Special Episode: Aducanumab and Anti-Amyloid-ß, One Year Later

Mind Moments™, a podcast from NeurologyLive®, brings you a special episode recap of aducanumab's journey from discovery to present, ahead of the June 2022 issue's in-depth cover story on the topic.

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The pathway through the clinical development pipeline for any therapy is often clear. Drugs are tested preclinically and pharmacokinetically; then into the phases of human testing; and then, once approved, postmarketing data is collected. In Alzheimer disease, few therapies have made it to that point. Many are halted without showing a therapeutic effect. The difficulty in modifying this disease has resulted in the journey of many drugs being complex, sometimes taking two steps forward only to take three steps back. The challenge Alzheimer has posed for the research and development and clinical communities has been a near Sisyphean task, with the growth in knowledge about the disease not yet matched by therapeutic success.

One year ago, on June 7, 2021, the FDA granted special approval to the disease’s first treatment in almost two decades. The therapy acted on a known target for the disease, and it had been assessed in a large, global population of individuals. But the joy of that milestone did not last. In Icarian fashion, aducanumab’s path through the pipeline catapulted it forward with accelerated approval, only to see it fall backward, hampered by controversy and debate.

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Click here for the June 2022 issue of NeuologyLive®, in which the cover story features an in-depth review of the aducanumab saga from David S. Knopman, MD, some of which is featured in this episode.

Transcript to follow.

After being discovered at the University of Zurich, the monoclonal antibody was developed by Biogen, with a 2016 phase 1 study showing that the drug dramatically reduced amyloid-β peptide levels in the brain, and appeared to possibly slow cognitive decline in a dose-dependent manner. With those promising phase 1 clinical trial results, Biogen then launched 2 large and identically designed, pivotal phase 3 studies—EMERGE and ENGAGE—in 2015.

During those trials, concerns were raised about Aß-related imaging abnormalities, known as ARIA, especially in those individuals who were APOE ɛ4 allele carriers. This led to a restriction on the highest dose in the ɛ4 genotype group, followed by a dose escalation was introduced midway through the trials in March 2017. A preplanned interim analysis for futility of data up to December 2018 was carried out, but this failed to take into account the dose escalation. Biogen terminated the studies in March 2019 as a result of the analysis, which showed no benefit in ENGAGE and a trend toward minimal clinical benefit in EMERGE.

One step forward, two steps back.

However, a revised analysis was then conducted after 3 additional months of data became available, showing a statistically significant benefit on the primary outcome measure—the Clinical Dementia Rating Scale sum of boxes—in EMERGE’s high-dose group. But the high-dose group in ENGAGE still lacked evidence of benefit.

With these data and the FDA’s permission to file a new BLA, Biogen presented the revised analysis, along with several additional post hoc analyses, to those gathered at the 2019 Clinical Trials in Alzheimer Disease conference. The results were met with rigorous debate. And this debate continued for several months, culminating in an FDA advisory committee in early November 2020. At this meeting Biogen, with support from the FDA, proposed that the EMERGE trial results were evidence of efficacy, questioning the failure of the ENGAGE to mimic this. The FDA advisory committee then voted, with 10 against 0—with 1 abstention—voting that aducanumab did not show substantial evidence of effectiveness.

The clinical community was left to absorb the results of the committee meeting while awaiting the FDA’s final decision in the following June. Those 7 months were met with continued discussion and debate about the therapy’s potential efficacy, safety concerns, and a pair of conflicting clinical trials. Then, one year ago, the FDA chose to approve aducanumab, now given the brand name Aduhelm, in an accelerated fashion, requiring a phase 4 postmarketing trial to confirm the efficacy that it showed in Biogen’s data.

The decision, again, was met with controversy. Some in the medical community penned articles and offered statements expressing their desire to not use the medication. Others expressed joy at the proposition of patients finally receiving an option after so many years without. This back and forth around the therapy continued for several months, until early April 2022, when, in a decision memo, CMS agreed to provide Medicare coverage for aducanumab or any other agent in the class that was approved on the basis of accelerated approval, but with a caveat. It would cover the drugs only in the setting of a randomized, controlled trial. Furthermore, CMS restricted coverage to persons with mild cognitive impairment and mild dementia due to Alzheimer.

Then, just one month later, Biogen announced that it was “substantially eliminating commercial infrastructure related to Aduhelm.” It pulled the applications it had submitted in the European Union.

One step forward, two steps back.

Aducanumab’s saga is not a sign that the research into Alzheimer or the development of treatments for it are set to slow down. But it does shine a light on something that the field has perhaps been heading toward all of these years. Regardless of its efficacy, it appears that amyloid-ß is just one piece of the puzzle. Alzheimer is a complex, multifaceted disease. It appears that successful treatment for it may need to be the same. I will leave you all today with a snippet of the cover story from the June 2022 issue of NeurologyLive®, in which Dr. David S. Knopman offers a far more in-depth chronicle of aducanumab’s story. From Dr. Knopman:

“The decision by Biogen to suspend commercialization of aducanumab would appear to seal the agent’s fate. If none of the other anti-Aß monoclonal antibodies show benefit, that will raise serious questions about the conceptual model on which therapy with anti-Aß monoclonal antibodies is based and seriously threaten the future of this class of treatments. On the other hand, if at least 1 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 monoclonal antibody. 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.

The sudden realization 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. 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 holds for the anti-Aß class of medicines.”

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This episode featured the songs "Dreams" and "Stronger" by Alan Špiljak, obtained under the CC BY-NC-ND 4.0 license.