Does new drug aducanumab offer a cure for Alzheimer’s disease? Scientia Professor Henry Brodaty AO, CHeBA UNSW Co-director and Montefiore Chair of Healthy Brain Ageing, explores the controversy.
Controversy has swirled about the approval by the USA Food and Drug Administration (FDA) of aducanumab, a new drug for Alzheimer’s disease. This drug is an antibody against a toxic protein (called the A-beta or amyloid beta protein) that builds up in people’s brains. This protein eventually leads to the formation of amyloid plaques which are hallmarks of the brain pathology of Alzheimer’s disease. More than 20 antibody or similar trials previously have yielded negative results.
The trial phase
The back story is important. Pharmaceutical company Biogen conducted two major trials for people with Mild Cognitive Impairment (MCI) or early Alzheimer’s Disease and evidence of amyloid plaque build-up in their brain (which can be confirmed by specialised PET scans). MCI is a pre-dementia stage defined as having subjective and objective evidence of decline in cognition, particularly memory. Biogen decided to halt their trials of aducanumab in March 2019 as analysis indicated further progress with the trials was futile. However, later that year, they presented a reanalysis of data showing that participants on the higher dose in one major trial showed benefit in cognition as well as a reduction in amyloid plaques in their brains.
FDA approval and controversy
Biogen began to work with the FDA to apply for approval of the drug. Deliberations within the FDA and their expert advisory group continued for more than 18 months. Despite this advisory group voting almost unanimously against approval, the FDA granted Accelerated Approval even though they noted the lack of convincing evidence of cognitive benefit. Instead, they based it on the intermediate outcome – the reduction of the amyloid protein build-up/plaque in the brain.
Many experts have decried the decision to approve aducanumab. Three members of the FDA Advisory Committee resigned, major US hospital groups Mt Sinai and Cleveland Clinic have ruled out its use, and editorials in top medical journals have denounced the move. Inquiries into the FDA decision have begun.
Proponents of the drug use the analogy with statins (such as Crestor, Lipitor) that are widely prescribed help to reduce heart attacks by lowering cholesterol. They point out that there is a good precedent for choosing an intermediate target, such as cholesterol reduction, rather than the ultimate target of heart attack prevention.
The downsides of aducanumab
What are the downsides of using aducanumab? The drug is expensive at US$56,000 p.a, and is administered monthly by intravenous infusion. It is not yet clear how long the drug will need to be given after the first year. One in three people will experience side effects in the first four months, including brain swelling or microhemorrhages. These side effects may cause headaches, vision problems and confusion.
Initially, the FDA’s approval allowed aducanumab for use in anyone with Alzheimer’s disease. After critics pointed out those in the trials did not have moderate or severe Alzheimer’s disease, the FDA narrowed its use to people with MCI or early Alzheimer’s disease. They have not mandated that recipients require PET scans confirming the presence of amyloid in the brain.
Is Australian approval for aducanumab likely?
Where does this leave Australia regarding aducanumab? Biogen would need to apply to the Therapeutic Goods Administration (TGA) to consider its efficacy and safety. My impression is that approval is unlikely. If it were granted, the next stage would be applying to the Pharmaceutical Benefits Scheme (PBS) to subsidise the high cost of the drug. But this may be even less likely to succeed.
Even if aducanumab proves to be successful, it’s only indicated for Alzheimer’s disease which is just one form of dementia. However, it will not work for other types such as vascular, Lewy body or fronto-temporal dementia. We also don’t know if it will be effective in people with more advanced Alzheimer’s. The hope is that this may halt progress to clinically diagnosed dementia in people showing symptoms of pre-Alzheimer’s (MCI).
Fighting dementia without drugs
There is now evidence that certain behavioural changes can reduce the risk of dementia by 40%. This highlights the importance of lifestyle intervention trials to delay or prevent dementia. We know that the brain changes underpinning most dementias continue for many years until symptoms become apparent. For example, Alzheimer’s disease develops over a 20-30 year period before symptoms appear, providing a window of opportunity during early and mid-life. As well as identifying risk factors, we need intervention studies to ensure better health outcomes.
There is a message for all of us
The danger with sensationalist news stories about breakthroughs and cures is that they lead to false hope. At this stage, there is not enough evidence to recommend aducanumab. Hopefully more data or alternative treatments will become available. One positive approach adopted by my team at CHeBA is the Maintain Your Brain trial. It’s the world’s largest clinical trials testing online interventions to reduce cognitive decline, delay onset of dementia and improve brain health among people aged 55-75 years. Visit: cheba.unsw.edu.au
Join Professor Brodaty to hear more about medical and other innovations in dementia in our new Spotlight Speaker series on September 23.