Biogen Withdraws Aducanumab Application to EMA Shortly Following CMS National Coverage Determination

Following an NCD that will allow for Medicare coverage of the therapy only in NIH- and FDA-approved studies and trials, Biogen has pulled its application to the European Medicines Agency for aducanumab treatment in Alzheimer disease.

This story was originally published on April 8, 2022, and has since been updated following news of the EMA application withdrawal on April 20, 2022.

Update April 26, 2022: The European Medicines Agency has announced that on April 20, Biogen Netherlands BV withdrew its application for marketing authorization of aducanumab (Aduhelm) for the treatment of Alzheimer disease in Europe.1

This news follows a recent announcement from the Centers for Medicare & Medicaid Services (CMS) that it had made its finalized national coverage determination (NCD) on aducanumab (Aduhelm; Biogen) and future monoclonal antibodies directed against amyloid that are approved by the FDA for the treatment of Alzheimer disease (AD).2 The NCD does not waver much from the proposed decision that the agency announced earlier this year, in January 2022.3

The NCD decision is ultimately that Medicare will be able to cover agents in this class of medication if they receive traditional approval from the FDA under coverage with evidence development. As such, CMS noted that it will “provide enhanced access and coverage for people with Medicare participating in CMS-approved studies, such as a data collection through routine clinical practice or registries,” and that registry data may be used to observed reproduced results in real-world populations. Additionally, the agency noted that new therapies in this class that are approved may be available in additional care settings— outpatient departments or infusion centers, as examples—that people with Medicare utilize.

CMS also determined that for those agents have not shown a clinical benefit as determined by the FDA—or that receive an accelerated approval, such as aducanuamb—Medicare will cover the cost of the treatment only in FDA or National Institutes of Health approved trials. CMS added that it will “support the FDA” by offering coverage of any related services required by trial protocol, as well, for those with Medicare in these trials.

Notably, this NCD decision was made specific to individuals who have a clinical diagnosis of mild cognitive impairment (MCI) due to AD or mild dementia with a confirmed presence of amyloid plaque on the brain. If the FDA updates the label to this class of medications, CMS will reevaluate the coverage policy appropriately.

“Alzheimer’s disease is a highly destructive illness that affects millions of Americans and their families. CMS has a responsibility to ensure that people with Medicare have equitable and appropriate access to therapies that are reasonable and necessary for use in the Medicare population,” Chiquita Brooks-LaSure, MPP, CMS administrator, said in a statement. “This final National Coverage Determination reflects CMS’ commitment to provide the American public with a transparent, trusted, evidence-based decision—without regard to cost—that is made only after a thorough analysis of public feedback. Through this decision, we are creating a pathway for people with Medicare to quickly access drugs the FDA determines have shown a clinical benefit and encourages manufacturers and trial administrators to ensure that the clinical trials recruit racially diverse participants.”

READ MORE: FDA Clears IND for Antiamyloid Antibody for Alzheimer Disease, Set to Initiate Trial

In a statement on the finalized NCD, Biogen noted that “this unprecedented CMS decision effectively denies all Medicare beneficiaries access to Aduhelm (aducanumab-avwa), the first and only FDA-approved therapy in a new class of Alzheimer’s drugs. It may also limit coverage for any future approved treatment in the class. These coverage restrictions, including the distinction between accelerated approval and traditional approval, have never been applied to FDA-approved medicines for other disease areas.”4

Biogen continued its urging of CMS to “reconsider today’s decision for all FDA-approved amyloid-beta targeting therapies,” specifically pointing to Eisai’s initiation of FDA filing through the accelerated approval pathway for lecanemab and the pending readout of its phase 3 Clarity AD trial (NCT03887455), expected in fall 2022.

“Biogen continues to advocate for patients to have rapid and equitable access to all FDA-approved therapies to treat Alzheimer’s disease and for the continuity of care for Medicare beneficiaries already on ADUHELM. Biogen is carefully considering its options and will provide updates as the company further evaluates the business impact of this decision,” the company concluded.

