safety of fresolimumab in the treatment of osteogenesis imperfecta

Conditions: Osteogenesis Imperfecta

Summary: osteogenesis imperfecta (oi) is a rare disorder that causes bones to break easily. people with oi may have broken bones with little or no trauma, dentinogenesis imperfecta (di), and, in adult years, hearing loss. oi can range from very severe to very mild. the current standard-of-care for severe types of oi involves the use of iv medications (bisphosphonates) and surgery to put rods in bones to strengthen them. these therapies, although often life-saving, are new and very little is known about their long-term effects on bone and other body systems. transforming growth factor beta (tgf-β) is a protein important in bone formation. fresolimumab is an antibody that can silence tgf-β . in studies with mice with oi, it has been shown that silencing tgf-β can lead to higher bone mass, quality and strength. the purpose of this study is to determine if fresolimumab is safe in the treatment of oi.

osteogenesis imperfecta (oi) is a rare disorder that causes bones to break easily. people with oi may have broken bones with little or no trauma, dentinogenesis imperfecta (di), and, in adult years, hearing loss. it is seen in both genders and all races. oi can range from very severe to very mild. individuals with the most severe type of oi may die at birth. people with severe oi who survive may have bowed arms and legs, very short stature and be unable to walk. people with the mildest form of oi may only break bones occasionally and have normal height and lifespan. breaks can occur in any bone, but are most common in the arms and legs. the current standard-of-care for severe types of oi involves the use of iv medications (bisphosphonates) and surgery to put rods in bones to strengthen them. these therapies, although often life-saving, are new and very little is known about their long-term effects on bone and other body systems. tgf-β is a protein important in bone formation. studies have shown that increased tgf-β activity leads to lower bone mass and strength and increased fractures. fresolimumab is an antibody that can silence tgf-β . in studies with mice with oi, it has been shown that silencing tgf-β can lead to higher bone mass, quality and strength.

Eligibility criteria:
inclusion criteria: 1. willing and able to provide signed informed consent. 2. are 18 years or older 3. have a diagnosis of moderate-to-severe oi based on various clinical features 4. have genetic mutations that include glycine substitution in col1a1 or col1a2, or pathogenic variants in crtap, ppib, or lepre1 (if genetic information is unavailable at screening, this may be assessed at screening visit on a clinical or research basis). 5. females of child-bearing potential must have a negative urine pregnancy test, agree to and have the ability to use acceptable birth control method for entire duration of the study. 6. for males enrolled in the study, partners must agree to use an acceptable form of birth control for the entire duration of the study. exclusion criteria: 1. fracture less than 3 months prior to the screening visit. 2. rodding or instruments that prevents reliable bone mineral density (bmd) assessment. 3. have a known unhealed fracture involving a long bone. 4. do not meet laboratory safety requirements such as: vitamin d \ 1.5 times upper limit of normal (uln), clinical or laboratory abnormality of grade iii or higher as assessed by ctcae v4.0 which in the view of investigator would compromise safety. 5. have an ekg with qtc of \> 450 ms 6. have a known allergy to fresolimumab. 7. have current clinically significant infection. 8. have a personal history of basal cell carcinoma, squamous cell carcinoma or keratoacanthomas, a personal history of cancer, recent or remote. 9. have evidence of untreated cavities or planned invasive dental work during the study period. 10. have had organ transplantation. 11. have known or suspected valvular heart disease. 12. plan to have skeletal surgery in the study period. 13. have had osteotomy 5 months prior to the screening visit. 14. being treated with zoledronic acid or pamidronate less than 12 months of screening or oral bisphosphonates less than 6 months of screening or teriparatide less than one year of screening. 15. being treated with systemic glucocorticoids 16. have autoimmune diseases being treated with glucocorticoids or other biologic agents. 17. enrolled in another clinical trial and receiving treatment with another investigational agent 18. pregnant or planning to get pregnant during the study period. 19. nursing mothers.