Bristol Myers Squibb Receives European Commission Approval for Onureg® (azacitidine tablets) as Frontline Oral Maintenance Therapy for Adults with Acute Myeloid Leukemia

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has granted full Marketing Authorization for Onureg^® (azacitidine tablets) as a maintenance therapy in adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT). Onureg is the first and only once-daily, frontline oral maintenance therapy to demonstrate significant overall survival and show a relapse-free survival benefit in patients with a broad range of AML subtypes.

The centralized Marketing Authorization approves use of Onureg in all EU member states, as well as Norway, Iceland and Liechtenstein.* Onureg is approved in the United States for the continued treatment of adult patients with AML who achieved first CR or CRi following intensive induction chemotherapy and who are not able to complete intensive curative therapy.¹ In Canada, Onureg is approved as a maintenance therapy for adult patients with AML who achieved CR or CRi following induction therapy with or without consolidation treatment, and who are not eligible for HSCT.²

“An unmet need exists for maintenance therapy options for acute myeloid leukemia in the European Union, given responses to induction therapy may be of short duration and the risk of relapse is high, especially for patients not eligible for stem cell transplant,” said Andrew Wei, MBBS, Ph.D., QUAZAR^® AML-001 lead investigator, Alfred Hospital and Monash University, Melbourne, Australia. “The approval of Onureg by the European Commission has the potential to clinically benefit and change the treatment paradigm of patients with acute myeloid leukemia, across a range of subtypes.”

The EC approval of Onureg was based on results from the QUAZAR^® AML-001 study, a Phase 3, international, randomized, double-blind trial. Eligible patients were ages 55 years or older, had newly diagnosed AML, intermediate or poor cytogenetics, had achieved first CR or CRi following intensive induction chemotherapy with or without consolidation treatment (per investigator preference prior to study entry), and were not candidates for HSCT at the time of screening.³

“Today’s approval of Onureg represents a significant advance for patients in the European Union living with acute myeloid leukemia, who have remained in urgent need of maintenance therapies for this aggressive blood cancer,” said Noah Berkowitz, M.D., Ph.D., senior vice president, Hematology Development, Bristol Myers Squibb. “We are committed to helping to improve long-term outcomes and greatly extending survival for patients with hard-to-treat diseases, as we work collaboratively with European Union member states to make Onureg available to eligible patients as quickly as possible.”

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

About QUAZAR^® AML-001

QUAZAR^® AML-001, is a Phase 3, international, randomized, double-blind study. Eligible patients were ages 55 years or older, had newly diagnosed AML, intermediate or poor cytogenetics, had achieved first CR or CRi following intensive induction chemotherapy with or without consolidation treatment (per investigator preference prior to study entry) within four months (+/- 7 days) before randomization, and were not candidates for HSCT at the time of screening. The study enrolled 472 patients, randomized 1:1 to receive either Onureg 300 mg (N=238) or placebo (N=234) orally, once daily, for 14 days of a 28-day cycle, plus best supportive care and results were published in the New England Journal of Medicine in December 2020.*^3,4

Median OS, the primary endpoint, from time of randomization was greater than two years (24.7 months; 95% CI: 18.7 to 30.5) in the Onureg arm compared to 14.8 months for placebo (HR: 0.69, 95% CI: 0.55 to 0.86; p=0.0009). The median duration of treatment was 12 cycles (1 to 82) for Onureg and 6 cycles with placebo (1 to 76). Median relapse-free survival was also significantly longer with Onureg than with placebo (10.2 months and 4.8 months, respectively; p<0.001). Overall health-related quality of life was preserved during Onureg treatment.⁴

The most common adverse events in both treatment arms were Grade 1 or 2 gastrointestinal events. Common Grade 3 or 4 adverse events were neutropenia (41% of patients treated with Onureg and 24% of patients with placebo) and thrombocytopenia (22% and 21%, respectively).⁴

*Individual results associated with regulatory authorities may differ from publication.

About AML

AML is one of the most common acute leukemias in adults.⁵ The worldwide incidence of AML has been estimated at more than 350,000 cases, and the estimated 5-year survival rate for AML in Europe is 17%.⁶ AML is characterized by the rapid growth of abnormal cells in the bone marrow and as such interferes with normal blood cell production and function. Because of the impaired production of red blood cells, platelets and white blood cells, it can present with signs of anemia, bleeding and infections.⁵ AML is a heterogeneous disease associated with diverse genetic mutations, and can rapidly progress and lead to death if not promptly treated.⁷ AML response to treatment may be of short duration, meaning following patients’ initial response to chemotherapy, about 50% of patients relapse within one year, thus representing a significant unmet need for maintenance treatment options that prolong overall survival.⁸

About Onureg^®

Onureg, the first and only frontline maintenance therapy approved in the European Union for patients with a broad range of AML subtypes, is a once-daily oral hypomethylating agent that incorporates into DNA and RNA. The main mechanism of action is thought to be hypomethylation of DNA, as well as direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Hypomethylation may restore normal function to genes that are critical for cell differentiation and proliferation.^9,10 Onureg is approved in the U.S. for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy. Onureg is also approved in Canada as maintenance therapy for adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment, and who are not eligible for hematopoietic stem cell transplantation (HSCT).

