On December 5, 2015 Amgen (NASDAQ:AMGN) reported that The Lancet Oncology published results from the pivotal Phase 3 head-to-head ENDEAVOR study comparing Kyprolis (carfilzomib) plus dexamethasone to Velcade (bortezomib) plus dexamethasone in patients with relapsed multiple myeloma (Press release, Amgen, DEC 5, 2015, View Source;p=RssLanding&cat=news&id=2120388 [SID:1234508408]). The data showed that patients treated with Kyprolis plus dexamethasone achieved progression-free survival (PFS) of 18.7 months compared to 9.4 months in those receiving bortezomib plus dexamethasone (HR=0.53; 95 percent CI: 0.44,0.65 p<0.0001), a current standard of care in relapsed multiple myeloma.

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These findings demonstrate that patients with relapsed multiple myeloma treated with Kyprolis lived twice as long without disease worsening as those treated with bortezomib. The most common adverse events (greater than 25 percent) in the Kyprolis arm were diarrhea, anemia, fatigue, dyspnea, pyrexia and insomnia. Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms.

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"In this head-to-head comparison, carfilzomib plus dexamethasone resulted in a twofold decrease in the risk of progression or death, compared with bortezomib plus dexamethasone, a result that was consistent regardless of age or prior bortezomib exposure," said study co-author and investigator, Meletios A. Dimopoulos, M.D., professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine. "For patients with multiple myeloma, these results are clinically meaningful and translate to more than nine months without disease progression."

"Coupled with results previously seen in the ASPIRE pivotal trial, data from the ENDEAVOR study support the use of Kyprolis as a backbone therapy for the management of relapsed multiple myeloma, a difficult-to-treat blood cancer," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This is an important publication because it provides clinical evidence of Kyprolis’ potential to extend the time patients live without their disease progressing and improve the depth and duration of a response."

Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse, and while new therapies have become available, a significant unmet need still remains for patients no longer responding to treatment.1,2 Multiple myeloma is an orphan disease and accounts for approximately one percent of all cancers.3,4

Regulatory Status
Data from the ENDEAVOR study are the basis of the supplemental New Drug Application (sNDA) of Kyprolis in combination with dexamethasone for patients with relapsed multiple myeloma. The sNDA was accepted Sept.19, 2015, for priority review by the U.S. Food and Drug Administration (FDA) and the Prescription Drug User Fee Act (PDUFA) target action date is Jan. 22, 2016. 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. Amgen also just announced submission of the ENDEAVOR data to the European Commission for potential authorization of Kyprolis in combination with dexamethasone in the European Union.

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.5

The superiority of the Kyprolis combination compared to the bortezomib combination with respect to PFS was seen across all pre-specified subgroups, including Velcade-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 vs. 62.6 percent; p<0.0001) and lower rate of grade 2 or higher neuropathy events (6 percent vs. 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 vs. 2.9 percent) and acute renal failure (grouped term; 8.2 percent vs. 4.8 percent). However, the rates of cardiac and renal failure for Kyprolis were comparable to those observed in the 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 vs. 2.6 percent), dyspnea (preferred term; 5.4 percent vs. 2.2 percent), cardiac failure (grouped term; 4.7 percent vs. 1.8 percent), acute renal failure (grouped term; 4.0 percent vs. 2.6 percent), ischemic heart disease (grouped term; 1.7 percent vs. 1.6 percent) and pulmonary hypertension (grouped term; 0.6 percent vs. 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.

Amgen Webcast Investor Meeting
Amgen will host a webcast investor meeting at the 57th Anuual American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting on Monday, Dec. 7, 2015, at 7 p.m. ET. Sean E. Harper, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team and clinical investigators will participate to discuss data presented at ASH (Free ASH Whitepaper) and Amgen’s broader oncology portfolio of products.

Live audio of the conference call will be simultaneously broadcast over the Internet and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given by management at certain investor and medical conferences, can be found on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About Kyprolis (carfilzomib) for Injection
Kyprolis is an irreversible proteasome inhibitor for use in the treatment of patients with relapsed multiple myeloma.2 Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.6 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 The irreversibility of Kyprolis’ binding has also been shown to offer a more sustained inhibition of the targeted enzymes.8

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

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.

For more information about Kyprolis, visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection U.S. Indication

Cardiac Toxicities
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, and 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, and 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, such as seizure, headache, lethargy, confusion, blindness, altered consciousness, along with hypertension. 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 of any grade occurring in at least 20 percent 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 of any grade occurring in at least 20 percent 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 U.S. prescribing information is available at 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, dyspnoea, hypertension including hypertensive crises, acute renal failure, tumour lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, posterior reversible encephalopathy syndrome (PRES) and thrombotic thrombocytopenic purpura/haemolytic uremic syndrome (TTP/HUS). The most common side effects are anaemia, fatigue, diarrhoea, thrombocytopenia, nausea, pyrexia, dyspnoea, respiratory tract infection, cough and peripheral oedema.