On June 10, 2016 Amgen (NASDAQ:AMGN) reported results from a post-hoc analysis of the pivotal Phase 3 ASPIRE study which highlighted the benefit of continued treatment with Kyprolis (carfilzomib) in combination with lenalidomide and dexamethasone (KRd) in patients with relapsed multiple myeloma (Press release, Amgen, JUN 10, 2016, View Source;p=RssLanding&cat=news&id=2176931 [SID:1234513208]). Separate sub-analyses of the Phase 3 ENDEAVOR study further confirmed efficacy and depth of response benefits of Kyprolis plus dexamethasone (Kd). These results were presented at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper).

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Results from the ASPIRE analysis showed that cumulative rates of complete response or better (>CR) continued to increase over time in the KRd arm, most quickly in the first 15 months of treatment. In addition, the progression-free survival (PFS) hazard ratio (HR) at 18 months was 0.58 (95 percent CI: 0.46-0.72), while the overall study HR at 31 months was 0.69 (95 percent CI: 0.57-0.83), possibly related to patients in the KRd arm receiving Kyprolis for a maximum of 18 months (EHA abstract #P275). Researchers assessed PFS HR at 18 months following discontinuation of Kyprolis treatment in the KRd arm per the trial protocol. The most common all grade treatment-related adverse events in the ASPIRE trial included neutropenia (34.2 percent), anemia (25.5 percent), fatigue (22.4 percent) and thrombocytopenia (22.4 percent).

Six additional abstracts presented at EHA (Free EHA Whitepaper) further demonstrate the benefit of Kyprolis-based regimens across a range of patient populations:

Data analyzed in four presentations across patient subgroups from the Phase 3 ENDEAVOR trial showed that patients with relapsed or refractory multiple myeloma who were treated with Kd achieved superior PFS compared to those receiving bortezomib plus dexamethasone (Vd). The subgroup analyses evaluated the Kyprolis combination based on prior treatment, cytogenetic risk status, age and in Asian patients, respectively (EHA abstracts #E1266, #E1267, #E1274 and #E1328).
A secondary analysis of data from the Phase 3 ENDEAVOR study found treatment with Kd compared to subcutaneous bortezomib led to prolonged PFS regardless of prior bortezomib treatment. The results suggest Kd has a favorable benefit-risk profile and delivers superior efficacy and improved clinical outcomes (EHA abstract #P659).
A separate presentation analyzed the efficacy and safety of Kyprolis according to baseline cytogenetic risk status, based on data from the Phase 3 ASPIRE trial in which KRd demonstrated a significant improvement in PFS compared to lenalidomide and dexamethasone alone (EHA abstract #P663).
"This week’s presentations at EHA (Free EHA Whitepaper) continue to confirm that compared to previous standard of care therapies, across patient populations and therapeutic combinations, treatment with Kyprolis can extend the time patients live without their disease progressing," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This abundant clinical research provides substantive, meaningful evidence for Kyprolis as a foundational therapy for relapsed or refractory multiple myeloma patients."

Abstracts are currently available on the EHA (Free EHA Whitepaper) website.

EHA Abstract #P275:
Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma: Analysis of Response and Progression-Free Survival Hazard Ratio Over Time
In this post-hoc analysis of data from the Phase 3 ASPIRE trial, researchers evaluated the time to cumulative >CR and PFS HR at 18 months from randomization for KRd-treated patients (n=396) versus Rd-treated patients (n=396). KRd and Rd patients were followed for a median of 31 and 30 months for PFS, respectively. Per trial protocol, Kyprolis was discontinued after 18 cycles (28 days/cycle), so optimal duration of KRd treatment was not determined. All patients continued to receive Rd treatment until disease progression.

