Amgen discovers, develops, manufactures and delivers innovative human therapeutics, announced new long-term data showing that Prolia (denosumab) treatment for up to eight years in post-menopausal women with low bone mass or osteoporosis was associated with a continued increase in Bone Mineral Density (BMD), an important determinant of bone strength, and a persistent reduction in markers of bone turnover. The data were presented at the annual meeting of the American Society for Bone and Mineral Research (ASBMR) in San Diego.

Results of the phase II study extension showed that for post-menopausal women with low bone mass or osteoporosis who received up to eight years of continued treatment with Prolia, BMD at the lumbar spine and total hip increased on average by 16.8 per cent and 6.9 per cent as compared to baseline, respectively. The overall adverse event profile is consistent with events previously reported.

“We don't yet have a cure for osteoporosis, and many post-menopausal women with this condition who are at high risk for fractures require long-term therapy for this serious disease,” said lead author Michael McClung, MD, founding director, Oregon Osteoporosis Centre. “This study provides additional data that Prolia continues to increase bone mineral density progressively over a treatment period of eight years. This study supports the long-term clinical experience of Prolia for women with this chronic condition.”

This phase II study extension sought to determine the effects of up to eight years of continued treatment with Prolia on BMD and bone turnover markers in post-menopausal women with low bone mass or osteoporosis.

In the original phase II dose-ranging trial for Prolia, 412 post-menopausal women with a BMD T-score (amount of matter per cubic centimeter of bones) between -1.8 and -4.0 (lumbar spine) and/or -1.8 and -3.5 (total hip or femoral neck) were enrolled. Of the 262 women who completed the parent study, 200 enrolled in the extension study, all of whom received Prolia (60 mg every 6 months). Results focused on patients who received Prolia treatment for up to eight years, where BMD showed gains at the lumbar spine and total hip of 16.8 per cent and 6.9 per cent, respectively, compared with their parent study baseline.

Osteoporosis is 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 (WHO) 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. Since 2001, the incidence of hip fractures in European countries has risen significantly. In the United States (US), the number of fractures due to osteoporosis is expected to rise to more than three million by 2025.

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. In 2005, osteoporosis-related fractures were responsible for an estimated $19 billion in cost in the US, and this cost is expected to rise to approximately $25 billion by 2025.

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 US for the treatment of post-menopausal 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 post-menopausal 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 US, 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. It is administered as a single subcutaneous injection of 60 mg once every six months.

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 Xgeva (denosumab), as both Prolia and Xgeva contain the same active ingredient, denosumab.

In the phase III 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 remodelling. The significance of these findings is unknown. The long-term consequences of the degree of suppression of bone remodelling 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.

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 post-menopausal 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 III 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 post-menopausal women with osteoporosis or in women undergoing aromatase inhibitor therapy for non-metastatic 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 60 mg every 6 months for osteoporosis.

In July 2009, Amgen and GlaxoSmithKline (GSK) announced a collaboration agreement to jointly commercialize Prolia for post-menopausal osteoporosis in Europe, Australia, New Zealand and Mexico once the product is approved in these countries. Amgen will commercialize Prolia's post-menopausal osteoporosis and potential oncology indications in the US and Canada and for all oncology indications in Europe and in other specified markets.

In addition, GSK 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.