The ‘Aducanumab Story’: Will the Last Chapter Spell the End of the ‘Amyloid Hypothesis’ or Mark a New Beginning?

Abstract

The paper entitled “Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease” by Budd Haeberlein, S., Aisen, P., Barkhof, F. et al in the current issue of J Prev Alzheimers Dis [https://doi.org/10.14283/jpad.2022.30] presents the much-anticipated results of two pivotal trials to demonstrate the safety and efficacy aducanumab as a therapy for early-stage Alzheimer’s disease [AD]. This phase 3 study shows a reduction of molecular imaging and biofluid markers of AD is associated with a slowing of cognitive decline. These results received an accelerated approval by FDA in June 2021 based on the drug’s effect on a surrogate endpoint that is ‘...reasonably likely to predict a clinical benefit to patients ...’ (1). This ‘conditional’ regulatory ruling requires further confirmatory [phase-4] trials to verify that drug effect on the surrogate endpoints actually predicts a clinically meaningful benefit. The subsequent decisions by EMA [in the EU] and the CMS [in the US] have not been favorable for the routine clinical use of this drug for treatment of dementia-AD. These landmark regulatory determinations by FDA, EMA and CMS have created controversy with passionate debates regarding: the methodological flaws of the two pivotal trials, questionable scientific rational, weak association between surrogate marker and cognitive function, financial implication of high cost of treatment and the uncertainty of the ultimate clinical utility; pending validation of a clinically meaningful benefit for the patient (2). Regardless of the various stances in ongoing debate over the regulatory ruling and the clinical merits of aducanumab, it is important to publish the results of the first phase-3 trial to show a putative association between a surrogate marker and a behavioral/clinical feature of dementia-AD. This study, and the ensuing ‘conditional’ regulatory decision, is a significant ‘teaching’ milestone in the 40-year struggle to develop effective diseasemodifying interventions of dementia-AD. Heated debates over controversial issues in science is not a new phenomenon or necessarily detrimental to progress. For example, nearly thirty years ago the study and the regulatory ruling regarding Tacrine, the first drug approved for AD, was also controversial. [DOI: 10.1177/106002809402800612]. The study was plagued with methodological problems; adverse events [re: liver toxicity] halted the trial before completion and as in the present situation FDA was concerned with the adequacy/validity/relevance of the outcome measures. Eventually by 2013 Tacrine [Cognex] was withdrawn from the market due to its limited clinically meaningful benefit and concerns over its link to liver toxicity. But, Tacrine was an important ‘teaching event’ in the history of therapy development for AD. In retrospect one of the important aspects of the Tacrine experiences was the fact that FDA set the regulatory hurdle-requirement for approval at ‘just right’ level, which might be the case in the debate over the pros and cons of the conditional approval the aducanumab. Thirty years ago, if the FDA’s ‘regulatory-bar’ for Tacrine was set too low, it would have encouraged the development of a plethora of junk treatments with questionable efficacy. On the other hand, a higher ‘regulatory-bar’ would have stifled further R&D on alternative putative interventions based on the cholinergic hypothesis. Now, both the FDACMS regulatory decisions regarding aducanumab might be the ‘just right’ level of regulatory hurdle-requirement for a complete approval. In the final chapter of ‘story’ it turned out that Tacrine was not an ideal drug, but its legacy paved the way to further research on improved drugs. So, the good news about aducanumab is that [even if in the long run it fails the promise of becoming treatment of choice], the FDA’s conditional approval has already created an encouraging environment for further investments in R&D of drugs in this class. But, the bad news is the challenge facing aducanumab in addressing the need for strong compelling evidence [e.g., a big drug effect (3)] to validate the regulatory premise for the conditional approval; namely the assumption that © Serdi and Springer Nature Switzerland AG 2022