Setrusumab Demonstrates Rapid Bone-Building Effects in OI Patients: Latest Phase 2/3 Orbit Study Results Reveal Promising Clinical Progress

Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) and Mereo BioPharma Group plc (NASDAQ: MREO) have disclosed encouraging findings from the ongoing Phase 2/3 Orbit trial investigating setrusumab (UX143), a novel therapeutic candidate targeting osteogenesis imperfecta (OI). The clinical data indicates that setrusumab rapidly stimulates bone formation in affected patients, marking a significant advancement in OI treatment.

Swift Bone Production: What the Early Data Shows

The dose-selection Phase 2 component of the Orbit study revealed that setrusumab induces bone production at a notably accelerated pace compared to conventional therapies. Across the patient cohort evaluated, the drug consistently produced statistically meaningful increases in serum P1NP—a key biochemical indicator of bone formation activity—alongside substantial improvements in bone mineral density (BMD) within just three months of commencing monthly setrusumab injections.

“The velocity at which bone mineralization increases, as visible on DXA imaging, is truly remarkable and surpasses what we typically observe with conventional bisphosphonate treatments. This expansion in bone mass suggests considerable potential for generating bones that are both thicker and more resilient,” noted Gary Gottesman, M.D., Professor of Pediatrics and Medicine at Washington University School of Medicine.

Breaking Down the Clinical Evidence

Among the 24 patients enrolled in the Orbit study at the data evaluation point, all had available serum P1NP measurements through at least one month of treatment. Results demonstrated that setrusumab substantially elevated serum P1NP levels in both treatment groups, with peak elevation occurring one to two weeks after initiation, and a secondary rise following the two-month dosing interval.

For patients receiving the 20 mg/kg dose, mean serum P1NP rose by 57% from baseline during the first month. Notably, younger patients exhibited an approximately 8-fold greater serum P1NP increase over this period relative to adult OI patients, reflecting higher baseline P1NP levels in the pediatric population. The 20 mg/kg regimen achieved roughly 80% of the serum P1NP elevation observed with the 40 mg/kg dose, establishing a clear dose-response relationship. In contrast, the four placebo-treated patients showed no meaningful change in baseline serum P1NP.

BMD Improvements Outpace Historical Benchmarks

The substantial BMD gains observed in Orbit participants during the initial three-month window mirrored the rapid serum P1NP elevation and remarkably paralleled outcomes that previously required a full year to accomplish in the ASTEROID trial of adult OI patients.

Among 17 Orbit patients with available lumbar spine BMD data at three months, setrusumab treatment produced a 9.4% increase in lumbar spine BMD at the 20 mg/kg dose (n=10), corresponding to a meaningful Z-score improvement of +0.65. The 40 mg/kg cohort (n=7) achieved a 9.8% BMD increase. Placebo recipients (n=2) experienced no significant BMD changes or Z-score modifications.

“These exceptional lumbar spine BMD gains in children at three months underscore that developing skeletal systems demonstrate greater biological responsiveness,” explained Eric Crombez, M.D., chief medical officer at Ultragenyx. “We expect this heightened bone remodeling capacity in younger patients with actively maturing skeletons may translate into amplified benefits for bone development and mechanical strength.”

Safety Profile Remains Reassuring

Through the current data cutoff, the study has documented no treatment-related serious adverse events. Documented side effects align with those previously recorded in the ASTEROID investigation and encompass infusion-related reactions, headache, and sinusitis. Notably, no hypersensitivity reactions attributable to setrusumab have been reported. The safety data showed no meaningful variations between dosing cohorts or age categories.

Moving Forward: Phase 3 Expansion Underway

The comprehensive dataset demonstrated robust response metrics in both serum P1NP and BMD across treatment groups, with the preponderance of therapeutic benefit achieved at the 20 mg/kg dose—the regimen selected for the complete setrusumab Phase 3 development program.

Patient screening for the Phase 3 segment has commenced, with the trial designed to enroll approximately 195 patients across more than 40 clinical sites spanning 12 countries. Ultragenyx and Mereo are advancing setrusumab through two Phase 3 trials—the pivotal Orbit study and the Phase 3 Cosmic study—both focusing on pediatric and young adult populations across OI subtypes I, III, and IV.

The companies hosted an investor webcast on June 5, 2023, to elaborate on the trial outcomes and provide additional context on the setrusumab development trajectory.