Application Based on Phase 3 Head-to-Head Trial Showing Superiority of Kyprolis and Dexamethasone Over Bortezomib Plus Dexamethasone

{{image}}Thousand Oaks, CA (Press Release) – Amgen (NASDAQ: AMGN) today announced the U.S. Food and Drug Admin­istra­tion (FDA) has accepted for priority review the supple­mental New Drug Application (sNDA) of Kyprolis^® (car­filz­o­mib) for Injection for patients with re­lapsed multiple myeloma. The sNDA is designed to expand the current indi­ca­tion to in­clude Kyprolis in com­bi­na­tion with dex­a­meth­a­sone for patients who have received at least one prior ther­apy. The Prescription Drug User Fee Act (PDUFA) target action date is Jan. 22, 2016.

The FDA's acceptance of this new sNDA for Kyprolis follows the recent FDA approval for Kyprolis in com­bi­na­tion with Revlimid® (lena­lido­mide) and dex­a­meth­a­sone for the treat­ment of patients with re­lapsed multiple myeloma who have received one to three prior lines of ther­apy.

Multiple myeloma is a rare and complex blood cancer that has historically been one of the most dif­fi­cult to treat diseases because of the in­her­ent complexities related to the recurring pattern of remission and relapse. Patients face poor out­comes, which worsen with each relapse.

"Clinicians need a range of options and robust clin­i­cal data to make informed choices that can ideally extend the time patients live without their cancer progressing," said Sean E. Harper, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "The acceptance of this sub­mission is an im­por­tant next step to­ward providing more options for patients with re­lapsed multiple myeloma and we look forward to work­ing with the FDA over the coming months."

The appli­ca­tion is based on data from the Phase 3 head-to-head ENDEAVOR study, which showed that patients with re­lapsed multiple myeloma treated with Kyprolis and low-dose dex­a­meth­a­sone lived twice as long without their disease worsening, demonstrating statistically and clin­i­cally sig­nif­i­cant superiority over bor­tez­o­mib and low-dose dex­a­meth­a­sone (median pro­gres­sion-free survival [PFS] 18.7 months versus 9.4 months, HR=0.53, 95 per­cent CI, 0.44 – 0.65; p<0.0001).

Treatment dis­con­tinu­a­tion due to adverse events and on-study deaths was com­parable be­tween the two arms. The rates of cardiac failure and renal failure for Kyprolis were com­parable to those observed in the Phase 3 ASPIRE study. In ENDEAVOR, the rates for cardiac and renal failure were higher in the Kyprolis arm versus the bor­tez­o­mib arm. There was also an in­­crease in the incidence of hyper­tension and dyspnea in the Kyprolis arm compared to bor­tez­o­mib in ENDEAVOR.

Priority review is assigned to appli­ca­tions for drugs that treat serious con­di­tions and would, if approved, provide sig­nif­i­cant im­prove­ments in the safety or effectiveness of the treat­ment, diag­nosis or prevention of serious con­di­tions.

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.

Patients received Kyprolis as a 30-minute infusion on two consecutive days, each week for three weeks followed by a 12 day rest period. Kyprolis was admin­istered 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 Multiple Myeloma

Multiple myeloma is the second most common hema­to­logic cancer and results from an ab­nor­mal­ity of plasma cells, usually in the bone marrow.^1,2 Worldwide, nearly 230,000 people are living with multiple myeloma and approx­i­mately 114,000 new cases are diag­nosed annually.³ In the U.S., there are nearly 96,000 people living with, or in remission from, multiple myeloma. The esti­mated number of new cases of multiple myeloma in 2014 was more than 24,000 in the U.S. and the esti­mated number of deaths was 11,090.⁴ In Europe, approx­i­mately 89,000 people are living with the disease and in 2012 there was an esti­mated 39,000 newly diag­nosed cases and 24,000 deaths.³

About Kyprolis^® (car­filz­o­mib) for Injection

Kyprolis^® (car­filz­o­mib) for Injection received approval from the U.S. FDA in July 2015 for 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 in July 2012 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. Kyprolis is also approved for use in Argentina, Israel, Kuwait, Mexico and Thailand. For more in­­for­ma­tion about Kyprolis, visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis® (car­filz­o­mib) for Injection

