By: Austėja Čiulkinytė
In June of 2021, the US Food and Drug Administration (FDA) granted landmark approval to aducanumab – a biopharmaceutical developed by Biogen, targeted to treat Alzheimer’s disease (AD). AD is the most common form of dementia, hallmarked by progressive cognitive decline and memory loss.
Historically, AD therapies have focused on alleviating the symptoms rather than targeting the root cause of the disease. Aducanumab, however, is the first approved drug that could tackle one of the putative pathogenetic pathways of AD: the formation of amyloid-β plaques in the brain. Nevertheless, is this truly the root cause of AD? And was the aducanumab trial data robust enough to warrant FDA approval? Questions such as these fuel the controversy within the scientific community.
Properties of aducanumab
Aducanumab targets amyloid-β aggregates, which are implicated to be involved in AD pathogenesis and regarded as a potentially lucrative target for treating this disease (Haass and Selkoe, 2007). Amyloid-β is derived by cleavage of amyloid precursor protein (APP), which is a membrane glycoprotein expressed in neuronal cells. There, it plays a role in normal neuronal development, homeostasis, signalling, and intracellular transport (Chen et al., 2017). The amyloid hypothesis proposes that the misfolding of amyloid-β leads to its aggregation in the extracellular space, and thus the formation of senile plaques. This leads to neuronal cell toxicity, neuron degeneration, loss of cognitive function, dementia, and, finally, development of AD (Chen et al., 2017).
Aducanumab is a fully human IgG1 monoclonal antibody, which was derived from an AD patient with an unusually good clinical outcome. This suggested there may be some inherent immune resistance to development of amyloid-β plaques. The isolated antibody from this patient was studied in vitro and found to have a high affinity for such plaques, but not for soluble amyloid-β. In vivo studies of mouse models showed the antibody is able to cross the blood-brain barrier, bind to amyloid‑β plaques, and reduce their load after a 6-month dosing period (Dunstan et al., 2011).
Phase 3 clinical trials
These results were validated in humans in a Phase 1 study, supporting the progression into Phase 2 and 3 clinical trials (Sevigny et al., 2016). Two identical, randomised, double-blind, placebo-controlled Phase 3 trials titled EMERGE and ENGAGE were run in parallel between June 2015 and August 2019. Over 3000 patients with mild AD from 20 countries in North America, Europe, and Australia were recruited. Patients were grouped into placebo, low-dose, and high-dose aducanumab groups. The primary outcome of the trials was a change from baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) score to assess patient cognition and function, where an increase in the score indicates clinical decline. While the ENGAGE study did not find a difference between placebo and treatment groups, the EMERGE study indicated a decline in CDR-SB score (p = 0.0120) for patients treated with high dose aducanumab. Similar results were seen for additional secondary outcomes, too, where the only statistically significant improvements were observed in the EMERGE trial for the high-dose aducanumab group (ClinicalTrials.gov, 2019a, 2019b).
The most common adverse events were amyloid-related imaging abnormalities (ARIA), specifically ARIA-E, as observed by a transient increase in MRI signals shown in brain scans. The causes and effects of ARIA-E are yet unknown. It is thought to represent transient leakage of fluid from brain vessels into the meninges, however, is not yet associated with tissue damage or other pathologies (Sperling et al., 2011). ARIA-E was observed in approx. 25% of patients receiving low-dose aducanumab and approx. 35% of patients receiving high-dose aducanumab, compared with approx. 2.5% of patients receiving placebo (ClinicalTrials.gov, 2019a, 2019b).
Approval of aducanumab
Aducanumab is the first AD drug to be approved in 18 years, and the first medication ever to target the root pathophysiological cause of the disease (FDA, 2021b). Prior to its approval, the only available therapies were targeted at alleviating AD symptoms rather than treating the disease itself. These are mainly cholinesterase inhibitors and glutamate regulators that increase excitatory neuronal transmission in the brain, allowing the remaining neurons to compensate for the loss of signalling caused by deterioration of those affected by AD (Alzheimer’s Association, 2021). However, as the disease progresses and these remaining neurons degenerate, the efficacy of such medications wears off. Aducanumab has shown a clear reduction in amyloid plaques, which are proposed to be one of the causes of neuronal degeneration. Therefore, the drug is expected to prevent further progression of the disease (Cavazzoni, 2021).
