Refractory cytopenia with multilineage dysplasia and ringed sideroblasts

PRINCETON, N.J., Jan. 23, 2024 /PRNewswire/ -- Taiho Oncology, Inc. announces publication of the final results from the pivotal ASCERTAIN clinical trial of fixed-dose oral decitabine and cedazuridine (INQOVI®) compared to intravenous decitabine in adults with intermediate and high-risk myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML).1 The ASCERTAIN trial was the first Phase 3 trial to demonstrate pharmacologic equivalence between an oral and an intravenous (IV) formulation of a hypomethylating agent for use in the treatment of patients with MDS or CMML. As reported in the January 2 issue of The Lancet Haematology, median overall survival (mOS) in the trial population was approximately 32 months.1 In addition, the overall response rate was 62% in the intent to treat patient population. The percentage of patients in this trial who moved to transplantation reached 20%, exceeding expected transplantation rates in patients receiving hypomethylating agents for MDS and CMML.1 Safety findings from the study were comparable with those previously observed with IV decitabine. The most common treatment-emergent adverse events of thrombocytopenia, neutropenia and anemia were consistent with expected adverse events with parenteral hypomethylating agent treatment. The data from the study supported the simultaneous approval of INQOVI® by the U.S. Food and Drug Administration and Health Canada in July 2020 for the treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.2 "Until recently, azacitidine and decitabine, both widely used hypomethylating agents, were available only in parenteral form, requiring patients with MDS and CMML to travel to treatment centers daily for 5 or 7 consecutive days of each 28-day treatment cycle," said Guillermo Garcia-Manero, MD, Professor, Department of Leukemia, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center, Houston, and the lead author on the publication. "The ASCERTAIN study has demonstrated that the orally delivered fixed dose combination of decitabine and cedazuridine is an alternative option to parenteral administration of decitabine for patients with these diseases. The observed median overall survival of greater than 30 months in the ASCERTAIN study compared with historical controls is encouraging." Added Tehseen Salimi, MD, MHA, Senior Vice President and Head of Medical Affairs, Taiho Oncology, Inc., "Patients living with MDS and CMML can benefit from the convenience of an at-home hypomethylating agent treatment that may potentially reduce the number of office visits and the travel that comes with it." About the ASCERTAIN Trial The Phase 3 ASCERTAIN clinical trial was a multicenter, randomized, open-label, crossover pharmacokinetics (PK) study comparing oral decitabine (35mg) and cedazuridine (100mg) fixed-dose combination tablet given once daily for 5 days on a 28-day cycle to IV decitabine (20mg/m2) administered as a daily 1-hour IV infusion for 5 days on a 28-day cycle, in the first 2 cycles in patients with MDS and CMML. Patients continued to receive oral decitabine and cedazuridine from Cycle 3 onwards. The primary endpoint of the study was total 5-day area-under-the-curve (AUC) equivalence of oral decitabine and cedazuridine and IV decitabine. For more information about ASCERTAIN, please visit: . INDICATIONS Decitabine and cedazuridine, marketed under the brand name INQOVI®, is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.2 INQOVI is the first and only oral hypomethylating agent approved by the FDA and by Health Canada for the treatment of adults with intermediate and high-risk MDS including CMML. Commercialization of INQOVI in the U.S. and Canada is conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc., respectively. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Myelosuppression Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS. Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%. Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti‑infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended. Embryo-Fetal Toxicity INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment and for 6 months (females) or 3 months (males) after last dose. ADVERSE REACTIONS Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death. The most common adverse reactions (≥ 20%) were fatigue (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and transaminase increased (21%). The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased (81%), platelet count decreased (76%), neutrophil count decreased (71%), and hemoglobin decreased (55%). USE IN SPECIFIC POPULATIONS Lactation Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose. Renal Impairment No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min). Please see the accompanying Full Prescribing Information . About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. U.S. incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.3,4 The prevalence has been estimated to be from 60,000 to 170,000 in the U.S.5 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.6 The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML. CMML is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the U.S. is approximately 1,100 new cases per year,7 and CMML may transform into AML in 15% to 30% of patients.8 About Decitabine and Cedazuridine Fixed-Dose Combination This product is an orally administered, fixed dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine,3 an inhibitor of cytidine deaminase.4 By inhibiting cytidine deaminase in the gut and the liver, the fixed dose combination is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over five days. The oral decitabine and cedazuridine fixed-dose combination has been evaluated in a Phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study, and a Phase 3 exposure equivalence study in patients with MDS and CMML – the ASCERTAIN study. About Taiho Oncology, Inc. The mission of Taiho Oncology, Inc. is to improve the lives of patients with cancer, their families and their caregivers. The company specializes in the development and commercialization of orally administered anti-cancer agents for various tumor types. Taiho Oncology has a robust pipeline of small molecule clinical candidates targeting solid tumor and hematological malignancies, with additional clinical candidates in pre-clinical development. Taiho Oncology is a subsidiary of Taiho Pharmaceutical Co., Ltd. which is part of Otsuka Holdings Co., Ltd. Taiho Oncology is headquartered in Princeton, New Jersey and oversees its parent company's European and Canadian operations, which are located in Zug, Switzerland and Oakville, Ontario, Canada. For more information, visit . Taiho Oncology, the Taiho Oncology logo and INQOVI are registered trademarks of Otsuka Holdings Co., Ltd. or its subsidiaries. Taiho Oncology Contact: Judy Kay Moore (574)526-2369 [email protected] SOURCE Taiho Oncology, Inc.

