Boudry, Switzerland (Press Release) – Celgene Inter­na­tional Sàrl, 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 continuous oral treat­ment with REVLIMID^® in adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for stem cell trans­plan­ta­tion.

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 in 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).

Multiple myeloma is a persistent and life-threatening blood cancer that is char­ac­ter­ised by tumour pro­lif­er­a­tion and sup­pres­sion of the immune system. ¹ It is a rare but deadly disease: around 38,900 people were newly diag­nosed with multiple myeloma in Europe in 2012, and 24,300 people died from the disease in the same year. ² On average, multiple myeloma is diag­nosed be­tween 65-74 years of age. ³ The majority of newly diag­nosed patients are not eli­gible for more aggressive treat­ment options such as high-dose chemo­therapy with stem cell trans­plant,⁴ and there is cur­rently no ther­apy option approved for continuous treat­ment to help man­age the disease over the long term. ⁵

"When recommending a ther­apy at first diag­nosis, our aim is to keep the disease under control for as long as possible," says Professor Thierry Facon, Services des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille, France. "The positive opinion for REVLIMID for the continuous treat­ment of adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for trans­plant is a sig­nif­i­cant step to­wards bring­ing a new ther­apy that could extend the time patients live without their disease progressing."

The antic­i­pated European Com­mis­sion decision would be the latest mile­stone for Celgene's flagship prod­uct in Europe and its con­tinued focus on delivering inno­va­tive medicines for rare hae­ma­to­log­i­cal diseases. REVLIMID is already indicated in com­bi­na­tion with dexa­metha­sone for the treat­ment of multiple myeloma in adult patients who have received at least one prior ther­apy. REVLIMID is also indicated for the treat­ment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelo­dys­plas­tic syn­dromes (MDS) asso­ci­ated with an isolated deletion 5q cytogenetic ab­nor­mal­ity when other thera­peutic options are insufficient or inadequate.

Tuomo Pätsi, Pres­i­dent of Celgene in Europe, the Middle East and Africa (EMEA), said, "The CHMP opinion reflects the im­por­tant role that ther­a­pies like REVLIMID play in treating rare hae­ma­to­log­i­cal cancers in­clud­ing multiple myeloma. Innovative medicines have been critical in helping to im­prove patient out­comes, but despite tremendous progress over the last 10 years, myeloma remains incurable for the vast majority of patients, so new treat­ments are needed. At Celgene, we will con­tinue to invest more than one-third of our revenues back into research and devel­op­ment to con­tinue finding new treat­ment options for these patients. Our hope is that one day, deadly diseases like multiple myeloma could become a man­ageable, long-term chronic con­di­tion."

The CHMP recom­men­da­tion in newly diag­nosed multiple myeloma was based on the results of two pivotal studies: MM-015 and MM-020 (also known as FIRST). The results of these studies have been reported pre­vi­ously.

• The FIRST study, MM-020,⁶ was the largest phase III, randomised study of 1,623 patients newly diagnosed with multiple myeloma and not eligible for stem cell trans­plan­ta­tion. It compared lena­lido­mide-dexa­metha­sone (Rd) administered in 28-day cycles until disease progression, with Rd for 72 weeks (18 cycles), and melphalan-pred­ni­sone-tha­lido­mide (MPT) for 72 weeks.
• MM-015⁷ was a phase III study of 459 patients that compared melphalan-pred­ni­sone-lena­lido­mide induction followed by lena­lido­mide maintenance (MPR-R) with melphalan-pred­ni­sone-lena­lido­mide (MPR) or melphalan-pred­ni­sone (MP) followed by placebo in patients ≥65 years or older with newly diagnosed multiple myeloma.

REVLIMID is not cur­rently indicated for the treat­ment of newly diag­nosed multiple myeloma in any country.

About REVLIMID^®

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 United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well asMalaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS asso­ci­ated with a deletion 5q cytogenetic ab­nor­mal­ity with or without addi­tional cytogenetic ab­nor­mal­i­ties and in Europe for the treat­ment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelo­dys­plas­tic syn­dromes asso­ci­ated with an isolated deletion 5q cytogenetic ab­nor­mal­ity when other thera­peutic options are insufficient or inadequate.