The FDA is aware of the complexities and uncertainties in the data of EMERGE and ENGAGE trials, which has sparked debate among the experts. Regardless, the FDA has focused on the data clearly showing the ability of aducanumab to reduce amyloid plaques. Therefore, they expect it to be “reasonably likely” to result in clinical benefit to the patients. (Cavazzoni, 2021). In 1992, the FDA had instituted the Accelerated Approval programme that allows drugs that address an unmet clinical need (in this case, treatment of AD) to be approved based on, for example, a surrogate clinical marker that is believed to result in clinical benefit (in this case, reduction in amyloid plaques) (FDA, 2018). This is the pathway that was used to grant approval to aducanumab despite the conflicting endpoint data.
One of the stipulations of the Accelerated Approval pathway is the requirement to conduct Phase 4 clinical studies post-approval to verify the effectiveness of the drug across a wider population (Cavazzoni, 2021). As of June 2021, 269 drugs, mainly cancer therapeutics, have been approved via this pathway. Of these, 22 have been withdrawn, 132 have been fully approved following Phase 4 studies, and 115 are awaiting a decision (FDA, 2021a). Statistically, aducanumab appears to be more likely than not to show evidence for clinical benefit in the upcoming studies. Therefore, a point could be made that aducanumab will either prove to be effective, benefiting patients and families worldwide; or it will not, having been given its best shot. In this context, the FDA’s decision makes sense, and it could truly be a breakthrough therapy for many. But is it this simple in practice?
The debate surrounding aducanumab
The approval of aducanumab has sparked many debates amongst the scientific community. Firstly, the role of amyloid-β in pathogenesis of AD is still unclear. Therapeutics targeted against amyloid-β plaques have repeatedly entered – and failed – clinical trials, suggesting that clearance of these plaques is insufficient to reverse AD, and does not necessarily correlate with cognitive improvement (Huang, Chao and Hu, 2020; Smith, 2021). Some scientists fear that the approval of aducanumab may encourage research efforts to shift to amyloid-β, instead of exploring other targets that are strongly implicated in this disease, such as tau or components of neuroinflammatory pathways (Huang, Chao and Hu, 2020; Mullard, 2021). This could prevent or delay the discovery of medicines with a greater clinical benefit (Mullard, 2021).
Historically, anti-amyloid-β drugs have failed to show a statistically significant benefit to AD patients, and the ENGAGE trial was not an exception (ClinicalTrials.gov, 2019a; Smith, 2021). In fact, both trials had been initially halted due to futility (Biogen, 2019), then resurfaced upon a later re-analysis of data showing a reduction in amyloid-β plaques following a high dose of aducanumab (Kuller and Lopez, 2021). There are fears that this is setting a precedent for other clinical trials to claim success over inconclusive or overly manipulated data. The FDA is counting on Phase 4 studies to account for this, having given Biogen a nine-year deadline to conclusively prove aducanumab’s benefit. Nonetheless, Phase 4 studies tend to have a more variable, less robust design, and receive less investment from the companies than pre-approval trials (Hill, 2012). Therefore, there is a risk of low quality data collection (Mullard, 2021).
There is no downplaying the immense benefit that the approval of aducanumab could bring to AD patients and their carers. However, there are still too many unanswered questions surrounding its efficacy, especially since the amyloid hypothesis is in no way the only explanation or viable target for AD. Although the FDA claims responsibility on protecting public health by ensuring the efficacy of medicines, in this case, it appears to have shifted over this responsibility back to Biogen. Time will tell if this will come at the expense of the patients, or if it will become a milestone step towards treating AD. Therefore, until its benefits are verified, the approval of aducanumab should be regarded with caution and should not become an example for other companies aiming to treat this devastating disease.
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