A Clinical Study of Mitapivat in Patients with Sickle Cell Disease and Kidney Disease

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• 1. Currently receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or VOC is permitted. 2. Have received an RBC transfusion within 60 days before providing informed consent/assent or during the Screening Period. 3. Hospitalized within 14 days before providing informed consent/assent or during the Screening Period either for an SCPC (defined in Section 8.2.1) or other vaso-occlusive event. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an ER or outpatient clinic visit. A visit to an ER that does not result in an in-patient admission does not meet the definition of hospitalization. 4. More than10 SCPCs (defined in Section 8.2.1) in the 52 weeks before providing informed consent/assent. 5. History of stroke or meeting criteria for primary stroke prophylaxis (history of 2 transcranial Doppler [TCD] measurements ≥200 cm/s by nonimaging TCD or ≥185 cm/s by imaging TCD) at any time. 6. Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), except for hydroxyurea. The last dose of such therapies must have been administered at least 90 days before Study Day 1. 7. History of malignancy (active or treated) ≤5 years before providing informed consent/assent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. 8. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before Study Day 1, including but not limited to: a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% d. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right heart failure, and oxygen indicated
• 9. Hepatobiliary disorders including but not limited to: a. Liver disease with histopathological evidence or clinical diagnosis of cirrhosis or severe fibrosis at any time b. Clinically symptomatic cholelithiasis or cholecystitis within 60 days before study drug administration (subjects with prior cholecystectomy are eligible) c. History of drug-induced cholestatic hepatitis within 90 days before study drug administration d. Aspartate aminotransferase >2.5× the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5× the ULN (unless due to hepatic iron deposition) within 60 days before study drug administration 10. Renal dysfunction as defined by an eGFR <45 mL/min/1.73 m² by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation (National Kidney Foundation, 2021b) at Screening. 11. History of renal disease due to another disorder (eg, diabetes, hypertension, primary focal segmental glomerulosclerosis, autoimmune) unrelated to SCD at any time. 12. Evidence of acute kidney injury (in the opinion of the Investigator) within 4 weeks before informed consent/assent or during Screening Period. 13. Currently undergoing renal replacement therapy (ie, hemodialysis, peritoneal dialysis, hemofiltration, kidney transplantation). 14. History of kidney transplant at any time. 15. Nonfasting triglycerides >440 mg/dL (5 mmol/L) at Screening. 16. Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mm Hg or diastolic BP >90 mm Hg) refractory to medical management. Please refer to Protocol, Section 5.2. for detailed list of Exclusion Criteria.