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Durable Fracture Rate Reduction in Patients with OI with Setrusumab Treatment: 14-Month Data from Phase 2 of the Orbit Study

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Osteogenesis imperfecta (OI) is a rare genetic disorder of bone fragility and low bone mass characterized by bone malformation, muscle weakness, joint laxity, short stature, hearing loss, and dental abnormalities, among other manifestations. Presently, there is no universally-accepted treatment. Setrusumab is a fully human anti-sclerostin monoclonal antibody that has been shown to improve bone mineral density (BMD), bone strength, and bone remodeling in adults with OI. The present study examines key safety and efficacy outcomes in pediatric and young-adult subjects with OI following 14 months of setrusumab treatment.

Methods:
In Phase 2 of the ongoing Phase 2/3 Orbit study (NCT05125809), key outcomes were examined to determine the efficacy and safety of setrusumab treatment for OI in pediatric and young-adult cohorts. Subjects between 5 and 26 years of age with OI Types I, III, or IV were randomized 1:1 to receive either 20 or 40 mg/kg setrusumab intravenously each month. After the last subject completed 6 months of setrusumab treatment, the 20 mg/kg dose was selected based on safety and efficacy outcomes, and all subjects received it for the remainder of the study. The present analysis examines longer-term findings from this pooled group through Month 14 of the Phase 2 portion of Orbit.

Results:
Phase 2 of Orbit included 24 subjects, of which 50% are female 75% are <18 years of age, and 71% and 29% have OI Types I or III/IV, respectively. The mean setrusumab treatment duration by Month 14 of Orbit was 16 months.



BMD was assessed at baseline and Months 6 and 12 of the study. Over this period, subjects continued to show meaningful improvement in BMD. A mean (SE) change from baseline in lumbar spine BMD of 14% (±2%) was seen at Month 6 and reached 22% (±3%) at M12 (p<0.0001). Similarly, the mean (SE) baseline BMD Z-score improved by 0.9 (±0.1) at Month 6, and by 1.235 (±0.2) at Month 12 (p<0.0001).



The median annualized pre-treatment skeletal fracture rate (excluding fingers, toes, face, skull, and morphometric vertebral fractures) decreased from 0.72 at baseline to 0 (p=0.0014) after a mean setrusumab treatment duration of 16 months. This represents a calculated reduction in fracture rate of 67%. No safety concerns were identified at Month 14.

Reported treatment-emergent adverse events (TEAE) were consistent with the anticipated safety profile of setrusumab. Most of the reported related TEAEs (11/12, 92%) were mild (Grade 1) in severity, with no related serious TEAEs. There were no cardiovascular adverse events reported through Month 14 of the study. Importantly, no TEAEs led to discontinuation from the study or disruption in setrusumab treatment.

 

Conclusion:
Overall, Phase 2 of Orbit showed significant, clinically meaningful improvements in lumbar spine BMD and BMD Z-score at Month 14 with setrusumab treatment. Skeletal fracture rate was reduced considerably with setrusumab (67%). These data further build upon those reported after 6 months of setrusumab treatment, demonstrating the robustness and durability of this therapy in patients with OI.

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