Background/Purpose: 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 insystemic lupus erythematosus (SLE). DS-7011a is an anti-TLR7 monoclonal antibody (mAb), 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 models. DS-7011a was generally safe and well tolerated and showed optimal pharmacokinetic (PK) and pharmacodynamic (PD) characteristics in a first-in-human (FIH), single ascending intravenous (IV) and subcutaneous (SC) dose studyin healthy volunteers (HV), including HV of Japanese descent [NCT05203692]. We report here the analysis of the PK and PD data from the non-Japanese HV (mainly Caucasian and African American) that were initially administered in this study IV doses of DS-7011a to select the doses for later SC administration to non-Japanese HV and IV administration to Japanese HV.

Methods: DS-7011a clinical PK and PD data from single ascending dose (SAD) IV cohorts (from 0.1 to 20 mg/kg, N = 34) of non-Japanese HV enrolled in the first stage of DS-7011a FIH study was used for PK/PD model development under blinded analysis. PK exposure of SC doses to non-Japanese HV was predicted by assuming human SC bioavailability identical to that observed in monkeys (55.6%). PK exposure of IV doses to Japanese HV was predicted by assuming mean body weight of 66 kg. Dose selection for three SAD SC cohorts of non-Japanese HV and one IV cohort of Japanese HV was informed by benchmarking simulated PK and PD profiles with selected IV reference doses (1, 3, and 10 mg/kg for SC cohorts of non-Japanese HV; 3 mg/kg for the IV cohort of Japanese HV) after interim review of blinded data.

Results: DS-7011a PK linearity started at 3 mg/kg after IV infusion, while the elimination of lower doses was accelerated by target-mediated disposition. DS-7011a PK profile after IV infusion was well described by a 2-compartment model, with parallel linear and saturable, non-linear clearance (CL). Weight was a covariate on linear CL and central volume, as higher weight resulted in increased CL and volume of distribution. DS-7011a showed ex vivo inhibition of TLR7-stimulated IL-6 production that was of large extent, early onset, and lasting duration at 3 mg/kg and above.Ex vivo IL-6 profile after DS-7011a IV infusion was adequately described by DS-7011a concentration-derived inhibition of ex vivo IL-6 production. By benchmarking simulated PK and IL-6 profile with IV reference dose data, SAD SC doses for non-Japanese HV were proposed as 100, 300, and 600 mg, and SAD IV dose for Japanese HV as 3 mg/kg.

Conclusion: Model prediction of SAD SC doses for non-Japanese HV and IV dose for Japanese HV is confirmed by emerging clinical PK data and demonstrates the value of model-informed dose selection for DS-7011a FIH. Additional analysis will be conducted to select DS-7011a dose for future treatment of SLE patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selection-of-the-dose-for-subcutaneous-administration-to-non-japanese-subjects-and-intravenous-administration-to-japanese-subjects-in-the-first-in-human-study-of-ds-7011a-an-anti-tlr7-monoclonal-anti/