Pyruvate Kinase Deficiency
Conditions
Brief summary
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).
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.
Interventions
BIOLOGICALRP-L301
Autologous genetically modified CD34+ hematopoietic stem cells containing the corrected PKLR (Pyruvate Kinase L/R) gene
Sponsors
Rocket Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 55 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Anemia | 12 months post-infusion | Hemoglobin (Hb) level increase of ≥1.5g/dL at 12 months post-infusion, compared to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Durability Improvement anemia sustained | 24 months post-infusion | Time to Hemoglobin level increase of ≥1.5g/dL post-infusion, compared to baseline. |
| Resolution of anemia | 12 months post-infusion | Hemoglobin level within normal range (≥ lower limit of normal) at 12 months post-infusion. |
| Reduction of transfusion requirements | 12 months post-infusion | * 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. |
| Improvements of hemolysis parameters (bilirubin) | 12 months post-infusion | Improvements in bilirubin, each evaluated at 12 months post-infusion, compared to baseline. |
| Improvements of hemolysis parameters (Lactate Dehydrogenase (LDH)) | 12 months post-infusion | Improvements in Lactate Dehydrogenase (LDH), each evaluated at 12 months post-infusion, compared to baseline. |
| Improvements of hemolysis parameters (erythropoietin) | 12 months post-infusion | Improvements in erythropoietin, each evaluated at 12 months post-infusion, compared to baseline. |
| Improvements of hemolysis parameters (reticulocyte) | 12 months post-infusion | Improvements in reticulocyte, each evaluated at 12 months post-infusion, compared to baseline. |
| Peripheral blood genetic correction | 12 months post-infusion | Genetic correction demonstrated by vector copy number (VCN) of 0.1 in Peripheral Blood mononuclear cells, evaluated at 12 months post-infusion. |
| Improvement in fatigue | 12 months post-infusion | Improvement in fatigue as compared with baseline, as assessed by: * Age ≥18: FACIT Fatigue; or, * Age \<18: PROMIS Fatigue Short Form 10a |
| Improvement in dyspnea | 12 months post-infusion | Improvement in Pyruvate Kinase Deficiency symptoms, compared with baseline, as assessed by: * PROMIS Dyspnea Severity SF10; or, * Dyspnea severity |
| Improvement in jaundice | 12 months post-infusion | Improvement in Pyruvate Kinase Deficiency symptoms, compared with baseline, as assessed by: * jaundice severity evaluated at 12 months post-infusion; or, * and jaundice severity |
| Safety and tolerability of RP-L301 | 24 months post-infusion | 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). |
| Evaluate durable resolution of anemia | 24 months post-infusion | Hemoglobin (Hb) level within normal range (≥ lower limit of normal). |
| Evaluate durable resolution of transfusion requirements (where relevant). | 24 months post-infusion | 1. ≥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, 2. Absence of PKD-related RBC transfusion requirements in the 24 months post-infusion. |
Countries
Spain, United States
Contacts
PRINCIPAL_INVESTIGATORAmi Shah, MD
Stanford University
PRINCIPAL_INVESTIGATORJulian Sevilla Navarro, MD, PhD
Hospital Infantil Universitario Niño Jesús
PRINCIPAL_INVESTIGATORJosé Luis López Lorenzo, MD
Hospital Universitario Fundación Jiménez Díaz
STUDY_DIRECTORMaria Chitty-Lopez, MD
Rocket Pharmaceuticals Inc.
Outcome results
None listed