FDA Approves REBLOZYL® (luspatercept-aamt) for the Treatment of Anemia in Adults With Beta Thalassemia Who Require Regular Red Blood Cell Transfusions

REBLOZYL is the first and only FDA-approved erythroid maturation agent, representing a new class of therapy for these patients

Approval of REBLOZYL marks the first FDA-approved treatment for anemia in beta thalassemia

SUMMIT, NJ & CAMBRIDGE, MA, USA I November 08, 2019 I Celgene Corporation (NASDAQ: CELG) and Acceleron Pharma Inc. (NASDAQ: XLRN) today announced the U.S. Food and Drug Administration (FDA) has approved REBLOZYL® (luspatercept-aamt) for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.1 REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.1 REBLOZYL is the first and only FDA-approved erythroid maturation agent, representing a new class of therapy which works by regulating late-stage red blood cell maturation to help patients reduce their RBC transfusion burden.1

“Today’s approval is an important milestone and underscores our continued commitment to patients with hematology disorders,” said Nadim Ahmed, President, Global Hematology and Oncology for Celgene. “There are very limited options for patients living with anemia due to beta thalassemia who are dependent on long term red blood cell transfusions. We are pleased to make REBLOZYL available as a new therapy for these patients to help address their anemia, a significant clinical complication of beta thalassemia.”2

“We’re thrilled that Acceleron’s first approved medicine is one with the potential to help patients with beta thalassemia, who have been in need of new treatments for this lifelong disease,” said Habib Dable, President and Chief Executive Officer of Acceleron. “We are enormously grateful to the patients, families and caregivers who participated in and supported our research. Their contributions have been essential in helping to ensure that REBLOZYL would emerge successfully from our longstanding collaboration with Celgene.”

Beta thalassemia is a rare, 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.2,3 Treatment options for anemia associated with beta thalassemia are limited, consisting mainly of RBC transfusions, which have the potential to contribute to iron overload, which can cause serious complications such as organ damage.4

The approval of REBLOZYL for beta thalassemia, which received a Priority Review designation from the FDA, is based on results from the pivotal, Phase 3, randomized, double-blind, placebo-controlled, multicenter BELIEVE trial evaluating the safety and efficacy of REBLOZYL for the treatment of anemia in adult patients with beta thalassemia who require regular RBC transfusions (defined as 6-20 RBC units per 24 weeks, with no transfusion-free period greater than 35 days during that period).1 All patients were eligible to receive best supportive care, which included RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed.1 The trial achieved a clinically meaningful and statistically significant improvement in the primary endpoint.1 In the REBLOZYL arm, 21.4% of patients (n=48) achieved a ≥33% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) during weeks 13–24 after randomization, compared to 4.5% (n=5) in the placebo arm (risk difference [95% CI]: 17.0 [10.4, 23.6], P<0.0001).1

The study also met key secondary endpoints, including transfusion burden reduction of at least 33% (with a reduction of at least 2 units), during weeks 37 to week 48, which was achieved in 19.6% (n=44) of patients in the REBLOZYL arm and 3.6% (n=4) in the placebo arm (risk difference [95% CI]: 16.1 [9.8, 22.4], P<0.0001).1

Other efficacy endpoints included transfusion burden reduction of ≥50% (with a reduction of at least 2 units) during weeks 13-24 and weeks 37-48.1 A ≥50% reduction in transfusion burden was observed in 7.6% of patients (n=17) receiving REBLOZYL vs. 1.8% of patients (n=2) in the placebo arm at weeks 13-24 (risk difference [95% CI]: 5.8 [1.6, 10.1], P=0.0303), and 10.3% of patients (n=23) vs. 0.9% of patients (n=1) at weeks 37-48 (risk difference [95% CI]: 9.4 [5, 13.7], P=0.0017), respectively.1

In the BELIEVE trial, thromboembolic events, including deep vein thromboses, pulmonary embolus, portal vein thrombosis, and ischemic stroke, were experienced in 3.6% (8/223) of REBLOZYL treated patients.1 Hypertension was reported in 10.7% (61/571) of REBLOZYL-treated patients across the clinical development program.1 REBLOZYL may cause fetal harm when administered to a pregnant woman. Serious adverse reactions occurred in 3.6% of patients receiving REBLOZYL.1 Serious adverse reactions reported in 1% of patients were cerebrovascular accident and deep vein thrombosis.1 One patient died due to an unconfirmed case of AML.1 The 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%).1

Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 5.4% of patients who received REBLOZYL.1 The most frequent adverse reactions requiring permanent discontinuation in patients who received REBLOZYL included arthralgia (1%), back pain (1%), bone pain (<1%), and headache (<1%).1 Dosage reductions due to an adverse reaction occurred in 2.7% of patients who received REBLOZYL.1 The most frequent adverse reactions requiring a dosage reduction in >0.5% of patients who received REBLOZYL included hypertension and headache.1 Dosage interruptions due to an adverse reaction occurred in 15.2% of patients who received REBLOZYL.1 The most frequent adverse reactions requiring a dosage interruption in >1% of patients who received REBLOZYL included upper respiratory tract infection, ALT increase, and cough.1

REBLOZYL is anticipated to be available 1 week following the FDA approval.

