Reduced Hb in red blood cells (RBCs), decreased RBC production, and anemia due to reduced or absent synthesis of the ß chain of hemoglobin (Hb) and mutations in the hemoglobin beta (HBB) gene in subjects with ß-thalassemia. Thalassemia
Conditions
Interventions
This study will enroll approximately 120 subjects with ß-thalassemia (60 subjects with TDT and 60 subjects with NTDT), aged 18 through 65 years.Subjects will receive either IMR-687 (lower dose [=3.0 t
Subjects will be advised to take two IMR-687 tablets orally with food qd for 36 weeks. In order to maintain an exposure of =3.0 to =4.5 mg/kg, subjects in the lower dose group weighing <67 kg will be
Sponsors
IMARA, Inc.
Eligibility
Sex/Gender
All
Age
18 Years to 65 Years
Inclusion criteria
Inclusion criteria: Subjects must meet all of the following inclusion criteria to be eligible for the study: 1. Subjects must understand and voluntarily provide informed consent and sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted. Although RBC transfusions and associated Hb laboratory measurements 12 weeks prior to the Screening visit are not study related, the ICF will specifically request subject consent to collect these data. 2. Subjects must be =18 to =65 years of age at the time of signing the ICF. 3. Subjects must have documented diagnosis of ß-thalassemia or HbE/ß-thalassemia. Concomitant single alpha gene deletion, duplication, or triplication is allowed. 4. For TDT subjects only: Subjects must be regularly transfused, defined as >3 to 10 RBC units1 in the 12 weeks prior to screening and no transfusion-free period for =35 days during that period. For NTDT subjects only: Subjects must be transfusion independent, defined as 0 to =3 units1 of RBCs received during the 12-week period prior to randomization, must not be on a regular transfusion program, must be RBC transfusion-free for at least = 4 weeks prior to randomization, and must not be scheduled to start a regular hematopoietic stem cell transplantation within 9 months. 5. Subjects must have documentation of dates of transfusions and the number of all RBC units within the 12 weeks prior to Screening. 6. Subjects must be willing and able to complete all study assessments and procedures, and to communicate effectively with the investigator and site staff. 7. Subjects must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 (Appendix 1). 8. Female subjects must not be pregnant, not be breast feeding, and be highly unlikely to become pregnant. Male subjects must be unlikely to impregnate a partner. Male or female subjects must meet at least one of the following criteria: • A female subject who is not of reproductive potential is eligible without requiring the use of contraception. A female subject who is not of reproductive potential is defined as one who: (1) has reached natural menopause (defined as 12 months of spontaneousamenorrhea without an alternative medical cause, and can be confirmed with serum follicle-stimulating hormone levels in the postmenopausal range as determined by the central laboratory); (2) is 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy; or (3) has undergone bilateral tubal ligation. Spontaneous amenorrhea does not include cases for which there is an underlying disease that causes amenorrhea (e.g., anorexia nervosa). • A female of reproductive potential must have 2 negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, at the end of treatment visit, and at the end of study visit. This applies even if the subject practices true abstinence from heterosexual contact. • A male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as one who has undergone a successful vasectomy. A successful vasectomy is defined as (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post-vasectomy. • A male or female subject who is of reproductive potential agrees to remain trul
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following criteria must be excluded from the study: 1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study, including the presence of laboratory abnormalities that may place the subject at unacceptable risk if he/she were to participate in the study. 2. Any situation or condition that confounds the ability to interpret data from the study (e.g., subjects also receiving RBC transfusions at centers not able to obtain laboratory samples for central processing). 3. Diagnosis of a-thalassemia (e.g., hemoglobin H [HbH]) or hemoglobin S (HbS)/ ß-thalassemia. 4. Body mass index (BMI) 35 kg/m². 5. Subjects with known active hepatitis A, hepatitis B, or hepatitis C, with active or acute event of malaria, or who are known to be positive for human immunodeficiency virus (HIV). 6. Stroke requiring medical intervention =24 weeks prior to randomization. 7. Subjects taking direct acting oral anti-coagulants (DOACs) apixaban, dabigatran, rivaroxaban, edoxaban, or ticagrelor, or taking warfarin, are excluded due to the possibility of a cytochrome P450 (CYP)3A-mediated drug interaction, unless they stopped the treatment at least 28 days prior to randomization (Day 1); other oral anti-coagulants and anti-platelet drugs are permitted. Anti-coagulant therapies for prophylaxis of venous thromboembolism, including pulmonary emboli including when undergoing surgery or high-risk procedures, are allowed if low molecular weight heparins are used in the peri-operative period. Aspirin use is allowed before and during the study. 