On September 25, 2015 Amgen (NASDAQ:AMGN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted positive opinions recommending marketing authorization for:

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Kyprolis (carfilzomib) in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (Press release, Amgen, SEP 25, 2015, View Source [SID:1234507550]).
BLINCYTO (blinatumomab) as a conditional marketing authorization for the treatment of adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

"We are pleased to receive positive CHMP opinions for Kyprolis and BLINCYTO as this is an important step in providing new treatment options for patients in Europe with rare forms of cancer," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "For patients with multiple myeloma, periods of remission become shorter following each new treatment regimen, underscoring the need for additional treatment options. The results of the ASPIRE study demonstrate that Kyprolis extended the time patients live without their disease progressing. Additionally, there is a critical need for new therapies for patients with relapsed or refractory B-cell precursor ALL."

Kyprolis is a proteasome inhibitor for use in the treatment of patients with relapsed multiple myeloma. Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed. Kyprolis blocks proteasomes, which leads to an excessive build-up of proteins within cells. 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.

BLINCYTO is the first clinical validation of the bispecific T cell engager (BiTE) platform, an innovative approach that can help the body’s own immune system fight cancer.

The CHMP positive opinions will now be reviewed by the European Commission and if granted, the two products will have marketing authorization in the 28 member countries of the European Union (EU), as well as Iceland, Lichtenstein and Norway.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse. Multiple myeloma is an orphan disease and accounts for approximately 1 percent of all cancers1,2.

About Kyprolis (carfilzomib)
Kyprolis was granted orphan drug designation by the EMA in 2008, and in February 2015, its Marketing Authorization Application (MAA) was granted accelerated assessment by the EMA. Kyprolis (carfilzomib) for Injection was approved as a monotherapy in the U.S. in July 2012, and in combination with lenalidomide and dexamethasone in July 2015. Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico and Thailand.

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 about Kyprolis, visit www.kyprolis.com.

About Kyprolis European Marketing Authorization Application
The MAA was based on data from the Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial. The study showed that patients treated with Kyprolis in combination with lenalidomide and dexamethasone (regimen referred to as KRd) had increased median time to progressive disease (PD) or death by 8.7 months compared to patients treated with lenalidomide and dexamethasone (regimen referred to as Rd) (26.3 months for KRd compared to 17.6 months for Rd with HR=0.69; 95 percent CI: 0.57-0.83; 1-sided p<0.0001). Discontinuation of treatment due to adverse events (AEs) occurred in 15 percent of patients in the KRd arm versus 18 percent of patients in the Rd arm.

About ASPIRE
The international, randomized Phase 3 ASPIRE trial evaluated Kyprolis in combination with lenalidomide and dexamethasone, versus lenalidomide and dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was progression-free survival (PFS), defined as the time from randomization to disease progression or death due to any cause, whichever is earlier. The study showed that patients treated with Kyprolis in combination with lenalidomide and low-dose dexamethasone had increased median time to PD or death by 8.7 months compared to patients treated with lenalidomide and dexamethasone (26.3 months for KRd compared to 17.6 months for Rd with HR=0.69; 95 percent CI: 0.57-0.83; 1-sided p<0.0001). Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one only, escalating to 27 mg/m2 subsequently), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and dexamethasone (40 mg per week in 4 week cycles), versus lenalidomide and dexamethasone alone. In the Kyprolis arm, patients were given a 10 minute infusion on days 1, 2, 8, 9, 15 and 16. Kyprolis was omitted on days 8 and 9 during cycles 13-18 and not administered beyond 18 cycles. The study randomized 792 patients at sites in North America, Europe and Israel.

While the data for median OS are not yet mature based on the prespecified statistical boundary at the interim (1-sided p-value of smaller than 0.0051), the analysis showed a trend in favor of KRd compared with Rd (HR=0.79; 95 percent CI: 0.63-0.99; one-sided p=0.018, two-sided p=0.04). Patients continue to be monitored for OS. The ORR was 87.1 percent with KRd and 66.7 percent with Rd. Median DOR was 28.6 months for patients receiving KRd (95 percent CI, 24.9 to 31.3 months) and 21.2 months for patients receiving Rd (95 percent CI, 16.7 to 25.8 months). In the KRd and Rd groups, 32 percent versus 9 percent of patients achieved a complete response or higher (stringent complete response [sCR] or complete response [CR]), a measurement indicating depth of response.

