• Expansion 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, CA (Press Release) – Amgen (NASDAQ: AMGN) today announced that the U.S. Food and Drug Admin­istra­tion (FDA) has approved the supple­mental Biologics License Application (sBLA) for XGEVA® (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 XGEVA® (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

Hypocalcemia

Pre-existing hypo­cal­cemia must be corrected prior to initiating ther­apy with XGEVA®. XGEVA® 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 XGEVA® 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.

Hypersensitivity

XGEVA® is con­tra­in­di­cated in patients with known clin­i­cally sig­nif­i­cant hypersensitivity to XGEVA®, in­­clud­ing anaphylaxis that has been reported with use of XGEVA®. 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 XGEVA® ther­apy perma­nently.

Drug Products with Same Active Ingredient

Patients receiving XGEVA® should not take Prolia® (denosumab).

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA®, 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 XGEVA® and periodically during XGEVA® ther­apy. Advise patients re­gard­ing oral hygiene practices. Avoid in­­vasive dental procedures during treat­ment with XGEVA®. Consider temporarily interrupting XGEVA® ther­apy if an in­­vasive dental procedure must be per­formed.

Patients who are sus­pected of having or who develop ONJ while on XGEVA® 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 XGEVA®. 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 XGEVA® 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 XGEVA® 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 XGEVA® treated patients with growing skeletons, weeks to months fol­low­ing treat­ment dis­con­tinu­a­tion. Monitor patients for signs and symp­toms of hypercalcemia and treat appro­pri­ately.

Embryo-Fetal Toxicity

XGEVA® can cause fetal harm when admin­istered to a pregnant woman. Based on findings in animals, XGEVA® 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 XGEVA®. Apprise the patient of the poten­tial hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions

The most common adverse reac­tions in patients receiving XGEVA® 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 XGEVA®, 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 XGEVA® was osteo­necrosis of the jaw.

The most common adverse reac­tions in patients receiving XGEVA® 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 XGEVA® were osteo­necrosis of the jaw and tooth abscess or tooth in­fec­tion.

The most common adverse reac­tions in patients receiving XGEVA® for hypercalcemia of malig­nan­cy were nausea, dyspnea, de­creased appetite, headache, periph­eral edema, vomiting, anemia, con­sti­pa­tion, and diarrhea.

Denosumab is also marketed as Prolia® 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.

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.

Forward-Looking Statements

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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.

References:

1. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed Aug. 25, 2017.
2. Multiple Myeloma Research Foundation. What is Multiple Myeloma? https://www.themmrf.org/multiple-myeloma/what-is-multiple-myeloma/. Accessed Aug. 25, 2017.
3. Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009;23(3):435–441.
4. 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.
5. Drake MT. Bone disease in multiple myeloma. Oncology (Williston Park). 2009;23(14 Suppl 5):28-32.
6. 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.
7. 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.

Source: Amgen.