Sickle cell disease (SCD) is a rare inherited red blood cell (RBC) disorder characterized by chronic hemolysis, debilitating pain, progressive multiorgan damage, and premature death. SCD is caused by a specific point mutation in the gene encoding hemoglobin subunit beta that results in the substitution of a hydrophobic valine residue for glutamic acid in the 6th position from the N-terminus of the beta-chain leading to the production of HbS. MedDRA version: 21.0 Level: PT Classification code 10
Conditions
Interventions
Product Name: IMR-687
Pharmaceutical Form: Tablet
INN or Proposed INN: No INN
CAS Number: 2062661-53-2
Current Sponsor code: IMR-687
Other descriptive name: 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl
Sponsors
Imara, Inc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Each patient must meet all of the following criteria to be enrolled in the study: 1. Male or female =18 or =50 years of age. 2. Confirmed diagnosis of SCA (HbSS or sickle-B0 thalassemia). Note, if not already documented in the patient’s record, the diagnosis of SCA must be confirmed via electrophoresis, HPLC, and/or genotyping. 3. Use of HU: • For patients in the Population A: Have not received HU within 90 days prior to Screening and are not planning to take HU within the next 6 months • For patients in Population B: Have received HU for at least 6 months, have been on a stable dose for at least 60 days prior to Screening, and are not planning to change the dose level, dose regimen, or discontinue HU within the next 6 months. 4. Female patients must not be pregnant and be highly unlikely to become pregnant. Male patients must be unlikely to impregnate a partner. Male or female patients must meet at least one of the following criteria: • A female patient who is not of reproductive potential is eligible without requiring the use of contraception. A female patient who is not of reproductive potential is defined as one who: (1) has reached natural menopause (defined as 12 months of spontaneous amenorrhea without an alternative medical cause, and can be confirmed with serum follicle-stimulating hormone levels in the postmenopausal range as determined by the local 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 (i.e., anorexia nervosa). • A male patient who is not of reproductive potential is eligible without requiring the use of contraception. A male patient 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 patient who is of reproductive potential agrees to remain truly abstinent or use (or have their partner use) acceptable methods of highly effective contraception starting from the time of consent through 3 months after the completion of study therapy. True abstinence is defined as abstinence that is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of the trial and withdrawal are not acceptable methods of contraception. Acceptable methods of highly effective birth control are combined or progestogen-only hormonal contraception that is associated with inhibition of ovulation, intrauterine device, and intrauterine hormone-releasing system. 5. Be capable of giving informed consent and reading and signing the informed consent form after the nature of the study has been fully explained by the investigator or investigator designee. 6. Be willing and able to complete all study assessments and procedures and to communicate effectively with the investigator and site staff. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 54 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Total Hb at Screening >12.5 g/dL or 7 hospitalizations (for at least 24 hours) for vaso-occlusive crises (VOC), including acute chest syndrome (ACS) and priapism, within the prior year. 4. Blood transfusion or donation of blood or any blood product within 60 days of Day 1 or on chronic transfusion therapy regimen. 5. Positive for human immunodeficiency virus (HIV), hepatitis C (HCV) antibodies (unless the patient has successfully completed drug therapy that results in cure/clearance of HCV), and hepatitis B surface antigen. 6. For female patients of childbearing potential, a positive serum human chorionic gonadotropin (hCG) test (Screening) or a positive urine hCG test on Day 1. 