The first pharmaceutical treatment for Alzheimer’s Disease (AD) to be approved by the US Food and Drug Administration (FDA) in almost 20 years, ‘aducanumab’ (commercially known as ‘Aduhelm’) gave a brief glimmer of hope to the 1 in 10 Australians over 65 years of age living with the disease.
But the decision has come under fire by the Australian medical community, who are strongly warning against the Therapeutic Goods Administration (TGA) blindly following suit.
In an article published in the Medical Journal of Australia (MJA), Dr Andrew Gleason, Associate Professor Scott Ayton and Professor Ashley Bush, from the Florey Institute of Neuroscience and Mental Health and the Concord Repatriation General Hospital, warn that despite FDA approval, trial data is not sufficient for Australian medical professionals to cite confidence in the treatment.
“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,” they write.
“Disease-modifying therapies for AD are urgently needed, but science, not desperation, should guide the approval process.”
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.
Australian medical experts
The drug, patent owned by American multi-national biotechnology company Biogen, has an inconsistent track record in clinical trials.
One of two phase 3 trials, called ENGAGE, was abandoned in 2019 when it failed a futility analysis: the statistical test occurring part way through the clinical trial to assess whether the new drug intervention would be likely to perform better than the control.
However, data from the second trial, EMERGE, showed a small yet statistically significant benefit; those being administered a high dose of the drug exhibited improvements in cognition, function, and behaviour.
This latter trial data was the basis for the drug company’s application to the FDA’s Accelerated Approval Program, which simplifies the approval process for drugs targeting serious conditions without existing therapies.
The US regulator, in turn, approved the drug for sale in the US on 7 June 2021
Less than a year after hitting the US market, the TGA has begun its own review to assess whether the drug is fit to enter the Australian market.
But Gleeson et al have warned against hastily welcoming the drug onto Australian shores.
“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 said.
Furthermore, they add that the potential cost to the Pharmaceutical Benefits Scheme, Australia’s publicly funded subsidy scheme for prescription medications, was found to be disproportionately hefty compared to the potential clinical benefit for Australian citizens on the whole.
Gleason and colleagues calculated that if just 10 per cent of eligible Australians were prescribed the drug, based on current US pricing, the annual cost to the Pharmaceutical Benefits Scheme would be approximately $600 million, nearly 5 per cent of the scheme’s total annual spend.
Questionable drug trials and a complacent regulator
Associate Professor Scott Ayton, director of the Centre of Research Excellence in Enhanced Dementia Diagnosis, deputy director of the Melbourne Dementia Research Centre, and co-author of the MJA article, tells Aged Care News that US approval of the drug rests questionable grounds.
“Most are unconvinced by this data, and even the FDA did not approve the drug based on any evidence of clinical change, rather that they deemed it ‘reasonably likely’ that amyloid lowering would result in clinical change,” he says.
Scientists’ doubts, he explains, come down to an ongoing debate as to the root aetiology — or the root cause — of the degenerative condition.
“AD is defined by the presence of amyloid beta (β-amyloid) plaque in the brain — other dementias do not show this pathology, and for a biologically confirmed diagnosis of AD, this pathology can be detected by PET scan, in the cerebrospinal fluid, and even now in the blood,” Ayton says.
“There has been a longstanding debate as to whether β-amyloid plaque causes/contributes to brain damage observed in AD, or if it is analogous to the ‘pox’ of smallpox — a defining lesion, but the disease is caused by another factor (in the case of smallpox, a virus).
Despite this, the theory has persisted, even in the face of failed clinical trials, with reduction of β-amyloid not contributing in any meaningful way towards the prevention of treatment of disease progression.
“This unshakeable belief was even evident in the FDA,” Ayton remarks.
“While conceding that the amyloid beta lowering drug, aducanumab, did not show convincing evidence of clinical improvement in clinical trials, the FDA shocked the field when they approved the drug because they judged it ‘reasonably likely’ that it would provide benefit – despite what the clinical trials showed.”
Furthermore, the lack of specificity in the FDA’s prescribing criteria causes Ayton to believe the medication will be overprescribed, in particular to patients with non-Alzheimer’s forms of dementia.
“The FDA’s decision on aducanumab controversially did not require that patients have confirmed β-amyloid plaque pathology, meaning that many people (a quarter of patients) who take this drug cannot possibly benefit from the treatment, yet they will still be exposed to the side effects.”
The FDA’s decision on aducanumab controversially did not require that patients have confirmed β-amyloid plaque pathology, meaning that many people (a quarter of patients) who take this drug cannot possibly benefit from the treatment, yet they will still be exposed to the side effects.
Associate Professor Scott Ayton
“Was it a mistake to target amyloid beta? Not at all. This was a perfectly reasonable hypothesis to test, although there was always a minority who argued against this approach.
“But I do believe it was a mistake that the field persisted, almost exclusively, with targeting amyloid beta despite scores of trial failures.
“Every excuse for why they failed was used to justify persisting with the anti-amyloid approach rather concede the simpler- but troubling- conclusion that amyloid beta is not a good drug target.
He notes that the persistence in drug development via this mechanism of action has come at the cost of “many other worthy targets to treat AD that for decades struggled to obtain funding.”
“I only hope that this is now starting to change, but it will be hard to test these drugs in clinical trials in the community if patients are treated with aducanumab; patients often do not want to enrol in an experimental clinical trial if there is already an approved drug.”
Uncertainty, lack of publicly available data regarding side effects
It is almost two-and-a-half years since the drug’s initial results were released by Biogen, but Ayton notes that this trial data has not yet been published in a peer reviewed journal; it has not even been uploaded to the pre-print site as is conventional within the field.
