FDA Approves Prolia® (Denosumab) For Glucocorticoid-Induced Osteoporosis

Amgen(NASDAQ:AMGN) today announced that the U.S. Food and Drug Administration (FDA) has approved the use of Prolia^® (denosumab) for the treatment of glucocorticoid-induced osteoporosis (GIOP) in men and women at high risk of fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. This approval is based on data from a Phase 3 study which showed patients on glucocorticoid therapy who received Prolia had greater gains in bone mineral density (BMD) compared to those who received active comparator (risedronate).

“As a leader in bone health with more than 20 years of osteoporosis research experience, we are pleased that Prolia will now be available for patients at high risk of fracture who are suffering from bone loss due to long-term glucocorticoid treatment,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “This is a serious condition that leads to rapid decreases in bone mineral density and increased risk of fracture. This approval gives patients and physicians a new treatment option.”

“Patients on long-term systemic glucocorticoid medications can experience a rapid reduction in bone mineral density within a few months of beginning treatment¹,” said study lead Kenneth F. Saag, M.D., M.Sc., professor of medicine at the University of Alabama at Birmingham School of Medicine. “With this approval, patients who receive treatment with glucocorticoids now have a new option to help improve their bone mineral density.”

The approval is supported by the 12-month primary analysis of a 24-month Phase 3, randomized, double-blind, double-dummy, active-controlled study evaluating the safety and efficacy of Prolia 60 mg subcutaneously every six months compared with oral risedronate 5 mg once daily in 795 patients receiving glucocorticoid treatment, greater than or equal to 7.5 mg/day oral prednisone (or equivalent).² The study included two patient groups: a glucocorticoid-initiating subpopulation, receiving treatment for less than three months prior to study enrollment and planning to continue treatment for a total of at least six months, and a glucocorticoid-continuing subpopulation, receiving treatment for greater than or equal to three months prior to study enrollment and planning to continue treatment for a total of at least six months. Study results showed that in the glucocorticoid-continuing subpopulation, Prolia demonstrated a significantly greater increase in lumbar spine BMD compared to risedronate at one year (3.8 percent versus 0.8 percent, respectively) with a treatment difference of 2.9 percent (p<0.001). Similarly, in the glucocorticoid-initiating subpopulation, Prolia demonstrated a significantly greater increase in lumbar spine BMD compared to risedronate at one year (4.4 percent versus 2.3 percent, respectively) with a treatment difference of 2.2 percent (p<0.001). Consistent effects on lumbar spine BMD were observed regardless of gender; race; geographic region; menopausal status; and baseline age, lumbar spine BMD T-score, and glucocorticoid dose within each subpopulation.

Safety results were consistent with the known safety profile of Prolia. The most common adverse reactions (greater than 3 percent and more common than active-control group) were back pain, hypertension, bronchitis, and headache. Atypical femoral fracture was reported in one patient treated with Prolia. Serious infection was reported in 15 patients (3.9 percent) in the active-control group and 17 patients (4.3 percent) in the Prolia group. No cases of osteonecrosis of the jaw were reported. Epidermal and dermal adverse events (such as dermatitis, eczema and rashes) were reported in 16 patients (4.2 percent) in the active-control group and 15 patients (3.8 percent) in the Prolia group.

About Glucocorticoid-Induced Osteoporosis (GIOP)
GIOP is the most common form of secondary osteoporosis.³ However, the proportion of patients that qualify for GIOP diagnosis and intervention is small and depends on the level of exposure to glucocorticoid medications.^4,5 In addition, a significant proportion of the patients treated long-term with glucocorticoid medications are already diagnosed with postmenopausal osteoporosis or treated with osteoporosis medications. Importantly, at similar levels of BMD, postmenopausal women taking glucocorticoids have considerably higher risk of fracture compared with nonusers of glucocorticoids.⁶ The most frequent chronic inflammatory diseases associated with long-term glucocorticoid use are chronic obstructive pulmonary disorder (COPD), asthma and rheumatoid arthritis.⁷ In the U.S., more than 10 percent of patients who receive long-term glucocorticoid treatment are diagnosed with a clinical fracture, and in an EU study, 30 to 40 percent had radiographic evidence of vertebral fractures. ^7,8

About Prolia^® (denosumab)
Prolia is the first approved therapy that specifically targets RANK Ligand, an essential regulator of bone-removing cells (osteoclasts). Prolia is approved and marketed in over 80 countries worldwide.