PRINCETON, N.J.--( BUSINESS WIRE )-- Bristol Myers Squibb (NYSE: BMY) today announced first results from the Phase 3 COMMANDS study, an open-label, randomized trial evaluating Reblozyl ® (luspatercept-aamt) versus epoetin alfa, an erythropoiesis-stimulating agent (ESA), for the treatment of anemia in adult patients with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) who require red blood cell (RBC) transfusions and are ESA-naïve. Results from the study will be featured as part of the press program at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 2, 3 p.m. EDT (Abstract #7003), and in an oral presentation of select abstracts during a plenary session at the European Hematology Association (EHA) Congress on June 10, 2:45 p.m. CEST (Abstract #S102). “Chronic anemia, low hemoglobin levels and transfusion dependency are the primary clinical challenges for patients with lower-risk MDS, increasing the risk of death by more than half compared to those who do not require transfusions,” said Guillermo Garcia-Manero, M.D., lead investigator and Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center. “Results from the COMMANDS study showed treatment with Reblozyl compared to epoetin alfa led to superior and statistically significant improvements in red blood cell transfusion independence and hemoglobin increase, improvements in response durability, and equal or better outcomes across all subgroups, with acceptable safety and tolerability for patients with ESA-naïve, lower-risk MDS.” The primary endpoint evaluated in the COMMANDS study is RBC transfusion independence (RBC-TI) for 12 weeks with a mean hemoglobin increase of ≥1.5 g/dL. Key secondary endpoints include erythroid response (HI-E) of at least 8 weeks during weeks 1-24 of the study, RBC-TI ≥12 weeks and RBC-TI for 24 weeks. Eligible patients were ≥18 years old with lower-risk MDS who require transfusions. Patients were randomized 1:1 to receive subcutaneous Reblozyl (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥24 weeks. COMMANDS Study Results at ASCO At the time of the interim analysis, 147 evaluable patients received Reblozyl and 154 evaluable patients received epoetin alfa, with median treatment durations of 41.6 and 27 weeks, respectively. Results showed 58.5% (n=86) of patients receiving Reblozyl vs. 31.2% (n=48) of patients receiving epoetin alfa achieved the primary endpoint of RBC-TI of at least 12 weeks with concurrent mean hemoglobin (Hb) increase of at least 1.5 g/dL within the first 24 weeks (p<0.0001). HI-E increase of at least 8 weeks was achieved by 74.1% (n=109) of Reblozyl patients vs. 51.3% (n=79) of epoetin alfa patients (p<0.0001). Patients treated with Reblozyl achieved more durable responses vs. epoetin alfa, with a median duration of response of RBC-TI ≥12 weeks (Week 1 to end of treatment) of 126.6 vs. 77 weeks. Within the first 24 weeks of treatment, RBC-TI of at least 24 weeks was achieved by 47.6% (n=70) of Reblozyl patients vs. 29.2% (n=45) of epoetin alfa patients (P=0.0006). Benefit with Reblozyl was also observed in clinically relevant subgroups, and results showed a consistent safety profile and no new safety signals. COMMANDS Study – ASCO Oral Presentation #7003 Safety Hematology-related treatment emergent adverse events (TEAEs) Reblozyl (n=178) Epoetin alfa (n=176) Anemia 9.6% (17) 9.7% (17) Thrombocytopenia 6.2% (11) 1.7% (3) Neutropenia 5.1% (9) 7.4% (13) Most common TEAEs Fatigue 14.6% (26) 6.8% (12) Diarrhea 14.6% (26) 11.4% (20) Peripheral edema 12.9% (23) 6.8% (12) Efficacy Reblozyl (n=147) Epoetin alfa (n=154) Primary Endpoint Red blood cell transfusion independence (RBC-TI) (≥12 weeks with mean hemoglobin (Hb) increase ≥1.5 g/dL) 58.5% (86) 31.2% (48) p<0.0001 Secondary Endpoints Hematologic improvement-erythroid (HI-E) ≥8 weeks 74.1% (109) 51.3% (79) p<0.0001 RBC-TI, 24 weeks 47.6% (70) 29.2% (45) p=0.0006 RBC-TI ≥12 weeks 66.7% (98) 46.1% (71) p=0.0002 Association of Baseline Characteristics Reblozyl n/N (%) Epoetin alfa n/N (%) Risk Difference (95% CI) Serum erythropoietin (sEPO) ≤200 U/L 74/118 (62.7%) 44/121 (36.4%) 26.35 (12.78 to 38.41) sEPO >200 U/L 12/29 (41.4%) 4/33 (12.1%) 29.26 (6.35 to 50.83) Ring sideroblast + 70/108 (64.8%) 29/112 (25.9%) 38.92 (25.87 to 50.70) Ring sideroblast - 16/39 (41.0%) 19/41 (46.3%) -5.32 (-27.71 to 16.74) SF3B1 mutated 64/92 (69.6%) 27/88 (30.7%) 38.88 (24.13 to 51.91) SF3B1 non-mutated 22/53 (41.5%) 20/62 (32.3%) 9.25 (-8.73 to 26.87) COMMANDS Study Results at EHA Data to be presented at EHA included both efficacy and safety consistent with results at ASCO, and showed Reblozyl demonstrated