"The data being presented at ASBMR underscore our steadfast focus for more than a decade to advance scientific understanding and care for the millions of people living with osteoporosis," said
The congress will feature the first presentation of full results from the EVENITY Phase 3 active-comparator ARCH study. Three abstracts from the EVENITY Phase 3 placebo-controlled FRAME study of more than 7,000 postmenopausal women with osteoporosis will also be highlighted as oral presentations. EVENITY is being co-developed by Amgen and UCB.
Prolia presentations will include new analyses from the Phase 3 FREEDOM study and its seven-year extension, including one that demonstrates 10-year continued nonvertebral fracture reduction. Additionally, data will be presented from the Phase 3 study in patients with glucocorticoid-induced osteoporosis (GiOP), as well as data demonstrating that treatment with Prolia prevents deterioration in the trabecular microstructure at the distal tibia.
ABSTRACTS OF INTEREST
About the ARCH study
ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture) is a Phase 3 multicenter, international, randomized, double-blind, alendronate-controlled study of EVENITY in postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history. The study evaluated 12 months of EVENITY treatment followed by at least 12 months of alendronate treatment, compared with alendronate treatment alone. The purpose of this study was to determine if EVENITY treatment is effective in reducing the incidence of clinical fracture (non-vertebral fracture and clinical vertebral fracture) and new vertebral fracture. The incidence of clinical fracture was event-driven and the primary analysis occurred when 330 fractures occurred or the last patient was on the study for 24 months, whichever was later.
Patients (4,093) were randomized 1:1 to receive either 210 mg EVENITY subcutaneously every month or 70 mg alendronate orally every week for the duration of the 12-month double-blind alendronate-controlled study period. After the double-blind active-comparator study period, patients received alendronate while remaining blinded to their initial treatment assignment.
About the FRAME study
FRAME (FRActure study in postmenopausal woMen with ostEoporosis) 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 EVENITY treatment, compared with placebo, in reducing the risk of new vertebral fractures through 12 months. The study also further evaluated if EVENITY 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 EVENITY 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.
About the FREEDOM Study
The pivotal Phase 3 FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every six Months) study enrolled 7,808 women with postmenopausal osteoporosis. In the fracture study, participants were randomly assigned to receive Prolia (60 mg) or placebo subcutaneously every six months for three years, after which they could choose to enter a seven-year extension study. Eligibility criteria for the extension study included completion of the pivotal Phase 3 fracture trial, not missing more than one dose of investigational product (either Prolia or placebo) in the pivotal Phase 3 fracture trial, and not receiving any other osteoporosis medications.
In the extension, all subjects, regardless of original randomization, received open-label Prolia (60 mg) every six months. The long-term group received up to 10 years of Prolia (three years in the pivotal Phase 3 fracture study and seven years in the extension) and the cross-over group received up to seven years of Prolia (three years placebo in the pivotal Phase 3 fracture study, seven years Prolia in the extension). Of the 4,550 participants who enrolled in the extension, 2,626 completed the extension study.
About EVENITY™ (romosozumab)
EVENITY is an investigational bone-forming monoclonal antibody and is not approved by any regulatory authority for the treatment of osteoporosis. It is designed to work by inhibiting the activity of sclerostin and has a dual effect on bone, increasing bone formation and decreasing bone resorption. EVENITY has been studied for its potential to reduce the risk of fractures in an extensive global Phase 3 program. This program included two large fracture trials comparing EVENITY to either placebo or active comparator in more than 10,000 postmenopausal women with osteoporosis.
About Prolia® (denosumab)
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.
Important Safety Information (U.S.)
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. 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®.
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 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 antiresorptive 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 antiresorptive therapy.
In a clinical trial (N= 7808) 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.
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.
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 (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.
Amgen Forward-Looking Statements
This news release contains forward-looking statements that are based on the current expectations and beliefs of
No forward-looking statement can be guaranteed and actual results may differ materially from those
The scientific information discussed in this news release related to
* The trade name EVENITY™ is provisionally approved for use by the U.S. Food and Drug Administration and the European Medicines Agency.
1 Abimanyi-Ochom J. Osteoporos Int. 2015;26:1781-1790
3 Boudreau D et al. A Survey of Women's Awareness of and Reasons for Lack of Postfracture Osteoporotic Care. J Am Geriatri Soc. 2017.
4 ASBMR Issues "Call to Action to Address the Crisis in the Treatment of Osteoporosis."
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