FDA Under Scrutiny: A Tale of Two Drugs

By Sarah Wade

Alzheimer’s disease (AD) is a devastating illness that gradually destroys the brain. This disease affects over 30 million people worldwide (Haque & Levey, 2019) and is the seventh leading cause of death in the United States (Centers for Disease Control and Prevention, 2022). Patients present with memory deficits and cognitive decline that can affect daily function, making it a debilitating condition for both patients and caregivers. Unfortunately, the underlying cause of AD remains unknown, which makes the disease difficult to diagnose and treat. Looking within the brain reveals two hallmark features of AD: “plaques” (clumps of beta amyloid protein) and “tangles” (twisted strands of tau protein; DeTure & Dickson, 2019). Despite this correlation between the presence of plaques/tangles and AD, the relationship between these cellular changes and patients’ cognitive decline has not been fully established. Once patients are diagnosed with AD, the available treatment options are ineffective at completely halting the disease’s progression. Therefore, there is a desperate need—and a massive financial market—for an effective therapeutic for AD.

The Food and Drug Administration (FDA), the government regulatory agency in charge of evaluating pharmaceuticals for human use, is facing backlash for green-lighting a new class of drugs for treating AD, known as monoclonal antibodies. This new class of drugs, currently composed of aducanumab (Aduhelm) and lecanemab (Leqembi), treats the cellular changes in the brain caused by AD instead of only the symptoms. Although the approval of new treatments is usually heralded as a milestone, many scientists argue that this class of drugs has not been effective in reducing the cognitive effects of AD and carries significant risks.

Prior to the approval of this new class of drugs in 2021, most of the treatment options on the market were aimed at treating the symptoms of AD. These drugs can help patients with mild symptoms, such as misplacing objects or difficulty problem-solving, to moderate symptoms, such as difficulty recognizing friends and family. The most common treatment for AD symptoms involves drugs that help the brain restore the balance of chemicals called neurotransmitters. While these drugs are the most common treatment for AD symptoms, they do not halt or cure the disease and can impose a significant financial burden on patients over many years of treatment.

Aducanumab, approved in June of 2021, was the first novel therapy approved for AD since 2003. Aducanumab introduced a new mechanism to treat AD by reducing the plaques of beta amyloid protein. However, aducanumab was not unique. Since 2018, nine other therapies targeting beta amyloid plaques in a similar manner to aducanumab entered the final stages of human testing—but all nine of these therapies failed, likely due to issues with safety or inability to change patients’ cognitive decline (Kim et al., 2022). So, why did aducanumab get the green light from regulators when so many similar therapies had failed before?

The FDA approval of aducanumab was riddled with controversy from the start. Biogen and Eisai, the pharmaceutical companies that jointly developed aducanumab, began testing the drug in the final stage of clinical trials by 2014 (CNBC, 2014). However, in March 2019, Biogen and Eisai decided to terminate all ongoing clinical trials of aducanumab following an interim analysis of the trial data that suggested the drug would not meet the FDA’s standard for efficacy (i.e., a significant reduction in beta amyloid plaques). Surprisingly, Biogen resumed clinical trials in early 2020, citing that more detailed analyses of the data showed that a higher dose of aducanumab was effective (ALZFORUM, 2022). Biogen also submitted requests for approval to regulatory agencies in the USA, Europe, and Japan.

In response to the request, the FDA convened an advisory panel of eleven experts to weigh in on the decision in November 2020 (expert list and full meeting transcript linked below in references). When put to a vote, ten of the experts voted against approving aducanumab, citing a failure to demonstrate efficacy, and one member abstained from voting. The expert panel believed that one successful trial did not negate the previously unsuccessful trial. In a shocking move, the FDA rejected the experts’ suggestion and approved aducanumab on June 7^th, 2021. The FDA stated that “it is expected that the reduction in amyloid plaque will result in a reduction in clinical decline” (FDA, 2022). After the FDA released their decision, three members of the expert panel quit in protest (Mahase, 2021).

The FDA approved aducanumab through its Accelerated Approval Program. In a press release, the FDA states: “We ultimately decided to use the Accelerated Approval pathway—a pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit” (FDA, 2022). The Accelerated Approval pathway requires additional studies, known as confirmatory trials, that happen in tandem with the drug’s release to the public. If the confirmatory trials do not meet the drug’s anticipated clinical benefit, the FDA can move to withdraw the drug from the market. However, the pharmaceutical companies have nine years to complete these studies—nine years that their drug can remain profitable on the market without demonstrated benefit to patients. Although aducanumab was approved in the US, the drug was rejected by regulatory agencies in Europe and Japan (NICE 2022; Biogen 2021b).

The scientific community’s reaction to aducanumab’s approval in the United States was swift and unforgiving. Rob Howard, a psychiatrist at University College London, believes “the approval of aducanumab represents a grave error that will have only negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade” (Boseley, 2021). Dr. Howard was not the only scientist who felt strongly about the approval – seven of the experts from the FDA’s panel on aducanumab wrote a biting perspective piece in New England Journal of Medicine where they called the approval “a regulatory failure” and called for measures to “ensure that it doesn’t occur again” (Alexander et al., 2021).

