(M-111) Exposure-Response Relationship Between Litifilimab and Clinical Outcomes in Systemic Lupus Erythematosus Populations

Jackson Burton – Biogen; Youmna Lahoud – Biogen; Julie Passarell – Simulations Plus; Yan Xu – Biogen

Objectives: Characterize the exposure-response (ER) relationship between litifilimab, a potential first-in-class anti-blood dendritic cell antigen 2 humanized monoclonal antibody, and two clinical outcomes: The continuous Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) [1] and the binary SLE Responder Index (SRI-4) [2] based on the part A Phase 2 LILAC (NCT02847598) study in participants with active SLE.

Methods: Part A of LILAC evaluated safety and efficacy in 132 SLE participants randomized to receive 6 subcutaneous doses (to week 20) of placebo, 50, 150, or 450 mg litifilimab (Q4W + W2 loading) up to 24 weeks, with the majority of active assigned to 450 mg. A previous population-pharmacokinetic (popPK) model was used to derive subject-specific exposure metrics based on dosing and input into each ER model [3]. Concentration was used for the SLEDAI-2K modeling while between visit AUC0 28d, Cmax, Cavg, and Ctrough were tested for the SRI-4 modeling.

The SLEDAI-2K ER model followed the semi-mechanistic approach [4] using a latent variable indirect response model and the SRI-4 response was modeled using logistic regression with a piece-wise linear function for exposure. Stepwise covariate analysis was used to test for statistically significant covariates including baseline body weight and SLEDAI 2K score at baseline, effects of corticosteroids  10 mg/day at baseline, concomitant medications, anti litifilimab antibodies, low interferon gene level at baseline, race, ethnicity, and sex in both models. The covariate effects were evaluated on baseline, logit of placebo fraction, EC50, and logit of Emax for the SLEDAI-2K model and evaluated on the intercept and drug slope for the SRI-4 model.

Results: The popPK model was used to generate subject-specific time-concentration profiles and Week 24 Cavg values for n = 6, 6, and 63 participants at the 50, 150, and 450 mg Q4W doses respectively for input into the SLEDAI-2K and SRI-4 ER models.

SLEDAI-2K model: A total of 829 SLEDAI-2K records from 130 participants (75 active, 55 placebo) were modeled. Fixed and random effect parameters were estimated with good precision (%RSE  26.6), except for the Emax (58.5 %RSE) and IIV in Emax (67.5 %RSE). Final estimates of the typical value of baseline b, placebo fraction F_(p,SLEDAI), and Emax were 10.4, 0.213, and 0.420, respectively. The only significant covariate was baseline SLEDAI-2K score. The half life estimate for the placebo response was calculated to be 5.1 weeks, suggesting stable placebo response was reached at 25.7 weeks.

SRI-4 model: A total of 758 SRI-4 records from 131 participants (75 active, 56 placebo) were modeled. Parameters were estimated with good precision ( < 33 %RSE). The only significant covariate was baseline SLEDAI-2K score. An additive error term, reflecting IIV, was estimated on the logit scale. A cutpoint for Cavg was estimated at 55 ug/ml for increased SRI-4 response based on higher exposure. Baseline SLEDAI 2K total score was a significant predictor of the intercept.

Conclusions: The ER models described the Phase 2 SLE data well offering a quantitative tool to characterize dose and efficacy for litifilimab in the treatment of SLE. Currently, litifilimab is being tested in Phase 3 (NCT04895241, NCT04961567).

Citations: 1. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2):288-91. PMID: 11838846.
2. Luijten KM, Tekstra J, Bijlsma JW, Bijl M. The Systemic Lupus Erythematosus Responder Index (SRI); a new SLE disease activity assessment. Autoimmun Rev. 2012 Mar;11(5):326-9. doi: 10.1016/j.autrev.2011.06.011. Epub 2011 Sep 18. PMID: 21958603.
3. Xu Y, Schmitz N, Jackson B, Barbey C. Population pharmacokinetic and exposure-response analyses of anti-BDCA2 antibody litifilimab support its clinical benefit for cutaneous lupus erythematosus. Clin Pharmacol Drug Dev. 2024;13(S1):Abstract 048. Presented at: American College of Clinical Pharmacology Annual Conference; 2024; Washington, DC.
4. Hu C, Xu Y, Zhuang Y, Hsu B, Sharma A, Xu Z, et al. Joint longitudinal model development: application to exposure–response modeling of ACR and DAS scores in rheumatoid arthritis patients treated with sirukumab. J Pharmacokinet Pharmacodyn. 2018;45(5):679-691.

Keywords: Population PK, Exposure-response, Systemic Lupus Erythematosus, anti-BDCA2