FDA Approves Eisai’s Lecanemab for the Treatment for Alzheimer Disease

Marketed as Leqembi, the agent was approved through the accelerated approval pathway and was based on a major study featuring almost 900 patients with early Alzheimer disease.

Marwan Sabbagh, MD

Marwan Sabbagh, MD

The FDA has approved lecanemab (Eisai), a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid-ß (Aß) soluble protofibrils, for the treatment of patients with early-stage Alzheimer disease (AD). Marketed as Leqembi, it becomes the second antiamyloid therapy in its class, joining aducanumab (Aduhelm), which earned approval in June 2021 and was developed by Biogen, which also partnered with Eisai on lecanemab's development.1

"Ultimately, it adds to the treatment options beyond symptomatic therapy," Marwan Sabbagh, MD, a behavioral neurologist Barrow Neurological Institute, and clinical investigator in the agent's development program, told NeurologyLive®. "Patients are highly motivated to change their future. This is an important first step in transforming AD from a terminal disease to a chronic disease."

Similar to its predecessor, lecanemab was greenlit via the accelerated approval pathway, with the application supported by data from the phase 2b proof-of-concept clinical trial, known as Study 201 (NCT01767311). The pivotal phase 3 Clarity AD trial (NCT03887455), which is anticipated to serve as supplementary data and is still pending review by the FDA, is expected to be submitted to the agency soon. In July 2022, when the FDA officially accepted and granted priority review to the biologics license application for lecanemab, the company claimed it would submit an application for traditional approval of the drug to the FDA.2

"Alzheimer’s disease immeasurably incapacitates the lives of those who suffer from it and has devastating effects on their loved ones," Billy Dunn, MD, director of the Officer of Neuroscience in the FDA's Center for Drug Evaluation and Research, said in a statement.1 "This treatment option is the latest therapy to target and affect the underlying disease process of Alzheimer’s, instead of only treating the symptoms of the disease."

Study 201, a bayesian design clinical trial, randomly assigned 856 patients with early AD with a confirmed presence of amyloid pathology to lecanemab at multiple doses (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, and 10 mg/kg biweekly) or placebo, identifying 10 mg/kg biweekly as the effective dose achieving at least 90% of the maximum treatment effect. At the end of the 18-month treatment period, 10-mg/kg biweekly lecanemab reduced brain amyloid by a mean of 0.306 standardized uptake value ratio units from a baseline mean of 1.37. Additionally, this treated group had a 76% probability of achieving 25% less decline on the primary end point, the change on the Alzheimer's Disease Composite Score (ADCOMS), than placebo.3

Joanne Pike, DrPH, the president and CEO of the Alzheimer’s Association, said in a statement issued to the media, “We now have a second approved treatment that changes the course of Alzheimer’s disease in a meaningful way for people in the early stages of the disease.” Notably, Pike added, “While this news is exciting, without insurance and Medicare coverage of this class of treatments, access will be limited to only those who can afford to pay out-of-pocket. The Alzheimer’s Association has submitted a formal request asking CMS to remove the requirement that Medicare beneficiaries be enrolled in a clinical trial in order to receive coverage of FDA-approved Alzheimer’s treatments.”

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Clarity AD is an 18-month, double-blind, multicenter trial that featured 1795 participants with early-stage AD with evidence of amyloid on PET or by cerebrospinal fluid testing. The study met its primary end point of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, with lecanemab-treated patients demonstrating a statistically significant 27% reduction over an 18-month treatment period. Overall, lecanemab-treated patients showed adjusted least-squares (LS) mean changes of 1.21 vs 1.66 for those on placebo (P <.001).4

The findings for Clarity AD were originally announced in September 2022, with additional analyses presented later in the year at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held November 29 to December 2, in San Francisco, California. At the time of the presentation, Eisai announced the full publication of the study in the New England Journal of Medicine.

Lecanemab also met secondary end points in Clarity AD, including change in amyloid PET centiloids (difference in LS, –50.12; <.0001) and Alzheimer’s Disease Assessment Scale-Cognitive 14 (LS difference, –1.442; = .00005) relative to placebo over the 18-month period. Additionally, it outperformed placebo on ADCOMS (LS difference, –0.00; = .00002), and Alzheimer’s Disease Cooperative Study–Activities of Daily Living (LS difference, 2.016; <.00001). Specifically, it slowed disease progression on ADsCOMS by 24% and disease progression on ADCS MCI-ADL by 37% at the same time point.

