Where Do We Go from Here?

Abstract

Budd Haeberlein and colleagues presented the data from the two randomized Phase 3 studies of aducanumab in early Alzheimer’s disease (AD) recently in JPAD (1). The data have been carefully evaluated by the field over the past few years and are now finally reported for closer scrutiny. Essentially, the two studies involved 3,285 participants with mild cognitive impairment or mild dementia due to underlying AD as documented by amyloid positivity. One study, EMERGE, demonstrated statistically significant findings on the primary outcome measure, three secondary measures and a tertiary measure. The parallel study, ENGAGE, failed to replicate these results. The sponsor did post hoc analyses on the ENGAGE study to rationalize its failure to replicate the EMERGE results and suggested several plausible hypotheses. Central to this discussion was the implementation of protocol amendments during the conduct of the study that may have differentially influenced the outcomes of the two studies. The studies were stopped for futility in March of 2019 according to predetermined guidelines. The sponsor, however, evaluated an expanded dataset beyond the data available to the iDMC and concluded that EMERGE demonstrated positive results while ENGAGE did not. The socio-political fallout of these studies has been enormous. From the original termination of the studies due to futility through the subsequent analyses of additional double-blinded data, the FDA’s willingness to entertain a filing, the FDA Advisory Committee’s recommendations, the accelerated approval by the FDA on June 7, 2021, and the subsequent consideration for coverage by CMS have resulted in a firestorm. As such, it may be time to step back from the media circus and look at the implications of these studies for the field and, most importantly, our patients. An interpretation of these data could conclude that there is a positive effect of aducanumab on clinical progression of AD, but the effect is modest. The combination of the positive results from the EMERGE study would be statistically quite unlikely to have happened by chance. However, these data need to be interpreted in the context of the negative results from the parallel study, ENGAGE. This may reflect reality. The impact of intervention on amyloid at the stage of plaque development, along with the symptoms of mild cognitive impairment or mild dementia, may be minimal. If one accepts the putative explanation of the development of AD pathophysiology with amyloid accumulation occurring over years to decades subsequently leading to tau hyperphosphorylation, synaptic dysfunction and cognitive impairment, then results of these types of amyloid interventions may be comprehensible. That is, if amyloid has built up over decades and if one is able to successfully reduce the plaque burden over the course of 12 to 18 months, what might be a reasonable clinical manifestation of that intervention? One could argue that the expectations should be quite modest but perhaps clinically real. The other monoclonal antibodies against amyloid that lower amyloid plaque levels currently under investigation are reporting congruent results of similar magnitude supporting the aducanumab data (2-4). As such, amyloid reduction at the plaque-formation stage might only be expected to have a minimal clinical impact. The EMERGE and ENGAGE studies suggest a positive effect on downstream biomarkers of the AD pathophysiologic cascade evidenced by tau PET, cerebrospinal fluid markers and plasma p-Tau181 measures. However, as the authors admit, these data are only suggestive due to the small number of participants involved in these substudies. Although the p-tau181 numbers were reasonable, this biomarker is least well validated in clinical trials. The only reliable biomarker data that resulted from this study involved the doseand time-dependent amyloid-lowering plaque measure obtained on amyloid PET. The other markers are certainly suggestive but hardly definitive regarding substantiation of the ultimate beneficial effect of aducanumab on lowering amyloid levels. The side effect profile of aducanumab is real and probably reflective of this class of therapies. The incidence of ARIA is significant but perhaps manageable with appropriate monitoring of the development of the ARIA-E and ARIA-H side effects (5). Subsequent data have suggested that these side effects, while real and potentially serious, can be managed and, in the appropriate setting, will allow the continuation of the therapy in most patients (6). I must take issue with the authors’ suggestion that the futility analysis was suspect. The iDMC made the correct decision given the data with which they were presented © Serdi and Springer Nature Switzerland AG 2022