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Celgene Receives Positive CHMP Opinion for ABRAXANE(R) for First-Line Treatment of Patients with Non-Small Cell Lung Cancer

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Celgene International S`arl, a wholly owned subsidiary of Celgene Corporation (NASDAQ:CELG) , today announced that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for ABRAXANE(R) (paclitaxel formulated as albumin-bound nanoparticles, or nab-paclitaxel) in combination with carboplatin for the first-line treatment of non-small cell lung cancer in adult patients who are not candidates for potentially curative surgery and/or radiation therapy.

Lung cancer is the fourth most commonly diagnosed cancer in both men and women, however it is the leading cause of cancer-related mortality in Europe. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for 85 to 90% of all cases. The predominant cause of lung cancer is cigarette smoking, although environmental and occupational factors also can cause the cancer. Treatment options generally include systemic chemotherapy or protein kinase inhibitors. In the most advanced cases, only the symptoms of the disease can be managed; there is a clear need for innovative new medicines for the treatment of lung cancer.

“Progress in lung cancer will come first from early diagnosis with patients presenting promptly with symptoms and second, with new drugs that are well tolerated and improve on current therapies. Incremental steps can lead to a meaningful impact on patients and society, given the frequency and aggressiveness of lung cancer,” says Dr. Mary O’Brien, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, UK. “The positive CHMP opinion for ABRAXANE in combination with carboplatin for the treatment of adult patients with NSCLC is a significant step toward bringing a new treatment option to patients in Europe. The clinical data show patients had a significant positive response rate to the treatment, combined with an established safety profile. The therapy has also shown a significant response benefit for a subset of patients with squamous cell lung cancer, where there have been limited treatment advances in recent years.”

The positive CHMP opinion was based on the results of a multicenter, randomized, open-label study including 1,052 chemotherapy-naive patients with Stage IIIb/IV non-small cell lung cancer. The study compared ABRAXANE in combination with carboplatin versus solvent-based paclitaxel in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. The primary efficacy endpoint, overall response rate, was significantly higher for patients in the ABRAXANE/carboplatin arm at 33%, compared with patients in the control arm, at 25%. The most common adverse reactions

(>= 20%) of ABRAXANE in combination with carboplatin for NSCLC were anaemia, neutropenia, thrombocytopenia, peripheral neuropathy, nausea, and fatigue.

Tuomo P”atsi, President of Celgene in Europe, the Middle East and Africa (EMEA), said, “The positive CHMP opinion is the first opportunity for Celgene to play a role in helping patients with NSCLC have access to an important treatment option in Europe. The anticipated European Commission decision would be the third approved indication for ABRAXANE, underscoring the value of this medicine. We are committed to ensuring that patients who need ABRAXANE will gain access to it once approved by the European Commission.”

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 approximately 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).

ABRAXANE is not currently indicated for the treatment of metastatic NSCLC in the European Union.

About ABRAXANE

ABRAXANE(R) is an albumin-bound form of paclitaxel that is manufactured using patented nab(R) technology. ABRAXANE is formulated with albumin, a human protein, and is free of solvents.

ABRAXANE was first approved in January 2005 by the U.S. Food and Drug Administration (FDA) for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. In Europe, ABRAXANE was approved in January 2008 as monotherapy for the treatment of metastatic breast cancer in adult patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated. ABRAXANE is now approved in more than 50 countries for the treatment of metastatic breast cancer.

In October 2012, ABRAXANE was approved by the FDA for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. ABRAXANE is also approved for the treatment of NSCLC in Argentina, Australia, Chile, Ecuador, Guatemala, Hong Kong, Japan, New Zealand and Singapore.

In September 2013, the FDA approved ABRAXANE as first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. In December 2013, ABRAXANE in combination with gemcitabine was approved for first-line treatment of adult patients with metastatic adenocarcinoma of the pancreas in Europe. ABRAXANE is also approved for the treatment of metastatic pancreatic cancer in more than 40 countries.