A total of 126 and 37 patients in the KRd and Rd groups achieved ≥CR with sample median time from treatment start to ≥CR of 6.7 and 8.3 months, respectively. The increase in rate of ≥CR patients over time was greater in the KRd group than the Rd group, most notably in the first 15 months; cumulative ≥CR rates increased steadily thereafter.
The overall PFS HR in ASPIRE for KRd versus Rd was 0.69 (95 percent CI: 0.57-0.83). For the first 18 months, the PFS HR was 0.58 (95 percent CI: 0.46-0.72). The 18-month PFS HR was lower than the overall study PFS HR, possibly related to KRd patients receiving Kyprolis for a maximum of 18 months.
The most common all grade treatment-related adverse events in the ASPIRE trial included neutropenia (34.2 percent), anemia (25.5 percent), fatigue (22.4 percent) and thrombocytopenia (22.4 percent).
EHA Abstract #E1266: Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone: Subgroup Analysis of the Phase 3 ENDEAVOR Study to Evaluate the Impact of Prior Treatment on Patients with Relapsed Multiple Myeloma
This subgroup analysis evaluated treatment with Kd versus Vd in patients after first relapse versus more than two prior lines of therapy, as well as the effect of previous exposure to bortezomib or lenalidomide.

For patients with prior bortezomib exposure, median PFS for Kd compared to Vd was 15.6 months versus 8.1 months, respectively (HR: 0.56; 95 percent CI: 0.44-0.73). For patients without prior bortezomib exposure, median PFS was not estimable (NE) for the Kd-treated patients versus 11.2 months for Vd-treated patients (HR: 0.48; 95 percent CI: 0.36-0.66). In patients with prior bortezomib exposure, overall response rates (ORRs) were 71.2 percent for Kd versus 60.3 percent for Vd (OR: 1.63; 95 percent CI: 1.12-2.36) and 83.6 percent for Kd compared to 65.3 percent for Vd (OR: 2.72; 95 percent CI: 1.72-4.31) in patients without prior bortezomib exposure.
For patients with prior lenalidomide exposure, median PFS for Kd-treated patients was 12.9 months compared to 7.3 months for Vd-treated patients (HR: 0.69; 95 percent CI: 0.52-0.92). For patients without prior lenalidomide exposure, median PFS for Kd-treated patients was 22.2 months compared to 10.2 months for Vd-treated patients (HR: 0.43; 95 percent CI: 0.32-0.56). For patients with prior lenalidomide exposure, ORRs were 70.1 percent for Kd versus 59.3 percent for Vd (OR: 1.60; 95 percent CI: 1.03-2.49), and 81.2 percent for Kd versus 64.6 percent for Vd (OR: 2.37; 95 percent CI: 1.62-3.47) in patients without prior lenalidomide exposure.
In patients with one prior line of therapy, grade 3 or higher adverse events were reported in 69.8 percent of patients in the Kd arm and 63.9 percent of patients in the Vd arm. In patients with two or more prior lines of therapy, grade 3 or higher adverse events were reported in 76.6 percent of patients in the Kd arm and 69.9 percent of patients in the Vd arm.
EHA Abstract #E1267: Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone: Subgroup Analysis of Patients with Relapsed Multiple Myeloma by Baseline Cytogenetic Risk Status (Phase 3 ENDEAVOR Study)
This pre-planned subgroup analysis evaluated the efficacy and safety outcomes in patients treated with Kd versus Vd according to patients’ baseline cytogenetic risk status.

