OI (commonly known as brittle bone disease) is a serious, rare genetic disorder caused by a problem in the formation of type I collagen, and characterized by fragile bones that fracture easily, often starting from birth. It can affect people’s lives in a multitude of ways, from frequent fractures and skeletal deformities to constant chronic pain, respiratory insufficiency and hearing loss. And each person’s experience is different.

Ingunn Westerheim, President of OIFE, shares her experiences of life with Osteogenesis Imperfecta in an April 2020 interview.

How is OI treated?

There are currently no FDA- or EU-approved treatments for OI. Current treatment is based on supportive care, using off-label, unapproved compounds to seek to improve bone density, on treating fractures as they occur (a common occurrence particularly in children with OI) and on maximizing mobility via physiotherapy, pain management and orthopaedic surgery.

The majority of cases of OI (up to 90%) are caused by a dominant mutation in the genes coding for Type I collagen – a key component of healthy bone. As setrusumab aims to act on pathways regulating both bone formation and bone resorption (breakdown and assimilation of old bone), our clinical studies are seeking to understand if setrusumab can play a role in improving the health and quality of life for people with OI.
OI is recognized as an area of high unmet medical need. Setrusumab (BPS-804) has been designated an ‘Orphan Drug’ in the USA and the EU, meaning it is officially acknowledged by the regulatory authorities to be targeting a rare and serious disease. Most recently, setrusumab has been granted Rare Pediatric Disease Designation by the FDA. This means that the FDA formally recognises the significant unmet medical need in children. In addition, setrusumab has been granted PRIority MEdicines (PRIME) designation by the European Medicines Agency (EMA) - a programme aimed at supporting the development of medicines that target an unmet medical need - and has been accepted in the EMA’s Adaptive Pathways programme.

Clinical Status

Ultragenyx and Mereo BioPharma are collaborating on the development of setrusumab globally, based on a joint collaboration and license agreement. Together, we have developed a comprehensive late-stage program to continue development of setrusumab in pediatric and young adult patients across OI sub-types I, III and IV.
Mereo BioPharma’s Phase 2b study (ASTEROID) treatment phase of the dose-finding study of setrusumab for the treatment of OI in 112 adults was concluded in 2019. The ASTEROID study demonstrated treatment with setrusumab resulted in a clear, dose-dependent and statistically significant effect on bone formation and bone density at multiple anatomical sites among adult participants with OI.

The Phase 3 clinical trial program, led by Ultragenyx, saw the first patients being dosed in July 2023.

In patients aged 5 to <26 years, the global, seamless Phase 2/3 Orbit study is designed to evaluate the effect of setrusumab 20 mg/kg versus placebo on annualized fracture rate. The study is designed to enroll 195 patients. Patients will be randomized 2:1 to receive setrusumab or placebo and all patients will transition to an extension period and receive open-label setrusumab after the Phase 3 primary analysis is complete.

In patients aged 2 to <7 years, the open-label, randomized, active-controlled Phase 3 Cosmic study is evaluating setrusumab versus standard-of-care intravenous bisphosphonates (IV-BP) therapy on reduction in annualized fracture rate, including morphometric vertebral fractures. The Cosmic study is anticipated to start mid-2023 and will enroll approximately 50-66 patients.

The Phase 3 initiation follows positive data from the Phase 2 portion of the Orbit study, announced in June 2023, showing that setrusumab rapidly induced bone production. 24 patients with OI were randomized 1:1 to receive setrusumab 20 mg/kg or 40 mg/kg to determine the optimal dosing strategy for Phase 3. Across all patients evaluated, as of the data cut off, setrusumab demonstrated statistically significant increases in levels of serum P1NP, a sensitive marker of bone formation, and a substantial and significant improvement in bone mineral density (BMD) by 3 months. There were no treatment-related serious adverse events and no reported hypersensitivity reactions. Reported adverse events include infusion associated events, headache and sinusitis. The totality of data demonstrated meaningful response across both cohorts, with the majority of the effect observed at 20 mg/kg, the dose planned across the setrusumab Phase 3 program.

“The rate of increasing bone mineralization we're observing on DXA scans is striking, unlike anything I have typically seen with bisphosphonate therapy. This increase in bone mass underscores the potential to make denser and stronger bone,” said Gary Gottesman, MD, Professor of Pediatrics and Medicine, Washington University School of Medicine.

Mereo retains rights to commercialization in Europe/EEA and UK. 

Scientific Publications

• Glorieux F. et al. 2017. BPS-804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial., J Bone Miner Res, 32: 1496-1504.
• Shapiro J. 2017. Osteogenesis Imperfecta: A Translational Approach to Brittle Bone Disease, Community Academic Press. Chapter 2: p15-22