Celgene Provides Update on Regulatory Submissions

REVLIMID(R) (lenalidomide) Capsules Marketing Authorisation Application Submitted to EMA for Treatment of Newly Diagnosed Multiple Myeloma And Maintenance Therapy
ISTODAX(R) (romidepsin) for Injection Supplemental New Drug Application Submitted to U.S. FDA for Previously Treated Peripheral T-Cell Lymphoma

BOUDRY, Switzerland, Jan 04, 2011 (BUSINESS WIRE) --

Celgene International Sàrl (NASDAQ: CELG) announced regulatory submissions for its blood cancer therapies REVLIMID (lenalidomide) and ISTODAX (romidepsin).


The company submitted a Marketing Authorisation Application (MAA) for the approval of REVLIMID (lenalidomide) for maintenance treatment of newly diagnosed multiple myeloma patients who have not progressed following initial treatment with melphalan, prednisone and REVLIMID, or following autologous stem cell transplantation. The application was submitted with the European Medicines Agency (EMA) on December 31, 2010.

The MAA will be reviewed by the Committee for Medicinal Products for Human Use (CHMP). Review of each application will be conducted by the EMA under the centralised licensing procedure, which, when finalised, provides one marketing authorisation in all 27 member states of the European Union.

The application was based on the results of MM-015, an international, randomised pivotal phase III study. The submission is also supported by two additional PHASE III studies comparing continuous REVLIMID therapy following autologous stem cell transplant versus placebo. Unprecedented results from these phase III studies were presented at the American Society of Hematology Annual Meeting in December 2010.

In addition to the European submission for REVLIMID, a Supplemental New Drug Application (sNDA) was submitted to the U.S. Food and Drug Administration (FDA) on December 17, 2010 for ISTODAX in the treatment of patients with peripheral t-cell lymphoma (PTCL) who have received at least one prior therapy. The sNDA submission was based on a pivotal, phase II, multicenter, international, open-label study of romidepsin in patients with progressive or relapsed PTCL following prior systemic therapy.

The sNDA will now be reviewed for acceptance under current FDA guidelines.

About REVLIMID(R)

REVLIMID is an IMiDs(R) compound. REVLIMID and other IMiDs continue to be evaluated in over 100 clinical trials. The IMiDs pipeline is covered by a comprehensive intellectual property estate of issued and pending patent applications in the US, EU and other regions, including composition-of- matter and use patents.

REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.

REVLIMID is also approved in the Americas, the Middle-East and Asia for transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Marketing Authorization Applications are currently being evaluated in a number of other countries.

REVLIMID(R) (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma (MM) patients who have received at least one prior therapy.

REVLIMID is indicated for patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Important Safety Information

WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid fetal exposure to lenalidomide, REVLIMID is only available under a restricted distribution program called "RevAssist(R)."

Information about the RevAssist program is available at www.REVLIMID.com or by calling the manufacturer's toll-free number 1-888-423-5436.

HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. (see DOSAGE and ADMINISTRATION)

DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with MM who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient's underlying risk factors.

CONTRAINDICATIONS:

Pregnancy Category X:


Lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. Females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy

Allergic Reactions:


REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

WARNINGS AND PRECAUTIONS:

Fetal Risk:


REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects. An embryofetal development study in non-human primates indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. If REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby
Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods should be used during therapy, during therapy interruptions, and for at least 4 weeks after completing therapy
Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving REVLIMID must always use a latex condom during any sexual contact with females of childbearing potential, even if they have undergone a successful vasectomy

Reproductive Risk and Special Prescribing Requirements (RevAssist Program):


Because of this potential toxicity and to avoid fetal exposure, REVLIMID is only available under a special restricted distribution program called "RevAssist." Prescribers and pharmacists registered with the program can prescribe and dispense the product to patients who are registered and meet all the conditions of the RevAssist program

Hematologic Toxicity--Multiple Myeloma:


REVLIMID can cause significant neutropenia and thrombocytopenia
Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter
In the pooled MM studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone
Patients may require dose interruption and/or dose reduction

Deep Vein Thrombosis:


Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MM treated with lenalidomide combination therapy and patients with MDS treated with lenalidomide monotherapy

Allergic Reactions:


Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation for these reactions

Tumor Lysis Syndrome:


Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken

Tumor Flare Reaction:


Tumor flare reaction has occurred during investigational use of lenalidomide for chronic lymphocytic leukemia (CLL) and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL or lymphoma with lenalidomide outside of a well-monitored clinical trial is discouraged

DRUG INTERACTIONS:


Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in MM patients receiving lenalidomide with dexamethasone

USE IN SPECIAL POPULATIONS:

Nursing Mothers:


It is not known whether REVLIMID is excreted in human milk
Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother

Geriatric Use:


Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function

Renal Impairment:


Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment (CLcr < 60 mL/min) and in patients on dialysis

ADVERSE REACTIONS:

Multiple Myeloma


In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group
Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group
Most adverse events and Grade 3/4 adverse events were more frequent in MM patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone
Adverse reactions reported in greater-than or equal to 15% of MM patients (REVLIMID/dexamethasone vs dexamethasone/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)

Myelodysplastic Syndromes


Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events observed in the del 5q MDS population
Other adverse events reported in greater-than or equal to 15% of del 5q MDS patients (REVLIMID): diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)

DOSAGE AND ADMINISTRATION:


Treatment is continued or modified based upon clinical and laboratory findings. Dosing modifications are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID
For other Grade 3 or 4 toxicities judged to be related to REVLIMID, hold treatment and restart at next lower dose level when toxicity has resolved to less-than or equal to Grade 2

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, PRECAUTIONS, and ADVERSE REACTIONS.

