In a landmark decision on June 7, 2021, the U.S. Food and Drug Administration (FDA) approved aducanumab (brand name Aduhelm) for the treatment of Alzheimer's disease, marking the first novel therapy approved for this devastating condition since 2003 and the first-ever treatment directed at the underlying disease pathology.
The approval comes through the FDA's Accelerated Approval pathway, which requires Biogen to conduct post-approval Phase 4 studies to confirm the anticipated clinical benefit. If these studies fail to verify clinical benefit, the FDA could potentially withdraw the approval.
A Controversial Decision
The FDA's decision has proven highly contentious within the medical community. The agency approved the drug despite its own independent advisory committee voting 10-0 against recommending approval based on the available efficacy data.
"We acknowledge that the data from the clinical trials has led to scientific debate," said Patrizia Cavazzoni, MD, director of the FDA Center for Drug Evaluation and Research, in the agency's statement. "However, the FDA has determined that there is substantial evidence that Aduhelm reduces amyloid-beta plaques in the brain and that the reduction in these plaques is reasonably likely to predict important benefits to patients."
The approval was based primarily on data from two Phase 3 clinical trials, EMERGE and ENGAGE, which yielded conflicting results. EMERGE met its primary endpoint, showing a statistically significant reduction in clinical decline, while ENGAGE failed to meet the same endpoint. However, the FDA noted that across all studies, aducanumab consistently reduced amyloid plaques in a dose- and time-dependent manner.
Mechanism and Administration
Aducanumab is a monthly intravenous infusion designed to target and remove beta-amyloid plaques in the brain, a hallmark pathological feature of Alzheimer's disease. The treatment is specifically intended for patients with mild cognitive impairment or mild dementia stage of Alzheimer's disease.
Biogen has set the list price at $56,000 per year, not including additional costs for diagnostic testing and brain imaging that will be required for patient selection and monitoring.
Safety Considerations
The most common adverse effect observed in clinical trials was amyloid-related imaging abnormalities-edema (ARIA-E), which occurred in approximately 35% of patients receiving the high dose of aducanumab. This side effect requires careful monitoring through MRI scans during treatment.
Dr. Marwan Sabbagh, director of Cleveland Clinic Lou Ruvo Center for Brain Health and an investigator in the aducanumab trials, emphasized the importance of patient selection and monitoring: "Not all patients will qualify for treatment, and patient selection should be done carefully and thoughtfully. This drug is given by monthly intravenous infusions and there needs to be comprehensive clinical and MRI monitoring for potential benefit and adverse effects."
Clinical Impact and Future Directions
The approval represents a significant shift in Alzheimer's treatment paradigm, moving from symptom management to disease modification. However, experts caution that aducanumab is not a cure and appears to slow rather than stop disease progression.
"This drug doesn't cure Alzheimer's but effectively removes amyloid from the brain and appears to slow disease progression, which I believe is meaningful for many patients with early symptomatic Alzheimer disease," said Anton P. Porsteinsson, MD, William B. and Sheila Konar Professor of Psychiatry at the University of Rochester School of Medicine and Dentistry.
Howard Fillit, MD, Founding Executive Director and Chief Science Officer at the Alzheimer's Drug Discovery Foundation, views this approval as just the beginning: "Aducanumab is just the first of several Alzheimer's drugs that will become available in the next five to 10 years. The robust Alzheimer's research pipeline, complemented by a growing number of biomarkers and other important research tools, means that the clinical trials underway today are more rigorous and more promising than ever."
Implications for Alzheimer's Research
Many experts believe this approval, despite its controversies, may accelerate drug development in Alzheimer's disease. Dr. Sabbagh compared it to early approvals in multiple sclerosis that eventually led to more effective treatments.
"Our future is going to be a 4- or 5- or 6-drug cocktail. The consequence, of course, is that it will slow the rate of decline," Sabbagh explained, suggesting that future Alzheimer's treatment will likely utilize combinations of therapies targeting multiple pathological mechanisms.
Patient Access and Next Steps
Following the approval, Biogen has initiated EMBARK (NCT04241068), a Phase 3b redosing trial for patients who previously participated in the clinical trial program when the studies were terminated early in March 2019.
For the estimated 6 million Americans living with Alzheimer's disease, this approval represents a new treatment option in a field that has seen little progress for nearly two decades. However, questions remain about insurance coverage, patient selection criteria, and the real-world effectiveness of the treatment.
As the first in a new class of Alzheimer's treatments, aducanumab's approval may be remembered as either a breakthrough moment or a controversial decision that lowered the bar for drug approval in this challenging therapeutic area. What remains clear is that the urgent need for effective treatments continues to drive innovation in Alzheimer's research.
