Initially, participants will be randomized 1:1 to 100 mg and 150 mg daily. Upon review of the 150 mg safety data from at least 6 participants, there will be 1:1:1 randomization: 100 mg, 150 mg, and up to 200 mg.

Participants will then receive maintenance once daily doses through Week 12.

Study drug arm: Adult participants will receive osivelotor at 300 mg QD loading dose for 7 days followed by 150 mg QD through Week 48.

Adolescent participant dose will be defined in a future protocol amendment.

Placebo arm: Participants will receive placebo tablets for 48 weeks.

Adult Participants will receive 150 mg open-label osivelotor up to 2 years after the last participant's visit in Part B or when the drug is commercially available in that region.

The appropriate doses for adolescents will be defined in a future protocol amendment.

Tablets which contain drug substance

Number of adult participants with change from baseline in hemoglobin (Hb) through week 12 as measured by change in osivelotor concentrations from baseline or percentage change from baseline of clinical measures of anemia Hb and hemolysis (including indirect bilirubin, reticulocytes and lactate dehydrogenase).

Co-primary endpoints: Hb response (increase from baseline of >1 g/dL) at Week 48 (based on average of Hb levels at Week 40 and Week 48) and the Annualized rate of VOC through end of Week 48.

A VOC is defined as an acute episode of pain that:

• Has no medically determined cause other than a vaso-occlusive event, and
• Results in a visit to a medical facility (hospitalization, emergency department, urgent care center, outpatient clinic, or infusion center), and
• Requires parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory drugs (NSAIDs), or an increase in treatment with oral narcotics.

Complicated VOCs of acute chest syndrome (ACS), hepatic sequestration, splenic sequestration, priapism, and dactylitis that meet the requirements listed above will be included in this co-primary endpoint.

Incidence of Treatment Emergent Adverse Events:

• Incidence of SAEs
• Incidence of AEs leading to discontinuation
• Change from baseline in laboratory parameters.