The rate of deaths due to AEs within 30 days of the last dose was balanced between the KRd arm and the Rd arm. The most common causes of death not due to PD occurring in patients in the KRd arm compared to the Rd arm included cardiac disorders (3 percent versus 2 percent), infection (2 percent versus 3 percent), renal (0 percent versus less than 1 percent) and other AEs (2 percent versus 3 percent). Serious AEs were reported in 60 percent of the patients in the KRd arm and 54 percent of the patients in the Rd arm. The most common serious AEs reported in the KRd arm compared to the Rd arm were pneumonia (14 percent versus 11 percent), respiratory tract infection (4 percent versus 2 percent), pyrexia (4 percent versus 2 percent) and pulmonary embolism (3 percent versus 2 percent). Discontinuation of treatment due to AEs occurred in 15 percent of patients in the KRd arm versus 18 percent of patients in the Rd arm. AEs leading to discontinuation of Kyprolis occurred in 12 percent of patients and the most common events included pneumonia (1 percent), myocardial infarction (1 percent) and upper respiratory tract infection (1 percent).

The ASPIRE data were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) and published in The New England Journal of Medicine in December 2014.3

About Acute Lymphoblastic Leukemia (ALL)
It is estimated that there are close to 600 adults with Ph- relapsed or refractory B-precursor ALL in France, Germany, Italy, Spain, and the U.K.4

About BLINCYTO (blinatumomab)
BLINCYTO is a bispecific CD19-directed CD3 T cell engager (BiTE) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

BiTE antibody constructs are a type of immunotherapy being investigated for fighting cancer by helping the body’s immune system to detect and target malignant cells. The modified antibodies are designed to engage two different targets simultaneously, thereby juxtaposing T cells (a type of white blood cell capable of killing other cells perceived as threats) to cancer cells. BiTE antibody constructs help place the T cells within reach of the targeted cell, with the intent of allowing T cells to inject toxins and trigger the cancer cell to die (apoptosis). BiTE antibody constructs are currently being investigated for their potential to treat a wide variety of cancers.

BLINCYTO was granted breakthrough therapy and priority review designations by the U.S. Food and Drug Administration, and is now approved in the U.S. for the treatment of Ph- relapsed or refractory B-cell precursor ALL. This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

About BLINCYTO European Conditional Marketing Authorization Application
The CHMP recommended granting BLINCYTO a conditional marketing authorization for the treatment of adults with Ph- relapsed or refractory B-precursor ALL.

Conditional license requires the license to be renewed every year and it will be converted to full standard license once post-licensing commitments have been fulfilled. Amgen expects a decision on the conditional MAA from the European Commission in the coming months.

The BLINCYTO conditional marketing authorization application is based on results of the ‘211 and ‘206 trials. In the ‘211 study:

42.9 percent of evaluable patients receiving BLINCYTO achieved complete remission or complete remission with partial hematological recovery (CR/CRh*).

17 percent of patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) in CR/CRh* induced with BLINCYTO
82.2 percent of those who achieved CR/CRh* achieved deep molecular remission, or minimal residual disease (MRD) response, a measure of eradication of residual disease at the molecular level.

The most serious adverse reactions included: infections (31.7 percent), neurologic events (16.4 percent), neutropenia/febrile neutropenia (15.3 percent), cytokine release syndrome (0.5 percent) and tumor lysis syndrome (0.5 percent).

About Study ‘211
Study ‘211 evaluated blinatumomab in an open-label, multicenter, single-arm Phase 2 study. Eligible patients were at least 18 years of age with Ph- relapsed or refractory B-precursor ALL. Relapsed or refractory was defined as relapsed with a first remission duration of less than or equal to 12 months in first salvage, or relapsed or refractory after the first salvage, or relapsed within 12 months of allogeneic hematopoietic stem cell transplantation (HSCT), and greater than or equal to 10 percent blasts in bone marrow. The primary endpoint was the CR/CRh* rate within two cycles of blinatumomab. Of the 189 patients evaluated in the trial, 42.9 percent (81/189; 95 percent CI, 35.7 – 50.2) achieved CR or CRh* within two cycles of treatment with blinatumomab with the majority of responses (79 percent [64/81]) occurring within the first cycle of treatment. In a prespecified exploratory analysis, 82.2 percent (60/73) of MRD evaluable patients with CR/CRh* also had a MRD response. The most common adverse reactions (greater than 20 percent) were infusion-related reactions (67.2 percent), infections (63 percent), pyrexia (59.8 percent), headache (34.4 percent), febrile neutropenia (28 percent), peripheral edema (25.9 percent), nausea (24.3 percent), hypokalemia (23.8 percent), constipation (20.6 percent) and anemia (20.1 percent). The most serious adverse reactions that occurred during blinatumomab treatment included: infections (31.7 percent), neurologic events (16.4 percent), neutropenia/febrile neutropenia (15.3 percent), cytokine release syndrome (0.5 percent) and tumor lysis syndrome (0.5 percent).