About BELIEVE
BELIEVE is a Phase 3, randomized, double-blind, placebo-controlled multicenter study comparing REBLOZYL + best supportive care (BSC) versus placebo + 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.1 Best supportive care included RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support as needed. The median age of patients was 30 years in both treatment arms.1 336 patients were randomized 2:1 to receive either REBLOZYL (224 patients) or placebo (112 patients) at a starting dose of 1.0 mg/kg by subcutaneous injection every 21 days for up to 48 weeks.1 Patients had the option to cross over to the luspatercept-aamt treatment groups only after all patients completed the treatment period, and after unblinding based on the recommendation of an independent Data Safety Monitoring Committee. Patients treated with luspatercept-aamt will be followed for up to 5 years. The study was conducted at 65 sites in 15 countries.1

About REBLOZYL®
REBLOZYL is a first-in-class erythroid maturation agent that promotes late-stage red blood cell maturation in animal models.1 Celgene and Acceleron are jointly developing REBLOZYL as part of a global collaboration.

Additional Clinical Investigation
The FDA is also evaluating luspatercept-aamt for the treatment of anemia in adults with very low- to intermediate-risk myelodysplastic syndromes (MDS) who have ring sideroblasts and require RBC transfusions. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of April 4, 2020 for this indication. In Europe, Celgene’s Marketing Authorization Application for the treatment of anemia in adults with beta thalassemia or MDS is currently under review.

A Phase 2 trial (BEYOND) in adult patients with non-transfusion-dependent beta thalassemia5; a Phase 3 trial (COMMANDS) in ESA-naïve, lower-risk MDS patients6; and a Phase 2 trial in myelofibrosis patients are ongoing.7 For more information, please visit www.clinicaltrials.gov.

REBLOZYL has not been approved as safe and effective for use in patients with MDS or myelofibrosis in any country.

Indication
REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions

REBLOZYL is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia

About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through next-generation solutions in protein homeostasis, immuno-oncology, epigenetics, immunology and neuro-inflammation. For more information, please visit www.celgene.com.

Follow Celgene on Social Media: Twitter, Pinterest, LinkedIn, Facebook and YouTube.

About Acceleron
Acceleron is a biopharmaceutical company dedicated to the discovery, development, and commercialization of therapeutics to treat serious and rare diseases. The Company's leadership in the understanding of TGF-beta superfamily biology and protein engineering generates innovative compounds that engage the body's ability to regulate cellular growth and repair.

Acceleron focuses its research and development efforts in hematologic, neuromuscular, and pulmonary diseases. In hematology, the Company and its global collaboration partner, Celgene, are co-promoting newly approved REBLOZYL® (luspatercept-aamt) in North America for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell transfusions and developing luspatercept for the treatment of chronic anemia in myelodysplastic syndromes and myelofibrosis. Acceleron is also advancing its neuromuscular program with ACE-083, a locally-acting Myostatin+ agent in Phase 2 development in Charcot-Marie-Tooth disease and is conducting a Phase 2 pulmonary program with sotatercept in pulmonary arterial hypertension.

For more information, please visit www.acceleronpharma.com. Follow Acceleron on Social Media: @AcceleronPharma and LinkedIn.

1 REBLOZYL U.S. Prescribing Information. Accessed November 2019.

2 National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. Beta-thalassemia. Available at: http://rarediseases.info.nih.gov/gard/871/beta-thalassemia/resources/1. Accessed October 2019.

3 National Institutes of Health: Genetics Home Reference. Beta-thalassemia. Available at: https://ghr.nlm.nih.gov/condition/beta-thalassemia#inheritance. Accessed October 2019.

4 Galanello R and Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010 May 21;5:11. Available at: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-11. Accessed October 2019.

5 ClinicalTrials.gov. A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia (BEYOND). Available at: https://www.clinicaltrials.gov/ct2/show/NCT03342404?term=BEYOND&cond=Beta-Thalassemia&rank=2. Accessed October 2019.

6 ClinicalTrials.gov. Efficacy and Safety Study of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions (COMMANDS). Available at: https://www.clinicaltrials.gov/ct2/show/NCT03682536?term=COMMANDS+luspatercept&rank=1. Accessed October 2019.

7 ClinicalTrials.gov. A Safety and Efficacy Study to Evaluate Luspatercept in Subjects With Myeloproliferative Neoplasm-associated Myelofibrosis Who Have Anemia With and Without Red Blood Cell-transfusion Dependence. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03194542?term=luspatercept&cond=Myelofibrosis&rank=1. Accessed October 2019.

SOURCE: Celgene

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