About ISTODAX

ISTODAX(R) (romidepsin) is a member of a new class of cancer drugs known as histone deacetylase (HDAC) inhibitors. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. HDAC inhibitors can be divided into four main classes: cyclic tetrapeptides (I), short-chain fatty acids (II), hydroxamic acids (III), and benzamides (IV). The cyclic peptide structure of ISTODAX is novel among the cyclic tetrapeptides. In vitro, ISTODAX causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines. For full prescribing information, visit www.ISTODAX.com.

ISTODAX is approved in the United States for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

Important Safety Information

ISTODAX is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

Warnings and Precautions

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX.

Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary.

Several treatment-emergent morphological changes in ECGs including T-wave and ST-segment changes have been reported in clinical studies. The clinical significance of these changes is unknown. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions, such as the monitoring of electrolytes and ECGs should be considered.

Based on its mechanism of action, ISTODAX may cause fetal harm. Woman should avoid becoming pregnant while being treated with ISTODAX and pregnant women should be advised of the potential harm to the foetus.

ISTODAX binds to estrogen receptors. Women of childbearing potential should be advised that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives.

Adverse Reactions

Safety data are available from 185 patients with CTCL from two clinical trials. Adverse reactions are presented separately for each study due to methodological differences between the studies. The most common reported adverse reactions in Study 1 were nausea (56%), fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 were nausea (86%), fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG T-wave changes (63%), neutropenia (57%), and lymphopenia (57%). Most of the adverse reactions were reported to be mild or moderate in severity. Most deaths in the studies were due to disease progression. Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Serious adverse reactions reported in > 2% of patients in Study 1 were infection, sepsis, and pyrexia. In Study 2, serious adverse reactions in > 2% of patients were infection, supraventricular arrhythmia, neutropenia, fatigue, edema, central line infection, ventricular arrhythmia, nausea, pyrexia, leukopenia, and thrombocytopenia.

Drug Interactions

Prothrombin time (PT) and International Normalized Ratio (INR) should be carefully monitored in patients concurrently administered ISTODAX and warfarin sodium derivatives.

Co-administration of strong CYP3A4 inhibitors may increase concentrations of ISTODAX and should be avoided.

Co-administration of potent CYP3A4 inducers may decrease concentrations of ISTODAX and should be avoided.

Caution should be exercised if ISTODAX is administered with drugs that inhibit P-glycoprotein.

Use in Specific Patient Populations

Patients with moderate and severe hepatic impairment or end-stage renal disease should be treated with caution.

About Multiple Myeloma

Multiple myeloma (also known as myeloma or plasma cell myeloma) is a cancer of the blood in which malignant plasma cells are overproduced in the bone marrow. Plasma cells are white blood cells that help produce antibodies called immunoglobulins that fight infection and disease. However, most patients with multiple myeloma have cells that produce a form of immunoglobulin called paraprotein (or M protein) that does not benefit the body. In addition, the malignant plasma cells replace normal plasma cells and other white blood cells important to the immune system. Multiple myeloma cells can also attach to other tissues of the body, such as bone, and produce tumours. The cause of the disease remains unknown.

About PTCL

Peripheral T-cell lymphoma comprises a heterogeneous group of lymphomas of T-cell origin, accounting for about 10-15% of all cases of non-Hodgkin's lymphoma. PTCL can occur at any age from young adulthood to old age and is slightly more common in men than in women. It is a particularly aggressive form of lymphoma with a short median duration of life expectancy (approximately two years) from diagnosis.

About Celgene International Sàrl

Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical 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.

This release contains certain forward-looking statements which involve known and unknown risks, delays, uncertainties and other factors not under the Company's control. The Company's actual results, performance, or achievements could be materially different from those projected by these forward-looking statements.The factors that could cause actual results, performance, or achievements to differ from the forward-looking statements are discussed in the Company's filings with the Securities and Exchange Commission, such as the Company's Form 10-K, 10-Q and 8-K reports.Given these risks and uncertainties, you are cautioned not to place undue reliance on the forward-looking statements.

###

ISTODAX(R) is a registered trademark of Astellas Pharma, Inc.

 

SOURCE: Celgene International Sàrl

Celgene International SàrlDirector of External RelationsKevin Loth, +41 32 729 86 21

 

Posted: January 2011


View comments

Hide
(web2)