Anemia
Conditions
Keywords
Myelodysplastic Syndrome
Brief summary
The purpose of this study is to evaluate the effects of luspatercept (MK-6143, formerly called ACE-536) on anemia in patients with low or intermediate-1 risk myelodysplastic syndrome (MDS). There is no primary hypothesis in this study.
Interventions
DRUGLuspatercept
Participants receive luspatercept up to 1.75mg/kg subcutaneously (SC) every 3 weeks for up to 5 cycles (each cycle length = 21 days).
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Documented diagnosis of idiopathic/de novo myelodysplastic syndrome (MDS) or non-proliferative chronic myelomonocytic leukemia (CMML), according to WHO criteria (white blood count, 13,000/uL), that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC) obtained during screening * Anemia defined as: * Mean hemoglobin concentration \<10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to Cycle 1 Day 1, not influenced by red blood cell (RBC) transfusion within 7 days of measurement for non-transfusion dependent patients (defined as having received \<4 units of RBCs within 8 weeks prior to Cycle 1 Day 1), or Transfusion dependent, defined as having received ≥4 units of RBCs within 8 weeks prior to Cycle 1 Day 1 * Serum erythropoietin levels and prior erythropoiesis-stimulating agent (ESA) treatment: * Dose escalation cohorts and expansion cohort 1 patients: Serum erythropoietin level \>500 U/L, OR, if ≤500 U/L, patient is non-responsive, refractory, or intolerant to erythropoiesis-stimulating agents (ESAs), or ESAs are contraindicated or unavailable * Expansion cohort 2 patients: If patient is RS+ (defined as having ≥15% ring sideroblasts in the bone marrow), no prior ESA treatment and serum erythropoietin level ≤ 200 U/L. If a patient is RS- (defined as having \<15% ring sideroblasts in the bone marrow), prior ESA treatment and any serum erythropoietin level is allowed * No alternative treatment options, per applicable MDS guidelines, are available and/or appropriate for the patient, at the discretion of the investigator * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (if related to anemia). * Adequate renal (creatinine ≤2 x upper limit of normal \[ULN\]) and hepatic (total bilirubin \<2 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3 x ULN) function * Adequate transferrin saturation (≥15%), ferritin (≥ 50 µg/L), folate (≥4.5 nmol/L \[≥2.0 µg/L\]) and vitamin B12 (≥148 pmol/L \[≥ 200 pg/mL\]) during screening (supplementation and retest during screening is acceptable) * Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of luspatercept. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of luspatercept, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of luspatercept * Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements * Patients understand and are able to provide written informed consent Key
Exclusion criteria
* Prior treatment with azacitidine or decitabine * Treatment within 28 days prior to Cycle 1 Day 1 with: * Erythropoiesis stimulating agent (ESA) * Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) * Lenalidomide * Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1 * Treatment with another investigational drug or device, or approved therapy for investigational use ≤28 days prior to Cycle 1 Day 1, or if the half-life of the previous product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer * Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1 * Platelet count \<30 x 109/L. * Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1 * History of stroke, deep venous thrombosis (DVT) or arterial embolism within 6 months prior to Cycle 1 Day 1 * Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV) * Any malignancy other than MDS which has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy or surgery, within the last year prior to Cycle 1 Day 1 * Uncontrolled hypertension, defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 100 mm Hg * Pregnant or lactating females * History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug * Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study * Transfusion event within 7 days prior to Cycle 1 Day 1 * Prior treatment with sotatercept (MK-7962, formerly called ACE-011) or luspatercept. * Secondary MDS
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) | Any consecutive 2 weeks during the study (up to approximately 75 weeks) | The mHI-E for LTB participants was defined as a hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days or rolling 2 weeks (in the absence of red blood cell \[RBC\] transfusions). Hemoglobin measurements within 7 days following RBC transfusion were excluded from analysis. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Rolling 2 weeks was defined as any consecutive 2 weeks during the study. The percentage of LTB participants with mHI-E were reported. |
| Percentage of High Transfusion Burden (HTB) Participants With mHI-E | Any consecutive 8 weeks during the study (up to approximately 75 weeks) | The mHI-E for HTB participants was defined as a ≥4 units or ≥50% reduction in RBC transfusion burden during any rolling 8-week window compared to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. The percentage of HTB participants with mHI-E were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks) | Per IWG 2006 response criteria, rate of HI-E is defined as the percentage of participants for whom the mean of all hemoglobin value from baseline during any rolling 8-week increased ≥1.5 g/dL in the absence of transfusion for LTB participants, or a reduction by ≥4 units of RBCs transfusion over any rolling 8-week window for HTB patients. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. |
| Rate of Platelet Response (HI-P) Per IWG 2006 Criteria | Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks) | Per IWG 2006 response criteria, HI-P was defined for participants with baseline value ≥20 x 10\^9/L as the platelet increase in any rolling 8 weeks ≥30 x 10\^9 and for participants with baseline value \<20 x 10\^9/L as the platelet increase in any rolling 8 weeks \>20 x 10\^9/L with increase of at least 100%. The rolling 8-week was defined as any consecutive 8 weeks during the study. The percentage of participants with HI-P were reported. |
| Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks) | Per IWG 2006 response criteria, HI-N was defined as the neutrophil increase in any rolling 8 weeks is at last 100% and an absolute increase \> 0.5 x 10\^9/L. The rolling 8-week was defined as any consecutive 8 weeks during the study. The percentage of participants with HI-N response were reported. |