In the high-risk group, median PFS was 8.8 months (95 percent CI: 6.9-11.3) for Kd-treated patients (n=97) versus 6.0 months for Vd-treated patients (n=113) (95 percent CI: 4.9-8.1) (HR: 0.646; 95 percent CI: 0.453-0.921). ORRs (≥ partial response) were 72.2 percent for Kd-treated patients versus 58.4 percent for Vd-treated patients. Median duration of response was 10.2 months for Kd versus 8.3 months for Vd.
In the standard-risk group, median PFS was NE (95 percent CI: 18.7-NE) for Kd-treated patients (n=284) compared to 10.2 months (95 percent CI: 9.3-12.2) for Vd-treated patients (n=291) (HR: 0.439; 95 percent CI: 0.333-0.578). ORRs were 79.2 percent for Kd-treated patients versus 66.0 percent for Vd-treated patients. Median duration of response was NE for Kd versus 11.7 months for Vd.
Grade 3 or higher adverse events were reported at higher rates with Kd versus Vd in both the high and standard-risk groups (70.1 percent versus 63.1 percent and 73.9 percent versus 68.3 percent, respectively).
EHA Abstract #E1274: Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: Analysis of the Phase 3 ENDEAVOR Study by Age Subgroup
This pre-planned subgroup analysis evaluated results of the ENDEAVOR study according to patients’ age (younger than 65, 65-74, and 75 and older). Of the 929 patients enrolled, 223 patients received Kd and 210 received Vd in the <65 years subgroup; 164 patients received Kd and 189 received Vd in the 65-74 years subgroup; and 77 patients received Kd and 66 received Vd in the ≥75 years subgroup.

For patients younger than 65 years, median PFS was NE for Kd-treated patients compared to 9.5 months for Vd-treated patients (HR: 0.58; 95 percent CI: 0.44-0.77). ORRs were 74 percent in the Kd arm versus 61 percent in the Vd arm (OR: 1.82; 95 percent CI: 1.21-2.74).
For patients aged 65–74 years, median PFS was 15.6 months for Kd-treated patients versus 9.5 months for Vd-treated patients (HR: 0.53; 95 percent CI: 0.38-0.73). ORRs were 77 percent in the Kd arm versus 66 percent in the Vd arm (OR: 1.80; 95 percent CI: 1.12-2.89).
For patients aged 75 years and older, median PFS was 18.7 months for Kd-treated patients versus 8.9 months for Vd-treated patients (HR: 0.38; 95 percent CI: 0.23-0.65). ORRs were 84 percent in the Kd arm versus 59 percent in the Vd arm (OR: 3.75; 95 percent CI: 1.71-8.24).
Grade ≥3 hypertension, dyspnea, cardiac failure, renal failure were more common with Kd versus Vd. Deaths within 30 days post-study drug due to adverse events occurred.
EHA Abstract #E1328: Outcomes for Asian Patients With Relapsed Multiple Myeloma Treated With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone: A Subgroup Analysis of the Phase 3 ENDEAVOR Study
This pre-planned subgroup analysis evaluated the efficacy and safety outcomes in Asian patients (n=109) with relapsed multiple myeloma from the ENDEAVOR study. The majority of patients were from Japan (n=44; 40.4 percent), followed by Taiwan (n=24; 22.0 percent), Singapore (n=20; 18.3 percent), Republic of Korea (n=16; 14.7 percent), and Thailand (n=5; 4.6 percent).

Median PFS follow-up was 8.4 months for Kd-treated patients and 7.6 months for Vd-treated patients. Median PFS was 14.9 months for Kd-treated patients (95 percent CI: 13.1-17.7) compared to 8.8 months for Vd-treated patients (95 percent CI: 6.6-NE) (HR: 0.57; 95 percent CI: 0.29-1.14), representing a greater than six month improvement.
The ORR was 79.6 percent in the Kd arm (95 percent CI: 66.5-89.4) versus 70.9 percent in the Vd arm (95 percent CI: 57.1-82.4) (OR: 1.604; 95 percent CI: 0.664-3.872). The proportion of patients who achieved a best overall response of a >CR was higher in the Kd arm (9.3 percent) versus the Vd arm (1.8 percent). The rate of very good partial response (VGPR) or greater in the Kd arm (63.0 percent) was more than twice of that in the Vd arm (23.6 percent).
Similar patient incidence rates of adverse events, grade 3 or higher adverse events, and grade 3 or higher treatment-related adverse events were observed between the Kd and Vd arms except for higher cardiovascular events and hypertension being observed in Kd arm.
EHA Abstract #P659: Carfilzomib and Dexamethasone Versus Subcutaneous Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: Secondary Analysis from the Phase 3 Study ENDEAVOR
This subset analysis assessed the efficacy and safety of Kd compared to subcutaneous (SC) delivery of Vd, consistent with current standard of care, and the effect of prior exposure to bortezomib. The analysis compared Kd patients who had selected SC bortezomib delivery pre-randomization if randomized to the Vd arm (n=356) with Vd patients who used SC bortezomib (n=360).

