Boudry, Switzerland (Press Release) - Celgene Inter­na­tional Sàrl, a wholly-owned sub­sid­i­ary of Celgene Corpo­ra­tion (NASDAQ: CELG) today announced that the European Com­mis­sion (EC) has granted approval for Poma­lido­mide Celgene^® (poma­lido­mide), in com­bi­na­tion with dexa­meth­a­sone, for the treat­ment of re­lapsed and refractory multiple myeloma (rrMM) in adult patients who have received at least two prior ther­a­pies in­­clud­ing both lena­lido­mide and bor­tez­o­mib and have dem­onstrated disease pro­gres­sion on the last ther­apy.¹ Celgene intends to launch Poma­lido­mide Celgene in the EU under the trade name “IMNOVID^®”, fol­low­ing sub­mission of a regu­la­tory notification to the European Medicines Agency (EMA) to change the trade name.

Multiple myeloma is a blood cancer where plasma cells, im­por­tant components of the immune system which are responsible for making anti­bodies that help fight in­fec­tions, replicate un­con­trol­lably and accu­mu­late in the bone marrow.² Almost all patients with multiple myeloma have a risk of eventual relapse, which means their disease may progress even if they have achieved initial response to treat­ment.^2,3

“Most patients diag­nosed with multiple myeloma will relapse at some point and I have seen many patients who have become refractory to a number of treat­ments. The urgency now is to develop novel agents that help those patients who have tried several ther­a­pies and exhausted current standards of care” said Dr Xavier Leleu, Hôpital Huriez, CHRU Lille, France. “The approval of poma­lido­mide, one of these novel agents, is great news and a major step forward for these patients across Europe who need a new effective treat­ment option to help man­age their disease.”

Adds Alan Colowick, Pres­i­dent of Celgene Europe, the Middle East and Africa (EMEA): “We are committed to devel­op­ing life-changing medicines for those living with rare diseases. With today’s approval, Celgene becomes one of the few com­pa­nies to deliver treat­ments across all stages of multiple myeloma, right from the start at diag­nosis, through to the sup­port that poma­lido­mide can now offer late-stage multiple myeloma patients who have exhausted other treat­ment options.”

The EC’s de­ci­sion was based on the results from the MM-003 study, a phase III, multi-center, ran­dom­ized (2:1), open-label study in 455 patients.¹ The results dem­onstrated sig­nif­i­cantly im­proved median pro­gres­sion-free survival of 15.7 weeks (p<0.001) for patients with rrMM who were treated with poma­lido­mide plus low-dose dexa­meth­a­sone, compared with 8.0 weeks (p<0.001) for those treated with high-dose dexa­meth­a­sone only (data cutoff 07/09/12).¹ Median over­all survival was also sig­nif­i­cantly im­proved for the poma­lido­mide plus low-dose dexa­meth­a­sone arm, compared with high-dose dexa­meth­a­sone only, (median not reached vs. 34 weeks; p<0.001).¹ The most commonly reported Grade 3 or 4 adverse reac­tions in­cluded neu­tro­penia, thrombo­cytopenia and in­fec­tions.¹

The de­ci­sion follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) in May 2013.⁴

Poma­lido­mide will be launched in the European Union under the name “IMNOVID” according to local re­quire­ments.

Important Safety Information based on approved U.S. Label for Pomalyst (Trade name for Poma­lido­mide Celgene in the U.S.)

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM

Embryo-Fetal Toxicity

• POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of re­pro­ductive potential, obtain 2 negative pregnancy tests before starting POMALYST treat­ment
• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treat­ment

POMALYST is only avail­able through a restricted distribution pro­gram called POMALYST REMS^TM.

Venous Thromboembolism

• Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple mye­loma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clin­i­cal trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy

• POMALYST can cause fetal harm and 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 a fetus
• Poma­lido­mide is a thalidomide analogue and is teratogenic in both rats and rabbits when ad­min­is­tered during the period of organogenesis.

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treat­ment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following dis­con­tin­u­a­tion of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy.
• Males: Poma­lido­mide 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 POMALYST and for up to 28 days after dis­con­tin­u­ing POMALYST, even if they have undergone a suc­cess­ful vasectomy. Males must not donate sperm
• Blood Donation: Patients must not donate blood during treat­ment with POMALYST 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 POMALYST

POMALYST REMS Program

Because of the embryo-fetal risk, POMALYST is avail­able only through a restricted distribution pro­gram un­der a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and phar­ma­cists must be certified with the pro­gram; patients must sign an agree­ment form and comply with the re­quire­ments. Further in­­for­ma­tion about the POMALYST REMS program is avail­able at celgeneriskmanagement.com or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thrombo­embolic events reported as serious adverse reac­tions. In the trial, all patients were required to receive prophylaxis or antithrombotic treat­ment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assess­ment of each patient’s under­lying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most fre­quent­ly reported Grade 3/4 adverse event, followed by anemia and thrombo­cytopenia. Monitor patients for hema­to­logic toxicities, especially neu­tro­penia, with com­plete blood counts weekly for the first 8 weeks and monthly there­after. Treatment is con­tinued or modified for Grade 3 or 4 hema­to­logic toxicities based upon clin­i­cal and laboratory findings. Dosing inter­rup­tions and/or modifications are recommended to man­age neu­tro­penia and thrombo­cytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity asso­ci­ated with thalido­mide or lena­lido­mide were excluded from studies and may be at higher risk of hyper­sensi­tivi­ty.

