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J2 - Cell Therapy and Cell-Based Gene Therapy Trails

4: Gene Therapy for Adult and Pediatric Patients with Severe Pyruvate Kinase Deficiency: Results from a Global Study of RP-L301

Type: Oral Abstract Session

Presentation Details
Session Title: Clinical Trials Spotlight Symposium

Pyruvate kinase deficiency (PKD) is a rare hemolytic anemia caused by PKLR gene mutations. Manifestations include anemia, splenomegaly and iron overload, which may be life-threatening. Current treatments are limited to chronic blood transfusions, iron chelation and splenectomy which are associated with significant side effects, or PK activators. A Phase 1 trial (NCT04105166) is evaluating lentiviral (LV)-mediated hematopoietic stem and progenitor cell (HSPC)-targeted gene therapy (RP-L301) in splenectomized patients with severe PKD (Hb < 8g/dL and/or transfusion-dependent anemia). Following apheresis, HSPCs were transduced with LV vector and cryopreserved, in part for analysis of the drug product. Myeloablative therapeutic drug monitoring-guided busulfan was administered prior to RP-L301 IV infusion. Follow-up was 2 years to assess safety (including insertion site analysis [ISA]) and efficacy (genetic correction, transfusion requirements, anemia and hemolysis markers), followed by a long-term follow-up study. As of November 2023, two adult and two pediatric patients have received RP-L301. All achieved neutrophil engraftment by day 15. Genetic correction (PB VCN up to 2.0) was observed in all patients. The adults demonstrated sustained Hb normalization and transfusion independence up to the latest follow-up visit (36 months). Concurrent improvement in anemia and hemolysis markers (bilirubin, haptoglobin, reticulocytes, and erythropoietin) were observed. Both adult patients reported improved quality of life (increased FACT-An and SF-36 scores, with marked improvement in SF-36 energy/fatigue, physical functioning, and general health domains). The pediatric cohort (with ≤9 months of follow up), had Hb improvement relative to pre-treatment baseline. No patients required transfusions following engraftment. No serious adverse events are attributed to RP-L301. PB ISA analyses up to 36 months follow-up indicate highly polyclonal patterns; longitudinal results delineating clonal diversity will be presented. RP-L301 is a potential treatment for patients with severe PKD, including those who did not derive benefit from available therapies (including splenectomy and mitapivat). Robust and sustained efficacy up to 36 months post-treatment is demonstrated by normalized Hb (adult cohort) and clinically significant Hb increases (pediatric cohort) with both cohorts demonstrating improved hemolysis parameters, with no transfusion requirements after engraftment.

Ami Shah1,2,3, Julián Sevilla4,5, Jóse Luis López Lorenzo6,7, Susana Navarro5,7,8, Lucía Llanos6,7, Belgoña Pérez de Camino Gaisse6,7, Sol Sanchez6,7, Josune Zubicaray4, Bert Glader2,3, May Chien2,3, Oscar Quintana Bustamante5,7,8, Marta Gonzalez Vicent4,5, June Iriondo4,5, Michael Rothe9, Philipp John-Neek9, Antonella Bastone9, Axel Schambach9, Miriam Zeini10, Grace Choi10, Eileen Nicoletti10, Gayatri Rao10, Maria-Grazia Roncarolo1,2,3, Juan A. Bueren5,7,8, Jonathan Schwartz10, Jose-Carlos Segovia5,7,8

1Ctr Definitive and Curative Med, Stanford Univ, Stanford, CA,2Dept Pediatrics, Div of Hematol Oncol Stem Cell Transplant Regenerative Med, Stanford Univ Sch Med, Stanford, CA,3Lucile Packard Children’s Hosp, Palo Alto, CA,4Hematol y Hemoterapia, Fundación Invest Bioméd, Hosp Infantil Univ Niño Jesús (HIUNJ), Madrid, Spain,5Ctr Invest Bioméd en Red de Enfermedades Raras (CIBERER), Madrid, Spain,6Hosp Univ Fundación Jiménez Díaz, Inst Invest Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain,7Unidad Mixta Terapias Avanzadas, Inst Invest Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain,8Unidad Innovación Bioméd, Ctr Invest Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain,9Hannover Med Sch, Hannover, Germany,10Rocket Pharmaceuticals, Cranbury, NJ"

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