RP-L301 Continues Favorable Trend in Updated PKD Data

Jonathan Schwartz, MD

The lentiviral-mediated gene therapy RP-L301 demonstrated improvements in hemoglobin (Hb) at 3- and 6-months for the first 2 patients treated in a phase 1 study for pyruvate kinase deficiency (PKD), according to updated preliminary results reported by Rocket Pharmaceuticals, the developer of the therapy.

The first patient enrolled in the study experienced a near doubling in Hb following treatment with the gene therapy. At baseline, this patient had an Hb of 7.4 g/dL, which improved to 13.9 g/dL at a 6-month assessment. There were no transfusions required following hematopoietic reconstitution. In the second patient dosed, a similar Hb trend was observed at 3 months' post-treatment. In this patient, Hb increased from a baseline level of approximately 7.0 g/dL to 13.8 g/dL following infusion of RP-L301.

“The positive updates on our PKD trial represent continued validation of RP-L301’s robust potential benefit in addressing the challenges of PKD," Jonathan Schwartz, MD, chief medical officer and senior vice president of Rocket, said in a statement. "We are excited to share this data as results show the potential of RP-L301 to address the extensive burden PKD places on patients and their families. We look forward to presenting more comprehensive and updated data at a scientific venue this year.”

PKD is a monogenic red blood cell disorder caused by a mutation in the PKLR gene. This alteration leads to disruptions in the red cell pyruvate kinase activity and erythrocyte metabolism. The main manifestation of the disease is anemia; however, reticulocytosis, splenomegaly, and iron overload from repeat transfusions are also common. 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.

The study was designed for initial safety evaluation in an adult cohort of 2 patients with PKD. Once this portion of the study is cleared, 2 additional cohorts will begin recruiting. The first will enroll 2 adolescent patients aged 12 to 17 and the second will include 2 pediatric patients age 8-11. All patients must have a confirmed PKLR mutation.

Following manufacturing, the first patient received RP-L301 at 3.9x10⁶ cells/kg and the second was dosed with 2.4x10⁶ cells/kg. With additional follow-up and a second patient enrolled, RP-L301 continued to show signs of tolerability. There were no serious adverse events (SAEs) or infusion-related complications. Both patients entered the study with elevated bilirubin counts. Following treatment with the gene therapy, the first patient saw significant improvement and the second patient experienced a normalization in levels.

Preliminary findings were also announced at the ASH annual meeting for the first patient with PKD infused with RP-L301. The peripheral blood VCN was 2.21 copies per genome at 1 month. In the 3-month data, this individual had an Hb level of 14.3 g/dL and the treatment was well-tolerated with no SAE or AEs. At the 6-month mark, the Hb was 13.9 g/dL, suggesting stabilization and persistence of response from 3 to 6 months.

The primary end point of the phase 1 study is the assessment of safety and toxicity with RP-L301. Secondary end points focus on genetic correction of the PKLR gene, transfusion independence or a reduction of 50% in transfusion requirements, a clinically significant decline in anemia (defined as an increase of 1.5 g/dL from baseline or a 2-fold improvement from nadir), and a reduction of hemolysis (NCT04105166).