Application Based on Pivotal Head-to-Head ENDEAVOR Study Showing Kyprolis Plus Dexametha­sone Doubled Progression-Free Survival Compared to Velcade^® (Bortezomib) Plus Dexamethasone

Thousand Oaks, CA (Press Release) – Amgen (NASDAQ: AMGN) today announced the sub­mission to the European Medicines Agency (EMA) of a Variation to the Marketing Authorization Application (MAA) to expand the indi­ca­tion for Kyprolis^® (car­filz­o­mib) in com­bi­na­tion with dexa­metha­sone for the treat­ment of adult patients with multiple myeloma who have received at least one prior ther­apy.

The appli­ca­tion is based on results from the Phase 3 head-to-head ENDEAVOR study in which patients with multiple myeloma treated with Kyprolis plus dexa­metha­sone achieved superior pro­gres­sion-free survival (PFS) compared to those receiving Velcade® (bor­tez­o­mib) plus dexa­metha­sone (18.7 versus 9.4 months, re­spec­tive­ly) (p<0.0001). The most common adverse events (greater than 25 per­cent) in the Kyprolis arm were diarrhea, anemia, fatigue, dyspnea, pyrexia and insomnia.

"Physicians need options to personalize treat­ment for complicated diseases like multiple myeloma," said Sean E. Harper, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "We look forward to con­tinued discussions with health author­i­ties with the goal of bringing new Kyprolis-based regi­mens to patients in Europe."

The European Com­mis­sion (EC) recently granted market­ing authori­za­tion fol­low­ing accelerated assess­ment for Kyprolis in com­bi­na­tion with lena­lido­mide and dexa­metha­sone for the treat­ment of adult patients with multiple myeloma who have received at least one prior ther­apy.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer, char­ac­ter­ized by a recurring pattern of remission and re­lapse.¹ It is a rare and very aggressive orphan disease that accounts for approx­i­mately one per­cent of all cancers.^2-4 In Europe, approx­i­mately 39,000 patients are diag­nosed with multiple myeloma each year and 24,000 patient deaths are reported on an annual basis.²

About ENDEAVOR

The ran­dom­ized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExa­methA­sone Vs Bortezomib Plus Dexa­metha­sOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients eval­u­ated Kyprolis in com­bi­na­tion with low-dose dexa­metha­sone, versus bor­tez­o­mib with low-dose dexa­metha­sone in patients whose multiple myeloma has re­lapsed after at least one, but not more than three prior thera­peutic regi­mens. The pri­mary end­point of the trial was PFS, defined as the time from treat­ment initiation to disease pro­gres­sion or death. In a clin­i­cal trial, measuring the PFS is one way to dem­onstrate how well a treat­ment works.

The superiority of the Kyprolis com­bi­na­tion compared to the bor­tez­o­mib com­bi­na­tion with respect to PFS was seen across key pre-specified subgroups, in­clud­ing bor­tez­o­mib-naïve patients, those with high- or standard-risk cytogenetics and with or without prior trans­plan­ta­tion. The Kyprolis com­bi­na­tion also dem­onstrated superiority over the bor­tez­o­mib com­bi­na­tion for sec­ond­ary end­points, achieving a higher over­all response rate (76.9 per­cent versus 62.6 per­cent; p<0.0001) and lower rate of grade 2 or higher neu­rop­athy events (6 per­cent versus 32 per­cent; p<0.0001). Treatment with the Kyprolis com­bi­na­tion resulted in a two-fold in­crease in the median duration of response (21.3 months) compared to the bor­tez­o­mib com­bi­na­tion (10.4 months).

In the Kyprolis and bor­tez­o­mib groups, 54.3 per­cent and 28.6 per­cent of patients achieved a very good partial response or better (p<0.0001), and 12.5 per­cent and 6.2 per­cent of patients achieved a com­plete response or better (p<0.0001), re­spec­tive­ly. Overall survival data are not yet mature and con­tinue to be monitored.

