FDA Accepts Supplemental BLA for Traditional Approval of Lecanemab

Sharon Cohen, MD, FRCPC

The FDA has accepted Eisai’s supplemental biologics license application (sBLA) for the traditional approval of lecenamab (Leqembi), an antiamyloid therapy approved for patients with early Alzheimer disease (AD). The agency placed a PDUFA action date of July 6, 2023, for the decision.¹

Approved under the accelerated approval pathway early January 2023, the sBLA is based on findings from the phase 3 confirmatory Clarity AD study (NCT03887455), an 18-month study that further demonstrated lecanemab’s effect in early AD. Designed as a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody, lecanemab was originally greenlit on data from the phase 2, Study 201 (NCT01767311), which demonstrated the drug’s significant effect on reducing amyloid-ß in the brain.

Days after it was approved under the accelerated approval pathway, Eisai filed for traditional approval. Sharon Cohen, MD, FRCPC, an investigator on both Study 201 and Clarity AD, told NeurologyLive® at the time, "The FDA has granted conditional approval based on the accelerated pathway and with that conditional approval, without confirmatory data, the FDA could withdraw its approval. Also, funding bodies, like CMS have opted, at this point, not to fund antiamyloid drugs that are approved conditionally or via the accelerated pathway. What that means is if they're successful, and the FDA grants full approval, we don't have this tenuous situation where approval could be withdrawn. We have a much greater opportunity to have insurers fund the drug so that it can be much more available and accessible to patients."

Under the accelerated approval, drug companies are still required to conduct phase 4 studies that confirm the anticipated clinical benefit of a therapy. As noted, in April 2022, the Centers for Medicare & Medicaid Services (CMS) published its final decision memo on its national coverage analysis for the class of monoclonal antibodies as treatments of AD, restricting the coverage of these products to certain scenarios. The finalization of this coverage framework included evidence available to the agency from up to that time point, which did not include updated data on lecanemab highlighting effects these therapies may bring.

In February 2023, CMS provided an update to the Alzheimer’s Association’s request to reconsider the final national coverage determination, stating the agency was not reconsidering changing its stance at this time. After a careful review of the request and supporting documentation, CMS believed there is not enough evidence yet to meet the criteria for reconsideration.²

Cohen added, "Originally, the role of accelerated pathway approval is to make a drug more accessible, not less accessible. If it looks promising, and it can help people especially in a progressive disease, you don't want people to have to wait."

Published in the New England Journal of Medicine, Clarity AD included 1795 patients with evidence of amyloid on PET or cerebrospinal fluid who were followed for an 18-month treatment period. At the conclusion of the analysis, 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. Overall, lecanemab-treated patients showed adjusted least-squares (LS) mean changes of 1.21 vs 1.66 for those on placebo (P <.001).³

Lecanemab also met secondary end points in Clarity AD, including change in amyloid PET centiloids (difference in 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 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 ADsCOMS by 24% and disease progression on ADCS MCI-ADL by 37% at the same time point.

In terms of safety, lecanemab continued to show a favorable profile that was within expectations, with amyloid-related imaging abnormalities- edema (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.

REFERENCES
1. FDA Accepets Eisai’s filing of a supplemental biologics license application and grants priority review for traditional approval of Leqembi (lecanemab-irmb) for the treatment of Alzheimer’s disease. News release. Eisai. March 5, 2023. Accessed March 6, 2023. https://www.prnewswire.com/news-releases/fda-accepts-eisais-filing-of-a-supplemental-biologics-license-application-and-grants-priority-review-for-traditional-approval-of-leqembi-lecanemab-irmb-for-the-treatment-of-alzheimers-disease-301762846.html
2. CMS Statement: response to Alzheimer’s Association’s request to reconsider the final national coverage determination. News release. February 22, 2023. Accessed March 6, 2023. https://www.cms.gov/newsroom/press-releases/cms-statement-response-alzheimers-associations-request-reconsider-final-national-coverage
3. 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