Amgen : Announces Top-Line Results From Phase 3 KYPROLIS® (Carfilzomib) CLARION Study In Newly Diagnosed Multiple Myeloma Patients

THOUSAND OAKS, Calif., Sept. 27, 2016 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced top-line results of the Phase 3 CLARION trial, which evaluated an investigational regimen of KYPROLIS (carfilzomib), melphalan and prednisone (KMP) versus Velcade (bortezomib), melphalan and prednisone (VMP) for 54 weeks in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem-cell transplant. The trial did not meet the primary endpoint of superiority in progression-free survival (PFS) (median PFS 22.3 months for KMP versus 22.1 months for VMP, HR = 0.91, 95 percent CI, 0.75 - 1.10). While the data for overall survival, a secondary endpoint, are not yet mature, the observed hazard ratio (KMP versus VMP) was 1.21 (95 percent CI, 0.90 - 1.64). Neither result was statistically significant.

Overall, the adverse events in the KMP arm were consistent with the known safety profile of KYPROLIS. The incidence of Grade 3 or higher adverse events was 74.7 percent in the KMP arm and 76.2 percent in the VMP arm. Fatal treatment-emergent adverse events occurred in 6.5 percent of KMP patients and 4.3 percent of VMP patients. The incidence of Grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5 percent in the KMP arm and 35.1 percent in the VMP arm.

These data will be submitted to a future medical conference and for publication.

'Based on studies in the KYPROLIS label, including the ENDEAVOR study, a head-to-head comparison of KYPROLIS to Velcade in patients with relapsed or refractory multiple myeloma, we know KYPROLIS to be a major advance in proteasome inhibitor therapy,' said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. 'The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we've seen in the second-line setting. However, the myeloma landscape has changed dramatically since the design of the CLARION study with very few newly diagnosed patients treated with melphalan-based regimens, particularly in the U.S. We remain committed to exploring KYPROLIS in combination with other agents to advance the treatment of multiple myeloma.'

Amgen supports a number of investigator-sponsored studies, and a Phase 3 study evaluating KYPROLIS in combination with lenalidomide plus dexamethasone (KRd) versus Velcade in combination with lenalidomide plus dexamethasone (VRd) in newly diagnosed multiple myeloma patients. This trial, called E1A11 or ENDURANCE, is underway independently by the ECOG-ACRIN Cancer Research Group with funding provided by the National Cancer Institute (NCI) and its National Clinical Trials Network. Over 750 institutions nationwide are currently enrolling patients in the study (NCT01863550).

The KYPROLIS clinical program continues to focus on providing solutions for physicians and patients in treating this frequently relapsing and difficult-to-treat cancer. KYPROLIS is available for patients whose myeloma has relapsed or become resistant to another treatment and continues to be studied in a range of combinations and patient populations.

About the CLARION Study
The CLARION study was a Phase 3 head-to-head multicenter, open-label, randomized study in transplant-ineligible patients with newly diagnosed multiple myeloma. A total of 955 patients were randomized 1:1 to receive KYPROLIS, melphalan and prednisone or Velcade, melphalan and prednisone for 54 weeks. The median patient age was 72.

The KMP regimen consisted of KYPROLIS as a 30 minute intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29 and 30 during each 42-day cycle (20 mg/m on days 1 and 2 of cycle 1; 36 mg/m thereafter), melphalan 9 mg/m on days 1-4, and prednisone 60 mg/m on days 1-4.

Amgen Webcast Investor Call
Amgen will host a webcast call for the investment community on Tuesday, Sept. 27, 2016, at 8:30 a.m. ET. Sean E. Harper, M.D., executive vice president of Research and Development at Amgen, along with KYPROLIS clinical investigators, will participate in the call to discuss the CLARION data.

Live audio of the investor 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 Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse. It is a rare and very aggressive disease that accounts for approximately one percent of all cancers. In the U.S., there are nearly 95,000 people living with, or in remission from, multiple myeloma. Approximately 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.

About Amgen's Commitment to Oncology
Amgen Oncology is committed to helping patients take on some of the toughest cancers, such as those that have been resistant to drugs, those that progress rapidly through the body and those where limited treatment options exist. Amgen's supportive care treatments help patients combat certain side effects of strong chemotherapy, and our targeted medicines and immunotherapies focus on more than a dozen different malignancies, ranging from blood cancers to solid tumors. With decades of experience providing therapies for cancer patients, Amgen continues to grow its portfolio of innovative and biosimilar oncology medicines.

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed. KYPROLIS has been shown to block proteasomes, leading to an excessive build-up of proteins within cells. 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.

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, Brazil and the European Union. Additional regulatory applications for KYPROLIS are underway and have been submitted to health authorities worldwide.

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

IMPORTANT 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.

Hemorrhage

• Fatal or serious cases of hemorrhage have been reported in patients receiving KYPROLIS. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.

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 andHepatic 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.

Please see full prescribing information atwww.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
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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.

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Velcade (bortezomib) is a registered trademark of Millennium Pharmaceuticals, Inc.

CONTACT: Amgen, Thousand OaksKristen Davis, 805-447-3008 (media)Kristen Neese, 805-313-8267 (media)Arvind Sood, 805-447-1060 (investors)

References

1. Jakubowiak A. Management Strategies for Relapsed/Refractory Multiple Myeloma: Current Clinical Perspectives. Seminars in Hematology. 2012; 49(3)(1),S16-S32.
2. GLOBOCAN 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. National Cancer Institute. SEER Stat Fact Sheets: Myeloma. Available at: http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed on August 5, 2016.
5. Moreau P, Richardson PG, Cavo M, et al. Proteasome Inhibitors in Multiple Myeloma: 10 Years Later. Blood. 2012; 120(5):947-959.
6. Kortuem KM and Stewart AK. Carfilzomib. Blood. 2012; 121(6):893-897.

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