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 (NEJM) and presented in an oral session at the Annual Meeting of the American Society for Bone Mineral Research (ASBMR) in Atlanta. Romosozumab works by binding and inhibiting the activity of the protein sclerostin, and as a result, has a dual effect on bone, both increasing bone formation and decreasing bone breakdown.

"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 Felicia Cosman, M.D., 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."

FRAME (FRActure study in postmenopausal woMen with ostEoporosis), which enrolled 7,180 women, showed that those randomly assigned to receive a monthly subcutaneous 210 mg dose of romosozumab experienced a statistically significant 73 per cent reduction in the relative risk of a new vertebral (spine) fracture through 12 months, the first co-primary endpoint, compared to those receiving placebo (fracture incidence 0.5 per cent versus 1.8 per cent, respectively [p<0.001]). Of interest, the data showed that by six months, new vertebral fractures occurred in 14 romosozumab and 26 placebo patients, and between six to 12 months, fractures occurred in two additional romosozumab patients versus 33 additional placebo patients.

For those patients who received romosozumab in year one, fracture risk reduction persisted through month 24 after both groups transitioned to denosumab treatment in 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 versus placebo followed by denosumab (fracture incidence 0.6 percent versus 2.5 percent, respectively [p<0.001]). In the second year of the study, new vertebral fractures occurred in five patients who transitioned from romosozumab to denosumab and 25 patients who transitioned from placebo to denosumab.

When looking at clinical fractures, which encompass all symptomatic fractures (both non-vertebral and painful vertebral fractures), patients receiving romosozumab experienced a statistically significant 36 per cent reduction in the relative risk of a clinical fracture, a secondary endpoint, through 12 months compared to those receiving placebo (fracture incidence 1.6 per cent versus 2.5 per cent, respectively [p=0.008]). A 33 per cent reduction in relative risk of clinical fracture was observed through 24 months after patients transitioned from romosozumab to denosumab compared to patients transitioning from placebo to denosumab (nominal p=0.002, adjusted p=0.096).

Romosozumab resulted in a 25 per cent reduction compared to placebo in the relative risk of non-vertebral fractures through month 12, another secondary endpoint, but the reduced risk was not statistically significant (fracture incidence 1.6 per cent versus 2.1 per cent, respectively, [p=0.096]). For the non-vertebral fracture endpoint, the overall fracture incidence in the study was lower than expected (2.1 per cent in the placebo group in year one versus an expected rate of 3.5 per cent).

In a sub-study of 126 subjects, romosozumab increased bone mineral density with gains of 9.7 per cent  and 4.7 per cent  from baseline by six months at the lumbar spine and total hip, respectively, and gains of 13.3 per cent  and 6.8 per cent  at 12 months (all comparisons versus placebo p<0.001). Bone mineral density continued to increase in the romosozumab group after transitioning to denosumab, reaching 17.6 per cent  and 8.8 per cent increases from baseline at the lumbar spine and total hip, respectively, at 24 months (p<0.001 compared to placebo-to-denosumab group for all comparisons).

"We are pleased to see nearly 15 years of sclerostin antibody research reinforced with these phase 3 data. Romosozumab, with its dual effect as a bone builder and anti-resorptive, has the potential to play a distinct and important role in the treatment of women with postmenopausal osteoporosis at increased risk of fracture," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "These positive FRAME study results are the basis of our Biologics Licensing Application that we submitted to the FDA in July, and we look forward to working with regulatory authorities to help make this potential treatment option available to patients."

"Osteoporotic fractures are common, resulting in far-reaching consequences for individuals and their families, as well as for society as a whole," said Dr. Pascale Richetta, head of bone and executive vice president, UCB. "To reduce the growing global burden of this prevalent chronic disease, more decisive steps need to be taken now for identifying, diagnosing and appropriately treating people with osteoporosis at an increased risk of fracture."  

The percentage of patients with adverse events and serious adverse events in the 12-month double-blind period and 24-month study period were balanced overall between the treatment groups. Injection site reactions, mostly mild in severity, were reported in 5.2 per cent of patients in the romosozumab treatment group and 2.9 per cent in the placebo group during the 12-month period. There were two positively adjudicated events of osteonecrosis of the jaw in the romosozumab treatment group, one after completing romosozumab dosing and the other after completing romosozumab treatment and receiving the initial dose of denosumab. There was one positively adjudicated event of atypical femoral fracture after three months of romosozumab treatment. Adjudicated serious cardiovascular events and cardiovascular deaths were balanced between treatment groups.

Romosozumab is an investigational bone-forming monoclonal agent and is not approved by any regulatory authority for the treatment of osteoporosis. It is designed to work by inhibiting the activity of the protein sclerostin and has a dual effect on bone, both increasing bone formation and decreasing bone breakdown. Romosozumab is being studied for its potential to reduce the risk of fractures in an extensive global Phase 3 program. This program includes two large fracture trials comparing romosozumab to either placebo or active comparator in more than 10,000 postmenopausal women with osteoporosis. Amgen and UCB are co-developing romosozumab.

FRAME is a multicenter, international, randomized, double-blind, placebo-controlled, parallel-group study in postmenopausal women with osteoporosis, defined as low bone mineral density at the total hip or femoral neck. The study evaluated the effectiveness of romosozumab treatment, compared with placebo, in reducing the risk of new vertebral fractures through 12 months. The study also further evaluated if romosozumab treatment for 12 months followed by denosumab treatment for 12 months, compared with placebo followed by denosumab treatment, was effective in reducing the risk of new vertebral fractures through 24 months. In addition, clinical fracture (a composite endpoint which encompasses all symptomatic fractures, both non-vertebral and painful vertebral fractures) risk reduction, non-vertebral fracture (fractures outside of the spine, excluding sites that are not considered osteoporotic, fractures due to high trauma or pathologic fractures) risk reduction and other endpoints were assessed at 12 and 24 months.

7,180 patients were randomized 1:1 to receive either 210 mg romosozumab subcutaneous (SC) monthly (QM) or placebo SC QM for the 12-month double-blind study period. After the placebo-controlled study period, patients entered the open-label phase where all patients received 60 mg denosumab SC every six months (Q6M) for 12 months, while remaining blinded to initial treatment. An additional 12 month extension period of open-label 60 mg denosumab SC Q6M is currently ongoing.

Prolia is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, nonvertebral, and hip fractures.

Prolia is indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.

Prolia is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients Prolia also reduced the incidence of vertebral fractures.

Prolia is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.