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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rocket Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

4 Nov 2019 → 10 Jun 2025

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511520-13-00

EudraCT number

2019-001656-19

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety

The primary objective of trial Phase 1 is to characterize the safety and
toxicity associated with infusion of the investigational product:
autologous CD34+ cells transduced with the therapeutic LV, PGK-coRPK-WPRE.

Conditions and MedDRA coding

Inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-003650-PIP01-24

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1. PKD diagnosis with a confirmed PKLR mutation. 2. Patient age at enrollment as follows: a. Adult Cohort (n=2): Age ≥18 years and ≤50 years. b. Pediatric Cohort (n=2-3): Age ≥8 to <18 years 3. History of severe and/or transfusion-dependent anemia, defined as: a. At least 6 RBC transfusion episodes over a prior 12-month period and Hb levels <9.5 g/dL in the previous 1 months despite prior splenectomy OR b. At least 3 RBC transfusion episodes per year over 2 prior years and Hb levels <9.5 g/dL in the previous 12 months despite prior splenectomy OR c. Hb levels <8.0 g/dL despite prior splenectomy in the absence of transfusions (documented during 2 or more assessments during the prior 1–-2 years) regardless of transfusion requirements. 4. Adequate cardiac, pulmonary, renal and hepatic function, as detailed in relevant exclusion criteria. 5. Availability of detailed medical records, including transfusion requirements, for at least the prior 2 years. 6. Willing and able to read and correctly understand the patient information sheet and provide consent (or informed assent for minors) regarding study participation. 7. Negative serum pregnancy test for female patients of childbearing potential.

Exclusion criteria 1

1. 1. Presence of other known causes of hemolysis (in addition to 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 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. Any evidence of severe iron overload that, per Investigator discretion, warrants exclusion. 4. Evidence of bridging fibrosis, cirrhosis or active hepatitis on liver biopsy. Liver biopsy is required when liver iron concentration (LIC) is ≥ 15 mg/g on T2* magnetic resonance imaging (MRI) of liver. If a liver biopsy has been performed less than 6 months prior to enrollment, it does not need to be repeated. 5. Significant medical conditions including documented HIV infection, active viral hepatitis, poorly-controlled hypertension, pulmonary hypertension, cardiac arrhythmia or congestive heart failure; or ATEs (including stroke or myocardial infarction) within the 6 prior months. 6. Active hematologic or solid organ malignancy, not including nonmelanoma 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. 7. Uncontrolled seizure disorder. 8. Cardiac T2* <10 ms by magnetic resonance imaging (MRI) or left ventricular ejection fraction (LVEF) <45% by echocardiogram or multiple gated acquisition scan (MUGA). 9. Hepatic dysfunction as defined by: • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × the upper limit of normal (ULN). 10. Renal dysfunction defined as serum creatinine >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, the revised Schwartz formula (for patients under 18 years old), or 24-hour urine collection. 11. Pulmonary dysfunction as defined by either: • Need for supplemental oxygen during the prior 2 weeks (in absence of acute infection) or • Oxygen saturation (by pulse oximetry) <90%. 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 adults or Lansky <70 in children. 15. Participation in another clinical trial with an investigational drug within 14 days before the informed consent signature. Participation in observational studies is allowed. 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. Women not willing to use highly effective contraceptive methods during the complete study period.* 17. Previous allogeneic or other hematopoietic stem cell transplant * Females of childbearing age potential and male patients with partners of childbearing potential must use highly effective contraceptive measures (according to Clinical Trials Facilitation Group recommendations).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1.Insertional mutagenesis:Evaluation of gene-modified clonal repertoire and lentiviral ISA in blood and, if feasible, BM cells via modified gene sequencing (MGS)-PCR. 2.RCL (as required and in settings where there is clinical suspicion of unexplained viral illness) in blood. 3. Immunogenicity: Evidence of antibodies against coRPK (or other LV components) in blood (serum)

Secondary endpoints 1

1. *Achievement of stem cell engraftment ≤42 days after infusion. Neutrophil engraftment is defined as the first of three consecutive days with an absolute neutrophil count ≥500/μL. Platelet engrafment is defined as the first of three consecutive days with a platelet count ≥ 20,000/μL in the absence of thrombopoietin mimetics and independent of platelet transfusions for at least 7 days. *Time to stem cell engraftment. *Incidence of respiratory complications

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rocket Pharmaceuticals Inc.

Sponsor organisation

Rocket Pharmaceuticals Inc.

Address

9 Cedarbrook Drive

City

Cranbury

Postcode

08512-3618

Country

United States

Scientific contact point

Organisation

Rocket Pharmaceuticals Inc.

Contact name

Clinical Trials

Public contact point

Organisation

Rocket Pharmaceuticals Inc.

Contact name

Clinical Trials

Third parties 7

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications