The Aducanumab Controversy: Accelerated FDA Approval Leads to Agency Distrust

Approval from the US Food and Drug Administration (FDA) does not always guarantee the success of a new drug, as recently seen with aducanumab (Aduhelm), Biogen’s Alzheimer disease (AD) drug. In 2021, aducanumab received FDA approval and was later on the market. However, a lack of solid efficacy data and a laundry list of dangerous side effects left physicians hesitant to prescribe the drug and insurers unwilling to pay for it. As a result, the drug was quickly pulled from the market in January 2024.¹

This became known as the aducanumab controversy. The story of this AD drug is multifaceted and intrinsic to the future of prescription medicine.

The Quest to Find a “Surrogate Endpoint” for AD

Researchers have long searched for a surrogate endpoint to measure the presence of AD and gauge its response to treatment. One classic example of a well-established surrogate endpoint is low-density lipoprotein (LDL) cholesterol for cardiovascular disease. Scientists have validated LDL as a marker of heart disease and justified the use of lipid-lowering drugs due to their ability to decrease LDL levels.²

Tau tangles and amyloid-beta proteins are widely viewed as promising surrogate endpoints for AD. Aducanumab is a monoclonal antibody that, based on the amyloid hypothesis, is believed to belong to a new generation of disease-modifying drugs.² Gaps in knowledge still exist, however. As a result, many experts remain skeptical of the true impact of beta-amyloid protein on the AD process and question whether drugs like aducanumab can deliver.

AD is a complex disease with no definitive diagnostic test. There are various forms of dementia with overlapping symptoms, and some patients may develop more than 1 type of dementia simultaneously. Physicians must rely on their professional judgment to determine which patients are affected by which type of dementia based on a combination of family history, cognitive tests, and, sometimes, brain imaging.³

Age is the biggest risk factor for AD. For every 5 years aged after 65, the risk for AD doubles. AD is estimated to affect about 6.2 million Americans who are age 65 and older. By 2060, this number is predicted to skyrocket to 13.8 million Americans.³ The growing aging population means the reach of this challenging disease is set to continue expanding. Five drugs are currently approved by the FDA for AD, including donepezil, galantamine, rivastigmine, memantinem, and donepezil/memantine combination. However, these drugs address the symptoms of AD, not the course of the disease. For drugmakers, the lack of disease-modifying treatment options leaves a significant, growing demand that’s desperate to be met.

The FDA Accelerated Approval

Although it’s generally accepted that amyloid-beta plays a role in AD, mixed opinions on the amyloid-beta theory of AD persist. The FDA approval board assumed that the reduction of amyloid plaques on a positron emission tomography (PET) scan was a surrogate endpoint for AD, despite the inability to demonstrate any meaningful clinical benefit of that observed change.⁴

In 2016, a team of researchers published phase 1b trials demonstrating aducanumab’s ability to lower amyloid plaque levels in patients’ brains. Two phase III trials (ENGAGE and EMERGE; ClinicalTrials.gov Identifiers: NCT02477800 and NCT02484547, respectively) included participants with early-stage AD. However, both of these trials were discontinued in 2019 after a futility analysis. Nonetheless, Biogen ran a post-hoc analysis later that year, which included 55% of the participants from both trials who had completed treatment. This analysis led Biogen to file a Biologic Application License with the FDA. The FDA then suggested Biogen file for approval to market the drug, which was granted in June 2021 against expert recommendations.⁴

Ultimately, aducanumab was widely criticized for lackluster evidence and harrowing side effects. Some of the more serious drug-related adverse events noted in clinical trials included brain edema, microhemorrhages, and superficial siderosis. Dizziness, falls, hallucinations, and vision changes were some of the more frequently reported side effects.⁴ In addition, when aducanumab trials failed to demonstrate improvements in cognitive test scores, the FDA accepted reduced amyloid levels as a revised surrogate endpoint, effectively making an assumption that was yet to be supported with data.¹

Medications for AD are not typically considered appropriate for the accelerated approval tract, so this decision was met with strong opposition. In fact, the FDA’s own expert advisory panel voted 10 to 0 (with 1 abstention) to reject the accelerated marketing approval. After it was granted anyway, 3 advisors on the panel resigned.¹

The Repercussions of Medicare’s Fatal Blowback

Despite its rapid approval and generous marketing budget, in April 2022, Medicare declined coverage to patients outside of a clinical trial setting and private insurers quickly followed suit.¹

With an initial annual price tag of $56,000 per patient, insurers couldn’t justify the cost of a treatment with no guaranteed functional improvement and potentially costly side effects. Even after the yearly expense was reduced to $28,200 per patient, insurers and clinicians were not on board.¹

In early 2024, Biogen announced plans to discontinue the “development and commercialization” of aducanumab, noting, “This decision is not related to any safety or efficacy concerns.”⁵ The company agreed to divert money from the production of aducanumab to lecanemab-irmb (Leqembi), another anti-amyloid beta treatment that had already received traditional FDA approval. Biogen also began to invest in 2 new treatments targeting tau tangles.

Read more: Lecanemab Side Effects in CV-Risk Patients

Lingering Distrust of the FDA Among Physicians

While Biogen maintains that aducanumab was a groundbreaking discovery that paved the way for innovative AD treatments, skeptical physicians are still not entirely convinced. The FDA’s shortcuts and decisions against their own advisory board’s recommendations have raised great concern. As the regulatory agency tasked with protecting patients, some experts fear that the FDA’s accelerated approval of aducanumab exposed underlying flaws in a once-trusted system of checks and balances.

According to the findings of a 2022 study published in the American Journal of Law & Medicine, speedy approvals have been steadily rising for decades.

“Over sixty-four percent of approved drugs between 2015-17 participated in expedited approval pathways. While this includes other expedited pathways besides the Accelerated Approval route, it emphasizes the growing FDA trend to approve drugs with abridged evidence of efficacy. Twenty years ago, only thirty-five percent of new drugs were approved through these expedited pathways.,” the researchers wrote.

They continued, “Even when Phase IV clinical trials fail to prove drugs have clinical efficacy, the FDA may take years or never act to remove the product from the market.”³

The aducanumab controversy calls for an immediate need for better AD therapy and restoring physicians’, insurers’, and patients’ confidence in the FDA.