A Phase 2b Study to Evaluate the Safety and Efficacy of IMR-687 in Subjects with Sickle Cell Disease

INTERVENTION: IMR‐687 IMR‐687 will be supplied as 100, 150, or 200 mg white tablets. Subjects will be advised to take 2 tablets orally, qd. The different doses of IMR‐687 are visually identical. Subjects will be directed to take their study drug with food.In order to main This study will enroll approximately 99 adult (18‐65 years) subjects with Sickle Cell Disease. Initially, subjects will be randomly assigned in a 2:1 ratio to receive either IMR‐687 lower dose or placebo.Prior to the introduction of IMR‐687 higher dose, the Data Monitoring Committee (DMC) will review safety data for at least 5 subjects who received IMR‐687. If the DMC recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio (IMR‐687 lower dose, IMR‐687 higher dose, or placebo). CONDITION: Sickle cell The population for this study includes subjects with the following forms of SCD: homozygous sickle hemoglobin (HbSS), sickle‐ß° (HbSB°) thalassemia, and sickle‐ß? (HbSB?) thalassemia. ; Sickle cell PRIMARY OUTCOME: Name: Changes in 12‐Lead ECG;Timepoints: All ECGs to be performed in triplicate. From Baseline (Day 1 visit) through EOT (Week 52 visit), ECGs will be obtained at both pre‐dose and 2 hours (±30 minutes) post‐dose. During the screening, ET, and EOS (Week 56) visits, ECG will be obtained irrespective of taking study drug.;Measure: heart rate, PR interval, QRS duration, QT interval, and QTcF interval Name: Changes in vital signs;Timepoints: Vital signs will be collected at every on‐site visit .At the Day 1 and Week 4 visits, vital signs will be taken predose and 2 hours (±20 minutes) postdose, during the 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: Clinical Laboratory Variables;Timepoints: over 52 weeks of treatment;Measure: hematology,coagulation,serum chemistry,urinalysis and pregnancy test Name: Incidence of Adverse Event AEs 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.;Measure: All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Name: Physical Examination;Timepoints: Complete PEs will be performed at Screening and at Weeks 12, 24, 36, 52, and 56; these consist of a general examination of the body, 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: abdomen, heart, lungs, lymph nodes, back/neck, neurological system, skin, extremities, head, eyes, nose, and throat. INCLUSION CRITERIA: 1. Male or female aged =18 to =65 years at the time of informed consent form (ICF) signing. 2. Confirmed diagnosis of SCD (HbSS, HbSB° thalassemia, or HbSB? thalassemia) in the medical record; if not available, the diagnosis must be confirmed at the site’s local laboratory instead. 3. Subjects must have had at least 1 and no more than 12 documented episodes of VOC in the past 12 months at the time of ICF signing and at randomization (Day 1). For study eligibility, VOC is defined as a documented episode of an acute painful crisis (for which there was not an explanation other than VOC) that involved moderate to severe pain lasting for at least 2 hours and at least one of the following: • Use of escalated analgesia (including healthcare professional‐instructed use of an analgesic prescription) • A hospital, emergency department, or clinic visit and/or healthcare telephone consultation at the time of occurrence SECONDARY OUTCOME: Name: Pharmacodynamic Assessment;Timepoints: Screening,baseline and throughout treatment period;Measure: E‐selectin, P‐selectin, ICAM‐1, VCAM‐1, MPO, and transferrin receptor. Name: Pharmacokinetic Assessment;Timepoints: At the Day 1 and Week 4 visits, serial blood samples for IMR‐687 (including metabolites and HU, if applicable) plasma concentrations will be drawn pre‐dose (within 30 minutes) and at 30 minutes (±5 minutes), 1.5 hours (±15 minutes), 6 hours (±1 hour), and 24 hours (±2 hours) after administration of study drug. On these full profile PK days, food details will also be recorded at the study sites. A trough blood sample will be drawn pre‐dose at Week 24 and on the last day of dosing (Week 52).;Measure: Cmax, tmax, and AUC(0‐24), 0 to the last measurable timepoint (AUC(last)), and extrapolated to infinity (AUC(0‐infinity) Name: Quality of life;Timepoints: at Baseline and weeks 4,12,24,36 and 52;Measure: ASCQ‐Me®, PROPr, SCSES • Diagnosis of acute chest syndrome (AC