A Study in Adult Patients With Type I, III or IV Osteogenesis Imperfecta Treated With BPS804

This study was previously posted by Mereo Biopharma and was transferred to Ultragenyx in February 2021.

• setrusumab (Drug), also known as BPS804: Intravenous infusion
• Calcium (Dietary supplement): tablets
• Vitamin D (Dietary supplement): capsules
• zoledronic acid (optional) (Drug): Following completion of the study treatment (Month 12) participants can receive an optional single dose of zoledronic acid. Participants can receive an optional further dose of zoledronic acid at Month 18 at the discretion of their treating physician.

Primary outcomes

• Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12 [Baseline, Month 12 (end of treatment [EOT])]: Assessed by high resolution peripheral quantitative computed tomography (HRpQCT). HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presents the ratio of the means between the visit and Baseline from analysis of covariance (ANCOVA).
• Change From Baseline in Radial Bone Strength (Failure Load) at Month 12 [Baseline, Month 12 (EOT)]: Assessed by finite element analysis (FEA) of models generated from HRpQCT images of the distal radius.
• Change From Baseline in Radial Bone Strength (Stiffness) at Month 12 [Baseline, Month 12 (EOT)]: Assessed by FEA of models generated from HRpQCT images of the distal radius.

Secondary outcomes

• Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set [Baseline, Months 6, 12 (EOT), 18, 24]: Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
• Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm [Baseline, Months 6, 12 (EOT)]: Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
• Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set [Baseline, Months 6, 12 (EOT), 18, 24]: Assessed by FEA of models generated from HRpQCT images of the distal radius.
• Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm [Baseline, Months 6, 12 (EOT)]: Assessed by FEA of models generated from HRpQCT images of the distal radius.
• Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set [Baseline, Months 6, 12 (EOT), 18, 24]: Assessed by FEA of models generated from HRpQCT images of the distal radius.
• Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm [Baseline, Months 6, 12 (EOT)]: Assessed by FEA of models generated from HRpQCT images of the distal radius.
• Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12 [Month 12 (EOT)]: Fracture assessment, confirmed by central radiographic reading, was carried out for peripheral including all major long bones, minor bone (digits, ribs) and vertebral fractures. Fractures without clinical symptoms, detected only by means of radiographic investigations, were not included in the analysis.
• Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6 [Baseline, Month 6]: BMD was evaluated by dual-energy x-ray absorptiometry (DXA). T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD.
• Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6 [Baseline, Month 6]: BMD was evaluated by DXA.
• Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12 [Baseline, Month 12 (EOT)]: BMD was evaluated by DXA. T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD.
• Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12 [Baseline, Month 12 (EOT)]: BMD was evaluated by DXA.
• Change From Baseline in Total vBMD (Radial and Tibial) Over Time [Baseline, Months 6, 12 (EOT), 18, and 24]: Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
• Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time [Baseline, Months 6, 12 (EOT), 18, and 24]: Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA.
• Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set [Baseline, Month 6, Month 12 (EOT)]
• Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12 [Baseline, Months 6, 12 (EOT)]: Lean and fat body mass was evaluated using whole body DXA (including the head).
• Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12 [Baseline, Months 1, 3, 6, 9, 12 (EOT)]
• Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12 [Baseline, Months 1, 3, 6, 9, 12 (EOT)]
• Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12 [Baseline, Months 6, 12 (EOT)]: The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Physical Component Summary ranges from 0 to 100, where higher scores reflect better physical functioning.
• Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12 [Baseline, Months 6, 12 (EOT)]: The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Mental Component Summary ranges from 0 to 100, where higher scores reflect better mental health functioning.
• Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12 [Baseline, Months 6 and 12 (EOT)]: The EQ-5D-5L is a standardised measure of health status comprised of a descriptive system of 5 health-related quality of life states (i.e., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) of overall health. Each dimension is rated on a 5-point response scale indicating severity of problems, where 1 is "no problems" and 5 is "extreme problems". The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1 (1 being perfect health).
• Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12 [Baseline, Months 6, 12 (EOT)]: The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The total score is calculated on a 0-100 scale, where higher scores indicate a greater (negative) impact on quality of life.
• Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12 [Baseline, Months 6, 12 (EOT)]: The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Pain subscale ranges from 0 to 10, with higher value representing worse pain.
• Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12 [Baseline, Months 6, 12 (EOT)]: The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Activities subscale ranges from 0 to 100, with higher value representing increased difficulty.
• Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14 [up to Month 14]: Serum samples were screened for antibodies binding to setrusumab using a validated assay method by or under the supervision of the sponsor.
• Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death [Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.)]: An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE (SAE) is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; is another important medical event. The intensity for each AE was graded as mild, moderate or severe, according to the investigator's judgement. An event was considered related to study drug if there were a "reasonable possibility" of a relationship, according to the investigator's clinical judgment. A TEAE was defined as an event occurring or worsening on or after the first dose of study medication.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Patients with a clinical diagnosis of OI Type I, III or IV with a confirmed defect in the COL1A1/COL1A2 genes, as confirmed by genetic testing
* One or more fractures in the past 5 years
* Capable of giving signed consent

