• Xgeva is Currently Indicated for the Prevention of Skeletal-Related Events Known as Bone Complications in Patients With Solid Tumors
• Applications Include Data From the Largest Inter­na­tional Trial Conducted in Multiple Myeloma

Thousand Oaks, CA (Press Release) – Amgen (NASDAQ: AMGN) today announced the sub­mission of a supple­mental Biologics License Application (sBLA) to the U.S. Food and Drug Admin­istra­tion (FDA) and an appli­ca­tion for a variation to the market­ing authori­za­tion to the European Medicines Agency (EMA) for XGEVA® (denosumab). The sub­missions to regu­la­tory author­i­ties seek to expand the cur­rently approved XGEVA indi­ca­tion for the prevention of skeletal-related events (SREs) in solid tumors to in­clude patients with multiple myeloma. The appli­ca­tions in­clude new data from the pivotal Phase 3 head-to-head '482 study, the largest inter­na­tional multiple myeloma trial ever conducted.

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 indicated for the prevention of SREs in patients with bone metastases from solid tumors based on results from three pre­vi­ous pivotal Phase 3 head-to-head studies. In these Phase 3 studies, XGEVA dem­onstrated superiority in the solid tumors stud­ied com­pared to zole­dronic acid. In the U.S., XGEVA has a limitation of use noting that it is not indi­cated for the prevention of SREs in patients with multiple myeloma.

"Bone lesions are a hallmark of multiple myeloma and often result in bone com­pli­ca­tions, which can be dev­as­tat­ing for patients. Current treat­ment options for bone com­pli­ca­tions are limited to bis­phos­pho­nates, which are asso­ci­ated with renal toxicity. Approximately 60 per­cent of all multiple myeloma patients have or will develop renal im­pair­ment over the course of the disease," said Sean E. Harper, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "XGEVA's unique mech­a­nism of action may offer mul­tiple myeloma patients a novel treat­ment option that is not renally cleared. We look forward to col­lab­o­rat­ing with regu­la­tory author­i­ties to make XGEVA avail­able to this patient pop­u­la­tion with an im­por­tant unmet medical need."

The sBLA is based on efficacy and safety data from the pivotal Phase 3 '482 study, which dem­onstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study SRE in patients with multiple myeloma (HR=0.98, 95 per­cent CI: 0.85, 1.14; p=0.01). The sec­ond­ary end­points of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. Overall survival (OS), another sec­ond­ary end­point, was also in favor of XGEVA over zoledronic acid (HR=0.90, 95 per­cent CI: 0.70, 1.16; p=0.41); how­ever, it was not statistically sig­nif­i­cant. The hazard ratio of XGEVA versus zole­dronic acid for pro­gres­sion-free survival (PFS) was 0.82 (95 per­cent CI: 0.68, 0.99; descriptive p=0.036). The median PFS dif­fer­ence be­tween arms was 10.7 months in favor of XGEVA. These results were presented during the late-breaking abstract session at the 16th Inter­na­tional Myeloma Workshop.

Adverse events observed in patients treated with XGEVA were con­sis­tent with the known safety profile of XGEVA. The most common adverse events (greater than 25 per­cent) were diarrhea (33.5 per­cent XGEVA and 32.4 per­cent zoledronic acid) and nausea (31.5 per­cent XGEVA and 30.4 per­cent zoledronic acid).

About '482 Study (NCT01345019)

The '482 study was an inter­na­tional, Phase 3, ran­domized, double-blind, multi­center trial of XGEVA com­pared with zoledronic acid in the prevention of SREs in adult patients with newly diag­nosed multiple myeloma and bone disease. In the study, a total of 1,718 subjects (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 SRE (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 SRE and first-and-subsequent on-study SRE and evaluation of OS. PFS was an exploratory end­point. The safety and tolerability of XGEVA were also compared with zoledronic acid.

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, which are 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.³ Current treat­ment options for bone complica­tions are limited to bis­phos­pho­nates, in­clud­ing zoledronic acid; these are cleared by the kidneys and asso­ci­ated with renal toxicity, which is a common com­pli­ca­tion with myeloma patients.⁵ Approximately 60 per­cent of all multiple myeloma patients have or will develop renal im­pair­ment over the course of the disease.⁶ Preventing bone com­pli­ca­tions is a critical aspect of caring for patients with multiple myeloma, because these events can cause sig­nif­i­cant morbidity.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 SREs in patients with bone metastases from solid tumors and 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. XGEVA is also indicated in the U.S. for the treat­ment of hypercalcemia of malig­nan­cy refractory to bis­phos­pho­nate ther­apy. XGEVA is not in­di­cated for the prevention of SREs in patients with multiple myeloma.

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.

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.