“This is especially outrageous, since doctors in America are currently prescribing this drug without access to the full safety data.”
Three people have died whilst taking the drug, but a lack of clinical data precludes any reliable investigation into whether it is pure coincidence, or directly causal.
“We do not know whether these deaths are related to the side effects of these drugs because Biogen has not released the data,” Ayton says.
The most significant safety concern relates to the potential for inflamation in the brain, called ‘amyloid related imaging abnormality’ (ARIA), a condition detectable via MRI.
“This occurs in about one third of patients [and] often resolves when the lesion is detected, and the patient is taken off drug for a period of time.”
However, on some occasions, the condition can be severe, “… causing significant migraine, confusion, dizziness and nausea , which can require hospitalisation and may take many months to recover.”
… trial data has not yet been published in a peer reviewed journal; it has not even been uploaded to the pre-print site as is conventional within the field. This is especially outrageous, since doctors in America are currently prescribing this drug without access to the full safety data.
Associate Professor Ayton
Long term consequences of this condition are yet to be determined, continues Ayton, but there is a likelihood they could be severe and even counterproductive to the treatment’s primary objective.
“One potential consequence is brain atrophy (death of brain cells).
“Brain volume loss is a common reported side effect of other anti-amyloid drugs — this is exactly the opposite result we want to achieve with these drugs (they are supposed to stop brain volume decreasing).”
Hence, Ayton explains that brain volume was a “key pharmacodynamic endpoint” in the trials, a key criterion against which the safety and efficacy of aducanumab could be assessed.
“If aducanumab slowed brain volume loss (that ordinarily occurs in Alzheimer’s disease) this would be objective evidence that the drug benefited the patient.
“If brain volume loss was accelerated by aducanumab, it would suggest that the drug was damaging.
“These data have not been released by Biogen or the FDA.
“It may be possible that ARIA resolves clinically and radiologically, but still causes further brain damage.
“This is another reason why it is critical that Biogen release the trial findings.”
The importance of an independent Australian regulator emphasised
As mentioned previously, Phase 3 trials for aducanumab were terminated early in 2019 after a futility analysis, but the drug was revived in 2021 through the FDA’s Accelerated Approval Program, which fast-tracks approval of drugs that target an “unmet need” in the pharmacopoeia.
“Accelerated Approval relies on a surrogate marker of disease progression, not clinically observable benefit,” Ayton explains.
“There may be a role for an Accelerated Approval Program, but in the case for AD, an accelerated approval is hard to justify.”
Ayton notes that the accelerated approval of aducanumab was predicated on the belief, as Dr Cavazzoni, director of FDA Center for Drug Evaluation and Research presented, that ‘reduction in plaques is reasonably likely to result in clinical benefit’.
“Yet Dr Massie, who led the FDA statistical Review and Evaluation of aducanumab, concluded that ‘there is no evidence that SUVR (measure of amyloid beta) is a surrogate for clinical change’.
Ayton posits that if an accelerated approval program is to be used, “we should adhere to the principles of conservatism and ‘do no harm’.”
In contrast, he lays out a variety of indicators that demonstrate the FDA have been too hasty in their approach to the new drug.
- Aducanumab was approved for all people with a diagnosis of Alzheimer’s disease, even those with advanced disease. The clinical trials only investigated very early Alzheimer’s disease.
- The indication for aducanumab did not limit this to people with confirmed amyloid beta pathology. A quarter of people with a clinical diagnosis of Alzheimer’s disease do not have amyloid beta pathology and cannot stand to benefit from aducanumab.
- The monitoring of ARIA side effects was limited, especially compared to the protocols used in the clinical trials.
- The clinical trial protocols for aducanumab were highly selective and not representative of the target population. A recent analysis reported that 92 per cent of people living with Alzheimer’s disease and receiving Medicare in the United States would not be eligible for enrolment in the aducanumab clinical trials. The FDA did not place restrictions on which Alzheimer patients could be prescribed aducanumab.
- The FDA required a confirmatory trial for aducanumab, but permitted them nine years to complete this.
What should the Australian regulator do, in light of this?
“The TGA should not blindly follow the FDA’s decision,” Ayton advises.
“The FDA’s decision was under an Accelerate Approval designation, not regular approval, which is even more reason why the TGA should assess what is right for Australia.”
“There is no compelling evidence that aducanumab benefits patients, even in artificial and highly controlled clinical trials. There is evidence that it causes harm. On this basis, aducanumab should not be approved by the TGA.”
More about Alzheimer’s Disease
Alzheimer’s disease is incurable degenerative disease, affecting up to 1 in 10 Australians over 65 years of age.
It is the most common type of dementia, comprising 7 out of 10 cases.
The most commonly recognised symptom is memory loss, though the disease affects various areas of cognitive and emotional functioning, including:
- vagueness in daily conversation
- lack of enthusiasm for activities you once enjoyed
- taking longer to do regular tasks
- forgetting well-known people or places
- difficulty processing questions and instructions
- a decline in social skills
- unpredictable emotions
Scientists have isolated three main pathological processes for the disease, though more research is needed to understand the best target for preventing its development.
These include:
- Amyloid plaques are deposits outside the brain cells — they prevent the brain from passing signals properly.
- Neurofibrillary tangles are deposits inside the brain cells — they kill the cells by blocking off food and energy, causing dementia that worsens over time.
- Neuronal death causes shrinking in the outer layer of the brain (the cortex) which is vital to memory, language and judgement — Alzheimer’s disease is characterised by this shrinkage.
