Image description: a model of the human brain on a deep-blue background, lit up with red and green neon lighting.
Neuroscience is a field notorious for many things: amazing discoveries, thought-provoking debates, controversial findings. But ask any neuroscientist and they’ll tell you that it is also a discipline plagued by failed clinical studies. In fact, several large pharmaceutical companies have moved away from neuroscience in recent years due to the high cost of investment but low chances of success.
Alzheimer’s disease is a perfect example of this problem. Despite being the most common form of dementia, affecting over 50 million people worldwide, there has not been a drug approved for therapeutic use in over 20 years. But this isn’t for a lack of trying. More than 100 potential Alzheimer’s treatments have failed during clinical trials in the last decade alone, and countless hours of work and vast quantities of money are spent each year on Alzheimer’s research.
Unsurprisingly, then, there was jubilation in the Alzheimer’s field this month when the US Food and Drug Administration (FDA) approved the use of aducanumab, a new drug produced by US company Biogen. Aducanumab (also known as Aduhelm) is the first approved drug to target the mechanisms underlying the pathophysiology of Alzheimer’s, unlike older drugs that simply reduce its symptoms.
Aducanumab is a monoclonal antibody, an immune protein that targets amyloid-beta, a molecule in the brain which is thought to cause Alzheimer’s disease. Over many years, high levels of amyloid-beta form toxic plaques on neurons, gradually destroying them and producing the symptoms of cognitive decline such as memory loss and difficulty conducting everyday tasks.
Research published in 2016 by Biogen showed that aducanumab could effectively bind to and reduce amyloid-beta plaques in the brain, which over the course of one year slowed the rate of clinical decline in a group of early-stage Alzheimer’s patients. These promising early results paved the way for a number of larger clinical trials and now the FDA’s approval of the drug.
To many, the approval of aducanumab is a huge step forward in combatting this debilitating neurodegenerative disease – and the FDA’s announcement certainly comes as welcome news to patients. “After years of disappointment and despair, this decision offers new hope for many families,” says George Vradenburg, Chairman and Co-Founder of US organisation UsAgainstAlzheimer’s.
Aducanumab (also known as Aduhelm) is the first approved drug to target the mechanisms underlying the pathophysiology of Alzheimer’s
It is also hoped that the approval of aducanumab will be a much-needed boost to Alzheimer’s research. Biogen’s stock price rose by 40% after the FDA’s announcement, which may encourage other pharmaceutical companies to re-enter the field and thus trigger more investment in the future.
“A grave error”
All that being said, aducanumab has not had an easy ride to approval, and many scientists have expressed their concerns about the recent change in policy. In March 2019, two trials of the drug in Alzheimer’s patients were suddenly halted as there was no evidence that it was slowing deterioration in memory and thinking ability. However, Biogen have since announced that they have reanalysed the data and discovered that aducanumab could slow the rate of cognitive decline, but only at the highest doses tested.
This finding is problematic for statisticians, including Scott Emerson, a biostatistician at the University of Washington. He believes this approach of fishing for statistical significance can overemphasise the positive results and lead people to ignore the negative data. Emerson likens these findings to the so-called Texas sharpshooter fallacy, where picking out one positive result from a pool of negative ones is akin to “firing a shotgun at a barn and then painting a target around the bullet holes.”
“Desperation should drive the funding of science, not drive the way we interpret the science,” says geriatrician Jason Karlwaish from the Penn Memory Centre in Philadelphia, highlighting how we need to be careful in drawing conclusions from the current data.
It’s also important to remember that this drug won’t cure Alzheimer’s disease. The current data merely shows that aducanumab can slow cognitive decline, not halt it altogether or, indeed, reverse it. Moreover, despite being approved for use by anyone with Alzheimer’s disease, the drug was only found to be effective in patients with mild forms of the condition, calling into question whether it will have any benefit in severe cases. In fact, there is currently no evidence that aducanumab can increase the life expectancy of users, meaning treatment may only produce minor, short-lasting improvements.
We ought not to get our hopes up that aducanumab is the life-changing therapy some have claimed it to be.
There are also more fundamental questions about how the drug works that may curb its potential benefit to patients. Research suggests that by the time a patient displays symptoms of Alzheimer’s, amyloid plaques have been accumulating in the brain for decades, and the damage to neurons has already been done. Thus, although aducanumab can reduce amyloid plaques in the brain, it cannot repair the neurons that have already been destroyed, so its impact on patients is inherently limited.
Moreover, some scientists are concerned that patients may drop out of ongoing clinical trials to take aducanumab, leading companies to abandon their work or divert funding away from potentially more effective therapies.
The future of aducanumab therapy
With aducanumab approved in the US, patient groups are calling for regulators to assess the drug for use in the UK. However, it’s clear that a decision will not be made soon. “Use within the NHS… remains some months away and it is critically important that the safe use of this intervention in those people most likely to benefit is fully considered,” says Professor Craig Ritchie, director of Brain Health Scotland. “We also need to ensure that we collect real-world data on the benefits and side effects of the medication to help us to refine how to use this intervention well.”
For example, a more cost-effective approach may be to target aducanumab to patients for whom it could have a greater effect. Given amyloid-beta builds up on neurons for many years before symptoms appear, identifying high-risk patients in the early stages of the disease before the plaques cause substantial damage to neurons may help to prevent some people from developing Alzheimer’s at all. Nonetheless, this is also a challenging approach, as there are a huge number of risk factors for the disease which may make it hard to identify eligible patients.
Aducanumab is “certainly a new chapter but by no means the end of the story”
The cost of aducanumab treatment is another barrier to its use in the UK. Aducanumab is delivered by monthly infusions into patients, which have to be conducted at specialist clinics. This treatment is estimated to cost several thousands of dollars a year. To ensure equal access to aducanumab in the UK, these costs would have to be met by the NHS, which is already struggling with the burden of neurodegenerative diseases. Thus, regulators must traverse a fine line between providing hope to patients and spending vast amounts of money on a treatment with evidence that Jason Karlwaish believes is “thin, at best.”
It’s clear, then, that the approval of aducanumab is a major milestone for treating Alzheimer’s disease, a field that has been held back for years due to the numerous failed attempts at getting drugs to market. However, we ought not to get our hopes up that aducanumab is the life-changing therapy some have claimed it to be. Much more research on the real-world use of the drug is needed before its effectiveness can be assessed, and before UK regulators consider it for use. Thus, as Prof Ritchie summarises, aducanumab is “certainly a new chapter but by no means the end of the story.”
Image credit: Natasha Connell