About Study ‘206
Study ‘206 evaluated the safety and efficacy of blinatumomab in an open-label, multicenter, dose-escalation Phase 2 study of 36 patients, who were at least 18 years of age with B-precursor ALL relapsed after at least induction and consolidation or having refractory disease with greater than 5 percent blasts in bone marrow, had an Eastern Cooperative Oncology Group (ECOG) performance status of at most 2, had a life expectancy of at least 12 weeks, and who did not have autologous HSCT within six weeks prior to start of treatment, allogeneic HSCT within three months prior to start of treatment, or previous treatment with blinatumomab.

The CR/CRh* rate was 69.4 percent (25/36) with 15 patients achieving CR (41.7 percent; 95 percent CI, 25.5 percent – 59.2 percent), and 10 patients achieving CRh* (27.8 percent; 95 percent CI, 14.2 percent – 45.2 percent). Of the patients with hematologic CR, 88 percent (22/25) also had MRD responses. The median duration of remission was 8.9 months, and the median relapse-free survival (RFS) was 7.6 months. The median OS was 9.8 months. Overall safety results from this study were consistent with the known blinatumomab safety profile.

Kyprolis U.S. Product Safety Information

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection U.S. Indication
This safety information is specific to the current U.S. approved indication

Cardiac Toxicities
New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, and decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/risk assessment.

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, and conduction abnormalities may be at greater risk for cardiac complications.

Acute Renal Failure
Cases of acute renal failure and renal insufficiency adverse events (renal impairment, acute renal failure, and 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. This risk was greater in patients with a baseline reduced estimated creatinine clearance. 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 and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Infusion Reactions
Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. 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. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura /Hemolytic Uremic Syndrome (TTP/HUS)
Cases of 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 and the potential hazard to the fetus if Kyprolis is used during pregnancy.

ADVERSE REACTIONS
The most common adverse events occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral.

The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

Full U.S. prescribing information is available at www.kyprolis.com.

BLINCYTO U.S. Product Safety Information
Important Safety Information Regarding BLINCYTO (blinatumomab) U.S. Indication
This safety information is specific to the current U.S. approved indication.
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Neurological toxicities, which may be severe, life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended.
Contraindications
BLINCYTO is contraindicated in patients with a known hypersensitivity to blinatumomab or to any component of the product formulation.

Warnings and Precautions
Cytokine Release Syndrome (CRS): Life-threatening or fatal CRS occurred in patients receiving BLINCYTO. Infusion reactions have occurred and may be clinically indistinguishable from manifestations of CRS. Closely monitor patients for signs and symptoms of serious events such as pyrexia, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin (TBILI), disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Interrupt or discontinue BLINCYTO as outlined in the Prescribing Information (PI).

Neurological Toxicities: Approximately 50% of patients receiving BLINCYTO in clinical trials experienced neurological toxicities. Severe, life-threatening, or fatal neurological toxicities occurred in approximately 15% of patients, including encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The median time to onset of any neurological toxicity was 7 days. Monitor patients for signs or symptoms and interrupt or discontinue BLINCYTO as outlined in the PI.

Infections: Approximately 25% of patients receiving BLINCYTO experienced serious infections, some of which were life-threatening or fatal. Administer prophylactic antibiotics and employ surveillance testing as appropriate during treatment. Monitor patients for signs or symptoms of infection and treat appropriately, including interruption or discontinuation of BLINCYTO as needed.

Tumor Lysis Syndrome (TLS): Life-threatening or fatal TLS has been observed. Preventive measures, including pretreatment nontoxic cytoreduction and on treatment hydration, should be used during BLINCYTO treatment. Monitor patients for signs and symptoms of TLS and interrupt or discontinue BLINCYTO as needed to manage these events.