| Duration of HI-E Per IWG 2006 Response Criteria | up to approximately 75 weeks | Per IWG 2006 response criteria, duration of HI-E response was defined as the time from the first day of the first rolling 8-week interval of showing response to the last day of the last consecutive rolling 8-week interval of showing response. HI-E response for LTB participants was defined as hemoglobin increase ≥ 1.5 g/dL during any rolling 8-week window and for HTB HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study. |
| Time to HI-E Per IWG 2006 Response Criteria | Any consecutive 8 weeks during the study (up to approximately 75 weeks) | Per IWG 2006 response criteria, the time to HI-E response was defined as the first date of the rolling 8-week interval of showing response minus first dose date plus 1. HI-E response for LTB participants was defined as hemoglobin increase ≥ 1.5 g/dL during any rolling 8 weeks window and for HTB HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study. |
| Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline (prior to first dose of luspatercept) and Day 113 | Frequency of RBC transfusion was defined as the total number of RBC transfusions received. Per protocol, the mean change from baseline to Day 113 in frequency of RBC transfusion was reported in the HTB participants (those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline). |
| Rate of RBC Transfusion Independence (RBC-TI) | Up to approximately 16 weeks | Rate of RBC-TI was defined as percentage of participants with ≥2 units of RBC transfusions at baseline who experienced transfusion independence which was defined as ≥8 weeks without a transfusion while on treatment. Per protocol, rate of RBC-TI was reported in HTB participants (those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline). |
| Time to Maximum Concentration (Tmax) of Luspatercept | Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days) | Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of luspatercept reached. Tmax was based on non-compartmental analysis and a mean Tmax value was presented. |
| Terminal Half-Life (t ½) of Luspatercept | Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days) | Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the luspatercept plasma concentration by two after reaching pseudo-equilibrium, following a single dose of luspatercept. t½ was based on non-compartmental analysis and a mean t1/2 value was presented. |
| Maximum Concentration (Cmax) of Luspatercept | Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days) | Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of luspatercept reached. Cmax was based on non-compartmental analysis and a mean Cmax value was presented. |
| Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | Cycle 1 Day 1: Predose, Cycle 1 Days 8, 11, 15 and Cycle 2 Day 1: Postdose (each cycle length = 21 days) | 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 Study Day 21. AUC0-21 was based on non-compartmental analysis and a mean AUC0-21 value was presented. |
| Percent Change From Baseline to Day 113 in Concentration of Serum Iron | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were to be collected at pre-specified time intervals to determine serum iron concentration. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline in TIBC was reported. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 24 weeks | An adverse event (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 can 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 were reported. |
| Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor concentration. The percentage change from baseline in concentration of soluble transferrin receptor was reported. |
| Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine serum ferritin concentration. The percentage change from baseline in concentration of serum ferritin was reported. |
| Percent Change From Baseline to Day 113 in Concentration of Non-Transferrin Bound Iron (NTBI) | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were to be collected at pre-specified time intervals to determine concentration of NTBI. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine soluble hepcidin concentration. The percentage change from baseline in concentration of soluble hepcidin was reported. |
| Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine serum erythropoietin concentration. The percentage change from baseline in concentration of serum erythropoietin was reported. |
| Percent Change From Baseline to Day 113 in Reticulocyte Count | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline in mean reticulocyte count was reported. |
| Percent Change From Baseline to Day 113 in Direct Bilirubin Level | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine serum direct bilirubin concentration. The percentage change from baseline in mean concentration direct bilirubin was reported. |
| Percent Change From Baseline to Day 113 in Total Bilirubin Level | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine total bilirubin concentration. The percentage change from baseline in mean concentration total bilirubin was reported. |
| Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine serum lactate dehydrogenase level. The percentage change from baseline in mean concentration lactate dehydrogenase level was reported. |
| Percent Change From Baseline to Day 113 in Nucleated RBC (nRBC) | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were to be collected at pre-specified time intervals to determine concentration of nRBC. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine serum BSAP concentration. The percentage change from baseline in concentration BSAP was reported. |
| Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were collected at pre-specified time intervals to determine serum CTX. The percentage change from baseline in concentration of CTX was reported. |
| Percent Change From Baseline to Day 113 in Concentration of Transferrin | Baseline (prior to first dose of luspatercept) and Day 113 | Blood samples were to be collected at pre-specified time intervals to determine concentration of transferrin. Baseline was prespecified to be the last measurement prior to the first dose of study drug. |
| Number of Participants Who Discontinued Study Treatment Due To an AE | Up to approximately 12 weeks | An adverse event (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 can 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 were reported. |
Countries
Germany
Participant flow
Pre-assignment details
A total of 116 participants were enrolled and received treatment.