Maria C. Carrillo, the chief science officer for Alzheimer’s Association, has a different view. In a statement following the approval announcement, she said, “History has shown us that approvals of the first drug in a new category invigorates the field, increases investments in new treatments and encourages greater innovation. We are hopeful and this is the beginning — both for this drug and for better treatments for Alzheimer’s” (Alzheimer’s Association, 2021). The approval of aducanumab did indeed blaze a path for similar drugs, namely other drugs targeting beta amyloid plaques, to gain approval. One-and-a-half years after aducanumab’s approval, the FDA approved another beta amyloid plaque drug: lecanemab (FDA 2023).

Lecanemab, created by Eisai (also one of the creators of aducanumab), was approved in January 2023 through the same Accelerated Approval Program (FDA 2023). The approval of lecanemab was less controversial than that of aducanumab due to the drug’s stronger efficacy in clinical trials. In addition to reducing the amount of beta amyloid plaques, the drug reversed some of the cognitive symptoms of AD. However, enthusiasm for lecanemab was tempered by concerns about the safety profile; at least three people taking the drug in clinical trials died due to brain bleeds or swelling (Couzin-Frankel, 2023). Regardless, the drug is now on the market and undergoing the same confirmatory studies required of aducanumab.

Despite their approval by the FDA, both aducanumab and lecanemab are fighting to gain the approval of another American regulatory agency: the Centers for Medicare & Medicaid Services (CMS). CMS is the federal agency that administers the nation’s major healthcare programs and serves over 135 million Americans (CMS, 2021). Without the endorsement of CMS to fund the therapies, many adults will not be able to afford the high cost of treatment. For aducanumab, Biogen originally charged close to $56,000 USD per year (Mullard, 2021). However, Biogen recently slashed this price in half—down to $28,200 USD for Americans—in order to compete with lecanemab (Biogen, 2021a). As the cheaper of the two drugs, lecanemab is estimated to cost $25,000 USD per year (Couzin-Frankel, 2023).

The CMS released a statement in April 2022 finalizing their coverage policy for this new drug class less than a year after the approval of aducanumab (CMS, 2022). In the statement, CMS outlined they will cover any therapy of this class that receives traditional approval from the FDA. For any drugs receiving the non-traditional Accelerated Approval, such as aducanumab and lecanemab, the drug will not be covered by CMS outside of clinical trials. This regulatory blow drastically stunted drug sales, which were already weak—in all of 2021, aducanumab brought only $3 million in sales compared with $485 million in selling, general, and administrative costs (Liu, 2022). As a result, Biogen’s CEO stepped down and the company effectively stopped marketing aducanumab (Robbins, 2022).

Although these trailblazing therapies are hitting regulatory bumps during their approval process, this fact has not stifled the new wave of therapies for AD. Currently, there are over 143 unique therapies in clinical trials—of the therapies in final stage clinical trials, 34% target beta amyloid and tau in the same manner as aducanumab and lecanemab (Cummings et al., 2022). In late January 2023, another promising drug against beta amyloid plaques, called donanemab, was rejected by the FDA for Accelerated Approval (Eli Lilly and Company, 2023; Mintun et al., 2021). In contrast with aducanumab and lecanemab, donanemab was rejected for having a limited number of trial participants instead of rejection due to lack of efficacy or safety. Therefore, the clinical trials for donanemab could resume once enough patients are enrolled.

While these drugs may not provide a complete solution to AD treatment, the insights gained from their chaotic approval will hopefully streamline future regulatory processes. The FDA has remained silent about the approvals since their initial press releases, but the backlash from the scientific community is surely still reverberating through the institution. The story of aducanumab and lecanemab should have been about scientific breakthroughs—a tale about the promise of a novel engineered drug and the potential for saving human lives after rigorous clinical trials. Instead, the tale of aducanumab and lecanemab is marred by regulatory missteps from the FDA. Although the FDA intended to help the millions of people suffering from AD by granting approval to aducanumab and lecanemab, their haste and dismissal of expert guidance has blurred the path forward for effective AD therapies.

