Setrusumab vs Placebo for Osteogenesis Imperfecta

Inclusion Criteria:

• Diagnosis of OI Type I, III, or IV as confirmed by identification of pathogenic orlikely pathogenic genetic variants in COL1A1 or COL1A2. If a variant of uncertainsignificance is identified, then clinical presence of the expected phenotype can beused to confirm the diagnosis

• ≥ 1 fracture in the past 12 months, ≥ 2 fractures in the past 24 months or ≥ 1tibia, femur or humerus fracture in the past 24 months

• Serum 25-hydroxyvitamin D ≥ 20 ng/mL at the Screening Visit. If 25-hydroxyvitamin Dlevels are below 20 ng/mL, 25-hydroxyvitamin D testing can repeated after a minimumof 14 days of vitamin D supplementation as directed by the treating physician

• Willing to not receive bisphosphonate therapy during the study

• From the period following informed consent to 60 days after the last dose of thestudy drug, females of childbearing potential and fertile males must consent to usehighly effective contraception. If female, agree not to become pregnant. If male,agree not to father a child or donate sperm

• Willing and able to provide informed consent for subjects greater than or equal to 18 years of age, or provide assent (if possible) and have a legally authorizedrepresentative provide informed consent, after the nature of the study has beenexplained and prior to any research-related procedures

• Willing to provide access to medical records for the collection of radiographicdata, fracture data, growth data, and disease history

• Must, in the opinion of the Investigator, be willing and able to complete allaspects of the study, adhere to the study visit schedule, and comply with theassessments

Exclusion Criteria:

• History of skeletal malignancies or bone metastases at any time

• History of neural foraminal stenosis (except if due to scoliosis)

• Clinical manifestations of Chiari malformation or basilar invagination. Presence ofany other neurologic disease that has been unstable within past 2 years requiresreview by the Medical Monitor

• History of or uncontrolled concomitant diseases such as hypo/hyperparathyroidism,Paget's disease, abnormal thyroid function, thyroid disease or other endocrinedisorders or conditions that could affect bone metabolism such as Stage IV/V renaldisease

• Rickets or any skeletal condition (other than OI) leading to long-bone deformitiesand/or increased risk of fractures

• History of stroke, myocardial infarction, transient ischemic attack or angina.

• Hypocalcemia, defined as serum calcium levels below the age-adjusted normal limitsafter a ≥ 4 hour fast

• Estimated glomerular filtration rate ≤ 29 mL/min/1.73 m2

• Prior treatment with the following:

1. Teriparatide, growth hormone, bone anabolic, or anti-resorptive medications (other than bisphosphonates) within 6 months of the first dose with study drug (Month 0)

2. Denosumab within 24 months of Screening

3. Romosozumab at any time

• Documented alcohol and/or drug abuse within 12 months prior to dosing or evidence ofsuch abuse as indicated by the laboratory results during the Screening assessments

• Presence or history of any condition that, in the view of the Investigator, wouldinterfere with participation, pose undue risk, or would confound interpretation ofresults

• Known hypersensitivity to setrusumab or excipients that, in the judgment of theInvestigator, places the subject at increased risk for adverse effects

• History of external radiation therapy

• Pregnant or breastfeeding or planning to become pregnant (self or partner) at anytime during the study

• Use of any investigational product or investigational medical device within 4 weeksor 5 half-lives of investigational drug (whichever is longer) prior to Screening, orduring the study (per discretion of the Investigator in consultation with theMedical Monitor)

• Concurrent participation in another clinical study without prior approval from theInvestigator in consultation with the Medical Monitor

• For Phase 2 Only: A history of bone surgery within the previous 6 months prior toScreening or planned bone surgery for the first 3 months of the study