On March 3, 2017 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported top-line results from FRESCO, its Phase III pivotal registration trial of fruquintinib in 416 patients with locally advanced or metastatic colorectal cancer ("CRC") in China, who failed at least two prior chemotherapies, including fluoropyrimidine, oxaliplatin and irinotecan (Press release, Hutchison China MediTech, MAR 3, 2017, http://www.chi-med.com/positive-ph3-fruquintinib-crc-fresco/ [SID1234517991]). The trial met its primary endpoint of demonstrating a clinically meaningful and a statistically significant increase in overall survival ("OS"), in the intention-to-treat (ITT) population of patients treated with fruquintinib plus best supportive care ("BSC") as compared to patients treated with placebo plus BSC. Chi-Med is currently preparing to submit a new drug application ("NDA") for fruquintinib to the China Food and Drug Administration.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In addition to OS, a statistically significant improvement in progression-free survival ("PFS"), a key secondary endpoint, was observed. The adverse events demonstrated in FRESCO did not identify any new or unexpected safety issues. Full detailed results are subject to ongoing analysis and are expected to be disclosed at an upcoming scientific meeting in mid-2017.

Simon To, Chairman of Chi-Med, said, "Well over a decade of effort and investment has now paid-off with these compelling Phase III top-line results. They reinforce fruquintinib’s potential to address major unmet clinical needs for patients in both China and around the world. They also open the way to our submitting a NDA on fruquintinib around the middle of this year."

"The success of the FRESCO trial is an important milestone not just for CRC patients and Chi-Med, but also for Chinese innovation," he added. "We believe this is one of the first home-grown, China-discovered and developed, mainstream innovation in the field of oncology to succeed in a pivotal Phase III registration trial. It shows that China has the resources, capability and perseverance to emerge as an innovator in the global oncology field. With eight small molecule drug candidates in over 30 clinical studies worldwide, Chi-Med is at the forefront of this important evolution."

"We are pleased to be working with the innovative biopharmaceutical company, Chi-Med, on the development of fruquintinib," said Kerry L. Blanchard, Senior Vice President of China Medicines Development Unit and External Innovation of Eli Lilly and Company ("Lilly") China Drug Development. "This relationship highlights our commitment to help build a vibrant innovation ecosystem in China, and we look forward to our further collaboration to bring this novel medicine to patients."

In addition to the FRESCO colorectal cancer trial, fruquintinib is being studied in China in a Phase III pivotal trial in non-small cell lung cancer ("NSCLC"), known as FALUCA; and a Phase II study using fruquintinib combined with Iressa (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. Other studies currently being planned, and soon to be initiated, include a Phase III study in gastric cancer in combination with paclitaxel in China, new studies in the U.S., and certain exploratory studies in combination with other oncology agents.

About VEGF and Fruquintinib
At an advanced stage, tumors secrete large amounts of vascular endothelial growth factors ("VEGF"), a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor to provide greater blood flow, oxygen, and nutrients to the tumor. VEGF and VEGF receptors ("VEGFR") play a pivotal role in tumor-related angiogenesis, and the inhibition of the VEGF/VEGFR pathway. This represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

Fruquintinib (HMPL-013) is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose. It is currently under the joint development in China by Chi-Med and its partner Lilly. Two clinical studies are ongoing in lung cancer, including a late stage, pivotal Phase III registration study (FALUCA). In addition, fruquintinib is also in clinical development for the treatment of gastric cancer.

About FRESCO and Colorectal Cancer
The FRESCO trial is a randomized, double-blind, placebo-controlled, multicenter, Phase III pivotal trial in patients with locally advanced or metastatic CRC who have failed at least two prior systemic antineoplastic therapies, including fluoropyrimidine, oxaliplatin and irinotecan. No drugs have been approved in third-line CRC in China, with BSC being the general standard of care. Enrollment was completed in May 2016. 416 patients were randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC; or placebo plus BSC. The primary endpoint is OS, with secondary endpoints including PFS, objective response rate ("ORR"), disease control rate ("DCR") and duration of response ("DoR"). Additional details of the FRESCO study may be found at clinicaltrials.gov, using identifier NCT02314819. Full results from the FRESCO study are planned to be published at a scientific event in mid-2017.

CRC is the second most common cancer type in China, with about 380,000 new cases per year, according to CA Cancer Journal for Clinicians 2016. There were approximately 1.5 million new CRC cases globally in 2015 which are expected to increase to approximately 1.7 million new cases per year by 2020, according to Frost & Sullivan.