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Written by Sarah Wade

Illustrated by Federica Raguseo

Edited by Mary Cooper, Justin McMahon, Lauren Wagner

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References:

Alexander, G. C., Knopman, D. S., Emerson, S. S., Ovbiagele, B., Kryscio, R. J., Perlmutter, J. S., & Kesselheim, A. S. (2021). Revisiting FDA Approval of Aducanumab. New England Journal of Medicine, 385(9), 769–771. https://doi.org/10.1056/NEJMp2110468

ALZFORUM. (2022, May 16). Aduhelm. https://www.alzforum.org/therapeutics/aduhelm

Alzheimer’s Association. (2021, June 7). Alzheimer’s Association Welcomes FDA Approval of Aducanumab. Alzheimer’s Disease and Dementia. https://alz.org/news/2021/alzheimers-association-fda-approval-aducanumab

Biogen. (2021a). Biogen Announces Reduced Price for ADUHELM® to Improve Access for Patients with Early Alzheimer’s Disease | Biogen. https://investors.biogen.com/news-releases/news-release-details/biogen-announces-reduced-price-aduhelmr-improve-access-patients

Biogen. (2021b). Japan’s First Committee on New Drugs of The Pharmaceutical Affairs and Food Sanitation Council Seeks Additional Data; Aducanumab Remains under Review. Biogen. https://investors.biogen.com/news-releases/news-release-details/japans-first-committee-new-drugs-pharmaceutical-affairs-and-food

Boseley, S. (2021, June 7). FDA approves first new Alzheimer’s drug in almost 20 years. The Guardian. https://www.theguardian.com/society/2021/jun/07/fda-announce-decision-new-alzheimers-drug-aducanumab

Centers for Disease Control and Prevention. (2022, September 6). FastStats – Leading Causes of Death. CDC. https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm

CMS. (2021, December 21). CMS Releases Latest Enrollment Figures for Medicare, Medicaid, and Children’s Health Insurance Program (CHIP) | CMS. https://www.cms.gov/newsroom/news-alert/cms-releases-latest-enrollment-figures-medicare-medicaid-and-childrens-health-insurance-program-chip

CMS. (2022, April 7). CMS Finalizes Medicare Coverage Policy for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease | CMS. https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment

Couzin-Frankel, J. (2023, January 6). FDA approves new antibody to slow Alzheimer’s disease, even as safety concerns linger. Science. https://www.science.org/content/article/fda-approves-new-antibody-slow-alzheimer-s-disease-even-safety-concerns-linger

Cummings, J., Lee, G., Nahed, P., Kambar, M. E. Z. N., Zhong, K., Fonseca, J., & Taghva, K. (2022). Alzheimer’s disease drug development pipeline: 2022. Alzheimer’s & Dementia : Translational Research & Clinical Interventions, 8(1), e12295. https://doi.org/10.1002/trc2.12295

DeTure, M. A., & Dickson, D. W. (2019). The neuropathological diagnosis of Alzheimer’s disease. Molecular Neurodegeneration, 14(1), 32. https://doi.org/10.1186/s13024-019-0333-5

Eli Lilly and Company. (2023, January 19). U.S. Food and Drug Administration Issues Complete Response Letter for Accelerated Approval of Donanemab | Eli Lilly and Company. https://investor.lilly.com/news-releases/news-release-details/us-food-and-drug-administration-issues-complete-response-0

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Kim, C. K., Lee, Y. R., Ong, L., Gold, M., Kalali, A., & Sarkar, J. (2022). Alzheimer’s Disease: Key Insights from Two Decades of Clinical Trial Failures. Journal of Alzheimer’s Disease, 87(1), 83–100. https://doi.org/10.3233/JAD-215699

Liu, A. (2022, April 8). Biogen’s troubled Aduhelm hit with CMS slapdown—Now what? Fierce Pharma. https://www.fiercepharma.com/pharma/aduhelm-slapped-down-cms-whats-next-biogen

Mahase, E. (2021). Three FDA advisory panel members resign over approval of Alzheimer’s drug. BMJ, 373, n1503. https://doi.org/10.1136/bmj.n1503

Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., Shcherbinin, S., Sparks, J., Sims, J. R., Brys, M., Apostolova, L. G., Salloway, S. P., & Skovronsky, D. M. (2021). Donanemab in Early Alzheimer’s Disease. New England Journal of Medicine, 384(18), 1691–1704. https://doi.org/10.1056/NEJMoa2100708

Mullard, A. (2021). More Alzheimer’s drugs head for FDA review: What scientists are watching. Nature, 599(7886), 544–545. https://doi.org/10.1038/d41586-021-03410-9

NICE. (2022). Aducanumab for treating mild cognitive impairment and mild dementia caused by Alzheimer’s disease [ID3763]. National Institute for Health and Care Excellence. https://www.nice.org.uk/guidance/indevelopment/gid-ta10739/documents

Robbins, R. (2022, May 3). Biogen’s C.E.O. will step down after disastrous launch of Alzheimer’s drug. The New York Times. https://www.nytimes.com/2022/05/03/business/biogen-aduhelm-michel-vounatsos.html

Tirrell M. (2014, December 2). Biogen shares up; Alzheimer’s drug shows promise. CNBC. https://www.cnbc.com/2014/12/02/biogen-shares-up-5-on-biib037-results-alzheimers-drug-showed-effect-on-cognition.html

Links:

FDA Advisory Committee Roster (Nov 6, 2020) – https://www.fda.gov/media/143512/download
FDA Advisory Committee Full Transcript (Nov 6, 2020) – https://www.fda.gov/media/145691/download