Participants by arm
| Arm | Count |
|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) Participants received luspatercept 0.125mg/kg as a subcutaneous (SC) injection every 3 weeks (Q3W) on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 3 |
| Luspatercept 0.25mg/kg (Cohort 2) Participants received luspatercept titrated up to 0.25mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 3 |
| Luspatercept 0.50mg/kg (Cohort 3) Participants received luspatercept titrated up to 0.50mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 3 |
| Luspatercept 0.75mg/kg (Cohort 4) Participants received luspatercept titrated up to 0.75mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 6 |
| Luspatercept 1.00mg/kg (Cohort 5) Participants received luspatercept titrated up to 1.00mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 3 |
| Luspatercept 1.33mg/kg (Cohort 6) Participants received luspatercept titrated up to 1.33mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 6 |
| Luspatercept 1.75mg/kg (Cohort 7) Participants received luspatercept titrated up to 1.75mg/kg via Fibonacci scheme, SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days). | 3 |
| Expansion Cohort Participants received an initial dose of luspatercept 1.0mg/kg SC on Day 1 of the Cycle 1 (Cycle length = 21 days). For each subsequent cycle (up to 5 cycles), the dose was titrated via Fibonacci scheme up to a maximum dose of 1.75mg/kg based on the safety review team (SRT) recommendations. | 89 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Not Reported | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Luspatercept 0.25mg/kg (Cohort 2) | Luspatercept 0.125mg/kg (Cohort 1) | Total | Expansion Cohort | Luspatercept 1.75mg/kg (Cohort 7) | Luspatercept 1.33mg/kg (Cohort 6) | Luspatercept 1.00mg/kg (Cohort 5) | Luspatercept 0.75mg/kg (Cohort 4) | Luspatercept 0.50mg/kg (Cohort 3) |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 27.8 | 70.0 years STANDARD_DEVIATION 19.1 | 70.4 years STANDARD_DEVIATION 10.7 | 71.6 years STANDARD_DEVIATION 9.6 | 63.7 years STANDARD_DEVIATION 19.6 | 68.2 years STANDARD_DEVIATION 7.1 | 73.7 years STANDARD_DEVIATION 3.8 | 64.8 years STANDARD_DEVIATION 11.3 | 66.3 years STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 105 Participants | 80 Participants | 3 Participants | 5 Participants | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 11 Participants | 9 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin level | 8.91 g/dl STANDARD_DEVIATION 0.81 | 10.30 g/dl STANDARD_DEVIATION 0.98 | 8.81 g/dl STANDARD_DEVIATION 0.98 | 8.79 g/dl STANDARD_DEVIATION 1.01 | 9.53 g/dl STANDARD_DEVIATION 0.06 | 8.42 g/dl STANDARD_DEVIATION 0.58 | 8.37 g/dl STANDARD_DEVIATION 1.1 | 8.55 g/dl STANDARD_DEVIATION 0.75 | 8.83 g/dl STANDARD_DEVIATION 0.31 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 116 Participants | 89 Participants | 3 Participants | 6 Participants | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 44 Participants | 30 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 72 Participants | 59 Participants | 1 Participants | 5 Participants | 3 Participants | 3 Participants | 1 Participants |
| Transfusion Status HTB | 2 Participants | 2 Participants | 51 Participants | 31 Participants | 1 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants |
| Transfusion Status LTB | 1 Participants | 1 Participants | 65 Participants | 58 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 89 |
| other Total, other adverse events | 1 / 3 | 2 / 3 | 3 / 3 | 5 / 6 | 3 / 3 | 3 / 6 | 2 / 3 | 62 / 89 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 0 / 3 | 0 / 6 | 1 / 3 | 3 / 6 | 1 / 3 | 14 / 89 |
Outcome results
Primary
Percentage of High Transfusion Burden (HTB) Participants With mHI-E
The mHI-E for HTB participants was defined as a ≥4 units or ≥50% reduction in RBC transfusion burden during any rolling 8-week window compared to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study. The percentage of HTB participants with mHI-E were reported.
Time frame: Any consecutive 8 weeks during the study (up to approximately 75 weeks)
Population: All enrolled HTB participants who received at least one dose of luspatercept and who required ≥4 units of RBC transfusions within 8 weeks prior to baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 50.0 Percentage of Participants |
| Luspatercept 0.25mg/kg (Cohort 2) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 50.0 Percentage of Participants |
| Luspatercept 0.50mg/kg (Cohort 3) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 33.3 Percentage of Participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 33.3 Percentage of Participants |
| Luspatercept 1.00mg/kg (Cohort 5) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 33.3 Percentage of Participants |
| Luspatercept 1.33mg/kg (Cohort 6) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 50.0 Percentage of Participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 100 Percentage of Participants |
| Expansion Cohort | Percentage of High Transfusion Burden (HTB) Participants With mHI-E | 54.8 Percentage of Participants |
Primary
Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E)
The mHI-E for LTB participants was defined as a hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days or rolling 2 weeks (in the absence of red blood cell \[RBC\] transfusions). Hemoglobin measurements within 7 days following RBC transfusion were excluded from analysis. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. Rolling 2 weeks was defined as any consecutive 2 weeks during the study. The percentage of LTB participants with mHI-E were reported.
Time frame: Any consecutive 2 weeks during the study (up to approximately 75 weeks)
Population: All enrolled LTB participants who received at least one dose of luspatercept and received \<4 units of RBCs within 8 weeks prior to baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) | 0 Percentage of participants |
| Luspatercept 0.25mg/kg (Cohort 2) | Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) | 0 Percentage of participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) | 66.7 Percentage of participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) | 100 Percentage of participants |
| Expansion Cohort | Percentage of Low Transfusion Burden (LTB) Participants With Modified Erythroid Response (mHI-E) | 69.0 Percentage of participants |
Secondary
Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21)
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 Study Day 21. AUC0-21 was based on non-compartmental analysis and a mean AUC0-21 value was presented.