Among the panel of presenters at CTAD was lead investigator Christopher Van Dyck, MD, director of the Yale Alzheimer’s Disease Research Center. He presented a sensitivity analysis in that highlighted a treatment difference of –0.394 on CDR-SB with lecanemab when repeated to evaluate the impact of the COVID-19 pandemic, similar to the overall difference of –0.45 between groups. When censoring assessments after the occurrence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), the treatment difference was –0.500, a 30% slowing of disease progression.5

Safety has been a major concern for antiamyloid therapies and was a point of contention during aducanumab’s approval process. In Clarity AD, lecanemab continued to show a safety profile that was within expectations, with ARIA-E rates of 12.5% in treated patients. Symptomatic ARIA-E occurred at a rate of 2.8% in the lecanemab group and 0.0% in the placebo group. ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis (ARIA-H) occurred at a rate of 17.3% in lecanemab-treated patients and 9.0% for those on placebo. Symptomatic ARIA-H was found in 1.4% of the lecanemab group and 0.2% of the placebo group.

Sharon Cohen, MD, FRCPC, a neurologist and assistant professor at the University of Toronto, and a trial investigator for Clarity AD

Sharon Cohen, MD, FRCPC

"The safety profile of lecanemab is actually better than with other drugs in the same class and is very reasonable, with a low rate of serious or life-threatening [adverse] effects," Sharon Cohen, MD, FRCPC, a neurologist and assistant professor at the University of Toronto, and a trial investigator for Clarity AD, told NeurologyLive®.

Events of ARIA-E with lecanemab were mostly mild to moderate (91%) based on central reading of imaging with the use of protocol definitions. The most common adverse events in the lecanemab group were infusion-related reactions (26.4%), followed by ARIA-H (17.3%), ARIA-E (12.6%), headache (11.1%), and falls (10.4%). ARIA-H that occurred with ARIA-E tended to occur early, within 6 months of treatment, while isolated ARIA-H occurred throughout the trial. ARIA-E and ARIA-H were numerically less common among noncarriers of apolipoprotein ε4 allele (APOE ε4) than among carriers, with higher frequency among APOE ε4 homozygotes than among APOE ε4 heterozygotes.

There were 3 patient deaths throughout the study, including 1 most recently reported in early January 2023. The case was of a 65-year-old man who was participating in the open-label extension and treated with lecanemab. The individual, homozygous for the APOE ε4 allele, was in the early stages of cognitive decline before being presented to an emergency department 30 minutes after the acute onset of aphasia and left gaze preference due to an ischemic stroke.

After using tissue plasminogen activator (t-PA) to treat the ischemic stroke, the individual experienced acute intracerebral hemorrhage, with the first symptom occurring 8 minutes after t-PA infusion. A CT scan immediately following alos showed the presence of cerebral hemorrhages. MRI was performed 3 days after the CT scan and death occurred after the decision by the family to withdraw life support 4 days after the CT scan.

The patient death was brought up at CTAD 2022, and later emphasized in a paper by Nicholas J. Reish, MD, PhD, et al.6 In a corresponding response letter, investigators from the trial agreed that this case raises important management issues for patients with AD, particularly those who are homozygous to APOE ε4. Sabbagh and Christopher H. van Dyck, MD, authors of the corresponding letter, wrote, "Although t-PA appears to be the proximate cause of death, this was an unusual case, and we understand why the authors want to highlight a potential concern."7

Despite its approval, questions remain about the access to antiamyloid therapies like lecanemab. For context, in April 2022, the Centers for Medicare & Medicaid Services (CMS) published its final decision memorandum on its national coverage analysis for the class of monoclonal antibodies as treatments of AD, restricting the coverage of these products to 2 scenarios. The first provided coverage for approved agents that show change in surrogate end points in randomized controlled trials conducted under an investigational new drug application, while the second provided coverage in CMS-approved prospective comparative studies.

"Access begins with early diagnosis," Cohen added. "Patients and physicians will need to take mild memory symptoms seriously so that treatment opportunities are not missed. Access to treatment will also depend on diagnostic tests and drug delivery being appropriately funded."