7. Estimated glomerular filtration rate (eGFR) 3x the upper limit of normal (ULN) 9. Body Mass Index (BMI) 35 kg/m2; a total body weight 450 ms in men and >470 ms in women or the presence of clinically significant abnormalities as determined by the investigator. 15. A history of major surgery within 4 weeks or minor surgery within 2 weeks of Day 1. 16. Any flu-like syndrome or other respiratory infection within 2 weeks of Day 1 or vaccination with attenuated live virus within 4 weeks of Day 1. 17. Participation in an investigational drug or device study within 30 days prior to Day 1. 18. Use within 30 days prior to Day 1, or planning to use during the study, of any drugs or substances that are known to strongly inhibit or induce cytochrome P450 (CYP) enzymes, including but not limited to cimetidine, cyclosporine, erythromycin, omeprazole, rifampin, ritonavir, and St. John’s wort. If there is any question as to whether a substance is permitted, please review the product labelling (if applicable) and consult the Sponsor. 19. Consumption of grapefruit, grapefruit juice, or grapefruit products within 24 hours prior to Day 1 or planning to consume grapefruit products during the study. 20. Use within 30 days prior to Day 1, or planning to use during the study, of any CYP3A sensitive substrates, (excluding opioids), including but not limited to alfentanil, avanafil, budeso
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): IMR-687 safety and tolerability as measured by: - Incidence and severity of adverse events (AEs) and serious adverse events (SAEs); - Change from baseline in 12-lead electrocardiogram (ECG) parameters, clinical laboratory tests (chemistry, haematology, coagulation, urine), and vital signs - Physical examination findings;Timepoint(s) of evaluation of this end point: 1. AEs/SAEs: continuous; 2. Change frm baseline in 12-lead ECG at weeks 1,13,14,17,21,25 (Pop A), 1,5,17 (Pop B); 1,5,13,14,17,21,25 (Pop A1) and 1,5,25 (Pop B1) 3. Change frm baseline in clin labs at weeks 1,2,5,9,13,17,21,25, 29 (Pop A), 1, 2,5,9,13,17, 21 (Pop B), 1,2,4,5,9,13,17,21, 25,29 (Pop A1) and 1,2,5,9,13,17,21,25,29 (Pop B1) 4. Change from baseline in vitals at weeks 1,2,3,4,5,9,13,14,15,16,17,21,25, 29 (Pop A), 1,2,3,4,5,6,7,8,9,13,17, 21 (Pop B), 1,2,3,4,5,9,13,14,15,16,17,21,25,29 (Pop A1) and 1,2,3,4,5,6,7,8,9,13,17,21,25,29 (Pop B1) 5. Physical exam at weeks 1,2,3,4,5,9,13,14,15,16,17,21,25, 29 (Pop A), 1,2,3,4,5,6,7,8,9,13, 17,21 (Pop B), 1,2,3,4,5,9,13,14, 15,16,17,21,25,29 (Pop A1) and 1,2,3,4,5,6,7,8,9,13,17,21,25,29 (Pop B1);Secondary Objective: To characterise the pharmacokinetic (PK) profile of IMR-687 in adult patients with SCA who are/are not receiving a stable dose of HU To characterise the PK profile of HU in adult patients with SCA before and after receiving IMR 687 to determine if there is a clinically relevant PK interaction. ;Main Objective: To assess the safety and tolerability of IMR-687 in adult patients with sickle cell anaemia (SCA), defined as homozygous sickle haemoglobin (HbSS) or sickle-ß0 thalassemia, who are not receiving hydroxyurea (HU) and in adult SCA patients who are receiving a stable dose of HU | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - The plasma PK profile of IMR-687 after oral administration to adult patients with SCA (Populations A and B) - The plasma PK profile of HU before and after oral administration of IMR-687 to adult patients with SCA (Population B only) ;Timepoint(s) of evaluation of this end point: 1. The plasma PK profile of IMR-687 after oral administration to adult subjects with SCA (Populations A and B) at week 1, 13 and 25 (Population A), at week 1, 5 and 17 (Population B), at weeks 1, 5, 25 (Population A1) and weeks 1, 5, 25 (Population B1) 2. The plasma PK profile of HU after oral administration of IMR-687 to adult subjects with SCA (Population B only) at lead-in (for 2 complete HU PK profiles, at least 48 hours apart), week 5, week 17, and one complete HU PK profile at lead-in, plus weeks 5 and 25 (Population B1) | — |
Countries
Ghana, Kenya, United Kingdom, United States
Contacts
Public ContactEarly Clinical Development
IQVIA (formerly: QuintilesIMS)
Outcome results
None listed