The approval for Biogen’s disease-modifying, anti-amyloid agent aducanumab follows a long regulatory journey.
The US Food and Drug Administration (FDA) has approved investigational anti-amyloid, disease-modifying agent aducanumab (Aduhelm) for treatment of Alzheimer disease.
The approval was granted to Biogen, Inc. It is the first novel approach for the neurogenerative condition since 2003.
The therapy approval met the Accelerated Approval pathway, which will require post-approval phase 4 studies to confirm the benefit of the treatment.
FDA noted that in the case the clinical benefit is not confirmed, it has procedures in place that could ultimately lead to the drug removed from market.
The decision noted the late-stage development program consisted of 2 trials, with 1 which met the primary end point and 1 that did not.
In all studies, data show aducanumab had a consistent reduction in amyloid plaques in both a dose- and time-dependent fashion. The FDA noted it anticipated the reduction will result in reduction in clinical decline.
The decision followed debate in the medical community in the path of development and evaluation of aducanumab.
In March 2019, Biogen announced they would discontinue the 2 phase 3 clinical trials evaluating the agent, EMERGE and ENGAGE and a phase 2 safety study EVOLVE. Then, in October 2019, the company announced they reversed course on the decision.
Data in EMERGE and a post hoc analysis of patients who received high-dose treatment in Engage were presented at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) annual meeting. It suggested statistically significant changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores, with P = .010 or P = .031 based on cutoff date.
Data show both trials included low-dose (EMERGE: n = 544; ENGAGE: n = 548) and high-dose (EMERGE: n = 547; ENGAGE: n = 558) treatment arms compared with placebo (EMERGE: n = 548; ENAGE: n = 541).
The analyses of EMERGE led to consistent reduction in clinical decline measured by secondary end points, including the Mini-Mental State Exam (MMSE; 15% versus placebo; P = .05), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; P = .01), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; P = .001).
Further, imaging of amyloid plaque deposits showed that both low- and high-dose aducanumab were associated with reduced burden in comparison with placebo at 26 and 78 weeks (P <.001).
Then, the company submitted the original biologics license application (BLA) to the FDA in July 2020 when it was accepted for review with a Prescription Drug User Fee Act date of March 2021.
Data was reviewed by the FDA Peripheral and Central Nervous System Drugs Advisory Committee in November 2020, which voted to not recommend regulatory approval.
The final vote of the Advisory Committee saw the committee vote 10 – 0 (10 no; 0 yes; 1 uncertain) that the EMERGE trial did not provide primary evidence for the effectiveness of aducanumab in Alzheimer disease.
The committee also voted 8 – 1 (8 no; 1 yes; 2 uncertain) that the phase 3 EMERGE study in patients with mild Alzheimer disease was enough to demonstrate efficacy and voted 7 – 0 (7 no; 0 yes; 4 uncertain) that the PRIME study demonstrated supporting evidence of efficacy.
For the presence of strong evidence of the pharmacodynamic effect on Alzheimer disease, the committee voted 5–0 (0 no; 5 yes; 6 uncertain).
In January 2021, the agency extended its review period by 3 months to June 2021, after Biogen submitted additional clinical data and analyses after an FDA information request.
Patrizia Cavazzoni, MD, director, FDA Center for Drug Evaluation and Research, noted that the approval was significant in the agency statement.
“Perhaps more significantly, Aduhelm is the first treatment directed at the underlying pathophysiology of Alzheimer disease, the presence of amyloid-beta plaques in the brain,” Cavazzoni said. “The clinical trials for Aduhelm were the first to show that a reduction in these plaques—a hallmark finding in the brain of patients with Alzheimer—is expected to lead to a reduction in the clinical decline of this devastating form of dementia."
Investigator Marwan Sabbagh, MD, director, Cleveland Clinic Lou Ruvo Center for Brain Health, noted the similar thought of seminal moment in the field in an interview with NeurologyLive.
"I was surprised at how polarizing it was—we really had strong opinions for and against—but if you take the pro-patient aspect and look at this in the context of the fact that many drugs are starting to show similar signals, I think this is a great step forward,” Sabbagh said. “People have to understand that contextually, medically speaking, we need the first drug in the class to get the class going forward. Otherwise, there's going to be no progress."
Sabbagh also noted that while they are unsure if aducanumab will be the final drug in this amyloid class, the team is sure of the consistency of clinical signals and it can remove amyloid robustly.
“I cannot tell you how excited I am to actually have a new treatment option for my patients—I've been waiting 2 decades to get it,” Sabbagh said.
A new phase 3b trial EMBARK is currently enrolling by invitation patients who were participating in the clinical trial program when the PRIME, EVOLVE, EMERGE, and ENGAGE studies were terminated in March 2019.
EMBARK will be an open-label, single-arm clinical safety study with a 24-month treatment period.
The study will evaluate long-term safety and efficacy of aducanumab in participants with Alzheimer Disease, who will be titrated to receive 10-mg/kg aducanumab by intravenous infusion every 4 weeks.
Primary endpoints include number of participants with adverse events (AEs), serious AEs, AEs leading to treatment discontinuation or study withdrawal, as well as amyloid-related imaging abnormality-edema (ARIA) or amyloid-related imaging abnormality-hemorrhage or superficial siderosis; and the number of participants with anti-aducanumab antibodies.