Median PFS has not been reached for patients treated with Kd but was 9.5 months for Vd patients treated with SC bortezomib (HR: 0.58; 95 percent CI: 0.46-0.72). Median overall survival has not been reached for Kd but was 24.3 months for SC Vd (HR: 0.75; 95 percent CI: 0.53-1.08). ORRs were 76.1 percent for Kd-treated patients compared to 64.4 percent for SC Vd-treated patients.
For patients with prior bortezomib exposure, median PFS for Kd was 13.4 months compared to 8.4 months for SC Vd patients (HR: 0.66; 95 percent CI: 0.50-0.87). ORRs were 70.4 percent for Kd-treated patients and 62.1 percent for SC Vd-treated patients.
Grade 3 or higher adverse events were 74.4 percent in the Kd arm and 67.5 percent in the SC Vd arm. For patients with prior bortezomib exposure, grade 3 or higher adverse events were 71.8 percent in the Kd arm compared to 64.5 percent in the SC Vd arm.
EHA Abstract #P663: Efficacy and Safety by Cytogenetic Risk Status: Phase 3 Study (ASPIRE) of Carfilzomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma
This pre-planned subgroup analysis assessed the efficacy and safety of KRd compared with lenalidomide and dexamethasone (Rd) according to baseline cytogenetic risk status in patients with relapsed multiple myeloma who had received one to three prior lines of therapy.

For high-risk patients (n=100) treated with KRd, median PFS was 23.1 months (95 percent CI: 12.5-24.2) compared to 13.9 months (95 percent CI: 9.5-16.7) for patients treated with Rd (HR: 0.639; 95 percent CI: 0.369-1.106). ORRs were 79.2 percent for patients treated with KRd versus 59.6 percent for Rd-treated patients.
In the standard risk group (n=317), median PFS was 29.6 months (95 percent CI: 24.1-NE) and 19.5 months (95 percent CI: 14.8-26.0), respectively (HR: 0.657; 95 percent CI: 0.480-0.901). ORRs for KRd-treated patients were 91.2 percent compared to 73.5 percent for patients treated with Rd.
Rates of grade 3 or higher adverse events were 89.1 percent for KRd-treated patients compared to 78.4 percent for Rd-treated patients in the high-risk group, and 85.6 percent for KRd-treated patients versus 84.5 percent for Rd-treated patients in the standard risk group.
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.2-4 In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year and 24,000 patient deaths are reported on an annual basis.2 Worldwide, more than 230,000 people are living with multiple myeloma.2

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

About Kyprolis (carfilzomib)
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed.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, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, Russia and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.

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.

For more information on Kyprolis in the U.S. please visit www.kyprolis.com.

Important EU Product Safety Information

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy. The most serious side effects that may occur during Kyprolis treatment include: Cardiac toxicity, pulmonary toxicities, pulmonary hypertension, dyspnea, hypertension including hypertensive crises, acute renal failure, tumor lysis syndrome, infusion reactions, thrombocytopenia, hepatic toxicity, posterior reversible encephalopathy syndrome (PRES) and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). The most common side effects are anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough and peripheral edema.

