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

A Phase 2 Clinical Trial to Evaluate the Efficacy of the Infusion of Autologous CD34+ Cells Transduced With a Lentiviral Vector Carrying the Codon Optimized Red Cell Pyruvate Kinase (coRPK) Gene in Subjects With Pyruvate Kinase Deficiency

This is an open-label Phase II trial to evaluate the efficacy of a hematopoietic cell-based gene therapy for patients with Pyruvate Kinase Deficiency (PKD).

Study Overview

• Status: Suspended
• Conditions: Pyruvate Kinase Deficiency
• Intervention / Treatment: Biological: RP-L301

Detailed Description

Autologous hematopoietic stem cells from mobilized peripheral blood will be transduced ex vivo (outside the body) with a lentiviral vector carrying a correct copy of the deficient PKLR (Pyruvate Kinase L/R) gene. The corrected stem cells will be infused intravenously back into the patient to correct the hematological manifestations of the disease.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28009
    • Hospital Infantil Universitario Niño Jesús
  • Madrid, Spain
    • Hospital Universitario Fundacion Jimenez Diaz
• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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
5. Adequate cardiac, pulmonary, renal and hepatic function, as detailed in relevant exclusion criteria
6. Availability of detailed medical records, including accurate transfusion history and blood count assessments, for the prior 2 years
7. Willing and able to read and correctly understand the patient information sheet and provide consent (or informed assent for minors) regarding study participation, willing and able to comply with all study-related procedures including follow-up visits.
8. Negative serum pregnancy test for female subjects of childbearing potential.

Exclusion Criteria

1. Presence of other known causes of hemolysis (in addition to Pyruvate Kinase Deficiency (PKD)). Patients with concurrent G6PD deficiency diagnosed during pre-study evaluation may be considered for eligibility if in the opinion of the Investigator, the hemolytic anemia is the result of PKD and the Glucose-6-phosphate dehydrogenase (G6PD) deficiency is considered an incidental finding.
2. A venous thromboembolic event (VTE; i.e., pulmonary embolism or deep vein thrombosis) or arteriothromboembolic event (ATE; including unstable angina, myocardial infarction, stroke or transient ischemic attack) during the prior 12 months.

3. Evidence of bridging fibrosis, cirrhosis or active hepatitis on liver biopsy.

   1. Liver biopsy is required when liver iron concentration (LIC) is ≥15 mg/g on T2* magnetic resonance imaging (MRI) of liver.
   2. If a liver biopsy has been performed less than 6 months prior to enrollment, it does not need to be repeated.
4. Cardiac T2* <10 ms by magnetic resonance imaging (MRI) or left ventricular ejection fraction (LVEF) <45% by echocardiogram or multiple gated acquisition scan (MUGA).
5. Any evidence of severe iron overload beyond parameters stipulated in exclusion criteria 3 and 4 that, per Investigator discretion, warrants exclusion.
6. Significant medical conditions including documented HIV (human immunodeficiency virus) infection, active viral hepatitis, poorly controlled hypertension, pulmonary hypertension, cardiac arrhythmia or congestive heart failure; or arteriothromboembolic events (ATEs) (including stroke or myocardial infarction) within the 12 prior months.
7. Active hematologic or solid organ malignancy, not including non-melanoma skin cancer or another carcinoma in situ. Patients with previously resected solid organ malignancies or definitively treated hematologic malignancies may be eligible if there has been no evidence of active malignancy during the prior 3 years.
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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participant Group/Arm; RP-L301 is a gene therapy product containing autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKLR (Pyruvate Kinase L/R) gene	Biological: RP-L301; Autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKLR (Pyruvate Kinase L/R) gene; Other Names: Intervention/Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Anemia	Hemoglobin (Hb) level increase of ≥1.5g/dL at 12 months post-infusion, compared to baseline.	12 months post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Durability Improvement anemia sustained	Time to Hemoglobin level increase of ≥1.5g/dL post-infusion, compared to baseline.	24 months post-infusion
Resolution of anemia	Hemoglobin level within normal range (≥ lower limit of normal) at 12 months post-infusion.	12 months post-infusion
Reduction of transfusion requirements	a: ≥50% reduction in Pyruvate Kinase Deficiency (PKD)-related Red Blood Cells (RBC) transfusion requirements in the 12 months post-infusion, relative to the annualized event rate for 24 months prior to enrollment; or,; b: Absence of PKD-related RBC transfusion requirements in the 12 months post-infusion.	12 months post-infusion
Improvements of hemolysis parameters (bilirubin)	Improvements in bilirubin, each evaluated at 12 months post-infusion, compared to baseline.	12 months post-infusion
Improvements of hemolysis parameters (Lactate Dehydrogenase (LDH))	Improvements in Lactate Dehydrogenase (LDH), each evaluated at 12 months post-infusion, compared to baseline.	12 months post-infusion
Improvements of hemolysis parameters (erythropoietin)	Improvements in erythropoietin, each evaluated at 12 months post-infusion, compared to baseline.	12 months post-infusion
Improvements of hemolysis parameters (reticulocyte)	Improvements in reticulocyte, each evaluated at 12 months post-infusion, compared to baseline.	12 months post-infusion
Peripheral blood genetic correction	Genetic correction demonstrated by vector copy number (VCN) of 0.1 in Peripheral Blood mononuclear cells, evaluated at 12 months post-infusion.	12 months post-infusion
Improvement in fatigue	Improvement in fatigue as compared with baseline, as assessed by: Age ≥18: FACIT Fatigue; or,; Age <18: PROMIS Fatigue Short Form 10a	12 months post-infusion
Improvement in dyspnea	Improvement in Pyruvate Kinase Deficiency symptoms, compared with baseline, as assessed by: PROMIS Dyspnea Severity SF10; or,; Dyspnea severity	12 months post-infusion
Improvement in jaundice	Improvement in Pyruvate Kinase Deficiency symptoms, compared with baseline, as assessed by: jaundice severity evaluated at 12 months post-infusion; or,; and jaundice severity	12 months post-infusion
Safety and tolerability of RP-L301	Incidence, type, severity, frequency, time to onset, and duration of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), clinical laboratory abnormalities, and adverse events of special interest (AESIs).	24 months post-infusion
Evaluate durable resolution of anemia	Hemoglobin (Hb) level within normal range (≥ lower limit of normal).	24 months post-infusion
Evaluate durable resolution of transfusion requirements (where relevant).	≥50% reduction in Pyruvate Kinase Deficiency (PKD)-related Red Blood Cell (RBC) transfusion requirements in the 24 months post-infusion, relative to the annualized event rate for 24 months prior to enrollment; or,; Absence of PKD-related RBC transfusion requirements in the 24 months post-infusion.	24 months post-infusion

Collaborators and Investigators

• Sponsor: Rocket Pharmaceuticals Inc.
• Investigators: Principal Investigator: Julian Sevilla Navarro, MD, PhD, Hospital Infantil Universitario Niño Jesús; Principal Investigator: José Luis López Lorenzo, MD, Hospital Universitario Fundacion Jimenez Diaz; Principal Investigator: Ami Shah, MD, Stanford University; Study Director: Maria Chitty-Lopez, MD, Rocket Pharmaceuticals Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: May 15, 2024
• First Submitted That Met QC Criteria: May 15, 2024
• First Posted (Actual): May 21, 2024

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 15, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Pyruvate Kinase Deficiency of Red Cells; Investigative Techniques; Methods; Therapeutics
• Other Study ID Numbers: RP-L301-0124

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No