• Approval of a More Convenient Once-Weekly Kd70 Regimen Based on Data From Phase 3 Head-to-Head A.R.R.O.W. Study
• Application Granted Priority Review Desig­na­tion
• Application Reviewed and Approved Under FDA's Real-Time Oncology Review and Assessment Aid Pilot Programs

Thousand Oaks, CA (Press Release) – Amgen (NASDAQ: AMGN) today announced that the U.S. Food and Drug Admin­istra­tion (FDA) has approved the supple­mental New Drug Application (sNDA) to expand the Prescribing Information for KYPROLIS® (car­filz­o­mib) to in­clude a once-weekly dosing option in com­bi­na­tion with dexa­meth­a­sone (once-weekly Kd70) for patients with re­lapsed or refractory multiple myeloma. The approval is based on data from the Phase 3 A.R.R.O.W. trial, which dem­onstrated that KYPROLIS admin­istered once-weekly at 70 mg/m² with dexa­meth­a­sone achieved superior pro­gres­sion-free survival (PFS) and over­all response rates (ORR), with a com­parable safety profile, versus twice-weekly KYPROLIS admin­istered at a dose of 27 mg/m² in com­bi­na­tion with dexa­meth­a­sone (twice-weekly Kd27). KYPROLIS is not approved for twice-weekly 27 mg/m² admin­istra­tion in com­bi­na­tion with dexa­meth­a­sone alone.

"In the fight against multiple myeloma, we are committed to con­tinued evi­dence generation and inno­va­tion to serve patients. KYPROLIS now offers patients with re­lapsed or refractory multiple myeloma the option of a more convenient dosing regi­men that provides better out­comes with a com­parable safety profile," said David M. Reese, M.D., exec­u­tive vice pres­i­dent of Research and Development at Amgen. "We're pleased that the FDA has recog­nized the importance of bringing more treat­ment options to cancer patients more quickly through its pilot pro­grams and proud to par­tic­i­pate with this KYPROLIS data."

The FDA reviewed the appli­ca­tion under its Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid pilot pro­grams, which aim to explore a more efficient review process to ensure that safe and effective treat­ments are avail­able to patients as early as possible. The FDA approved the appli­ca­tion in just over one month after the final component of the appli­ca­tion was submitted.

"While great progress has been made in the last decade, multiple myeloma remains an incurable disease char­ac­ter­ized by a recurring pattern of remission and relapse, and it is im­por­tant that patients have treat­ment options that meet their individual needs," said David S. Siegel, M.D., Ph.D., chief of the Division of Multiple Myeloma at John Theuer Cancer Center at Hackensack University Medical Center. "The avail­a­bil­ity of a more convenient once-weekly dosing regi­men, with superior efficacy, com­parable safety, and longer duration of ther­apy versus the twice-weekly regi­men studied in the trial could allow patients to spend more time outside of the infusion center."

A.R.R.O.W. in­cluded 478 patients with re­lapsed and refractory multiple myeloma who received at least two or three prior lines of ther­apy, in­­clud­ing a pro­te­a­some inhibitor and an immuno­modu­la­tory agent. Patients in the trial treated with once-weekly Kd70 achieved a statistically sig­nif­i­cant 3.7 month im­prove­ment in PFS compared to the Kd27 twice-weekly regi­men (median PFS 11.2 months for once-weekly Kd70 versus 7.6 months for twice-weekly Kd27; HR=0.69; 95 per­cent CI: 0.54-0.88; one-sided p=0.0014).The ORR in patients treated with once-weekly Kd70 was 62.9 per­cent versus 40.8 per­cent for those treated with twice-weekly Kd27 (p<0.0001). In addi­tion, 7.1 per­cent had com­plete responses or better in the once-weekly arm versus 1.7 per­cent in the twice-weekly arm in this refractory patient pop­u­la­tion.

The over­all safety profiles of the two arms in A.R.R.O.W. were com­parable, with no new safety risks identified in the once-weekly arm. Discontinuation rates due to adverse events were similar in the two arms. The most frequently reported treat­ment-emergent adverse events (greater than or equal to 20 per­cent) in either treat­ment arm were anemia, diarrhea, fatigue, hyper­tension, insomnia and pyrexia.

The interim data were presented during an oral session at the 54th Annual Meeting of the American Society of Clinical Oncology and simultaneously published in The Lancet Oncology.

About A.R.R.O.W.

The A.R.R.O.W. (RAndomized, Open-label, Phase 3 Study in Subjects with Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination with Dexamethasone, Comparing Once-Weekly versus Twice-weekly Carfilzomib Dosing) trial eval­u­ated 478 patients with re­lapsed and refractory multiple myeloma who have received at least two but no more than three prior ther­a­pies, in­­clud­ing bor­tez­o­mib and an immuno­modu­la­tory drug. Those in­cluded in the study were ran­dom­ized to receive a 30-minute infusion of once-weekly KYPROLIS (20 mg/m² on day 1 of cycle 1; 70 mg/m² on days 8 and 15 of cycle 1; and 70 mg/m² on days 1, 8 and 15 of sub­se­quent cycles) with dexa­meth­a­sone (40 mg) versus a 10-minute infusion of twice-weekly KYPROLIS (20 mg/m² on days 1 and 2 of cycle 1; 27 mg/m² on days 8, 9, 15 and 16 of cycle 1; and 27 mg/m² on days 1, 2, 8, 9, 15 and 16 of sub­se­quent cycles) with dexa­meth­a­sone (40 mg). The pri­mary end­point of the trial was PFS, defined as the time from ran­domization to disease pro­gres­sion or death. Secondary end­points in­cluded ORR, over­all survival, and safety and tolerability.

