The journey of aducanumab (Aduhelm; Biogen) from development to the FDA is a tortured one, but its path may serve to teach the Alzheimer disease field valuable lessons as it strives forward to develop disease-modifying therapies.
THE STORY OF ADUCANUMAB-AVWA (Aduhelm; Biogen) is a tortured one.
It started with promise after a phase 1 study in 2016 demonstrated that the drug dramatically reduced amyloid-β peptide levels in the brain and appeared to slow cognitive decline in a dose-dependent manner.1 However, it quickly descended into controversy with a wrongly conceived interim analysis, followed by the agent’s resurrection and favorable treatment by the FDA, its disastrous reception by an FDA advisory committee, and its controversial accelerated approval.2 The rejection by Canada and the European Union and the very restricted coverage offered by Medicare were further blows to the drug. Then, on May 3, 2022, Biogen Inc announced that it was “substantially eliminating commercial infrastructure related to Aduhelm.”3
This review describes a few of the many issues that were part of this chain of events.
Aducanumab is an anti–amyloid-ß (Aß) monoclonal antibody that targets amino acids 3 through 7 of the Aß peptide.4 With the promising phase 1 clinical trial results, Biogen chose to launch 2 large, identically designed, pivotal phase 3 studies dubbed EMERGE (NCT02484547) and ENGAGE (NCT02477800) in 2015. The trials had 3 arms: placebo, low dose, and high dose. Patients were stratified according to APOE genotype. Because of concerns about Aß-related imaging abnormalities (ARIA) especially in the APOE ɛ4 allele carriers, the highest dose in the ɛ4 genotype group was restricted to 6 mg/kg monthly. A dose escalation to 10 mg/ kg for APOE ɛ4 carriers in the high-dose arms was introduced midway through the trials in March 2017.
A preplanned interim analysis for futility was carried out based on data available in December 2018.5,6 Unfortunately, the timing failed to consider the dose escalation, and the findings of this interim analysis led Biogen to terminate the 2 studies in March 2019. According to the interim analysis, ENGAGE failed to show any benefit and EMERGE was trending toward a small clinical benefit.
The fate of aducanumab was revisited when 3 months of additional data became available. The EMERGE study that had been trending positive for the high-dose group showed a statistically significant benefit on the primary outcome measure—the Clinical Dementia Rating Scale sum of boxes—but the results from the high-dose group in ENGAGE continued to show no benefit.
Biogen adopted a strategy after viewing the revised futility analysis that touted the positive EMERGE study and devised several post hoc analyses to demonstrate how the same benefits could have occurred in the ENGAGE study.5 The FDA acknowledged this approach and gave Biogen permission to file a new biologics license application. Biogen presented its version of the results of the 2 trials at a public meeting in December 2019, after which commentators questioned the validity of Biogen’s claims.7,8
The FDA convened a public advisory committee hearing on November 6, 2020. For the record, this writer, who had been a member of the FDA Peripheral and Central Nervous System Drugs Advisory Committee, was recused from that meeting because he was an investigator in one of the aducanumab clinical trials. The position of Biogen, supported by the FDA, was to accept the results of the EMERGE trial as compelling evidence of efficacy and to question the failure of the ENGAGE trial to provide a similar outcome. This was opposite of the usual approach that the FDA takes when presented with studies claiming benefit—because it typically looks for flaws in claims of efficacy. It was even more unusual because the FDA statistician highlighted numerous substantive deficiencies in the 2 trials.9
The FDA advisory committee voted 10 to 0 with 1 abstention to reject the claim that aducanumab showed substantial evidence of effectiveness.10 The combination of the small effect size in the nominally positive EMERGE trial and the null result in the ENGAGE trial clearly did not provide confidence for clinical benefits. Moreover, from an interpretive perspective, it should be the totality of the results from both studies that counts. Taking the 2 studies jointly, either by frequentist11 or Bayesian12,13 statistical analyses, compelling evidence for benefit from aducanumab was not demonstrated by these phase 3 trials.