Treatment dis­con­tinu­a­tion due to adverse events and on-study deaths were com­parable be­tween the two arms. A number of known adverse drug reac­tions were reported at a higher rate in the Kyprolis group com­pared with the bor­tez­o­mib group, in­clud­ing any-grade dyspnea, hyper­tension, pyrexia, and cough (pre­ferred terms) as were any-grade cardiac failure (grouped term; 8.2 per­cent versus 2.9 per­cent) and acute renal failure (grouped term; 8.2 per­cent versus 4.8 per­cent). The rates of cardiac and renal failure for Kyprolis were com­parable to those observed in pre­vi­ous Phase 3 ASPIRE study.

Rates of grade 3 or higher adverse events were 73.2 per­cent in the Kyprolis group and 66.9 per­cent in the bor­tez­o­mib group. Grade 3 or higher adverse events of interest in the Kyprolis and bor­tez­o­mib groups in­cluded hyper­tension (preferred term; 8.9 per­cent versus 2.6 per­cent), dyspnea (preferred term; 5.4 per­cent versus 2.2 per­cent), cardiac failure (grouped term; 4.7 per­cent versus 1.8 per­cent), acute renal failure (grouped term; 4.0 per­cent versus 2.6 per­cent), ischemic heart disease (grouped term; 1.7 per­cent versus 1.6 per­cent) and pul­mo­nary hyper­tension (grouped term; 0.6 per­cent versus 0.2 per­cent).

Patients received treat­ment until pro­gres­sion with Kyprolis as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of 28 day treat­ment cycles, along with low-dose dexa­metha­sone (20 mg). For Cycle 1 only, Kyprolis was admin­istered at 20 mg/m2 on days 1 and 2, followed by escalation to 56 mg/m2 from day 8. Patients who tolerated 56 mg/m2 in Cycle 1 were kept at this dose for sub­se­quent cycles. Patients who received bor­tez­o­mib (1.3 mg/m2) with low-dose dexa­metha­sone (20 mg) were admin­istered bor­tez­o­mib sub­cu­tane­ously or in­tra­venously at the discretion of the investigator and in accordance with regu­la­tory approval of bor­tez­o­mib. More than 75 per­cent of the patients in the control arm re­ceived bor­tez­o­mib sub­cu­taneously. This study was conducted at 235 sites world­wide. For in­­for­ma­tion about this trial, please visit www.clinicaltrials.gov under trial identi­fi­ca­tion number NCT01568866.

About Kyprolis^® (car­filz­o­mib)

Proteasomes play an im­por­tant role in cell function and growth by breaking down proteins that are damaged or no longer needed.⁵ Kyprolis has been shown to block pro­te­a­somes, leading to an excessive build-up of proteins within cells.⁶ In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to con­tain a higher amount of ab­nor­mal proteins.⁶ The irreversibility of Kyprolis' binding has also been shown to offer a more sustained inhibition of the targeted enzymes.⁷

Kyprolis is cur­rently approved in the United States (U.S.), European Union, Argentina, Israel, Kuwait, Mexico, Thailand and Colombia. Additional regu­la­tory appli­ca­tions for Kyprolis are underway and have been submitted to health author­i­ties world­wide.

Kyprolis is approved in the U.S. in com­bi­na­tion with lena­lido­mide and dexa­metha­sone for the treat­ment of patients with multiple myeloma who have received one to three prior lines of ther­apy.

Kyprolis is also indicated under FDA accelerated approval as a single agent for the treat­ment of patients with multiple myeloma who have received at least two prior ther­a­pies in­clud­ing bor­tez­o­mib and an immuno­modu­la­tory agent and have dem­onstrated disease pro­gres­sion on or within 60 days of completion of the last ther­apy. Approval is based on response rate. Clinical benefit, such as im­prove­ment in survival or symp­toms, has not been verified.

Kyprolis is a prod­uct of Onyx Pharma­ceu­ticals, Inc. Onyx Pharma­ceu­ticals is a sub­sid­i­ary of Amgen and holds devel­op­ment and com­mer­cial­iza­tion rights to Kyprolis globally, excluding Japan.

Important EU Product Safety Information

This medicinal prod­uct is subject to addi­tional monitoring. This will allow quick identi­fi­ca­tion of new safety in­­for­ma­tion. Healthcare professionals are asked to report any sus­pected adverse reac­tions.

