New Data Show Consistent Safety Profile For Up To 10 Years With Prolia® (Denosumab) In Postmenopausal Women With Osteoporosis

THOUSAND OAKS, Calif., Oct. 12, 2015 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced results from a seven-year, single-arm, open-label extension of the three-year randomized, double-blind, placebo-controlled, multicenter, international Phase 3 Fracture Reduction Evaluation of Denosumab in Osteoporosis every six Months (FREEDOM) study. In this final analysis, treatment with Prolia^® (denosumab) for up to 10 years showed that the overall incidence of adverse events (AEs) and serious AEs remained consistent over the duration of the study with a low fracture incidence. In addition, postmenopausal women with osteoporosis on Prolia continued to show gains in bone mineral density (BMD) over 10 years. The findings were presented during a late-breaking oral presentation session at the American Society for Bone and Mineral Research (ASBMR) 2015 Annual Meeting in Seattle today.

"Osteoporosis generally requires long-term therapy, and it is important to maintain a favorable balance of benefit versus risk over that course of treatment," said lead investigator Henry G. Bone III, M.D., director of the Michigan Bone and Mineral Clinic, Detroit. "Long-term therapy with denosumab for up to 10 years produced progressively increased bone density measurements. The safety profile remained consistent over the duration of the study, including a low fracture incidence. These long-term results are important for patients and those who care for them."

The findings are from an extension of the pivotal Phase 3 FREEDOM fracture study (NCT00089791), which 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 7 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.

David Kendler, M.D., FRCP(C), director, Prohealth Clinical Research in Vancouver, British Columbia and study investigator, noted, "Osteoporosis is a chronic condition, and many patients will be on lifelong therapy to help reduce the risk of fragility fractures. As a physician treating many patients with osteoporosis, long-term safety data is very important when considering the right treatment regimen."

Subjects treated for 10 years with denosumab achieved an average cumulative 10-year gain in BMD of 21.7 percent at the lumbar spine and 9.2 percent at the total hip, compared to baseline in the pivotal Phase 3 fracture study. Overall rates of AEs and serious AEs were consistent with data reported previously in the extension study. Yearly rates of new vertebral and nonvertebral fractures remained low. During the seven years of the extension, 13 oral events were confirmed as osteonecrosis of the jaw (ONJ) and two events were confirmed as atypical femoral fracture by independent adjudication committees. No atypical femoral fractures or ONJ cases were reported in the original three-year core study.

"These 10-year findings from the final year of this open-label extension study provide important additional data to the significant body of evidence generated to inform long-term safety, including more than 100 original publications and presentations over the last seven years," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Together, the evidence from this pivotal Phase 3 fracture trial and its extension highlights the value of Prolia in the treatment of women with postmenopausal osteoporosis at high risk for fracture, as well as Amgen's commitment to continued research in the field of osteoporosis."

About Osteoporosis
Osteoporosis affects many women after menopause as their ability to form new bone cannot counter balance the rate at which bone is being removed.^1,2 This bone loss leads to weakened bones over time, increasing the potential for a break.^3,4

About half of all women over age 50 will have an osteoporosis-related fracture in their remaining lifetime.⁵ Additionally, patients with a previous hip fracture have a threefold greater risk of a subsequent fracture within two years.^6,7

The World Health Organization has officially declared osteoporosis a public health crisis, while the International Osteoporosis Foundation urges governments worldwide to make osteoporosis a healthcare priority.

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 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 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.

Prolia is administered as a single subcutaneous injection of 60 mg once every six months. Please see the Important Safety Information below.

Important Safety Information (U.S.)
Prolia is contraindicated in patients with hypocalcemia. Preexisting 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.

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.

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^®. 

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 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.

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.

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.

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

The Prolia Postmarketing Active Safety Surveillance Program is available to collect information from prescribers on specific adverse events.  Please see https://www.proliasafety.com/ or call 1-800-772-6436 for more information.

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 biologics manufacturing 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.

Forward Looking Statements
This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission (SEC) reports filed by Amgen, including Amgen's most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and Form 8-K. Please refer to Amgen's most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. Unless otherwise noted, Amgen is providing this information as of Oct. 12, 2015, and expressly disclaims any duty to update information contained in this news release.

No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and products liability claims. We depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.

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CONTACT: Amgen, Thousand Oaks
Kristen Davis, 805-447-3008 (media)
Kristen Neese, 805-313-8267 (media)
Arvind Sood, 805-447-1060 (investors)

References

¹ U.S. Department of Health and Human Services, Office of the Surgeon General. The 2004 Surgeon General's Report on Bone Health and Osteoporosis: What It Means to You. http://www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf. Published October 14, 2004. Accessed August 5, 2015.
² National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. http://nof.org/files/nof/public/content/file/344/upload/159.pdf. Published January 2010. Accessed August 5, 2015.
³ Chavassieux P, et al. Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease. Endocr Rev. 2007;28:151-164.
⁴ Seeman E, Delmas PD. Bone quality – the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-2261.
⁵  American Academy of Orthopedic Surgeons. Osteoporosis and Bone Health. http://www.aaos.org/news/aaosnow/may09/clinical8.asp. Accessed August 5, 2015.
⁶ Colón-Emeric C, Kuchibhatla M, Pieper C, et al. The contribution of hip fracture to risk of subsequent fractures: data from two longitudinal studies. Osteoporos Int. 2003;14:879-883.
⁷ Lyles KW, Schenck AP, Colón-Emeric CS. Hip and other osteoporotic fractures increase the risk of subsequent fractures in nursing home residents. Osteoporos Int. 2008;19:1225-1233.

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