Beta Thalassemia Intermedia
Conditions
Keywords
Thalassaemia, Beta Thalassemia, IONIS TMPRSS6-LRx
Brief summary
The purpose was to evaluate the efficacy, safety, tolerability, pharmacokinetics and pharmacodynamics of sapablursen administered subcutaneously to participants with non-transfusion dependent β-Thalassemia Intermedia.
Detailed description
This was a multi-center, randomized, open-label study in up to 29 participants. The duration of participation for each subject in the study was approximately 29 months and included an approximately 2-month screening period, a 24-month treatment period, and a 3-month post-treatment period.
Interventions
DRUGsapablursen
sapablursen administered subcutaneously
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Willingness to comply with study procedures * Clinical diagnosis of Beta-Thalassemia Intermedia with genotypic confirmation * Non-transfusion dependent, as defined by: no more than 6 transfusions in the past 12-month period, and no transfusions in the 8-week period prior to Day 1 * Mean Hb within the range of 6.0-10.0 g/dL, inclusive at Screening * LIC within the range of 3.0-20.0 mg Fe/g dry weight, inclusive * If using chelators, must be on a stable dose for at least 3 months with liver iron concentration (LIC) \> 5.0 mg iron (Fe) per gram of dry weight of liver (Fe/g) dry weight and serum ferritin \> 300 nanograms per milliliter (ng/mL) * Females must be non-pregnant and non-lactating, and either surgically sterile or postmenopausal * Males must be surgically sterile, abstinent or using an acceptable contraceptive method
Exclusion criteria
* Clinically significant abnormalities in lab values, medical history, or physical examination * α-globin gene triplication * Symptomatic splenomegaly * Platelet count \< lower limit of normal (LLN) or \> 1,000 x 10\^9/L * Significant concurrent/recent coagulopathy, history of non-traumatic significant bleeding; history of immune thrombocytopenic purpura (ITP); current use of SC anti-coagulants; history of thrombotic events, including stroke or DVT * Clinically significant renal, liver or cardiac dysfunction * Uncontrolled hypertension (\> 140 mm Hg systolic or \> 90 mm Hg diastolic) * Fasting blood glucose \> 2.0 × upper limit of normal (ULN) * Inability to have a magnetic resonance imaging (MRI) scan * Known history or positive test for human immunodeficiency virus (HIV), hepatitis C (HCV), or hepatitis B (HBV) * Active infection requiring systemic antiviral or antimicrobial therapy * Regular excessive use of alcohol * Recent start of hydroxyurea (6 months prior to Day 1) * Treatment with or recent exposure to another investigational drug, biological agent, antisense oligonucleotide (ASO), small interfering ribonucleic acid (siRNA), or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer; or treatment with or exposure to: * sotatercept (ACE-011), luspatercept (ACE-536), or ruxolitinib within 4 months of Screening * hematopoietic stimulating agents or any hypoxia-inducible factor prolyl hydroxylase inhibitors within 8 weeks of Day 1 * prior bone marrow transplant, stem cell transplant, or gene therapy * Surgery associated with significant blood loss within 4 months of Screening, splenectomy within 12 months of Screening, or splenectomy scheduled during treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27 | Baseline and Week 27 | Blood hemoglobin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a ≥1.5 g/dL Increase From Baseline in Hb at Week 53 | Week 53 | Blood hemoglobin |
| Percentage of Participants With a ≥1.0 Milligrams of Iron Per Grams of Dry Weight of Liver (mg Fe/g) Decrease From Baseline in Liver Iron Concentration (LIC) at Week 53 | Week 53 | Liver iron content |
Countries
Australia, Greece, Lebanon, Thailand, Turkey (Türkiye)
Participant flow
Recruitment details
Participants were enrolled in the study at 15 investigative sites in Australia, Greece, Lebanon, Thailand, and Turkey from 24 September 2020 to 28 March 2023.
