For the first time since 2003, The US Food and Drug Administration (FDA) has approved the use of a new treatment for Alzheimer’s disease (AD). Known by the brand name Aduhelm, the drug is purported to be the first to combat the underlying cause of the condition rather than its symptoms, yet a lack of convincing data regarding its efficacy has generated huge controversy.

Aduhelm is a monoclonal antibody that targets amyloid proteins, which are known to accumulate in the brains of people suffering from Alzheimer’s. Two Phase III clinical trials, conducted simultaneously, illustrated the drug’s ability to reduce amyloid plaques in patients’ brains, thereby leading to the conclusion that it probably helps to treat the condition.

However, this isn’t necessarily the case, as numerous previous studies have shown that clearing amyloid proteins doesn’t actually generate clinical improvements among AD patients. In spite of this, the FDA decided to activate its Accelerated Approval pathway, which allows certain drugs to be brought to market faster, even when some uncertainty exists regarding their benefit.

Accelerated approval can also be based on a drug’s effect on a “surrogate endpoint” rather than actual clinical benefit. In this case, the reduction of amyloid plaques was taken as a surrogate endpoint for improvements in AD pathology, despite a lack of evidence to support this.

Yet the controversy doesn’t end there, as both of the Phase III studies were in fact shut down in March 2019 after initial results showed that Aduhelm was ineffective at slowing cognitive decline in Alzheimer’s sufferers. The drug’s manufacturer, Biogen, then surprised everybody by placing it before the FDA for approval in November 2020.

In its application, the company noted that additional data from 318 study participants had come in after the trials had been suspended. Analyzing this extra information revealed that a high dose of the drug slowed cognitive decline by 22 percent in one of the studies, but not in the other. Given that the two trials were identical, the fact that they have produced contradictory findings would appear to suggest that the data simply isn’t strong enough for any firm conclusions to be drawn.

On its website, the FDA admits that “the data included in the applicant’s submission were highly complex and left residual uncertainties regarding clinical benefit.” While its advisory committee was not unanimous in granting approval, the decision to do so was ultimately taken due to Aduhelm’s potential to provide therapeutic benefit to patients suffering from a disease that is currently extremely difficult to treat.

The announcement has split opinions within the scientific community, with some Alzheimer’s experts welcoming the approval of a long-awaited new treatment, while others have pointed out that the data simply doesn’t stack up. 

“The approval of aducanumab to treat Alzheimer’s disease in the US is phenomenal news for researchers as it is the first approved drug that attacks disease pathology; however, the drug’s ability to slow memory decline is less convincing," said Professor Tara Spires-Jones from the UK Dementia Research Institute at the University of Edinburgh (UoE) and Deputy Director of the Centre for Discovery Brain Sciences, UoE. "This drug lowers the amount of amyloid plaques in the brain, which is hoped to slow disease progression if given to people in early stages of Alzheimer’s. This is very exciting for scientists trying to develop truly life-changing treatments, but we still have a long way to go.”

Furthermore, given that 40 percent of participants in the two trials experienced side effects such as brain swelling or bleeding, some doctors say the risks associated with this new drug outweigh any potential benefits.

"What comes next will be an assessment of the value for money for healthcare systems of this treatment, the development of capacity to deliver it if so as well as the start of data accumulation on the effectiveness of the drug on hard outcomes in Alzheimer’s disease (loss of cognitive and day-to-day abilities) as well as studies testing the effect of the drug in individuals in preclinical stages of the disease," Dr Ivan Koychev, senior clinical researcher at the University of Oxford and clinician scientist at Dementias Platforms UK, commented.

Despite receiving Accelerated Approval, Aduhelm will still have to undergo a final Phase IV trial before it can be brought to market. If results show a lack of clinical efficacy then the FDA could still withdraw approval, though it would not be bound to do so.