Exclusion Criteria:

* History of skeletal malignancies or other bone diseases (other than OI)
* History of neural foraminal stenosis (except if due to scoliosis)
* History of myocardial infarction, angina pectoris, ischaemic stroke or transient ischaemic attack
* History of endocrine or thyroid/parathyroid conditions that could affect bone metabolism
* Treatment with bisphosphonates within 3 months of randomisation
* Treatment with teraparatide, denosumab or other anabolic/anti-reabsorptive medications within 6 months of randomisation

Participant flow

Outcome results

• Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12 (Primary), Number, ratio: Setrusumab 20 mg/kg (Blinded) 1.004 (0.987 to 1.021); Setrusumab 8 mg/kg (Blinded) 0.993 (0.975 to 1.012); Setrusumab 2 mg/kg (Blinded) 0.992 (0.974 to 1.011) (p 0.644)
• Change From Baseline in Radial Bone Strength (Failure Load) at Month 12 (Primary), Least squares mean, newton (N): Setrusumab 20 mg/kg (Blinded) 61.25 +/- 21.669; Setrusumab 8 mg/kg (Blinded) 32.25 +/- 24.342; Setrusumab 2 mg/kg (Blinded) 8.86 +/- 23.200 (p 0.006)
• Change From Baseline in Radial Bone Strength (Stiffness) at Month 12 (Primary), Least squares mean, N/mm: Setrusumab 20 mg/kg (Blinded) 1638.70 +/- 625.808; Setrusumab 8 mg/kg (Blinded) 1422.00 +/- 703.275; Setrusumab 2 mg/kg (Blinded) 209.89 +/- 671.777 (p 0.011)
• Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set (Secondary), Number, ratio: Setrusumab 20 mg/kg (Blinded) 1.007 (0.993 to 1.021); Setrusumab 8 mg/kg (Blinded) 1.000 (0.986 to 1.015); Setrusumab 2 mg/kg (Blinded) 0.998 (0.984 to 1.013) (p 0.329)
• Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm (Secondary), Number, ratio: Setrusumab 20 mg/kg (Open-Label) 0.994 (0.972 to 1.017) (p 0.615)
• Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set (Secondary), Least squares mean, N: Setrusumab 20 mg/kg (Blinded) 31.22 (-1.80 to 64.23); Setrusumab 8 mg/kg (Blinded) 39.95 (6.63 to 73.27); Setrusumab 2 mg/kg (Blinded) -3.28 (-36.57 to 30.00) (p 0.064)
• Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm (Secondary), Least squares mean, N: Setrusumab 20 mg/kg (Open-Label) 110.16 (61.30 to 159.01) (p < 0.001)
• Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set (Secondary), Least squares mean, N/mm: Setrusumab 20 mg/kg (Blinded) 795.67 (-34.71 to 1626.04); Setrusumab 8 mg/kg (Blinded) 1048.61 (209.47 to 1887.75); Setrusumab 2 mg/kg (Blinded) 109.65 (-728.52 to 947.82) (p 0.060)
• Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm (Secondary), Least squares mean, N/mm: Setrusumab 20 mg/kg (Open-Label) 5056.51 (3404.58 to 6708.45) (p < 0.001)
• Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12 (Secondary), Number, percentage of participants: Setrusumab 20 mg/kg (Blinded) 6.5; Setrusumab 8 mg/kg (Blinded) 17.2; Setrusumab 2 mg/kg (Blinded) 13.3
• Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6 (Secondary), Least squares mean, T-score: Setrusumab 20 mg/kg (Blinded) 0.273 (0.142 to 0.405); Setrusumab 8 mg/kg (Blinded) 0.338 (0.213 to 0.464); Setrusumab 2 mg/kg (Blinded) 0.110 (-0.014 to 0.233) (p < 0.001)
• Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6 (Secondary), Least squares mean, g/cm^2: Setrusumab 20 mg/kg (Blinded) 4.06 (2.12 to 6.00); Setrusumab 8 mg/kg (Blinded) 4.70 (2.86 to 6.55); Setrusumab 2 mg/kg (Blinded) 1.58 (-0.24 to 3.40) (p < 0.001)
• Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12 (Secondary), Least squares mean, T-score: Setrusumab 20 mg/kg (Blinded) 0.587 (0.427 to 0.746); Setrusumab 8 mg/kg (Blinded) 0.486 (0.324 to 0.648); Setrusumab 2 mg/kg (Blinded) 0.174 (0.022 to 0.327) (p < 0.001)
• Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12 (Secondary), Least squares mean, g/cm^2: Setrusumab 20 mg/kg (Blinded) 8.55 (6.13 to 10.97); Setrusumab 8 mg/kg (Blinded) 6.79 (4.34 to 9.25); Setrusumab 2 mg/kg (Blinded) 2.50 (0.19 to 4.81) (p < 0.001)
• Change From Baseline in Total vBMD (Radial and Tibial) Over Time (Secondary), Number, ratio: Setrusumab 20 mg/kg (Blinded) 1.011 (0.999 to 1.022); Setrusumab 8 mg/kg (Blinded) 0.995 (0.984 to 1.007); Setrusumab 2 mg/kg (Blinded) 1.000 (0.989 to 1.012) (p 0.065)
• Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time (Secondary), Number, ratio: Setrusumab 20 mg/kg (Blinded) 1.004 (0.997 to 1.010); Setrusumab 8 mg/kg (Blinded) 1.002 (0.996 to 1.009); Setrusumab 2 mg/kg (Blinded) 0.998 (0.992 to 1.005) (p 0.285)
• Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set (Secondary), Count of participants, Participants: Setrusumab 20 mg/kg (Blinded) 0; Setrusumab 8 mg/kg (Blinded) 0; Setrusumab 2 mg/kg (Blinded) 0
• Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12 (Secondary), Least squares mean, grams: Setrusumab 20 mg/kg (Blinded) 519.152 (13.020 to 1025.284); Setrusumab 8 mg/kg (Blinded) -410.664 (-903.724 to 82.395); Setrusumab 2 mg/kg (Blinded) 168.206 (-306.981 to 643.393) (p 0.045)
• Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12 (Secondary), Least squares mean, µg/L: Setrusumab 20 mg/kg (Blinded) 24.349 (18.604 to 30.095); Setrusumab 8 mg/kg (Blinded) 14.288 (8.221 to 20.354); Setrusumab 2 mg/kg (Blinded) 0.060 (-5.827 to 5.948) (p < 0.001)
• Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12 (Secondary), Least squares mean, µg/L: Setrusumab 20 mg/kg (Blinded) -0.077 (-0.100 to -0.054); Setrusumab 8 mg/kg (Blinded) -0.047 (-0.071 to -0.022); Setrusumab 2 mg/kg (Blinded) -0.041 (-0.064 to -0.017) (p < 0.001)
• 8 more outcome measures not shown.

Adverse events

Time frame: Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.)

Serious adverse events by term

Other adverse events by term

25 more terms not shown.

• Results publication: Glorieux FH, Langdahl B, Chapurlat R, De Beur SJ, Sutton VR, Poole KES, Dahir KM, Orwoll ES, Willie BM, Mikolajewicz N, Zimmermann E, Hosseinitabatabaei S, Ominsky MS, Saville C, Clancy J, MacKinnon A, Mistry A, Javaid MK. Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study. J Bone Miner Res. 2024 Sep 2;39(9):1215-1228. doi: 10.1093/jbmr/zjae112. PMID 39012717

• Study Protocol (PDF, 2019-07-19)
• Statistical Analysis Plan (PDF, 2019-10-22)

• Medical Director, Study director, Mereo BioPharma

NIH grants: 2016