Kyprolis treat­ment should be supervised by a physician ex­peri­enced in the use of anti-cancer ther­apy. The most serious side effects that may occur during Kyprolis treat­ment in­clude: Cardiac toxicity, pul­mo­nary toxicities, pul­mo­nary hyper­tension, dyspnea, hyper­tension in­clud­ing hypertensive crises, acute renal failure, tumor lysis syn­drome, infusion reac­tions, thrombo­cytopenia, hepatic toxicity, posterior reversible en­ceph­a­lopathy syn­drome (PRES) and thrombotic thrombo­cytopenic purpura/hemolytic uremic syn­drome (TTP/HUS). The most common side effects are anemia, fatigue, diarrhea, thrombo­cytopenia, nausea, pyrexia, dyspnea, res­pira­tory tract in­fec­tion, cough and periph­eral edema.

Please refer to the Summary of Product Characteristics for full European pre­scrib­ing in­­for­ma­tion.

Important U.S. Product Safety Information

Cardiac Toxicities

New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pul­mo­nary edema, de­creased ejection fraction), restrictive cardio­myopathy, myo­cardial ischemia, and myo­cardial infarction in­clud­ing fatalities have occurred fol­low­ing admin­istra­tion of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis admin­istra­tion.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until re­cov­ery, and con­sider whether to restart Kyprolis based on a benefit / risk assess­ment.

Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evi­dence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clin­i­cally appro­pri­ate in patients with base­line cardiac failure or who are at risk for cardiac failure.

Patients > 75 years, the risk of cardiac failure is in­­creased. Patients with New York Heart Association Class III and IV heart failure, recent myo­cardial infarction, and conduction ab­nor­mal­i­ties may be at greater risk for cardiac com­pli­ca­tions.

Acute Renal Failure

Cases of acute renal failure and renal insufficiency adverse events (renal im­pair­ment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with ad­vanced re­lapsed and refractory multiple myeloma who received Kyprolis mono­therapy. This risk was greater in patients with a base­line reduced esti­mated creatinine clearance. Monitor renal function with regular mea­sure­ment of the serum creatinine and/or esti­mated creatinine clearance. Reduce or withhold dose as appro­pri­ate.

Tumor Lysis Syndrome

Cases of Tumor Lysis Syndrome (TLS), in­­clud­ing fatal out­comes, have occurred in patients receiving Kyprolis. Patients with multiple myeloma and a high tumor burden should be con­sidered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in sub­se­quent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evi­dence of TLS during treat­ment and man­age promptly. Withhold Kyprolis until TLS is resolved.

Pulmonary Toxicity

Acute Respiratory Distress Syndrome (ARDS), acute res­pira­tory failure, and acute diffuse in­fil­tra­tive pul­mo­nary disease such as pneu­mo­nitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pul­mo­nary toxicity, dis­con­tinue Kyprolis.

Pulmonary Hypertension

Pulmonary arterial hyper­tension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH until resolved or returned to base­line and con­sider whether to restart Kyprolis based on a benefit / risk assess­ment.

Dyspnea

Dyspnea was reported in patients treated with Kyprolis. Evaluate dyspnea to exclude car­dio­pul­mo­nary con­di­tions in­clud­ing cardiac failure and pul­mo­nary syn­dromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to base­line. Consider whether to restart Kyprolis based on a benefit / risk assess­ment.

Hypertension

Hypertension, in­clud­ing hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hyper­tension cannot be adequately controlled, withhold Kyprolis and eval­u­ate. Consider whether to restart Kyprolis based on a benefit / risk assess­ment.

Venous Thrombosis

Venous thrombo­embolic events (including deep venous thrombosis and pul­mo­nary embolism) have been observed with Kyprolis. Thrombo­pro­phylaxis is recommended and should be based on an assess­ment of the patient's under­lying risks, treat­ment regi­men, and clin­i­cal status.

