First Phase 3 Study Combining KYPROLIS and DARZALEX, Two Critical Mechanisms of Action in Treatment of Multiple Myeloma

{{image}}Thousand Oaks, CA (Press Release) -- Amgen (NASDAQ:AMGN) today announced the Phase 3 CANDOR study eval­u­ating KYPROLIS® (car­filz­o­mib) in com­bi­na­tion with dexa­meth­a­sone and DARZALEX® (dara­tu­mu­mab) (KdD) com­pared to KYPROLIS and dexa­meth­a­sone alone (Kd) met its pri­mary end­point of pro­gres­sion-free survival (PFS). The regi­men resulted in a 37% reduction in the risk of pro­gres­sion or death in patients with re­lapsed or refractory multiple myeloma treated with KdD (HR=0.630; 95% CI: 0.464, 0.854; p=0.0014). The median PFS for patients treated with Kd alone was 15.8 months, while the median PFS for patients treated with KdD has not been reached by the cut-off date.

"The poten­tial to combine KYPROLIS with DARZALEX, two powerful targeted agents, rep­re­sents an addi­tional thera­peutic ap­proach for patients with re­lapsed or refractory multiple myeloma," said David M. Reese, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "The results from the CANDOR study con­firm the poten­tial for KYPROLIS to be used in com­bi­na­tion with an anti-CD38 mono­clonal anti­body."

There was a higher frequency of adverse events reported in KdD, a three-agent regi­men, than in Kd, a two-agent regi­men. The types of observed adverse events were con­sis­tent with the known safety profiles of the in­di­vid­ual agents. The most frequently reported treat­ment-emergent adverse events (greater than or equal to 20%) in the KdD arm were thrombo­cyto­penia, anemia, diarrhea, hyper­tension, upper res­pira­tory tract in­fec­tion, fatigue and dyspnea.

"While treat­ment ad­vances have im­proved out­comes for patients with multiple myeloma, there remains a need for addi­tional thera­peutic options for patients who have re­lapsed," said Ajai Chari, M.D., asso­ci­ate pro­fessor of med­i­cine, the director of clin­i­cal research in the Multiple Myeloma Program and the asso­ci­ate director of clin­i­cal research, Mount Sinai Cancer Clinical Trials Office. "CANDOR con­firms in a large Phase 3 study the benefit for patients dem­onstrated in the earlier Phase 1 study using the same com­bi­na­tion."

The CANDOR data will be sub­mitted to a future medical meeting and discussed with health author­i­ties in preparation for regu­la­tory sub­missions.

About CANDOR

CANDOR, a ran­dom­ized, open-label Phase 3 study of KYPROLIS, dexa­meth­a­sone and DARZALEX (KdD) com­pared to KYPROLIS and dexa­meth­a­sone (Kd), has eval­u­ated 466 re­lapsed or refractory multiple myeloma patients who have received one to three prior ther­a­pies. Patients were treated until dis­ease pro­gres­sion. The pri­mary end­point was PFS, and the key sec­ond­ary end­points were over­all response rate, minimal residual dis­ease and over­all survival. PFS was defined as time from ran­dom­i­za­tion until dis­ease pro­gres­sion or death from any cause.

In the first arm, patients received KYPROLIS twice weekly at 56 mg/m² and dexa­meth­a­sone in com­bi­na­tion with DARZALEX. In the second arm (control), patients received KYPROLIS twice weekly at 56 mg/m² and dexa­meth­a­sone.

CANDOR was ini­ti­ated as part of a col­lab­o­ration with Janssen, and under the terms of the agree­ment, Janssen co-funded the study. For more in­for­ma­tion about this trial, please visit www.clinicaltrials.gov under trial identi­fi­ca­tion number NCT03158688.

About Multiple Myeloma

Multiple myeloma is an incurable blood cancer, char­ac­ter­ized by a recurring pattern of remission and relapse.¹ It is a rare and life-threatening dis­ease that accounts for approx­i­mately one per­cent of all cancers.^2,3 Worldwide, approx­i­mately 160,000 people are diag­nosed with multiple myeloma each year, and 106,000 patient deaths are reported on an annual basis.²

About KYPROLIS® (car­filz­o­mib)

Proteasomes play an im­por­tant role in cell function and growth by breaking down proteins that are damaged or no longer needed.⁴ KYPROLIS has been shown to block pro­te­a­somes, leading to an excessive build-up of proteins within cells.⁵ 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.^4,5

Since its first approval in 2012, approx­i­mately 130,000 patients world­wide have received KYPROLIS. 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 Algeria, Argentina, Australia, Bahrain, Belarus, Brazil, Canada, Chile, Colombia, Ecuador, Egypt, European Union, Hong Kong, India, Israel, Japan, Jordan, Kuwait, Lebanon, Macao, Malaysia, Mexico, Morocco, New Zealand, Oman, Philippines, Qatar, Russia, Saudi Arabia, Singapore, S. Korea, Switzerland, Taiwan, Thailand, Turkey and United Arab Emirates.

