Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta

A Randomized, Open Label Intra-patient Dose Escalation Study With an Untreated Reference Group to Evaluate Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Infusions of BPS804 in Adults With Moderate Osteogenesis Imperfecta

This is a randomized, open label intra-patient dose escalation study to evaluate safety and tolerability, pharmacokinetics, and pharmacodynamics of BPS804 in adults with osteogenesis imperfecta (OI).

Pharmacodynamic effect will be determined by serological biomarkers and radiologic assessments. In addition, tolerability and pharmacokinetics (PK) will be evaluated.

Study Overview

• Status: Completed
• Conditions: Osteogenesis Imperfecta
• Intervention / Treatment: Drug: BPS804

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3GIA6
      • Novartis Investigative Site
• Germany
  • Wuerzburg, Germany, 97074
    • Novartis Investigative Site
• United States
  • California
    • Anaheim, California, United States, 92801
      • Novartis Investigative Site
  • Florida
    • Miramar, Florida, United States, 33025
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Osteogenesis imperfecta
• Two or more previous fractures
• Bone mineral density Z-score of ≤ -1.0 and > -4.0

Exclusion Criteria:

• Open epiphyses
• Fracture within last 2 weeks
• Treatment with bisphosphonates/teriparatide (last 6 months)
• Surgery within last year

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment group	Drug: BPS804
No Intervention: Untreated reference group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability (composite outcome: standard laboratory, (serious) adverse events)	The assessment of safety will be based on primarily on the frequency of adverse events, laboratory abnormalities, and serious adverse events suspected by the investigators to be related to study treatments. The AE collection period extends from the time of first study drug administration drug until study completion. The intensity of each AE will be characterized and classified into 1 of the 3 generic categories (mild, moderate, or severe). The number and percentage of patients with adverse events will be tabulated by treatment group, body system and preferred term. The periods for adverse event tabulation will be from dose administration up to next dose administration if a further dose is given, and from dose administration to EOS for the last dose administration of a patient.	Day 1 through 141
Determination of pharmacodynamic effect by means of biomarkers	Biomarker data from serum bone formation biomarkers: procollagen type I N-terminal propeptide, procollagen type I C-terminal propeptide, osteocalcin, and bone-specific alkaline phosphatase, and from serum bone resporption mbiomarkers: C-telopeptides of type I collagen cross-links, and N-telopeptides of type I collagen cross-links will be reported as concentration results, measured using a specific assay with a working range defined by the Lower limit of quantification and Upper limit of quantification. It will be considered a sign for efficacy, if any of the above show significant (2-sided, alpha=0.05) increase versus baseline in the BPS804 group on day 43.	Day 1 and Day 43
Change in Z-score from baseline to Day 141	Bone mineral density will be assessed by dual-energy X-ray absorptiometry of the lumbar spine. Analysis will include four vertebral levels from L1 to L4. Individual vertebral levels may be excluded due to artifact. Bone mineral density Z-scores will be used as these are a comparison of a patient's BMD to that of a patient of the same age, sex, and ethnicity. The comparison of change from baseline with the matching change in the reference group will be done by 2-sample t-tests (1-sided). It will be considered a sign for efficacy, if any of the above show significant (2-sided, alpha=0.05) increase versus baseline in the BPS804 group on day 141.	Day 1 and Day 141

