Aducanumab: A new hope?
Alzheimer's disease (AD) is a brain disease that gradually impairs memory and thinking skills. The disease can disrupt a person's ability to carry out the most straightforward tasks. It is the most common cause of dementia among older adults, with symptoms appearing in their mid-60s. Nearly 50 million people worldwide have been diagnosed with dementia - AD being the most common form. The number of cases is projected to reach 82 million by 2030.
Dr Thaarvena Retinasamy's interest in discovering possible treatment strategies for AD is motivated by the need to comprehend the disease's pathophysiology better. "I want to specifically explore the gaps in the neural basis of the disease, including the changes observed in learning and memory, thus potentially slowing down the cognitive deterioration typical of Alzheimer's disease," stated the research fellow from the Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia.
AD is the fifth leading cause of death in the United States, with the disease seeing a steep increase of 146 per cent between 2000 to 2018. In June 2021, after a two-decade hiatus, the US FDA approved Aducanumab as the first drug to treat AD, directed at improving the disease's pathophysiology. The drug's approval has sparked a contentious debate among the scientific community over its effectiveness. Many experts, including an independent panel of neurologists and biostatisticians, have advised the FDA against approving Aducanumab as the clinical-trial data did not conclusively demonstrate that it can slow cognitive decline.
Accelerated Approval
The FDA consented to the therapy under its Accelerated Approval pathway, which grants earlier approval for drugs of severe conditions that fill unmet medical needs. The program relies on surrogate endpoints that indicate the drug is likely to be of clinical benefit to patients with AD but do not guarantee it. These surrogate endpoints are viable substitutes for hard clinical endpoints because they are linked to the desired clinical outcomes.
In the case of Aducanumab, the desired clinical endpoint was to observe a reduction in clinical decline. Since the clinical endpoint was not met, the surrogate endpoint, which is the reduction of amyloid-beta plaque, was considered in approving this drug. However, the accelerated approval pathway requires the company to verify clinical benefits in a post-approval trial. If clinical benefits cannot be verified, the FDA may initiate proceedings to withdraw the approval.
Problematic data set
AD is an irreversible, progressive brain disorder characterised by the accumulation of amyloid-beta plaques and neurofibrillary, or tau, tangles in the brain that result in loss of neurons and neural connections.
Aducanumab, a human IgG1 monoclonal antibody that selectively binds to aggregated forms of amyloid-beta to help reduce its build-up, raised considerable controversy in the wake of findings from two identical Phase Three studies, EMERGE and ENGAGE.
In December 2018, both studies went through a futility analysis to evaluate if trials were worth continuing to completion based on preliminary data. The studies were terminated in March 2019 as they were unable to show the drug's effectiveness. However, further analysis of additional data proved to be conflicting, especially the efficacy between the two trials.
Both studies revealed a significant dose-and time-dependent reduction of amyloid-beta plaques. While only one of the Phase Three studies met the primary endpoint of reduction in clinical decline, it is expected that lowered amyloid plaque levels will lead to a reduction in clinical deterioration.
Controversies and questionable efficacy
Evidence for Aducanumab's efficacy has been highly contested. While the FDA has declared Aducanumab will likely benefit patients, numerous experts have argued that there is insufficient data to establish this.
The reliability of Aducanumab appeared to be questionable when it did not demonstrate any improvement in memory which is crucial in most AD drug trials. Critics have also argued that its clinical trials were only conducted on early to mild stages of AD with evidence of amyloid plaques. However, the drug was approved for AD in general — not specific AD stages.
The infusion of Aducanumab is also associated with significant side effects that include amyloid-related imaging abnormalities (ARIA), which causes swelling and bleeding in the brain. It was observed in 40 per cent of trial participants. Those who proceed to take this treatment will still need to undergo routine brain scans to avoid serious complications, thus exerting a burden on patients, neurologists, and the healthcare system.
Silver linings?
Despite the controversy surrounding the drug, given that there is currently no approved disease-modifying treatment available for AD, it is understandable that most are in a desperate search for one that will delay the onset or reduce the progression of this devastating disease.
However, any treatment made available must be beneficial and not unleash a risky precedent that could derail the work being done to develop an effective treatment for AD. Furthermore, approval of a drug or treatment that is not effective has serious potential to impair future research into new medicines that may effectively treat AD. Thus, if Aducanumab turns out to be not as effective, this could, in turn, lower the bar for future drugs and fewer effective therapies.
"We need to continue looking at other targets like tau, which are greatly involved in the disease. Uncontrollable neuroinflammation, which can be caused by many factors, including injury, disease, or stress, is also common in patients with AD and may promote the development of the disease," shared Dr Tharveena.
Dr Thaarvena works alongside Associate Professor Mohmad Farooq Shaikh in exploring the gaps involved in determining the possible treatment strategies for AD. They are now exploring potential neuroinflammatory markers and treatments targeting this aspect of AD.