Aducanumab is back for Alzheimer’s, and it might be a game changer

By Maria Teresa Ferretti (co-founder and Chief Scientific Officer of the Women’s Brain Project) for the Women's Brain Project

Earlier this week on October 22,  Biogen and EISAI announced new, updated results of their phase 3 clinical trials of the drug aducanumab, a human monoclonal antibody directed against amyloid beta peptide. The results indicate a therapeutic effect of the drug, leading the company to file an application for FDA approval in 2020. 

If it is accepted, this could be the first treatment to cure Alzheimer in history.

While it is early days and caution is needed, this news has filled the Alzheimer’s community with joy and excitement. At the Women’s Brain Project (WBP) we are particularly touched by this announcement, as two of the organization co-founders – including the author of this article – spent several years in the Swiss academic laboratory were the initial discoveries were made, working as postdocs and group leaders under the supervision of mentors such as Dr Roger Nitsch and Dr Cristoph Hock. As such, we have followed the pre-clinical and early clinical development of this antibody very closely. 

(MTF in the lab of prof Nitsch, Zurich; image credit: Davide Caenaro)

The story

The drug was discovered thanks to the Reverse Translational Medicine, a patented technology originally developed in the laboratory of Professor Nitsch and Christoph Hock at University of Zurich in Switzerland, and now proprietary technology platform of the biotech Neurimmune.

The idea was simple:  take a group of ‘successfully aged’ individuals, free of Alzheimer or other pathologies, and check what antibodies their body produces. Indeed, several antibodies against a plethora of pathological peptides were discovered with this approach, and aducanumab was one of the first to demonstrate high in vitro and in vivo potential for therapeutic application. In preliminary experiments, the antibody avidly bound and cleared the neurotoxic amyloid beta peptide, thought to be the culprit of Alzheimer’s pathology. 

In 2016, a groundbreaking phase 1b clinical study PRIME showed dramatic, dose-dependent reduction in amyloid load in patients treated with aducanumab, with a hint of clinical benefit. Two phase-3 trials, EMERGE and ENGAGE, each with over 1600 patients, were immediately launched. 

 In March 2019, a futility analysis of the two phase-3 trials led to their early termination, amidst the dismay of researchers and families alike. The failure of aducanumab felt like a deadly blow against the amyloid cascade hypothesis, and caught everybody off guard after the promising results of phase 1b study PRIME. 

Biogen and EISAI did not give up, but continued to analyze the data as they became available. 

It is after all the evidence was collected and analyzed that came the shocking announcement of October 22 this year. The futility analysis, while based on robust statistical methods overall, was incorrect. It was run on a subset of data, and it did not consider the heterogeneity in doses that the patients received over time. 

In the new analysis, which included all the data, a clinical signal was clearly evident in one of the two trials (EMERGE), and in some patients of the second trial (ENGAGE). 

The positive data from the EMERGE trial indicated amelioration on several clinical scales. In particular, a striking 40% of reduction in activities of daily living means a significant improvement in the patient’s ability to manage his or her life, running errands and housekeeping, as reported by the caregiver.This would represent a huge relief for patients and caregivers, a delay in hospitalization, and an enormous reduction of societal and economic costs of Alzheimer. 

Unfortunately, the results of the second trial, ENGAGE, were not equally strong, as only a subset of patients responded positively to the drug. The company argues that only the patients that received the highest dosis of aducanumab had clinical benefit. 

What now?

It remains to be seen whether these data, in addition to the promising phase 1b PRIME trial data, will be deemed sufficient by FDA for approval.

Is data from one trial sufficient for getting the green light? Or will more data will be required in post-marketing phase, in a conditional approval?

Even if the drug is approved, a lot of questions remain:

• What will be the price for such a treatment? 
• What population will receive the drug? 
• What will be the diagnostic criteria for eligibility? 
• Will it be necessary to have evidence of amyloid pathology, and if so, will it be required to have PET scans or CSF analysis? 
• Will we need to genotype all patients for APOE? 
• Will the medical systems of Europe and US be prepared to administer such a drug with such diagnostics? (Recent reports such as this one and this other one suggest they are not.)

The significance

The significance of aducanumab in history of neurology is manifold. If aducanumab works, it will be not just the first treatment for Alzheimer. It will open a new era in neuroscience and neurology. It will open an era of biomarker-enriched population in Alzheimer treatment, which will get us closer to precision medicine.

It will also prove that minimal amounts of antibody (it is estimated only 0.1% of the injected antibody passes the blood brain barrier and enters the brain) are sufficient to target a pathological peptide and clear it. It will ushers a new series of investigations aimed at better understanding the interactions between the immune system and the brain, well beyond the now-old concept of brain immune privilege.

And, as the data will become available, it will allow us to investigate further subpopulations responses –to WBP, a crucial question is of course whether there are sex-differences in the efficacy and safety profile of aducanumab.

There is a lot of work to do until then, but this is an incredibly exciting adventure and WBP will keep following it. To be continued!

(special thanks to Shahnaz Radji for editorial support)