Time frame: Cycle 1 Day 1: Predose, Cycle 1 Days 8, 11, 15 and Cycle 2 Day 1: Postdose (each cycle length = 21 days)
Population: All participants who received at least one dose of luspatercept and had sufficient pharmacokinetic samples collected and assayed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 9.29 day*ug/m | Geometric Coefficient of Variation 32.16 |
| Luspatercept 0.25mg/kg (Cohort 2) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 12.56 day*ug/m | Geometric Coefficient of Variation 94.99 |
| Luspatercept 0.50mg/kg (Cohort 3) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 36.90 day*ug/m | Geometric Coefficient of Variation 4.19 |
| Luspatercept 0.75mg/kg (Cohort 4) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 51.82 day*ug/m | Geometric Coefficient of Variation 35.93 |
| Luspatercept 1.00mg/kg (Cohort 5) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 62.46 day*ug/m | Geometric Coefficient of Variation 25.2 |
| Luspatercept 1.33mg/kg (Cohort 6) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 112.56 day*ug/m | Geometric Coefficient of Variation 17 |
| Luspatercept 1.75mg/kg (Cohort 7) | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 137.56 day*ug/m | Geometric Coefficient of Variation 1.13 |
| Expansion Cohort | Area Under the Concentration-Time Curve of Luspatercept From Time 0 to Day 21 (AUC0-21) | 80.02 day*ug/m | Geometric Coefficient of Variation 27.77 |
Secondary
Duration of HI-E Per IWG 2006 Response Criteria
Per IWG 2006 response criteria, duration of HI-E response was defined as the time from the first day of the first rolling 8-week interval of showing response to the last day of the last consecutive rolling 8-week interval of showing response. HI-E response for LTB participants was defined as hemoglobin increase ≥ 1.5 g/dL during any rolling 8-week window and for HTB HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study.
Time frame: up to approximately 75 weeks
Population: All enrolled participants who received at least one dose of luspatercept. Per protocol, the participants with response were pooled into low and high dose groups to increase the accuracy of the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Duration of HI-E Per IWG 2006 Response Criteria | 78 Days | Standard Deviation 7.8 |
| Luspatercept 0.25mg/kg (Cohort 2) | Duration of HI-E Per IWG 2006 Response Criteria | 88 Days | Standard Deviation 22.8 |
Secondary
Maximum Concentration (Cmax) of Luspatercept
Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of luspatercept reached. Cmax was based on non-compartmental analysis and a mean Cmax value was presented.
Time frame: Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days)
Population: All participants who received at least one dose of luspatercept and had sufficient pharmacokinetic samples collected and assayed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Maximum Concentration (Cmax) of Luspatercept | 0.64 ug/mL | Geometric Coefficient of Variation 34.88 |
| Luspatercept 0.25mg/kg (Cohort 2) | Maximum Concentration (Cmax) of Luspatercept | 0.96 ug/mL | Geometric Coefficient of Variation 92.99 |
| Luspatercept 0.50mg/kg (Cohort 3) | Maximum Concentration (Cmax) of Luspatercept | 2.33 ug/mL | Geometric Coefficient of Variation 27.16 |
| Luspatercept 0.75mg/kg (Cohort 4) | Maximum Concentration (Cmax) of Luspatercept | 3.76 ug/mL | Geometric Coefficient of Variation 42.29 |
| Luspatercept 1.00mg/kg (Cohort 5) | Maximum Concentration (Cmax) of Luspatercept | 4.35 ug/mL | Geometric Coefficient of Variation 12.87 |
| Luspatercept 1.33mg/kg (Cohort 6) | Maximum Concentration (Cmax) of Luspatercept | 7.46 ug/mL | Geometric Coefficient of Variation 14.55 |
| Luspatercept 1.75mg/kg (Cohort 7) | Maximum Concentration (Cmax) of Luspatercept | 9.66 ug/mL | Geometric Coefficient of Variation 7.52 |
| Expansion Cohort | Maximum Concentration (Cmax) of Luspatercept | 5.73 ug/mL | Geometric Coefficient of Variation 26.93 |
Secondary
Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions
Frequency of RBC transfusion was defined as the total number of RBC transfusions received. Per protocol, the mean change from baseline to Day 113 in frequency of RBC transfusion was reported in the HTB participants (those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline).
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled HTB participants who received at least one dose of luspatercept and who required ≥4 units of RBC transfusions within 8 weeks prior to baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 2.50 Number of RBC transfusions | Standard Deviation 0.71 |
| Luspatercept 0.125mg/kg (Cohort 1) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | -0.70 Number of RBC transfusions | Standard Deviation 0.71 |
| Luspatercept 0.25mg/kg (Cohort 2) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 2.50 Number of RBC transfusions | Standard Deviation 2.12 |
| Luspatercept 0.25mg/kg (Cohort 2) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | 0.11 Number of RBC transfusions | Standard Deviation 0.69 |
| Luspatercept 0.50mg/kg (Cohort 3) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 4.00 Number of RBC transfusions | Standard Deviation 0 |
| Luspatercept 0.50mg/kg (Cohort 3) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | 0.38 Number of RBC transfusions | Standard Deviation 2.08 |
| Luspatercept 0.75mg/kg (Cohort 4) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 2.00 Number of RBC transfusions | Standard Deviation 0 |
| Luspatercept 0.75mg/kg (Cohort 4) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | 0.40 Number of RBC transfusions | Standard Deviation 2.12 |
| Luspatercept 1.00mg/kg (Cohort 5) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 4.00 Number of RBC transfusions | Standard Deviation 1 |
| Luspatercept 1.00mg/kg (Cohort 5) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | -0.31 Number of RBC transfusions | Standard Deviation 1.21 |
| Luspatercept 1.33mg/kg (Cohort 6) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 2.83 Number of RBC transfusions | Standard Deviation 0.75 |
| Luspatercept 1.33mg/kg (Cohort 6) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | -0.36 Number of RBC transfusions | Standard Deviation 1.03 |
| Luspatercept 1.75mg/kg (Cohort 7) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | -2.46 Number of RBC transfusions | — |
| Luspatercept 1.75mg/kg (Cohort 7) | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 3.00 Number of RBC transfusions | — |
| Expansion Cohort | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline | 3.06 Number of RBC transfusions | Standard Deviation 1.34 |
| Expansion Cohort | Mean Change From Baseline to Day 113 in Frequency of RBC Transfusions | Baseline to Day 113 | -0.85 Number of RBC transfusions | Standard Deviation 1.14 |
Secondary
Number of Participants Who Discontinued Study Treatment Due To an AE
An adverse event (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 can 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 were reported.