Infusion Reactions

Infusion reac­tions, in­­clud­ing life-threatening reac­tions, have occurred in patients receiving Kyprolis. Symp­toms in­clude fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, short­ness of breath, hypo­tension, syncope, chest tightness, or angina. These reac­tions can occur immedi­ate­ly fol­low­ing or up to 24 hours after admin­istra­tion of Kyprolis. Pre­medicate with dexa­metha­sone to reduce the incidence and severity of infusion reac­tions. Inform patients of the risk and of symp­toms of an infusion reac­tion and to contact a physician immedi­ately if they occur.

Thrombocytopenia

Kyprolis causes thrombo­cyto­penia with re­cov­ery to base­line platelet count usually by the start of the next cycle. Thrombo­cyto­penia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treat­ment with Kyprolis. Reduce or withhold dose as appro­pri­ate.

Hepatic Toxicity and Hepatic Failure

Cases of hepatic failure, in­­clud­ing fatal cases, have been reported during treat­ment with Kyprolis. Kyprolis can cause in­­creased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appro­pri­ate.

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome (TTP/HUS)

Cases of TTP/HUS in­­clud­ing fatal out­come have occurred in patients receiving Kyprolis. Monitor for signs and symp­toms of TTP/HUS. Discontinue Kyprolis if diag­nosis is sus­pected. If the diag­nosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of re­initiating Kyprolis ther­apy in patients pre­vi­ously experiencing TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leuko­en­ceph­alopathy Syndrome. Consider a neuro-radiological imaging (MRI) for onset of visual or neurological symp­toms. Discontinue Kyprolis if PRES is sus­pected and eval­u­ate. The safety of re­initiating Kyprolis ther­apy in patients pre­vi­ously experiencing PRES is not known.

Embryo-fetal Toxicity

Kyprolis can cause fetal harm when admin­istered to a pregnant woman based on its mech­a­nism of action and findings in animals.

Females of reproductive poten­tial should be advised to avoid becoming pregnant while being treated with Kyprolis and the poten­tial hazard to the fetus if Kyprolis is used during pregnancy.

ADVERSE REACTIONS

The most common adverse events occurring in at least 20% of patients treated with Kyprolis in mono­therapy trials: anemia, fatigue, thrombo­cyto­penia, nausea, pyrexia, de­creased platelets, dyspnea, diarrhea, de­creased lym­pho­cyte, headache, de­creased hemoglobin, cough, edema periph­eral.

The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the com­bi­na­tion ther­apy trial: de­creased lym­pho­cytes, de­creased absolute neu­tro­phil count, de­creased phosphorus, anemia, neu­tro­penia, de­creased total white blood cell count, de­creased platelets, diarrhea, fatigue, thrombo­cyto­penia, pyrexia, muscle spasm, cough, upper res­pira­tory tract in­fec­tion, de­creased hemoglobin, hypo­kalemia.

Full pre­scrib­ing in­­for­ma­tion for the U.S. is avail­able at www.kyprolis.com.

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 the current ex­pec­ta­tions and beliefs of Amgen Inc. and its sub­sid­i­aries (Amgen, we or us) 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 Inc., in­clud­ing Amgen Inc.'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 Inc.'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 Dec. 5, 2015, and expressly disclaims any duty to update in­­for­ma­tion con­tained in this news release.

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References

1. Jakubowiak A. Management Strategies for Relapsed/Refractory Multiple Myeloma: Current Clinical Perspectives. Seminars in Hematology. 2012; 49(3)(1),S16-S32.
2. GLOBCAN 2012, Global Prevalence and Incidence, available at http://globocan.iarc.fr/old/summary_table_pop_prev.asp?selection=224900&title=World&sex=0&window=1&sort=0&submit=%C2%A0Execute%C2%A0, accessed on March 9, 2015.
3. American Cancer Society. Multiple myeloma. http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Accessed on: October 30, 2015.
4. Palumbo A and Anderson K, Multiple myeloma, N Engl J Med,2011;364:1046–60
5. Moreau P, Richardson PG, Cavo M, et al. Proteasome Inhibitors in Multiple Myeloma: 10 Years Later. Blood. 2012; 120(5):947-959.
6. Kyprolis® [package insert]. Thousand Oaks, CA: Amgen; 2015.
7. Kortuem KM and Stewart AK. Carfilzomib. Blood. 2012; 121(6):893-897.

Source: Amgen.