U.S. Regulatory Information for ABRAXANE

WARNING – NEUTROPENIA

  • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
  • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS

Neutrophil Counts

  • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3

Hypersensitivity

  • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug

WARNINGS AND PRECAUTIONS

Hematologic Effects

  • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer
  • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer)
  • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
  • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC
  • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1500 cells/mm3 and platelets recover to a level >100,000 cells/mm3
  • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle
  • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended

Nervous System

  • Sensory neuropathy is dose- and schedule-dependent
  • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
  • If >= Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to Grade 1 or 2 for MBC or until resolution to <= Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE

Sepsis

  • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine
  • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis
  • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics
  • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC >=1500 cells/mm3, then resume treatment at reduced dose levels

Pneumonitis

  • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine
  • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis
  • Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis

Hypersensitivity

  • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
  • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug

Hepatic Impairment

  • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
  • Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
  • For MBC and NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
  • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST <=10 x ULN)

Albumin (Human)

  • ABRAXANE contains albumin (human), a derivative of human blood

Use in Pregnancy: Pregnancy Category D

  • ABRAXANE can cause fetal harm when administered to a pregnant woman
  • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
  • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE

Use in Men

  • Men should be advised not to father a child while receiving ABRAXANE

ADVERSE REACTIONS

Randomized Metastatic Breast Cancer (MBC) Study

  • The most common adverse reactions (>=20%) with single-agent use of ABRAXANE vs paclitaxel injection in the MBC study are alopecia (90%, 94%), neutropenia (all cases 80%, 82%; severe 9%, 22%), sensory neuropathy (any symptoms 71%, 56%; severe 10%, 2%), abnormal ECG (all patients 60%, 52%; patients with normal baseline 35%, 30%), fatigue/asthenia (any 47%, 39%; severe 8%, 3%), myalgia/arthralgia (any 44%, 49%; severe 8%, 4%), AST elevation (any 39%, 32%), alkaline phosphatase elevation (any 36%, 31%), anemia (any 33%, 25%; severe 1%, <1%), nausea (any 30%, 22%; severe 3%, <1%), diarrhea (any 27%, 15%; severe <1%, 1%) and infections (24%, 20%), respectively
  • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients
  • Other adverse reactions of note with the use of ABRAXANE vs paclitaxel injection included vomiting (any 18%, 10%; severe 4%, 1%), fluid retention (any 10%, 8%; severe 0%, <1%), mucositis (any 7%, 6%; severe <1%, 0%), hepatic dysfunction (elevations in bilirubin 7%, 7%), hypersensitivity reactions (any 4%, 12%; severe 0%, 2%), thrombocytopenia (any 2%, 3%; severe <1%, <1%), neutropenic sepsis (<1%, <1%), and injection site reactions (<1%, 1%), respectively. Dehydration and pyrexia were also reported
  • Renal dysfunction (any 11%, severe 1%) was reported in patients treated with ABRAXANE (n=229)
  • In all ABRAXANE-treated patients (n=366), ocular/visual disturbances were reported (any 13%; severe 1%)
  • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension
  • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported

Non-Small Cell Lung Cancer (NSCLC) Study

  • The most common adverse reactions (>=20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
  • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
  • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
  • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
  • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
  • The following common (>=10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group
  • Adverse reactions with a difference of >=2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively
  • Adverse reactions with a difference of >=5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
  • Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin

Pancreatic Adenocarcinoma Study

  • Among the most common (>=20%) adverse reactions in the phase III study, those with a >=5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)
  • Of these most common adverse reactions, those with a >=2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%)
  • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group
  • The most common serious adverse reactions of ABRAXANE (with a >=1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%)
  • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%)
  • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%)
  • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%)
  • Other selected adverse reactions with a >=5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%), headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%)
  • Other selected adverse reactions with a >=2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

  • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
  • There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
  • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration

DRUG INTERACTIONS

  • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

USE IN SPECIFIC POPULATIONS

Nursing Mothers

  • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric

  • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

Geriatric

  • No toxicities occurred notably more frequently among patients >=65 years of age who received ABRAXANE for MBC
  • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients >=65 years of age treated with ABRAXANE and carboplatin in NSCLC
  • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas

Renal Impairment

  • There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min)

DOSAGE AND ADMINISTRATION

  • Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
  • For MBC and NSCLC, reduce starting dose in patients with moderate to severe hepatic impairment
  • For adenocarcinoma of the pancreas, do not administer ABRAXANE to patients who have moderate to severe hepatic impairment
  • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity
  • Monitor patients closely

Please see full Prescribing Information, including Boxed WARNING.

About Celgene

Celgene International S`arl, located in Boudry, in the Canton of Neuch^atel, Switzerland, is a wholly-owned subsidiary and International Headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company’s website at www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn and YouTube.

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