Dizziness and Confusional State: 18% of patients ex­peri­enced dizzi­ness and 12% of patients ex­peri­enced a confusional state; 1% of patients ex­peri­enced grade 3/4 dizzi­ness, and 3% of patients ex­peri­enced grade 3/4 confusional state. Instruct patients to avoid situations where dizzi­ness or confusion may be a problem and not to take other medications that may cause dizzi­ness or confusion without adequate medical advice.

Neuropathy: 18% of patients ex­peri­enced neu­rop­athy (approximately 9% periph­eral neu­rop­athy). There were no cases of grade 3 or higher neu­rop­athy adverse reac­tions reported.

Risk of Second Primary Malignancies: Cases of acute mye­log­e­nous leukemia have been reported in pa­tients receiving POMALYST as an inves­ti­ga­tional ther­apy outside of multiple myeloma.

ADVERSE REACTIONS

In the clin­i­cal trial MM-002 of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexa­meth­a­sone (low-dose dex) (n=112), all patients had at least one treat­ment-emergent adverse reac­tion.

• In the POMALYST alone versus POMALYST + low dose dexa­meth­a­sone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%,22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%)
• 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treat­ment-emergent NCI CTC Grade 3 or 4 adverse reaction
• In the POMALYST alone versus POMALYST + low dose dexa­meth­a­sone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treat­ment and restart treat­ment at 1 mg less than the pre­vious dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion
• 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treat­ment-emergent serious adverse reaction
• In the POMALYST alone versus POMALYST + low dose dexa­meth­a­sone arms, respectively, most com­mon serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%),urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS

No formal drug inter­action studies have been conducted with POMALYST. Poma­lido­mide is primarily me­tab­o­lized by CYP1A2 and CYP3A. Poma­lido­mide is also a substrate for P-glycoprotein (P-gp). Coad­min­istra­tion of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be a­voided. Cigarette smoking may reduce poma­lido­mide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of poma­lido­mide.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treat­ment, im­medi­ately dis­con­tinue the drug and refer patient to an obstetrician/gynecologist ex­peri­enced in reproductive toxicity for further evaluation and counseling. Report any sus­pected fetal exposure to POMALYST 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 if poma­lido­mide is excreted in human milk. Poma­lido­mide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the poten­tial for adverse reac­tions in nursing infants from POMALYST, a de­ci­sion should be made whether to dis­con­tinue nursing or to dis­con­tinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been es­tab­lished.

Geriatric Use: No dosage ad­just­ment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to ex­peri­ence pneu­monia.

Renal and Hepatic Impairment: Poma­lido­mide is metabolized in the liver. Poma­lido­mide and its me­tab­o­lites are primarily excreted by the kidneys. The influence of renal and hepatic im­pair­ment on the safety, efficacy, and phar­ma­co­ki­netics of poma­lido­mide has not been eval­u­ated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

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

About Multiple Myeloma

Multiple myeloma (MM) is a blood cancer in which plasma cells, im­por­tant components of the immune system which are responsible for making anti­bodies that help fight in­fec­tions, replicate un­con­trol­lably and accumulate in the bone marrow.² MM remains incurable, although recent ad­vances in treat­ments have resulted in higher rates of remission and prolonged survival than pre­vi­ously seen.² Almost all patients with multiple myeloma have a risk of eventual relapse, which means their disease may progress even if they have achieved initial response to treat­ment.^2,3

About poma­lido­mide

Poma­lido­mide is an oral immuno­modu­la­tory drug (IMiD^®) with a multimodal mech­a­nism of action con­sist­ing of three main effects: direct antimyeloma, stromal inhibitory effects and immuno­modu­la­tory effects. Poma­lido­mide Celgene in com­bi­na­tion with dexa­meth­a­sone has been approved in the EU for the treat­ment of adult patients with re­lapsed and refractory multiple myeloma who have received at least two prior ther­a­pies in­­clud­ing lena­lido­mide and bor­tez­o­mib and have dem­onstrated disease pro­gres­sion on the last ther­apy.

In addi­tion to the EC de­ci­sion for the EU, poma­lido­mide is approved in the United States under the brand name POMALYST^® and is under review in other countries.

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 the Company's website at www.celgene.com.

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 our Annual Report on Form 10-K and our other reports filed with the Securities and Exchange Com­mis­sion.

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References

¹ Poma­lido­mide Celgene Summary of Product Characteristics
² Kyle RA, et al. Multiple myeloma. N Engl J Med. 2004; 351(18):1860–1873
³ Jagannath S. et al 2011: Multiple Myeloma and Other Plasma Cell Dyscrasias., Cancer Network. Available online (http://www.cancernetwork.com/display/article/10165/1802756) [Accessed July 2013]:
⁴ European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Summary of opinion – Poma­lido­mide Celgene http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002682/WC500143815.pdf [Accessed August 2013]

Source: Celgene Inter­na­tional.