About Fruquintinib in Lung and Gastric Cancer
Lung: The FALUCA trial is a randomized, double-blind, placebo-controlled, multi-center, Phase III registration study targeted at treating patients with advanced non-squamous NSCLC, who have failed two lines of systemic chemotherapy. Enrollment began in December 2015. Patients are randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC; or placebo plus BSC. The primary endpoint is OS, with secondary endpoints including PFS, ORR, DCR and DoR. Chi-Med plans to enroll approximately 520 patients in about 45 centers across China. Additional details about this study can be found at clinicaltrials.gov, using identifier NCT02691299. Topline results from the FALUCA study are expected to be released in early 2018.

In January 2017 Chi-Med initiated a multi-center, single-arm, open-label Phase II study of a combination therapy using fruquintinib and Iressa (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. The objectives are to evaluate the safety and tolerability as well as preliminary efficacy of the combination therapy in the first-line setting for advanced or metastatic non-squamous NSCLC patients with epidermal growth factor receptor (EGFR) activating mutations. Additional details about this study may be found at clinicaltrials.gov, using identifier NCT02976116.

Gastric: Chi-Med completed a Phase I/II dose finding study of fruquintinib in combination with paclitaxel, which established a combination regimen that was well tolerated. Results of this study were published at the 2017 Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in January 2017. Additional details about this study can be found at clinicaltrials.gov, using identifier NCT02415023. A pivotal Phase III registration study is expected to start during the first half of 2017.

On March 3, 2017 Navidea Biopharmaceuticals (NYSE MKT: NAVB) reported the completion of the sale to Cardinal Health (NYSE: CAH) of its Lymphoseek product for lymphatic mapping, lymph node biopsy and the diagnosis of metastatic spread to lymph nodes for the staging of cancer in North America (Press release, Navidea Biopharmaceuticals, MAR 3, 2017, View Source [SID1234517982]). Navidea received approximately $83 million at closing, and will have the opportunity to earn up to $227 million of contingent consideration based on certain milestones through 2026, with $17.1 million of that amount guaranteed over the next three years.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Cardinal Health will license a portion of the acquired intellectual property back to Navidea to allow Navidea to develop and sell new immunodiagnostic and immunotherapeutic products for specific purposes in North America, and to continue to produce and sell Lymphoseek, mostly under a different brand name, outside of North America.

As a result of this transaction, CRG has provided a full release of all liens on Navidea’s assets, and all frozen accounts will be transferred back to Navidea control. The unsecured loan from Platinum Partners has been also been repaid.

"This transaction is transformative for Navidea, as we will have the financial flexibility to invest in our deep pipeline of activated macrophage targeted imaging agents and therapeutics. We want to commend Cardinal Health for their professionalism throughout this trying process for Navidea," said Dr. Michael M. Goldberg, President and CEO of Navidea Biopharmaceuticals.

Post-closing and post paying off all outstanding notes and transaction-related expenses, Navidea will have $15.6 million in cash and $3.3 million in payables, a large portion of which is tied to the 4694 program which Navidea is seeking to divest in the near term now that the liens have been released.

Navidea will hold an investor webinar at 4:30pm Eastern time on Monday, March 6, 2017. Slides will be posted on the Navidea website a few minutes prior to the start of the webinar. Investor Q&A will be entertained after the conclusion of the presentation.

Call in details are as follows. United States: +1 (415) 655-0060, Access Code: 808-819-426. You will be in listen only mode.

The call and presentation will also be simulcast with the following details View Source

After registering, you will receive a confirmation email containing information about joining the call. You must be connected on-line in order to participate in the Q&A session.

On March 3, 2017 Amgen (NASDAQ:AMGN) reported positive results from a planned overall survival (OS) interim analysis of the Phase 3 head-to-head ENDEAVOR trial (Press release, Amgen, MAR 3, 2017, View Source [SID1234517977]). The study met the key secondary endpoint of OS, demonstrating that patients with relapsed or refractory multiple myeloma treated with KYPROLIS (carfilzomib) and dexamethasone (Kd) lived 7.6 months longer than those treated with Velcade (bortezomib) and dexamethasone (Vd) (median OS 47.6 months for Kd versus 40.0 for Vd, HR=0.79; 95 percent CI: 0.65 – 0.96; p=0.01). The OS benefit was consistent regardless of prior Velcade therapy (HR 0.75 for no prior Velcade; HR 0.84 for prior Velcade). These data will be presented today during the late-breaking abstract session at the 16th International Myeloma Workshop (IMW) in New Delhi.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Results from the ENDEAVOR primary analysis proved KYPROLIS is the superior proteasome inhibitor, having doubled progression-free survival compared to Velcade," said Meletios A. Dimopoulos, M.D., professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine. "Results presented today showed that progression-free survival advantage translated into significantly improved survival for patients, a clinical endpoint that creates confidence for physicians and patients, especially in a relapsing disease like multiple myeloma."