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. In the U.S., Prolia is also approved 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 also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer in the U.S. Prolia is indicated as a treatment for patients with glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least six months. High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

U.S. Important Safety Information

Contraindications
Prolia is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating Prolia. Prolia is contraindicated in women who are pregnant and may cause fetal harm. In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with Prolia. Prolia is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria.

Same Active Ingredient
Prolia contains the same active ingredient (denosumab) found in XGEVA^®. Patients receiving Prolia should not receive XGEVA^®.

Hypersensitivity
Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Prolia.

Hypocalcemia
Hypocalcemia may worsen with the use of Prolia, especially in patients with severe renal impairment. In patients predisposed to hypocalcemia and disturbances of mineral metabolism, clinical monitoring of calcium and mineral levels is highly recommended within 14 days of Prolia injection. Adequately supplement all patients with calcium and vitamin D.

Osteonecrosis of the Jaw (ONJ)
ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients receiving Prolia. An oral exam should be performed by the prescriber prior to initiation of Prolia. A dental examination with appropriate preventive dentistry is recommended prior to treatment in patients with risk factors for ONJ such as invasive dental procedures, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders. Good oral hygiene practices should be maintained during treatment with Prolia. The risk of ONJ may increase with duration of exposure to Prolia.

For patients requiring invasive dental procedures, clinical judgment should guide the management plan of each patient. Patients who are suspected of having or who develop ONJ should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia should be considered based on individual benefit-risk assessment.

Atypical Femoral Fractures
Atypical low-energy, or low trauma fractures of the shaft have been reported in patients receiving Prolia. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with anti-resorptive agents.

During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be evaluated to rule out an incomplete femur fracture. Interruption of Prolia therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment
Following discontinuation of Prolia treatment, fracture risk increases, including the risk of multiple vertebral fractures. New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose of Prolia. Prior vertebral fracture was a predictor of multiple vertebral fractures after Prolia discontinuation. Evaluate an individual’s benefit/risk before initiating treatment with Prolia. If Prolia treatment is discontinued, consider transitioning to an alternative anti-resorptive therapy.

Serious Infections
In a clinical trial (N=7,808) in women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Prolia group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear were more frequent in patients treated with Prolia.

Endocarditis was also reported more frequently in Prolia-treated patients. The incidence of opportunistic infections and the overall incidence of infections were similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. In patients who develop serious infections while on Prolia, prescribers should assess the need for continued Prolia therapy.

Dermatologic Adverse Reactions
In the same clinical trial in women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema and rashes occurred at a significantly higher rate with Prolia compared to placebo. Most of these events were not specific to the injection site. Consider discontinuing Prolia if severe symptoms develop.

Musculoskeletal Pain
Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia. Consider discontinuing use if severe symptoms develop.

Suppression of Bone Turnover
In clinical trials in women with postmenopausal osteoporosis, Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment are unknown. Monitor patients for these consequences, including ONJ, atypical fractures, and delayed fracture healing.

Adverse Reactions
The most common adverse reactions (>5% and more common than placebo) in women with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions (> 5% and more common than placebo) in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. Pancreatitis has been reported with Prolia.

In women with postmenopausal osteoporosis, the overall incidence of new malignancies was 4.3% in the placebo group and 4.8% in the Prolia group. In men with osteoporosis, new malignancies were reported in no patients in the placebo group and 4 (3.3%) patients in the Prolia group. A causal relationship to drug exposure has not been established.

The most common adverse reactions (>3% and more common than active-control group) in patients with glucocorticoid-induced osteoporosis were: back pain, hypertension, bronchitis, and headache. The most common (per patient incidence ≥ 10%) adverse reactions reported with Prolia in patients with bone loss receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. Additionally, in Prolia-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed.

Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity.

For more information, please see the Prolia Prescribing Information, and Medication Guide.

About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. A biotechnology pioneer since 1980, Amgen has grown to be one of the world’s leading independent biotechnology companies, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

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