Clinical Trial to Evaluate the Efficacy of Gene Therapy for Pyruvate Kinase Deficiency

Inclusion Criteria

• •1. Pyruvate Kinase Deficiency (PKD) diagnosis with a confirmed PK-LR mutation
• •2. Significant anemia defined as:
• •* Hemoglobin (Hb) levels \<9.5 g/dL documented during 2 or more assessments in the 12 months prior to screening and either:
• •1. at least 6 Red Blood Cell (RBC) transfusion episodes over the 12- month period prior to screening or
• •2. at least 3 Red Blood Cell (RBC) transfusion episodes each year for 2 years prior to screening; or
• •* Hemoglobin (Hb) levels \<8.5 g/dL irrespective of transfusions (documented during 2 or more assessments during the prior 2 years); or
• •* Hemoglobin (Hb) levels \<10.0 g/dL irrespective of transfusions (documented during 2 or more assessments during the prior 2 years) and the presence of either:
• •* Fatigue or energy-related symptoms limiting activities of daily living (The National Cancer Institute Common Terminology Criteria for Adverse Events v 5.0 (NCI CTCAE v5.0 grade 3)); or
• •* Fatigue or energy-related symptoms limiting activities of daily living (The National Cancer Institute Common Terminology Criteria for Adverse Events v 5.0 (NCI CTCAE v5.0 grade 2)) not responsive to available medical therapy; or
• •* Icterus limiting social interactions, education or work activities and not responsive to available medical therapy;
• •3. Subject age: age ≥8 years and ≤55 years
• •4. Prior splenectomy
• •8. Uncontrolled seizure disorder.
• •9. Hepatic dysfunction as defined by Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2.5× the upper limit normal (ULN).
• •10. Renal dysfunction defined as serum creatinine \>upper limit normal (ULN). Patients with creatinine above ULN may be eligible pending documentation of a glomerular filtration rate ≥60 mL/min/1.73m2 as calculated by Modification of Diet in Renal Disease equation (Stevens 2006), or 24-hour urine collection.
• •11. Pulmonary dysfunction as defined by either:
• •1. Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection) OR
• •2. Clinically significant pulmonary disease that may impair ability to tolerate study procedures and treatments.
• •12. Any medical or other contraindication for leukapheresis as determined by the treating Investigator.
• •13. Any medical or psychiatric condition that in the opinion of the Investigator renders the patient unfit for trial participation or at higher than acceptable risk for participation.
• •14. Poor functional status evidenced by Karnofsky Index \<70 in subjects ≥16 years old and Lansky Play-Performance Scale \<70 in subjects \<16 years old.
• •15. Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed. Patients who are receiving mitapivat in non-investigational settings are eligible provided they discontinue mitapivat at least 90 days prior to the start of mobilization.
• •16. Pregnant women or women with a positive serum pregnancy test at screening or breast feeding or planning to become pregnant within the next 24 months. Female participants or female partners of male participants not willing to use highly effective contraceptive methods during the complete study period.
• •17. Previous allogeneic or other hematopoietic stem cell transplant.