Neutropenia and Febrile Neutropenia, including life-threatening cases, have been observed. Monitor appropriate laboratory parameters during BLINCYTO infusion and interrupt BLINCYTO if prolonged neutropenia occurs.

Effects on Ability to Drive and Use Machines: Due to the possibility of neurological events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness, and should be advised against driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

Elevated Liver Enzymes: Transient elevations in liver enzymes have been associated with BLINCYTO treatment. The majority of these events were observed in the setting of CRS. The median time to onset was 15 days. Grade 3 or greater elevations in liver enzymes occurred in 6% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor ALT, AST, gamma-glutamyl transferase (GGT), and TBILI prior to the start of and during BLINCYTO treatment. BLINCYTO treatment should be interrupted if transaminases rise to > 5 times the upper limit of normal (ULN) or if TBILI rises to > 3 times ULN.

Leukoencephalopathy: Although the clinical significance is unknown, cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients previously treated with cranial irradiation and anti-leukemic chemotherapy. Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration in the PI strictly to minimize medication errors (including underdose and overdose).

Adverse Reactions
The most commonly reported adverse reactions (≥ 20%) in clinical trials were pyrexia (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), diarrhea (20%) and constipation (20%). Serious adverse reactions were reported in 65% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia, and headache.

U.S. Dosage and Administration Guidelines
BLINCYTO is administered as a continuous intravenous infusion at a constant flow rate using an infusion pump which should be programmable, lockable, non-elastomeric, and have an alarm. It is very important that the instructions for preparation (including admixing) and administration provided in the full Prescribing Information are strictly followed to minimize medication errors (including underdose and overdose). Please see full U.S. Prescribing Information and medication guide for BLINCYTO at www.BLINCYTO.com.

On September 25, 2015 Genmab A/S (OMX: GEN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted accelerated assessment to the Marketing Authorization Application (MAA) for daratumumab (Press release, Genmab, SEP 25, 2015, View Source [SID:1234507548]). The MAA is for daratumumab as a treatment for patients with relapsed and refractory multiple myeloma. The MAA was submitted to the EMA on September 9, 2015 by Janssen-Cilag International NV. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

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The CHMP grants accelerated assessment when a medicinal product is expected to be of major public health interest particularly from the point of view of therapeutic innovation.

"Patients with multiple myeloma, particularly those who have exhausted all approved treatment options, are waiting for new medicines to treat this incurable disease. An accelerated approval optimizes the potential for daratumumab to provide a new therapy for this patient group more rapidly than under a standard review time," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

The MAA submission includes data from the Phase II study (Sirius MMY2002) of daratumumab in multiple myeloma patients who have received at least three prior lines of therapy including both a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), or who are double refractory to a PI and an IMiD. Safety and efficacy data from the Phase I/II study (GEN501) and safety data from three other studies have also been included in the submission. A regulatory application for daratumumab has also been submitted to the U.S. Food and Drug Administration and has been granted Priority Review with a PDUFA date of March 9, 2016.

About multiple myeloma
Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excess proliferation of plasma cells.1 Multiple myeloma is the third most common blood cancer in the U.S., after leukemia and lymphoma.2 Approximately 26,850 new patients will be diagnosed with multiple myeloma and approximately 11,240 people will die from the disease in the U.S. in 2015.3 Globally, it is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015.4 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.5 Patients who relapse after treatment with standard therapies, including PIs or IMiDs, have poor prognoses and few treatment options.6

About daratumumab
Daratumumab is an investigational human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It induces rapid tumor cell death through multiple immune-mediated mechanisms7, including complement-dependent cytotoxicity7, antibody-dependent cellular phagocytosis8 and antibody-dependent cellular cytotoxicity7, as well as via induction of apoptosis9 . Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma. Daratumumab has been granted Breakthrough Therapy Designation from the US FDA.

On September 25, 2015 Exelixis, Inc. (NASDAQ:EXEL) reported that the European Medicines Agency’s Committee for Medical Products for Human Use (CHMP) has adopted a positive opinion of the Marketing Authorization Application for cobimetinib, a selective MEK inhibitor discovered by Exelixis, in combination with vemurafenib for the treatment of BRAF V600 mutation-positive unresectable or metastatic melanoma (Press release, Exelixis, SEP 25, 2015, View Source [SID:1234507546]).

