Approval Expands Kyprolis Indication

Patients Treated With Kyprolis in Combination With Standard of Care Lived 50 Percent Longer Without Disease Worsening Compared to Standard of Care Alone in Pivotal Study

Thousand Oaks, CA (Press Release) – Amgen (NASDAQ:AMGN) today announced that the U.S. Food and Drug Admin­istra­tion (FDA) approved the supple­mental New Drug Application (sNDA) for Kyprolis® (car­filz­o­mib) for Injection in com­bi­na­tion with Revlimid® (lena­lido­mide) and dexa­meth­a­sone (KRd) for the treat­ment of patients with multiple myeloma who have received one to three prior lines of ther­apy.

"The expanded indi­ca­tion of Kyprolis provides patients with re­lapsed multiple myeloma a new thera­peutic option, helping to address a real unmet need for this common blood cancer," said Sean E. Harper, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "The approval of a second indi­ca­tion for Kyprolis in just three years dem­onstrates that it is becoming a critical component in the treat­ment of multiple myeloma, and underscores our commitment to ad­vanc­ing care for patients with this chal­leng­ing disease."

The FDA approved the expanded indi­ca­tion for Kyprolis based on data from the ASPIRE study. The study showed that patients treated in the KRd arm lived 50 per­cent longer (8.7 months) without their disease worsening compared to patients treated with Revlimid and low-dose dexa­meth­a­sone (Rd) alone. The median pro­gres­sion-free survival (PFS) was 26.3 months (95 per­cent CI, 23.3 to 30.5 months) in the KRd arm compared to 17.6 months (95 per­cent CI, 15.0 to 20.6 months) in the Rd arm. The most common adverse events in the Kyprolis arm in­cluded pneu­monia (1 per­cent), myo­cardial infarction (0.8 per­cent) and upper res­pira­tory tract in­fec­tion (0.8 per­cent).

"The ability of this Kyprolis treat­ment regi­men to produce deep and durable responses is critical to­wards extending the time patients live without their disease progressing," said ASPIRE prin­ci­pal investigator Keith Stewart, M.D., Ch.B.

Additional regu­la­tory appli­ca­tions for Kyprolis are underway and have been submitted to health author­i­ties world­wide.

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 ASPIRE

The inter­na­tional, ran­dom­ized Phase 3 ASPIRE (CArfilzomib, Lena­lido­mide, and DexamethaSone versus Lena­lido­mide and Dexamethasone for the treat­ment of PatIents with Relapsed Multiple MyEloma) trial eval­u­ated Kyprolis in com­bi­na­tion with lena­lido­mide and low-dose dexa­meth­a­sone, versus lena­lido­mide and low-dose dexa­meth­a­sone alone, in patients with re­lapsed multiple myeloma fol­low­ing treat­ment with one to three prior regi­mens. The pri­mary end­point of the trial was PFS, defined as the time from treat­ment initiation to disease pro­gres­sion or death. Secondary end­points in­cluded over­all survival (OS), over­all response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were ran­dom­ized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one only, escalating to 27 mg/m2 on days 8, 9, 15 and 16 of cycle one and continuing on days 1, 2, 8, 9, 15 and 16 of sub­se­quent cycles), in addi­tion to a standard dosing schedule of lena­lido­mide (25 mg per day for 21 days on, 7 days off) and low-dose dexa­meth­a­sone (40 mg per week in four-week cycles), versus lena­lido­mide and low-dose dexa­meth­a­sone alone. The study ran­dom­ized 792 patients at sites in North America, Europe and Israel.

The OS results did not cross the pre-specified early stopping boundary for the interim analysis. At the time of the interim analysis, there were 143 deaths (36.1 per­cent) in the KRd group, compared to 162 deaths (40.9 per­cent) in the Rd group. The ORR was 87 per­cent with KRd and 67 per­cent with Rd. In the KRd and Rd groups, 14 per­cent versus 4 per­cent of patients achieved a stringent com­plete response, a mea­sure­ment indicating depth of response. Median DOR was 28.6 months for patients receiving KRd (95 per­cent CI, 24.9 to 31.3 months) and 21.2 months for patients receiving Rd (95 per­cent CI, 16.7 to 25.8 months).

