A Study Evaluating the Efficacy and Safety of Mitapivat (AG-348) in Participants With Sickle Cell Disease (RISE UP)

Inclusion Criteria:

• Age 16 years or older (18 years or older [France and Germany]); participants age 16or 17 years must physically have completed puberty;

• Documented diagnosis of sickle cell disease (SCD) (HbSS, HbSC [combinedheterozygosity for hemoglobins S and C], HbS/beta 0- thalassemia, HbS/ beta plusthalassemia, or other sickle cell syndrome variants);

• At least 2 SCPCs and no more than 10 SCPCs in the past 12 months;

• Hemoglobin at least 5.5 and 10.5 gram per deciliter (g/dL) at the most. Hemoglobinconcentration must be based on an average of at least 2 Hb concentrationmeasurements (separated by ≥7 days) collected during the Screening Period;

• If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 daysbefore starting study drug. Discontinuation of hydroxyurea requires a 90-day washoutprior to informed assent/consent;

• Women capable of becoming pregnant must agree to use 2 forms of contraception.

Exclusion Criteria:

• Pregnant, breastfeeding, or parturient;

• Receiving regularly scheduled transfusions;

• Hepatobiliary disorders including but not limited to significant liver disease orgallbladder disease;

• Severe kidney disease;

• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;

• Currently receiving treatment with a disease-modifying therapy for SCD (eg,voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The lastdose of voxelotor, crizanlizumab, and L-glutamine must have been administered atleast 90 days before randomization;

• Currently receiving treatment with hematopoietic stimulating agents; the last dosemust have been administered at least 90 days before starting study drug;

• Received treatment on another investigational trial within 90 days prior to start ofstudy drug or plans to participate in another investigational drug trial;

• Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers ofCYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor).