ProliaÂ® (denosumab) Open-Label Extension Trial Showed Continued Increase in Bone Mineral Density Over Six Years With Similar Safety Profile Observed in Original Fracture Trial
THOUSAND OAKS, Calif., Nov. 5, 2011 /PRNewswire/ — Amgen (NASDAQ: AMGN) today announced positive data from the first three years of the open-label extension study of the pivotal Phase 3 fracture trial showing that six years of ProliaÃ‚® (denosumab) treatment in postmenopausal women with osteoporosis was associated with continued increase in bone mineral density (BMD) and consistent reduction in markers of bone turnover. These results will be presented on Nov. 8, 2011, at the 2011 American College of Rheumatology Annual Scientific Meeting in Chicago.
Results of the open-label extension study showed that postmenopausal women with osteoporosis who received up to six years of continued Prolia treatment experienced cumulative gains of 15.2 percent at the lumbar spine and 7.5 percent at the total hip compared with baseline. The overall adverse event profile is consistent with events previously reported.
“These data are consistent with the pivotal Phase 3 fracture study, which first established the efficacy and safety of Prolia in women with postmenopausal osteoporosis at high risk for fractures,” said study author Jacques Brown, M.D., CHUQ-CHUL Research Centre, Laval University. “This study provides further evidence of Prolia’s long-term clinical potential for women with this chronic disease.”
The FREEDOM Study and the 6-Year Prolia Data
The pivotal Phase 3 fracture trial was based on three years of data from approximately 7,800 postmenopausal women. The open-label study extension is evaluating the long-term (up to 10 years) efficacy and safety of Prolia in 4,550 postmenopausal women. Seventy percent of eligible women from the pivotal Phase 3 fracture study enrolled in the study extension; 2,343 women continued to receive Prolia treatment (long-term group), and 2,207 transitioned from placebo to Prolia (cross-over group).
The long-term group experienced significant mean increases in BMD for cumulative 6-year gains of 15.2 percent at the lumbar spine and 7.5 percent at the total hip. Fracture incidence remained low in the long-term group. During the first three years of the extension study, the cross-over group had significant mean gains of 9.4 percent at the lumbar spine and 4.8 percent at the total hip; yearly incidences of new vertebral and nonvertebral fractures were lower than in the pivotal Phase 3 fracture study placebo group.
Incidences of adverse events (AEs) and serious AEs did not increase over time with Prolia treatment. Four subjects developed osteonecrosis of the jaw (ONJ) during the extension study that healed without further complications. One of these subjects continued Prolia, and one subject discontinued. Follow-up is ongoing for the other two subjects. No atypical femoral fractures were reported in either group.
Osteoporosis: Impact and Prevalence
Referred to as a “silent epidemic” by the International Osteoporosis Foundation (IOF), osteoporosis is a global problem that is increasing in significance as the population of the world both increases and ages. The World Health Organization has officially declared osteoporosis a public health crisis, and the IOF is urging governments worldwide to make osteoporosis a healthcare priority.
Osteoporosis-associated fractures are a significant cause of mortality and morbidity. In 2000, the number of osteoporotic fractures in Europe was estimated at 3.79 million, of which 890,000 were hip fractures.(1) Since 2001, the incidence of hip fractures in European countries has risen significantly.(2) In the United States (U.S.), the number of fractures due to osteoporosis is expected to rise to more than three million by 2025.(3)
The direct medical cost of osteoporotic fractures in Europe is expected to rise from euro 31.7 billion in 2000 to euro 76.7 billion in 2050.(4) In 2005, osteoporosis-related fractures were responsible for an estimated $19 billion in cost in the U.S., and this cost is expected to rise to approximately $25 billion by 2025.(5)
Prolia is the first approved therapy that specifically targets RANK Ligand, an essential regulator of osteoclasts (the cells that break down bone).
Prolia is approved in the U.S. 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.
Prolia is approved in the European Union (EU) for the treatment of osteoporosis in postmenopausal women at increased risk of fractures, and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures.
Prolia is approved in the U.S., Canada, Australia and in all 27 EU member states as well as in Norway, Iceland and Liechtenstein. Applications in the rest of the world are pending.
Prolia is administered as a single subcutaneous injection of 60mg once every six months. For further information on Prolia, including prescribing information and medication guide, please visit www.prolia.com.
Important U.S. Safety Information
Prolia is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating Prolia. Hypocalcemia may worsen, especially in patients with severe renal impairment. All patients should be adequately supplemented with calcium and vitamin D. Patients receiving Prolia should not receive XGEVAÃ‚® (denosumab), as both Prolia and XGEVA contain the same active ingredient, denosumab.
In the Phase 3 pivotal study, serious infections leading to hospitalizations were reported more frequently in the Prolia-treated patient group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear, were more frequent in patients treated with Prolia. Patients should be advised to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis. Endocarditis was reported more frequently in the Prolia-treated patient group. Epidermal and dermal adverse events such as dermatitis, rashes and eczema have been reported. Discontinuation of Prolia should be considered if severe symptoms develop.
Prolia resulted in significant suppression of bone remodeling. The significance of these findings is unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Prolia may contribute to adverse outcomes such as osteonecrosis of the jaw (ONJ), atypical fractures and delayed fracture healing. ONJ has been reported in patients with Prolia. Patients should be monitored for these adverse outcomes. The most common adverse reactions (> 5 percent and more common than placebo) were back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia and cystitis. Pancreatitis has also been reported with Prolia.
Important EU Safety Information
The most common adverse reactions with Prolia were urinary tract infection, upper respiratory tract infection, sciatica, cataracts, constipation, rash and pain in extremity. The most serious adverse reactions were those of skin infections, predominantly cellulitis, reported more commonly in the Prolia group compared with placebo (0.4 percent vs. 0.1 percent) in postmenopausal osteoporosis studies. In breast and prostate cancer studies, serious adverse reactions of skin infection were similar in the Prolia and placebo groups (0.6 percent vs. 0.6 percent). In the Phase 3 placebo-controlled clinical trial in patients with prostate cancer receiving ADT, an imbalance in cataract adverse events was observed with Prolia compared with placebo (4.7 percent vs. 1.2 percent placebo). No imbalance in cataract adverse events was observed in postmenopausal women with osteoporosis or in women undergoing aromatase inhibitor therapy for nonmetastatic breast cancer.
Prolia may lead to hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiating therapy. ONJ has been reported rarely in clinical studies in patients receiving denosumab at a dose of 60mg every 6 months for osteoporosis.
Denosumab Commercialization Collaborations
In July 2009, Amgen and GlaxoSmithKline announced a collaboration agreement to jointly commercialize Prolia for postmenopausal osteoporosis in Europe, Australia, New Zealand and Mexico once the product is approved in these countries. Amgen will commercialize Prolia’s postmenopausal osteoporosis and potential oncology indications in the U.S. and Canada and for all oncology indications in Europe and in other specified markets.
In addition, GlaxoSmithKline will register and commercialize denosumab for all indications in countries where Amgen does not currently have a commercial presence, including China, India and South Korea but excluding Japan. The structure of the collaboration allows Amgen the option of an expanded role in commercialization in both Europe and certain emerging markets in the future.
Amgen and Daiichi-Sankyo Company Limited have a collaboration and license agreement for the development and commercialization of denosumab in Japan.
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe, effective medicines from lab to manufacturing plant to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, bone disease and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. To learn more about our pioneering science and vital medicines, visit www.amgen.com. Follow us on www.twitter.com/amgen.
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(1)”Facts and statistics about osteoporosis and its impact.” International Osteoporosis Foundation. Accessed at http://www.iofbonehealth.org/facts-and-statistics.html#factsheet-category-22 February 4, 2011
(2)”Osteoporosis in the European Union in 2008: Ten years of progress and ongoing challenges.” Accessed at http://www.iofbonehealth.org/publications/eu-policy-report-of-2008.html on February 4, 2011
(3)Burge R, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007: 22:465-475
(4)”Facts and statistics about osteoporosis and its impact.” International Osteoporosis Foundation. Accessed at http://www.iofbonehealth.org/facts-and-statistics.html on February 4, 2011
(5)”Fast Facts” National Osteoporosis Foundation. Accessed at http://www.nof.org/node/40 on February 4, 2011