POS0538 PHARMAco*kINETIC-PHARMACODYNAMIC RELATIONSHIP JUSTIFIES DOSE SELECTION OF DS-7011A, AN ANTI-TLR7 MONOCLONAL ANTIBODY, FOR THE TREATMENT OF ASIAN PARTICIPANTS IN AN ONGOING GLOBAL PHASE 1B STUDY OF DS-7011A IN SYSTEMIC LUPUS ERYTHEMATOSUS (2024)

Abstract

Background: Toll-like receptor (TLR)7 is a pattern recognition receptor whose ligands include nucleic acids and whose gain-of-function mutations have been reported to result in systemic lupus erythematosus (SLE)^[1]. DS-7011a is an anti-TLR7 monoclonal antibody, which inhibits in vitro production of cytokines and antibodies stimulated by TLR7. A surrogate anti-TLR7 mAb improved survival and reduced autoantibody production in murine lupus model^[2]. DS-7011a was generally safe and well tolerated and showed optimal pharmaco*kinetic (PK) and pharmacodynamic (PD) characteristics in a first-in-human (FIH), single ascending intravenous (IV) and subcutaneous (SC) dose study in healthy volunteers (HV), including HV of Japanese descent^[3]. A global, randomized, double-blind, placebo-controlled Phase 1b study is ongoing to investigate safety, tolerability, and preliminary efficacy of DS-7011a in SLE patients [NCT05638802].

Objectives: This study was conducted with the objective to justify dose selection for the treatment of Asian SLE patients participating in the ongoing Phase 1b study of DS-7011a through the analysis of DS-7011a PK-PD relationship in HV from FIH study.

Methods: DS-7011a PK and PD data from non-Asian HV (mainly Caucasian and African American, N = 50) and Asian HV (N = 7, 0.1 or 3 mg/kg IV) enrolled in IV (0.1 - 20 mg/kg) and SC cohorts (100 - 600 mg) of DS-7011a FIH study were used for PK-PD relationship assessment. DS-7011a PK exposure in SLE patients from Asia (China and Japan) after 20 mg/kg IV administration was predicted by assuming mean body weight (BW) of 55.2 kg. PK and PD profiles in Asian vs. non-Asian SLE patients were simulated and compared to justify the selection of 20 mg/kg IV Q4W regimen in the ongoing Phase 1b study of DS-7011a, which is expected to also enroll Asian SLE patients from China and Japan.

Results: DS-7011a PK profile was well described by a 2-compartment model, with parallel linear and saturable clearance (CL) and with first-order SC absorption. BW was a covariate on linear CL and volume, as higher BW resulted in increased CL and volume of distribution. After correcting for subject BW, no additional patient factors (race, sex) appear to significantly influence DS-7011a PK. After DS-7011a administration, the time to reach maximum ex vivo IL-6 inhibition was delayed by approximately 24 hours in comparison to plasma peak concentration. This delay is probably mainly driven by internalization of DS-7011a into the endosome. After exclusion of PK and PD data that were collected on Day 1 after DS-7011a IV or SC administration, DS-7011a exhibited concentration-dependent, saturable inhibition of ex vivo IL-6 production in HV. Ex vivo IL-6 profile after DS-7011a administration was adequately described by DS-7011a concentration-derived inhibition of ex vivo IL-6 production. PK-PD relationship of DS-7011a is similar between Caucasian and African American, and the maximum inhibition of ex vivo IL-6 production (Imax) after DS-7011a administration is comparable across all races (Caucasian, African American, and Asian HV), regardless of IV or SC administration. Model simulation predicts similar PK exposure in Asian to non-Asian SLE patients after DS-7011a 20 mg/kg IV Q4W for 12 weeks. Simulated DS-7011a PK exposure in Asian SLE patients 12 weeks after DS-7011a 20 mg/kg IV Q4W is expected to robustly suppress TLR7-mediated ex vivo IL-6 production, similarly to non-Asian patients.

Conclusion: DS-7011a exhibited concentration-dependent, saturable inhibition of ex vivo IL-6 production in HV, across all the evaluated races. Simulated DS-7011a PK exposure and ex vivo IL-6 inhibition after DS-7011a 20 mg/kg IV Q4W is comparable between Asian and non-Asian SLE patients, supporting the inclusion of Asian participants at this dosing regimen selected for the ongoing Phase 1b study of DS-7011a in SLE.

Acknowledgements: Daiichi Sankyo, Inc. sponsored study/project.

Disclosure of Interests: Li Zhang Daiichi Sankyo, Daiichi Sankyo, Jun Tanaka Daiichi Sankyo, Daiichi Sankyo, Anthony Gebhart Daiichi Sankyo, Michael Dodds Daiichi Sankyo, Mirjam Trame Daiichi Sankyo, Sophia Xu Daiichi Sankyo, Masafumi Kumazaki Daiichi Sankyo, Yoshiaki Tomimori Daiichi Sankyo, Takaaki Oka Daiichi Sankyo, Yoshiyuki Igawa Daiichi Sankyo, Samarth Patel Daiichi Sankyo, Aparna Mohan Daiichi Sankyo, Giorgio Senaldi Daiichi Sankyo, Tarek Leil Daiichi Sankyo.