Victoria Werth, MD

There have been no approved therapies for 

 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 

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.

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

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?

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?

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?

 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?

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?

 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.

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

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.

Articles

Litifilimab, an anti-BDCA2 subcutaneous monoclonal antibody targeting plasmacytoid dendritic cells to downregulate type I interferon signaling, is being advanced to address major unmet need in CLE refractory or intolerant to antimalarials. In AMETHYST Part A (n=93), early efficacy separated from placebo by week 4 on CLASI-50 and met the week-16 CLA-IGA-R erythema 0–1 endpoint. Open-label extension data through week 52 suggest continued response maturation and acceptable longer-term tolerability without serious viral infections.

Werth discusses what the 52-week AMETHYST Part A data add to the case for litifilimab in antimalarial-refractory cutaneous lupus erythematosus.

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

Evolving Research Landscape Drives Progress in CLE at AAD 2026

Cutaneous lupus erythematosus (CLE) is a disease whose therapeutic stagnation has stood in stark contrast to the scientific progress made in understanding its underlying biology. Over the past two decades, advances in immunology have illuminated the central role of plasmacytoid dendritic cells, type I interferon signaling, and innate immune dysregulation in driving the skin inflammation, tissue injury, and scarring that define the disease.¹ That growing mechanistic clarity has not only reframed how clinicians think about CLE pathophysiology but has begun to translate into a new generation of rationally designed therapeutic candidates targeting the specific immunological pathways responsible for disease activity.

Litifilimab is perhaps the clearest example of that translation. Its development as a BDCA2-targeting monoclonal antibody was predicated on the understanding that pDC-driven type I interferon production is a proximal driver of lupus pathogenesis, and its two positive Phase 2 trials in CLE represent the most advanced clinical validation of that mechanistic hypothesis to date.² The progress made in CLE is also inseparable from broader advances in lupus research, where a deepening understanding of immune dysregulation across the spectrum of disease has created shared scientific infrastructure that benefits both systemic and cutaneous manifestations.

For patients who have lived with inadequate treatment options for generations, the convergence of scientific understanding and clinical evidence now underway represents a genuine inflection point. In this final segment, Joseph Merola, MD, MMSc, and Victoria Werth, MD, reflect on how the field's evolving understanding of CLE pathophysiology has shaped the current moment in drug development, and what the trajectory of innovation suggests for the future of care in this long-underserved disease.

Furie R, Werth VP, Merola JF, et al. Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. 

 2019;129(3):1359-1371. doi:10.1172/JCI124466

Biogen Inc. Biogen announces second positive Phase 2 litifilimab trial in cutaneous lupus erythematosus at 2026 American Academy of Dermatology Annual Meeting, showing a significant reduction in skin disease activity. Published March 28, 2026. 

https://investors.biogen.com/news-releases/news-release-details/biogen-announces-second-positive-phase-2-litifilimab-trial

Videos

Experts reflect on how advances in understanding CLE have fueled drug development and what the trajectory of innovation holds for the field.

Potential of Targeting BDCA2 in Cutaneous Lupus Erythematosus Management

Cutaneous lupus erythematosus (CLE) is driven by a complex interplay of innate and adaptive immune dysregulation, with plasmacytoid dendritic cells (pDCs) occupying a central role in disease pathogenesis. Activated pDCs produce substantial quantities of type I interferon and other pro-inflammatory cytokines and chemokines that perpetuate skin inflammation, drive keratinocyte injury, and contribute to the irreversible tissue damage that defines the most severe presentations of the disease. For a patient population that has long been managed with broadly immunosuppressive agents carrying significant toxicity profiles, a therapy designed to interrupt this pathway at its source represents a meaningful mechanistic departure from the standard of care.

Litifilimab targets BDCA2, a receptor selectively expressed on pDCs. Binding of litifilimab to BDCA2 suppresses pDC activation and downstream production of type I interferon and associated inflammatory mediators, offering a targeted approach to interrupting the immunological cascade thought to underlie CLE pathology. The specificity of this mechanism is clinically relevant: by acting on pDCs rather than broadly suppressing immune function, litifilimab has the potential to attenuate disease-driving inflammation while preserving broader immune competence.

That mechanistic rationale is now supported by a pair of positive Phase 2 trials. In the phase 2 portion of the AMETHYST study, litifilimab demonstrated a statistically significant 11.8% higher rate of clear or almost clear skin versus placebo at Week 16 (14.7% vs 2.9%; 95% CI: 1.39, 22.27; P < .05), with separation from placebo observed as early as Week 4. At Week 24, 40.8% of litifilimab-treated participants achieved a CLASI-50 response compared with 21% receiving placebo, and 1 in 6 participants in the litifilimab group achieved a CLASI score of 0 to 3, indicating no or minimal disease activity, compared with none in the placebo group. These results are consistent with the earlier LILAC Phase 2 study and collectively represent the only investigational program with positive efficacy data across multiple CLE trials to date.¹

In this segment, Joseph Merola, MD, MMSc, and Victoria Werth, MD, examine how the mechanism of action of litifilimab maps onto the immunopathology of CLE, what the AMETHYST results reveal about the durability and depth of response, and what these findings may mean for patients who have exhausted current treatment options.

Drenkard C, Barbour KE, Greenlund KJ, Lim SS. The burden of living with cutaneous lupus erythematosus. 

 2022;9:897987. doi:10.3389/fmed.2022.897987

Experts explore how litifilimab's BDCA2-targeting mechanism maps onto CLE pathophysiology.

Navigating Multidisciplinary Care for CLE in an Evolving Landscape

Cutaneous lupus erythematosus (CLE) does not exist in a clinical vacuum. While skin disease is the defining feature, CLE frequently intersects with systemic manifestations, comorbid autoimmune conditions, and the ever-present risk of progression to systemic lupus erythematosus. Managing this complexity has historically required coordination across specialties, with dermatologists, rheumatologists, and primary care clinicians each playing a role in the care of a patient population whose needs often exceed what any single specialty can address alone. Yet in the absence of approved targeted therapies, that collaboration has had limited tools to work with, and management decisions have largely defaulted to the same narrow, off-label options regardless of disease severity or phenotype.

The question of who owns CLE therapeutically is one the field has not fully resolved. Dermatologists are often the first to diagnose and treat, given the primacy of skin involvement, but rheumatologists bring expertise in systemic disease monitoring and immunosuppressive management that is frequently essential. For patients with refractory or severe disease, navigating this divide can translate into fragmented care, delayed escalation, and outcomes that reflect the limitations of the system as much as the limitations of available therapies.

An approved targeted therapy for CLE would not just add a treatment option, it could reframe the clinical conversation. A therapy with a defined mechanism, a validated efficacy profile, and a manageable safety record would give both dermatologists and rheumatologists a shared reference point around which to organize care, set treatment goals, and evaluate response in a more structured and collaborative way. It could also expand access for patients who are currently undertreated because no specialist feels sufficiently equipped to escalate beyond standard of care.

In this segment, Joseph Merola, MD, MMSc, and Victoria Werth, MD, reflect on how CLE patients move through the health care system today, where the gaps in multidisciplinary coordination are most acute, and how the availability of a first approved targeted therapy could reshape not only treatment paradigms but the broader infrastructure of collaborative care for this disease.

Experts discuss how an approved targeted therapy could restructure collaboration between dermatology and rheumatology.