048: Population Pharmacokinetic and Exposure-response Analyses of anti-BDCA2 Antibody Litifilimab Support Its Clinical Benefit for Cutaneous Lupus Erythematosus

Statement of Purpose, Innovation or Hypothesis: Litifilimab is a humanized immunoglobulin G1 monoclonal antibody that binds blood dendritic cell antigen 2 (BDCA2), resulting in downregulation of Type I Interferon (IFN-I), cytokine, and chemokine production, and is under development for the treatment of cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). In the Part B of the Phase 2 dose-ranging trial (LILAC; NCT02847598) involving participants with active CLE, 16-week litifilimab treatment demonstrated superior efficacy over placebo, with an acceptable safety profile.¹ Population pharmacokinetics (PK) and exposure-response (E-R) modeling analyses were conducted to further characterize the PK and dose/exposure-response (D/E-R) relationship of litifilimab in CLE participants and to identify clinically relevant covariates.

Description of Methods & Materials: Population PK analysis used litifilimab PK data from the LILAC study Part B in CLE participants following its subcutaneous administrations (50 mg, 150 mg, 450 mg every 4 weeks with an additional dose at Week 2). Additionally, the PK analyses incorporated data from completed Phase 1 studies (NCT02106897; NCT03224793) in healthy volunteers (HVs) and SLE participants^2,3 and LILAC study Part A in SLE participants receiving either subcutaneous (Phase 1 and Phase 2) or intravenous administrations (Phase 1).  To provide a thorough assessment of D/E-R relationship in CLE, two E-R modeling approaches were conducted using the data from LILAC Part B: longitudinal analysis with indirect response modeling of the time course of disease activity measured by CLE Disease Area and Severity Index – Activity (CLASI-A) score and landmark analysis linking clinical response (CLASI-A score percent change from baseline) at Week 16 to model predicted litifilimab trough concentrations at Week 16. All analyses were performed using NONMEM.

Data & Results: Litifilimab PK was adequately described by a 2-compartment PK model with first-order absorption and parallel linear and nonlinear Michaelis–Menten elimination. Body weight, anti-drug antibody status, and participant type were identified as PK-influencing covariates, with lower exposure in heavier participants, in those who developed anti-litifilimab antibodies, and in SLE or CLE participants (versus HVs). However, the magnitudes of the effects of these covariates were not considered clinically relevant. Longitudinal and landmark E-R analyses results were generally consistent, and collectively suggested a positive E-R relationship, supporting the effectiveness of litifilimab in CLE. The model estimated EC₉₀ (concentration associated with 90% of maximal drug effect) on CLASI-A response was comparable to IC₉₀ on the ex vivo biomarker of IFNα^4,5, aligned with the known mechanisms of action.

Interpretation, Conclusion or Significance: Our analyses provide a comprehensive evaluation of litifilimab PK and D/E-R in CLE in a modeling framework, supporting its clinical benefit in the treatment of CLE. There is an on-going Phase 2/3 trial (AMETHYST; NCT05531565) to further assess the efficacy and safety of litifilimab for patients with CLE. Results from current analyses may help elucidate how patients treated with litifilimab would respond to different doses in related disease indications like SLE, guiding the clinical development programs beyond CLE.

Disclosures: This work is supported by Biogen. All authors are employees of Biogen and may own stock in the company.

Citations/References: 1. Werth VP, et al. N Engl J Med. 2022 Jul 28;387(4):321-331. 2. Furie R, et al. J Clin Invest. 2019 Mar 1;129(3):1359-1371. 3. Musselli C, et al. Arthritis Rheumatol. 2019; 71 (suppl 10). [abstract] 4. Hartmann S, et al. J Pharmacokinet Pharmacodyn. 2020 Jun;47(3):255-266. 5. Francois G, et al. PAGE 2018.[abstract]

Additional Information/Authors: The authors would like to thank the contributions made by Dr. Francois Gaudreault and Dr. Xiao Tong, who were employees of Biogen at the time of study.