Please refer to the Summary of Product Characteristics for full European prescribing information.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection

INDICATION(S)

KYPROLIS (carfilzomib) is indicated 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.
KYPROLIS (carfilzomib) is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.
IMPORTANT U.S. 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.
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 neuroradiological 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 events 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 events occurring in at least 20% of patients treated with KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

On June 10, 2016 Diadexus, Inc. (OTCQB: DDXS), a diagnostics company developing and commercializing products that aid in assessing the prognosis of cardiac disease, reported that it is filing for relief under Chapter 7 of Title 11 of the US Bankruptcy Code in order to initiate an orderly liquidation of the assets of the Company (Press release, diaDexus, JUN 10, 2016, View Source [SID:1234513213]). The Company has been notified that its lender, Oxford Finance LLC, exercised certain of its rights under the August 2014 Loan and Security Agreement, including with respect to acceleration of obligations and demand for repayment and the removal of all of the available cash and investments from the accounts of the Company.

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The Chapter 7 case will be filed in the US Bankruptcy Court for Northern District of California. Upon the filing, a Chapter 7 trustee will be appointed in the case and the assets of the Company will be liquidated in accordance with the bankruptcy code. Additional information on the process may be obtained through the bankruptcy court.

The Company has been in discussions with Oxford Finance LLC for several months in an attempt to restructure its current loan agreement and reduce near-term financial constraints on its business but has been unable to reach an agreement. As of March 31, 2016, $13.3 million in principal remained outstanding under the Loan and Security Agreement with Oxford. As part of this process, the Company engaged Alvarez & Marsal Healthcare Industry Group, LLC as its restructuring advisor.

The Company also announced that Leone Patterson, the Company’s Chief Financial Officer (CFO) since March 2015, has notified Diadexus that she will be leaving effective immediately.

On June 10, 2016 Novartis reported Phase III data from RESPONSE-2 showing that Jakavi (ruxolitinib) helped patients with polycythemia vera (PV), who did not have an enlarged spleen and were resistant to or intolerant of hydroxyurea, achieve superior hematocrit control compared to best available therapy (BAT) at 28 weeks (62.2% vs 18.7%, respectively; p<0.0001)[1] (Press release, Novartis, JUN 10, 2016, View Source [SID:1234513182]). The findings were presented for the first time at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) in Copenhagen, Denmark.

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Polycythemia vera is a rare and incurable blood cancer associated with an overproduction of blood cells that can cause serious cardiovascular complications, such as blood clots, stroke and heart attack[4]. As the disease progresses, the spleen can become enlarged as it works to clear a greater number of blood cells than normal[5]. In this study, patients did not have an enlarged spleen as assessed by physical examination at baseline (spleen palpation) and a majority (approximately 70%) were previously treated with hydroxyurea only, therefore considered less advanced. The remaining patients were treated with multiple lines of therapy (approximately 30%)[1].

"RESPONSE-2 is the first study of this scale to focus on patients with inadequately controlled polycythemia vera in a less advanced phase of the disease," said lead study investigator, Francesco Passamonti, MD, the University of Insubria, Varese, Italy. "The study supports the use of Jakavi as a second-line treatment option to help this patient population gain better control of their disease."

Patients with PV in the study were classified as inadequately controlled based on the modified European LeukemiaNet (ELN) criteria, which defines resistance to or intolerance of hydroxyurea as hematocrit levels greater than 45%, elevated white blood cell count and/or platelet count, and the presence of hydroxyurea-related non-hematologic toxicities[6].

"Given the limited research and treatment options for polycythemia vera, this trial was initiated to gain a better understanding of Jakavi in patients whose disease is not adequately controlled with hydroxyurea," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The results demonstrate the potential benefit of Jakavi to help manage the disease in patients who have few other options."

In addition to meeting its primary endpoint of proportion of patients achieving hematocrit control, the RESPONSE-2 study showed that nearly five times more patients with PV achieved complete hematologic remission with Jakavi compared to BAT at 28 weeks (23.0% vs 5.3%, respectively; p=0.0019). Patients taking Jakavi also experienced complete resolution of their symptoms related to PV compared to BAT (50.0% vs 7.7%, respectively). Overall, Jakavi was well tolerated. Findings from this study are consistent with data from the RESPONSE pivotal trial evaluating patients with inadequately controlled PV with an enlarged spleen[1,2].