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The CHMP’s positive opinion will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union. The European Commission is expected to release its final decision regarding the approval of the combination of cobimetinib and vemurafenib by the end of 2015.

"The CHMP’s positive opinion on cobimetinib for use in combination with vemurafenib is an important milestone in bringing this new therapeutic option to patients in Europe," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "We congratulate Genentech and Roche on this latest milestone in the European regulatory process. We also look forward to the regulatory decision anticipated this year in the United States, where we are fully prepared to co-promote cobimetinib with our partners."

The CHMP’s recommendation is based on data from coBRIM, the international, randomized double-blind controlled phase 3 pivotal trial evaluating cobimetinib in combination with vemurafenib in previously untreated patients with unresectable locally advanced or metastatic melanoma harboring a BRAF V600 mutation.

The combination of cobimetinib and vemurafenib recently received its first approval in Switzerland, where cobimetinib is marketed as Cotellic.

The coBRIM trial was conducted by Roche and Genentech, a member of the Roche Group. Genentech filed a New Drug Application (NDA) for cobimetinib in the United States, for which the Prescription Drug User Fee Act action date is November 11, 2015.

About the Cobimetinib Development Collaboration

After discovering cobimetinib internally, Exelixis advanced the product to investigational new drug (IND) status. In late 2006, the company entered into its worldwide collaboration with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib. Under the terms of the collaboration, Exelixis is eligible to receive royalties on sales of cobimetinib outside the United States.

If cobimetinib is approved in the United States, Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share in U.S. marketing and commercialization costs. In November 2013, Exelixis exercised its option to co-promote cobimetinib in the United States and, under the terms of the agreement, the company is prepared to field up to 25 percent of the U.S. sales force.

About the cobimetinib and vemurafenib Combination

Cobimetinib is a selective inhibitor that blocks the activity of MEK, a protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK pathway) that promotes cell division and survival. This pathway is frequently activated in human cancers including melanoma, where mutation of one of its components (BRAF) causes abnormal activation in about 50 percent of tumors. About 50 percent of patients with BRAF mutation positive melanoma experience a tumor response when treated with a BRAF inhibitor, however development of resistance and subsequent tumor progression limits treatment benefit. Clinical and preclinical analyses indicated that reactivation of the MEK-ERK pathway may underlie development of resistance to BRAF inhibitors in many progressing tumors, and that co-treatment with a BRAF and MEK inhibitor delays the emergence of resistance in the preclinical setting, providing the rationale for testing the combination of vemurafenib and cobimetinib in clinical trials. In addition to the combination with vemurafenib in melanoma, cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types, including non-small cell lung cancer, colorectal cancer, triple-negative breast cancer and melanoma.

About Melanoma and its BRAF V600 Mutation-Positive Form

Melanoma is the less common, but more serious category of skin cancer that starts in the skin’s pigment producing cells known as melanocytes. According to the American Cancer Society, approximately five percent of skin cancer diagnoses are melanoma, but melanoma accounts for a large majority of skin cancer deaths. In recent years, there have been significant advances in treatment for metastatic melanoma and people with the disease have more options. However, it continues to be a serious health issue with a high unmet need and a steadily increasing incidence over the past 30 years. It is projected that approximately half of all melanomas, and eight percent of solid tumors, contain a mutation of the BRAF protein. BRAF is a key component of the RAS-RAF-MEK-ERK pathway involved in normal cell growth and survival. However, mutations that keep the BRAF protein in an active state may cause excessive signaling in the pathway, leading to uncontrolled cell growth and survival. The BRAF V600 mutation-positive form of melanoma is associated with high-risk characteristics of the disease, including early onset, the absence of chronic skin damage, and decreased survival.

On September 25, 2015 Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation (NASDAQ: CELG) reported that that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for an expanded indication of VIDAZA (azacitidine for injection) for the treatment of adult patients aged 65 years or older with acute myeloid leukaemia (AML) who are not eligible for haematopoietic stem cell transplantation (HSCT) (Press release, Celgene, SEP 25, 2015, View Source [SID:1234507540]).

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The expanded indication now covers patients who have > 30% myeloblasts according to the WHO classification; previously, the indication covered AML patients with < 30% blasts.

Myeloblasts are white cells in the bone marrow; in AML, their functioning is disrupted and results in numerous non-functioning white cells, which can potentially interfere with the body’s ability to control infections and can lead to anaemia and haemorrhages.

