Filing Based on Data From Phase 3 Head-To-Head ENDEAVOR Study

Relapsed Multiple Myeloma Patients Treated With Kyprolis in Study Lived Twice as Long Without Disease Worsening

{{image}}Thousand Oaks, CA (Press Release) – Amgen (NASDAQ:AMGN) today announced the sub­mission of a supple­mental New Drug Application (sNDA) to the U.S. Food and Drug Admin­istra­tion (FDA) for Kyprolis® (car­filz­o­mib) for Injection to seek an expanded indi­ca­tion for the treat­ment of patients with a form of blood cancer, re­lapsed multiple myeloma, who have received at least one prior ther­apy. Kyprolis cur­rently has accelerated approval in the U.S. for the treat­ment of patients with re­lapsed multiple myeloma as a mono­ther­a­py.

The sNDA is based on data from the global Phase 3 ENDEAVOR trial. The ENDEAVOR study is the first of two head-to-head Phase 3 trials of Kyprolis versus Velcade (bor­tez­o­mib). Relapsed multiple myeloma patients treated with Kyprolis and dexa­meth­a­sone in the ENDEAVOR study lived twice as long without their disease worsening, demonstrating statistically and clin­i­cally sig­nif­i­cant superiority over Velcade (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).

"Submission of this new sNDA for Kyprolis is im­por­tant because if approved, it will mean more treat­ment options for patients with this serious disease. Multiple myeloma 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," said Sean E. Harper, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "The ENDEAVOR study showed that patients who had failed at least one prior ther­apy were half as likely to see their disease worsen if they received Kyprolis. This is yet another data set that illustrates Kyprolis' poten­tial to extend the time patients live without their disease progressing and im­prove the depth and duration of a response."

The Kyprolis com­bi­na­tion dem­onstrated superiority over the Velcade com­bi­na­tion for sec­ond­ary objectives of higher over­all response rate and lower neu­rop­athy events. Overall survival data are not yet mature and con­tinue to be monitored.

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 Velcade arm. There was also an in­­crease in the incidence of hyper­tension and dyspnea in the Kyprolis arm compared to Velcade in ENDEAVOR and than that observed in the ASPIRE study.

Based on the Phase 3 ASPIRE study Amgen con­tinues to work with the FDA on the related sNDA in the U.S. and with the European Union (EU) regu­la­tory author­i­ties for the Marketing Authorization Application for Kyprolis. Following poten­tial approval based on the ASPIRE study, Amgen plans to submit ENDEAVOR for poten­tial authori­za­tion in the EU.

Kyprolis Head-to-Head Studies

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 dexa­meth­a­sone, versus Velcade with 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 along with dexa­meth­a­sone (20 mg). Administer Kyprolis at a starting dose of 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to a target dose of 56 mg/m² on Day 8 of Cycle 1. Patients were kept at 56 mg/m² on days 9, 15 and 16 on a 28 day cycle. Patients who tolerated 56 mg/m² in Cycle 1 were kept at this dose for sub­se­quent cycles on days 1, 2, 8, 9, 15 and 16 on a 28 day cycle. Patients who received Velcade (1.3 mg/m²) with dexa­meth­a­sone (20 mg) were ad­min­is­tered Velcade sub­cu­tane­ously or in­tra­venously at the discretion of the investigator and in accordance with regu­la­tory approval of Velcade. More than 75 per­cent of the patients in the control arm received Velcade sub­cu­tane­ous­ly. This study was conducted at 235 sites world­wide. For in­­for­ma­tion about this trial, please visit www.clinicaltrials.gov under trial identi­fi­ca­tion number NCT01568866.

Kyprolis is also being eval­u­ated in the CLARION study, a head-to-head Phase 3 multi­center, open-label, ran­dom­ized study in trans­plant-ineligible patients with newly diag­nosed multiple myeloma. The study is eval­u­ating the safety and efficacy of car­filz­o­mib, mel­phalan and pred­ni­sone versus bor­tez­o­mib, mel­phalan and pred­ni­sone. For in­­for­ma­tion about this trial, please visit www.clinicaltrials.gov under trial identi­fi­ca­tion number NCT01818752.

