Phase 2
N=64
Study to Evaluate the Safety and Efficacy of Luspatercept (ACE-536) in Participants With Beta-thalassemia (A536-04/MK-6143-002)
B-Thalassemia
Bottom Line
View on ClinicalTrials.gov: NCT01749540 ↗Enrolled (actual)
64
Serious AEs
1.6%
Results posted
Jul 2024
Primary outcome: Primary: Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline for ≥14 Days — 0.0; 0.0; 0.0; 66.7 Percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- luspatercept (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- Primary completion
- Nov 2015
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline for ≥14 Days |
0.0; 0.0; 0.0; 66.7; 50.0; 0.0 | — |
| PRIMARY Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval |
100; 66.7; 100; 75.0; 78.9 | — |
| SECONDARY Number of Participants Who Experienced an Adverse Event (AE) |
5; 6; 5; 6; 6; 5 | — |
| SECONDARY Number of Participants Who Experienced a Serious Adverse Event (SAE) |
0; 1; 0; 0; 0; 0 | — |
| SECONDARY Number of Participants Who Experienced an Adverse Event (AE) of Grade 3 or Greater |
0; 1; 0; 1; 2; 0 | — |
| SECONDARY Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) |
0; 0; 1; 2; 0; 0 | — |
| SECONDARY Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT) |
0; 0; 0; 1; 0; 0 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 8-week Interval |
16.7; 16.7; 80.0; 66.7; 50.0; 0.0 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 8-week Interval |
0.0; 0.0; 0.0; 33.3; 50.0; 0.0 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 12-week Interval |
16.7; 0.0; 80.0; 66.7; 50.0; 0.0 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 12-week Interval |
0.0; 0.0; 0.0; 33.3; 50.0; 0.0 | — |
| SECONDARY Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-week Interval |
100; 100; 100; 75.0; 78.9 | — |
| SECONDARY Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval |
100; 66.7; 100; 50.0; 42.1 | — |
| SECONDARY Percentage of Transfusion Dependent (TD) Participants Who Maintained Red Blood Cell (RBC) Transfusion Independence For ≥8 Weeks |
100; 0.0; 75.0; 0.0; 10.5 | — |
| SECONDARY Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL During a Rolling 12-week Interval by Pooled Dose Groups |
8.0; 9.9 | — |
| SECONDARY Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% During a Rolling 12-week Interval |
4.8 | — |
| SECONDARY Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL During a Rolling 12-week Interval |
126.0; 118.0 | — |
| SECONDARY Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% During a Rolling 12-week Interval |
105.0 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Mean Bone-specific Alkaline Phosphatase (BSAP) |
42.6; 3.4; 8.4; 23.6; 12.7; -20.9 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Mean C-telopeptide of Type I Collagen (CTX) |
-35.1; 15.5; 17.7; 20.1; 0.7; -0.2 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Serum Iron |
-15.8; -9.0; 7.8; -12.9; -5.4; -12.4 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Total Iron Binding Capacity (TIBC) |
2.9; -1.5; 3.5; -4.9; -2.1; -0.8 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Transferrin |
4.0; -1.5; 3.0; -4.7; -1.0; -1.6 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Soluble Transferrin Receptor |
3.6; -5.9; 10.6; 36.3; 68.2; 83.3 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Ferritin |
-18.5; 8.4; -4.5; -23.7; -23.2; -25.2 | — |
| SECONDARY Percent Change From Baseline to Day 113 in Serum Non-transferrin Bound Iron (NTBI) |
— | — |
| SECONDARY Percent Change From Baseline to Day 113 in Calculated Transferrin Saturation |
— | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hepcidin |
7.5; 58.4; -4.8; 0.7; -41.2; -13.6 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Reticulocytes |
-12.41; -2.03; -9.91; 73.38; 25.35; 136.03 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Erythropoietin |
-11.18; 10.44; 88.57; 210.69; 97.54; 183.79 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Nucleated Red Blood Cell (nRBC) Count |
-70.19; 17.20; 211.82; 163.63; 176.62; 385.71 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hemoglobin A (Hb A) |
-1.96; 308.31; -5.41; -5.00; -22.70; -32.91 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hemoglobin A2 (Hb A2) |
1.14; -14.97; 6.72; -11.49; 26.34; 38.04 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hemoglobin C (Hb C) |
0.00; 0.00; 0.00; 0.00; 0.00; 0.00 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hemoglobin D (Hb D) |
0.00; 0.00; 0.00; 0.00; 0.00; 0.00 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hemoglobin F (Hb F) |
