From LILAC to AMETHYST: The Rapid Efficacy of Litifilimab in CLE

Victoria Werth, MD, professor of Dermatology and Medicine at the University of Pennsylvania and Chief of Dermatology at the Philadelphia VA Medical Center, discussed key data from the phase 2 LILAC study of litifilimab in cutaneous lupus erythematosus (CLE), the rationale for the ongoing phase 3 AMETHYST program, and the broader implications of its recent FDA Breakthrough Therapy Designation.

The LILAC trial, published in The New England Journal of Medicine, evaluated 3 dose regimens of litifilimab and demonstrated significant improvements in skin disease activity compared with placebo, as measured by reductions in CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index) activity scores. Clinical responses were observed relatively rapidly, distinguishing litifilimab from standard therapies such as hydroxychloroquine, which may require months to achieve effect and are ineffective in a substantial proportion of patients. All dose groups showed benefit, supporting both the biologic relevance of the target and the therapeutic potential of the agent. The magnitude and speed of response contributed to the therapy’s recent designation.

Werth highlighted that improvements in CLASI scores translate into meaningful patient-centered benefits. Prior studies have shown that achieving CLASI-50 (≥50% improvement) correlates with significant gains in skin-specific quality of life measures, including instruments such as the Skindex-29. Higher response thresholds (eg, CLASI-70) represent more stringent disease control but may not be necessary for clinically meaningful improvement from a patient perspective. Ongoing analyses aim to further clarify how different response levels align with real-world functional and psychosocial outcomes. The phase 3 AMETHYST program builds on LILAC by evaluating a single selected dose in a larger patient population over a longer duration to more definitively characterize efficacy and safety. This trial is designed to support potential regulatory approval and broader access.

FDA Breakthrough Therapy Designation is particularly notable in CLE, a field with no therapies approved under modern regulatory pathways. Werth emphasized that dedicated CLE trials are essential, as medications approved for systemic lupus erythematosus may not be readily accessible for patients with predominantly cutaneous disease. The designation signals recognition of both the unmet need and litifilimab’s potential to meaningfully improve outcomes in a disease associated with significant physical and psychosocial burden.

“Those of us who take care of patients with cutaneous lupus have been very excited to see the advances,” Werth concluded. “So it's really important to be able to do this kind of study, and to be able to have access to new therapies that will be beneficial to the patients.”