Litifilimab Shows Early Skin Benefits in CLE

Cutaneous lupus erythematosus (CLE) is an autoimmune dermatosis with chronic inflammatory features that significantly impacts patients’ quality of life through photosensitivity, painful or pruritic lesions, alopecia, and scarring. CLE includes acute, subacute, and chronic subtypes such as discoid lupus erythematosus (DLE), and may occur either with or without systemic lupus erythematosus (SLE) manifestations. Historically, no targeted therapies have been approved for CLE, and current management with antimalarials, corticosteroids or broad immunosuppressives often yields limited efficacy and notable toxicity concerns.¹ This unmet need has driven ongoing research into more specific therapeutic biologics.

Pathogenic Rationale and Mechanism

Evidence implicates plasmacytoid dendritic cells (pDCs) and dysregulated type I interferon (IFN) pathways in CLE pathogenesis. Elevated expression of IFN‑regulated genes correlates with disease severity, and pDCs — potent producers of IFN — are found in CLE lesions. Targeting pDC‑mediated IFN production is hypothesized to reduce inflammatory cascades underlying cutaneous lesions.²

Litifilimab (BIIB059) is a humanized monoclonal antibody that binds to blood dendritic cell antigen 2 (BDCA2) on pDCs. Engagement of BDCA2 induces internalization of the receptor, attenuating downstream production of type I and III IFNs and related pro‑inflammatory cytokines and chemokines. Prior phase 1 data showed that litifilimab decreased IFN response gene expression in blood and IFN‑regulated proteins in skin lesions, correlating with reductions in the Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity (CLASI‑A).³

Study Design: LILAC Part B

Part B of the multicenter, randomized, double‑blind, placebo‑controlled phase 2 LILAC study (NCT02847598) evaluated 3 doses of litifilimab (50 mg, 150 mg, 450 mg subcutaneously every 4 weeks with a week 2 loading dose) versus placebo in adult participants with histologically confirmed active CLE (baseline CLASI‑A ≥ 8), enrolled with or without concomitant SLE. The treatment period extended through 12 weeks with assessment through week 16. Skin‑specific exploratory outcomes were analyzed to further characterize litifilimab’s impact on cutaneous disease activity.

Clinical Endpoints and Assessments

The primary measure in part B was the percentage change in CLASI‑A score from baseline to week 16, with additional exploratory endpoints focused on CLASI‑based thresholds of response (≥20%, ≥50%, ≥70%, and ≥90% improvement), absolute point reductions (≥7‑point improvement), attainment of ‘clear’ (CLASI‑A 0–1) or ‘almost clear’ (CLASI‑A 0–3) skin status, and shifts in categories of disease severity. Physician’s Global Assessment (PGA) and Physician’s Global Impression (PGI) scales provided complementary clinician‑reported measures of overall skin condition and change from baseline.

Efficacy Results

A total of 132 participants were randomized across 4 groups (litifilimab 50 mg, 150 mg, 450 mg, and placebo). At baseline, mean CLASI‑A scores were comparable across groups. Litifilimab demonstrated greater reductions in skin disease activity compared with placebo at week 16: in dose‑response modeling, differences in CLASI‑A percentage change from baseline versus placebo ranged from approximately −24 to −33 percentage points across litifilimab doses.

Across multiple efficacy measures, higher proportions of participants treated with litifilimab achieved CLASI‑20, CLASI‑50, CLASI‑70, and CLASI‑90 responses relative to placebo. Improvements were observed as early as week 4 and generally maintained through week 16, with a dose‑response trend favoring the 150 mg and 450 mg doses. From weeks 4 to 16, more litifilimab‑treated participants achieved a clinically meaningful ≥7‑point CLASI‑A decrease than those receiving placebo. Achievements of ‘clear’ or ‘almost clear’ skin status at week 16 were numerically greater with litifilimab treatment, and mean absolute CLASI‑A reductions were greater in those attaining these stringent endpoints.

Physician assessments aligned with CLASI‑based measures, with higher proportions of litifilimab‑treated patients categorized as having ‘mild’ overall disease activity at week 16 and more participants rated as ‘much improved’ on PGI scales compared with placebo. Shifts from moderate or severe disease categories to milder categories were more frequently observed in litifilimab arms.

Safety

Litifilimab was generally well tolerated in CLE participants. Most adverse events were mild or moderate in severity, consistent with prior reports. Common events reported in pooled litifilimab groups included nasopharyngitis, headache, injection‑site erythema, arthralgia, upper respiratory tract infections, pruritus, and cough. Serious infections and hypersensitivity reactions occurred at low frequencies.

Mechanistic Correlates

Pharmacodynamic analyses showed that litifilimab rapidly and sustainably reduced IFN gene signature scores and serum IFN‑α concentrations in participants with a high baseline IFN signature. Dose‑response relationships for these biomarker changes paralleled clinical responses measured by CLASI‑A scores, supporting the hypothesized mechanism of action through inhibition of pDC‑derived IFN pathways.

Interpretation and Future Directions

These expanded analyses from LILAC part B provide further evidence that litifilimab can modulate cutaneous disease activity in a CLE population with moderate to severe skin involvement. The consistency of findings across CLASI thresholds and global physician assessments reinforces the clinical relevance of observed improvements. However, the relatively modest sample sizes and the exploratory nature of some endpoints highlight the need for larger, longer‑term studies to define optimal dosing, durability of response, and impact on skin damage endpoints. Importantly, the ongoing phase 2/3 AMETHYST trial is anticipated to extend these observations with greater power and extended treatment duration.

Litifilimab represents a promising pDC‑targeted biologic approach in CLE, with evidence of meaningful improvements in skin disease activity over 16 weeks compared with placebo and a tolerability profile amenable to further clinical evaluation.

References

1. Klein B, Billi AC, Abernathy-Close L, Kahlenberg JM. Cutaneous lupus erythematosus - from pathogenesis to targeted therapy. Nat Rev Rheumatol. 2025;21(12):703-718. doi:10.1038/s41584-025-01318-6
2. Kim JM, Park SH, Kim HY, Kwok SK. A plasmacytoid dendritic cells-type I interferon axis is critically implicated in the pathogenesis of systemic lupus erythematosus. Int J Mol Sci. 2015;16(6):14158-14170. Published 2015 Jun 23. doi:10.3390/ijms160614158
3. Furie R, Werth VP, Milliman E, et al. Pharmacodynamic effects of litifilimab in lupus in a randomized, placebo-controlled phase 2 study: rapid and sustained reductions in type I interferon-associated gene expression and cytokines. Arthritis Rheumatol. 2025;77(12):1726-1738. doi:10.1002/art.43271
4. Werth VP, Merola JF, Furie R, et al. Litifilimab efficacy on skin outcomes in cutaneous lupus erythematosus in the Phase 2 LILAC study. J Eur Acad Dermatol Venereol. Published online January 23, 2026. doi:10.1111/jdv.70291