The conflicting results did not meet the usual FDA standards of convincing evidence of efficacy, as eventually acknowledged by the agency.14 On the other hand, the findings from the EMERGE trial clearly justified pursuing development of aducanumab by conducting another trial with the 10 mg/kg dose that took advantages of the lessons learned. That did not happen.
Six months after the advisory committee meeting, the FDA announced in June 2021 that it was granting aducanumab accelerated approval based on the dramatic reduction in Aß levels at the high dose. Based on the belief that the strength of the amyloid cascade hypothesis was sufficiently compelling, the FDA stated that it was reasonably likely that Aß lowering would result in clinical benefits.15 Accelerated approval was a strategy given to the FDA by Congress to speed up access to medications when a drug showed promising results but the time frame for obtaining definitive evidence of efficacy was felt to be too long, and it has been used in cancer treatments with mixed success.16 Biogen agreed to perform a phase 4 trial as part of the accelerated approval decision, but the status of this trial is now in doubt with the announcement in May 2022 about the company’s elimination of the aducanumab program.
The basis for the accelerated approval decision by the FDA was the prediction that reduction in brain Aß was reasonably likely to provide clinical benefit at some point in the future.14 The amyloid cascade model of Alzheimer disease (AD) asserts that Aß is the key molecule in the development of the neurodegeneration in AD.4,17 There is no question that dominantly inherited AD is caused by mutations in genes involved in the cleavage of amyloid precursor protein that ultimately leads to Aß deposition.17 In addition, brain Aß level is an outstanding biomarker for AD that tracks its severity and downstream consequences.18
But the ultimate proof of the model lies in therapeutic Aß removal producing clinical benefit. Previously, ß-site amyloid precursor protein cleaving enzyme-inhibitors such as verubecestat showed that Aβ reduction itself does not necessarily result in clinical benefit,19 and clinical benefits were not present with aducanumab despite very robust Aß lowering. Aducanumab is the first of the monoclonal antibodies (mAbs) with potent Aß lowering effects that was subject to an 18-month large-scale trial6; 3 others that dramatically lower Aß have unique molecular targets and may exhibit different outcomes.4 We will learn within the next year whether other anti-Aß mAbs that induce substantial Aß lowering produce clinical benefits, which in turn would support this mechanism of action as a therapeutic strategy. Prior anti-Aß therapies that barely reduced Aß20 may be inappropriate for claiming failure of the amyloid-lowering model as many earlier trials lacked confirmatory information on the presence of Aß pathology in the study cohorts.
A few weeks after the FDA’s accelerated approval decision, the Centers for Medicare & Medicaid Services (CMS) announced the initiation of a review of coverage for aducanumab therapy. The CMS decision was more complicated because the agency chose to address anti-Aß mAbs as a class.
While the saga of aducanumab was playing out, the other 3 anti-Aß mAbs were moving through the phase 3 pipeline, with results expected to be reported at the end of 2022 or early 2023. Their outcomes will be equally as or more important than aducanumab because those agents and their sponsors are in the position of seeking regular FDA approval. One of them, gantenerumab, uses a subcutaneous route of administration.21 Another one, donanemab, for which phase 2 results were reported in 2021,22 was so effective in lowering brain Aß that it was discontinued in a large number of patients within the first year because their brain Aß levels had decreased into the background range. The third drug, lecanemab, which also has reported phase 2 results,23 has a lower rate of amyloid-related imaging abnormalities (ARIA) than others in the class; however, lecanemab’s ARIA rate must be viewed with caution due to a restriction on using the highest dose in APOE ɛ4 carriers in the phase 2 trial.
