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Biogen announces topline results from the EMERGE and ENGAGE Phase III clinical trials of Aducanumab

Thursday 05 December 2019

On 5 December, Biogen presented the topline results from its Phase III clinical trials of Aducanumab, during a special opening session for day 2 of the 12th Clinical Trials in Alzheimer’s Disease (CTAD) conference. Aducanumab is an antibody that binds specifically to aggregated amyloid-beta proteins, facilitating their clearance by inflammatory cells in the brain. A previous Phase Ib clinical trial showed that Aducanumab could reduce brain amyloid-beta in a dose- and time-dependent manner, also slowing clinical decline in participants receiving monthly intravenous infusions of the drug.

EMERGE and ENGAGE were two global Phase III trials designed to validate the results of this Phase Ib trial, evaluating the safety and efficacy of Aducanumab in participants in the early stages of Alzheimer’s disease (AD). Together, they enrolled 3,285 participants with mild cognitive impairment due to AD or mild AD, as diagnosed by a positive amyloid PET scan. The two trials had identical designs and enrolment criteria, comparing monthly infusions of high- or low-dose Aducanumab or a placebo control over an 18-month period.

The presentation was particularly high-profile as EMERGE and ENGAGE were originally halted in March 2019, due to negative futility analyses that suggested neither trial would reach its pre-specified primary endpoint. However, in October 2019 Biogen and its partner Eisai announced that new data showed EMERGE had, in fact, met its primary endpoint; a subgroup of ENGAGE participants also met the primary endpoint.  This turnaround was the focus of Biogen’s presentation at CTAD, which was delivered by Samantha Budd Haeberlein, VP for Late State Development at Biogen.

Dr Haeberlein started by providing an overview of the design used for the two trials, with a particular focus on the dosing regimen. In both trials, participants were titrated up to a low dose (3mg/kg) or high dose (10mg/kg) of Aducanumab or placebo. She underlined the fact that a new protocol (Pv4) was instituted in March 2017, 18 months into the trial enrolment process.  The Pv4 protocol was instituted so that carriers of theApoE4risk allele could receive the high dose of 10mg/kg.  Prior to this amendment, concerns about an adverse effect known as ARIA (amyloid-related imaging abnormalities) had meant thatApoE4carriers could only be titrated up to 6mg/kg. However, a by-product of this protocol change was that participants who enrolled early in the ‘high dose’ arm received a lower median cumulative dose of Aducanumab over the duration of the trials (116mg/kg) compared to those who enrolled under the changed protocol (153mg/mg).

Next, Dr Haeberlein showed the final results for the primary and secondary endpoints in the EMERGE trial, for participants who completed 78 weeks on trial. These endpoints consisted of four cognitive and functional tests: CDR-SB, MMSE, ADAS-Cog13 and ADCS-ADL-MCI. In the high-dose group, there was a statistically significant reduction in clinical decline as measured by each of these scores, ranging between a 22% reduction in decline as measured by CDR-SB score and a 40% reduction in decline as measured by ADCS-ADL-MCI score. This cognitive and functional benefit of Aducanumab treatment was accompanied by reduced brain amyloid levels, as measured by PET scans. Together, these results confirmed that the March futility analysis of EMERGE was wrong, and that Aducanumab treatment did in fact confer a cognitive benefit for participants enrolled in this particular trial.

Dr Haeberlein then moved on to the ENGAGE trial results, which were much less clear-cut. In ENGAGE, unlike in EMERGE, there was no obvious benefit of Aducanumab over placebo when analysing the final cognitive test datasets from all participants who had completed 78 weeks on the trial. To understand why two identical trials could have such different results, Biogen went back to the full dataset and did a detailed analysis of the dosing regimens. Their aim was to see whether there was a difference in the total amount of Aducanumab received by participants in EMERGE (which had positive results) compared to those enrolled in the ENGAGE trial (which had negative results). In particular, they wanted to see whether the timing of the protocol change to Pv4 might account for this difference.

In her presentation, Dr Haeberlein showed that when Pv4 was initiated, ENGAGE had already recruited ~800 participants, whereas EMERGE had only recruited ~600 participants. She highlighted that for pre-Pv4 participants, 21% in EMERGE and 15% in ENGAGE received the full possible 14 doses of 10 mg/kg. After Pv4 was started, 51% in EMERGE and 47% in ENGAGE received the full possible 14 doses of 10 mg/kg. This means that fewer participants in ENGAGE received the highest dose of Aducanumab for a sufficiently long duration; this difference may account for ENGAGE not meeting its endpoints. In other words, for Aducanumab to be effective, Biogen believes that it needs to be taken in sufficiently high doses, for a sufficiently long duration.

Biogen now plans to file a regulatory submission for Aducanumab to the US Food and Drug Administration (FDA) in early 2020.

Link to Biogen presentation: https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3b557697c06f

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