"We are proud to share these results with leading multiple myeloma experts at IMW as we continue to explore the complex biology of treating this presently incurable disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "KYPROLIS continues to demonstrate advancement in proteasome inhibition, and we look forward to submitting these findings to regulatory agencies worldwide to support a potential label update."

This Kd regimen administered with 56 mg/m2 KYPROLIS twice weekly is approved in the U.S., European Union and other countries based on the primary analysis of progression-free survival (PFS) in the ENDEAVOR study.

Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. The most common adverse events (greater than or equal to 20 percent) in the KYPROLIS arm were anemia, diarrhea, pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia and headache.

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 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 (Kd), versus bortezomib with low-dose dexamethasone (Vd) 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. The primary analysis was published in The Lancet Oncology and is described in the Prescribing Information.

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, and if tolerated was escalated to 56 mg/m2 from day 8 Cycle 1 onwards. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were treated with bortezomib administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regional 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 or the News Release section of Amgen.com.

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 very aggressive disease that accounts for approximately one percent of all cancers.2,3 In the U.S., there are nearly 95,000 people living with, or in remission from, multiple myeloma.4 Approximately 30,330 Americans are diagnosed with multiple myeloma each year and 12,650 patient deaths are reported on an annual basis.4

About KYPROLIS (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.5 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.5,6

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 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 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 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 at www.kyprolis.com.

On March 3, 2017 Amgen (NASDAQ:AMGN) reported positive data from the Phase 3 ‘482 study, the largest international multiple myeloma trial ever conducted (Press release, Amgen, MAR 3, 2017, View Source [SID1234517976]). In this study, XGEVA (denosumab) met the primary endpoint, demonstrating non-inferiority to zoledronic acid in delaying the time to first on-study skeletal-related event (SRE) in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The median time to first on-study SRE was similar between XGEVA (22.83 months) and zoledronic acid (23.98 months). These data will be presented today during the late-breaking abstract session at the 16th International Myeloma Workshop (IMW) in New Delhi.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Bone complications are devastating for patients with multiple myeloma. Renal function is a constant consideration in the treatment of multiple myeloma patients, often preventing the use of bisphosphonates, the only approved class of agents for prevention of bone complications, underscoring the need for new treatment options," said Noopur Raje, M.D., director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston. "The results of this study showed that denosumab may be an effective novel option that is not cleared through the kidneys that may help prevent bone complications in patients with multiple myeloma."

The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. There was a suggested trend in overall survival (OS) in favor of XGEVA over zoledronic acid (HR=0.90, 95 percent CI: 0.70, 1.16; p=0.41); however, it was not statistically significant. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival (PFS) was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median PFS difference between arms was 10.7 months in favor of XGEVA.

"XGEVA is currently approved for the prevention of bone complications in patients with solid tumors based on superior clinical benefits over zoledronic acid in this setting," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "The results being presented today reinforce that XGEVA’s unique mechanism of action and subcutaneous administration may also offer patients with multiple myeloma a valuable alternative to the current standard of care. Amgen plans to submit these results to regulatory agencies worldwide to support a potential update to the XGEVA label."

Adverse events observed in patients treated with XGEVA were consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) were diarrhea (33.5 percent XGEVA and 32.4 percent zoledronic acid) and nausea (31.5 percent XGEVA and 30.4 percent zoledronic acid).

Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 Bone lesions appear in the vast majority of patients with multiple myeloma and weaken the bone.3 Myeloma cells induce RANK ligand (RANKL) expression, a protein essential for the formation, function and survival of osteoclasts, which break down bone. In addition, direct RANKL expression by myeloma cells may enhance osteoclast activity in the bone microenvironment.4 Excessive RANKL can increase the risk of bone complications, including pathologic fractures, radiation therapy or surgery to the bone, and spinal cord compression.5,6

About ‘482 Study (NCT01345019)
The ‘482 study was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of bone complications in patients with newly diagnosed multiple myeloma. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE (fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE and first-and-subsequent on-study SRE and OS. PFS was an exploratory endpoint. The safety and tolerability of XGEVA were also compared with zoledronic acid.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 It is characterized by a recurring pattern of remission and relapse, with patients eventually becoming refractory to treatment.7 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

Bone lesions are a hallmark of multiple myeloma and often result in bone complications.3,6 Additionally, renal impairment is a common complication of multiple myeloma.8 Approximately 60 percent of all multiple myeloma patients have or will have renal impairment over the course of the disease.8 Current treatment options including zoledronic acid are cleared by the kidneys and associated with renal toxicity.6 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.9

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the United States (U.S.) for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA is not indicated for the prevention of SREs in patients with multiple myeloma.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has occurred in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroid, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least five months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.