Earlier this week the U.S. Food and Drug Administration approved the first new treatment for Alzheimer’s disease in almost 20 years, giving the go ahead for Biogen to develop the drug Aducanumab. However, this announcement was met with controversy surrounding whether the treatment actually works. But what exactly is wrong with the data behind the approval of this new drug?
The new Alzheimer’s drug – Aducanumab (Aduhelm)
On the 7th June 2021, the FDA approved Aduhelm for the treatment of Alzheimer’s disease. This is the first drug to be approved for the treatment of Alzheimer’s since 2003. It is also the first therapy that targets the underlying pathophysiology of the disease, rather than just its symptoms. More specifically, Aduhelm is a monoclonal antibody that targets the amyloid beta plaques that form in the brains of Alzheimer’s patients. These amyloid plaques build up in the brains of Alzheimer’s patients, forming neurofibrillary tangles that affect neuronal function and connectivity.
Aduhelm clinical trials
Researchers evaluated Aduhelm’s efficacy in three separate studies, which represented 3,482 patients in total. The studies consisted of double-blind, randomised, placebo-controlled dose-ranging studies in patients suffering from Alzheimer’s disease. Patients receiving the treatment had a significant reduction of amyloid beta plaques, while the patients in the control arm of the study had no reduction of amyloid beta plaques. The researchers quantified amyloid beta plaques using positron emission tomography (PET) imaging. This allowed them to estimate the brain levels of amyloid beta plaques in composite brain regions in areas of the brain expected to be widely affected by Alzheimer’s disease pathology, compared to brain regions expected to remain untouched by such pathology.
This result led to the FDA granting Aduhelm accelerated approval. This type of approval is designed to provide early access to potentially valuable therapies for patients with serious diseases where there is an unmet need for treatment, and where there is an expectation of clinical benefit despite some remaining uncertainty regarding that benefit. Recognising that the existing clinical trials of Aduhelm have provided incomplete evidence to demonstrate its effectiveness, the FDA now requires Biogen to conduct another trial. If the data from this new phase 4 trial fails to show that the drug is effective, the FDA can rescind its approval.
Data issues surrounding the approval of the new Alzheimer’s drug Aduhelm
In 2019, Biogen announced that they were halting their two ongoing Aduhelm trials after interim analysis of the data suggested that the drug provided no benefit to patients. These trials included more than 3,000 people in 20 countries. However, later that year they reversed their decision, providing a new analysis based on newly available patient data. That analysis revealed that in one study a 22% reduction in cognitive decline was seen in the group getting the higher of two aducanumab doses, compared with the group getting a placebo. The other study still found no benefit with Aduhelm treatment.
In November 2020, an independent advisory committee was convened by the FDA. The committee experts voted overwhelmingly that the data from the positive trial were not “primary evidence of effectiveness” of the drug. Moreover, the possibility of accelerated approval based on amyloid reduction was not discussed.
The FDA rarely makes decisions that go against its advisers’ recommendations. In an analysis of FDA rulings between 2008 and 2015, Ross et al. found that 89% of drug approval decisions aligned with an advisory committees’ recommendations. Even more interestingly, of those that didn’t, 77% involved a more restrictive ruling than advisers recommended, with the FDA opting to reject a drug that the committee voted to approve.
Moreover, Dr Caleb Alexander, a John Hopkins epidemiologist who served on the FDA’s advisory panel voted against the approval of Aduhelm, saying, “It’s hard to find any scientist who thinks the data are persuasive. Unmet need is an important contextual factor but it’s not an evidentiary threshold.” He went on to say that he was unhappy that the data that was put forward to regulators was a reanalysis after the trial was terminated, suggesting that the researchers could have inadvertently selected data that was consistent with the outcome they were hoping for.
Aduhelm provides a promising opportunity for the treatment of Alzheimer’s disease, and is an exciting breakthrough that has the potential to dramatically impact the lives of Alzheimer’s patients and their families. However, the FDA’s approval went against the recommendations of their independent advisory board, who voted against the drugs approval based on insufficient data to support its clinical impact. Aduhelm still needs to go through an additional Phase 4 trail, and if that does not produce data that supports the drug’s clinical benefit, the FDA can rescind its approval.
Image credit: jarun011 – Canva