Pyruvate Kinase Deficiency Gene-Edited Cell Therapy Sustains Hemoglobin Normalization

Neither patient treated with RP-L301 required RBC transfusions at any point post-engraftment.

RP-L301, a gene-edited lentiviral mediated hematopoietic stem and progenitor cell (HSPC) therapy, has demonstrated normalization of hemoglobin levels in 24-month follow-up data from 2 patients with pyruvate kinase deficiency (PKD) treated in a phase 1 clinical trial (NCT04105166). Interim results were presented in a poster at the 2023 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in Orlando, Florida, February 15-19, 2023.

The 2 treated patients included L301-006-1001, a 31 year old female patient, and L301-001-1002, a 47 year old male patient. L301-006-1001 achieved sustained hemoglobin normalization to 13.2 g/dL at 24 months post-treatment, up from a baseline of ~7.4 g/dL. Similarly, L301-001-1002 achieved sustained hemoglobin normalization to 14.7 g/dL at 24 months, up from a baseline of ~7.0 g/dL. In addition, neither patient required red blood cell (RBC) transfusions at any point post-engraftment. Both patients anecdotally reported improvements in quality of life (QoL) after treatment, and the patients’ scores improved on the SF-36 QoL survey over 24 months, with substantial improvements noted for physical functioning, energy/fatigue, and general health components. By 24 months, L301-006-1001 additionally showed a significant decrease in bilirubin levels from 13.4 mg/dL at baseline to 1.1 mg/dL, sustained improvements in reticulocytes from 49.5% to 2.5%, haptoglobin levels remaining in the normal range, and continued erythropoietin normalization. Meanwhile, by 24 months L301-001-1002 showed normalization of bilirubin levels from 7.4 mg/dL at baseline to 0.9 mg/dL, significant improvement in reticulocytes from 25.5% to 3.0%, sustained haptoglobin normalization, and a significant decrease in erythropoietin levels.

In terms of safety, no serious adverse events related to RP-L301 had been reported at 24 months post-treatment. Following conditioning and infusion, transient elevation of transaminase was observed in both patients, which fully resolved with no clinical signs of liver injury. It was noted that neutrophil engraftment was achieved within 2 weeks of RP-L301 infusion. No evidence of insertional mutagenesis was reported.

Both patients have confirmed mutations in the PKLR gene and had previously undergone splenectomy, as per the trial’s eligibility criteria. L301-006-1001 had 14 transfusion episodes in the 2 years prior to enrollment and L301-001-1002 had 5 transfusion episodes in the 2 years prior to enrollment. L301-006-1001 was noted to have a clinical history of multiple infections precipitating hemolytic crises and requiring multiple transfusions and hospitalizations, as well as hepatic iron overload secondary to transfusions and underlying PKD. L301-001-1002 was noted to have a clinical history of severe anemia, though he declined frequent RBC infusions. He also had a history of complications including iron overload and a foot ulcer requiring a skin graft. He had previously received mitapivat without experiencing a significant hemoglobin increase.

Presenting author Gayatri Rao, MD, JD, chief development officer of LVV, Rocket Pharmaceuticals, and colleagues concluded that RP-L301 has potential as a treatment for patients with PKD, including patients who did not attain benefit from currently approved therapies, such as mitapivat. The investigators also noted that hematopoietic stem and progenitor cell collection seemed to be safe and feasible, with RP-L301 being successfully manufactured for both patients. It was also announced that the trial had completed enrollment of its pediatric cohort, and that a phase 2 trial is expected to be initiated later this year.

For more coverage of the 2023 Tandem Meetings, click here.

Shah AJ, López Lorenzo JL, Sevilla J, et al. Lentiviral-Mediated Gene Therapy for Severe Pyruvate Kinase Deficiency: Results from an Ongoing Global Phase 1 Study. Presented at: 2023 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.February 15-19, 2023; Orlando, FL.Abstract 293
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