Important EU Product Safety Information

Special Warnings and Precautions: Pre-existing hypocalcaemia must be corrected prior to initiating ther­apy with XGEVA. Hypocalcaemia can occur at any time during ther­apy. Monitor cal­cium prior to initial dose, within two weeks of initial dose and if sus­pected symp­toms of hypocalcaemia occur. Severe symp­to­matic hypocalcaemia has been reported. Consider addi­tional monitoring of cal­cium level in patients with risk factors for hypocalcaemia or if other­wise indicated based on clin­i­cal con­di­tion of the patient. If hypo­cal­caemia occurs while receiving XGEVA, addi­tional cal­cium supple­mentation and addi­tional monitoring may be nec­es­sary.

Patients with severe renal im­pair­ment (creatinine clearance < 30ml/min) or receiving dialysis are at greater risk of devel­op­ing hypocalcaemia; this risk and accompanying elevations in parathyroid hormone in­­creases with in­creas­ing degree of renal im­pair­ment. Regular monitoring of cal­cium levels in these patients is especially im­por­tant.

Osteonecrosis of the jaw (ONJ) has occurred commonly in patients treated with XGEVA. Delay treat­ment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assess­ment is recommended prior to treat­ment. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to main­tain good oral hygiene, receive routine dental check-ups and im­medi­ately report oral symp­toms during treat­ment with XGEVA. While on treat­ment, in­­vasive dental procedures should be per­formed only after careful con­sid­er­a­tion and avoided in close proximity to XGEVA admin­istra­tion. The man­agement plan of patients who develop ONJ should be set up in close col­lab­o­ration be­tween the treating physician and a dentist or oral surgeon with expertise in ONJ.

Atypical femoral fracture (AFF) has been reported in patients receiving XGEVA. Discontinuation of XGEVA ther­apy in patients sus­pected to have AFF should be con­sidered pending evaluation of the patient based on an individual benefit risk assess­ment. XGEVA is not recommended in patients with growing skeletons. Clinically sig­nif­i­cant hypercalcaemia has been reported in XGEVA-treated patients with growing skeletons weeks to months fol­low­ing treat­ment dis­con­tinu­a­tion. Patients being treated with XGEVA should not be treated concomitantly with other denosumab con­taining medicinal prod­ucts (for osteoporosis indi­ca­tions) or with bis­phos­pho­nates. Patients with rare hereditary problems of fructose intolerance should not use XGEVA.

Adverse reac­tions in patients receiving XGEVA to prevent the occurrence of skeletal related events: very common (≥ 1/10) dyspnea, diarrhea and musculo­skeletal pain; common (≥ 1/100 to < 1/10) hypo­cal­caemia, hypo­phos­phatemia, tooth extraction, hyper­hidrosis and osteo­necrosis of the jaw; rare (≥ 1/10,000 to < 1/1000) drug hypersensitivity, anaphylactic reac­tion, atypical femoral fracture. In three phase III clin­i­cal trials, ONJ was con­firmed in 1.8% of patients treated with XGEVA and 1.3% of patients treated with zole­dronic acid (primary treat­ment phase). Among subjects with con­firmed ONJ, most (81% in both treat­ment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. Hypo­cal­caemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zole­dronic acid. Neutralizing anti­bodies have not been observed in clin­i­cal studies. In the post­market­ing setting, severe symp­tomatic hypo­cal­caemia (in­clud­ing fatal cases), hypersensitivity (in­clud­ing rare events of anaphylactic reac­tion) and musculo­skeletal pain (in­clud­ing severe cases) have been reported. Please consult the SmPC for a full description of undesirable effects.

Contraindications: Severe, untreated hypocalcaemia; hypersensitivity to the active substance or to any of the excipients; unhealed lesions from dental or oral surgery.

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

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 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. 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 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 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.

The scientific in­­for­ma­tion discussed in this news release relating to new indi­ca­tions for our prod­ucts is pre­lim­i­nary and investigative and is not part of the labeling approved by the U.S. Food and Drug Admin­istration for the prod­ucts. The prod­ucts are not approved for the inves­ti­ga­tional use(s) discussed in this news release, and no conclusions can or should be drawn re­gard­ing the safety or effectiveness of the prod­ucts for these uses.

References:

1. Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalence in 2012. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed April 3, 2017.
2. Multiple Myeloma Research Foundation. What is Multiple Myeloma? https://www.themmrf.org/multiple-myeloma/what-is-multiple-myeloma/. Accessed April 3, 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 April 3, 2017.
5. 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.
6. Amgen Data on File.
7. Drake MT. Bone disease in multiple myeloma. Oncology (Williston Park). 2009;23(14 Suppl 5):28-32.

Source: Amgen.