Is the First Disease-Modifying Therapy for Alzheimer Disease on the Horizon?

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NEWS BRIEF

The medical science and research company Clarivate has named aducanumab, a potential Alzheimer disease (AD) treatment, as one of its top 5 “Drugs to Watch 2021.”¹ Clarivate, which has published the “Drugs to Watch” list since 2013, included aducanumab on the list because it has a new mechanism of action and would be the first novel therapeutic for AD in more than 15 years. The company selects drugs in phase 2 or 3 trials that have the potential to bring in $1 billion in sales by 2025. Aducanumab is in phase 3 trials, and the US Food and Drug Administration (FDA) has promised to render its verdict in June.

If approved, Helen Lavretsky, MS, MD, expects it will be a game changer. Lavretsky, professor in-residence in the Department of Psychiatry at the University of California, Los Angeles, told Psychiatric Times^TM, “It will revolutionize Alzheimer disease treatment and care, and will have a profound impact on the lives of millions of family caregivers, who will be relieved from caring for their relatives, or the time of caregiving will be shortened, improving lives of millions of people around the world, and reducing the cost of the disease to the society.”

Aducanumab would be the first approved drug in the last 15 years that could slow down the cognitive decline associated with AD. Existing treatments, for cases across the spectrum from mild to severe, are generally symptomatic therapies.

The drug might address a root cause of AD. It builds on the amyloid cascade hypothesis, in which “production and accumulation of excessive amyloid-β (Aβ) may be the main cause in the onset and progression of Alzheimer's disease.”² If so, removing or lowering of Aβ in patients with presymptomatic and early AD could be an effective therapy, and even used as a preventive, subunit vaccine.² 

If approved, Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, noted, “this drug will be the first antiamyloid therapy and disease modifying therapy for Alzheimer disease.” Tampi is professor and chairman of the Department of Psychiatry & Behavioral Sciences at the Cleveland Clinic. Lavretsky described aducanumab as a “breakthrough treatment with a novel mechanism as recombinant chimeric human IgG1 mAb targeting beta-amyloid.”

Excitement is especially strong for the drug since innovation in therapies for AD has been frustratingly slow. The problem, Tampi explained, is that AD is caused by neurological degeneration, and “it is very difficult to develop different therapies to reverse these neurobiological changes in the brain.”

Finding effective treatments has also been difficult due to “uncertainty about the underlying mechanisms of the disease, the reliance on postmortem diagnosis, and the lack of reliable biomarkers for disease early diagnosis and progression, despite almost 120-year history of research,” Lavretsky added. “Many potential therapies failed to document efficacy and did not achieve the FDA approvals.”

Sure enough, despite its promise, aducanumab has had its own set of struggles. Last November brought disappointment, when the FDA published a negative review of aducanumab, citing insufficient evidence of clinical efficacy.³ 

The news was especially disappointing, given aducanumab’s success in previous trials. In 2015, aducanumab underwent two phase 3 efficacy trials.⁴ The 221AD301 ENGAGE study enrolled 1350 participants with mild cognitive impairment due to AD. It compared monthly infusions of 1 or 3 doses of aducanumab with placebo over an 18-month period, and their effects on cognitive decline. In 2017 and 2018, data from the trials showed that the treatment was slowing cognitive decline. Consequently, aducanumab became the first such DMT for AD to demonstrate clinical efficacy in a phase 3 trial.^1,5

However, in March 2019 Biogen and Eisai announced termination of ongoing aducanumab trials, due to missing primary endpoints.⁵ Despite the termination, further analysis of the data suggested that a subgroup of participants experienced slower cognitive decline.⁴

Trials resumed on January 27, 2020, when Biogen announced a phase 3b study of 2400 participants who had previously used aducanumab.⁴ Participants were scheduled to receive monthly injections over the next 2 years. Based on this trial, Biogen requested priority review from the FDA for licensing. The FDA turned down the application in November 2020, citing the weakness of efficacy data.

After aducanumab’s developers, Biogen Inc and Eisai Co Ltd, submitted additional data, the FDA extended its decision date to June 7, 2021.⁶

If approved, aducanumab would meet an enormous need. “It will offer a new hope to patients and their families and therapeutic optimism to geriatric clinicians and researchers,” said Lavretsky.

References

1. Aducanumab. Drugs to Watch 2021. Clarivate. Accessed March 9, 2021. https://clarivate.com/drugs-to-watch/drugs-to-watch-listing/aducanumab/

2. Yu YZ, Xu Q. Prophylactic immunotherapy of Alzheimer's disease using recombinant amyloid-β B-cell epitope chimeric protein as subunit vaccine. Hum Vaccin Immunother. 2016;12(11):2801-2804.

3. Talan J. FDA Panel Votes ‘No’ to Approving Audcanumab for Alzheimer’s, Citing Inconsistent Data. Neurology Today. December 3, 2020. Accessed March 9, 2021. https://journals.lww.com/neurotodayonline/Fulltext/2020/12030/FDA_Panel_Votes__No__to_Approving_Aducanumab_for.1.aspx

4. Aducanumab. Therapeutics. Alzforum: networking for a cure. Accessed March 9, 2021. https://www.alzforum.org/therapeutics/aducanumab

5. Biogen/Eisai Halt Phase 3 Aducanumab Trials. Alzforum: networking for a cure. March 21, 2019. Accessed March 9, 2021. https://www.alzforum.org/news/research-news/biogeneisai-halt-phase-3-aducanumab-trials

6. Biogen and Eisai Announce FDA’s 3-Month Extension of Review Period for the Biologics License Application for Aducanumab. News release. GlobeNewswire. January 29, 2021. Accessed March 9, 2021. https://www.globenewswire.com/news-release/2021/01/29/2166560/0/en/Biogen-and-Eisai-Announce-FDA-s-3-Month-Extension-of-Review-Period-for-the-Biologics-License-Application-for-Aducanumab.html