Healthcare Industry News: HSMN NewsFeed
News Release - January 5, 2018
FDA Approves XGEVA(R) (denosumab) For The Prevention Of Skeletal-Related Events In Patients With Multiple MyelomaExpansion of Indication Offers Patients a New Treatment Option
Approval Based on Safety and Efficacy Data From the Largest International Multiple Myeloma Clinical Trial Ever Conducted
THOUSAND OAKS, Calif., Jan. 5, 2018 -- (Healthcare Sales & Marketing Network) -- Amgen (NASDAQ: AMGN) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental Biologics License Application (sBLA) for XGEVAŽ (denosumab) to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma. The approval is based on data from the pivotal Phase 3 '482 study, the largest international multiple myeloma clinical trial ever conducted, which enrolled 1,718 patients.
"Up to 40 percent of patients remain untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis," said Noopur Raje, M.D., director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston. "Denosumab, which is not cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, providing patients with a novel treatment option."
"Bone complications can be devastating for patients with multiple myeloma. Previously, treatment options for the prevention of bone complications were limited to bisphosphonates, which unlike XGEVA, are cleared by the kidneys," said David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen. "We are pleased that the FDA has approved the expanded indication for XGEVA, providing a new option for patients and physicians, underscoring our commitment to advancing care for patients with multiple myeloma."
XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) a protein essential for the formation, function and survival of osteoclasts, which break down bone thereby inhibiting osteoclast-mediated bone destruction. XGEVA is currently the number one prescribed bone-targeting agent in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Additional regulatory applications for XGEVA for the prevention of skeletal-related events in patients with multiple myeloma are underway and have been submitted to health authorities worldwide.
About '482 Study (NCT01345019)
The '482 study was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid for the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event and first-and-subsequent on-study skeletal-related event and evaluation of overall survival. Progression-free survival was an exploratory endpoint. The safety and tolerability of XGEVA were also compared with zoledronic acid.
The study met the primary endpoint, demonstrating non-inferiority of XGEVA to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The secondary endpoints, delaying time to first skeletal-related event and delaying time to first-and-subsequent skeletal-related events, did not demonstrate superiority. Overall survival was comparable between XGEVA and zoledronic acid, with a hazard ratio of 0.90 (95 percent CI: 0.70, 1.16; p=0.41). The median difference in progression-free survival favored XGEVA by 10.7 months (HR=0.82, 95 percent CI: 0.68-0.99; descriptive p=0.036). Median progression-free survival was 46.1 months (95 percent CI: 34.3 months, not estimable [NE], n=219) for XGEVA and 35.4 months (95 percent CI: 30.2 months, NE, n=260) for zoledronic acid.
Adverse events observed in patients treated with XGEVA were generally consistent with the known safety profile of XGEVA. The most common adverse reactions (greater than or equal to 10 percent) were diarrhea (34 percent), nausea (32 percent), anemia (22 percent), back pain (21 percent), thrombocytopenia (19 percent), peripheral edema (17 percent), hypocalcemia (16 percent), upper respiratory tract infection (15 percent), rash (14 percent) and headache (11 percent). The most common adverse reaction resulting in discontinuation of XGEVA (greater than or equal to 1.0 percent) was osteonecrosis of the jaw (ONJ). In the primary treatment phase of the '482 study, ONJ was confirmed in 4.1 percent of patients in the XGEVA group (median exposure of 16 months; range: 1 - 50) and 2.8 percent of patients in the zoledronic acid group (median 15 months, range: 1 - 45 months).
About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 It is typically characterized by osteolytic bone lesions as well as renal failure, which are both part of diagnosis (CRAB criteria).3,4 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1
More than 90 percent of patients develop osteolytic lesions during the course of the disease.4 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.5 Current treatment options for fractures and other bone complications are limited to bisphosphonates, including zoledronic acid, which are cleared through the kidneys.6 Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease.7
About XGEVAŽ (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. XGEVA is also indicated for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity and for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
U.S. Important Safety Information
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVAŽ. XGEVAŽ can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVAŽ is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.
An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.
XGEVAŽ is contraindicated in patients with known clinically significant hypersensitivity to XGEVAŽ, including anaphylaxis that has been reported with use of XGEVAŽ. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVAŽ therapy permanently.
