AMETHYST: Litifilimab Sustains CLE Gains at 52 Weeks, With Victoria Werth, MD

There have been no approved therapies for cutaneous lupus erythematosus (CLE) in more than 80 years, and only about 50% to 55% of patients adequately respond to antimalarials, the foundation of current systemic therapy. Litifilimab is a subcutaneous monoclonal antibody binding blood dendritic cell antigen 2 on plasmacytoid dendritic cells, reducing type I interferon and other proinflammatory cytokines implicated in CLE. The earlier phase 2 LILAC Part B trial met its primary endpoint, showing a significant dose response in CLASI activity at week 16.¹

AMETHYST Part A, a phase 2 portion of an operationally seamless phase 2/3 study, randomized 93 participants with active CLE refractory or intolerant to antimalarials to subcutaneous litifilimab or placebo every 4 weeks. Fifty-nine participants received litifilimab and 34 received placebo, with baseline CLASI-A scores well balanced between groups. The primary endpoint was CLA-IGA-R erythema score of 0 to 1, or clear to almost clear, at week 16.²

Among participants who started litifilimab during the double-blind period, response rates continued improving from week 24 through week 52: CLA-IGA-R erythema 0-1 rose from 19.0% to 27.2%, CLASI-70 from 21.7% to 28.8%, and CLASI-50 from 40.8% to 46.0%. Participants who switched from placebo to litifilimab at week 24 began responding within about 4 weeks, reaching week 52 response rates of 33.7% for CLA-IGA-R erythema 0-1 and 48.5% for CLASI-50.

Adverse events in the extended treatment period were similar between groups, at 76.8% for participants who started litifilimab early and 78.1% for later starters, with all but 2 events mild or moderate. Serious adverse events occurred in 3.6% and 3.1% of these groups, respectively, and no serious viral infections were observed through week 52.

Victoria Werth, MD, professor of dermatology and medicine at the University of Pennsylvania and a co-author on the AMETHYST Part A abstract, spoke with HCPLive at the European Academy of Dermatology and Venereology (EADV) 2026 Congress held in Vienna from September 30-October 3. In the following interview, Werth discusses what the 52-week data add to the case for litifilimab in refractory CLE.

HCPLive: Where does therapy stand today for patients who do not respond to antimalarials, and what gap was AMETHYST built to address?

Victoria Werth, MD: This is an amazingly exciting time. There have been no approved therapies for over 80 years in cutaneous lupus, and we're really on the cusp of changing the way we practice. Antimalarials are the foundation of systemic therapy, but patients only respond maybe 50 to 55 percent of the time, and some patients are intolerant of them or experience side effects. There is unresolved disease activity that often persists, especially with discoid lupus, along with dyspigmentation and scarring that can be very disfiguring for patients. In LILAC Part B, which was published in the New England Journal of Medicine in 2022, the trial met its primary endpoint, showing a significant dose response and percent change in CLASI activity from baseline to week 16. CLASI is an outcome measure that's been validated and is now accepted as a primary outcome for cutaneous lupus, and that really allowed this trial to go forward. We were very excited about the results of the phase 2 trial.

HCPLive: What did the 24-week AMETHYST Part A data show, and what does the 52-week readout add?

Victoria Werth, MD: These results were reported at the American Academy of Dermatology meeting in 2026. The primary endpoint was CLA-IGA-R erythema score of 0 to 1, meaning clear or almost clear, at week 16. At that time point, about 14.7% of patients who got litifilimab had a statistically significant improvement versus only 2.9% with placebo. The CLASI-50 response separated from placebo as early as week 4, at 19.3% versus 5.5%, which was exciting to see this early, since it suggests a therapy that can respond quickly. At week 24, CLASI-50 was 40.8% versus 21% with placebo, CLASI-70 was 21.7% versus 5.8% with placebo, and CLASI 0 to 3, or minimal residual activity, was 16.3% versus 0% with placebo.

HCPLive: Why does durability specifically matter for patients with refractory cutaneous lupus, beyond the drug itself?

Victoria Werth, MD: In Part A, the patients enrolled were refractory or intolerant to antimalarial therapy. That's a population with very few remaining systemic options, other than immunosuppressives or other medicines that can have potential side effects, and there's ongoing risk of dyspigmentation and scarring while you're trying to find a therapy that controls the unresolved disease activity.

HCPLive: After week 24, every participant is on active drug. How should clinicians interpret continued improvement through week 52?

Victoria Werth, MD: The point of this type of open-label long-term extension is really to see whether the drug maintains efficacy and to evaluate safety better. Placebo-assigned participants crossed over to open-label litifilimab starting at week 24, and from that point, week 52 comparisons are largely within-group, the change from week 24 for the people who only started the drug at that point, rather than placebo-controlled. This design lets investigators assess durability and continued improvement in the original litifilimab arm, and separately, whether the late-starting patients begin to catch up.

HCPLive: In your own practice, how would a validated CLASI threshold change how you counsel patients on treatment response?

Victoria Werth, MD: CLASI activity is increasingly used as a trial outcome measure in CLE. A defined minimal clinically important difference gives clinicians and patients a shared benchmark beyond raw score changes.

HCPLive: What did the additional 28 weeks of safety exposure show, and does it support chronic use?

Victoria Werth, MD: Adverse events (AEs) were carefully recorded through week 24. 74.6% of patients on litifilimab had some kind of AE, not necessarily attributed to the drug, versus 64.7% with placebo, so there wasn't really a difference between placebo and drug, and most of these were mild to moderate in severity. Serious AEs were seen in 6.8% with litifilimab and 2.9% with placebo. The sponsor characterized the overall safety profile through the 24-week readout as generally well tolerated and consistent with prior studies.

Editor's Note: This transcript has been edited for grammar and clarity using artificial intelligence tools. Werth’s disclosures include Xoma, RPS, Janssen/Centocor, Biogen-Idec, Sanofi-Aventis, UVC, Novartis, Idera, Pfizer, Lupus Foundation of America, Medimmune, Rigel, Merck, Genentech, GSK Stiefel and Celgene.

REFERENCES:

1. Werth VP, Furie RA, Romero-Diaz J, et al. Trial of anti-BDCA2 antibody litifilimab for cutaneous lupus erythematosus. N Engl J Med. 2022;387(4):321-331. doi:10.1056/NEJMoa2118024

2. Merola JF, Werth V, Chong B, et al. Efficacy and safety of litifilimab in cutaneous lupus erythematosus (CLE): 52-week results of the Phase 2 study, AMETHYST Part A. Presented at: EADV Congress 2026; September 30-October 3, 2026; Vienna, Austria. Abstract AS-1846.