Pivotal Head-to-Head ENDEAVOR Study Shows Kyprolis Plus Dexamethasone Doubled Progression-Free Survival Compared to Velcade® (Bortezomib) and Dexamethasone

Thousand Oaks, CA (Press Release) – Amgen (NASDAQ:AMGN) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted a positive opinion to extend the current indi­ca­tion for Kyprolis® (car­filz­o­mib) to in­clude treat­ment in com­bi­na­tion with dexa­meth­a­sone alone for adult patients with multiple myeloma who have received at least one prior ther­apy.

"In the first ever comparative Phase 3 head-to-head study of two pro­te­a­some inhibitors in re­lapsed multiple myeloma, Kyprolis in com­bi­na­tion with dexa­meth­a­sone nearly doubled pro­gres­sion-free survival compared to a current standard of care regi­men," said Sean E. Harper, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "We are pleased that the CHMP has recog­nized these robust data with a positive opinion, and we look forward to ensuring approval of this extended indi­ca­tion of Kyprolis."

The CHMP positive opinion is based on data 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) of 18.7 months compared to 9.4 months in those receiving Velcade® (bor­tez­o­mib) plus dexa­meth­a­sone, (HR=0.53; 95 per­cent CI: 0.44,0.65 p<0.0001). The most common adverse reac­tions that occurred in greater than 20 per­cent of patients in the Kyprolis arm were anemia, fatigue, diarrhea, thrombo­cyto­penia, nausea, pyrexia, dyspnea, res­pira­tory tract in­fec­tion, cough and periph­eral edema.

The CHMP positive opinion will now be reviewed by the European Com­mis­sion (EC) and if granted, the market­ing authori­za­tion will be extended to in­clude Kyprolis in com­bi­na­tion with dexa­meth­a­sone in the 28 member countries of the European Union, as well as Iceland, Lichtenstein and Norway. The extended indi­ca­tion adopted by the CHMP is: Kyprolis in com­bi­na­tion with either lena­lido­mide and dexa­meth­a­sone or dexa­metha­sone alone is indicated for the treat­ment of adult patients with multiple myeloma who have received at least one prior ther­apy.

The EC pre­vi­ously granted market­ing authori­za­tion 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 based on results of the ASPIRE study in November 2015. Today's CHMP positive opinion follows the U.S. Food and Drug Admin­istra­tion's approval of a supple­mental New Drug Application based on the ENDEAVOR results in January 2016.

About Multiple Myeloma

Multiple myeloma is 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 world­wide.^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.⁵

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.⁶

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.⁷ Kyprolis has been shown to block pro­te­a­somes, leading to an excessive build-up of proteins within cells.7 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.^7,8

Kyprolis is approved in the U.S. for the fol­low­ing:

• In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
• As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, Russia and the European Union. Additional regu­la­tory appli­ca­tions for Kyprolis are underway and have been submitted to health author­i­ties world­wide.

For more in­­for­ma­tion, please visit www.kyprolis.com.

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. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of KYPROLIS administration.
• Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart KYPROLIS at 1 dose level reduction based on a benefit/risk assessment.
• While 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, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure and fluid management) prior to starting treatment with KYPROLIS and remain under close follow-up.

Acute Renal Failure

• Cases of acute renal failure and renal insufficiency adverse events (including 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. 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 for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient's underlying risks.
• Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with KYPROLIS in combination with dexamethasone or lenalidomide plus dexamethasone.

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 regardless of baseline values. Reduce or withhold dose as appropriate.

Thrombotic Microangiopathy

• Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (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. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.

ADVERSE REACTIONS

• The most common adverse reactions occurring in at least 20% of patients treated with KYPROLIS in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.

The most common adverse reac­tions occurring in at least 20% of patients treated with KYPROLIS in mono­therapy trials: anemia, fatigue, thrombo­cytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema periph­eral.

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 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. 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 or the European Medicines Agency 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. 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 May 9, 2016.
3. American Cancer Society. Multiple myeloma. http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Accessed on: May 9, 2016.
4. Palumbo A and Anderson K, Multiple myeloma, N Engl J Med,2011;364:1046–60
5. GLOBCAN 2012, Global Prevalence and Incidence, available at http://globocan.iarc.fr/Pages/fact_sheets_population.aspx, accessed on, May 10, 2016.
6. FDA.gov. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics.http://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf. Accessed on May 10, 2016.
7. Moreau P, Richardson PG, Cavo M, et al. Proteasome Inhibitors in Multiple Myeloma: 10 Years Later. Blood. 2012; 120(5):947-959.
8. Kortuem KM and Stewart AK. Carfilzomib. Blood. 2012; 121(6):893-897.

Source: Amgen.