In addi­tion, REVLIMID is approved in the United States for the treat­ment of patients with mantle cell lym­pho­ma (MCL) whose disease has re­lapsed or progressed after two prior ther­a­pies, one of which in­cluded bor­tez­o­mib. In Switzerland, REVLIMID is indicated for the treat­ment of patients with re­lapsed or refractory MCL after prior ther­apy that in­cluded bor­tez­o­mib and chemo­ther­apy/rituximab.

U.S. Regulatory Information for REVLIMID^®

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

REVLIMID (lena­lido­mide) is indicated for the treat­ment of 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

REVLIMID (lena­lido­mide) is indicated for the treat­ment of patients with mantle cell lym­phoma (MCL) whose disease has re­lapsed or progressed after two prior ther­a­pies, one of which in­cluded bor­tez­o­mib

REVLIMID is not indicated and not recommended for the treat­ment of patients with chronic lym­pho­cytic leukemia (CLL) outside of controlled clin­i­cal trials

Important Safety Information

 
CONTRAINDICATIONS

Pregnancy:

• REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus

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

Embryo-Fetal Toxicity:

• REVLIMID is an analogue of tha­lido­mide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys 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
• Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy
• Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
• Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS^® Program

Because of embryo-fetal risk, REVLIMID is avail­able only through a restricted pro­gram under a Risk Evalu­a­tion and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the "RevAssist" Program). Prescribers and pharmacies must be certified with the pro­gram and patients must sign an agree­ment form and comply with the require­ments. Further in­­for­ma­tion about the REVLIMID REMS program is avail­able at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

Hematologic Toxicity: REVLIMID can cause sig­nif­i­cant neu­tro­penia and throm­bo­cyto­penia. MM: 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 trials 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. MCL: Patients taking REVLIMID for MCL should have their com­plete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly there­after. In the MCL trial, Grade 3 or 4 neu­tro­penia was reported in 43% of the patients. Grade 3 or 4 throm­bo­cyto­penia was reported in 28% of the patients. Patients may require dose inter­rup­tion and/or dose reduction

Venous Thromboembolism: 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 or MCL treated with lena­lido­mide mono­therapy. It is not known whether pro­phy­lactic anticoagulation or antiplatelet ther­apy prescribed in conjunction with REVLIMID may lessen the poten­tial for venous thromboembolism

Increased Mortality in Patients With CLL: In a clin­i­cal trial in the first line treat­ment of patients with CLL, single agent REVLIMID ther­apy in­­creased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treat­ment arm compared to 18 deaths among 211 patients in the chlorambucil treat­ment arm, and hazard ratio for over­all survival was 1.92 [95% CI: 1.08-3.41] con­sis­tent with a 92% in­­crease in risk of death. Serious adverse cardiovascular reac­tions, in­­clud­ing atrial fibrillation, myo­cardial infarction, and cardiac failure occurred more frequently in the REVLIMID treat­ment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clin­i­cal trials

Second Primary Malignancies: Patients with MM treated with lena­lido­mide in studies in­­clud­ing mel­phalan and stem cell trans­plan­ta­tion had a higher incidence of second pri­mary malig­nan­cies, particularly acute mye­log­e­nous leukemia (AML) and Hodgkin lym­phoma, compared to patients in the control arms who received similar ther­apy but did not receive lena­lido­mide. Monitor patients for the devel­op­ment of second malig­nan­cies. Take into account both the poten­tial benefit of lena­lido­mide and the risk of second pri­mary malig­nan­cies when con­sidering treat­ment with lena­lido­mide

Hepatotoxicity: Hepatic failure, in­­clud­ing fatal cases, has occurred in patients treated with lena­lido­mide in com­bi­na­tion with dexa­metha­sone. The mech­a­nism of drug-induced hepato­tox­ic­ity is unknown. Pre-existing viral liver disease, elevated base­line liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to base­line values, treat­ment at a lower dose may be con­sidered

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. REVLIMID capsules con­tain lactose. Risk-benefit of REVLIMID treat­ment should be eval­u­ated in patients with lactose intolerance

Tumor Lysis Syndrome: Fatal instances of tumor lysis syn­drome (TLS) have been reported during treat­ment with lena­lido­mide. The patients at risk of TLS 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 (TFR) has occurred during inves­ti­ga­tional use of lena­lido­mide for CLL and lym­phoma, and is char­ac­ter­ized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clin­i­cal trials

Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the pro­gression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treat­ment with lena­lido­mide until TFR resolves to ≤ Grade 1. In the MCL trial, approx­i­mately 10% of subjects ex­peri­enced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lena­lido­mide may be con­tinued in patients with Grade 1 and 2 TFR without inter­rup­tion or modification, at the physician's discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for man­agement of TFR symp­toms. Patients with Grade 3 or 4 TFR may be treated for man­agement of symp­toms per the guidance for treat­ment of Grade 1 and 2 TFR

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, 76% (269/353) vs 57% (199/350), 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
• Grade 3/4 neu­tro­penia occurred in 33.4% vs 3.4%; 2.3% experienced Grade 3/4 febrile neu­tro­penia vs 0%
• Deep vein thrombosis (DVT) was reported as a serious adverse drug reaction (7.4%) or Grade 3/4 (8.2%) compared to 3.1% and 3.4%. Discontinuations due to DVT were reported at comparable rates between groups
• Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) compared to 0.9% and 0.9%. Discontinuations due to PE were reported at comparable rates between groups
• Adverse reactions reported in ≥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
• Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neu­tro­penia (53%), throm­bo­cyto­penia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
• Other adverse events reported in ≥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%)

Mantle Cell Lymphoma

• Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neu­tro­penia (43%), throm­bo­cyto­penia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neu­tro­penia (6%)
• Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia
• Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neu­tro­penia (49%), throm­bo­cyto­penia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
• Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clin­i­cal judgment and based on standard clin­i­cal practice in patients receiving this medication, is recommended during admin­istra­tion of REVLIMID. It is not known whether there is an inter­action be­tween dexa­metha­sone and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. 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 SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treat­ment, im­medi­ately dis­con­tinue the drug. Under these con­di­tions, refer patient to an obstetrician/gynecologist ex­peri­enced in reproductive toxicity for further evaluation and counseling. Any sus­pected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch pro­gram at 1-800-332-1088 and also to Celgene Corpo­ra­tion at 1-888-423-5436

Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and 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

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been estab­lish­ed

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 (CLcr 30-60 mL/min) or severe renal im­pair­ment (CLcr < 30 mL/min) and in patients on dialysis

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

About Celgene

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 www.celgene.com. Follow us on Twitter @Celgene, and on Pinterest and LinkedIn.

Forward-Looking Statements

This press release con­tains forward-looking state­ments, which are generally state­ments that are not historical facts. Forward-looking state­ments can be identified by the words "expects," "antic­i­pates," "believes," "intends," "estimates," "plans," "will," "outlook" and similar ex­pres­sions. Forward-looking state­ments are based on man­agement's current plans, esti­mates, assump­tions and projections, and speak only as of the date they are made. We under­take no obli­ga­tion to update any forward-looking state­ment in light of new in­­for­ma­tion or future events, except as other­wise required by law. Forward-looking state­ments involve in­her­ent risks and un­cer­tain­ties, most of which are dif­fi­cult to predict and are generally beyond our control. Actual results or out­comes may differ ma­teri­ally from those implied by the forward-looking state­ments as a result of the impact of a number of factors, many of which are discussed in more detail in Celgene Corporation's Annual Report on Form 10-K and other reports filed with the Securities and Exchange Com­mis­sion.

All registered trademarks are owned by Celgene Corpo­ra­tion.

References

1. Palumbo A & Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046-1060.

2. Ferlay J et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-1403.

3. National Cancer Institute. SEER Stat Fact Sheets: Myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html

4. Jagannath S. Treatment of myeloma in patients not eli­gible for trans­plan­ta­tion. Curr Treat Options Oncol 2005;6(3):241-53.

5. Moreau P et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diag­nosis, treat­ment and follow-up. Ann Onc 2013;24 (Suppl 6):vi133-vi137.

6. Benboubker B et al. Lena­lido­mide and dexa­metha­sone in trans­plant-ineligible patients with myeloma. N Engl J Med 2014;371:906-917.

7. Palumbo A et al. Continuous lena­lido­mide treat­ment for newly diag­nosed multiple myeloma. N Engl J Med 2012;366:1759-69.

Source: Celgene.