Time frame: Up to approximately 12 weeks
Population: All enrolled participants who received at least one dose of luspatercept.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Luspatercept 0.25mg/kg (Cohort 2) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Luspatercept 0.50mg/kg (Cohort 3) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Luspatercept 1.00mg/kg (Cohort 5) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Luspatercept 1.33mg/kg (Cohort 6) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Number of Participants Who Discontinued Study Treatment Due To an AE | 0 Participants |
| Expansion Cohort | Number of Participants Who Discontinued Study Treatment Due To an AE | 5 Participants |
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An adverse event (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 can 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 were reported.
Time frame: Up to approximately 24 weeks
Population: All enrolled participants who received at least one dose of luspatercept.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Number of Participants Who Experienced an Adverse Event (AE) | 1 Participants |
| Luspatercept 0.25mg/kg (Cohort 2) | Number of Participants Who Experienced an Adverse Event (AE) | 2 Participants |
| Luspatercept 0.50mg/kg (Cohort 3) | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Number of Participants Who Experienced an Adverse Event (AE) | 5 Participants |
| Luspatercept 1.00mg/kg (Cohort 5) | Number of Participants Who Experienced an Adverse Event (AE) | 3 Participants |
| Luspatercept 1.33mg/kg (Cohort 6) | Number of Participants Who Experienced an Adverse Event (AE) | 4 Participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Number of Participants Who Experienced an Adverse Event (AE) | 2 Participants |
| Expansion Cohort | Number of Participants Who Experienced an Adverse Event (AE) | 75 Participants |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Non-Transferrin Bound Iron (NTBI)
Blood samples were to be collected at pre-specified time intervals to determine concentration of NTBI. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: No data were collected for the percent change from baseline to day 113 in concentration of NTBI.
Secondary
Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP)
Blood samples were collected at pre-specified time intervals to determine serum BSAP concentration. The percentage change from baseline in concentration BSAP was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for BSAP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | -6.41 Percent change | Standard Deviation 3.698 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | -36.70 Percent change | Standard Deviation 9.43 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | -24.60 Percent change | Standard Deviation 16.413 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | 47.48 Percent change | Standard Deviation 42.431 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | 14.15 Percent change | Standard Deviation 13.191 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | -6.43 Percent change | Standard Deviation 25.559 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | 15.27 Percent change | — |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Concentration of Serum Bone-Specific Alkaline Phosphatase (BSAP) | 8.31 Percent change | Standard Deviation 23.8 |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX)
Blood samples were collected at pre-specified time intervals to determine serum CTX. The percentage change from baseline in concentration of CTX was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for CTX.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | -4.42 Percent change | — |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | 16.26 Percent change | — |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | 26.37 Percent change | Standard Deviation 24.669 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | 15.94 Percent change | Standard Deviation 35.018 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | 13.04 Percent change | Standard Deviation 62.513 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | -70.97 Percent change | — |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Concentration of Serum Cross-Linked C-Telopeptide of Type I Collagen (CTX) | 22.66 Percent change | Standard Deviation 51.177 |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin
Blood samples were collected at pre-specified time intervals to determine serum erythropoietin concentration. The percentage change from baseline in concentration of serum erythropoietin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All participants who received at least one dose of luspatercept and had data available for serum erythropoietin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 144.48 Percent change | Standard Deviation 232.336 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 110.51 Percent change | Standard Deviation 85.751 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 122.85 Percent change | Standard Deviation 163.5 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 1.81 Percent change | Standard Deviation 48.208 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 749.10 Percent change | Standard Deviation 902 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 146.49 Percent change | Standard Deviation 160.087 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 29.07 Percent change | Standard Deviation 80.426 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Concentration of Serum Erythropoietin | 238.85 Percent change | Standard Deviation 974.226 |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin
Blood samples were collected at pre-specified time intervals to determine serum ferritin concentration. The percentage change from baseline in concentration of serum ferritin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for serum ferritin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | -19.55 Percent change | Standard Deviation 32.845 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | 58.63 Percent change | Standard Deviation 24.342 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | 74.31 Percent change | Standard Deviation 160.308 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | 1.16 Percent change | Standard Deviation 23.487 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | 19.38 Percent change | Standard Deviation 25.666 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | 8.56 Percent change | Standard Deviation 41.532 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | -16.07 Percent change | Standard Deviation 27.172 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Concentration of Serum Ferritin | -1.51 Percent change | Standard Deviation 46.269 |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin
Blood samples were collected at pre-specified time intervals to determine soluble hepcidin concentration. The percentage change from baseline in concentration of soluble hepcidin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for serum hepcidin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | -42.40 Percent change | Standard Deviation 5.907 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | 6.56 Percent change | Standard Deviation 35.74 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | -14.55 Percent change | Standard Deviation 39.855 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | -15.62 Percent change | Standard Deviation 20.814 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | -5.54 Percent change | Standard Deviation 49.144 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | 65.41 Percent change | Standard Deviation 179.249 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | -64.51 Percent change | — |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Concentration of Serum Hepcidin | 30.15 Percent change | Standard Deviation 143.118 |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Serum Iron
Blood samples were to be collected at pre-specified time intervals to determine serum iron concentration. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: No data were collected for the percent change from baseline to day 113 in concentration of serum iron.
