The investigational Alzheimer disease treatment from Biogen will be re-administered to patients who were previously enrolled in aducanumab trials as they prepare to submit for FDA approval.
A new phase 3b clinical trial of aducanumab has been registered on ClinicalTrials.gov, with the FDA giving Biogen the green light to proceed with the re-dosing study as the company seeks to demonstrate the drug’s long-term safety and tolerability in patients with Alzheimer disease.
“The protocol of the re-dosing study that aims at offering access to aducanumab to all eligible patients who were actively enrolled in the aducanumab studies in March 2019 has been successfully submitted to the FDA,” Biogen said in a statement to NeurologyLive. “We are now working with US trial sites to initiate this open-label clinical trial, which does not include a placebo-controlled arm. In the US, we expect the first patients to be re-dosed starting in March of this year.”
The phase 3b, open-label study (NCT04241068) has an estimated enrollment of 2400 participants and an estimated start date of March 31, 2020. The study will aim to evaluate the long-term safety and tolerability of the anti-amyloid drug in patients who previously participated in aducanumab clinical trials, including those who had received the study drug as well as those who received placebo. Participants in the phase 3b study will hail from all 4 previous clinical trials in the aducanumab development program, including the previously terminated phase 2 EVOLVE trial and the phase 3 ENGAGE and EMERGE trials.
According to the clinical trial website, participants in the trial will receive 10 mg/kg of aducanumab via intravenous infusion every 4 weeks for 100 weeks. Primary end points include adverse and serious adverse events, adverse events leading to treatment discontinuation or study withdrawal, the number of participants with amyloid-related imaging abnormalities, including edema, hemorrhage, or superficial siderosis, and the number of participants with anti-aducanumab antibodies in serum.
Notably, only patients who were actively participating in the previous clinical trials at the time that the early terminations were announced are eligible for inclusion in the phase 3b study.
“We are also actively working in Europe and Japan to re-open sites there, and will then engage in other markets around the world, which requires seeking approval by regional regulatory authorities and institutional review boards,” the company added.
The re-dosing trial comes as Biogen prepares to file aducanumab for approval with the FDA after it did an about-face in October 2019, when they announced that additional analyses of ENGAGE and EMERGE revealed significant positive results in patients who were treated with higher doses of the drug for longer periods of time. The announcement came as a big surprise, as the company had previously terminated the trials in March 2019 after a failed futility analysis.
In October, the company explained that the population included in the futility analysis had enrolled earlier in the studies and had a lower average exposure to the study drug. A protocol amendment later put in place allowed APOE e4 carriers originally randomized to a 6 mg dose to receive the higher 10 mg dose and for a longer duration.
“We did know that the protocol amendments could have had differential effects on the two studies due to the relative timing of enrollment, but we did not anticipate the magnitude of the effect this would have on the data,” the company said at the time.
Biogen presented additional data from the expanded analysis at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) meeting, December 4-7, 2019 in San Diego, California.1
In the EMERGE trial, the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) was statistically significant in the high-dose aducanumab group (change, —0.40 [23%]; P = .0101) compared with placebo. Significant differences were also observed in the high-dose group compared with placebo on Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog 13) scores (change, —1.395 [27%]; P = .0098) and Alzheimer’s Disease Cooperative Study Activities of Daily Living scale for mild cognitive impairment (ADCS-ALD-MCI) scores (change, 1.7 [40%]; P = .0009).
“The ability to hold onto activities of daily living…if you think about a 40% reduction in decline on the ADCS-ADL-MCI, you’re talking about people at a mild stage of disease still being able to work, bank, shop, travel, enjoy leisure activities for longer—I submit to you that this matters a lot more to our patients than what score they get on a memory test,” principal investigator Sharon Cohen, MD, a behavioral neurologist at the University of Toronto, said at the time.1,2 “I also believe that results on this functional scale of daily activity translates better to our nonspecialist colleagues in medicine, our family physicians who bear the brunt of Alzheimer’s care, as well as to the non-medical community who struggle to understand clinical meaningfulness.”
The ultimate fate of aducanumab remains questionable, with many experts in the field raising concerns about the data, given that the positive signs observed in EMERGE were not exactly corroborated in ENGAGE.
Lon Schneider, MD, professor of psychiatry, neurology, and gerontology at the Keck School of Medicine at the University of Southern California wrote in an editorial published in Lancet Neurology that “although Biogen claims that the positive results of the EMERGE trial were driven by greater exposure to a higher dose in the larger dataset, the effect could just as likely been due to greater worsening in the placebo group.”3
It remains to be seen whether the FDA will grant the drug regular or priority review, which could substantially impact the drug’s potential approval timeline.
“We remain dedicated to working with urgency with the purpose of meaningfully changing the course of Alzheimer’s disease,” the company said.
1. Budd Haeberlein S, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s Disease. Presented at: 12th Annual CTAD Meeting. December 4-7, 2019; San Diego, CA.
2. Biogen plans regulatory filing for aducanumab in Alzheimer’s Disease based on new analysis of larger dataset from phase 3 studies [news release]. Cambridge, MA and Tokyo: Biogen and Eisai. October 22, 2019. biospace.com/article/releases/biogen-plans-regulatory-filing-for-aducanumab-in-alzheimer-s-disease-based-on-new-analysis-of-larger-dataset-from-phase-3-studies. Accessed December 5, 2019.
3. Schneider L. A resurrection of aducanumab for Alzheimer's disease. Lancet Neurol. Published online December 4, 2019. doi: 10.1016/S1474-4422(19)30480-6.