Study to Evaluate the Safety and Efficacy of Luspatercept (ACE-536) in Participants With Beta-thalassemia (A536-04/MK-6143-002)

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who experienced an AE is presented.

An SAE was any adverse event, occurring at any dose level/regimen and regardless of causality that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or was an important medical event. The number of participants who experienced an SAE is presented.

AEs were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) and graded as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening consequences; and Grade 5=death related to AE. An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who experienced an AE of ≥Grade 3 is presented.

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who discontinued study treatment due to an AE is presented.

DLTs were determined using the National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) and graded as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening consequences; and Grade 5=death related to AE. The occurrence of any of the following toxicities occurring up to 28 days after the first dose was considered a DLT: treatment-related serious adverse event (SAE) ≥ Grade 3; treatment related non-hematologic adverse event (AE) ≥ Grade 3; and treatment related hematologic AE ≥ Grade 4. The number of participants who experienced a DLT is presented.

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline during an 8-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from analysis. NTD participants were participants who had received <4 units of red blood cells (RBCs) within 8 weeks prior to the first dose of study drug. An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.0 g/dL from baseline is presented.

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline during an 8-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from analysis. NTD participants were participants who had received <4 units of red blood cells (RBCs) within 8 weeks prior to the first dose of study drug. An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline is presented.

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline during a 12-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from analysis. NTD participants were participants who had received <4 units of red blood cells (RBCs) within 8 weeks prior to the first dose of study drug. A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.0 g/dL from baseline is presented.

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline during a 12-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from analysis. NTD participants were participants who had received <4 units of red blood cells (RBCs) within 8 weeks prior to the first dose of study drug. A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline is presented.

Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during an 8-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a ≥50% reduction in RBC transfusion burden from baseline is presented.

Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a ≥50% reduction in RBC transfusion burden from baseline is presented.

Transfusion independence for TD participants was defined as the percentage of participants who did not require RBC transfusion units (or milliliters) transfused for ≥8 weeks in the study after start of treatment. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants who maintained transfusion independence for ≥8 weeks is presented.

Time to erythroid response was defined as the time from first dose to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.0 g/dL. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by analysis cutoff were censored. The time to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.0 g/dL is presented.

Time to erythroid response was defined as the time from the first dose to the first date of any rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction of ≥50% compared to pretreatment. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by analysis cutoff were censored. The time to the first date of any rolling 12-week window achieving a red blood cell transfusion burden reduction of ≥50% compared to pretreatment is presented.

Duration of erythroid response was defined as the time from the first rolling 12-week window achieving a hemoglobin increase of ≥1.0 g/dL to the date of the last consecutive rolling 12-week window achieving a hemoglobin increase of ≥1.0 g/dL. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by analysis cutoff were censored. The duration of response for participants achieving a hemoglobin increase ≥1.0 g/dL is presented.

Duration of erythroid response was defined as the time from the first rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction of ≥50% compared to pretreatment to the last consecutive rolling 12-week window achieving a RBC transfusion burden reduction of ≥50% compared to pretreatment. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by analysis cutoff were censored. The duration of response for participants achieving a RBC transfusion burden reduction of ≥50% compared to pretreatment is presented.

Blood samples were collected at pre-specified time intervals to determine BSAP. The percent change from baseline in BSAP was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine CTX. The percent change from baseline in CTX was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine serum iron. The percent change from baseline in serum iron was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine TIBC. The percent change from baseline in TIBC was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine transferrin. The percent change from baseline in transferrin was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor. The percent change from baseline in soluble transferrin receptor was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine ferritin. The percent change from baseline in ferritin was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were to be collected at pre-specified time intervals to determine NTBI. Baseline was pre-specified to be the last measurement prior to the first dose of study drug.