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the serum concentration-time profiles of BPS804	Individual and overlaying individual serum concentration-time profiles of BPS804 will be constructed from the serial sampling on Day 1 (prior to administration and 3x after administration) and Days 2, 8, 15 (2x), 16, 29 (4x), 30, 36, 43, 57, 85, 113,141. In addition arithmetic and geometric mean serum concentration-time profiles of BPS804 will be constructed from the above data points.	Day 1 (prior to administration and 3x after administration) and Days 2, 8, 15 (2x), 16, 29 (4x), 30, 36, 43, 57, 85, 113,141
Determination of the area under the serum concentration-time curve from time zero to the end of the dosing interval tau after the first dose	The area under the serum concentration-time curve from time zero to the end of the dosing interval tau after the first dose will be derived using using non-compartmental methods from data collected on Day 1 (4x) and Days 2, and 8.	Day 1 (prior to administration and 3x after administration) and Days 2, and 8
Determination of the maximal concentration after the first dose	The maximal concentration after the first dose will be derived using using non-compartmental methods from data collected Day 1 (4x) and Days 2, and 8.	Day 1 (prior to administration and 3x after administration) and Days 2, and 8
Determination of the time of maximal concentration after the first dose	The time of maximal concentration after the first dose will be derived using using non-compartmental methods from data collected Day 1 (4x) and Days 2, and 8.	Day 1 (prior to administration and 3x after administration) and Days 2, and 8
Determination of the maximal concentration after the second dose	The maximal concentration after the second dose will be derived using using non-compartmental methods from data collected from days 15 (2x) and 16.	Day 15 (prior to administration and 1x after administration) and Day 16
Determination of the time of maximal concentration after the second dose	The time of maximal concentration after the second dose will be derived using using non-compartmental methods from data collected from days 15 (2x) and 16.	Day 15 (prior to administration and 1x after administration) and Day 16
Determination of the area under the serum concentration-time curve from time zero to infinity after the third dose	The area under the serum concentration-time curve from time zero to the end of the dosing interval tau after the third dose will be derived using non-compartmental methods from data collected on Days 29 (4x), 30, 36, 43, 57, 85, 113, and 141.	Days 29 (prior to administration and 3x after administration) and 30, 36, 43, 57, 85, 113, and 141
Determination of the area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration after the third dose	The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration after the third dose will be derived using non-compartmental methods from data collected on Days 29 (4x), 30, 36, 43, 57, 85, 113, and 141.	Days 29 (prior to administration and 3x after administration) and 30, 36, 43, 57, 85, 113, and 141
Determination of the area under the serum concentration-time curve from time zero to the end of the dosing interval tau after the third dose	The area under the serum concentration-time curve from time zero to the end of the dosing interval tau after the third dose will be derived using non-compartmental methods from data collected on Days 29 (4x), 30, 36, 43, 57, 85, 113, and 141.	Days 29 (prior to administration and 3x after administration) and 30, 36, 43, 57, 85, 113, and 141
Determination of the maximal serum concentration after the third dose	The maximal serum concentration after the third dose will be derived using using non-compartmental methods from data collected on Days 29 (4x), 30, 36, 43, 57, 85, 113, and 141.	Days 29 (prior to administration and 3x after administration) and 30, 36, 43, 57, 85, 113, and 141
Determination of the time of maximal concentration after the third dose	The time of maximal concentration after the third dose will be derived using using non-compartmental methods from data collected on Days 29 (4x), 30, 36, 43, 57, 85, 113, and 141.	Days 29 (prior to administration and 3x after administration) and 30, 36, 43, 57, 85, 113, and 141
Determination of the terminal elimination half-life after the third dose	The terminal elimination half-life after the third dose will be derived from data collected on Days 29 (4x), 30, 36, 43, 57, 85, 113, and 141 using a compound-specific modeling approach.	Days 29 (prior to administration and 3x after administration) and 30, 36, 43, 57, 85, 113, and 141
Determination of the concentration of total sclerostin in serum	The function of sclerostin is described as an endogenous negative regulator of bone formation. Total serum sclerostin will be measured from samples collected at screening and on days 1, 8, 15, 29, 36, 43, 57, 85, 113, and 141	Screening, Days 1, 8, 15, 29, 36, 43, 57, 85, 113, 141
Immunogenicity evaluation in serum	Immunogenicity will only be assessed in patients randomized to the treatment group. Anti-BPS804 antibodies will be measured in human serum on Days 1, 29, 85, and 141 An immunogenicity positive patient at end of study will be followed up until anti-BPS804 antibody levels are back to levels measured on Day 1.	Days 1, 29, 85, and 141

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc

Publications and helpful links

General Publications

• Glorieux FH. Osteogenesis imperfecta. Best Pract Res Clin Rheumatol. 2008 Mar;22(1):85-100. doi: 10.1016/j.berh.2007.12.012.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: August 4, 2011
• First Submitted That Met QC Criteria: August 12, 2011
• First Posted (Estimate): August 16, 2011

Study Record Updates

• Last Update Posted (Actual): May 11, 2021
• Last Update Submitted That Met QC Criteria: May 6, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: fracture; Brittle bone disease; inherited; connective tissue disorder
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Collagen Diseases; Osteogenesis Imperfecta
• Other Study ID Numbers: CBPS804A2201; 2011-001465-41 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No