Gene therapy is being studied as an approach to therapy for individuals with pyruvate kinase deficiency. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme. PKD recessive inheritance trait and its curative treatment by allogeneic bone marrow transplantation provide an ideal scenario for developing gene therapy approaches.

RP-L301 is a lentiviral vector (LVV)-based gene therapy for the treatment of Pyruvate Kinase Deficiency (PKD) and it represents the first gene therapy candidate in development for PKD.

A Phase I 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).

During the EHA 2024 conference, Interim results from this global study of RP-L301 were presented.

Preliminary Interim results from an ongoing clinical trial with data cut-off as of February 5, 2024, reveal that RP-L301 has demonstrated significant clinical benefits in patients with severe PKD. These include sustained normalization of hemoglobin levels for up to 36 months and achievement of transfusion independence in all patients. In the adult cohort, RP-L301 improved quality of life metrics such as SF-36 scores, particularly in physical functioning, energy levels, and general health perception, up to 36 months. Hemolysis parameters also showed concurrent improvement. 

L301-006-1001: Integration Site Abundance Over Time:

• Top 10 integrations accounted for <5% of all identified UISS through 36 months

• Representative data from one patient; similar highly polyclonal insertion patterns identified in other adult patient with available longitudinal follow up

• No clonal dominance or insertional mutagenesis observed

• Pediatric patients more recently treated; ISA testing ongoing

The infusion of RP-L301 was well tolerated, with no RP-L301-related serious adverse events reported up to 36 months post-infusion. Analysis of insertion sites in peripheral blood and bone marrow indicated highly polyclonal patterns without evidence of clonal dominance or insertional mutagenesis throughout the 36-month period post-RP-L301 administration. 

KOL insights

“The positive updates on PKD trial represent continued validation of RP-L301’s robust potential benefit in addressing the challenges of PKD. RP-L301 consists of autologous hematopoietic stem cells harvested by leukapheresis and transduced with a lentiviral vector for a correct copy of the deficient PKLR gene. Once modified, the corrected stem cells are infused into the patient,” – MD, United States.

Conclusion 

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. PKD has an estimated prevalence of 4,000 to 8,000 patients in the US and Europe. Patients with PKD have a high unmet medical need, as currently available treatments include splenectomy and red blood cell transfusions, which are associated with immune defects and chronic iron overload. Recently, mitapivat, an oral enzyme activator, was approved for use in adult patients, however its efficacy is limited in more severely-afflicted patients, most notably in those who are splenectomized, transfusion-dependent, or whose disease results from deleterious mutations.

RP-L301, a promising treatment for PKD, has demonstrated sustained and clinically significant improvements in hemoglobin levels across all patients for up to 36 months post-therapy. Notably, hemoglobin levels get normalized in 3 out of 4 patients, ranging from 12.9 g/dl to 13.7 g/dl. Following neutrophil engraftment, no patients required red blood cell transfusions. Additionally, there was a reduction in hemolysis and reported improvements in quality of life. Infusions were well tolerated without any serious adverse events (SAEs) reported to date, including no SAEs related to the product. The busulfan conditioning regimen was well tolerated, with neutrophil engraftment achieved by day +15 in all patients, leading to hospital discharge within one month post-therapy. Activation of Phase 2 trial is underway.

Rocket Pharmaceuticals Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for RP-L301 Gene Therapy for Pyruvate Kinase Deficiency (PKD). RMAT designation was granted based on robust safety and efficacy data from the ongoing Phase 1 RP-L301 clinical trial and its potential to cure a life-threatening disease for which no curative therapies currently exist.