THOUSAND OAKS, Calif. & BRUSSELS, Belgium—Amgen and UCB announced findings from the FRAME study showing that the investigational agent romosozumab significantly reduced the incidence of new vertebral fractures in postmenopausal women with osteoporosis through 12 and 24 months, meeting the study’s co-primary endpoints. The results from the Phase 3 study, the first to evaluate fracture risk reduction as early as one year as a primary endpoint, were published in the New England Journal of Medicine and presented at the Annual Meeting of the American Society for Bone Mineral Research in Atlanta.
An estimated two million osteoporotic fractures occur per year in the United States alone, and this number is projected to grow to three million by 2025. The National Osteoporosis Foundation has estimated that 10 million people in the United States (eight million women and two million men) already have osteoporosis, while 44 million more people have low bone mass.
Romosozumab, an investigational monoclonal agent that binds and inhibits the activity of the protein sclerostin, increases bone formation and decreases bone breakdown. Romosozumab is being studied for its potential to reduce the risk of fractures in an extensive global Phase 3 program.
Romosozumab works by binding and inhibiting the protein sclerostin, and as a result has a dual effect on bone, both increasing bone formation and decreasing bone breakdown. The FRAME study results, along with other clinical data, show that romosozumab helped to accelerate bone building in postmenopausal women with osteoporosis. The FRAME data show significant reductions in new vertebral fractures in postmenopausal women with osteoporosis.
Patients receiving a monthly subcutaneous 210 mg dose of romosozumab experienced a statistically significant 73-percent reduction in the relative risk of a vertebral fracture through 12 months, the co-primary endpoint, compared to those receiving placebo (fracture incidence 0.5 percent vs. 1.8 percent, respectively).
In patients who received romosozumab in year one, fracture risk reduction continued through month 24 after both groups transitioned to denosumab treatment through the second year of the study. There was a statistically significant 75-percent reduction in the risk of vertebral fracture at month 24 (the other co-primary endpoint) in patients who received romosozumab followed by denosumab vs. placebo followed by denosumab (fracture incidence 0.6 percent vs. 2.5 percent, respectively).
“Treatment data show that only one in five women who have experienced an osteoporotic fracture are started on treatment for the disease, despite the fact that patients who experience an osteoporotic fracture are twice as likely to suffer a future fracture,” said study lead author Dr. Felicia Cosman, medical director of the Clinical Research Center at Helen Hayes Hospital and professor of medicine at Columbia University College of Physicians and Surgeons in New York. “The FRAME results demonstrate that romosozumab, with its dual effect of increasing bone formation and decreasing bone resorption, has the potential to reduce the risk of new vertebral and clinical fractures within 12 months, in addition to showing improvements in bone mass, with sustained benefits upon transition to denosumab, thereby addressing a critical treatment need for patients at increased risk of fracture.”
In the mid 1990’s, researchers hoped that by looking for the genetic mutation in people with sclerosteosis, they would find a mechanism through which a bone-building drug for osteoporosis might work. Amgen scientist Chris Paszty independently identified sclerostin in 1999 as a novel gene of unknown function while searching for new families of cystine-knot proteins. Sclerostin emerged as a potential pharmacological target for increasing bone formation, bone mass and bone strength. After that, the search was on for an antibody that would inhibit sclerostin. Through collaboration, Amgen and Celltech R&D Limited (which UCB acquired in 2004) screened more than 1,000 antibodies. In 2002, as the Amgen team moved forward, they discovered that sclerostin behaved very unusually in cell-based screening assays. After an intense, more than yearlong effort, the team succeeded in developing the screening assay that was used, along with subsequent preclinical studies, to ultimately identify AMG 785 as the lead clinical candidate. Romosozumab (AMG 785) was identified as the best candidate to inhibit sclerostin and move from research into the clinical testing stage.
Since 2004, Amgen and UCB have been working together under a collaboration and license agreement to research, develop and market antibody products targeting the protein sclerostin. As part of this agreement, the two companies continue to collaborate on the development of romosozumab for the treatment of osteoporosis. This gene-to-drug project demonstrates how Amgen and UCB are joining forces to turn genetic discoveries into new medicine, turning conceptual science into a reality.
As Dr. Sean E. Harper, executive vice president of research and development at Amgen, explained, “One in three women over the age of 50 will experience an osteoporotic fracture. Additionally, patients who experience an osteoporosis-related fracture are twice as likely to experience a future fracture. We believe physicians and patients need additional treatment options to address this high unmet need. Romosozumab reduced the incidence of new vertebral fractures through months 12 and 24, and clinical fractures as early as 12 months. Furthermore, romosozumab demonstrated significant gains in bone mineral density at six and 12 months at the lumbar spine, total hip and femoral neck. These results show that romosozumab has the potential to be an important treatment option for postmenopausal women with osteoporosis.”