In March 2019, a decision to discontinue the global Phase III trials of aducanumab for Alzheimer’s disease (AD) shook the field. Little to no information was provided about why the compound failed at the time – did it not lower plaque burden? Was there too much measurement variability? The answer remained uncertain.
However, in a big turn of events, Biogen (MA, USA) and Eisai (Tokyo, Japan) decided in October 2019 that they were going to pursue regulatory approval for the drug after analysis with a larger data set indicated that there was a reduction in clinical decline compared with the control group in the EMERGE trial, but not ENGAGE.
Once again, very little information was provided about the two trials – for example, what was different between them? Why did the ENGAGE trial fail? At the Clinical Trials on Alzheimer’s Disease Congress (4–7 December, San Diego, CA, USA) yesterday, Biogen presented detailed data on this to illustrate that the difference in the results were due to the effects of a late change that the company made to their studies – that is, allowing study participants to receive higher doses of the compound.
EMERGE versus ENGAGE
STAT news reported that within the main study analysis for EMERGE, individuals receiving a low dose of aducanumab had a rate of decline on the CDR-SB by 14%, whereas individuals on the low dose of aducanumab had a score of 23%. According to the presented data, only the result from the high-dose group was statistically significant. In comparison with the ENGAGE trial, the CDR-SB score in individuals receiving the low dose was reported to be a decrease of 12%, whereas the high-dose group had an increase of 2% .
“Biogen stated that the difference between these results can be explained by the change that was introduced midway through the study, which resulted in more participants receiving a high dose of aducanumab.”
Biogen stated that the difference between these results can be explained by the change that was introduced midway through the study, which resulted in more participants receiving a high dose of aducanumab. Additionally, ENGAGE had enrolled an additional 200 study participants compared with EMERGE at the time of their protocol amendment, which they believe could have affected how many individuals in each trial ultimately received the higher dose .
Before the protocol amendment was taken into consideration, 29% of the participants in the EMERGE trial and 22% of those in ENGAGE received the full 14 doses of the highest 10 mg/kg dose. After the protocol amendment, 51% of the participants in EMERGE and 47% of those in ENGAGE received the full dose .
Following this amendment, there was a 24% reduction in the rate of decline of the participants on the low dose and 30% in the high dose when looking at the EMERGE data. On the other hand, these figures were 20% and 27% in the ENGAGE trial, respectively. Still, the only statically significant value was reported for the high-dose group .
When observing the topline safety results from these studies, the adverse events were reported to be consistent with AD apart from ARIA. Across the two clinical trials, 16 deaths were noted and a third of these were from the placebo arm, with Biogen stating that none of the deaths were related to the event of ARIA. In addition to this, the company mentioned that the majority of ARIA was asymptomatic. On average, 75% of patients did not report symptoms during their ARIA event and when they did, they were generally mild (e.g., headaches, dizziness, nausea and vomiting). Biogen concluded that in terms of safety, ARIA in EMERGE and ENGAGE were similar to that reported in the prime study.
Speaking more about the results, Ivan Koychev (Dementia Platform UK), commented: “This is an important announcement showing that an antibody targeting the build-up of amyloid in the brain results in a meaningful reduction (20–30%) in the speed of decline as measured by memory/thinking skills loss but also crucially how well individuals manage day-to-day tasks” .
“The drug appears to be safe although a proportion of people (10–40%) developed a reaction to the drug (ARIAs) that can be seen using head scans (MRIs) – while it was said that this was not associated with significant symptoms and resolved spontaneously, it is unclear what the impact of this side effect will be in people treated long-term” .
Overhyped or the great hope?
During the panel discussion that took place following the results, all panelists were seen to be supportive of the clinical benefits of aducanumab. However, when observing the group of participants who received the highest dose of the drug for the longest period of time, aducanumab was reported to outperform placebo by only 0.5 points on a three-point scale of dementia .
To some, this number doesn’t provide meaningful benefits but to the panelists, it was mutually agreed that it was clinically meaningful. Below is a selection of quotes transcribed from a few of the panelists when they were asked to provide their initial impression of the data presented and its meaningfulness:
“It’s challenging but when we consider the difference in the timing of enrollment into ENGAGE, relative to the protocol version change and the resulting reduced exposure to the effective high dose of aducanumab, I think the data from ENGAGE and EMERGE can be considered consistent.”
Paul Aisen (University of Southern California, CA, USA) stated: “The futility decision was highly unfortunate and puts us in a situation of interpreting complex data. But clearly, the EMERGE final analysis is positive – the primary analysis of EMERGE is positive and the analysis of all the key secondaries was consistent and positive, and as important, the biomarker evidence supports the mechanism with significant amyloid reduction leading to tauopathy, reduction in tauopathy indicated by both tau PET and CSF phospho-tau.”
“The results of the final analysis of ENGAGE are negative – is this truly discordant? Can we understand this? It’s challenging but when we consider the difference in the timing of enrollment into ENGAGE, relative to the protocol version change and the resulting reduced exposure to the effective high dose of aducanumab, I think the data from ENGAGE and EMERGE can be considered consistent,” added Aisen.
Principal investigator, Sharon Cohen (Toronto Memory Program, Canada) commented: “I share with Paul the fact that the positive results, the first time for an AD-modifying agent being positive for primary and secondary biomarker endpoints is exhilarating not only to the scientific community but to patients as well. The ability to hold on the daily living – if you think about a 40% reduction in decline on the ADCS-ADL-MCI, you’re talking about people at a mild stage of disease still able to bank, work, shop and enjoy leisure activities for longer. This matters a lot more to patients than what score they got on a memory test.”
Despite the positive outlook from the panel, the in-depth data reported on aducanumab has been met with some skepticism. Robert Howard, a psychiatrist at the University College London (UK) mentioned that he doesn’t “think that it should be given market approval on the basis of these data” and that “more positive results from a subset of patients that weren’t preselected at the trial’s launch are not convincing” .
So, what’s next for aducanumab following this detailed report? Will the US FDA determine that there is enough evidence to approve the drug, or will they ask Biogen to perform a final Phase III trial of the full high dose? These questions remain uncertain but alongside the rest of the scientific community, we’re eagerly waiting to hear more about the outcomes from further discussions surrounding this.
 STAT news. Detailed data on Biogen’s resurrected Alzheimer’s drug raise more questions than answers.
[Accessed 5 December]
 Science Media Centre. Expert reaction to Biogen’s presentation on the drug aducanumab for Alzheimer’s at the CTAD Conference.
[Accessed 5 December]
 Science Magazine. Skepticism persists about revived Alzheimer’s drug after conference presentation.
[Accessed 5 December]