Slide 1: Lentiviral-Mediated Gene Therapy for Adults and Children with Severe Pyruvate Kinase Deficiency
Lentiviral-Mediated Gene Therapy for Adults and Children with Severe Pyruvate Kinase Deficiency: Results from an Ongoing Global Phase 1 Study Ami J. Shah, MD Center for Definitive and Curative Medicine Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenera
Slide 2: Disclosures
Disclosures • Advisory Board: Vertex Pharmaceuticals and Bluebird Bio
Slide 3: Introduction
Introduction • Pyruvate kinase deficiency (PKD) is a rare inherited hemolytic Complications of PKD anemia caused by mutations in the PKLR gene which result in Failure to Fatigue decreased red cell pyruvate kinase activity and impaired thrive erythrocyte energy production (glycolysis). • Clinical man
Slide 4: Gene Therapy For PKD: Rationale
Gene Therapy For PKD: Rationale • Involves insertion of a functional PKLR gene into autologous hematopoietic stem and progenitor cells (HSPCs) with the intent of enabling lifelong red blood cell (RBC) pyruvate kinase enzyme production and normalized RBC function and lifespan • Preclinical studies ut
Slide 5: Global Phase 1 PKD Gene Therapy Study
RP-L301-0119 NCT#04105166 Global Phase 1 PKD Gene Therapy Study Clinical Sites: Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain Key Eligibility Criteria Hospital Infantil Universitario Niño Jesús, Madrid, Spain Inclusion: Stanford University, Palo Alto, California, United States • PKD d
Slide 6: Study Design
Study Design CD34+ cell mobilization protocol with G-CSF Schematic diagram of product manufacture and treatment: and plerixafor: HSPC apheresis & immunoselection G-CSF Minimum cell dose (+24 hrs) 2×106 CD34+ cells/kg Plerixafor (G-CSF +16-20 hrs) RP-L301 1 Transduction w/ viral vector CD34+ cell cou
Slide 7: Patient L301-006-1001's Clinical Course Prior to RP-L301 Administration
Patient L301-006-1001’s Clinical Course Prior to RP-L301 Administration Pre-treatment Characteristics Product Metrics Transfusion Requirement Age (y) & Hemoglobin Bilirubin Erythropoietin Nucleated CD34+ Cells/kg CFCs/kg Mean VCN: PKD Mutation for 2 Years Prior to Gender (g/dL) (mg/dL) (mIU/mL) Cell
Slide 8: Patient L301-006-1001 Preliminary Efficacy Results
Patient L301-006-1001 Preliminary Efficacy Results --- Normal Range --- Normal Range (0.3–1.2 mg/dL) (0.5–1.5%) Significant bilirubin decrease from Sustained improvements in 13.4 mg/dL to 1.1 mg/dL reticulocytes from 49.5% to 2.5% • Sustained hemoglobin normalization from ~7.4 g/dL to 13.2 g/dL ---
Slide 9: Patient L301-001-1002's Clinical Course Prior to RP-L301 Administration
Patient L301-001-1002’s Clinical Course Prior to RP-L301 Administration Pre-treatment Characteristics Product Metrics Transfusion Requirement Nucleated CD34+ CFCs/kg Mean VCN: Age (y) & Hemoglobin Bilirubin Erythropoietin PKD Mutation for 2 Years Prior to Cells/kg Cells/kg Liquid Culture Gender (g/d
Slide 10: Patient L301-001-1002 Preliminary Efficacy Results
Patient L301-001-1002 Preliminary Efficacy Results --- Normal Range --- Normal Range (0–1.4 mg/dL) (0.45–2.28%) Normalized bilirubin from 7.4 mg/dL Significant improvement in to 0.9 mg/dL reticulocytes from 25.5% to 3.0% • Sustained hemoglobin normalization from ~7.0 to 14.7 g/dL 24 months --- Norma
Slide 11: Improved QoL by FACT-Anemia
Preliminary Results Indicate Improved Quality of Life by FACT-Anemia over 24 months subsequent to RP-L301 therapy Pre-treatment Post-treatment Total Score increase (↑QoL) at 24 months compared to Pre-conditioning : 55 L301-006-1001 Trial Outcome Index (TOI) Score (Score range: 0–136) General (G) Sco
Slide 12: Improved QoL by SF-36
Preliminary Results Indicate Improved Quality of Life by SF-36 over 24 months subsequent to RP-L301 therapy Pre-treatment Post-treatment L301-006-1001 RAND 36-Item Short Form (SF-36) generic quality-of-life measures: Physical functioning Improved QoL Role functioning/physical Role functioning/emotio
Slide 13: Safety Profile of RP-L301 appears highly favorable
Safety Profile of RP-L301 appears highly favorable • Hematopoietic stem and progenitor cell mobilization and collection appears safe and feasible in the initial adult patients with severe PKD • Hematopoietic reconstitution occurred within 2 weeks post RP-L301 administration - Infusion well tolerated
Slide 14: Conclusions
Conclusions • Clinical efficacy and safety data indicate that RP-L301 is a potential treatment for patients with severe PKD, including those who did not derive benefit from available therapies (i.e. mitapivat) • Investigational product RP-L301 was successfully manufactured ◦ Liquid culture VCNs >2.0
Slide 15: Acknowledgements
Acknowledgements José Luis Lopez Lorenzo, MD Lucía Llanos, MD, PhD Maria Grazia Roncarolo, MD Bert Glader, MD, PhD Susana Navarro, PhD Begoña Pérez Camino de Gaisse, MD May Chien, MD José-Carlos Segovia, PhD Sol Sanchez, MD Javier Cornago, MD Eileen Nicoletti, MD Gayatri R. Rao, MD, JD Grace Choi, B