Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Pociredir

This is a Phase 1 multicenter, international, open-label study evaluating the safety, tolerability, pharmacokinetics (PK), fetal hemoglobin (HbF) induction and biological activity of Pociredir in participants 18-65 years of age, inclusive, with SCD.

Participants will receive 12 weeks of dosing with 4 weeks of follow-up. Approximately 10 participants will be enrolled in each cohort. A maximum of 3 participants with SCD HbSC+ genotype may be enrolled in each cohort.

Cohort 1 will receive 6 milligrams (mg) of Pociredir by mouth once daily. Doses for subsequent cohorts will be determined following review by the Data Monitoring Committee [DMC]. A total of seven cohorts may be included. Cohort 2 will be dosed at 2 mg once daily by mouth, and cohort 3 will be dosed at 12 mg once daily by mouth. The Sponsor will reinitiate enrolment in the 3rd cohort (12 mg cohort) with the updated inclusion and exclusion criteria. Based on review of available safety and biomarker data and with the recommendation of the DMC, a subsequent 4th cohort of 20 mg and potentially a 5th cohort of 30 mg may be initiated. Additional cohorts using alternative dosing schedules may be considered based on available data.

The primary endpoints of the study are to evaluate the safety and tolerability of Pociredir as measured by the frequency of adverse events and to evaluate single and multiple-dose pharmacokinetics of Pociredir in participants with sickle cell disease. Secondary endpoints include evaluating the effect of Pociredir on fetal hemoglobin induction in peripheral blood and evaluating the effects of Pociredir on hemolysis in participants with sickle cell disease.

Key Inclusion Criteria:

• Participant is 18 to 65 years of age, inclusive at the time informed consent is obtained.
• Documented SCD at the time of screening (S/S, S/β0, S/β+, and S/C only) as confirmed through review of medical records or HPLC.
• Participants who meet at least one the following criteria:

• ≥4 to 10 episodes of SCD pain crisis over 12 months, or ≥2 to 5 over 6 months prior to screening
• ≥2 episodes of SCD pain crisis plus at least one of the following over previous 12 months: i) Acute chest syndrome (ACS) ii. Hepatic or splenic sequestration iii. Priapism
• ≥2 of the following events over the previous 12 months:i. ACS ii. Hepatic or splenic sequestration iii. Priapism
• Tricuspid regurgitant jet velocity (TRV) ≥ 3.0 meter/second(m/s) OR TRV ≥ 2.5 m/s + N-terminal pro b-type natriuretic peptide (NT-proBNP) plasma level ≥ 160 picogram per milliliter; OR documented ongoing pulmonary hypertension diagnosed from previous echocardiogram or right-sided heart catheterization with mean pulmonary artery pressure > 25 millimeter of mercury;
• SCD-related chronic kidney disease (CKD)
• Meet medical criteria to receive (e.g., post-cerebrovascular accident) but are contraindicated for chronic transfusions (e.g., alloimmunization, transfusion reactions)
• Previous experience with Hydroxyurea (HU) but have shown to be unresponsive and/or intolerant or ineligible AND
• Previous experience with a stable dose of voxelotor, crizanlizumab, and/ or L-glutamine but have shown to be unresponsive and/or intolerant or ineligible
• Per Investigator's recommendation, participants may continue crizanlizumab and/or L-glutamine but must be on a stable dose for at least 6 months
• HbF ≤ 20% of total Hb
• Total Hb ≥ 5.5 g/dL and ≤ 12 g/dl (males) or ≤ 10.6 g/dl (females) at screening.
• Participant must meet both of the following laboratory values at screening:

• Absolute neutrophil count ≥ 1.5 × 10^9 per liter (/l)
• Platelets ≥ 80 × 10^9/l
• Absolute reticulocyte count at screening ≥ 100 x 10^9/l.

Key Exclusion Criteria:

• Sickle cell complication requiring care from a medical provider in hospital or emergency care setting in the 14 days prior to starting study drug.
• History of bone marrow transplant or human stem cell transplant or gene therapies.
• • Participants with a history of severe renal disease defined as estimated glomerular filtration rate < 30 mL/min/1.73m^2. Participants on dialysis of any kind are excluded.
• Participants receiving regularly scheduled transfusions or therapeutic phlebotomies, or any participant who has been transfused within 60 days prior to initiating study drug.
• Participant with active malignancy, or history of cancer (except for squamous cell skin cancer, basal cell skin cancer, and stage 0 cervical carcinoma in situ, with no recurrence for the last 5 years), or has an immediate family member with known or suspected familial cancer syndrome. Known presence of a chromosomal abnormality or genetic mutation that may put the participant at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Participant currently on HU, or have received HU, within 60 days prior to initiating study drug.