EU Regulatory Review Adopts Negative Opinion of Lecanemab as Treatment for Alzheimer Disease

Lynn Kramer, MD

Recently, Eisai announced that the European Medicines Agency (EMA) adopted a negative opinion for the approval of lecanemab as a treatment for patients with early-stage Alzheimer disease (AD). The company plans to re-examine the CHMP opinion and work swiftly with the parties involved to ensure the treatment becomes available for those living with the disease in the European Union (EU).¹

Lecanemab, a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid-ß, gained traditional approval in the US in July 2023, marketed under the name Leqembi. It is also approved in Japan, China, South Korea, Honk Kong, and Isreal for the treatment of mild cognitive impairment (MCI) due to AD and mild AD dementia.

"We are extremely disappointed by the CHMP’s negative opinion and understand that this may also be disappointing for the wider Alzheimer’s disease (AD) community. AD is an irreversible, neurodegenerative disease that poses significant challenges to those living with AD, their care partners and society," Lynn Kramer, MD, chief clinical officer at Eisai, said in a statement.¹ "There is a significant unmet need for new innovative treatment options that target an underlying cause of disease progression. We remain focused on making a meaningful difference to those living with early AD and those closest to them."

Lecanemab was originally approved under the accelerated approval pathway but was transitioned to traditional approval following a review of the large-scale, phase 3 Clarity AD trial (NCT03887455).2 Prior to its approval, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee ruled that the results of Clarity AD verified the benefit of lecanemab as a treatment for AD. At the time of its approval, it became the second antiamyloid therapy, behind aducanumab (Aduhelm; Biogen), which was removed earlier this year.³

In Clarity AD, lecanemab met its primary end point of change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, with treated patients demonstrating a statistically significant 27% reduction vs placebo. The study, published in the New England Journal of Medicine, included 1795 patients with evidence of amyloid on PET or cerebrospinal fluid who were followed for an 18-month period.⁴

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

READ MORE: Open Label Extension Data Shows Lecanemab’s Continued Effect on Alzheimer Disease After 3 Years

The therapy is also currently being tested in the phase 3 AHEAD 3-45 study (NCT04468659), a National Institute on Aging-funded trial that comprises patients with preclinical AD. In addition, the company recently submitted a supplemental biologics license application for an intravenous maintenance dosing, as well as a maintenance dosing of a subcutaneous injection formulation, which is being developed to enhance convenience for patients.

At the recently concluded Alzheimer’s Association International Conference (AAIC), held July 28-August 1, in Philadelphia, Pennsylvania, Kramer discussed the AHEAD 3-45 study, noting “we expect to end enrollment in that 1400-patient study later this year.”

"Those [participants] are people that are asymptomatic, but have lots of amyloid," he added. "They have amyloid in their brain at about the same level as the people in the early-tau group, but they don’t yet have cognitive impairment and don’t yet have high levels of tau. So, I think that’s an important group."

Eisai also presented 36-month data from Clarity AD’s open-label extension at the meeting, with results showing continued clinically and personally meaningful benefit in treated patients. Over 3 years of treatment across the core study and OLE, lecanemab reduced cognitive decline on the CDR-SB by –0.95 compared with the expected decline based on those in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) group. For context, a change of –0.45 (P = .00005) was observed between lecanemab and placebo at the 18-month mark of the core study.⁵

REFERENCES
1. Update on Regulatory Review of Lecanemab for Early Alzheimer’s Disease in the European Union. Biogen. July 26, 2024. Accessed August 2, 2024. https://investors.biogen.com/news-releases/news-release-details/update-regulatory-review-lecanemab-early-alzheimers-disease
2. FDA Converts Novel Alzheimer’s Disease Treatment to Traditional Approval. FDA. News release. July 6, 2023. Accessed August 2, 2024. https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval
3. Biogen to realign resources for Alzheimer’s disease franchise. News release. Biogen. January 31, 2024. Accessed August 2, 2024. https://finance.yahoo.com/news/biogen-realign-resources-alzheimers-disease-123000872.html
4. van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9-21. doi:10.1056/NEJMoa2212948
5. New Clinical Data Demonstrates Three Years of Continuous Treatment with Dual-Acting LEQEMBI® (lecanemab-irmb) Continues to Significantly Benefit Early Alzheimer’s Disease Patients Presented at The Alzheimer’s Association International Conference (AAIC) 2024. News release. Eisai. July 30, 2024. Accessed August 2, 2024 https://www.multivu.com/players/English/9282551-eisai-leqembi-clinical-data-aaic-2024-alzheimers/