The US Food and Drug Administration (FDA) today announced the results of its investigation into Biogen’s investigational treatment for Alzheimer’s disease (AD), the monoclonal antibody aducanumab. The agency announced that the compound, under the trade name Aduhelm, is to be approved for treatment via the FDA’s accelerated approval pathway.
The announcement followed the unanimous rejection of the drug by the FDA’s independent advisory committee in November 2020. The approval comes at the end of a rollercoaster process, that has taken wild turns since clinical trials of aducanumab were originally suspended by Biogen in March 2019. At that time, a statement was released on two Phase III AD trials, ENGAGE (NCT 02477800) and EMERGE (NCT 02484547), summarizing that the trials were “unlikely to meet their primary endpoint upon completion”.
What is adunacumab?
The brains of AD patients are often found to be riddled by amyloid plaques that disrupt healthy neuronal function and cause toxicity, ultimately leading to cognitive decline. Aducanumab is a monoclonal antibody (mAb) designed to bind to aggregated forms of β-amyloid to clear it. The drug was originally developed by Neurimmune via a reverse translational medicine approach, in which the antibody was extracted from older individuals that have not developed AD.
A wild ride
The original announcement could have been the end of the story and would have seen aducanumab join a litany of other compounds in the AD pharmaceutical scrapheap. No new drugs have been licensed for the condition since the NMDA-receptor antagonist memantine was approved in 2003. Instead, the approval is a vindication for Biogen’s decision to not give up on aducanumab.
“AD is a devastating illness that can have a profound impact on the lives of people diagnosed with the disease as well as their loved ones,” said Patrizia Cavazzoni, MD, director of the FDA’s Center for Drug Evaluation and Research, in a press release. “Currently available therapies only treat symptoms of the disease; this treatment option is the first therapy to target and affect the underlying disease process of AD.”
In October 2019, Biogen took the declared that subsequent analysis had suggested the drug could be considered for approval. This extremely unusual development warrants some explanation.
The pair of Phase III trials each split participants into a placebo, low-dose or high-dose group, depending on their APOE ε4 genotype, a key genetic risk factor for AD. Subject performance in a battery of cognitive tests served as the trials’ primary endpoints. The study underwent a futility analysis in December 2018, a test that assesses whether a trial is worth continuing to completion based on preliminary data. That analysis readout in March 2019 led to the trial’s discontinuation.
The original futility analysis consisted of 945 and 803 patients in ENGAGE and EMERGE respectively. However,in its October statement Biogen announced that further analysis had been conducted using the original data and additional data recorded in the three-month period between the futility analysis’s start and the trial’s end. This incorporated data from an additional 139 ENGAGE participants and 179 EMERGE participants. This additional analysis, said Biogen, implied that the drug could be considered for FDA approval, despite the fact that significance was only calculated when analyzing the larger EMERGE data set.
An unusual step
The FDA have taken the unusual step of going against the advice of their independent advisory board to approve aducanumab. The approval comes with a caveat; the FDA has asked Biogen to conduct a new randomized controlled clinical trial, called a Phase IIII trial, to verify the drug’s clinical benefit. If the drug fails that trial, approval may be withdrawn. The FDA pointed to the drug’s noted effectiveness at reducing amyloid burden as evidence for its acceptance via the accelerated approval program. The FDA’s statement suggested that this reduction is being used as a “surrogate endpoint”, a reflection of the complex and contradictory nature of the cognitive test data from the trial.
John Hardy, professor of neuroscience at UCL, is a central figure in the amyloid hypothesis of AD, a theory that places the aberrant physiological action of the protein amyloid at the center of the disease’s pathology. The amyloid hypothesis continues to be the dominant theory in AD drug design – aducanumab targets the buildup of amyloid plaques in the brain as part of its mechanism of action. Hardy commented: “While I am pleased that aducanumab has received approval, we have to be clear that, at best, this is a drug with marginal benefit which will help only very carefully selected patients. We will need better amyloid drugs down the line and we will need other drugs which, for example, help deal with the tau/tangle pathology and which help microglia (the immune system of the brain) deal effectively with amyloid deposition.”
There is conflict among patient and medical groups on whether approval of aducanumab is the right way forward for the field. The Alzheimer’s Association, the largest non-profit funder of AD research, has enthusiastically backed the drug, while the American Geriatrics Society, a group of nearly 6,000 geriatrics health professionals, issued a letter prior to the FDA’s decision that encouraged the rejection of the mAb based on the drug’s evidence base, side effect profile and cost.
In a statement to the UK Science Media Centre, Dr Richard Oakley, head of research at the non-profit Alzheimer’s Society, called the decision “promising.” Hilary Evans, chief executive at Alzheimer’s Research UK, said, “Today’s decision by the FDA marks a pivotal moment in the search for life-changing new treatments for AD . The approval is a positive step forward for people with early AD in the US and we welcome the opportunity for Biogen to conduct a post-approval clinical trial to reveal more about the potential real-world benefits of aducanumab. Aducanumab will be the first ever drug to reach patients in the US that tackles the underlying disease process itself. The findings of these additional studies could pave the way for a new generation of life-changing drug treatments."
In opposition, Robert Howard, professor of old age psychiatry at UCL, took a different line, “I consider [that] the approval of aducanumab represents a grave error that will have only a negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade.” The FDA was guilty of “sidestepping” data suggesting the “drug probably doesn’t work", said Howard. “Now, we'll wait a decade before it becomes obvious to everyone that there are no benefits – only high healthcare costs –- associated with the treatment,” he added.
In his statement, Hardy summarized the uncertain reaction to this decision, one marked by both cautious hope and by skeptical criticism: “One could characterize this, not as the beginning of the end of Alzheimer’s, but as the end of the beginning in terms of treatments.”