BeiGene Announces Approval of REVLIMID® for Newly Diagnosed Multiple Myeloma in China
BEIJING, China, and CAMBRIDGE, Mass., Feb. 27, 2018 (GLOBE NEWSWIRE) -- BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, today announced that REVLIMID® (lenalidomide) has been approved by the China Food and Drug Administration (CFDA) for the treatment of multiple myeloma (MM) in combination with dexamethasone in adult patients with previously untreated MM who are not eligible for transplant. REVLIMID is an oral immunomodulatory drug that was first approved by the CFDA in China in 2013 for the treatment of MM in combination with dexamethasone, in adult patients who have received at least one prior therapy. It is currently marketed in China by BeiGene under an exclusive license from Celgene Corporation.
“REVLIMID is an important part of our commercial and development plans in China, where we are expanding our portfolio and commercial footprint. In China, where the incidence of multiple myeloma is on the rise due to an aging population and improved diagnosis, we are hopeful that newly diagnosed patients will have a meaningful long-term benefit from this approval,” commented John V. Oyler, Founder, Chief Executive Officer, and Chairman of BeiGene.
In a large randomized, three-arm, open-label Phase 3 trial (CC-5013-MM-020) conducted to compare the efficacy and safety of REVLIMID and low dose dexamethasone (Rd) to that of melphalan, prednisone and thalidomide (MPT) in patients with newly diagnosed multiple myeloma (NDMM) who were not eligible for transplant, continuous REVLIMID plus dexamethasone (Rd continuous) significantly improved median progression-free survival (PFS) compared to the MPT arm with a hazard ratio (HR) of 0.72 (95% Confidence Interval (CI): 0.61-0.85, p <0.0001) and a median PFS of 25.5 vs. 21.2 months. The median overall survival was 10.4 months longer with Rd continuous vs. MPT (58.9 vs. 48.5 months, HR of 0.75 (95% CI: 0.62-0.90)). Similarly, the response rate was also higher with Rd continuous compared with MPT (75.1% vs. 62.3%); with a complete response in 15.1% of Rd continuous arm patients vs. 9.3% in the MPT arm.
The most common grade 3/4 adverse events (occurring in ≥ 10% of patients in any subgroup) in the Rd continuous arm, Rd for 72 weeks (18 cycles; Rd18 arm) or MPT arm in the trial included neutropenia (28%, 27%, 45%, respectively), anemia (18%, 16%, 19%), thrombocytopenia (8%, 8%,11%) and pneumonia (11%, 11%, 8%).
About Multiple Myeloma
Multiple myeloma is an incurable and life-threatening blood cancer that is characterized by tumor proliferation and suppression of the immune system.i It can appear as both a tumor and/or an area of bone loss, and it affects the places where bone marrow is active in an adult: the hollow area within the bones of the spine, skull, pelvis, rib cage, and the areas around the shoulders and hips.ii MM is the second most commonly diagnosed blood cancer. According to the International Myeloma Foundation, there are an estimated 750,000 MM patients worldwide.iii
In China, REVLIMID is now approved in combination with dexamethasone for the treatment of adult NDMM patients who are not eligible for transplant. It received approval in China in 2013 for the treatment of MM in combination with dexamethasone, in adult patients who have received at least one prior therapy.
REVLIMID, in combination with dexamethasone, is approved in the United States, in Europe, in Japan and in around 25 other countries for the treatment of adult patients with previously untreated MM who are not eligible for transplant. REVLIMID is also approved in combination with dexamethasone for the treatment of MM patients 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 as Malaysia and Israel, for 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 and in Europefor the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk MDS 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 and Europe 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.
REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.
Important Safety Information
Below is the important safety information related to distribution of REVLIMID in China
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM
Do not use lenalidomide 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 embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide treatment.
Hematologic Toxicity (Neutropenia and Thrombocytopenia)
Lenalidomide can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. Patients may require use of blood product support and/or growth factors
Venous and Arterial Thromboembolism
Lenalidomide has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks.
• Women who are pregnant
• Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Program (PPP) are met
• Hypersensitivity to lenalidomide or to any of the excipients
Pregnancy warning: See Boxed WARNINGS: Lenalidomide is a chemical analog of thalidomide structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Lenalidomide induced monkey malformations similar to those described with thalidomide. If lenalidomide is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
REVLIMID RMP Program: To minimize the risks associated with the use of lenalidomide, particularly the risk of fetal exposure, lenalidomide may only be prescribed under a Risk Management Program (RMP) that includes a PPP.