About Multiple Myeloma

Multiple myeloma is the second most common hema­to­logic cancer.¹ In the U.S., there are nearly 96,000 people living with, or in remission from, multiple myeloma.2 The esti­mated number of new cases of multiple myeloma in 2014 was more than 24,000 and the esti­mated number of deaths was 11,090.²

About Kyprolis® (car­filz­o­mib) for Injection

Kyprolis® (car­filz­o­mib) for Injection is indicated 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, Mexico and Thailand. For more in­­for­ma­tion about Kyprolis, visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis® (car­filz­o­mib) for Injection

This safety in­­for­ma­tion is specific to the current U.S. approved indi­ca­tion, which is based on Phase 2 studies.

Safety data have been eval­u­ated in 526 patients with re­lapsed and/or refractory multiple myeloma who re­ceived single-agent Kyprolis. There were 37 deaths in the Phase 2 studies, or 7 per­cent of patients. The most common causes of death, other than disease pro­gres­sion, were cardiac (5 patients), end-organ failure (4 patients) and in­fec­tion (4 patients). Important warnings and precautions in­clude cardiac arrest, congestive heart failure, myo­cardial ischemia, pul­mo­nary hyper­tension, pul­mo­nary com­pli­ca­tions, infusion reac­tions, tumor lysis syn­drome, thrombo­cytopenia, hepatic toxicity and embryo-fetal toxicity.

Death due to cardiac arrest has occurred within a day of Kyprolis admin­istra­tion. Patients with New York Heart Association Class III and IV heart failure, myo­cardial infarction in the preceding 6 months and con­duc­tion ab­nor­mal­i­ties uncontrolled by medications were not eli­gible for the clin­i­cal trials. These patients may be at greater risk for cardiac com­pli­ca­tions.

Pulmonary arterial hyper­tension (PAH) was reported in 2 per­cent of patients treated with Kyprolis and was Grade 3 or greater in less than 1 per­cent of patients. Dyspnea was reported in 35 per­cent of patients enrolled in clin­i­cal trials. Grade 3 dyspnea occurred in 5 per­cent; no Grade 4 events and 1 death (Grade 5) was re­ported.

Infusion reac­tions, char­ac­ter­ized by a spectrum of systemic symp­toms in­­clud­ing fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypo­­tension, syncope, chest tightness, or angina can occur im­medi­ately fol­low­ing or up to 24 hours after admin­istra­tion of Kyprolis. Ad­min­is­tra­tion of dexa­meth­a­sone prior to Kyprolis reduces the incidence and severity of reac­tions. Tumor lysis syn­drome (TLS) occurred fol­low­ing Kyprolis admin­istra­tion in <1 per­cent of patients. Patients with multiple myeloma and a high tumor burden should be con­sidered to be at greater risk for TLS.

Thrombocytopenia fol­low­ing Kyprolis admin­istra­tion resulted in a dose reduction in 1 per­cent of patients and dis­con­tinu­a­tion of treat­ment with Kyprolis in <1 per­cent of patients.

Cases of hepatic failure, in­­clud­ing fatal cases, have been reported (<1 per­cent). Kyprolis can cause ele­va­tions of serum transaminases and bilirubin.

Cases of thrombotic thrombocytopenic purpura/hemolytic uremic syn­drome (TTP/HUS) in­­clud­ing fatal out­come have been reported. Treatment with Kyprolis should be dis­con­tinued if signs and symp­toms of TTP/​HUS occur.

Cases of posterior reversible encephalopathy syn­drome (PRES) have been reported. Treatment with Kyprolis should be dis­con­tinued if PRES is sus­pected.

There are no adequate and well-controlled studies in pregnant women using Kyprolis. Females of re­pro­duc­tive poten­tial should be advised to avoid becoming pregnant while being treated with Kyprolis.

The most common serious adverse reac­tions were pneu­monia, acute renal failure, pyrexia and congestive heart failure. The most common adverse reac­tions (incidence of 30 per­cent or greater) observed in clin­i­cal trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombo­cytopenia, dyspnea, diarrhea and pyrexia. Serious adverse reac­tions were reported in 45 per­cent of patients.

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

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1. Dimopoulos, MA and Terpos E. Multiple Myeloma. Annals of Oncology 21 (Supplement 7): vii143–vii150, 2010.
2. Leukemia & Lymphoma Society. Facts 2014-2015. Available at: http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/pdf/facts.pdf Accessed July 2015.

Source: Amgen.