PII-093 - A PHASE 1, OPEN-LABEL STUDY TO EVALUATE THE PHARMACOKINETICS OF A SINGLE DOSE OF DAZODALIBEP IN HEALTHY JAPANESE AND CAUCASIAN PARTICIPANTS.

K. Der¹, Z. Wang², L. Bosoro², L. Hewitt², T. Wilson², J. Huang²; ¹Horizon Therapeutics, San Francisco, CA, United States, ²Horizon Therapeutics.

Background: Dazodalibep (DAZ), a novel non-antibody biologic antagonist of CD40 ligand (CD40L), inhibits the costimulatory signals between immune cells. DAZ is currently under clinical evaluation for the treatment of Sjögren’s, a chronic, systemic autoimmune disease caused by aberrant activation and infiltration of lymphocytes. The primary objective of this study was to evaluate the pharmacokinetics (PK) of DAZ after a single intravenous (IV) dose administered to healthy Japanese and Caucasian participants (pts).

Methods: DAZ 3000 mg was administered to 12 healthy Japanese and 12 Caucasian adult pts. Blood samples were collected up to 56 days post dose. Plasma concentrations and presence of antidrug antibody were measured using validated methods. PK parameters were estimated using non-compartmental methods. A parametric analysis of variance model was fitted to the natural logarithmic transformation of relevant PK parameters (AUCinf and Cmax) with cohort (Japanese vs Caucasian) as a fixed effect. The 90% confidence intervals (CIs) were constructed for the ratio of the geometric least squares means (GLSMs) of PK parameters for DAZ in Japanese vs Caucasian pts. Safety was monitored throughout the study.

Results: DAZ concentration declined in a biphasic manner typical of biologic molecules administered IV. The GLSMs (90% CI) of PK parameters for DAZ in Japanese vs Caucasian pts were 1.35 (1.13, 1.61) and 1.25 (1.05, 1.49) for AUCinf and Cmax, respectively. The mean (SD) body weight in Japanese and Caucasian pts differed: 60.5 (7.69) kg and 80.4 (15.4) kg, respectively, accounting for the difference in exposure. The GLSMs ratios with weight as a covariate for DAZ were 0.97 (0.84, 1.11) and 0.99 (0.82,1.20) for AUCinf and Cmax, respectively.

Conclusion: Following administration of DAZ, statistical analysis showed that peak (Cmax) and extent of exposure (AUCinf) were higher in Japanese pts by about 25% – 35%. However, when weight was considered as a covariate in the statistical model, the peak and extent of exposure were similar between the two groups. The difference in weight between the groups attributed to the differences in exposure. Although there is a statistical PK weight effect, moderate changes in PK did not translate to clinically meaningful changes in efficacy. DAZ was safe and generally well tolerated.