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Business & Regulation Standards & Regulation, Clinical Trials

Addressing the Aduhelm Controversy

In June 2021, the FDA approved the country’s first new Alzheimer’s treatment in almost two decades. Aduhelm (aducanumab), developed by Biogen and Eisai, attaches to beta amyloid in the brain, helping the immune system to remove it. A focus on beta amyloid – and its aggregation into plaques in the brain – has dominated Alzheimer’s research for years, but investigational drugs targeting beta amyloid have failed to show any benefit. Alzheimer’s is a complex disease – and scientists still can’t fully agree on the root cause. Some have theorized that, by the time Alzheimer’s symptoms become apparent, it may be too late for treatments to work.

The controversy
 

In 2019, Biogen halted two phase III trials of Aduhelm in patients with early stage Alzheimer’s after an independent data monitoring committee found they were unlikely to meet their primary endpoint. However, later the same year, Biogen said that one of the trials did, in fact, meet its primary goal, with patients seeing a reduction in cognitive decline. In this trial, patients received a high dose of the drug.

After reviewing the drug’s marketing application, an FDA advisory panel was doubtful about the evidence proving Aduhelm’s efficacy. Ten out of 11 members of the panel voted against the drug’s approval – and the eleventh was unsure of the data. Despite the panel’s recommendation, the FDA approved the drug under its accelerated approval pathway – where approval can, according to the FDA, be based on a “surrogate endpoint that is reasonably likely to predict a clinical benefit to patients.” In the case of Aduhelm, the approval was based on the fact that the drug reduces amyloid plaques in the brain. In a statement, Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, described the treatment as, “the first therapy to target and affect the underlying disease process of Alzheimer’s.”

The problem? There appears to be little evidence on the likelihood of Aduhelm’s action translating into meaningful benefits for patients with Alzheimer’s. It’s worth noting that other investigational mAbs targeting and reducing amyloid in the brain have not translated into clinical benefits. Consider bapineuzumab – originally being developed by Elan and Wyeth (and then J&J and Pfizer following acquisitions) – which failed phase III trials. The drug did lower amyloid plaques, but it didn’t improve clinical outcomes in Alzheimer’s patients. Development of the drug was abandoned in 2012.

After the drug was approved, three members of the panel (Joel Perlmutter, David Knopman, and Aaron Kesselheim) resigned in protest. Kesselheim reportedly said, “This might be the worst approval decision that the FDA has made that I can remember” and that “there’s no good evidence that the drug works.”

The US Department of Health and Human Services Inspector General has also announced an investigation into how the drug was approved. A statement said, “The FDA’s approval of Aduhelm raised concerns due to alleged scientific disputes within the FDA, the advisory committee’s vote against approval, allegations of an inappropriately close relationship between the FDA and the industry, and the FDA’s use of the accelerated approval pathway. In response to these concerns, we will assess how the FDA implements the accelerated approval pathway.”

In the EU, the EMA refused a marketing authorization for the drug in December 2021. “The European Medicines Agency noted that although Aduhelm reduces amyloid beta in the brain, the link between this effect and clinical improvement had not been established. Results from the main studies were conflicting and did not show overall that Aduhelm was effective at treating adults with early stage Alzheimer’s disease.

“In addition, the studies did not show that the medicine was sufficiently safe as images from brain scans of some patients showed abnormalities suggestive of swelling or bleeding, which could potentially cause harm. Furthermore, it is not clear that the abnormalities can be properly monitored and managed in clinical practice.

“Therefore, the Agency’s opinion was that the benefits of Aduhelm did not outweigh its risks.”

Insurers react
 

Aduhelm was initially priced at $56,000 per year in the US, but this was reduced in December 2021 to around $28,000. In January 2022, the Centers for Medicare & Medicaid Services (CMS) said it would cover mAbs that target amyloid plaques but only for patients enrolled in “qualifying” clinical trials, which would need to meet specific criteria set by CMS. Right now, Aduhelm is the only approved drug that falls into this category – but other similarly-acting mAbs are progressing through pipelines, such as Eli Lilly’s donanemab.

CMS seems unsure of the risk-benefit balance of the drug. In a statement, Lee Fleisher, CMS Chief Medical Officer and Director of the Center for Clinical Standards and Quality, said, “This proposed National Coverage Determination is the result of robust evidence analysis conducted through a thorough review process that found while there may be the potential for promise with this treatment, there is also the potential for harm to patients. This harm may range from headaches, dizziness, and falls, to other potentially serious complications such as brain bleeds.”

CMS asked for comments on its proposal – which closed in mid-February. More than 9900 comments were submitted; though, notably, many are “copy and paste” statements – posted by citizens with no listed affiliation – that criticize the FDA’s decision to approve the drug in the first place. That said, comments were also received from pharmaceutical companies, doctors, and patient advocacy groups. Some support the CMS decision; for example, Doctors for America said, “Given the significant lack of evidence regarding aducanumab’s safety and continued safety concerns, we applaud CMS’s proposed decision to restrict coverage of this drug and others with similar mechanisms of action under Coverage for Evidence Development." 

Others are against it. The patient advocacy group Alzheimer’s Association said, “The Association strongly disagrees with the restrictive approach of CMS’s proposed NCD for the class of monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (anti-amyloid mAbs). We believe that CMS should continue to apply its long-standing precedent to each treatment in this class: If approved by the Food and Drug Administration (FDA), CMS should cover a treatment in this class when administered in accordance with that treatment’s FDA label, including tests and procedures required for treatment administration and management.”

The industry association BIO also submitted a comment against the CMS decision. “BIO questions CMS’s authority to apply CED to restrict coverage for on-label uses of FDA-approved drugs, especially where CMS is doing so both for a currently approved drug and an entire class of drugs that are in the pipeline for approval in the near future.”

Since the period for comments closed, patient advocacy group UsAgainstAlzheimer’s has launched a campaign involving television and digital adverts, where patients call for Medicare to cover treatments for Alzheimer’s. The advocacy group is reportedly spending millions on the campaign. 

The CMS’ final decision on coverage will be made in April 2022 – but the controversy will almost certainly linger for much longer.

Image Credit: sbtlneet / Pixaby.com

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