Secondary
Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor
Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor concentration. The percentage change from baseline in concentration of soluble transferrin receptor was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for soluble transferrin receptor.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | 60.88 Percent change | Standard Deviation 76.427 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | -31.46 Percent change | Standard Deviation 5.135 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | -4.62 Percent change | Standard Deviation 6.527 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | 36.35 Percent change | Standard Deviation 21.718 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | -17.11 Percent change | Standard Deviation 32.861 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | 19.25 Percent change | Standard Deviation 7.793 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Concentration of Soluble Transferrin Receptor | 35.35 Percent change | Standard Deviation 44.228 |
Secondary
Percent Change From Baseline to Day 113 in Concentration of Transferrin
Blood samples were to be collected at pre-specified time intervals to determine concentration of transferrin. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: No data were collected for the percent change from baseline to day 113 in concentration of transferrin.
Secondary
Percent Change From Baseline to Day 113 in Direct Bilirubin Level
Blood samples were collected at pre-specified time intervals to determine serum direct bilirubin concentration. The percentage change from baseline in mean concentration direct bilirubin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for direct bilirubin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | -18.45 Percent change | Standard Deviation 6.569 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | 12.38 Percent change | Standard Deviation 38.465 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | 2.33 Percent change | — |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | 7.22 Percent change | Standard Deviation 20.592 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | -5.00 Percent change | — |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | -7.41 Percent change | Standard Deviation 12.83 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | 6.78 Percent change | — |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Direct Bilirubin Level | -0.50 Percent change | Standard Deviation 27.541 |
Secondary
Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level
Blood samples were collected at pre-specified time intervals to determine serum lactate dehydrogenase level. The percentage change from baseline in mean concentration lactate dehydrogenase level was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for lactate dehydrogenase.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | 13.09 Percent change | Standard Deviation 28.85 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | -10.28 Percent change | Standard Deviation 6.589 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | 0.03 Percent change | Standard Deviation 32.694 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | 2.76 Percent change | Standard Deviation 7.848 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | -15.20 Percent change | Standard Deviation 25.355 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | -2.52 Percent change | Standard Deviation 18.669 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | -11.91 Percent change | Standard Deviation 35.318 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Lactate Dehydrogenase Level | 20.58 Percent change | Standard Deviation 46.589 |
Secondary
Percent Change From Baseline to Day 113 in Nucleated RBC (nRBC)
Blood samples were to be collected at pre-specified time intervals to determine concentration of nRBC. Baseline was prespecified to be the last measurement prior to the first dose of study drug.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: No data were collected for the percent change from baseline to day 113 in concentration of nRBC.
Secondary
Percent Change From Baseline to Day 113 in Reticulocyte Count
Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percentage change from baseline in mean reticulocyte count was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for reticulocyte count.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 110.82 Percent change | Standard Deviation 127.489 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 8.10 Percent change | — |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 79.77 Percent change | Standard Deviation 45.816 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 28.29 Percent change | Standard Deviation 28.434 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 76.16 Percent change | Standard Deviation 54.003 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 0.45 Percent change | Standard Deviation 19.77 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Reticulocyte Count | 84.06 Percent change | Standard Deviation 108.298 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Reticulocyte Count | 41.37 Percent change | Standard Deviation 73.445 |
Secondary
Percent Change From Baseline to Day 113 in Total Bilirubin Level
Blood samples were collected at pre-specified time intervals to determine total bilirubin concentration. The percentage change from baseline in mean concentration total bilirubin was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for total bilirubin.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | -25.41 Percent change | Standard Deviation 5.596 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | 4.32 Percent change | Standard Deviation 26.094 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | 47.43 Percent change | Standard Deviation 51.076 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | 4.02 Percent change | Standard Deviation 10.439 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | -25.08 Percent change | Standard Deviation 17.24 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | -25.84 Percent change | Standard Deviation 19.893 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Total Bilirubin Level | 10.68 Percent change | Standard Deviation 20.258 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Total Bilirubin Level | 13.26 Percent change | Standard Deviation 37.239 |
Secondary
Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC)
Blood samples were collected at pre-specified time intervals to determine TIBC. The percentage change from baseline in TIBC was reported.
