Aducanumab for Alzheimer’s disease: The never‐ending story that nurses should know

Abstract

In October 2019, the American pharmaceutical company Biogen stated intention to apply to the US Food and Drug Administration (FDA) for the candidate drug aducanumab to be licenced as a therapeutic agent for the treatment of Alzheimer s disease (AD). If approved, aducanumab would become the first new medication licenced specifically for the treatment of AD in the past decade; and approval in the US may be a precipitant for approval elsewhere. Predictably, the potential advent of a new drug for AD has resulted in considerable excitement amongst the general population, healthcare professionals and AD charities alike (Alzheimer’s Research UK, 2019). This enthusiasm is understandable as aducanumab has been posited as a medication that can reduce brain amyloid accumulations and reduce clinical decline seen in AD (Biogen, 2019a; Wang & Holtzman, 2020), which is currently viewed as a progressive and irreversible neurodegenerative condition with cerebral atrophy, cognitive decline and a loss of functionality for the individual (Wang & Holtzman, 2020). Currently approved evidencebased pharmacological agents for AD include acetylcholinesterase inhibitors, such as donepezil and galantamine, and the glutamatergic antagonist memantine (BNF, 2021). An important distinction to make is that presently approved medications are considered to slow the progression of AD whereas aducanumab has been stated to reverse the pathological process, and associated clinical decline, by way of clearance of extracellular amyloid beta plaques observed within AD (Carroll, 2020). If aducanumab really can reverse these features and reduce the cognitive decline, this would be a revolutionary treatment. Whilst on the surface this sounds a very positive advance with significant potential, the decision by Biogen to pursue FDA approval has raised some concerns (Carroll, 2020). Aducanumab – a highaffinity, fully human IgG1 monoclonal antibody – is actually not a new drug; it was first produced by Neurimmune and its licence was sold to Biogen in 2007 (Neurimmune, 2020). There have been several earlier studies exploring aducanumab within the treatment of AD which failed to demonstrate efficacy when compared to placebo. This apparent lack of response to aducanumab within clinical trials had led to Biogen s own phase three trials being discontinued in early 2019 (Biogen, 2019a). Despite discontinuing the trials, Biogen undertook a retrospective data trawl which has appeared to uncover incorrect analysis earlier in the study, leading Biogen to claim that the original trial dose was too small and that one of the twophase three clinical trials [the EMERGE trial] actually did reduce clinical decline in patients with early AD (Biogen, 2019b). This statement of success appeared conflicted with an earlier disclosure highlighting that the trial did not need the prespecified end point, so confusion abounds. This new analysis of the data was reported to have observed a “statistically significant reduction in clinical decline in early AD patients,” and it has been claimed that greater exposure to high dose aducanumab was the primary driver for the apparent positive results (Biogen, 2019a). Following Biogen s announcement to seek FDA approval which was declared without full disclosure of supporting data at the timeindependent analyses was undertaken following public presentation of the data during on 5th December 2020. These data have split opinion with regard to the potential efficacy for AD with protocol amendments, initiated midstudy in 2017, proving problematic for many reviewing the data. The conflict as to whether the data presented were a true reflection of an objective and transparent trial remains palpable. Indeed, the UK Alzheimer’s Society (2019; Alzheimer’s Research UK, 2019) state it is not possible to determine whether aducanumab is effective, yet the US Alzheimer s Association are currently strongly advocating for approval by the FDA (Alzheimer’s Association, 2020); even stating that a further delay to undertake additional clarifying trials would not be acceptable. AD charities have an influence about the hopes of people living with dementia, their carers and many healthcare professionals; and it could be argued that advocating for FDA approval may be providing a higher level of optimism than is perhaps realistic. Given the important role of many charitable organisations, it is of paramount importance that the public are aware of the conflicting messages emanating from what are two of the most wellknown AD charities, to permit objective discussions based on the evidence. Currently, we are still awaiting a decision by FDA as to whether approve aducanumab for clinical practice. This decision was due to be made in March 2021 but has now been delayed until 7 June 2021. This delay is following an FDA request for additional data from Biogen, which has been provided. This should be viewed in the context of an FDA advisory committee which met in November 2020 and raised significant concerns questioning the effectiveness of aducanumab. The outcome of this advisory committee appeared to