The controversial Alzheimer disease drug aducanumab needs more scientific evidence of benefit and its approval for use in Australia could overwhelm and bankrupt dementia services, local experts have said.
Currently under review by the Therapeutic Goods Administration, the drug has been shown to reduce amyloid plaque but this does necessarily translate into clinical benefit, according to Dr Andrew Gleason of the Melbourne Dementia Research Centre at the Florey Institute of Neuroscience and Mental Health.
In a MJA perspective article co-written with Professor Ashley Bush and Dr Scott Ayton, he argues that regulatory approval should be made on the basis of evidence of clinically meaningful benefit from controlled clinical trials, rather than surrogate outcomes.
The US Food and Drug Administration (FDA) gave accelerated approval for aducanumab to be used in Alzheimer disease despite Phase 3 trials being terminated early in 2019 after a futility analysis, the article notes. This unusual decision, contrary to the recommendations of 10 of the 11 members of the advisory committee led to three FDA advisors resigning in protest.
Proponents of the drug have defended the approval by arguing that Alzheimers is a serious disease with a large unmet need, and patients should be allowed access to a promising therapy while more data are collected.
However the Australian authors say an “expectation of benefit” does not provide a compelling case for clinical use, especially when there are also doubts about the amyloid-β hypothesis itself.
“There are no data from clinical trials of aducanumab, or any other source, to indicate that lowering amyloid-β has clear clinically significant benefit,” they write.
“Data from other trials to date suggest that amyloid lowering does not have an appreciable effect on cognition, and in some studies, patients treated with amyloid-β-lowering therapies were cognitively worse.”
Dr Gleason and colleagues say that regulatory approval based on a post hoc analysis is akin to “winning a sharpshooter contest by drawing a bull’s-eye around a bullet hole”.
The authors also highlight the high costs of the drug, which currently costs the equivalent of AU$40 000 a year in the US.
Even on conservative assumptions of 10% of Australians eligible for treatment receiving the drug, the annual cost would be approximately AU$600 million or nearly 5% of the $12.6 billion PBS scheme budget. And the actual costs would be even higher because of the need to account for the staff time and infrastructure needed for infusions as well as the MRI screening scans needed for amyloid‐related imaging abnormality (ARIA), they state.
“A scarcity of dementia specialists to make Alzheimer disease diagnoses, limited access to infusion centres, and poor availability of amyloid imaging are bottlenecks. An increase in demand for diagnosis would likely overwhelm our limited dementia diagnostics services,” the authors write.
“Premature approval without evidence of clinically meaningful benefit from controlled clinical trials is costly to government as well as patients (who are exposed to side effects), may make it harder to recruit to experimental placebo-controlled clinical trials, and could divert research funding away from the development of more effective treatments,” they conclude.
“Disease-modifying therapies for AD are urgently needed, but science, not desperation, should guide the approval process.”
A spokesperson for Biogen, said the company “stands by the safety and efficacy of aducanumab as supported by our data.”
“Data from the Phase 3 EMERGE trial demonstrated a statistically significant change across all four primary and secondary clinical endpoints, showing significant reduction in clinical decline. ENGAGE did not meet its primary or secondary endpoints. Reductions in amyloid beta plaques and phosphorylated tau, the two pathophysiological markers of AD, were observed in both trials,” a spokesperson said.