PII-182 - POPULATION PHARMACOKINETICS (PK) AND PK/PHARMACODYNAMICS ANALYSES TO REFINE PHASE 3 DOSE OF SETRUSUMAB IN PEDIATRIC PATIENTS WITH OSTEOGENESIS IMPERFECTA: RESULTS FROM PHASE 2 OF THE ORBIT STUDY

H. Tai¹, G. Wang², H. Wang², R. Hawtin², H. Byers², S. Krolczyk², E. Peng², S. Lee², E. Imel³, T. Carpenter⁴, G. Gottesman⁵, W. Putnam²; ¹Ultragenyx Pharmaceutical, ²Ultragenyx Pharmaceutical Inc., ³Indiana University School of Medicine, ⁴Yale New Haven Children's Hospital, ⁵Washington University School of Medicine in St. Louis.

Background: Orbit (NCT05125809) is an ongoing Phase 2/3 trial that consists of a Phase 2 randomized single-blind dose-evaluation period, and a Phase 3 double-blind, placebo-controlled period designed to evaluate the efficacy and safety of setrusumab in subjects 5 to < 26 years of age with osteogenesis imperfecta (OI).

Methods: We designed Phase 2 of Orbit to refine the dosing strategy for pediatric patients in preparation for the Phase 3 trial. The Phase 2 cohort comprises pediatric (5 to < 12 years; n=9), adolescent (12 to < 18 years; n=9), and adult (18 to 26 years; n=6) subjects with OI Types I, III, or IV confirmed by mutation analysis of COL1A1 or COL1A2. In the Phase 2 dose-evaluation period, subjects were randomized 1:1 to receive setrusumab 20 (n=14) or 40 mg/kg (n=10) IV QM. At least 1 month of PK or PD biomarker P1NP (a marker of bone formation) data from each subject was used to build population PK and PK/PD models combined with data from previous adult setrusumab studies.

Results: We observed an approximately dose-proportional increase in systemic exposure across body weight ranges at 40 mg/kg dose versus the 20 mg/kg dose. The population PK model adequately described available pediatric, adolescent, and adult data. The final model was a two-compartmental disposition model with a linear elimination including the effect of baseline body weight on clearance and volume terms, inter-individual variability (IIV) for all PK parameters, and a combined proportional and additive residual error model.

The exposure-response relationship of percent change from baseline P1NP showed a saturating response over increasing concentrations of setrusumab (Figure 1). This relationship was similar across age groups although the pediatric and adolescent groups had higher baseline P1NP levels and higher absolute changes in P1NP. The baseline-corrected area under the effect curve in serum P1NP with 20 mg/kg was approximately 80% of that achieved with 40 mg/kg. A greater exposure-response relationship for bone mineral density was observed in the pediatric group, suggesting an enhanced response to setrusumab in growing skeletons of children with OI.

Conclusion: From the population PK and PK/PD analyses, the overall pharmacodynamic response is expected to approach a plateau at 20 mg/kg, supporting the selection of the 20 mg/kg dose across age groups for the Phase 3 period of Orbit.