Important U.S. KYPROLIS® (car­filz­o­mib) 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 admin­istra­tion.
• Monitor patients for signs or symp­toms of cardiac failure or 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 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.
• For 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 prior to starting treat­ment with KYPROLIS and remain under close follow-up with fluid man­agement.

Acute Renal Failure

• Cases of acute renal failure, in­clud­ing some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred. 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. Patients with 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, and withhold until 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. Some events have been fatal. In the event of drug‐induced pul­mo­nary toxicity, dis­con­tinue KYPROLIS.

Pulmonary Hypertension

• Pulmonary arterial hyper­tension (PAH) was reported. 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 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 based on a benefit / risk assess­ment.

Hypertension

• Hypertension, in­clud­ing hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hyper­tension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hyper­tension cannot be adequately controlled, withhold KYPROLIS and eval­u­ate. Consider whether to restart based on a benefit / risk assess­ment.

Venous Thrombosis

• Venous thrombo­embolic events (including deep venous thrombosis and pul­mo­nary embolism) have been observed. 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 hormonal con­tra­cep­tion asso­ci­ated with a risk of thrombosis should con­sider an alter­na­tive method of effective con­tra­cep­tion during treat­ment.

Infusion Reactions

• Infusion reac­tions, in­clud­ing life‐threatening reac­tions, have occurred. 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. Premedicate with dexa­meth­a­sone to reduce the in­ci­dence and severity of in­fusion reac­tions. Inform patients of the risk and of symp­toms and seek im­medi­ate medical attention if they occur.

Hemorrhage

• Fatal or serious cases of hemorrhage have been reported. 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. Monitor platelet counts frequently during treat­ment. Reduce or withhold dose as appro­pri­ate.

Hepatic Toxicity and Hepatic Failure

• Cases of hepatic failure, in­clud­ing fatal cases, have occurred. 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. Monitor for signs and symp­toms of TTP/HUS. Discontinue if diag­nosis is sus­pected. If the diag­nosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

• Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is sus­pected, dis­con­tinue and eval­u­ate with appro­pri­ate imaging. The safety of reinitiating KYPROLIS is not known.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

• In a clin­i­cal trial of trans­plant-ineligible patients with newly diag­nosed multiple myeloma com­par­ing KYPROLIS, mel­phalan, and pred­ni­sone (KMP) vs bor­tez­o­mib, mel­phalan, and pred­ni­sone (VMP), a higher in­ci­dence of serious and fatal adverse events was observed in patients in the KMP arm. KMP is not indicated for trans­plant-ineligible patients with newly diag­nosed multiple myeloma.

Embryo-fetal Toxicity

• KYPROLIS can cause fetal harm when admin­istered to a pregnant woman.
• Females of reproductive poten­tial should be advised to avoid becoming pregnant while being treated with KYPROLIS and for 6 months fol­low­ing the final dose. Males of reproductive poten­tial should be advised to avoid fathering a child while being treated with KYPROLIS and for 3 months fol­low­ing the final dose. 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 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 in mono­therapy trials: anemia, fatigue, thrombo­cyto­penia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema periph­eral

Please see full Prescribing Information at www.kyprolis.com.

About Amgen Oncology

Amgen Oncology is search­ing for and finding answers to incredibly complex questions that will ad­vance care and im­prove lives for cancer patients and their families. Our research drives us to under­stand the dis­ease in the context of the patient's life – not just their cancer journey – so they can take control of their lives.

For the last four decades, we have been dedicated to discovering the firsts that matter in on­col­ogy and to finding ways to reduce the burden of cancer. Building on our heritage, Amgen con­tinues to ad­vance the largest pipe­line in the Company's history, moving with great speed to ad­vance those inno­va­tions for the patients who need them.

At Amgen, we are driven by our commitment to transform the lives of cancer patients and keep them at the center of everything we do.

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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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References:

1. Jakubowiak A. Management strategies for re­lapsed / refractory multiple myeloma: current clin­i­cal perspectives. Semin Hematol. 2012 Jul; 49 Suppl 1:S16-S32.
2. GLOBOCAN 2018. 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: July 18, 2019.
3. American Cancer Society. About Multiple Myeloma. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/8738.00.pdf. Accessed on: July 18, 2019.
4. Moreau P, Richardson PG, Cavo M, et al. Proteasome inhibitors in multiple myeloma: 10 years later. Blood. 2012 Aug 2;120(5):947-59.
5. Kortuem KM and Stewart AK. Carfilzomib. Blood. 2013 Feb 7;121(6):893-7.

Source: Amgen