Background/Purpose: Litifilimab is a humanized IgG1 mAb targeting BDCA2, a receptor expressed on plasmacytoid dendritic cells (pDCs), that negatively regulates the production of Type I IFN and proinflammatory chemokines and cytokines.^1,2 In the Phase 2 LILAC study of litifilimab (NCT02847598), Part A (participants with SLE, active arthritis and rash) and Part B (participants with active CLE, with or without SLE) met their primary endpoints at Weeks (W) 24 and 16, respectively.^1,2 We evaluated the effects of litifilimab on IFN gene signature (IFNGS) scores from whole blood samples, serum IFNα concentrations, and other serum cytokine concentrations in LILAC participants.^3,4

Methods: Expression of 22-gene panel IFNGS scores and concentrations of IFNα and other cytokines were examined over time in the modified intent-to-treat population (Part A N=120, Part B N=132) with available data at baseline (BL) and ≥1 post-BL visit. Treatment effects were estimated using a mixed model repeated measures approach. In Part A, IFNα concentration changes over time were compared with W24 total active joint counts and CLASI-A scores (Spearman rank correlations) and SLE Responder Index (SRI-4) status. In Part B, Pearson correlations between percent changes in CLASI-A score and IFNGS score were estimated and the dose-response relationship was estimated using a previously described MCP-Mod method.²

Results: As too few participants were IFNGS-low at BL, only data for the IFNGS-high subgroups are described. Litifilimab induced rapid, substantial, and sustained reductions in 22-gene IFNGS scores and IFNα concentrations that were greater (nominal P< 0.05) vs placebo (PBO) with litifilimab 150 mg (Part B) and 450 mg (Parts A and B) (Table 1 and Figure 1). In Part A, TNFα and IL-10 concentrations were reduced (nominal P< 0.05) with litifilimab 450 mg at W24 (Table 1); no strong evidence of this was seen in Part B. Change in IFNα concentration and change in total active joint count with litifilimab 450 mg in Part A were correlated (Spearman correlation estimates: PBO −0.15 [95% CI: −0.41, 0.16]; 450 mg 0.34 [0.07, 0.55]), as were changes in IFNα concentration and CLASI-A score (PBO −0.01 [−0.34, 0.31]; 450 mg 0.35 [0.10, 0.58]) at W24. A trend of greater median IFNα concentration reduction in W24 SRI-4 responders relative to non-responders was seen with litifilimab 450 mg. Confirmation of these findings in larger sample sizes is warranted. In Part B, the dose-response relationship was similar to that observed with the clinical responses (Figure 2) and percent change in CLASI-A score was correlated with percent change in IFNGS score in all treatment groups.

Conclusion: Litifilimab induced a rapid, substantial, and sustained reduction in 22-gene IFNGS scores and IFNα concentrations, and reductions in some biomarkers correlated with clinical responses. These results further support the mechanism of action for litifilimab and the role of Type I IFN and pDCs in SLE and CLE.^5,6

1Furie R et al. N Engl J Med 2022;387:894–904
²Werth V et al. N Engl J Med 2022;387:321–331
³Werth V et al. J Invest Dermatol 2023;143(5 Supp):S101
⁴Furie R et al. Ann Rheum Dis 2023;82(1 Supp):1453–1454
⁵Fetter T et al. Front Med (Lausanne) 2022;9:915828
⁶Rönnblom L, Leonard D. Lupus Sci Med 2019;6:e000270

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/litifilimab-modulates-type-i-ifn-biomarkers-in-patients-with-sle-or-cle-in-the-phase-2-lilac-study/