favorable outcomes compared to epoetin alfa across common MDS mutations (SF3B1, SF3B1a, ASXL1, TET2, DNMT3A, EZH2, IDH2, U2AF1) and had a higher probability of achieving clinical benefit, regardless of overall mutational burden. COMMANDS Study – EHA Oral Presentation #S102 Association of MDS-Related Mutations Reblozyl n/N Epoetin alfa n/N Risk Difference 95% CI ASXL 1 15/31 3/29 0.38 (0.17 to 0.59) CBL 0/5 2/5 -0.40 (-0.85 to 0.05) DNMT3A 19/28 11/25 0.24 (-0.02 to 0.50) DTA.SF3B1.n 12/31 12/40 0.09 (-0.14 to 0.31) EZH2 5/10 2/9 0.28 (-0.13 to 0.69) IDH2 3/6 1/5 0.30 (-0.23 to 0.83) RUNX1 1/4 0/9 0.25 (-0.17 to 0.67) SF3B1 64/92 27/90 0.40 (0.26 to 0.53) SF3B1.alpha 41/55 16/55 0.45 (0.29 to 0.62) SF3B1.beta 1/4 0/8 0.25 (-0.18 to 0.68) SRSF2 5/14 2/14 0.21 (-0.10 to 0.53) TET2 30/48 16/53 0.32 (0.14 to 0.51) U2AF1 6/16 4/19 0.16 (-0.14 to 0.46) A supplemental Biologics License Application for Reblozyl is currently under Priority Review with the U.S. Food and Drug Administration (FDA) for treatment of anemia in ESA-naïve adult patients with very low- to intermediate-risk MDS who may require RBC transfusions with an assigned Prescription Drug User Fee Act (PDUFA) goal date of August 28, 2023. The European Medicines Agency has also validated the Type II Variation for Reblozyl in this patient population. Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. “Clinical experience has demonstrated that just one in three patients with low-risk myelodysplastic syndromes experience responses to erythroid stimulating agents over 6-18 months, leaving a significant need for more effective options to address chronic anemia,” said Matteo Giovanni Della Porta, study investigator and head of Leukemia Unit at Humanitas Cancer Center in Milan, Italy. “In the COMMANDS study, the median duration of red blood cell transfusion independence was nearly one year longer with Reblozyl than with epoetin alfa and showed safety consistent with its known profile, demonstrating its potential as a first-line treatment in patients with transfusion-dependent, very low- to intermediate-risk MDS.” “Results being presented at ASCO and EHA reinforce the notion that Reblozyl should be used as the initial treatment of anemia in patients with lower- to intermediate-risk myelodysplastic syndromes,” said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. “As a potentially more effective and durable upfront treatment option, Reblozyl could shift the paradigm for standard of care among these patients.” About MDS Myelodysplastic syndromes (MDS) are a group of closely related blood cancers characterized by ineffective production of healthy red blood cells (RBC), white blood cells and platelets, which can lead to anemia and frequent or severe infections. 1,2 People with MDS who develop anemia often require regular blood transfusions to increase the number of healthy red blood cells in circulation. 3 Frequent transfusions are associated with an increased risk of iron overload, transfusion reactions and infections. 4 Patients who become RBC transfusion-dependent have a significantly shorter overall survival than those who are not dependent on transfusions, partially due to iron overload or to more severe bone marrow disease than in non-transfusion dependent patients. 5 About Reblozyl ® (luspatercept-aamt) Reblozyl , a first-in-class therapeutic option, promotes late-stage red blood cell maturation in animal models. 6 Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. 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 syndrome 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. In the U.S., Reblozyl is not indicated for use in patients with non-transfusion-dependent beta thalassemia. U.S. Important Safety Information WARNINGS AND PRECAUTIONS Thrombosis/Thromboembolism In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) of 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. Extramedullary Hematopoietic Masses (EMH) In adult patients with transfusion-dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study). In a study of adult patients with non-transfusion-dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double- blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia. Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses. 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 and Summary of Product Characteristics for REBLOZYL. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , Twitter , YouTube , Facebook and Instagram . Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that Reblozyl ® (luspatercept-aamt) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. It should also be noted that acceptance of the sBLA does not change the standards for FDA approval and that the validation by the EMA of the application does not change the standards for EMA approval. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news References: Mount Sinai. Myelodysplastic Syndrome. Available at: https://www.mountsinai.org/care/cancer/services/mds . Accessed March 2023. Myelodysplastic Syndromes Foundation. What is MDS? Available at: https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html . Accessed March 2023. Johns Hopkins Medicine. Myelodysplastic Syndrome. Available at: https://www.hopkinsmedicine.org/kimmel_cancer_center/types_cancer/myelodysplastic_syndrome.html . Accessed March 2023. Rasel M, Mahboobi SK. Transfusion Iron Overload. PubMed. 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK562146/ . Accessed March 2023. Triantafyllidis I, Ciobanu A, Stanca O, Lupu AR. Prognostic factors in myelodysplastic syndromes. Maedica (Bucur). 2012 Dec;7(4):295-302. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593279 . Accessed March 2023. Galanello R, Origa R. Beta thalassemia. Orphanet Journal of Rare Diseases. 2010;5(11). Available at: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-11 . Accessed March 2023.

Applications based on results from Phase 3 COMMANDS study in which first-in-class Reblozyl demonstrated a highly statistically significant and clinically meaningful improvement compared to an erythropoiesis-stimulating agent in patients with very low/low/intermediate-risk MDS U.S. FDA has assigned a target action date of August 28, 2023 PRINCETON, N.J.--(BUSINESS WIRE)--Bristol-Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has accepted the supplemental Biologics License Application (sBLA) and the European Medicines Agency (EMA) has validated the Type II Variation Application for Reblozyl® (luspatercept-aamt), a first-in-class treatment option, to expand its current indication to include treatment of anemia without previous use of erythropoiesis-stimulating agents (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require red blood cell (RBC) transfusions. In the U.S., the FDA has granted the application Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) goal date of August 28, 2023. Priority Review designation underscores the high unmet need and value that Reblozyl could bring to this patient population. In Europe, the EMA’s validation of the application confirms the submission is complete and begins the EMA’s centralized review process. “Initial treatment options for very low- to intermediate-risk myelodysplastic syndromes, including erythropoiesis-stimulating agents, can alleviate anemia in some patients but others will either not respond or become resistant to therapy, and additional therapy options have remained urgently needed,” said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. “Results from the COMMANDS study showed Reblozyl significantly improved transfusion independence and elevated hemoglobin compared to ESA therapy epoetin alfa. Reblozyl is an important option available for the treatment of anemia in patients with transfusion-dependent, lower-risk MDS who have experienced ESA failure, and we look forward to working with the FDA and EMA to expand its potential use as a first-line therapy in eligible patients.” The submissions are based on results from the COMMANDS study, a Phase 3, open-label, randomized trial evaluating Reblozyl versus epoetin alfa, an ESA, for the treatment of anemia in adult patients with very low-, low- or intermediate-risk MDS who require RBC transfusions and are ESA-naïve. Results demonstrated a highly statistically significant and clinically meaningful improvement in red blood cell transfusion independence (RBC-TI) for ≥12 weeks with concurrent hemoglobin (Hb) increase (≥1.5 g/dL) in the first-line treatment of adult patients with very low-, low- or intermediate-risk MDS who require RBC transfusions. Safety results in the trial were consistent with the safety pro Reblozyl for the treatment of anemia in adult patients with low-risk MDS who require regular RBC transfusions, observed in previous clinical trials as well as in the post-marketing setting. Full results from the COMMANDS study will be presented at upcoming medical meetings. Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. About COMMANDS COMMANDS (NCT03682536) is a Phase 3, open-label, randomized study evaluating the efficacy and safety of Reblozyl versus epoetin alfa for the treatment of anemia due to very low-, low- or intermediate-risk (IPSS-R) myelodysplastic syndromes (MDS) in patients who are red blood cell (RBC) transfusion-dependent and were erythropoiesis-stimulating agent (ESA)-naïve. The primary endpoint evaluated in this study is red blood cell transfusion independence (RBC-TI) for 12 weeks with a mean hemoglobin (Hb) increase ≥1.5 g/dL. Key secondary endpoints include RBC-TI for 24 weeks, RBC-TI ≥12 weeks and erythroid response of at least 8 weeks during weeks 1-24 of the study. About MDS Myelodysplastic syndromes (MDS) are a group of closely related blood cancers characterized by ineffective production of healthy red blood cells (RBC), white blood cells and platelets, which can lead to anemia and frequent or severe infections.1,2 People with MDS who develop anemia often require regular blood transfusions to increase the number of healthy red blood cells in circulation.3 Frequent transfusions are associated with an increased risk of iron overload, transfusion reactions and infections.4 Patients who become RBC transfusion-dependent have a significantly shorter overall survival than those who are not dependent on transfusions, partially due to iron overload or to more severe bone marrow disease than in non-transfusion-dependent patients.5 About Reblozyl® (luspatercept-aamt) Reblozyl, a first-in-class therapeutic option, promotes late-stage red blood cell maturation in animal models.6 Reblozyl is being developed and commercialized through a global collaboration with Merck following Merck’s acquisition of Acceleron Pharma, Inc. in November 2021. 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. In the U.S., Reblozyl is not indicated for use in patients with non-transfusion-dependent beta thalassemia. U.S. Important Safety Information WARNINGS AND PRECAUTIONS Thrombosis/Thromboembolism In adult patients with beta thalassemia, thromboembolic events (TEE) were reported in 8/223 (3.6%) of 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. Extramedullary Hematopoietic Masses In adult patients with transfusion-dependent beta thalassemia, EMH masses were observed in 3.2% of REBLOZYL-treated patients, with spinal cord compression symptoms due to EMH masses occurring in 1.9% of patients (BELIEVE and REBLOZYL long-term follow-up study). In a study of adult patients with non-transfusion-dependent beta thalassemia, a higher incidence of EMH masses was observed in 6.3% of REBLOZYL-treated patients vs. 2% of placebo-treated patients in the double- blind phase of the study, with spinal cord compression due to EMH masses occurring in 1 patient with a prior history of EMH. REBLOZYL is not indicated for use in patients with non-transfusion-dependent beta thalassemia. Possible risk factors for the development of EMH masses in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL). Signs and symptoms may vary depending on the anatomical location. Monitor patients with beta thalassemia at initiation and during treatment for symptoms and signs or complications resulting from the EMH masses and treat according to clinical guidelines. Discontinue treatment with REBLOZYL in case of serious complications due to EMH masses. Avoid use of REBLOZYL in patients requiring treatment to control the growth of EMH masses. 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 and Summary of Product Characteristics for REBLOZYL. Bristol Myers Squibb: Creating a Better Future for People with Cancer Bristol Myers Squibb is inspired by a single vision — transforming people’s lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that Reblozyl® (luspatercept-aamt) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, that any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. It should also be noted that acceptance of the sBLA does not change the standards for FDA approval and that the validation by the EMA of the application does not change the standards for EMA approval. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2022, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news References: Mount Sinai. Myelodysplastic Syndrome. Available at: . Accessed March 2023. Myelodysplastic Syndromes Foundation. What is MDS? Available at: . Accessed March 2023. Johns Hopkins Medicine. Myelodysplastic Syndrome. Available at: . Accessed March 2023. Rasel M, Mahboobi SK. Transfusion Iron Overload. PubMed. 2021. Available at: /. Accessed March 2023. Triantafyllidis I, Ciobanu A, Stanca O, Lupu AR. Prognostic factors in myelodysplastic syndromes. Maedica (Bucur). 2012 Dec;7(4):295-302. Available at: . Accessed March 2023. Galanello R, Origa R. Beta thalassemia. Orphanet Journal of Rare Diseases. 2010;5(11). Available at: . Accessed March 2023.