Biogen responded to the initial coverage proposal in February 2022 with a similar tone, noting in a letter addressed to Tamara Syrek Jensen, JD, director, Coverage and Analysis Group, Center for Clinical Standard and Quality, CMS, who was among the authors of the proposal, that a 3-pronged approach could be taken to generate real-word evidence—including a focused registry, a novel AD Clinical Data Research Network, and prospective studies of Medicare claims to better understand patterns of use. Biogen explained that the plan provided for patient choice in accessing FDA-approved medications, stating that patients may otherwise be confined to randomized controlled trials where they may receive placebo or limited by coverage with evidence development policies.5

Maha Radhakrishnan, MD, chief medical officer, Biogen, said in a statement provided to NeurologyLive® in February 2022 that the company was committed to patient choice and stressed that it was pushing for CMS to provide coverage for FDA-approved treatments. “Biogen is committed to generating data from real world usage and with coverage, Alzheimer disease patients will be able seek treatment instead of being restricted to enrolling in randomized controlled trials where they may receive a placebo or be limited by other coverage criteria,” she said at the time.

The 100 mg/mL IV injection was approved for use in AD in June 2021 with the accelerated pathway based on biomarker data. The controversial approval has continued to be a topic of discussion among AD and policy experts pertaining to its potential efficacy and associated costs.6,7

This news follows the recent announcement that Biogen had submitted its final study protocol for the phase 4 ENVISION trial of aducanumab to be reviewed by the FDA, adding that it anticipates the first patient to be screened in May 2022.8 The trial will be conducted as part of the accelerated approval, and will be global in scale, with a targeted enrollment of 1500 patients with AD and confirmed amyloid-ß pathology. The 100 mg/mL injection was approved for intravenous infusion in early AD, including those with MCI because of AD and mild AD.

ENVISION’s primary end point, which was originally detailed in an announcement from January 2022, will be cognitive decline at 18 months, measured by the Clinical Dementia Rating-Sum of Boxes. Additionally, a long-term extension is planned to collect data for up to 48 months. The secondary end points include change in amyloid PET and tau PET, as well as scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory–MCI Version, Integrated Alzheimer's Disease Rating Scale, Mini-Mental State Examination, and Neuropsychiatric Inventory.

“Our unwavering commitment is to ensure that the trial is completed swiftly and that the diversity of patients in it reflects that of Americans diagnosed with early Alzheimer’s disease. We plan to work hand-in-hand with underrepresented communities and Alzheimer’s disease groups to achieve our diversity and inclusion goal,” Samantha Budd Haeberlein, PhD, senior vice president and head of Neurodegeneration Development, Biogen, said in a statement at the time of the announcement.8

REFERENCES
1. Aduhelm: Withdrawal of the marketing authorization application. EMA website. April 20, 2022. Accessed April 26, 2022. https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/aduhelm
2. CMS Finalizes Medicare Coverage Policy for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. News release. CMS. April 7, 2022. Accessed April 8, 2022. https://www.cms.gov/newsroom/press-releases/cms-finalizes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment
3. Jensen TS, Chin J, Baldwin J, et al. Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. CMS website. January 11, 2022. Accessed April 8, 2022. https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&ncaid=305&doctype=all&timeframe=30&sortBy=updated&bc=20
4. Biogen’s Statement on the Final National Coverage Determination for Amyloid-Beta Targeting Therapies for the Treatment of Alzheimer’s Disease. News release. Biogen. April 7, 2022. Accessed April 8, 2022. https://investors.biogen.com/news-releases/news-release-details/biogens-statement-final-national-coverage-determination-amyloid
5. Re: Proposed decision memorandum for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease (CAG-00460N). February 10, 2022. Accessed April 8, 2022. https://investors.biogen.com/static-files/48bc8500-bf36-4be1-ae87-81d4bab2d05f
6. FDA’s Decision to Approve New Treatment for Alzheimer’s Disease. FDA. June 7, 20121. Accessed April 8, 2022. https://www.fda.gov/drugs/news-events-human-drugs/fdas-decision-approve-new-treatment-alzheimers-disease
7. 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 April 8, 2022. https://icer.org/assessment/alzheimersdisease-2021/
8. Biogen Submits Final Protocol for ADUHELM® (aducanumab-avwa) Phase 4 ENVISION Trial to FDA. News release. Biogen. March 30, 2022. Accessed April 8, 2022. https://www.biospace.com/article/releases/biogen-submits-final-protocol-for-aduhelm-aducanumab-avwa-phase-4-envision-trial-to-fda/