On April 30, 2020 Bristol Myers Squibb (NYSE: BMY) and Acceleron Pharma Inc. (NASDAQ: XLRN) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion, recommending the approval of Reblozyl (luspatercept) for the treatment of (Press release, Acceleron Pharma, APR 30, 2020, View Source [SID1234561666]):
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Adult patients with transfusion-dependent anemia due to very low-, low- and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who had an unsatisfactory response or are ineligible for erythropoietin-based therapy.
Adult patients with transfusion-dependent anemia associated with beta thalassemia.
This CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU). If approved, Reblozyl would be the first erythroid maturation agent approved in the EU, representing a new class of therapy for eligible patients. The safety and efficacy results provided in the application are from the pivotal Phase 3 MEDALIST and BELIEVE studies, evaluating the ability of Reblozyl to effectively address anemia associated with MDS and beta thalassemia, respectively.
"Patients with myelodysplastic syndromes who experience anemia have limited treatment options, and some have been shown to not respond to available erythropoietin-based therapies," said Uwe Platzbecker, M.D., Head of Clinic and Policlinic for Hematology and Cell Therapy, Leipzig University Hospital and lead investigator of the MEDALIST study. "If approved, the introduction of a new class of therapy in Reblozyl could provide a promising option to help relieve patients from the burden of regular transfusions to manage their disease."
"Today’s positive CHMP opinion of Reblozyl is an important milestone for adult beta thalassemia patients in the EU who have limited treatment options to address anemia, a serious consequence of the disease," said Maria Domenica Cappellini, M.D., Professor of Medicine, University of Milan, Fondazione IRCCS Ca Granda and lead investigator of the BELIEVE study. "Reblozyl has the potential to significantly decrease the number of red blood cell transfusions patients need."
"This decision by the CHMP is an important step towards making this first-in-class therapy an option for eligible patients with anemia due to beta thalassemia or myelodysplastic syndromes," said Diane McDowell, M.D., vice president, Hematology Global Medical Affairs, Bristol Myers Squibb. "We, and our partners at Acceleron, look forward to the opportunity to make this treatment option available in the EU and are extremely appreciative of the patients, families and individuals who continue to help us progress important research in a range of serious diseases."
About MEDALIST
MEDALIST is a Phase 3, randomized, double-blind, placebo-controlled, multi-center study evaluating the safety and efficacy of luspatercept plus best supportive care (BSC) versus placebo plus BSC in adults with IPSS-R-defined very low-, low- or intermediate-risk non-del(5q) myelodysplastic syndromes (MDS). All patients were red blood cell (RBC) transfusion-dependent and were either refractory or intolerant to prior erythropoiesis stimulating agent (ESA) therapy, or were ESA naïve and unlikely to respond due to endogenous serum erythropoietin levels of ≥ 200 U/L, and had no prior treatment with disease modifying agents. Results of the MEDALIST trial were first presented during the Plenary Session of the 2018 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and were selected for the Best of ASH (Free ASH Whitepaper). The New England Journal of Medicine published the MEDALIST trial results in January 2020.
About MDS
MDS are a group of closely related blood cancers characterized by ineffective production of healthy red blood cells, white blood cells and platelets, which can lead to anemia and frequent or severe infections. People with MDS who develop anemia often require regular blood transfusions to increase the number of healthy red blood cells in circulation. Frequent transfusions are associated with an increased risk of iron overload, transfusion reactions and infections. There are approximately 50,000 patients with MDS in the EU5 countries.
About BELIEVE
BELIEVE is a Phase 3, randomized, double-blind, placebo-controlled multi-center study comparing luspatercept plus BSC versus placebo plus BSC in adults who require regular RBC transfusions (6-20 RBC units per 24 weeks with no transfusion-free period greater than 35 days during that period) due to beta thalassemia. Results of the BELIEVE trial were first presented at the 2018 ASH (Free ASH Whitepaper) Annual Meeting and selected for the Best of ASH (Free ASH Whitepaper). The New England Journal of Medicine published the BELIEVE trial results in March 2020.
