The US Food & Drug Administration (FDA) approval of aducanumab to treat Alzheimer’s disease has proved controversial, with dementia researchers hailing it as a major step forward while geriatricians have condemned it as premature and lacking sufficient evidence of benefit.
Biogen’s US$56,000/year drug was granted accelerated approval based on surrogate endpoint of reduction of amyloid beta plaque in the brain, but without strong evidence of cognitive benefits.
The FDA’s accelerated approval pathway allows a novel drug to be used for a serious or life-threatening illness if offers a reasonable chance of meaningful therapeutic advantage over existing treatments, with a required post-approval trial to verify that the drug provides the expected clinical benefit.
The decision was welcomed by Professor Christopher Rowe, consultant neurologist to the Memory Disorders Clinic at the Austin Hospital, Melbourne and Director of the Australian Dementia Network, who described it as “great news for people living with dementia and their loved ones.”
“It is the first treatment approved for Alzheimer’s disease in 18 years and the first ever approved disease-modifying therapy,” Professor Rowe said.
“Aducanumab has been convincingly shown to reduce amyloid beta plaques in the brain, which are the likely trigger for Alzheimer’s disease. Clearing the brain from the amyloid plaques appears to slow down further damage to the brain. While treating patients showing symptoms of the disease may delay its further progression, the damage that has already occurred is not yet reversible so early treatment is essential.”
Dementia researchers in the UK also hailed the approval as “exciting news for Alzheimer’s disease and good news for dementia research.”
“Apart from the chance for patient benefit, the scientific impact of this decision will be the real-world evidence it creates as the progress of people taking the drug is monitored, said Professor John Gallacher, Director of Dementias Platform UK.
“The decision will also act as a catalyst for further drug development: it will be interesting to see how many other companies dust down their own monoclonal antibodies for further work.”
However critics have pointed out that the drug showed weak results in two key phase III randomised controlled trials, ENGAGE and EMERGE, that were terminated due to futility before their planned 18-month outcome data in patients with MCI and AD.
The American Geriatrics Society wrote to the FDA to advise against fast tracking the drug for use in clinical practice, saying the trial results were hypothesis generating rather than the basis for drug approval.
“The analysis found no benefit versus the placebo at either the low or high doses. Further analysis of additional data, however, found conflicting data regarding efficacy between the two trials, with only one, EMERGE, showing a benefit in a sub-analysis of data limited to the higher dose,” it noted
In its letter to the FDA, the Society also warned of the potential for adverse events with aducanumab, with 30-40% of individuals developing amyloid-related imaging abnormalities (ARIA). It said patients using the drug would also incur other significant support costs such as such as testing to establish amyloid-positivity (amyloid PET scans, CSF biomarkers, or other proprietary tests), and repeated brain MRI scans to monitor for the common ARIA adverse effects.
Professor Robert Howard, Professor of Old Age Psychiatry, UCL Division of Psychiatry, UCL, London, described the approval as “a grave error that will have only negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade.”
“The FDA have ignored the data we already have from over 3,000 aducanumab trial participants treated for 18 months. These indicate there is no consistent efficacy signal in terms of slowing decline in cognition or function.
“FDA Approval closes the door on further placebo-controlled trials of aducanumab that might have helped to resolve disputes about efficacy quickly and cleanly. 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.”