Time frame: Baseline (prior to first dose of luspatercept) and Day 113
Population: All enrolled participants who received at least one dose of luspatercept and had data available for TIBC.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | -1.49 Percent change | Standard Deviation 8.94 |
| Luspatercept 0.25mg/kg (Cohort 2) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | 1.61 Percent change | Standard Deviation 1.392 |
| Luspatercept 0.50mg/kg (Cohort 3) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | -6.70 Percent change | Standard Deviation 6.05 |
| Luspatercept 0.75mg/kg (Cohort 4) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | 10.91 Percent change | Standard Deviation 11.806 |
| Luspatercept 1.00mg/kg (Cohort 5) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | 7.46 Percent change | Standard Deviation 11.727 |
| Luspatercept 1.33mg/kg (Cohort 6) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | -12.27 Percent change | Standard Deviation 22.144 |
| Luspatercept 1.75mg/kg (Cohort 7) | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | -4.16 Percent change | Standard Deviation 2.435 |
| Expansion Cohort | Percent Change From Baseline to Day 113 in Total Iron Binding Capacity (TIBC) | -2.40 Percent change | Standard Deviation 9.916 |
Secondary
Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria
Per IWG 2006 response criteria, rate of HI-E is defined as the percentage of participants for whom the mean of all hemoglobin value from baseline during any rolling 8-week increased ≥1.5 g/dL in the absence of transfusion for LTB participants, or a reduction by ≥4 units of RBCs transfusion over any rolling 8-week window for HTB patients. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. Rolling 8 weeks was defined as any consecutive 8 weeks during the study.
Time frame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)
Population: All enrolled participants who received at least one dose of luspatercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 33.3 Percentage of participants |
| Luspatercept 0.25mg/kg (Cohort 2) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 0 Percentage of participants |
| Luspatercept 0.50mg/kg (Cohort 3) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 33.3 Percentage of participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 33.3 Percentage of participants |
| Luspatercept 1.00mg/kg (Cohort 5) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 33.3 Percentage of participants |
| Luspatercept 1.33mg/kg (Cohort 6) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 50.0 Percentage of participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 100 Percentage of participants |
| Expansion Cohort | Rate of Erythroid Response (HI-E) Per International Working Group (IWG) 2006 Response Criteria | 53.9 Percentage of participants |
Secondary
Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria
Per IWG 2006 response criteria, HI-N was defined as the neutrophil increase in any rolling 8 weeks is at last 100% and an absolute increase \> 0.5 x 10\^9/L. The rolling 8-week was defined as any consecutive 8 weeks during the study. The percentage of participants with HI-N response were reported.
Time frame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)
Population: All enrolled participants who received at least one dose of luspatercept and had baseline neutrophil count \<1.0×10\^9/L.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | 0 Percentage of Participants |
| Luspatercept 0.50mg/kg (Cohort 3) | Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | 100 Percentage of Participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | 0 Percentage of Participants |
| Luspatercept 1.33mg/kg (Cohort 6) | Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | 66.7 Percentage of Participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | 100 Percentage of Participants |
| Expansion Cohort | Rate of Neutrophil Response (HI-N) Per IWG 2006 Criteria | 25.0 Percentage of Participants |
Secondary
Rate of Platelet Response (HI-P) Per IWG 2006 Criteria
Per IWG 2006 response criteria, HI-P was defined for participants with baseline value ≥20 x 10\^9/L as the platelet increase in any rolling 8 weeks ≥30 x 10\^9 and for participants with baseline value \<20 x 10\^9/L as the platelet increase in any rolling 8 weeks \>20 x 10\^9/L with increase of at least 100%. The rolling 8-week was defined as any consecutive 8 weeks during the study. The percentage of participants with HI-P were reported.
Time frame: Any consecutive 8 Weeks during the study treatment (up to approximately 75 weeks)
Population: All enrolled participants who received at least one dose of luspatercept and had baseline platelet count \<100x10\^9/L.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Luspatercept 0.50mg/kg (Cohort 3) | Rate of Platelet Response (HI-P) Per IWG 2006 Criteria | 0 Percentage of participants | 95% Confidence Interval 0 |
| Luspatercept 1.00mg/kg (Cohort 5) | Rate of Platelet Response (HI-P) Per IWG 2006 Criteria | 0 Percentage of participants | 95% Confidence Interval 0 |
| Luspatercept 1.33mg/kg (Cohort 6) | Rate of Platelet Response (HI-P) Per IWG 2006 Criteria | 0 Percentage of participants | 95% Confidence Interval 0 |
| Expansion Cohort | Rate of Platelet Response (HI-P) Per IWG 2006 Criteria | 23.5 Percentage of participants | 95% Confidence Interval 6.8 |
Secondary
Rate of RBC Transfusion Independence (RBC-TI)
Rate of RBC-TI was defined as percentage of participants with ≥2 units of RBC transfusions at baseline who experienced transfusion independence which was defined as ≥8 weeks without a transfusion while on treatment. Per protocol, rate of RBC-TI was reported in HTB participants (those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline).
Time frame: Up to approximately 16 weeks
Population: All enrolled HTB participants who received at least one dose of luspatercept and had ≥2 units of RBC transfusions at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Rate of RBC Transfusion Independence (RBC-TI) | 50.0 Percentage of participants |
| Luspatercept 0.25mg/kg (Cohort 2) | Rate of RBC Transfusion Independence (RBC-TI) | 0.0 Percentage of participants |
| Luspatercept 0.50mg/kg (Cohort 3) | Rate of RBC Transfusion Independence (RBC-TI) | 0.0 Percentage of participants |
| Luspatercept 0.75mg/kg (Cohort 4) | Rate of RBC Transfusion Independence (RBC-TI) | 66.7 Percentage of participants |
| Luspatercept 1.00mg/kg (Cohort 5) | Rate of RBC Transfusion Independence (RBC-TI) | 0 Percentage of participants |
| Luspatercept 1.33mg/kg (Cohort 6) | Rate of RBC Transfusion Independence (RBC-TI) | 33.3 Percentage of participants |
| Luspatercept 1.75mg/kg (Cohort 7) | Rate of RBC Transfusion Independence (RBC-TI) | 100 Percentage of participants |
| Expansion Cohort | Rate of RBC Transfusion Independence (RBC-TI) | 43.9 Percentage of participants |
Secondary
Terminal Half-Life (t ½) of Luspatercept
Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the luspatercept plasma concentration by two after reaching pseudo-equilibrium, following a single dose of luspatercept. t½ was based on non-compartmental analysis and a mean t1/2 value was presented.