For many patients, AML is typically associated with a poor prognosis and deteriorating quality of life, particularly for those patients who cannot tolerate curative therapies like stem cell transplantation. In Europe, more than 14,000 people suffer from AML, and most of these patients will die within less than 1 year. As an acute leukaemia, AML progresses rapidly and is typically fatal within months if stem cell transplant is not an option. Specific to elderly patients, overall survival with AML has not improved in more than 40 years1, and there is a clear need for treatments that can support this patient population.

"While progress has been made in treating younger, fitter AML patients who can undergo intensive and potentially curative therapies such as stem cell transplant, there is still a clear need for treatments for elderly and more frail patients," said Hervé Dombret, M.D., Chief, Blood Disease Department (Leukaemia Unit), University Hospital Saint-Louis, AP-HP, Paris, France. "Azacitidine has demonstrated a median overall survival of 10.4 months, and these results suggest that, if approved, azacitidine could provide a valuable treatment option for patients who have limited options today."

Adds Tuomo Pätsi, President of Celgene in Europe, Middle East and Africa (EMEA): "Celgene is committed to bringing innovative medicines to patients with haematological diseases including AML. With the positive CHMP opinion for VIDAZA in AML, Celgene has an opportunity to advance the treatment options available to patients with AML. And, we will continue to focus on meeting the unmet needs of patients with myeloid disease, as we have several partnerships and development programmes that will build on what we are learning about treating these diseases."

The CHMP decision was based on data from AML-001, a global, multi-centre, randomized, open-label pivotal study of patients at least 65 years old with newly diagnosed or secondary AML with > 30% bone marrow blasts. VIDAZA plus best supportive care (n=241) was compared with conventional care regimens (n=247). Median overall survival (OS), the primary endpoint of the study, was 10.4 months (95% CI 8.0-12.7 months) for patients receiving azacitidine compared with 6.5 months (95% CI: 5.0-8.6) for patients receiving conventional treatment regimens (HR=0.85 [95% CI 0.69, 1.03], stratified log-rank p=0.1009). One-year survival rates with azacitidine and conventional treatment regimens were 46.5% and 34.2%, respectively (difference 12.3% [95% CI: 3.5% – 21%]).

In the study, grade 3-4 anaemia, neutropenia, febrile neutropenia, and thrombocytopenia rates, respectively, were 16%, 26%, 28%, and 24% with azacitidine; 5%, 5%, 28%, 5% with best supportive care; 23%, 25%, 30%, 28% with low-dose Ara-Cytarabine; and 14%, 33%, 31%, 21% with intensive chemotherapy.

In addition to recommending the marketing authorisation for the new indication to the European Commission, the CHMP also noted that this new therapeutic indication brings significant clinical benefit in comparison with existing therapies; if the European Commission adopts the CHMP decision in full, VIDAZA will receive extended market protection in all its indications for an additional year throughout the European Economic Area.

The CHMP reviews applications for all 28 member states in the European Union (EU), as well as Norway, Liechtenstein and Iceland. The European Commission, which generally follows the recommendation of the CHMP, is expected to make its final decision within two months. If approval is granted, detailed conditions for the use of this product will be described in the Summary of Product Characteristics (SmPC), which will be published in the revised European Public Assessment Report (EPAR).

The anticipated European Commission decision would add to the portfolio of indications VIDAZA is authorised for across high-risk myeloid diseases, including myelodysplastic syndromes (MDS) and AML. VIDAZA has been approved in the EU since 2008 for the treatment of adult patients ineligible for transplantation diagnosed with intermediate 2 and high-risk MDS; chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder; or acute myeloid leukaemia (AML) with 20-30 % blasts and multi-lineage dysplasia.

In the United States, VIDAZA is not indicated for treatment of patients with AML. VIDAZA is indicated for treatment of patients with the following French-American-British (FAB) myelodysplastic syndrome subtypes: refractory anaemia (RA) or refractory anaemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS:

VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol and in patients with advanced malignant hepatic tumors

WARNINGS AND PRECAUTIONS:

Anemia, Neutropenia and Thrombocytopenia:

Because treatment with VIDAZA causes anemia, neutropenia, and thrombocytopenia, monitor complete blood counts frequently for response and/or toxicity, at a minimum, prior to each dosing cycle

VIDAZA Toxicity in Patients with Severe Pre-existing Hepatic Impairment:

Because azacitidine is potentially hepatotoxic in patients with severe preexisting hepatic impairment, caution is needed in patients with liver disease.