The trial was conducted in approx­i­mately 100 sites world­wide. For more in­­for­ma­tion about this trial, please visit www.clinicaltrials.gov under trial identi­fi­ca­tion number NCT02412878.

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 114,000 people are diag­nosed with multiple myeloma each year and 80,000 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 80,000 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 Argentina, Australia, Bahrain, Canada, Hong Kong, Israel, Japan, Kuwait, Lebanon, Macao, Mexico, Thailand, Colombia, S. Korea, Canada, Qatar, Switzerland, United Arab Emirates, Turkey, Russia, Brazil, India, Oman and addi­tional U.S. regu­la­tory appli­ca­tions for KYPROLIS are underway and have been submitted to health author­i­ties world­wide.

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.

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

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.

For more in­­for­ma­tion, follow us on www.twitter.com/amgenoncology.

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

This news release con­tains forward-looking state­ments that are based on the current ex­pec­ta­tions and beliefs of Amgen. All state­ments, other than state­ments of historical fact, are state­ments that could be deemed forward-looking state­ments, in­­clud­ing esti­mates of revenues, operating margins, capital ex­pen­di­tures, cash, other financial metrics, ex­pec­ted legal, arbitration, political, regu­la­tory or clin­i­cal results or practices, customer and prescriber patterns or practices, reim­burse­ment activities and out­comes and other such esti­mates and results. Forward-looking state­ments involve sig­nif­i­cant risks and un­cer­tain­ties, in­­clud­ing those discussed below and more fully described in the Securities and Exchange Com­mis­sion reports filed by Amgen, in­­clud­ing our most recent annual report on Form 10-K and any sub­se­quent periodic reports on Form 10-Q and current reports on Form 8-K. Unless other­wise noted, Amgen is providing this in­­for­ma­tion as of the date of this news release and does not under­take any obli­ga­tion to update any forward-looking state­ments con­tained in this document as a result of new in­­for­ma­tion, future events or other­wise.

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, in­­clud­ing our devices, after they are on the market.

Our results may be affected by our ability to suc­cess­fully market both new and existing prod­ucts domestically and inter­na­tionally, clin­i­cal and regu­la­tory devel­op­ments involving current and future prod­ucts, sales growth of recently launched prod­ucts, com­pe­ti­tion from other prod­ucts in­­clud­ing bio­sim­i­lars, dif­fi­culties or delays in manu­fac­tur­ing our prod­ucts and global economic con­di­tions. In addi­tion, sales of our prod­ucts are affected by pricing pressure, political and public scrutiny and reim­burse­ment policies imposed by third-party payers, in­­clud­ing gov­ern­ments, private insurance plans and man­aged care providers and may be affected by regu­la­tory, clin­i­cal and guideline devel­op­ments and domestic and inter­na­tional trends to­ward man­aged care and health­care cost con­tainment. Further­more, our research, testing, pricing, market­ing and other operations are subject to extensive reg­u­la­tion by domestic and foreign gov­ern­ment regu­la­tory author­i­ties. Our business may be impacted by gov­ern­ment in­ves­ti­ga­tions, litigation and prod­uct liability claims. In addi­tion, our business may be impacted by the adoption of new tax legislation or exposure to addi­tional tax liabilities. If we fail to meet the compliance obli­ga­tions in the corporate integrity agree­ment be­tween us and the U.S. gov­ern­ment, we could become subject to sig­nif­i­cant sanctions. Further, while we routinely obtain patents for our prod­ucts and tech­nology, the protection offered by our patents and patent appli­ca­tions may be chal­lenged, invalidated or circumvented by our com­pet­i­tors, or we may fail to prevail in present and future intellectual property litigation. We per­form a sub­stan­tial amount of our commercial manu­fac­tur­ing activities at a few key facilities, in­­clud­ing in Puerto Rico, and also depend on third parties for a portion of our manu­fac­tur­ing activities, and limits on supply may constrain sales of certain of our current prod­ucts and prod­uct can­di­date devel­op­ment. In addi­tion, we compete with other com­pa­nies with respect to many of our marketed prod­ucts as well as for the discovery and devel­op­ment of new prod­ucts. Further, some raw ma­teri­als, medical devices and component parts for our prod­ucts are supplied by sole third-party suppliers. Certain of our distributors, customers and payers have sub­stan­tial purchasing leverage in their dealings with us. The discovery of sig­nif­i­cant problems with a prod­uct similar to one of our prod­ucts that implicate an entire class of prod­ucts could have a ma­teri­al adverse effect on sales of the affected prod­ucts and on our business and results of operations. Our efforts to acquire other com­pa­nies or prod­ucts and to integrate the operations of com­pa­nies we have acquired may not be suc­cess­ful. A breakdown, cyberattack or in­­for­ma­tion security breach could compromise the con­fi­den­tiality, integrity and avail­a­bil­ity of our systems and our data. Our stock price is volatile and may be affected by a number of events. Our business per­for­mance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase our common stock. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all.

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 Aug. 27, 2018.
3. American Cancer Society. About Multiple Myeloma. Available at https://www.cancer.org/content/dam/CRC/PDF/Public/8738.00.pdf. Accessed on Aug. 27, 2018.
4. Moreau P, Richardson PG, Cavo M, et al. Proteasome Inhibitors in Multiple Myeloma: 10 Years Later. Blood. 2012; 120(5):947-959.
5. Kortuem KM and Stewart AK. Carfilzomib. Blood. 2012; 121(6):893-897.

Source: Amgen.