At the 15th International Virtual Conference on Alzheimer’s disease (AD) and Parkinson’s disease (PD) 2021, during the Aβ targeting therapies symposium, Biogen presented positive data regarding cerebrospinal fluid (CSF) biomarker concordance with amyloid positron emission tomography (PET) in patients from the Phase III trials of aducanumab, EMERGE and ENGAGE.
Aducanumab is a recombinant human monoclonal antibody that binds primarily to aggregated forms of Aβ, including soluble oligomers and insoluble fibrils, but reportedly does not bind Aβ monomers. Aducanumab’s two main Phase III studies, ENGAGE and EMERGE, were halted in March 2019 after a futility analysis concluded that trials would not reach their primary endpoint, the slowing of cognitive decline as measured by the Clinical Dementia Rating scale Sum of Boxes score. However, in October 2019, Biogen announced that it was seeking FDA marketing approval for aducanumab, as a reanalysis of the data indicated that the EMERGE trial showed significant findings that were supported by a subset from the ENGAGE trial.
During the conference, Biogen presented the objective of the sub-trial, which was assessing the use of CSF biomarkers (Aβ42, Aβ 40, p-tau 181, and t-tau) as an alternative to PET imaging for amyloid confirmation by conducting a concordance analysis using data from the EMERGE and ENGAGE studies. CSF samples were collected during screening in subjects who consented to the CSF sub-study and also in subjects who had an invaluable amyloid PET scan. In the trial, amyloid PET scans were performed using one of the three approved PET tracers: Lilly’s Amyvid (florbetapir), GE Healthcare’s Vizamyl (flutemetamol), and Piramal’s Neuraceq (florbetaben). A lumbar puncture was performed to collect the CSF, and the CSF biomarker data were generated for the analyses using the Lumipulse G1200 automated immunoassay.
The results from the sub-trial demonstrated a robust concordance between the CSF biomarkers of amyloid confirmation and amyloid PET results at screening. Moreover, the CSF biomarker ratio had higher concordance with amyloid PET that single CSF biomarkers for the CSF ratio. Additionally, the observed sensitivity of 94%, the specificity of 88%, and overall per cent agreement of 94% seen in EMERGE and ENGAGE were comparable to the approved PET tracers. By demonstrating concordance between amyloid PET and CSF biomarkers, Biogen could enable efficient patient screening both in clinical trials and clinical practice, providing alternatives to the existing diagnostic tools for AD.
Biogen submitted the aducanumab Biologics License Application to the FDA in July 2020, and it was accepted in August 2020. The FDA also granted Priority Review to the drug. A final decision was expected in March 2021, but the FDA extended the review period by three months by asking for more information and clinical data, which Biogen has submitted. The Prescription Drug User Fee Act (PDUFA) action date is now June 7, 2021.
Key opinion leaders (KOLs) interviewed by GlobalData expressed mixed opinions about the potential for aducanumab to receive approval from the FDA, noting that the cumulative data around efficacy and safety for aducanumab are not substantial enough to meet the FDA’s standard. This concern was also expressed by a few FDA reviewers, who asked for an additional trial to confirm the evidence of aducanumab slowing the disease. However, KOLs believe that the FDA is unlikely to turn down aducanumab, even if it only has a modest benefit, given the lack of any truly efficacious therapy in the space.