The RMP has the following mandatory parts:
- Information for healthcare professionals and patients
- Distribution control system
- Follow-up assessment of the effectiveness of the RMP by Celgene
The RMP segments lenalidomide patients into different risk categories:
- Women of childbearing potential
- Women of non-childbearing potential
To minimize the risk of a pregnancy occurring under the treatment of lenalidomide, there are different requirements for each of these risk categories.
The conditions of the Celgene RMP to prevent pregnancy must be fulfilled for all patients, unless there is reliable evidence that the patient does not have childbearing potential.
Myocardial infarction: Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and within the first 12 months when used in combination with dexamethasone. Patients with known risk factors – including prior thrombosis – should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Venous and Arterial Thromboembolic: See Boxed WARNINGS: In patients with MM, the combination of lenalidomide with dexamethasone is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) and was seen to a lesser extent with lenalidomide in combination with melphalan and prednisone. Lenalidomide monotherapy was associated with a lower risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event) than lenalidomide in combination therapy in patients with MM.
Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in MM patients receiving lenalidomide with dexamethasone.
Neutropenia and thrombocytopenia: See Boxed WARNINGS: The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A complete blood cell count, including white blood cell count with differential count, platelet count, haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of lenalidomide treatment and monthly thereafter to monitor for cytopenias.
In case of neutropenia, the physician should consider the use of growth factors in patient management. Patients should be advised to promptly report febrile episodes. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce bleeding. Co-administration of lenalidomide with other myelosuppressive agents should be undertaken with caution.
Thyroid disorders: Both hypothyroidism and hyperthyroidism have been reported in patients treated with lenalidomide. Optimal control of co-morbid conditions that can affect thyroid function is recommended before start of lenalidomide treatment. Baseline and ongoing monitoring of thyroid function is recommended.
Peripheral neuropathy: Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral neuropathy. There was no increase in peripheral neuropathy observed with long term use of lenalidomide for the treatment of NDMM.
Tumour flare reaction and tumour lysis syndrome: Because lenalidomide has anti-neoplastic activity, the complications of tumour lysis syndrome (TLS) may occur. Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS and tumor flare reaction are those with high tumour burden prior to treatment. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions should be taken. There have been rare reports of TLS in patients with MM treated with lenalidomide.
Severe Cutaneous Reactions Including Hypersensitivity Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of grade 4 rash associated with thalidomide treatment should not receive lenalidomide. Lenalidomide interruption or discontinuation should be considered for grade 2-3 skin rash. Lenalidomide must be discontinued for angioedema, grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected and should not be resumed following discontinuation for these reactions.
Lactose intolerance: REVLIMID capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Unused capsules: Patients should be advised never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of the treatment.
Second Primary Malignancies: An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma patients receiving lenalidomide/dexamethasone (3.98 per 100 person-years) compared to controls (1.38 per 100 person-years). Non-invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour malignancies. The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with lenalidomide either in combination with melphalan or immediately following high-dose melphalan and autologous stem cell transplant. Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.
Hepatic disorders: Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination therapy. Abnormal liver function tests were commonly reported and were generally asymptomatic and reversible upon dosing interruption. Once parameters have returned to baseline, treatment at a lower dose may be considered. Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection or when lenalidomide is combined with medicinal products known to be associated with liver dysfunction.
Infection with or without neutropenia: Patients with MM are prone to develop infections including pneumonia. Patients with known risk factors for infections should be closely monitored. All patients should be advised to seek medical attention promptly at the first sign of infection (e.g. cough, fever, etc) thereby allowing for early management to reduce severity.
Cases of viral reactivation have been reported in patients receiving lenalidomide, including serious cases of herpes zoster or hepatitis B virus (HBV) reactivation. Some of the cases of viral reactivation had a fatal outcome. Hepatitis B virus status should be established before initiating treatment with lenalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when lenalidomide is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.
Cataract: Cataract has been reported with a higher frequency in patients receiving lenalidomide in combination with dexamethasone particularly when used for a prolonged time. Regular monitoring of visual ability is recommended.
Increased Mortality in Patients with CLL: In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent lenalidomide therapy increased the risk of death as compared to single agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the lenalidomide treatment arm. Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials.
Additional Precautions: Patients should not donate blood during therapy or for one week following discontinuation of lenalidomide.
Effects on ability to drive and use machines: Lenalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or operating machines.
Cardiac electrophysiology: At a dose two times the maximum recommended dose, lenalidomide does not prolong the QTc interval.
USE IN SPECIFIC POPULATIONS
- PREGNANCY AND LACTATION: See Boxed WARNINGS: If pregnancy occurs in a woman treated with lenalidomide, treatment must be stopped immediately and the patient should be referred to a physician specialized or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a physician specialized or experienced in teratology for evaluation and advice. It is not known whether lenalidomide is excreted in human milk. Therefore, breast-feeding should be discontinued during therapy with lenalidomide.
- PEDIATRIC USE: There is no experience in children and adolescents. Therefore, lenalidomide should not be used in the paediatric age group (0-17 years).
- GERIATRIC USE: In patients with newly diagnosed MM, the frequency in most of the AE categories (e.g. all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. In patients with MM with at least one prior therapy, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of lenalidomide. No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.
• In newly diagnosed: Data from the CC-5013-MM-020 trial showed the most frequently reported grade 3 or 4 reactions from either Arm Rd18 or Arm Rd Continuous included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18
- The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms (21%), and thrombocytopenia (20%)
• After at least one prior therapy: Data from CC-5013-MM-009/-010 trials showed the most common adverse reactions reported in ≥20% (REVLIMID/dex vs. dex/placebo) included 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%), and weight decreased (20% vs. 15%)
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.
Oral contraceptives: Induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected if lenalidomide is administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid pregnancy must be taken (see Precautions).
Warfarin: Close monitoring of warfarin concentration is advised during the treatment.
Digoxin: Monitoring of the digoxin concentration is advised during lenalidomide treatment.
Statins: There is an increased risk of rhabdomyolysis when statins are administered with lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring is warranted notably during the first weeks of treatment.
Dexamethasone: Co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg once daily).
Interactions with P-glycoprotein (P-gp) inhibitors: Co-administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.
Please see full prescribing information of REVLIMID outside of China, including Boxed WARNINGS in the link below:https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s055lbl.pdf
Additional important safety information related to distribution of REVLIMID outside of China is available here: https://www.revlimid.com/homepage/important-safety-information/
BeiGene is a global, commercial-stage, research-based biotechnology company focused on molecularly targeted and immuno-oncology cancer therapeutics. With a team of over 850 employees in China, the United States, and Australia, BeiGene is advancing a pipeline consisting of novel oral small molecules and monoclonal antibodies for cancer. BeiGene is also working to create combination solutions aimed to have both a meaningful and lasting impact on cancer patients. BeiGene markets ABRAXANE® (nanoparticle albumin–bound paclitaxel), REVLIMID (lenalidomide), and VIDAZA® (azacitidine) in China under a license from Celgene Corporation.iv
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws, including statements regarding BeiGene’s commercialization of REVLIMID in China, the potential benefits of REVLIMID, and BeiGene’s plans to commercialize additional drugs in China. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including BeiGene's ability to demonstrate the efficacy and safety of its drug candidates; the clinical results for its drug candidates, which may not support further development or marketing approval; actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials and marketing approval; BeiGene's ability to achieve commercial success for its marketed products and drug candidates, if approved; BeiGene'sability to obtain and maintain protection of intellectual property for its technology and drugs; BeiGene's reliance on third parties to conduct drug development, manufacturing and other services; BeiGene’s limited operating history and BeiGene's ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates, as well as those risks more fully discussed in the section entitled “Risk Factors” in BeiGene’s most recent quarterly report on Form 10-Q, as well as discussions of potential risks, uncertainties, and other important factors in BeiGene'ssubsequent filings with the U.S. Securities and Exchange Commission. All information in this press release is as of the date of this press release, and BeiGene undertakes no duty to update such information unless required by law.
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i Palumbo A, et al. N Engl J Med. 2011;364:1046-1060.
iv ABRAXANE®, REVLIMID®, and VIDAZA® are registered trademarks of Celgene Corporation.