Time frame: Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days)
Population: All participants who received at least one dose of luspatercept and had sufficient pharmacokinetic samples collected and assayed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Terminal Half-Life (t ½) of Luspatercept | 23.78 Days | Geometric Coefficient of Variation 22.29 |
| Luspatercept 0.25mg/kg (Cohort 2) | Terminal Half-Life (t ½) of Luspatercept | 9.15 Days | Geometric Coefficient of Variation 44.83 |
| Luspatercept 0.50mg/kg (Cohort 3) | Terminal Half-Life (t ½) of Luspatercept | 15.14 Days | Geometric Coefficient of Variation 5.94 |
| Luspatercept 0.75mg/kg (Cohort 4) | Terminal Half-Life (t ½) of Luspatercept | 14.45 Days | Geometric Coefficient of Variation 16.02 |
| Luspatercept 1.00mg/kg (Cohort 5) | Terminal Half-Life (t ½) of Luspatercept | 13.75 Days | Geometric Coefficient of Variation 7.37 |
| Luspatercept 1.33mg/kg (Cohort 6) | Terminal Half-Life (t ½) of Luspatercept | 14.76 Days | Geometric Coefficient of Variation 24.43 |
| Luspatercept 1.75mg/kg (Cohort 7) | Terminal Half-Life (t ½) of Luspatercept | 26.56 Days | Geometric Coefficient of Variation 9.19 |
| Expansion Cohort | Terminal Half-Life (t ½) of Luspatercept | 14.74 Days | Geometric Coefficient of Variation 44.35 |
Secondary
Time to HI-E Per IWG 2006 Response Criteria
Per IWG 2006 response criteria, the time to HI-E response was defined as the first date of the rolling 8-week interval of showing response minus first dose date plus 1. HI-E response for LTB participants was defined as hemoglobin increase ≥ 1.5 g/dL during any rolling 8 weeks window and for HTB HI-E was defined as RBC transfusion reduction ≥4 units during any rolling 8 weeks. LTB participants were those who received \<4 units of RBCs within 8 weeks prior to baseline. HTB participants were those who required ≥4 units of RBC transfusions within 8 weeks prior to baseline. The rolling 8-week was defined as any consecutive 8 weeks during the study.
Time frame: Any consecutive 8 weeks during the study (up to approximately 75 weeks)
Population: All enrolled participants who received at least one dose of luspatercept. Per protocol, the participants with response were pooled into low and high dose groups to increase the accuracy of the analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Time to HI-E Per IWG 2006 Response Criteria | 35 Days | Standard Deviation 48.1 |
| Luspatercept 0.25mg/kg (Cohort 2) | Time to HI-E Per IWG 2006 Response Criteria | 17 Days | Standard Deviation 18.3 |
Secondary
Time to Maximum Concentration (Tmax) of Luspatercept
Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as time to the maximum concentration of luspatercept reached. Tmax was based on non-compartmental analysis and a mean Tmax value was presented.
Time frame: Cycle 1 Day 1: Predose, Cycle 1: Days 8, 11, 15: Postdose; Cycle 2 Day 1, Cycle 2 Day 8, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 5 Days 8, 15: Postdose (each cycle length = 21 days)
Population: All participants who have received at least one dose of luspatercept and had sufficient pharmacokinetic samples collected and assayed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Luspatercept 0.125mg/kg (Cohort 1) | Time to Maximum Concentration (Tmax) of Luspatercept | 9.93 Days | Geometric Coefficient of Variation 35.73 |
| Luspatercept 0.25mg/kg (Cohort 2) | Time to Maximum Concentration (Tmax) of Luspatercept | 7.23 Days | Geometric Coefficient of Variation 20.68 |
| Luspatercept 0.50mg/kg (Cohort 3) | Time to Maximum Concentration (Tmax) of Luspatercept | 10.16 Days | Geometric Coefficient of Variation 39.56 |
| Luspatercept 0.75mg/kg (Cohort 4) | Time to Maximum Concentration (Tmax) of Luspatercept | 7.16 Days | Geometric Coefficient of Variation 5.46 |
| Luspatercept 1.00mg/kg (Cohort 5) | Time to Maximum Concentration (Tmax) of Luspatercept | 7.23 Days | Geometric Coefficient of Variation 20.68 |
| Luspatercept 1.33mg/kg (Cohort 6) | Time to Maximum Concentration (Tmax) of Luspatercept | 8.47 Days | Geometric Coefficient of Variation 31.58 |
| Luspatercept 1.75mg/kg (Cohort 7) | Time to Maximum Concentration (Tmax) of Luspatercept | 6.65 Days | Geometric Coefficient of Variation 8.92 |
| Expansion Cohort | Time to Maximum Concentration (Tmax) of Luspatercept | 7.77 Days | Geometric Coefficient of Variation 21.76 |