U.S. IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

• ONUREG is contraindicated in patients with known severe hypersensitivity to azacitidine or its components.

WARNINGS AND PRECAUTIONS

• Risks of Substitution with Other Azacitidine Products: Due to substantial differences in the pharmacokinetic parameters, the recommended dose and schedule for ONUREG are different from those for the intravenous or subcutaneous azacitidine products. Treatment of patients using intravenous or subcutaneous azacitidine at the recommended dosage of ONUREG may result in a fatal adverse reaction. Treatment with ONUREG at the doses recommended for intravenous or subcutaneous azacitidine may not be effective. Do not substitute ONUREG for intravenous or subcutaneous azacitidine.
• Myelosuppression: New or worsening Grade 3 or 4 neutropenia and thrombocytopenia occurred in 49% and 22% of patients who received ONUREG. Febrile neutropenia occurred in 12%. A dose reduction was required for 7% and 2% of patients due to neutropenia and thrombocytopenia. Less than 1% of patients discontinued ONUREG due to either neutropenia or thrombocytopenia. Monitor complete blood counts and modify the dosage as recommended. Provide standard supportive care, including hematopoietic growth factors, if myelosuppression occurs.
• Increased Early Mortality in Patients with Myelodysplastic Syndromes (MDS): In AZA-MDS-003, 216 patients with red blood cell transfusion-dependent anemia and thrombocytopenia due to MDS were randomized to ONUREG or placebo. 107 received a median of 5 cycles of ONUREG 300 mg daily for 21 days of a 28-day cycle. Enrollment was discontinued early due to a higher incidence of early fatal and/or serious adverse reactions in the ONUREG arm compared with placebo. The most frequent fatal adverse reaction was sepsis. Safety and effectiveness of ONUREG for MDS have not been established. Treatment of MDS with ONUREG is not recommended outside of controlled trials.
• Embryo-Fetal Toxicity: ONUREG can cause fetal harm when administered to a pregnant woman. Azacitidine caused fetal death and anomalies in pregnant rats via a single intraperitoneal dose less than the recommended human daily dose of oral azacitidine on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ONUREG and for at least 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ONUREG and for at least 3 months after the last dose.

ADVERSE REACTIONS

• Serious adverse reactions occurred in 15% of patients who received ONUREG. Serious adverse reactions in ≥2% included pneumonia (8%) and febrile neutropenia (7%). One fatal adverse reaction (sepsis) occurred in a patient who received ONUREG.
• Most common (≥10%) adverse reactions with ONUREG vs placebo were nausea (65%, 24%), vomiting (60%, 10%), diarrhea (50%, 21%), fatigue/asthenia (44%, 25%), constipation (39%, 24%), pneumonia (27%, 17%), abdominal pain (22%, 13%), arthralgia (14%, 10%), decreased appetite (13%, 6%), febrile neutropenia (12%, 8%), dizziness (11%, 9%), pain in extremity (11%, 5%).

LACTATION

• There are no data regarding the presence of azacitidine in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with ONUREG and for 1 week after the last dose.

Please see full Prescribing Information and Summary of Product Characteristics for ONUREG.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision—transforming patients’ 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.

Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.

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 historical performance and 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 the outcome of pricing and reimbursement negotiations in individual countries in Europe may delay or limit the commercial potential of Onureg^® (azacitidine tablets) for the additional indication described in this release, that continued approval of such product candidate for such additional indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials, and whether such product candidate for such additional indication described in this release will be commercially successful. No forward-looking statement can be guaranteed. 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, 2020, 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.

References:

1. ONUREG U.S. Prescribing Information. Accessed February 2021.
2. ONUREG Canada Product Monograph. Accessed January 2021.
3. Clinical Trials.gov. Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia in Complete Remission (QUAZAR AML-001). Available at https://clinicaltrials.gov/ct2/show/NCT01757535. Accessed February 2021.
4. Wei, A. et al. New England Journal of Medicine 2020; 383:2526-2537; Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2004444.
5. American Cancer Society. What is AML?. https://www.cancer.org/cancer/acute-myeloid-leukemia/about/what-is-aml.html. Accessed on: July 23, 2020.
6. Maynadie et al. Haematologica. 2013 Feb; 98(2): 230–238.
7. Int J Hematol Oncol Stem Cell Res. Acute Myeloid Leukemia—Genetic Alterations and Their Clinical Prognosis. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767295/.
8. Leukaemia Care. Relapse in Acute Myeloid Leukaemia (AML). https://media.leukaemiacare.org.uk/wp-content/uploads/Relapse-in-Acute-Myeloid-Leukaemia-AML-Web-Version.pdf. Accessed on July 23, 2020.
9. Laille et al. PLoS One. 2015;10(8):e0135520
10. Garcia-Manero et al. J Clin Oncol. 2011;29(18):2521–7

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