In the final CMS decision memo issued April 7, 2022,24 Medicare agreed to provide coverage for aducanumab or any other agent in the class that was approved on the basis of accelerated approval, but only in the setting of a randomized, controlled trial. This effectively made aducanumab accessible on a very limited basis in the United States. CMS stated that for other anti-Aß mAbs that obtained regular FDA approval based on clinical efficacy, coverage would be available in the context of prospective observational registries. It is not entirely clear how restrictive or expansive access might be in the CMS-mandated observational registries. Further, CMS restricted coverage to persons with mild cognitive impairment and mild dementia due to AD.
The CMS decision reflected a much greater concern about the adverse consequences of aducanumab treatment, mainly ARIA. Approximately 40% of those treated with aducanumab experienced some form of ARIA, with higher rates in APOE ɛ4 carriers.25 Most ARIA edema (ARIA-e) occurred within the first 8 doses of treatment. The number of serious complications from aducanumab-related ARIA was low (1.4%).25 If ARIA-e is promptly recognized and aducanumab therapy paused or discontinued, ARIA-e often will resolve spontaneously over weeks to months. In many patients, aducanumab can be restarted without recurrence of ARIA-e.
Microhemorrhages are a different matter. Microhemorrhages occur in untreated persons with AD dementia—at a rate of 6.6% in the placebo groups in the aducanumab trials—but at 3 times that rate in aducanumab-treated patients.25 Excess microhemorrhages were typically associated with ARIA-e. Although there is no evidence on how many new microhemorrhages represent a higher risk of future macrohemorrhage in the context of anti-Aß mAb treatment, caution would dictate that if even a few new microhemorrhages occur, an anti-Aß mAb should be permanently discontinued.
Appropriate-use recommendations have been formulated that call for a conservative approach to screening for cortical microhemorrhages or other lesions indicative of amyloid angiopathy and that 3 T MRI should be performed every 12 weeks for the first year after initiating aducanumab treatment.26,27 The concern of both proponents and opponents of aducanumab use is that the level of neuroradiological expertise available in the clinical trial setting (with skilled central readers) is not readily available even in academic settings outside a clinical trial and would likely be unavailable in community care settings. If ARIA-e were overlooked and dosing continued, a rapid expansion of the area of edema may become life threatening. Therefore, if aducanumab were prescribed, a high level of neuroradiological expertise must be engaged.26,27 This necessarily places some constraints on where it would be feasible to administer aducanumab and who could prescribe it—a restriction that will apply to other agents of the class as well.
The decision by Biogen to suspend commercialization of aducanumab would appear to seal the agent’s fate. If none of the other anti-Aß mAbs show benefit, that will raise serious questions about the conceptual model on which therapy with anti-Aß mAbs is based and seriously threaten the future of this class of treatments. On the other hand, if at least one of the other drugs shows a benefit on clinical grounds, the debate will shift to the magnitude of the clinical benefit in relation to risks.
A genuine clinical benefit, however modest, would be a powerful selling point for a successful anti-Aß mAb. This writer hopes that these future discussions will be conducted in a thoughtful and collegial manner. A full appraisal of the evidence must be the starting point, but weighing the benefits vs the risks is a matter of judgment that should be dictated by the needs of our patients.28
The sudden realization that there may be a therapy that could be prescribed to a large number of patients with mild cognitive impairment and AD in the US revealed a striking lack of preparedness and highly unequal access in our health care system. There are not enough dementia care specialists with the expertise to make an accurate diagnosis and manage aducanumab therapy.29 There are also unmet needs for infrastructure that will limit access in underserved rural areas and in diverse urban communities, including prompt access to 3 T MRI scanners, infusion centers, and neurological intensive care units in the rare instances when ARIA becomes symptomatic in a serious way. Addressing these challenges will be a necessary step forward for the care of this patient population, regardless of what the future hold for the anti-Aß class of medicines.
Correspondence to: David Knopman, MD, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905
Disclosures: Knopman serves on a data safety monitoring board for the DIAN study. He served on a data safety monitoring board for a tau therapeutic for Biogen but received no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Eli Lilly, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics Inc, Magellan Health Inc, and Alzeca Biosciences Inc but received no personal compensation. He receives funding from the National Institutes of Health.