8. Treatment with an investigational drug or device or participation in an investigational drug or device study =28 days prior to randomization. 9. Platelet count >1000 × 10?/L. 10. Subjects on iron chelation therapy (ICT) at the time of ICF signing must have initiated the treatment with ICT at least 24 weeks before the predicted randomization date. ICT can be initiated at any time during treatment and should be used according to the label. 11. Subjects who have had treatment with erythropoietin-stimulating agents =24 weeks prior to randomization. 12. Uncontrolled hypertension as defined by systolic BP =160 mm Hg or diastolic BP =100 mm Hg, medical intervention indicated, and more than one drug or more intensive therapy than previously used indicated. 13. Poorly controlled diabetes mellitus as defined by 1) fructosamine levels of >340 µmol/L within 12 weeks prior to randomization; 2) short term hyperglycemia leading to hyperosmolar or ketoacidotic crisis; and/or 3) history of diabetic cardiovascular complications. 14. Subjects who have major organ damage, including: a. Liver disease with ALT or AST >3× ULN, direct bilirubin >2× ULN, or history/evidence of cirrhosis, as well as presence of masses/tumor. b. Heart disease, heart failure as classified by the New York Heart Association classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization, or significant cardiac iron T2* <15 ms, or left ventricular ejection fraction <56%. c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, i.e., =Grade 3 NCI CTCAE version 5.0. d. Estimated glomerular filtration rate <45 mL/min/1.73 m2 (per Modification of Diet in Renal Disease formula). e. Nephrotic range proteinu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: Changes in Vital Signs;Timepoints: Vital signs will be taken predose and 12 hours (±20 minutes) postdose on Day 1 and Week 3 for TDT subjects and on Day 1 and Week 4 for NTDT subjects (during PK assessments). At all other timepoints, vital signs can be taken irrespective of taking study drug.;Measure: heart rate, respiratory rate, blood pressure, and body temperature;Name: Changes from baseline in 12-Lead-ECG;Timepoints: ECGs to be performed in triplicate. At Baseline and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36, ECGs will be obtained at predose and 2 hours (±30 minutes) postdose. At all other timepoints, ECGs can be taken irrespective of taking study drug. ;Measure: heart rate, PR interval, QRS duration, QT interval, and QTcF interval;Name: Incidence and severity of Adverse Event and Serious Adverse Event.;Timepoints: All AEs and SAEs, related and unrelated, will be recorded from the signing of informed consent through the end of study safety follow-up visit (Week 40).;Measure: AEs will be coded using MedDRA: Abnormal test findings ,Clinically significant symptoms and signs, Changes in physical examination findings, Hypersensitivity ,Drug abuse ,Drug dependency, Drug overdose , Drug withdrawal , Drug misuse, Drug interactions, Extravasation , Exposure during pregnancy , Exposure via breastfeeding , Medication error;Name: Physical Examinations findings;Timepoints: Complete PEs will be performed at Screening, Week 24, and Week 36 and will include a general examination including the abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. At all other visits, symptom-directed PEs will be obtained after identification of AEs deemed by the investigator to be of significant clinical concern.;Measure: general examination of the body, including the abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat.;Name: Changes in Clinical laboratory | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: Pharmacodynamic markers;Timepoints: Blood samples should be obtained prior to administration of study drug. PD markers will need to be collected prior to each RBC transfusion (if applicable);Measure: 1) serum ferritin, soluble transferrin receptor, hepcidin-25, and haptoglobin levels; 2) WBC adhesion markers: sE-sel, sP-sel, sICAM-1; VCAM-1, hsCRP; 3) cardiovascular marker: serum NT-proBNP.;Name: Quality of life;Timepoints: at Baseline and at Weeks 12, 24, and 36.;Measure: TranQOL and SF-36 QoL tools in the TDT population and the NTDT-PRO and SF-36 QoL tools in the NTDT population ;Name: Pharmacokinetic Analyses;Timepoints: At Baseline (all subjects) and either Week 3 (TDT) or Week 4 (NTDT), serial blood samples will be drawn pre-dose (within 30 minutes) and at 30 minutes (±5 minutes), 1.5 hours (±15 minutes), 4 hours (±15 minutes), 6 hours (±1 hour) and 24 hours (±2 hours) after administration of study drug. A trough blood sample will be drawn pre-dose at Week 1, Week 24, and Week 36.;Measure: Maximum concentration (Cmax); Time to maximum concentration (tmax); Apparent terminal half-life (t½); and • AUC from time 0 to 24 hours (AUC(0-24)), 0 to the last measurable timepoint (AUClast), and extrapolated to infinity (AUC(0-8)). | — |
Countries
Denmark, Egypt, France, Georgia, Greece, Italy, Lebanon, Malaysia, Morocco, Netherlands, Tunisia, Turkey, United Kingdom, United States of America
Contacts
Public ContactAziz Zoghbi
Regional Manager
Outcome results
None listed