The calculated transferrin saturation is the ratio of the serum iron concentration and the total iron binding capacity (TIBC) expressed as a percentage. Blood samples were to be collected at pre-specified time intervals for serum iron and TIBC to determine the calculated transferrin saturation. Baseline was pre-specified to be the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine hepcidin. The percent change from baseline in hepcidin was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine reticulocytes. The percent change from baseline in reticulocytes was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine erythropoietin. The percent change from baseline in erythropoietin was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine nRBC count. The percent change from baseline in nRBC count was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine Hb A. The percent change from baseline in Hb A was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine Hb A2. The percent change from baseline in Hb A2 was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine Hb C. The percent change from baseline in Hb C was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine Hb D. The percent change from baseline in Hb D was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine Hb F. The percent change from baseline in Hb F was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine Hb S. The percent change from baseline in Hb S was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine alpha globin gene. The percent change from baseline in alpha globin gene was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine beta globin gene. The percent change from baseline in beta globin gene was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine gamma globin gene. The percent change from baseline in gamma globin gene was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine haptoglobin. The percent change from baseline in haptoglobin was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine indirect bilirubin. The percent change from baseline in indirect bilirubin was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine LDH. The percent change from baseline in LDH was measured. Baseline was the last measurement prior to the first dose of study drug.

Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for NTD participants with baseline LIC <3 mg/g dry weight was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The change from baseline to Day 113 in mean LIC for NTD participants with baseline LIC <3 mg/g dry weight is presented.

Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for NTD participants with baseline LIC ≥3 mg/g dry weight was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The change from baseline to Day 113 in mean LIC for NTD participants with baseline LIC ≥3 mg/g dry weight is presented.

LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in NTD participants with a baseline LIC of ≥3 mg/g dry weight. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of NTD participants with baseline LIC ≥3 mg/g dry weight who have demonstrated an LIC response is presented.

LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in NTD participants with a baseline LIC of ≥3 mg/g dry weight and who have used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of NTD participants with baseline LIC ≥3 mg/g dry weight, who have used ICT, and who have demonstrated an LIC response is presented.

LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in NTD participants with a baseline LIC of ≥3 mg/g dry weight and who have not used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of NTD participants with baseline LIC ≥3 mg/g dry weight, who have not used ICT, and who have demonstrated an LIC response is presented.

Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for TD participants with baseline LIC <3 mg/g dry weight was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The change from baseline to Day 113 in mean LIC for TD participants with baseline LIC <3 mg/g dry weight is presented.

Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for TD participants with baseline LIC ≥3 mg/g dry weight was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The change from baseline to Day 113 in mean LIC for TD participants with baseline LIC ≥3 mg/g dry weight is presented.

LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in TD participants with a baseline LIC of ≥3 mg/g dry weight. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of TD participants with baseline LIC ≥3 mg/g dry weight who have demonstrated an LIC response is presented.

LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in TD participants with a baseline LIC of ≥3 mg/g dry weight and who have used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of TD participants with baseline LIC ≥3 mg/g dry weight, who have used ICT, and who have demonstrated an LIC response is presented.

LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in TD participants with a baseline LIC of ≥3 mg/g dry weight and who have not used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of TD participants with baseline LIC ≥3 mg/g dry weight, who have not used ICT, and who have demonstrated an LIC response is presented.

Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of luspatercept observed after administration. Cmax was based on non-compartmental analysis.

Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as the time to maximum concentration of luspatercept observed after administration. Tmax was based on non-compartmental analysis.

Blood samples were collected at specified intervals for the determination of AUC0-21. AUC0-21 was defined as the area under the concentration time curve of luspatercept from time zero to Day 21. AUC0-21 was based on non-compartmental analysis and calculated by the linear trapezoidal method.

Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the serum concentration of luspatercept by two after reaching pseudo-equilibrium. t½ was based on non-compartmental analysis.

Blood samples were collected at specified intervals for the determination of apparent terminal rate constant. Apparent terminal rate constant was defined as the amount of luspatercept that was eliminated from the body during a given period of time and was calculated by linear regression of the terminal portion of the log-concentration-time curve in serum. Apparent terminal rate constant was based on non-compartmental analysis.