A Dose-Finding Study of AG-348 in Sickle Cell Disease

• INCLUSION CRITIERIA:

For enrollment, subjects must meet all of the following criteria during the screening period:

• Have provided signed written informed consent prior to performing any study procedure, including screening procedures.
• Age between 18-70 years
• Unequivocal diagnosis of HbSS confirmed by hemoglobin electrophoresis performed on patients at least 90 days after a blood transfusion if previously transfused, or DNA genotyping
• No transfusion in the 90 days prior to the first dose of study drug or absence of HbA on hemoglobin analysis (by high-performance liquid chromatography; HPLC)
• Have adequate organ function, as defined by:
• Serum aspartate aminotransferase (AST) less than or equal to 2.5 (SqrRoot) Upper Limit of Normal (ULN) (unless the increased AST is assessed by the Investigator as due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) less than or equal to 2.5 (SqrRoot) ULN (unless the increased ALT is assessed by the Investigator as due to hepatic iron deposition).
• Serum creatinine less than or equal to 1.25 (SqrRoot) ULN. If serum creatinine is >1.25 (SqrRoot) ULN, then glomerular filtration rate (based on creatinine) must be greater than or equal to 60 mL/min.
• Absolute neutrophil count greater than or equal to 1.0 (SqrRoot) 10^9/L.
• Hemoglobin greater than or equal to 7 g/dL
• Platelet count greater than or equal to 100 (SqrRoot) 10^9/L.
• Activated partial thromboplastin time and international normalized ratio less than or equal to 1.5 (SqrRoot) ULN, unless the subject is receiving therapeutic anticoagulants.
• For women of reproductive potential, have a negative serum or urine pregnancy test during the screening period. Women of reproductive potential are defined as sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion; or who have not been naturally postmenopausal (i.e., who have not menstruated at all for at least the preceding 12 months prior to signing informed consent and have an elevated follicle-stimulating hormone level indicative of menopause during the screening period).
• For women of reproductive potential as well as men and their partners who are women of reproductive potential, be abstinent as part of their usual lifestyle, or agree to use 2 effective forms of contraception from the time of giving informed consent, during the study, and for 28 days for women and 90 days for men following the last dose of study treatment. An effective form of contraception is defined as hormonal oral contraceptives, injectables, patches, and barrier methods.
• Be willing to comply with all study procedures for the duration of the study.

EXCLUSION CRITERIA

Subjects who meet any of the following criteria during screening will not receive AG348 and will not be counted toward the final enrollment count for statistical purposes:

• Documented pyruvate kinase deficiency
• Have a significant medical condition that confers an unacceptable risk to participating in the study, and/or that could confound the interpretation of the study data. Such significant medical conditions include, but are not limited to the following:
• Poorly controlled hypertension (defined as systolic blood pressure [BP] >150 mmHg or diastolic BP >90 mmHg) refractory to medical management.
• History of recent (within 6 months prior to signing informed consent) congestive heart failure; myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism.
• Cardiac dysrhythmias judged as clinically significant by the Investigator.
• Heart-rate corrected QT interval-Fredericia's method (QTcF) >480 msec with the exception of subjects with right or left bundle branch block.
• Clinically symptomatic cholelithiasis or cholecystitis. Prior cholecystectomy is not exclusionary. Subjects with symptomatic cholelithiasis or cholecystitis may be rescreened