About Beta Thalassemia
Beta thalassemia is an inherited blood disorder caused by a genetic defect in hemoglobin. The disease is associated with ineffective erythropoiesis, which results in the production of fewer and less healthy RBCs, often leading to severe anemia – a condition that can be debilitating and can lead to more severe complications for patients – as well as other serious health issues. Treatment options for anemia associated with beta thalassemia are limited, consisting mainly of frequent RBC transfusions that have the potential to contribute to iron overload, which can cause serious complications such as organ damage. Across the United States, Germany, France, Italy, Spain and the United Kingdom, there are approximately 17,000 patients with beta thalassemia.
About Reblozyl
Reblozyl (luspatercept-aamt), a first-in-class erythroid maturation agent, promotes late-stage red blood cell maturation in animal models. Bristol Myers Squibb and Acceleron are jointly developing Reblozyl as part of a global collaboration. Reblozyl is currently approved in the U.S. for the treatment of:
anemia in adult patients with beta thalassemia who require regular red blood cell transfusions, and
anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).
Reblozyl is not indicated for use as a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
Important Safety Information
WARNINGS AND PRECAUTIONS
Thrombosis/Thromboembolism
In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) REBLOZYL-treated patients. TEEs included deep vein thrombosis, pulmonary embolus, portal vein thrombosis, and ischemic stroke. Patients with known risk factors for thromboembolism (splenectomy or concomitant use of hormone replacement therapy) may be at further increased risk of thromboembolic conditions. Consider thromboprophylaxis in patients at increased risk of TEE. Monitor patients for signs and symptoms of thromboembolic events and institute treatment promptly.
Hypertension
Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients. Across clinical studies, the incidence of Grade 3 to 4 hypertension ranged from 1.8% to 8.6%. In patients with beta thalassemia with normal baseline blood pressure, 13 (6.2%) patients developed systolic blood pressure (SBP) ≥130 mm Hg and 33 (16.6%) patients developed diastolic blood pressure (DBP) ≥80 mm Hg. In adult patients with MDS with normal baseline blood pressure, 26 (29.9%) patients developed SBP ≥130 mm Hg and 23 (16.4%) patients developed DBP ≥80 mm Hg. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.
Embryo-Fetal Toxicity
REBLOZYL may cause fetal harm when administered to a pregnant woman. REBLOZYL caused increased post-implantation loss, decreased litter size, and an increased incidence of skeletal variations in pregnant rat and rabbit studies. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the final dose.
ADVERSE REACTIONS
Beta Thalassemia
Serious adverse reactions occurred in 3.6% of patients on REBLOZYL. Serious adverse reactions occurring in 1% of patients included cerebrovascular accident and deep vein thrombosis. A fatal adverse reaction occurred in 1 patient treated with REBLOZYL who died due to an unconfirmed case of acute myeloid leukemia (AML)
Most common adverse reactions (at least 10% for REBLOZYL and 1% more than placebo) were headache (26% vs 24%), bone pain (20% vs 8%), arthralgia (19% vs 12%), fatigue (14% vs 13%), cough (14% vs 11%), abdominal pain (14% vs 12%), diarrhea (12% vs 10%) and dizziness (11% vs 5%)
Myelodysplastic Syndromes
Grade >3 (≥2%) adverse reactions included fatigue, hypertension, syncope and musculoskeletal pain. A fatal adverse reaction occurred in 5 (2.1%) patients
The most common (≥10%) adverse reactions included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection
LACTATION
It is not known whether REBLOZYL is excreted into human milk or absorbed systemically after ingestion by a nursing infant. REBLOZYL was detected in milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because many drugs are excreted in human milk, and because of the unknown effects of REBLOZYL in infants, a decision should be made whether to discontinue nursing or to discontinue treatment. Because of the potential for serious adverse reactions in the breastfed child, breastfeeding is not recommended during treatment and for 3 months after the last dose.
Please see full Prescribing Information for REBLOZYL
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