Rocket Pharmaceuticals: Positive Clinical Outcome of Gene Therapy for Pyruvate Kinase Deficiency (PKD)

  Gene Therapy for Pyruvate Kinase Deficiency (PKD) Highlights

- Rocket Pharmaceutical is developing lentiviral ex-vivo gene therapy for the treatment of Pyruvate kinase deficiency
- Preliminary clinical results for RP-L301 Phase 1 study showed a potential path to transform the management of PKD 
- This hematopoietic stem cell therapy approach targets to treat the underlying cause of the disease. 
- Preliminary Data from First Patient Demonstrates Initial Safety and Tolerability of RP-L301, Near Doubling of Hemoglobin to Normal Range and Additional Normalization of Hemolysis Markers

Pyruvate kinase deficiency (PKD) is a rare, monogenic red blood cell disorder resulting from a mutation in the PKLR gene encoding for the pyruvate kinase enzyme, a key component of the red blood cell glycolytic pathway. Mutations in the PKLR gene result in increased red blood cell destruction and the disorder ranges from mild to life-threatening anemia. 

PKD has an estimated prevalence of 3,000 to 8,000 patients in the United States and the European Union. Children are the most commonly and severely affected subgroup of patients. Currently available treatments include splenectomy and red blood cell transfusions, which are associated with immune defects and chronic iron overload.

Gene Therapy for Pyruvate Kinase Deficiency (PKD) (NCT04105166)
Brief Summary:
This is an open-label Phase I trial to evaluate the safety of a hematopoietic cell-based gene therapy for patients with Pyruvate Kinase Deficiency (PKD).
RP-L301 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKD gene. Autologous hematopoietic stem cells from mobilized peripheral blood are transduced ex vivo (outside the body) with a lentiviral vector carrying a correct copy of the deficient PKD gene. The corrected stem cells are infused intravenously back to the patient with the goal of correcting the hematological manifestations of the disease.
Overview of RP-L301 Treatment 
Overview of Study Design
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 6 participants
Intervention Model: Sequential Assignment
Intervention Model Description: Initial safety evaluation will occur in an adult cohort (n=2) patients, followed by pediatric patients ages 12-17 (n=2), and pediatric patients ages 8-11 (n=2).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Gene Therapy for Pyruvate Kinase Deficiency (PKD): A Phase I Clinical Trial to Evaluate the Safety of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the Codon Optimized Red Cell Pyruvate Kinase (coRPK) Gene in Adult and Pediatric Subjects With PKD

Primary Outcome Measures :

  • Evaluation of the safety and toxicity of RP-L301: number of participants with treatment-related adverse events [ Time Frame: 2 years ]. The number of participants with treatment-related adverse events as assessed by United States (US) National Cancer Institute (NCI) v.5.0.

Secondary Outcome Measures :
  • Genetic correction following administration of RP-L301 [ Time Frame: 2 years ]. Evidence of mult-lineage gene correction in peripheral blood (PB) and bone marrow (BM cells) will be assessed by measuring vector copy number
  • Transfusion independence [ Time Frame: 1 year ]. Transfusion independence (when relevant) at 12 months defined as need for less than or equal to 1 red blood cell transfusion in the previous 6 months
  • Reduction in transfusion requirements [ Time Frame: 1 year ]. 50% reduction in transfusion requirements (when relevant) at 12 months (assessed in the previous 6 months for the 12-month assessment) relative to the 1-year period prior to enrollment
  • Clinically significant reduction in anemia [ Time Frame: 2 years ]. Increase in pre-transfusion hemoglobin (Hb) levels of 1.5 g/dL (determined by 2 assessments separated at least three months over the first and second year of follow up) relative to the average of patient's Hb levels before blood transfusions over the year prior to enrollment OR, Increase of at least two-fold in the time to pre-transfusion Hb nadir relative to the average transfusion interval over the year prior to enrollment, where pre-transfusion Hb nadir is defined as the average Hb value (during the year prior to enrollment) prior to red blood cell (RBC) transfusions
  • Reduction of hemolysis [ Time Frame: 1 year ]. Reduction of reticulocytosis, defined as the number of patients with a reduction of 50% from the average of a patient's absolute reticulocyte counts (obtained prior to therapeutic blood transfusions) over the year prior to enrollment at 12 months subsequent to investigational therapy
Key highlights Phase1 Study
  • RP-L301 was well tolerated, with no serious safety issues or infusion-related complications observed 3-months post treatment
  • Patient L301-006-1001 received a cell dose of 3.9x106 cells/kilogram (kg) with a drug product mean vector copy number (VCN) of 2.73
  • Hematopoietic reconstitution in less than 2 weeks
  • Peripheral blood VCN of 2.21 at 1-month, normalized hemoglobin (Hb) and hemolysis markers (baseline Hb ~7.4 grams (g)/deciliter (dL); Hb 14.3 g/dL at 3-months post treatment with RP-L301)
  • No red blood cell transfusion requirements following engraftment
  • In the two years prior to enrollment, the patient underwent approximately 14 transfusion episodes
  • Normalization of bilirubin, lactate dehydrogenase (LDH) and erythropoietin levels at 3-months post treatment, each of which had been substantially elevated prior to study enrollment
  • Patient L301-006-1002 was recently treated with RP-L301
  • The patient received a cell dose of 2.4x106 cells/kg with a mean drug product VCN of 2.08

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