U.S. FDA Accepts for Priority Review Supplemental Biologics License Application and EMA Validates Application for Reblozyl® (luspatercept-aamt) as First-Line Treatment of Anemia in Adults with Lower-Risk Myelodysplastic Syndromes (MDS)

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)--$BMY #BMS--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 profile of 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.

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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.

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References:

1. Mount Sinai. Myelodysplastic Syndrome. Available at: https://www.mountsinai.org/care/cancer/services/mds. Accessed March 2023.
2. Myelodysplastic Syndromes Foundation. What is MDS? Available at: https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html. Accessed March 2023.
3. Johns Hopkins Medicine. Myelodysplastic Syndrome. Available at: https://www.hopkinsmedicine.org/kimmel_cancer_center/types_cancer/myelodysplastic_syndrome.html. Accessed March 2023.
4. Rasel M, Mahboobi SK. Transfusion Iron Overload. PubMed. 2021. Available at: https://www.ncbi.nlm.nih.gov/books/NBK562146/. Accessed March 2023.
5. 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.
6. 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.

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