Reblozyl® (luspatercept-aamt) Studies Evaluating Treatment of Anemia in Rare Blood Diseases Presented at American Society of Hematology (ASH) Annual Meeting
Initial results from phase 2 study evaluating an investigational use of luspatercept-aamt in myelofibrosis-associated anemia showed promising clinical activity – companies plan to initiate pivotal, phase 3 study called INDEPENDENCE in 2020
Longer-term follow-up from pivotal phase 3 studies of MEDALIST in MDS-associated anemia and BELIEVE in beta thalassemia-associated anemia showed patients experiencing sustained clinical benefit
Data from investigational uses of luspatercept-aamt included the initial results from a phase 2 study in myelofibrosis-associated anemia. Presentations also included updated results from two pivotal phase 3 studies presented at last year’s ASH meeting—the MEDALIST study in adult patients with anemia associated with very low-, low- and intermediate-risk myelodysplastic syndromes (MDS) who have ring sideroblasts and require red blood cell (
“The data presented at ASH this year underscore the role that Reblozyl, the first and only erythroid maturation agent, plays for patients with beta thalassemia-associated anemia and may serve in further investigational uses in myelofibrosis and MDS,” said
“We’re encouraged to see positive study results from luspatercept-aamt in patients with myelofibrosis-associated anemia, including among those receiving concomitant ruxolitinib, as JAK inhibitors are a mainstay of myelofibrosis symptomatology management,” said
Phase 2 Results in Myelofibrosis-associated Anemia
Seventy-six patients were enrolled in the phase 2 study in multiple cohorts of patients including two groups with anemia only (hemoglobin level equal to or below 9.5 grams per deciliter (g/dL) in a 12-week period prior to the first dose) and without concomitant ruxolitinib (Cohort 1; n=22) or with concomitant ruxolitinib (Cohort 3A; n=14). Two other groups included transfusion dependent (TD; received 2-4
Patients in Cohort 3A or 3B were required to be on a stable dose of ruxolitinib for at least 16 weeks prior to initiating luspatercept-aamt. All patients received luspatercept-aamt at a starting dose of 1 mg/kg subcutaneously in three-week treatment cycles and dose increases were allowed up to a maximum dose level of 1.75 mg/kg.
For anemia-only patients (Cohorts 1 and 3A), the primary endpoint was a hemoglobin (Hb) increase of at least 1.5 g/dL from baseline for at least 12 consecutive weeks at every assessment within the first 24 weeks on the study, in the absence of any
As of the clinical data cutoff (
For patients receiving
In Cohorts 2 and 3B, 10% (2/21) and 32% (6/19) of patients achieved the primary endpoint, respectively. Additionally, 38% (8/21) of Cohort 2 and 53% (10/19) of Cohort 3B patients achieved at least a 50% reduction in
Four percent (3/76) of patients had grade 3 or higher treatment-emergent adverse events (TEAEs). The most commonly occurring TEAEs of any grade greater than 3% were hypertension (12%), bone pain (9%) and diarrhea (5%). Treatment discontinuations as the result of TEAEs occurred in seven (9%) patients. There were no treatment-related deaths.
As a result of the phase 2 study,
Updated Results from the Phase 3 MEDALIST Study
In an assessment of efficacy and safety, updated results from the pivotal phase 3 MEDALIST study of an investigational use of luspatercept-aamt in patients with IPSS-R very low-, low- or intermediate-risk MDS with ring sideroblasts who require regular
This updated analysis measured the achievement and number of individual periods of RBC-TI of at least 8 weeks throughout the course of the study. Additionally, clinical benefit (RBC-TI) of at least 8 weeks and/or modified hematologic improvement-erythroid (HI-E) was also assessed, along with the total duration of the clinical benefit, which was defined as time from achieving clinical benefit until discontinuation due to loss of benefit, adverse events or other causes.
In the analysis, the median baseline
As of the clinical cutoff (
The median total duration of clinical benefit was 92.3 weeks for luspatercept-aamt responders (n=98) and 26.8 weeks for placebo (n=20), with 26.8% of luspatercept-aamt-treated patients remaining on treatment. No placebo-treated patients remain on treatment. The median treatment duration for all RBC-TI responders was 109.1 weeks for luspatercept-aamt-treated patients and 53.6 weeks for patients on placebo.
Adverse events (AEs) occurring more frequently with luspatercept-aamt compared to placebo were fatigue, asthenia and headache. These occurred during cycles 1-4 and were mainly grade 1 or 2, with the incidence decreasing over time. Progression to acute myeloid leukemia was similar between the luspatercept-aamt (2%) and placebo (2.6%) arms.
Updated Results from the BELIEVE Study
The companies also presented an updated analysis of the pivotal phase 3 BELIEVE study evaluating luspatercept-aamt in adult patients with beta thalassemia who require regular
As of the clinical cutoff (
The median duration of clinical benefit (defined as the time from first response of at least a 33% reduction in
The most commonly observed AEs in the safety population (n=332) included in luspatercept-aamt and placebo patients, respectively, bone pain (20.2% vs. 8.3%), arthralgia (21.1% vs. 14.7%) and dizziness (12.1% vs. 4.6%). These AEs typically occurred early on, and incidence decreased over time.
Reblozyl is currently being reviewed by the
Reblozyl is not approved for use in patients with MDS or myelofibrosis in any country.
Building upon our transformative work and legacy in hematology and Immuno-Oncology that has changed survival expectations for many cancers, our researchers are advancing a deep and diverse pipeline across multiple modalities. In the field of immune cell therapy, this includes registrational chimeric antigen receptor (CAR) T-cell agents for numerous diseases, and a growing early-stage pipeline that expands cell and gene therapy targets, and technologies. We are developing cancer treatments directed at key biological pathways using our protein homeostasis platform, a research capability that has been the basis of our approved therapies for multiple myeloma and several promising compounds in early to mid-stage development. Our scientists are targeting different immune system pathways to address interactions between tumors, the microenvironment and the immune system to further expand upon the progress we have made and help more patients respond to treatment. Combining these approaches is key to delivering new options for the treatment of cancer and addressing the growing issue of resistance to immunotherapy. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines a reality for patients.
About Reblozyl (luspatercept-aamt)
Reblozyl is an erythroid maturation agent (EMA) that promoted late-stage red blood cell maturation in animal models.
REBLOZYL is indicated for the treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (
REBLOZYL is not indicated for use as a substitute for
Important Safety Information
WARNINGS AND PRECAUTIONS
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 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. Monitor blood pressure prior to each administration. Manage new or exacerbations of preexisting hypertension using anti-hypertensive agents.
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 last dose.
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%).
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.
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,
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Bristol-Myers Squibb Company
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