Renal Toxicity:

Azacitidine and its metabolites are primarily excreted by the kidneys and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. These patients, including the elderly should be closely monitored for toxicity

Use in Pregnancy:

VIDAZA may cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be apprised of the potential hazard to the fetus. Men should be advised not to father a child while receiving VIDAZA

USE IN SPECIFIC POPULATIONS:

Nursing Mothers:

Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother

ADVERSE REACTIONS:

In Studies 1 and 2, the most commonly occurring adverse reactions by SC route were nausea (70.5%), anemia (69.5%), thrombocytopenia (65.5%), vomiting (54.1%), pyrexia (51.8%), leukopenia (48.2%), diarrhea (36.4%), injection site erythema (35.0%), constipation (33.6%), neutropenia (32.3%), and ecchymosis (30.5%). Other adverse reactions included dizziness (18.6%), chest pain (16.4%), febrile neutropenia (16.4%), myalgia (15.9%), injection site reaction (13.6%), and malaise (10.9%). In Study 3, the most common adverse reactions by IV route also included petechiae (45.8%), weakness (35.4%), rigors (35.4%), and hypokalemia (31.3%)

In Study 4, the most commonly occurring adverse reactions were thrombocytopenia (69.7%), neutropenia (65.7%), anemia (51.4%), constipation (50.3%), nausea (48.0%), injection site erythema (42.9%), and pyrexia (30.3%). The most commonly occurring Grade 3/4 adverse reactions were neutropenia (61.1%), thrombocytopenia (58.3%), leukopenia (14.9%), anemia (13.7%), and febrile neutropenia (12.6%)

About Acute Myeloid Leukaemia

For many patients, AML is a disease that is associated with a poor prognosis and deteriorating quality of life. AML patients tend to be older with poor-risk features; as such, a large proportion are ineligible for intensive but potentially curative therapies, and while there have been some advances recently, treatment options remain limited. Celgene is committed to providing breakthrough treatments and innovative technologies for patients with AML, including those with a poor prognosis. Multiple Celgene products are under investigation and are at various stages of development in AML.

On September 25, 2015 Bristol-Myers Squibb Company (NYSE:BMY) and Moffitt Cancer Center reported that they have entered into a collaboration agreement as part of Bristol-Myers Squibb’s Immuno-Oncology Rare Population Malignancy (I-O RPM) program in the U.S. The I-O RPM program is a multi-institutional initiative with academic-based cancer centers focused on the clinical investigation of immuno-oncology therapeutics as potential treatment options for patients with high risk, poor prognostic cancers, defined as a rare population malignancy (Press release, Bristol-Myers Squibb, SEP 25, 2015, View Source [SID:1234507539]).

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As part of the I-O RPM program, Bristol-Myers Squibb and Moffitt will conduct a range of early phase clinical studies, including clinical investigations by young investigators to strengthen their development as clinical research scientists.

"Moffitt Cancer Center has had a long-standing commitment to immuno-oncology research, including in partnership with Bristol-Myers Squibb, and we look forward to our continued work with them as part of the I-O RPM program," said Laura Bessen, MD, head of U.S. Medical, Bristol-Myers Squibb.

"This new partnership with Bristol-Myers Squibb will foster new Moffitt investigator-initiated studies for rare tumors and gives our faculty the opportunity to educate research students about innovative clinical trials," said Dan Sullivan, M.D., Associate Center Director for Clinical Science at Moffitt.

About I-O RPM

Immuno-oncology is an innovative approach to cancer research and treatment that is designed to harness the body’s own immune system to fight cancer. The I-O RPM program focuses on significant areas of high unmet need marked by poor outcomes among patients with rare population malignancies. A rare population malignancy is a subpopulation within a higher incident disease population (e.g. BRCA 1 and 2 breast cancer). These patients have aggressive disease with an increased potential for early metastasis to multiple sites and/or are initially refractory or subject to early recurrences with conventional cancer therapies. Existing clinical research provide a strong rationale for further research into the potential of immunotherapies for these cancers.

The I-O RPM builds on Bristol-Myers Squibb’s formation in 2012 of the International Immuno-Oncology Network (II-ON). II-ON is a global collaboration between Bristol-Myers Squibb and academia focused on facilitating the translation of scientific research findings into clinical trials and, eventually, clinical practice.