Controversial Alzheimer’s drug under TGA review ‘should not be approved’

Dementia affects nearly half a million people in Australia, and researchers predict that number will double by 2056.
 
With Alzheimer’s disease already accounting for almost two-thirds of cases, the search for effective disease modifying treatments is one of the highest priorities.
 
One such drug, aducanumab, is currently under review by the Therapeutic Goods Administration (TGA).
 
But while this may be perceived as a positive step forward, Australian experts are advocating against its approval, citing both safety and efficacy concerns.
 
In a Perspective article, published in the Medical Journal of Australia (MJA), the authors note that while the drug has received US Food and Drug Administration (FDA) approval, phase 3 clinical trials were terminated early after a futility analysis.
 
‘A subsequent post hoc reanalysis of additional data led to approval on 7 June 2021 via the Accelerated Approval Program, not on the basis of demonstrated clinical efficacy, but on the unproven presumption that reduction of amyloid plaques is “likely to predict clinical benefit”,’ the authors wrote.
 
‘This approval took place despite the recommendations of 10 of the 11 members of the advisory committee [one abstained]. Three FDA advisors subsequently resigned in protest and the FDA commissioner requested an independent inquiry into the process that led to approval of the drug.
 
‘Proponents of the approval, including the FDA and the Alzheimer’s Association, defended the decision by arguing that Alzheimer’s disease is a serious disease where there is unmet need, and, if there is a chance that a drug could provide a benefit, patients should be allowed access while more data are collected.’
 
Aducanumab has been tested in two phase 3 randomised controlled trials. While no statistically significant benefits emerged from the ENGAGE trial, statistically significant results favouring the drug, with a small effect size, were found at 78 weeks for participants in the EMERGE trial for those on a high dose.
 
However, the authors say that a negative trial raises questions about reliability of the results, and whether the positive findings could be ‘due to chance alone’.
 
‘Even if the findings from EMERGE are true, the magnitude of benefit is unlikely to be clinically meaningful,’ the authors wrote.
 
Article co-author Professor Ashley Bush, the Director of the Melbourne Dementia Research Centre at the Florey Institute of Neuroscience and Mental Health, told newsGP he holds grave concerns should the drug be approved. 
 
‘We wanted to make sure that some of the arguments concerning doubts about it were clear for the TGA to appreciate,’ Professor Bush said.
 
‘Also, the data haven’t been published in peer-reviewed journals; they have only been presented at conferences or through the FDA.
 
‘So, we agree with the consultants that the FDA used to advise them – 10 out of 11 of whom did not recommend registering the drug.’
 
Beyond efficacy, the authors also raise significant safety concerns about amyloid related imaging artifact (ARIA), a common side effect of the treatment noted among 41% of participants receiving the effective trial dose.
 
Clinical symptoms of ARIA, such as headache, delirium, dizziness and visual disturbance, were present in 24% of those on high dose and remained unresolved in 12% over the study period. And while serious symptoms were only seen in 0.3%, many required hospital admission and treatment with steroids or antiepileptics.
 
Professor Bush says there is growing evidence that ARIA ‘could be hazardous’.
 
‘It’s not just an imaging anomaly, it actually can be associated with a variety of neurological complications, which indicate that it might not be as safe as has been proposed,’ he said.
 
While the cause of Alzheimer’s disease is thought to be multifactorial, a common theory is that there is an abnormal build-up of amyloid-β in and around the brain cells.
 
Aducanumab, a human monoclonal antibody, is thought to target that build up, by selectively reacting with amyloid-β to reduce plaque around the cells. 
 
However, Professor Bush and his co-authors have even questioned the hypothesis, noting that ‘there are no data from clinical trials of aducanumab, or any other source, to indicate that lowering amyloid-β has clear clinically significant benefit’.
 
On the contrary, Professor Bush said that some studies from other trials indicate that patients treated with amyloid-β-lowering therapies were cognitively worse, with significant adverse effects such as shrinking of the brain.
 
‘But Biogen, the company that owns the drug, has not reported anything about this as a readout,’ he said.
 
‘They must have the data, but they’ve been completely silent on it.
 
‘So that’s another level of hazard that we, as authors, were worrying about – whether this drug actually increases atrophy. We don’t know until the company actually reveals these results.’
 
Beyond safety and efficacy concerns, the authors also warn about the economic impact should the drug be approved and made available at a similar level to its sale price in the US.
 
Under this scenario, even if just 10% of eligible Australians receive aducanumab, the annual cost would be approximately $600 million – equivalent to almost 5% of the Pharmaceutical Benefits Scheme’s annual spend.
 
But despite the concerns, the paper’s authors are not totally opposed to the drug potentially being used in Australia – they just would like to see more data first.
 
‘There are still too many questions to be asked about the ARIA,’ Professor Bush said.
 
‘When you add that to the efficacy problem, it would seem to me that the prudent thing to do is to go back into phase 3 clinical trials and try to get an efficacy signal that’s clear and better information about the safety.
 
‘Let’s see whether it’s worth the trouble.
 
‘Really, I think it’s too soon for this drug to be launched in Australia – and I think it’s too soon for it to be launched worldwide. This is an instance where regulatory authorities need to tread very carefully.’
 
Aside from the potential costs for patients and governments, the authors conclude that premature approval of the drug may make it harder to recruit to experimental placebo-controlled clinical trials for other Alzheimer’s medication, and could divert research funding from the development of more effective treatments.
 
‘Disease-modifying therapies for Alzheimer’s disease are urgently needed,’ the authors wrote. ‘But science, not desperation, should guide the approval process.’
 
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