1379: Population Pharmacokinetic/Pharmacodynamic Modeling of Dazodalibep, a CD40L Antagonist, in Healthy Volunteers and Patients with Rheumatoid Arthritis and Sjogren’s Syndrome

Kenneth Der¹, Ryan Crass², Brendan Smith³, Wonkyung Byon⁴, Yan Xin⁵ and Jiayin Huang⁶, ¹Horizon Therapeutics, Danville, CA, ²Apellis Pharmaceuticals, Michigan, ³A2-Ai, Michigan, ⁴Amador Bioscience, Michigan, ⁵Horizon Therapeutics, South San Francisco, CA, ⁶Horizon Therapeutics, Chicago, IL

Background/Purpose: Sjögren's (SjS) is a chronic, systemic autoimmune disease caused by aberrant activation and infiltration of lymphocytes. Dazodalibep (DAZ), a novel non-antibody biologic antagonist of CD40 ligand (CD40L), inhibits the costimulatory signals between immune cells. The concentration of DAZ and immune biomarker data from existing clinical trials were analyzed using a population pharmacokinetic (PK)/pharmacodynamic (PD) model to inform dose selection for future studies.

Methods: PK and PD data from 4 clinical trials in healthy volunteers (HV) and subjects with rheumatoid arthritis (RA) and SjS were pooled and analyzed to characterize the PK of DAZ, including the effects of demographic covariates, and evaluate the PK/PD relationship on immune biomarkers (Ki67+ B cells, rheumatoid factor [RF], and CXCL13).

Results: Population PK modeling demonstrated that the PK of DAZ was adequately described by a two-compartment model with first-order elimination pathway from the central compartment. Following intravenous administration (IV), estimated clearance (CL; 0.347 L/day), distributional clearance (Q; 0.242 L/day), central volume of distribution (Vc; 3.4 L), and peripheral volume of distribution (Vp; 1.39 L) were consistent with typical biologics. Age, sex, race, ADA (anti-drug antibody) and renal function had no clinically relevant impact on DAZ CL. Body weight and patient population (HV or RA vs SjS) were identified as statistically significant covariates of DAZ PK. DAZ CL and VC increased less than linearly with increasing body weight. Healthy volunteers and RA patients had increase clearance relative to SjS patients. DAZ reduced circulating immune biomarkers which was well described with an indirect response model with DAZ effect applied as an inhibitory maximal effect (Imax) on the zero order production (Kin) for RF and CXCL13 and a direct effect model with DAZ effect applied as a proportional inhibitory maximal effect reduction from baseline for Ki67+ B cells. The proposed phase 3 doses are supported by the PK/PD modeling results and are expected to achieve sustained average drug concentration above the IC50 of Ki67+ B cells and RF within the dose interval.

Conclusion: The PK and PK/PD of DAZ were successfully described by population modeling. The modeling results supported the selection of dose to be further evaluated in upcoming phase 3 studies.


K. Der: Horizon Therapeutics, 3; R. Crass: Amador Bioscience, 3, Apellis Pharmaceuticals, 3; B. Smith: A2-Ai, 3, Amador Bioscience, 3; W. Byon: Amador Bioscience, 3, Pfizer, 3; Y. Xin: Horizon Therapeutics, 3; J. Huang: Astellas Pharma, 3, Horizon Therapeutics, 3.