Poma­lido­mide plus low-dose dexa­metha­sone dem­onstrated sig­nif­i­cantly longer median pro­gres­sion-free survival and over­all survival at a median follow-up of 10 months

Boudry, Switzerland (Press Release) - Celgene Inter­na­tional Sàrl, a wholly-owned sub­sid­i­ary of Celgene Corpo­ra­tion (NASDAQ:CELG), today announced that updated results from MM-003, a phase III multi-center, ran­dom­ized open-label study (n=455) of poma­lido­mide (marketed as POMALYST^® in the U.S. and IMNOVID^® in the E.U.) plus low-dose dexa­metha­sone, were published online ahead of print in The Lancet Oncology.

The study compared oral poma­lido­mide plus low-dose dexa­metha­sone with high-dose dexa­metha­sone in patients with refractory or re­lapsed and refractory multiple myeloma who have failed at least two prior thera­pies with both bor­tez­o­mib and lena­lido­mide, ad­min­is­tered alone or in com­bi­na­tion.

At the interim analysis (ASH 2012, median follow-up 4.2 months), the study met its pri­mary end­point as poma­lido­mide plus low-dose dexa­metha­sone dem­onstrated a sig­nif­i­cant im­prove­ment in pro­gres­sion-free survival (PFS) (3.8 months vs 1.9 months HR 0.41 p<0.0001) compared with high-dose dexa­metha­sone. There was also a sig­nif­i­cant im­prove­ment in the key sec­ond­ary end­point of over­all survival (OS) (11.9 months vs 7.8 months HR 0.53 p<0.0002) compared with high-dose dexa­metha­sone even though 45 patients in the high-dose dexa­metha­sone arm crossed over and received poma­lido­mide.

Additionally, the Data Monitoring Committee recommended that patients who had not yet progressed in the high-dose dexa­metha­sone arm should have access to poma­lido­mide with or without low-dose dexa­metha­sone.

At a median follow-up of 10.0 months, an updated PFS analysis and final OS analysis were conducted. Poma­lido­mide plus low-dose dexa­metha­sone con­tinued to dem­onstrate sig­nif­i­cantly longer PFS, the pri­mary end­point, compared with high-dose dexa­metha­sone (4.0 months vs. 1.9 months, HR=0.48, p<0.0001). Additionally, poma­lido­mide plus low-dose dexa­metha­sone dem­onstrated a sig­nif­i­cant im­prove­ment in OS compared with high-dose dexa­metha­sone (12.7 months vs. 8.1 months, HR=0.74, p=0.0285). Overall response rate for patients receiving poma­lido­mide plus low-dose dexa­metha­sone was 31% compared with 10% for patients receiving high-dose dexa­metha­sone (p<0.0001).

The most common grade 3-4 hema­to­logical adverse events in the poma­lido­mide plus low-dose dexa­metha­sone and high-dose dexa­metha­sone arms, re­spec­tive­ly, were: neu­tro­penia (48% 143/300 vs. 16% 24/150), anemia (33% 99/300 vs. 37% 55/150) and thrombo­cytopenia (22% 67/300 vs. 26% 39/150). Grade 3-4 non-hematological adverse events in the poma­lido­mide plus low-dose dexa­metha­sone and high-dose dexa­metha­sone arms, re­spec­tive­ly, in­cluded: pneu­monia (13% 38/300 vs. 8% 12/150), bone pain (7% 21/300 vs. 5% 7/150) and fatigue (5% 16/300 vs. 6% 9/150). Four patients in the poma­lido­mide plus low-dose dexa­metha­sone arm and one patient in the high-dose dexa­metha­sone arm developed second pri­mary malig­nan­cies. Of these, two patients in the poma­lido­mide plus low-dose dexa­metha­sone arm had in­­vasive solid tumor cancers and two patients in this group and the one in the high-dose dexa­metha­sone group had non-invasive cancers (basal-cell skin cancers). Treatment-related adverse events led to treat­ment dis­con­tinu­a­tion in 4% of patients in the poma­lido­mide plus low-dose dexa­metha­sone arm and 6% of patients in the high-dose dexa­metha­sone arm.

Patients in the poma­lido­mide plus low-dose dexa­metha­sone arm received 4 mg of oral poma­lido­mide on days 1-21 of each 28-day cycle. Oral dexa­metha­sone was given at 40 mg on days 1, 8, 15, and 22); for patients older than 75 years, dexa­metha­sone was ad­min­is­tered at 20 mg weekly.

Patients in the comparator arm were treated with 40 mg oral high-dose dexa­metha­sone on days 1-4, 9-12 and 17-20 of each 28-day cycle, until disease pro­gres­sion; patients older than 75 years received 20 mg oral dexa­metha­sone on the same schedule.

Results of the MM-003 trial formed the basis of an August 2013 approval by the European Medicines Agency in patients with re­lapsed and refractory multiple myeloma who have received at least two prior ther­a­pies in­­clud­ing both lena­lido­mide and bor­tez­o­mib and have dem­onstrated disease pro­gres­sion on the last ther­apy.

For more in­­for­ma­tion, visit http://www.thelancet.com/journals/lanonc/onlinefirst .

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

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 Corpo­ra­tionat 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 poma­lido­mide

Poma­lido­mide is an oral immuno­modu­la­tory drug (IMiD^®) with a multimodal mech­a­nism of action consisting of three main effects dem­onstrated in vitro: direct antimyeloma, stromal inhibitory effects and immuno­modu­la­tory effects. Poma­lido­mide 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 Statesunder the brand name POMALYST^® and is under review in other countries.

In the United States, Pomalyst is approved for use in patients with multiple myeloma who have received at least two prior ther­a­pies in­­clud­ing lena­lido­mide and bor­tez­o­mib and have dem­onstrated disease pro­gres­sion on or within 60 days of completion on the last ther­apy. Approval is based on response rate. Clinical benefit, such as im­prove­ment in survival or symp­toms, has not been verified.

About Celgene

Celgene Inter­na­tional Sàrl, located in Boudry, 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.

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.

Source: Celgene Corpo­ra­tion.