08 June 2021

Article by Mark Watling

Download as PDF

This week’s news that the FDA has approved aducanumab for the treatment of Alzheimer’s Disease (AD) under its Accelerated Approval Program – despite its almost unanimous rejection by the FDA’s own Peripheral and Central Nervous System Drugs Advisory Committee in November 2020 – is being hailed by the world’s media and patient advocacy groups as a major breakthrough in the fight against this awful disease. FDA approve aducanumab for the treatment of Alzheimer’s Disease

However, closer examination of the rationale for this decision – as provided by the FDA’s own analysis – reveals an astonishing shift in position by the Agency, with the admission that although the clinical data “left residual uncertainties regarding clinical benefit”, the drug had been “shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients”.  Use of the phrase ‘reasonably likely’ is remarkable enough – but surely this should mean that the labelling will indicate aducanumab is approved for the reduction in brain β-amyloid load in the setting of AD, rather than treatment of the disease itself?

Most of the controversy, however, arises from the departure from the usual standard of requiring two confirmatory trials – with the reanalysis of the first EMERGE study producing results that were not confirmed by the second ENGAGE study, and the apparent disregard for concerns over the possible deleterious effects of targeting B-amyloid revealed in other recent studies.

Breaking through… or moving the goalposts…?The FDA’s decision to use the Accelerated Approval pathway (“pathway intended to provide earlier access to potentially valuable therapies for patients with serious diseases where there is an unmet need, and where there is an expectation of clinical benefit despite some residual uncertainty regarding that benefit”) would perhaps be a little more understandable in the absence of any evidence of risk associated with this therapeutic approach.  However, a significant number of studies with other immunotherapeutic products targeting B-amyloid have shown increased rates of cognitive decline and worsened neuropsychiatric symptoms compared to placebo – with many being terminated early for this reason (Panza, 2019; Imbimbo, 2020). In this context, the FDA’s assertion that this course of action is justified because “the benefits of Aduhelm for patients with Alzheimer’s disease outweighed the risks of the therapy” appears extraordinary.

While understanding the desire to provide something to those whose lives are being devastated by AD, it will be interesting to see whether this largesse extends to those who actually have to pay for a therapy with “an expectation of clinical benefit”.  Furthermore, it will be interesting to see what other manufacturers make of this precedent, and whether it opens the gates to a flood of applications for the approval of products with similarly equivocal evidence…

Further reading 
1.    FDA Press Release on aducanumab approval: https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease
2.    FDA Advisory Committee Minutes, 6 Nov 2020: https://www.fda.gov/media/145690/download
3.    Panza F, Lozupone M, Bellomo A, Imbimbo BP. Do anti-amyloid-β drugs affect neuropsychiatric status in Alzheimer's disease patients? Ageing Res Rev. 2019; 55:100948. doi: 10.1016/j.arr.2019.100948
4.    Imbimbo BP, Lozupone M, Watling M, Panza F. Discontinued disease-modifying therapies for Alzheimer's disease: status and future perspectives. Expert Opin Investig Drugs 2020; 29(9): 919-933. doi: 10.1080/13543784.2020.1795127