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Biogen and Eisai Offer Update on Phase 4 Post-Marketing Aducanumab Study

The post-marketing study of aducanumab (Aduhelm) is expected to enroll 1300 patients with early Alzheimer, with the final protocol to be submitted to the FDA in March 2022, and plans to initiate patient screening in May 2022.

Biogen and Eisai have announced an update on the status of the pending phase 4 study, ICARE AD, of the recently approved Alzheimer disease treatment aducanumab (Aduhelm), stating that the final protocol for the post-marketing study will be submitted to the FDA in March 2022, and that the pair plans to initiate patient screening in May 2022.1

The 100 mg/mL intravenous injection was approved for use in Alzheimer disease in June 2021 with the accelerated pathway based on biomarker data, driving much discussion in the field about its potential efficacy and costs.2,3 The phase 4 placebo-controlled study is a post-marketing requirement of that accelerated approval pathway and is expected to enroll 1300 patients with early Alzheimer. The study’s design was originally announced during a late-breaking presentation at the 2021 Alzheimer’s Association International Conference (AAIC), July 26-30.4

“I am very encouraged by this update and Biogen’s and Eisai’s goal to complete the trial in 4 years after its initiation, approximately half of the time that the FDA provided as part of the accelerated approval,” said Marwan Sabbagh, MD, FAAN, professor of neurology, Alzheimer's and Memory Disorders Division, Barrow Neurological Institute, and investigator in the aducanumb trials, said in a statement.1 “This is a significant commitment from the companies. It takes time to execute a complex, global trial of this nature, so I am pleased to see the high level of priority being afforded to this study.”

READ MORE: Powering Alzheimer Drug Development With Biomarkers and Composite Instruments

Eisai and Biogen noted that they plan to continue to work with FDA, the external stakeholders, and other regulators around the world on the study design. “We are delivering on our commitment to accelerate the timelines with the goal to complete the confirmatory study well ahead of schedule. Together with EMBARK, Biogen’s redosing study, and the ICARE AD study, we aim to provide data from real-world practice and clinical trials to further inform patient and physician decisions about treatment,” Priya Singhal MD, MPH, Head of Global Safety & Regulatory Sciences, and interim Head of Research & Development, Biogen, said in a statement.1

In early November 2021, at the 14th Clinical Trials on Alzheimer’s Disease Conference (CTAD), Oskar Hansson, MD, PhD, professor of neurology, Lund University and Skåne University Hospital, and several colleagues presented new data from the phase 3 EMERGE (NCT02484547) and ENGAGE (NCT02477800) clinical trials of aducanumab in their late-breaking panel session. They offered insight into the findings from analyses of more than 7000 plasma samples from more than 1800 individuals suggest that treatment with the amyloid-ß targeting agent results in a significant correlation between the reduction in plasma p-tau and lessened decline in cognition and function in those with Alzheimer disease.5,6

The high-dose group data from EMERGE (n = 514-521) showed a 13% reduction from baseline in tau pathology that was associated with aducanumab treatment in a dose- and time-dependent fashion compared with placebo, which experienced an 8% rise (P <.001). ENGAGE’s high-dose group (n = 577-581) showed a p-tau reduction of 16% in the treatment group, compared with a 9% rise for placebo (P <.001). Additionally, a greater reduction in plasma p-tau181 was shown to be correlated with a lessened level of clinical decline in all 4 of the trials’ outcome measures.5,6

At the time, Ivana Rubino, PhD, Head of Medical, Global Alzheimer's, Biogen, told NeurologyLive® that together with other promising data from other agents, the overall data trends tell the field that "we can indeed intervene in 2 of the most critical pathologies in the brain for Alzheimer patients, being the amyloid pathology and the tau pathology."

"All in all, of course, we are very enthusiastic, but also, we're thinking about what does it mean practically? With biomarkers in the blood, they've always been the holy grail for the Alzheimer community, we hope that there will be soon tests available for the real world. But in the meantime, these data represent and speak to how much progress we have made as a community and that, most likely, the near future will change and the way we manage these patients in the real world by means of introducing the blood biomarker as a screening tool, as a recruitment tool in the trials, but also artfully, as a monitoring tool for patients on treatment," Rubino said.

Shortly thereafter, in November, the American Academy of Neurology (AAN) published a position statement on the use of aducanumab for the treatment of patients with Alzheimer disease, assessing the ethical considerations related to its use and offering recommendations for informed consent. The AAN acknowledged that the antiamyloid antibody has been the subject of much controversy because of its nontraditional route through the pipeline and the accelerated pathway of approval. The statement covered the role of the principles of beneficence, nonmaleficence, justice, and patient autonomy related to the use of the therapy in this patient population.7,8

“Aducanumab is not a cure for Alzheimer’s disease, yet since it has been approved by the FDA, patients are asking their doctors if this is an option for them,” position statement author Winston Chiong, MD, PhD, associate professor of neurology, and interim director, UCSF Bioethics, University of California San Francisco; and member, AAN Ethics, Law, and Humanities Committee, said in a statement at the time.7 “This is a high-cost drug that was approved by the FDA without convincing evidence of benefits and with known harms, so the purpose of this position statement is to offer ethical guidance on how neurologists can help patients make informed decisions about this treatment.”

REFERENCES
1. Update on the Phase 4 Confirmatory Study of ADUHELM®. Biogen. News release. December 16, 2021. Accessed December 16, 2021. https://investors.biogen.com/news-releases/news-release-details/update-phase-4-confirmatory-study-aduhelmr
2. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. FDA. June 7, 20121. Accessed December 16, 2021. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease
3. Lin GA, Whittington MD, Synnott PG, McKenna A, Campbell J, Pearson SD, Rind DM. Aducanumab for Alzheimer’s Disease: Effectiveness and Value; Evidence Report. Institute for Clinical and Economic Review, June 30, 2021. Accessed December 16, 2021. https://icer.org/assessment/alzheimersdisease-2021/
4. Biogen and Eisai announce design of Aduhelm ICARE AD-US study, the first real-world observational phase 4 study in Alzheimer’s Disease at AAIC 2021. News release. Biogen. July 29, 2021. Accessed December 16, 2021. https://www.globenewswire.com/news-release/2021/07/29/2271775/0/en/Biogen-and-Eisai-Announce-Design-of-ADUHELM-ICARE-AD-US-Study-the-First-Real-World-Observational-Phase-4-Study-in-Alzheimer-s-Disease-at-AAIC-2021.html
5. New Phase 3 Data Show Positive Correlation Between ADUHELM™ Treatment Effect on Biomarkers and Reduction in Clinical Decline in Alzheimer’s Disease. News release. Biogen. November 11, 2021. Accessed November 15, 2021. https://investors.biogen.com/news-releases/news-release-details/new-phase-3-data-show-positive-correlation-between-aduhelmtm
6. Hansson O, Nisenbaum L, Chen T, et al. Dose and time dependent changes in plasma p tau 181 in patients treated with aducanumab in the ENGAGE and EMERGE trials. Presented at: CTAD; November 9-12, 2021; Virtual & Boston, MA. Late Breaking Readout Roundtable.
7. AAN Issues Ethical Guidance on Aducanumab. AAN. News release. November 17, 2021. Accessed November 23, 2021. https://www.aan.com/PressRoom/Home/PressRelease/4937
8. Chiong W, Tolchin BD, Bonnie RJ, et al. Decisions With Patients and Families Regarding Aducanumab in Alzheimer Disease, With Recommendations for Consent: AAN Position Statement. Neurology. Published online November 17, 2021. doi:10.1212/WNL.0000000000013053