14.45; -1.96; 37.52; 20.94; 70.89; 308.66 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Hemoglobin S (Hb S) |
0.00; 0.00; 0.00; 0.00; 0.00; 0.00 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Alpha Globin Gene |
42.27; -49.73; -7.11; 389.87; 396.72; -10.85 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Beta Globin Gene |
36.29; -49.17; -15.50; 51.75; 276.26; -6.51 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Gamma Globin Gene |
81.70; -44.57; -3.32; 468.05; 229.46; -45.40 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Haptoglobin |
21.8; 281.0; -16.2; -31.2; 30.3; -55.1 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Indirect Bilirubin |
13.9; -25.2; 4.8; 6.3; 3.7; 2.8 | — |
| SECONDARY Percent Change From Baseline to End of Treatment in Lactate Dehydrogenase (LDH) |
0.4; -0.9; 8.7; 29.2; 37.4; 53.8 | — |
| SECONDARY Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Non-transfusion Dependent (NTD) Participants With Baseline LIC <3 mg/g Dry Weight |
-0.1; -0.5; 0.9; 0.4 | — |
| SECONDARY Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Non-transfusion Dependent (NTD) Participants With Baseline LIC ≥3 mg/g Dry Weight |
0.0; -0.6; -0.6; -1.1; -4.5; 0.7 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight Who Have Demonstrated an LIC Response at End of Treatment |
25.0; 60.0; 50.0; 50.0; 100; 0.0 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment |
0.0; 100; 100; 100; 0.0 | — |
| SECONDARY Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment |
50.0; 50.0; 33.3; 50.0; 0.0 | — |
| SECONDARY Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Transfusion Dependent (TD) Participants With Baseline LIC <3 mg/g Dry Weight |
-0.4; 0.2; 0.2 | — |
| SECONDARY Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Transfusion Dependent (TD) Participants With Baseline LIC ≥3 mg/g Dry Weight |
-2.1; -0.7; -0.2; -0.6; -0.6 | — |
| SECONDARY Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight Who Have Demonstrated an LIC Response at End of Treatment |
100; 33.3; 50.0; 0.0; 33.3 | — |
| SECONDARY Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment |
100; 33.3; 50.0; 0.0; 40.0 | — |
| SECONDARY Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment |
0.0 | — |
| SECONDARY Maximum Concentration (Cmax) of Luspatercept |
0.84; 1.52; 2.47; 4.04; 5.73; 6.85 | — |
| SECONDARY Time to Maximum Concentration (Tmax) of Luspatercept |
7.00; 7.00; 7.50; 7.00; 7.00; 7.00 | — |
| SECONDARY Area Under the Concentration Time Curve of Luspatercept From Time Zero to Day 21 (AUC0-21) |
11.68; 20.66; 31.43; 54.30; 70.39; 93.79 | — |
| SECONDARY Terminal Elimination Half Life (t½) of Luspatercept |
11.56; 10.12; 9.65; 11.22; 9.42; 10.37 | — |
| SECONDARY Apparent Terminal Rate Constant (Lambda z) of Luspatercept |
0.06; 0.07; 0.07; 0.06; 0.07; 0.07 | — |
Summary
The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics, of ascending doses of luspatercept in participants with β-thalassemia.
The primary objective of this study is to evaluate erythroid response, defined as:
1. a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions) in non-transfusion dependent participants, or
2. a ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent participants.
Eligibility Criteria
Key Inclusion Criteria
- Men or women ≥18 years of age
- For the dose escalation phase of the study: documented diagnosis of β-thalassemia intermedia (transfusion dependent participants must not have begun regular transfusions at age 450 msec on screening electrocardiogram (ECG)
- Platelet count 1,000 x10^9/L
- Proteinuria ≥Grade 2
- 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
- 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 investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer
- Transfusion event within 7 days prior to Cycle 1 Day 1
- Participants receiving or planning to receive hydroxyurea treatment. Participants must not have had hydroxyurea within 90 days of Cycle 1 Day 1
- Splenectomy within 56 days prior to Cycle 1 Day 1
- Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Participants must have completely recovered from any previous surgery prior to Cycle 1 Day 1
- Iron chelation therapy initiated within 56 days prior to Cycle 1 Day 1
- Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/day is permitted)
- Pregnant or lactating women
- History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug
- Prior treatment with sotatercept (ACE-011) or luspatercept (ACE-536)
Data sourced from ClinicalTrials.gov (NCT01749540). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.