The rate of deaths due to adverse events (AEs) within 30 days of the last dose was bal­anced be­tween the KRd arm and the Rd arm. The most common causes of death occurring in patients in the KRd arm compared to the Rd arm in­cluded cardiac disorders (3 per­cent versus 2 per­cent), in­fec­tion (2 per­cent versus 3 per­cent), renal (0 per­cent versus less than 1 per­cent), and other AEs (2 per­cent versus 3 per­cent). Serious AEs were reported in 60 per­cent of the patients in the KRd arm and 54 per­cent of the patients in the Rd arm. The most common serious AEs reported in the KRd arm compared to the Rd arm were pneu­monia (14 per­cent versus 11 per­cent), res­pira­tory tract in­fec­tion (4 per­cent versus 1.5 per­cent), pyrexia (4 per­cent versus 2 per­cent), and pul­mo­nary embolism (3 per­cent versus 2 per­cent). Discontinuation due to any AE occurred in 26 per­cent of patients in the KRd arm versus 25 per­cent of patients in the Rd arm. Adverse events leading to dis­con­tin­u­a­tion of Kyprolis occurred in 12 per­cent of patients.

The ASPIRE data were presented at the 56th Annual Meeting of the American Society of Hematology and published in The New England Journal of Medicine in December 2014.

About Kyprolis® (car­filz­o­mib) for Injection

Kyprolis® (car­filz­o­mib) for Injection is indicated 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 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

WARNINGS AND PRECAUTIONS

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. In clin­i­cal studies with Kyprolis, these events typically occurred early in the course of Kyprolis ther­apy (< 5 cycles). 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 at 1 dose level reduction based on a benefit / risk assess­ment. While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored 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. In patients > 75 years of age, 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 uncontrolled by medications were not eli­gible for the clin­i­cal trials. These patients may be at greater risk for cardiac com­pli­ca­tions.

Acute Renal Failure:
Cases of acute renal failure have occurred in patients receiving Kyprolis. Renal insufficiency adverse events (renal im­pair­ment, acute renal failure, renal failure) have occurred with an incidence of approx­i­mately 8% in a ran­dom­ized controlled trial. 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 (calculated using Cockcroft and Gault equation). 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 been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be con­sidered to be at greater risk for TLS. Ensure that patients are well hydrated before admin­istra­tion of Kyprolis 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 in­­clud­ing inter­rup­tion of 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 less than 1% of 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 approx­i­mately 1% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for pul­mo­nary 11 hyper­tension until resolved or returned to base­line and con­sider whether to restart Kyprolis based on a benefit / risk assess­ment.

Dyspnea:
Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. 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. In the com­bi­na­tion study, the incidence of venous thrombo­embolic events in the first 12 cycles was 13% in the Kyprolis com­bi­na­tion arm versus 6% in the control arm. With Kyprolis mono­ther­a­py, the incidence of venous thrombo­embolic events was 2%. 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. Administer dexa­meth­a­sone prior to Kyprolis to reduce the incidence and severity 12 of infusion reac­tions. Inform patients of the risk and of symp­toms and to contact a physician im­medi­ately if symp­toms of an infusion reac­tion occur.

Thrombocytopenia:
Kyprolis causes thrombo­cytopenia with platelet nadirs observed be­tween Day 8 and Day 15 of each 28-day cycle with re­cov­ery to base­line platelet count usually by the start of the next cycle. Thrombocytopenia was reported in approx­i­mately 40% of patients in clin­i­cal trials with 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 (< 1%) 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:
Cases of thrombotic thrombocytopenic purpura/hemolytic uremic syn­drome (TTP/HUS) in­­clud­ing fatal out­come have been reported in patients who received Kyprolis. Monitor for signs and symp­toms of TTP/HUS. If the diag­nosis is sus­pected, stop Kyprolis and eval­u­ate. 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 been reported in patients receiving Kyprolis. Posterior reversible encephalopathy syn­drome (PRES), formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hyper­tension, and the diag­nosis is con­firmed by neuro-radiological imaging (MRI). 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. There are no adequate and well-controlled studies in pregnant women using Kyprolis. Kyprolis caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive poten­tial should be advised to avoid becoming pregnant while being treated with Kyprolis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the poten­tial hazard to the fetus.

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.

USE IN SPECIFIC POPULATIONS

Patients on dialysis: Administer Kyprolis after the dialysis procedure.

POST-MARKETING EXPERIENCE

The fol­low­ing adverse reac­tions were reported in the post-marketing ex­peri­ence: dehydration, thrombotic thrombocytopenic purpura/hemolytic uremic syn­drome (TTP/HUS), tumor lysis syn­drome in­­clud­ing fatal out­comes, and posterior reversible encephalopathy syn­drome (PRES). Because these reac­tions are reported voluntarily from a pop­u­la­tion of uncertain size, it is not always possible to reliably esti­mate their frequency or estab­lish­ a causal rela­tion­ship to drug exposure.

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.

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References

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.