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 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) 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 Amgen's business. Unless other­wise noted, Amgen is providing this in­­for­ma­tion as of Sept. 18, 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 Amgen projects. 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 Amgen and its partners to com­plete clin­i­cal trials and obtain regu­la­tory approval for prod­uct market­ing has in the past varied and Amgen ex­pec­ts similar variability in the future. Amgen develops 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 Amgen may have believed at the time of entering into such rela­tion­ship. Also, Amgen or others could identify safety, side effects or manu­fac­tur­ing problems with Amgen's prod­ucts after they are on the market. Amgen's business may be impacted by gov­ern­ment in­ves­ti­ga­tions, litigation and prod­uct liability claims. If Amgen fails to meet the compliance obli­ga­tions in the corporate integrity agree­ment be­tween Amgen and the U.S. gov­ern­ment, Amgen could become subject to sig­nif­i­cant sanctions. Amgen depends on third parties for a sig­nif­i­cant portion of its manu­fac­tur­ing capacity for the supply of certain of its current and future prod­ucts and limits on supply may constrain sales of certain of its current prod­ucts and prod­uct can­di­date devel­op­ment.

In addi­tion, sales of Amgen's prod­ucts (including prod­ucts of Amgen's wholly-owned sub­sid­i­aries) are affected by the 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 as well as U.S. legislation affecting pharma­ceu­tical pricing and reim­burse­ment. Government and others' reg­u­la­tions and reim­burse­ment policies may affect the devel­op­ment, usage and pricing of Amgen's prod­ucts. In addi­tion, Amgen competes with other com­pa­nies with respect to some of its marketed prod­ucts as well as for the discovery and devel­op­ment of new prod­ucts. Amgen believes that some of its newer prod­ucts, prod­uct can­di­dates or new indi­ca­tions for existing prod­ucts, may face com­pe­ti­tion when and as they are approved and marketed. Amgen's prod­ucts may compete against prod­ucts that have lower prices, estab­lish­ed reim­burse­ment, superior per­for­mance, are easier to admin­ister, or that are other­wise competitive with its prod­ucts. In addi­tion, while Amgen and its partners routinely obtain patents for their prod­ucts and tech­nology, the protection of Amgen's prod­ucts offered by patents and patent appli­ca­tions may be chal­lenged, invalidated or circumvented by its com­pet­i­tors and there can be no guar­an­tee of Amgen's or its partners' ability to obtain or main­tain patent protection for Amgen's prod­ucts or prod­uct can­di­dates. Amgen cannot guar­an­tee that it will be able to produce commercially suc­cess­ful prod­ucts or main­tain the commercial success of its existing prod­ucts. Amgen's stock price may be affected by actual or perceived market oppor­tu­ni­ty, competitive position and success or failure of its prod­ucts or prod­uct can­di­dates. Further, the discovery of sig­nif­i­cant problems with a prod­uct similar to one of Amgen's prod­ucts that implicate an entire class of prod­ucts could have a ma­teri­al adverse effect on sales of the affected prod­ucts and on Amgen's business and results of operations. Amgen's efforts to integrate the operations of com­pa­nies it has acquired may not be suc­cess­ful. Amgen may ex­peri­ence dif­fi­culties, delays or unexpected costs and not achieve antic­i­pated cost savings from its ongoing restructuring plan. Amgen's business per­for­mance could affect or limit the ability of Amgen's Board of Directors to declare a dividend or their ability to pay a dividend or repurchase Amgen common stock.

The scientific in­­for­ma­tion discussed in this news release relating to new indi­ca­tions for Amgen's 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.

Kyprolis^® is a registered trademark of Onyx Pharma­ceu­ticals, Inc., an Amgen Inc. sub­sid­i­ary.

Revlimid^® is registered trademark of Celgene Corpo­ra­tion.

References

1. Dimopoulos, MA. Multiple Myeloma. Annals of Oncology 21 (Supplement 7): vii143–vii150, 2010.
2. National Cancer Institute. Surveillance, Epidemiology, and End Results Program Turning Cancer Data Into Discovery. http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed Sept. 2015.
3. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/. Accessed Sept. 2015.
4. Leukemia & Lymphoma Society. Facts 2014-2015. http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf. Accessed Sept. 2015.

Source: Amgen.