Pre-assignment details
A total of 71 participants were screened with a diagnosis of β-Thalassemia, of which 29 participants were enrolled in either cohorts A, B, or C to receive sapablursen.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Sapablursen Subjects initially received 30 mg/0.3 mL of sapablursen by SC injection once every four weeks up to Week 105. After the protocol Amendment 2 the dose was increased to a maximum of 160 mg. | 6 |
| Cohort B: Sapablursen Subjects initially received 50 mg/0.5 mL of sapablursen by SC injection once every four weeks up to Week 105. After the protocol Amendment 2 the dose was increased to a maximum of 160 mg. | 6 |
| Cohort C: Sapablursen Subjects initially received 80 mg/0.8 mL of sapablursen by SC injection once every four weeks up to Week 105. After the protocol Amendment 2 the dose was increased to a maximum of 160 mg. | 17 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Early Treatment Termination | 5 | 5 | 15 |
Baseline characteristics
| Characteristic | Cohort A: Sapablursen | Cohort B: Sapablursen | Cohort C: Sapablursen | Total |
|---|---|---|---|---|
| Age, Continuous | 35.0 years STANDARD_DEVIATION 12.12 | 31.7 years STANDARD_DEVIATION 10.44 | 32.0 years STANDARD_DEVIATION 10.88 | 32.6 years STANDARD_DEVIATION 10.72 |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 6 Participants | 6 Participants | 17 Participants | 29 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 1 Participants | 8 Participants | 12 Participants |
| Race/Ethnicity, Customized Race White | 3 Participants | 5 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 10 Participants | 18 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 7 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 17 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 14 / 17 |
| serious Total, serious adverse events | 0 / 6 | 2 / 6 | 1 / 17 |
Outcome results
Primary
Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27
Blood hemoglobin
Time frame: Baseline and Week 27
Population: Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of sapablursen and who had at least 1 Hb assessment collected after Day 1. Here, the overall number of participants analyzed signifies the number of participants available for analysis for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Sapablursen | Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27 | 0 percentage of participants |
| Cohort B: Sapablursen | Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27 | 0 percentage of participants |
| Cohort C: Sapablursen | Percentage of Participants With a ≥1.0 Grams Per Deciliter (g/dL) Increase From Baseline in Hemoglobin (Hb) at Week 27 | 6.7 percentage of participants |
Secondary
Percentage of Participants With a ≥1.0 Milligrams of Iron Per Grams of Dry Weight of Liver (mg Fe/g) Decrease From Baseline in Liver Iron Concentration (LIC) at Week 53
Liver iron content
Time frame: Week 53
Population: FAS included all randomized participants who received at least 1 dose of sapablursen and who had at least 1 Hb assessment collected after Day 1. Here, the overall number of participants analyzed signifies the number of participants available for analysis for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Sapablursen | Percentage of Participants With a ≥1.0 Milligrams of Iron Per Grams of Dry Weight of Liver (mg Fe/g) Decrease From Baseline in Liver Iron Concentration (LIC) at Week 53 | 33.3 percentage of participants |
| Cohort B: Sapablursen | Percentage of Participants With a ≥1.0 Milligrams of Iron Per Grams of Dry Weight of Liver (mg Fe/g) Decrease From Baseline in Liver Iron Concentration (LIC) at Week 53 | 50.0 percentage of participants |
| Cohort C: Sapablursen | Percentage of Participants With a ≥1.0 Milligrams of Iron Per Grams of Dry Weight of Liver (mg Fe/g) Decrease From Baseline in Liver Iron Concentration (LIC) at Week 53 | 28.6 percentage of participants |
Secondary
Percentage of Participants With a ≥1.5 g/dL Increase From Baseline in Hb at Week 53
Blood hemoglobin
Time frame: Week 53
Population: FAS included all randomized participants who received at least 1 dose of sapablursen and who had at least 1 Hb assessment collected after Day 1. Here, the overall number of participants analyzed signifies the number of participants available for analysis for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A: Sapablursen | Percentage of Participants With a ≥1.5 g/dL Increase From Baseline in Hb at Week 53 | 0 percentage of participants |
| Cohort B: Sapablursen | Percentage of Participants With a ≥1.5 g/dL Increase From Baseline in Hb at Week 53 | 0 percentage of participants |
| Cohort C: Sapablursen | Percentage of Participants With a ≥1.5 g/dL Increase From Baseline in Hb at Week 53 | 0 percentage of participants |