By Qinyi Wang + Kah Yan
Biogen has recently announced that their approval application for aducanumab, an immunotherapeutic drug aimed at halting the progression of Alzheimer’s disease (AD), has been controversially accepted by the U.S. Food and Drug Administration (FDA) with priority review. This review will shed light on the potential of aducanumab in AD therapy and examine the clinical trial data that has brought about debate within the scientific community.
AD is a progressive neurodegenerative disease characterised by the build-up of amyloid-beta (Aβ) protein and neurofibrillary tangles in the brain. The most common symptom is memory loss, though other higher cognitive functions are affected as the disease develops (Ising et al., 2015). Despite the prevalence of AD, the causes are poorly understood and there are currently no cures or treatments that slow its progression. Aducanumab is a human monoclonal antibody that selectively targets Aβ. Antibody-based immunotherapy against Aβ has been previously investigated to identify whether it can trigger the clearance of the aggregated protein or mitigate its neurotoxic effect (Sevigny et al., 2017). However, none so far have been successful, which makes the prospect of aducanumab therapy very appealing .
The development of aducanumab started with selecting human B-cell clones that react to neo-epitopes on pathological Aβ aggregates. Eventually, this led to the production of BIIB037 (aducanumab), an antibody that selectively reacts with both soluble oligomers and insoluble fibrils of Aβ (Sevigny et al., 2017). Pre-clinical studies in plaque-infested mouse brains found that an aducanumab analogue could successfully cross the blood-brain barrier and target Aβ (Sevigny et al., 2017).
This prompted the progression onto a phase I clinical trial. 165 patients with prodromal or mild AD and visually positive Aβ PET scans were randomised and given placebo or varying doses of aducanumab (Sevigny et al., 2017).The trial showed that aducanumab decreases Aβ in AD patients in a time- and dose-dependent manner, possibly attributed to enhanced microglia recruitment and phagocytosis. This reduction in Aβ was linked to the stabilisation of two cognitive benefit indicators, Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Mini Mental State Examination (MMSE). However, as this study was not powered for clinical assessment, cognition results are only exploratory. Amyloid-related imaging abnormalities vasogenic oedema (ARIA-E) was found to be the most prominent adverse effect (AE), shown to be dose-dependent and more common in high-risk variant Apolipoprotein (ApoE) ε4 carriers (Sevigny et al., 2017). This is consistent with findings from other anti-Aβ antibodies, posing a possible limit on the dose of antibody that can be given to patients.
Biogen then launched two multi-centre phase III trials in 2015 to further explore the clinical effects and AE of aducanumab. EMERGE and ENGAGE were two identical studies that compared low-dose/high-dose treatments and placebo in patients with mild AD (Haeberlein et al., 2019). Interestingly, Biogen scrapped the trials in March 2019 after failing a futility analysis. 8 months later, the company restarted the trials, arguing that their previous decision was based on a smaller dataset with fewer patients receiving the high-dose treatment (Lowe, 2019).
Upon analysing additional data, the EMERGE high-dose cohort showed a 22% improvement in CDR-SB scores, suggesting a statistically significant reduction in cognitive decline compared to the placebo. Secondary trial endpoints such as amyloid aggregation and MMSE were also promising (Haeberlein et al., 2019). To place a damper on this success, the low-dose EMERGE group as well as both low and high dose ENGAGE cohorts revealed no statistically significant changes in CDR-SB (Haeberlein et al., 2019). Biogen’s head of the neurodegeneration development unit explained that the inconsistent results of the two trials stem from protocol amendments, where more EMERGE patients received a higher dose of aducanumab (10 mg/kg) than ENGAGE patients (6 mg/kg) (Servick, 2019). While 6 mg/kg was initially chosen as the high-dose for precaution against ARIA-E, it was later decided that increasing the dose was safe. Overall, around 1/3 of high-dose patients developed ARIA-E, though the condition generally resolved in 4-16 weeks and the majority of these patients continued treatment. Post-hoc analysis conducted on around 570 patients consistently receiving 10 mg/kg showed a 30% improvement in CDR-SB, supporting the EMERGE data (Haeberlein et al., 2019).
While many medical experts agree that these results show promise, the initial decision to stop trials, the conflicting results and the small margins separating the treatment and placebo cohorts have prompted much scepticism (Servick, 2019). Experts concur that another clear-cut phase III trial may be needed to meet the regulatory threshold of the FDA and to fully convince the scientific community (Lowe, 2019). The FDA expects to make a decision on aducanumab by March 7 2021 after reviewing the data generated in the phase I and III trials.
If aducanumab gains regulatory approval, it will become the first treatment to address AD pathology and slow the resultant clinical decline. Not only can this benefit numerous patients with mild AD and improve their quality of life, the vast economic burden of AD may also be alleviated. However, while the potential of the drug cannot be understated, the need for more consistent and conclusive evidence should not be overshadowed.
Haeberlein, S., von Hehn, C., Tian, Y., Chalkias, S., Muralidharan, K., Chen, T., Wu, S., Li, J., Skordos, L., Nisenbaum, L., Rajagovindan, R., Dent, G., Harrison, K., Nestorov, I., Zhu, Y., Mallinckrodt, C., Sandrock, A. 2019, “EMERGE and ENGAGE Topline Results: Two Phase 3 Studies to Evaluate Aducanumab in Patients With Early Alzheimer’s Disease”, Biogen (Cambridge, MA), viewed 25 August 2020, https://investors.biogen.com/static-files/8e58afa4-ba37-4250-9a78-2ecfb63b1dcb
Ising, C., Stanley, M. & Holtzman, D.M. 2015, “Current thinking on the mechanistic basis of Alzheimer’s and implications for drug development”, Clinical pharmacology and therapeutics, vol. 98, no. 5, pp. 469-471.
Lowe, D., 2019, “The Return of Aducanumab”, Science Translational Medicine, viewed on 25 August 2020, https://blogs.sciencemag.org/pipeline/archives/2019/10/23/the-return-of-aducanumab
Servick, K. 2019, “Doubts persist for claimed Alzheimer’s drug”, Science (New York, N.Y.), vol. 366, no. 6471, pp. 1298.
Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P.H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O’Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M.S., Quintero-Monzon, O., Scannevin, R.H., Arnold, H.M., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R.M. & Sandrock, A. 2017, “Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease”, Nature, vol. 546, no. 7659, pp. 564.