Additionally, Phase III data from the COMFORT-I study were also presented at EHA (Free EHA Whitepaper). These data suggest an overall survival advantage in patients with intermediate-2 or high-risk myelofibrosis (MF) randomized to Jakavi compared to patients randomized to placebo. The five-year survival showed a 31% reduced risk of death (HR=0.69; 95% CI: 0.50, 0.96; p=0.025) in the Jakavi arm despite more than 70% of patients randomized to the placebo arm crossing over to receive treatment with Jakavi (median time to crossover was 41.1 weeks). Patients treated with Jakavi maintained spleen response (>=35% reduction in size) for an average of three years. These findings further support the durable efficacy and long-term safety profile of Jakavi in MF[3].

About the RESPONSE-2 Study
The Phase IIIb RESPONSE-2 (Randomized Study of Efficacy and Safety in POlycythemia Vera with JAK INhibitor Ruxolitinib VerSus BEst Available Care) study evaluated the efficacy and safety of Jakavi versus BAT. The trial randomized 149 patients with PV who were resistant to or intolerant of hydroxyurea, dependent on phlebotomy for hematocrit control and did not have an enlarged spleen. Patients were randomized 1:1, to receive either Jakavi (10 mg twice daily) or BAT, which was defined as investigator-selected monotherapy or observation only[1].

The primary endpoint of the trial was the proportion of patients who achieved hematocrit control at week 28 (without phlebotomy from week 8 to 28 with no more than one phlebotomy eligibility between randomization and week 8). The key secondary endpoint was the proportion of patients who achieved complete hematologic remission (CHR) at week 28. CHR was defined as achieving hematocrit control without the use of phlebotomy, platelet count <=400 x 109/L and white blood cell count <=10 × 109/L, which are all important markers of disease control in PV[1].

In the study, anemia occurred in 16.2% of patients in the Jakavi-treatment arm compared to 2.7% in the BAT arm. The most common non-hematologic adverse events (>=10% of patients) in either the Jakavi or BAT arm were headache (12.2% vs 10.7%, respectively), constipation (10.8% vs 5.3%, respectively), hypertension (10.8% vs 4.0%, respectively), pruritus (10.8% vs 20.0%, respectively), and weight increase (10.8% vs 1.3%, respectively), which were mainly Grade 1 or 2. Patients treated with Jakavi had fewer thromboembolic events compared to patients taking BAT (1 vs 3, respectively)[1].

About the COMFORT-I Study
The Phase III COMFORT-I (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study included 309 patients with primary MF, post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF) in 89 study locations in Canada, Australia and the United States. Half of the patients (155) received Jakavi (starting dose 15 or 20 mg twice daily) and half (154) received placebo. Patients receiving placebo could crossover to the Jakavi arm after the primary analysis or at any time if they had pre-specified worsening of their enlarged spleen. A final analysis of the study at five years was performed to evaluate the safety and efficacy of Jakavi in patients with MF[3].

Notable adverse events (AE) at the five-year analysis included herpes zoster (10.3% and 13.5% in Jakavi patients and patients who crossed over from placebo, respectively), basal cell carcinoma (7.7% and 9.0%, respectively) and acute myeloid leukemia (5 patients in each arm)[3].

About Polycythemia Vera
Polycythemia vera affects up to three per 100,000 people globally each year[7]. The disease is driven by the dysregulation of the JAK-STAT pathway[8]. It is typically characterized by elevated hematocrit, the volume percentage of red blood cells in whole blood, which can lead to a thickening of the blood and an increased risk of blood clots, as well as an elevated white blood cell and platelet count[4]. This can cause serious cardiovascular complications, such as stroke and heart attack, resulting in increased morbidity and mortality[9]. PV can also persist for many years and in some cases evolve to myelofibrosis (post-PV MF) or acute myeloid leukemia (AML)[10].

