Sickle Cell Disease (SCD) / Patients with SCD endure chronic hemolytic anemia and acute and recurrent clinical events that vary in frequency and severity, the most common being VOCs (vaso-occlusions). The use of curative options for SCD is currently limited to a small subgroup of patients who are deemed fit for bone marrow transplantation and have available donors. The current treatment options are not universally effective or globally available, tend to address only a single component of the
Conditions
Interventions
This is a three-part, multicenter, Phase 2/3 study of orally administered GBT021601 in participants with SCD.
Part A: Initially, participants will be randomized 1:1 to 100 mg and 150 mg daily. Upon r
Sickle Cell Disease
Sponsors
Global Blood Therapeutics, Inc.
Eligibility
Sex/Gender
All
Age
1 Years to 65 Years
Inclusion criteria
Inclusion criteria: Key Inclusion Criteria (Part A, Part B, and Part C): 1. Male or female with SCD. Documentation of SCD genotype homozygous for sickle cell allele (HbSS) or double heterozygote for sickle hemoglobin (HbS) and ß-0 thalassemia (HbSB) may be based on history of laboratory testing or must be confirmed by laboratory testing during Screening. 2. Hb = 5.5 and = 10.5 g/dL during Screening and considered stable by the Investigator. 3. For participants taking hydroxyurea (HU) and/or L-glutamine, the dose must be stable for at least 90 days prior to signing the ICF or assent and with no anticipated need for dose adjustments during the study in the opinion of the Investigator. 4. Female participants of child-bearing potential, must agree to use highly effective methods of contraception or practice abstinence from study start to 120 days after the last dose of study drug. Males who are not surgically sterile with partners of childbearing potential must agree to use a highly effective method of birth control during the study and for 120 days after the last dose of study drug. In addition, males who are not surgically sterile with a partner who is pregnant must agree to condom use or maintain sexual abstinence during the study and for 120 days after the last dose of study drug. 5. Female participants of child-bearing potential must have a negative pregnancy test before administration of study drug. 6. Participant has provided documented informed consent (Part A and Part B for adult participants) or written informed parental/guardian consent and participant assent has been obtained per institutional review board (IRB)/Ethics Committee (EC) policy and requirements, consistent with International Council for Harmonisation (ICH) guidelines (Part B for pediatric participants and Part C). Additional Key Inclusion Criteria (Part A): 1. Age 18 to = 65 years, inclusive at Screening. 2. Males must agree to not donate sperm from study start through 120 days after the final dose. Additional Key Inclusion Criteria (Part B): 1. Age 12 to = 65 years, inclusive at Screening. Participants 12 to < 18 years will only be enrolled in Part B after evaluation of safety in Part C Cohort C1. 2. Males must agree to not donate sperm from study start through 120 days after the final dose. Additional Key Inclusion Criteria (Part B only): 1. More than or equal to 2 and = 10 VOCs within 12 months of Screening. Additional Key Inclusion Criteria (Part C only): 1. Age by cohort at Screening: ? Cohort C1: 12 to < 18 years ? Cohort C2: 6 to < 12 years ? Cohort C3: 2 to < 6 years ? Cohort C4: 6 months to < 2 years
Exclusion criteria
Exclusion criteria: Key Exclusion Criteria (Part A, Part B, and Part C): 1. More than 10 VOCs within 12 months of Screening. 2. Female participant who is breastfeeding or pregnant. 3. Receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or has received an RBC or exchange transfusion for any reason within 90 days of Day 1. 4. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days of signing the ICF. 5. Screening laboratory test of alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN) for age. 6. Acute illness or clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy, including acute bacterial infection requiring antibiotics within 14 days prior to the study drug administration. 7. Participants known to have active hepatitis A, B, or C or human immunodeficiency virus (HIV). 8. Participants with active, symptomatic coronavirus disease 2019 (COVID-19) infection. 9. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at the Screening Visit, calculated by the central laboratory, or is on chronic dialysis. 10. History of malignancy within the past 2 years prior to treatment Day 1 requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy). 11. History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent. 12. Has received COVID-19 vaccine (first dose, second dose, or booster dose), authorized by regional regulatory authority, within 7 days prior to Day 13. Received EPO or other hematopoietic growth factor treatment within 28 days of signing ICF or is anticipated to require such agents during the study. 14. Current or recent use of voxelotor. Recent use is defined as within 10 days prior to Day 1. 15. Current or recent use of crizanlizumab. Recent use is defined as within 90 days prior to Day 1. 16. Ongoing or recent use of strong or moderate inducers of cytochrome P450 (CYP) or CYP3A4/CYP3A5. Recent is defined as within 5 elimination half-lives or 14 days, whichever is longer prior to Day 1. 17. Ongoing or recent use of strong or moderate inhibitors of CYP3A4/CYP3A5. Recent is defined as within 5 elimination half-lives prior to Day 1. 18. Ongoing or recent use of the P-glycoprotein substrates digoxin or dabigatran. Recent is defined as within 5 elimination half-lives prior to Day 1. 19. Use of prohibited prescription or nonprescription drugs and dietary supplements (including herbal and alternative medications). Marijuana use is allowed, except for 24 hours prior to neurocognitive assessments as outlined in the Schedule of Assessments. 20. Known allergy to GBT021601 or other Hb polymerization inhibitors. 21. History of severe allergic reaction (including anaphylaxis) to any substance, or previous status asthmaticus. 22. Unlikely to comply with the study procedures. Key Exclusion Criteria (Part C only): 1. History of stroke or meeting criteria for primary stroke prophylaxis (history of two transcranial doppler [TCD] measurements = 200 cm/sec by nonimaging TCD or = 185 cm/sec by TCDi).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Name: Part A;Timepoints: Through week 12;Measure: Number of adult participants with change from baseline in hemoglobin (Hb) through week 12 as measured by change in GBT021601 concentrations from baseline or percentage change from baseline of clinical measures of anemia (hemoglobin) and hemolysis (including indirect bilirubin, reticulocytes and lactate dehydrogenase).;Name: Part B;Timepoints: Through week 48;Measure: Proportion of participants with an increase from baseline of >1 g/dL in Hb at week 48 as measured by change in GBT021601 concentrations from baseline or percentage change from baseline of clinical measures of anemia (hemoglobin) and hemolysis (including indirect bilirubin, reticulocytes and lactate dehydrogenase).;Name: Part C;Timepoints: Through Week 6;Measure: Assess the pharmacokinetics, while observing maximum concentration (Cmax) after a single dose as measured by a noncompartmental PK analysis or population PK analysis using nonlinear mixed-effect modeling.;Name: Part C;Timepoints: Through Week 2 ;Measure: Assess the pharmacokinetics, while observing minimum concentration (Cmin) and maximum concentration after multiple dose administration as measured by a noncompartmental PK analysis or population PK analysis using nonlinear mixed-effect modeling will be performed to characterize GBT021601 PK in plasma and whole blood following multiple doses | — |
Secondary
| Measure | Time frame |
|---|---|
| Name: Part A;Timepoints: Through Week 12;Measure: To evaluate the effects of GBT021601 on total hemoglobin and clinical measures of hemolysis. To evaluate the safety and tolerability as well as the PK and pharmacodynamic (PD) properties of multiple dose GBT021601 administration.;Name: Part B;Timepoints: Through end of Week 48;Measure: To evaluate the effects of GBT021601 compared to placebo on total hemoglobin, clinical measures of hemolysis, and relevant clinical outcomes. To evaluate the safety and tolerability of 48 weeks of daily GBT021601 administration.;Name: Part C;Timepoints: Through Week 2;Measure: To evaluate the safety and change in total hemoglobin and clinical measures of hemolysis after multiple doses of GBT021601. | — |
Countries
Lebanon
Contacts
Public ContactAziz Zoghbi
Director of Country Oversight and Management MENA, Gulf and Africa
Outcome results
None listed