Drug Products with Same Active Ingredient
Patients receiving XGEVAŽ should not take ProliaŽ (denosumab).
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVAŽ, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.
Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.
Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVAŽ and periodically during XGEVAŽ therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVAŽ. Consider temporarily interrupting XGEVAŽ therapy if an invasive dental procedure must be performed.
Patients who are suspected of having or who develop ONJ while on XGEVAŽ should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.
Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVAŽ. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVAŽ 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 suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVAŽ therapy should be considered, pending a risk/benefit assessment, on an individual basis.
Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons Clinically significant hypercalcemia has been reported in XGEVAŽ treated patients with growing skeletons, weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.
XGEVAŽ can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVAŽ is expected to result in adverse reproductive effects.
Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVAŽ. Apprise the patient of the potential hazard to a fetus if XGEVAŽ is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVAŽ.
The most common adverse reactions in patients receiving XGEVAŽ with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.
For multiple myeloma patients receiving XGEVAŽ, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVAŽ was osteonecrosis of the jaw.
The most common adverse reactions in patients receiving XGEVAŽ for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVAŽ were osteonecrosis of the jaw and tooth abscess or tooth infection.
The most common adverse reactions in patients receiving XGEVAŽ for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Denosumab is also marketed as ProliaŽ in other indications.
Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.
About Amgen's Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen's supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.
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.
This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen. 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 reports filed by Amgen, including our most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise.
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. Even when clinical trials are successful, regulatory authorities may question the sufficiency for approval of the trial endpoints we have selected. 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, including our devices, after they are on the market.
Our results may be affected by our ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing our products and global economic conditions. In addition, sales of our products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, our research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. Our business may be impacted by government investigations, litigation and product liability claims. In addition, our business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. If we fail to meet the compliance obligations in the corporate integrity agreement between us and the U.S. government, we could become subject to significant sanctions. Further, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors, or we may fail to prevail in present and future intellectual property litigation. We perform a substantial amount of our commercial manufacturing activities at a few key facilities, including in Puerto Rico, and also depend on third parties for a portion of our manufacturing activities, and limits on supply may constrain sales of certain of our current products and product candidate development. In addition, we compete with other companies with respect to many of our marketed products as well as for the discovery and development of new products. Further, some raw materials, medical devices and component parts for our products are supplied by sole third-party suppliers. Certain of our distributors, customers and payers have substantial purchasing leverage in their dealings with us. The discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations. Our efforts to acquire other companies or products and to integrate the operations of companies we have acquired may not be successful. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all. We are increasingly dependent on information technology systems, infrastructure and data security. Our stock price is volatile and may be affected by a number of events. Our business performance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase our common stock.
- Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed Aug. 25, 2017.
- Multiple Myeloma Research Foundation. What is Multiple Myeloma? https://www.themmrf.org/multiple-myeloma/what-is-multiple-myeloma/. Accessed Aug. 25, 2017.
- Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009;23(3):435441.
- International Myeloma Working Group. International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma. http://imwg.myeloma.org/international-myeloma-working-group-imwg-criteria-for-the-diagnosis-of-multiple-myeloma/. Accessed Aug. 25, 2017.
- Drake MT. Bone disease in multiple myeloma. Oncology (Williston Park). 2009;23(14 Suppl 5):28-32.
- Terpos E, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol. 2013;31(18):2347-57.
- Bhowmik D, et al. Prevalence Of Renal Impairment In Patients With Multiple Myeloma: Analysis Of Real-World Database. Journal of the International Society for Pharmacoeconomic and Outcomes Research. 2016;9(3):A141.
Issuer of this News Release is solely responsible for its
Please address inquiries directly to the issuing company.
Related News ItemsFDA Approves Aimovig(TM) (erenumab-aooe), A Novel Treatment Developed Specifically For Migraine Prevention
Amgen Receives Positive CHMP Opinion To Expand Use Of Prolia(R) (denosumab) To Patients With Glucocorticoid-Induced Osteoporosis
Amgen Receives Positive CHMP Opinion Recognizing That Repatha(R) (evolocumab) Prevents Heart Attacks And Strokes