A common PV treatment includes phlebotomy, a procedure to remove blood from the body to reduce the concentration of red blood cells, which is used to help maintain a hematocrit level below 45%[4,9]. However, for a subset of patients, phlebotomy may be unsuitable as a permanent treatment option due to its inability to control symptoms or effectively manage the overproduction of red blood cells, therefore cytoreductive agents, such as hydroxyurea, may be added[9]. For patients requiring phlebotomy in combination with hydroxyurea, hematocrit may fluctuate and remain at unsafe levels for significant periods of time[11]. Unfortunately, approximately 25% of patients with PV become resistant to or intolerant of hydroxyurea treatment according to ELN criteria, resulting in inadequate disease control and an increased risk of progression[12].

About Myelofibrosis
Myelofibrosis is a rare and life-threatening blood cancer that affects approximately one in every 100,000 people and has similar survival rates as other malignancies, such as breast cancer and colon cancer[7,13,14,15,16]. In patients with MF, their bone marrow can no longer produce enough normal blood cells, causing the spleen to enlarge[13]. As a result, patients may suffer from debilitating symptoms and have a poor quality of life[17]. Approximately 90% of patients with MF have mutations that directly or indirectly activate the JAK/STAT signaling pathway, which may explain the development of the disease[18].

Although allogeneic stem cell transplantation may cure MF, the procedure is associated with significant morbidity and transplant-related mortality, and is available to less than 5% of patients who are young and fit enough to undergo the procedure[19].

About Jakavi
Jakavi (ruxolitinib) is an oral inhibitor of the JAK 1 and JAK 2 tyrosine kinases. Jakavi is approved by the European Commission for the treatment of adult patients with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea and for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (MF) (also known as chronic idiopathic MF), post-polycythemia vera MF or post-essential thrombocythemia MF. Jakavi is approved in more than 95 countries for patients with MF, including countries in the European Union, Canada, Japan and countries in Asia, Latin and South America, and in 60 countries for patients with PV, including countries in the European Union, Japan and Canada. The exact indication for Jakavi varies by country. Additional worldwide regulatory filings are underway in MF and PV.

Novartis licensed ruxolitinib from Incyte Corporation for development and commercialization outside the United States. Jakavi is marketed in the United States by Incyte Corporation as Jakafi for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea and for the treatment of patients with intermediate or high-risk MF.

The recommended starting dose of Jakavi in PV is 10 mg given orally twice daily. The recommended starting dose of Jakavi in MF is 15 mg given orally twice daily for patients with a platelet count between 100,000 cubic millimeters (mm3) and 200,000 mm3, and 20 mg twice daily for patients with a platelet count of >200,000 mm3. Doses may be titrated based on safety and efficacy. There is limited information to recommend a starting dose for MF and PV patients with platelet counts between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these patients is 5 mg twice daily, and patients should be titrated cautiously[20].

Jakavi is a registered trademark of Novartis AG in countries outside the United States. Jakafi is a registered trademark of Incyte Corporation. The safety and efficacy profile of Jakavi has not yet been established outside the approved indications.

Jakavi Important Safety Information for Treatment of Myelofibrosis (MF) and Polycythemia Vera (PV)
Jakavi can cause serious side effects, including a decrease in blood cell count and infections. Complete blood count monitoring is recommended. Dose reduction or interruption may be required in patients with any hepatic impairment or severe renal impairment or in patients developing hematologic adverse reactions such as thrombocytopenia, anemia and neutropenia. Dose reductions are also recommended when Jakavi is co-administered with strong CYP3A4 inhibitors or fluconazole. Use of Jakavi during pregnancy is not recommended, and women should avoid becoming pregnant during Jakavi therapy. Women taking Jakavi should not breast feed. Progressive multifocal leukoencephalopathy (PML) has been reported. Physicians should be alert for neuropsychiatric symptoms suggestive of PML. Hepatitis B viral load (HBV-DNA titer) increases have been reported in patients with chronic HBV infections. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines. Non-melanoma skin cancer (NMSC) has been reported in Jakavi treated patients. Periodic skin examination is recommended. Very common adverse reactions in MF (>10%) include urinary tract infections, anemia, thrombocytopenia, neutropenia, hypercholesterolemia, dizziness, headache, alanine aminotransferase increased, aspartate aminotransferase increased, bruising and weight gain. Common adverse reactions in MF (1 to 10%) include herpes zoster and flatulence. Uncommon adverse reactions in MF include tuberculosis. Very common adverse reactions in PV (>10%) include anemia, thrombocytopenia, hypercholesterolemia, hypertriglyceridemia, dizziness, alanine aminotransferase increased and aspartate aminotransferase increased. Common adverse reactions in PV (1 to 10%) include urinary tract infections, herpes zoster, weight gain, constipation and hypertension.

