On 7th June 2021, the Food and Drug Administration (FDA) approved a new treatment for Alzheimer’s patients in the US. This is the first treatment to be approved in almost two decades, and the first to target the cause of Alzheimer’s disease rather than just the related symptoms. However, gaps in clinical trial data have left developers, Biogen, requiring further trials. What is new about this treatment and what do the data show so far?
Alzheimer’s disease is the most common type of dementia, encompassing brain disorders which often lead to a progressive loss of brain f unction with symptoms such as memory loss and confusion. Alzheimer’s affects between 50-75% of those diagnosed with dementia and it is a terminal condition. The number of patients suffering with dementia in the UK, is projected to rise from the current figure of 850,000 to 1.6 million by 2040, with those over 80 at highest risk of developing the disease. Despite decades of research, new approved treatments for Alzheimer’s disease have stagnated. Until now, medicated treatments had targeted the symptoms of the disease, rather than the root cause, temporarily easing symptoms such as memory loss, or slowing disease progression in patients in mild to moderate stages of the disease.
“Delaying the onset of dementia by five years would halve the number of deaths, saving 30,000 lives a year.”Alzheimer’s Society, UK
Even the cause of Alzheimer’s disease is contentious however, with numerous theories under investigation. The leading hypothesis, which led to the recently approved Biogen treatment, targets the build-up of a protein (called amyloid) in the brain which is considered an indicator (or biomarker) of the disease. It had been observed that Alzheimer’s patients, with no other conditions, were producing an immune response and generating antibodies against the amyloid protein which clumped around neurons, forming plaques, and eventually leading to neuron degeneration. Biogen focused on creating Aducanumab (brand name Aduhelm), an antibody which specifically binds to these amyloid plaques in the brain. Researchers collected Alzheimer’s patients’ memory B cells and selected those capable of producing antibodies which were highly selective towards amyloid. Their aim was to interrupt and remove the plaques, hopefully preserving neuronal function. After Adhuhelm’s approval, the FDA’s director of the Center for Drug Evaluation and Research, Dr Cavazzoni reported the “FDA has determined that there is substantial evidence that Aduhelm reduces amyloid plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients”.
Despite the prediction of further benefits, the approval of Aduhelm has not been without controversy, with critics arguing that the idea that there is a link between the plaques and further benefits is untested. Many agree that reducing amyloid plaques is not the same as slowing the symptoms of Alzheimer’s and previously tested amyloid-reducing drugs have failed to address symptoms. Additionally, the Aduhelm clinical trials provided incomplete evidence to demonstrate the drug’s effectiveness, leading the FDA to request a further Phase IV trial, post-approval. The two clinical trials to date, named EMERGE and ENGAGE, were conducted on patients with mild cognitive impairment or early-stage Alzheimer’s, who had elevated amyloid levels, but the trial results contradicted one another. Initial analysis showed those on a higher dose of Aduhelm in the EMERGE trial appeared to slow cognitive decline very slightly, yet those on a lower dose in the same trial, and both doses in the ENGAGE trial, showed no statistical significance over the placebo. However, later analysis of additional data concluded that the high dose used in the EMERGE trial could have delayed cognitive decline by 22%. Alongside the question many researchers have raised over these additional trial results, of those patients who trialled the higher dose of Aduhelm, 40% experienced brain swelling or bleeding, whilst the majority were either asymptomatic or suffered headaches, dizziness or nausea. Previous amyloid-lowering drugs have also caused such side-effects at trial stage and some doctors consider these manageable if patients are evaluated regularly with brain scans. However, others argue that even if the Phase IV trial does demonstrate an ability to slow cognitive decline, it would be so slight that it would not outweigh the risk of swelling or bleeding in the brain.
Overall, both critics and supporters agree that Aduhelm substantially reduces amyloid levels and supporters believe that clearing amyloid plaques earlier could help slow the progression of the disease, although this is untested. If the Phase IV trial fails to show a benefit to symptoms, or a slowing of cognitive decline, the FDA can (but is not required to) rescind its approval. Whilst Aduhelm has not yet been approved for use outside the US, Biogen has filed for regulatory approval elsewhere. Alzheimer’s Society UK quotes that “delaying the onset of dementia by five years would halve the number of deaths, saving 30,000 lives a year”. All eyes are now on Biogen, Aduhelm and the Phase IV trial.
While You’re Here:
If you want to read previous articles I’ve written about dementia, such as if bacteria can cause Alzheimer’s, or how the common cough could be linked to Parkinson’s, use the links below.