7706: Multicenter study to evaluate safety of fresolimumab treatment in adults with moderate-to-severe Osteogenesis Imperfecta

Background
Osteogenesis Imperfecta (OI) is a rare disorder that makes bones break more easily. People with OI may break bones with little to no injury, have dentinogenesis imperfecta (DI, a disorder of tooth development), and/or have hearing loss in adult age. OI presents in both males and females, as well as all races. OI can range from very serious to mild. Individuals with the most serious type of OI may die at birth. People with severe OI who survive may have arms and legs that are not straight, be very short, and be unable to walk. People with the mildest form of OI may only break bones sometimes 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 serious types of OI involves the use of medications delivered through blood vessels (bisphosphonates), and surgery to put rods in bones to strengthen them. These treatments, 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 in bones. Fresolimumab is an antibody compound that can inactivate TGF-β. In studies with mice that have OI, silencing TGF-β has led to higher bone mass, quality, and strength.

The research questions are:

• How safe is a single dose injection of fresolimumab in adult patients with OI (Stage 1).
• How safe is a repeated dose delivery of fresolimumab in adult patients with OI (Stage 2).

About this Study:
The purpose of this study is to see if fresolimumab is safe as a treatment for OI. We will check the safety of a single dose of fresolimumab in the 1^st stage of the study. We will check the safety of multiple doses of fresolimumab in the 2^nd stage of the study. The Researchers will look at the effect of the two doses of fresolimumab in Stage 1on indicators of bone change and see the dose that shows the greatest reduction in bone change indicators compared to no treatment. This dose will be chosen for the repeat dose studies. If there were no big changes between the bone change indicators with either dose, the 4 mg/kg dose will be chosen for the repeat dose study.

There will be 16 participants in this study.

Participants that agree to be in the study will be asked to participate in the following:

Stage 1 study

You will have 6 study visits within about a 6 month timespan. At each study visit, you may have the following testing done:

• Physical exam
• Vitals
• Blood draw for safety labs, pharmacokinetics, etc
• If you are female, you will have a pregnancy test
• Echocardiogram (EKG)
• Bone density test (DXA)
• Infusion of the study drug

Stage 2 study

You will have 8 study visits within approximately a 12 month timespan. At each study visit, you may have the following testing done:

• Physical exam
• Vitals
• Blood draw for safety labs, pharmacokinetics, etc
• If you are female, you will have a pregnancy test
• EKG
• DXA
• Infusion of the study drug
• Skeletal survey
• Peripheral quantitative CT (pQCT) of the forearm
• Take Quality of Life Surveys
• Lung function test
• Walk test

Targeted Enrollment

To be able to participate, you must be:

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. If you are a female of child-bearing potential, you 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. If you are a male enrolling in the study, your partner must agree to use an acceptable form of birth control for the entire duration of the study.

You are not eligible to participate if:

1. You fracture less than 3 months prior to the screening visit.
2. You have rodding that prevents reliable bone mineral density (BMD) assessment.
3. You have a known unhealed fracture involving a long bone.
4. You do not meet laboratory safety requirements such as: Vitamin D < 15 ng/dL Serum albumin-corrected calcium levels below 8 mg/dL, Hemoglobin < 10 g/dL, Platelet count < 75,000mm^3;, Prothrombin time/(PT/INR) international normalized ratio > 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. You have an EKG with QTc of > 450 ms.
6. You have a known allergy to fresolimumab.
7. You have current clinically significant infection.
8. You have a personal history of basal cell carcinoma, squamous cell carcinoma or keratoacanthomas, apersonal history of cancer, recent or keratoacanthomas, apersonal history of cancer, recent or remote.
9. You have evidence of untreated cavities or planned invasive dental work during the study period.
10. You have had organ transplantation.
11. You have known or suspected valvular heart disease.
12. You plan to have skeletal surgery in the study period.
13. You have had osteotomy 5 months prior to the screening visit.
14. You are 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. You are being treated with systemic glucocorticoids.
16. You have autoimmune diseases being treated with glucocorticoids or other biologic agents.
17. You are on another clinical trial and receiving treatment with another investigational agent.
18. You are pregnant or planning to get pregnant during the study period.
19. You are nursing mothers.

How to participate:

We greatly appreciate your interest in this study and in advancing the understanding of Osteogenesis Imperfecta.

In order to participate, you must personally contact the study coordinator of any of the participating institutions by phone or by e-mail. Please use the information below to inquire about participation

ClinicalTrials.gov Identifier: NCT03064074

Please Note: The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate.