On October 22nd, 2019, headlines read “Biogen plans regulatory filing for Aducanumab for Alzheimer’s disease based on new analysis of larger dataset from phase 3 studies”. Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by cognitive dysfunction and memory loss. It is the 6th leading cause of adult deaths in the United States. Biogen is a multinational biotech company that specializes in neurological disease, and in 2007, the company bought aducanumab from Neuroimmune, a small pharmaceutical company, and the research team from the University of Zurich who discovered it. Aducanumab is a monoclonal antibody that is injected intravenously and targets aggregated forms of amyloid-β (one of the two physiological hallmarks of AD) in hopes to reduce amyloid-β buildup. What makes this drug novel is its potential to slow the progression of AD. It would be the first drug on the market that treats the disease as a whole, not just the symptoms of AD. However, this announcement stirred up much skepticism in the field.
Aducanumab first entered clinical trials in the early 2010s, and the results from its Phase 1b study were reported in March 2015. Sevigny et al.’s paper showed that aducanumab reduced amyloid-β plaque load measured by PET scans and reduced cognitive decline measured by standard dementia scales in patients with mild AD in a dose-dependent manner. The data suggested aducanumab may be the answer for the millions of patients waiting for a treatment. The data were strong enough to push the drug into two phase 3 trials, which started in September of 2016, called ENGAGE and EMERGE. Combined, the two studies enrolled over 3,000 patients across the US and Europe. During a routine mid-point analysis to determine whether a drug is likely to be as effective as predicted, an independent group’s analysis showed that the trials were unlikely to ‘meet their primary endpoint’; and in March 2019, Biogen cancelled all aducanumab trials. Then in a twist of events, Biogen revived aducanumab and announced their plans for regulatory filing to bring the drug to market. This unexpected development resulted in a unanimous question: what happened?
Those following the life, death, and resurrection of aducanumab got answers when a panel of Biogen representatives presented at the Clinical Trials on Alzheimer’s Disease 2019 annual meeting. There we learned that during the trials, the doses were increased from 6mg/kg to 10mg/kg for ApoE4 carriers. ApoE4 is the greatest genetic risk factor for developing late onset AD. Approximately two-thirds of the trial participants carried this ε4 mutation, which is consistent with AD populations. After Biogen cancelled the trials due to the futility analysis, they stopped drug administration but continued to collect data. As time went on, more promising data was reviewed from patients who had been switched to the higher doses, indicating the higher dose was more efficacious than previously thought. Currently, ENGAGE does not show significantly improved outcomes in AD patients; however, EMERGE, which started a month later, does. The scientists at Biogen explained this difference by noting that the average patient in ENGAGE received a cumulative 126mg/kg dose, while EMERGE patients received 140mg/kg over the 14-week course of treatment. Researchers consulted FDA officials about this change and were encouraged to file for licensing of the product.
While many still question the effectiveness of the drug, the importance of the data collected cannot be understated. At the very least, it provides support for targeting amyloid-β to halt progression of the disease. At most, 2020 could be the year that a much-needed form of treatment enters the clinical setting. Regardless of the FDA decision, aducanumab has shown it won’t be forgotten so easily.
By Stephanie Baringer