Breaking Down the Approval of Biogen’s Aducanumab

June 09, 2021 - FDA has approved Biogen’s drug for Alzheimer’s disease, Aduhelm (aducanumab), despite ongoing debate over the drug’s efficacy. 

Aducanumab is a monoclonal antibody selected from a population of elderly, healthy donors and cognitively stable patients and is now the first Alzheimer's drug approved in over 20 years, as well as the first one to address cognitive decline in those with the illness. But for nearly five years before FDA’s approval, there was notable controversy surrounding aducanumab. 

Where it all started

In 2007, biopharmaceutical company Nurimmune Therapeutics licensed worldwide exclusive rights to aducanumab to Biogen. Biogen then took over the development and marketing responsibility of the drug. 

Ten years later, Biogen and Eisai expanded their existing agreement to jointly develop and commercialize investigational Alzheimer’s disease treatments.

Under the terms of the agreement, Eisai exercised the option to co-develop and co-promote aducanumab. 

Biogen Launches Phase 1b PRIME Study

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In 2015, Biogen announced data from a pre-specified interim analysis of PRIME, the Phase 1b study of aducanumab. The study included fixed dosing at one, three, six, and ten milligrams of aducanumab, as well as an arm with a titration regimen and pooled placebo. 

In the analysis, the drug demonstrated an “acceptable safety profile” and positive results on radiologic and clinical measurement in patients with prodromal or mild Alzheimer’s disease. 

 Amyloid-related imaging abnormalities, or ARIA, were the most commonly reported adverse events in the fixed-dose arms of the Phase 1b study. 

But at 54 weeks, a statistically significant reduction of amyloid plaque versus placebo was observed in all participants. 

Nature published results from pre-clinical research and PRIME in August 2016. The pre-clinical animal model in the study demonstrated that aducanumab reduced amyloid-beta in the brain and the reduction was dose-dependent.

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Overall, trial results for aducanumab continued to stay the same. Specifically, the Phase 1b study of aducanumab had nearly four years of consistent results. 

Due to positive trial findings, FDA granted fast track designation to aducanumab one month later. 

Biogen Launches Two Phase 3 Studies for Aducanumab 

In September 2015, Biogen enrolled the first patients in two Phase 3 studies, ENGAGE and EMERGE, for aducanumab. 

ENGAGE and EMERGE assessed the efficacy and safety of aducanumab in nearly 2,700 individuals with early Alzheimer’s disease. The studies were identical in design and eligibility criteria. Each study was conducted in more than 20 countries in North America, Europe, and Asia.

Biogen Discontinues Phase 3 Trials

In March 2019, Biogen and Eisai discontinued the ENGAGE and EMERGE trials based on results of a futility analysis conducted by an independent data monitoring committee.

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Specifically, analysis of the data from the final database lock showed that EMERGE met its primary endpoint. Patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline at 78 weeks. 

But ENGAGE did not meet its primary endpoint. Notably, data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE.

Overall, trial results showed that the drug administered as a monthly infusion was not better at slowing memory loss and cognitive impairment than placebo. Therefore, the committee explained that the trials were unlikely to meet their primary endpoint upon full completion.  

Biogen Submits Biologic License Application to FDA

Despite the odds, Biogen analyzed additional data from another trial and concluded the drug did work if administered in higher doses. Biogen and Eisai announced in 2019 that new data showed the EMERGE trial had met its primary endpoint.

Patients who received aducanumab experienced reduction in clinical decline, as well as significant benefits on measures of cognition and function, such as memory, orientation, and language. 

Therefore, the companies announced that after consulting with FDA, they would pursue regulatory approval for aducanumab.

In July 2020, Biogen completed submission of a biologics license application to FDA for the approval of aducanumab. The completed submission followed ongoing collaboration with FDA, including clinical data from the EMERGE and ENGAGE studies, as well as the PRIME study.

In August, FDA accepted the biologics license application and granted priority review.

But in November 2020, FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted one yes, eight no, and two uncertain when asked if the EMERGE trial, viewed independently and without regard for ENGAGE, provided strong evidence that supports the effectiveness of the drug for the treatment of Alzheimer’s disease. 

The committee also voted seven no and four uncertain on a question about if the PRIME study provided supportive evidence of the effectiveness of aducanumab for the treatment of Alzheimer’s diseases. No person voted yes.

Finally, the committee voted ten no and one uncertain on if the overall primary evidence demonstrates that aducanumab is effective for the treatment of Alzheimer’s disease. Again, no one voted yes to this question.

In January 2021, FDA extended the review period for its biologics license application for aducanumab by three months.

FDA Approves Aducanumab, Eliciting Major Concerns 

Finally, after years of debate, FDA granted accelerated approval for aducanumab after years of speculation about the drug’s efficacy. 

Although brain scans revealed that aducanumab is effective at reducing A-beta in the brain, it is unclear whether this reduction comes with consistent improvements in quality of life. 

Therefore, some doctors and scientists see FDA’s move as premature because they aren’t convinced that the drug actually works, given the mixed trial results over the years. Approving a drug that’s not effective will set Alzheimer’s research back, critics argue. 

Additionally, FDA's approval may make it difficult for Biogen and Eisai to find enough patients to participate in its next clinical trials as patients might not want to risk getting the placebo now that they can get the drug without being in a study.

“This is a great day for Biogen and its shareholders, but a bleak day for the field of Alzheimer’s research,” Michael Greicius, a neurologist at Stanford University, said in a statement. “Pushing forward on the ‘illusion of progress’ will come at a cost to genuine progress in finding an effective treatment for this devastating disease.”