In December 2022, the Alzheimer’s Association filed a formal request to remove the requirements for access to these therapies, as Pike mentioned, stating that the agency had never limited coverage of a drug or biologic when used according to its FDA-approved label.8 The finalization of this coverage framework included evidence to the agency from up to April 2022, thus excluding any of the new analyses of lecanemab highlighting the potential impacts of these antiamyloid therapies.

CMS’s decision to limit access to antiamyloid therapies stems from aducanumab, which was approved based on a submission that consisted of 2 trials assessing the agent, 1 which met its primary end point and 1 that did not. Following its approval, gaining coverage for the drug became a challenge for both patients and industry leaders, leading to Biogen’s termination of its phase 4 ICARE-AD trial and a withdrawal of its application to the European Medicines Agency.9,10

The price of aducanumab is currently $56,000 a year, which was found to be not cost-effective, according to a 2021 revised report from the Institute for Clinical and Economic Review.11 Recently, a released congressional investigation report on aducanumab documented how both the FDA and Biogen unfairly collaborated to have the drug approved and priced high in the market. The report, announced by the House Committee on Energy and Commerce, claimed that the FDA lacked a clear record of meetings between the agency staff and Biogen, interactions were "atypical," as well as failed documentation protocol of the agency. Based on the findings, the committee produced recommendations for the FDA to advise how to restore people’s trust in the agency’s processes for drug safety and efficacy.12

Amid the recent CTAD conference, NeurologyLive® convened a panel of experts in the care of AD, including Sabbagh; Cohen; Alireza Atri, MD, PhD; and Eric McDade, DO, to offer their perspectives on some of the data. Hear their thoughts in the video below:

REFERENCES
1. FDA grants acclerated approval for Alzheimer's disease treatment. FDA. News release. January 6, 2023. Accessed January 6, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
2. Eisai completes rolling submission to the US FDA for biologics license application of lecanemab for early Alzheimer disease under the accelerated approval pathway. News release. Eisai. May 9, 2022. Accessed May 10, 2022. https://eisai.mediaroom.com/2022-05-09-EISAI-COMPLETES-ROLLING-SUBMISSION-TO-THE-U-S-FDA-FOR-BIOLOGICS-LICENSE-APPLICATION-OF-LECANEMAB-FOR-EARLY-ALZHEIMERS-DISEASE-UNDER-THE-ACCELERATED-APPROVAL-PATHWAY
3. Swanson CJ, Zhang Y. Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer disease with lecanemab, an anti-Aß protofibril antibody. Alzheimers Res Ther. 2021;13(80). doi:10.1186/s13195-021-00813-8
4. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer disease. N Engl J Med.
Published online November 29, 2022. doi:10.1056/NEJMoa2212948
5. Irizarry M, van Dyck C, Sabbagh M, Bateman R, Cohen S. Clarity AD: A phase 3 placebo-controlled, double-blind, parallel-group, 18-month study evaluating lecanemab in early Alzheimer disease. Presented at: CTAD Conference, November 29-Dec 2.
6. Reish NJ, Jamshidi P, Stamm B, et al. Multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Engl J Med. Published online January 4, 2023. doi:10.1056/NEJMc2215148
7. Sabbagh M, van Dyck CH. Response to: multiple cerebral hemorrhages in a patient receiving lecanemab and treated with t-PA for stroke. N Engl J Med. Published online January 4, 2023. doi:10.1056/NEJMcc221515907
8. Alzheimer’s Association calls on CMS to reverse its decision to severely limit access to FDA-approved Alzheimer’s disease treatments. News release. Alzheimer’s Association. December 20, 2022. Accessed January 4, 2023. https://www.alz.org/news/2022/alzheimers-association-calls-on-cms-to-reverse-its
9. 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 January 4, 2023. 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
10. Aduhelm: Withdrawal of the marketing authorization application. EMA website. April 20, 2022. Accessed January 4, 2023. https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/aduhelm
11. 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 January 4, 2022.https://icer.org/assessment/alzheimersdisease-2021/.
12. Maloney and Pallone Release Staff Report on Review, Approval, and Pricing of Biogen’s Alzheimer’s Drug Aduhelm. News Release. House Committee on Energy and Commerce. Accessed January 4, 2023. https://energycommerce.house.gov/newsroom/press-releases/maloney-and-pallone-release-staff-report-on-review-approval-and-pricing-of
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