambitious DIAN-TU trial evaluated pre-symptomatic treatment with gantenerumab or solanezumab vs placebo among patients with a dominant genetic mutation causing them to develop AD. Genetic AD is rare, but is the form that is most similar to our animal models and with the pre-symptomatic treatment paradigm, many experts felt this was best opportunity to demonstrate the efficacy of anti-β-amyloid immunotherapies. However, again, both arms of this trial failed show an improvement over placebo. Multiple high-quality trials have convincingly reduced brain β-amyloid levels without a benefit in cognitive trajectory. This background should lead to a cautious interpretation of the equivocal data around aducanumab. The efficacy of aducanumab should not be in doubt prior to FDA approval.

Several patient advocacy organizations, including the Alzheimer’s Association and UsAgainstAlzheimer’s⁶, have strongly promoted FDA approval of aducanumab, going so far as saying it would be “a black eye” on the FDA if the drug is not approved. In a recent letter, the President of the Alzheimer’s Association wrote: “We believe the accumulated science, the publicly released data on aducanumab and the absence of other treatment justifies FDA approval, accompanied by a Phase 4 post marketing surveillance study.”

These organizations do important work. Nevertheless, I would argue that proving the efficacy and safety of aducanumab is Biogen’s responsibility; accomplishing this in a phase 4 post marketing surveillance study will not have the same level of rigor and transfers the risk and the cost of validating this drug to our patients. This may be aligned with corporate interests, but not the health and well-being of our patients. Aducanumab may well be the first disease-altering drug for AD, and I hope it is, but for the sake of our patients, it should not be approved until its efficacy has been demonstrated in a new, complete clinical trial.

References:

1. Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50-56. doi:10.1038/nature19323
2. Carroll J. Eisai, Biogen battered by controversy over PhII Alzheimer's study after posting positive results. EndpointsNews. Published July 25, 2018. Accessed February 16, 2021. https://endpts.com/eisai-biogen-outline-an-impressive-30-and-47-advantage-for-their-alzheimers-drug-ban2401/
3. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease. Biogen. https://investors.biogen.com/static-files/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb
4. Knopman DS, Jones DT, Greicius MD. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer Dement. Published online November 1, 2020. doi:10.1002/alz.12213
5. UsAgainstAlzheimer’s. Letter to FDA. January 19, 2021. Accessed February 16, 2021. https://www.usagainstalzheimers.org/sites/default/files/2021-01/UsA2-FDA%20re%20aducanumab%20review%201-19-21%20%28002%29.pdf