Please see full Prescribing Information available at www.jakavi.com (link is external).

On June 10, 2016 Stemline Therapeutics, Inc. (Nasdaq:STML) reported that its SL-401 Phase 2 clinical data in blastic plasmacytoid dendritic cell neoplasm (BPDCN) will be the subject of an oral presentation this weekend at the 21st Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) being held in Copenhagen, Denmark (Press release, Stemline Therapeutics, JUN 10, 2016, View Source [SID:1234513196]).

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Details on the EHA (Free EHA Whitepaper) presentation are as follows:

Title: Results from ongoing Phase 2 registration study of SL-401 in patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Presenter: Naveen Pemmaraju, M.D., MD Anderson Cancer Center
Abstract No.: S812
Session: Treatment in Specific AML Subgroups
Date/Time: Sunday, June 12, 2016; 9:00 – 9:15 AM CET
Location: Hall C13

Ivan Bergstein, M.D., Stemline’s Chief Executive Officer, commented, "We believe the selection by the EHA (Free EHA Whitepaper) of the SL-401 clinical results in BPDCN for oral presentation, to be delivered this weekend, highlights SL-401’s significant clinical activity in BPDCN, a devastating malignancy of high unmet medical need. Awareness of BPDCN is increasing across both the U.S. and Europe, driven in part by the emergence of this targeted agent, its high level of activity, and a greater understanding of the BPDCN diagnostic criteria."

Dr. Bergstein concluded, "Over the remainder of the year, we plan to continue to enroll first-line and relapsed/refractory patients in this ongoing trial and advance our ongoing interactions with the regulatory authorities. Our goal is to bring this promising agent to market as soon as possible."

On June 9, 2016 argenx (Euronext Brussels: ARGX), a clinical-stage biopharmaceutical company focused on creating and developing differentiated therapeutic antibodies for the treatment of cancer and severe autoimmune diseases, reported the presentation of efficacy and safety data from its Phase 1 expansion study of ARGX-110 in patients with T-cell lymphoma (TCL) during an e-poster session at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (Copenhagen, Denmark) (Press release, arGEN-X, JUN 9, 2016, View Source [SID:1234513200]).

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The data from the Phase 1 expansion study show evidence of clinical and/or biological anti-tumor activity with ARGX-110 in highly refractory cutaneous TCL & peripheral TCL patients with confirmed overexpression of CD70. The abstract can be accessed here.

"The data presented today during EHA (Free EHA Whitepaper) 2016 are very encouraging and further support the important role of CD70 in the TCL patient population. We are seeing signs of biological activity in both CTCL and PTCL patients that have failed standard therapy, as well as favourable safety profiles, so we are eager to present the full data set later this year in this critical indication," said Tim van Hauwermeiren, Chief Executive Officer of argenx. "We remain on track with patient recruitment, which we expect to complete by mid 2016."

About ARGX-110

ARGX-110 is a SIMPLE Antibody targeting CD70, an immune checkpoint target involved in hematological malignancies, several solid tumors and severe autoimmune diseases. ARGX-110 works in three ways: i) blocks growth of tumor cells, ii) kills cancer cells and iii) restores immune surveillance against tumors (Silence K. et al. mAbs 2014; 6 (2):523-532). ARGX-110 is currently being evaluated in both hematological and solid tumors.