Nula-cel is intended to directly correct the mutation that causes sickle cell disease.
The first patient in Graphite Bio’s phase 1/2 clinical trial (CEDAR; NCT04819841) for GPH101, an investigational sickle cell disease (SCD) gene editing therapy now known as nulabeglogene autogedtemcel (nula-cel), has been dosed.1 Nula-cel is an autologous CD34+ hematopoietic stem cell (HSC) therapy intended to directly correct the mutation that causes SCD, thus reducing the production of sickle hemoglobin (HbS) and increasing the production of adult hemoglobin (HbA).
“For decades, the goal of gene editing has been to precisely correct genetic mutations that cause disease,” Josh Lehrer, MD, chief executive officer, Graphite Bio, said in a statement.1 “Today, we took an important step toward achieving that goal by dosing our first patient with nula-cel, the first investigational therapy designed to correct a mutated gene to normal. This first use of high-efficiency precision DNA repair to correct a genetic mutation is an important milestone not only for our company but also for the gene editing field and, hopefully, for the sickle cell community.”
The open-label, multicenter trial aims to enroll around 15 participants aged 12 to 40 years with severe SCD. In order to be included, patients must either have experienced 4 or more episodes of recurrent severe vaso-occlusive crisis (VOC) in the past 2 years or have experienced 2 or more episodes of acute chest syndrome (ACS) in the past 2 years with at least 1 episode in the past year. Participants must additionally have a Lansky/Karnofsky performance status of 80 or greater. Patients who have an available 10/10 HLA-matched sibling donor or who have previously received HSCT or gene therapy will be excluded from the study, along with those who have a prior or current malignancy, myeloproliferative, significant coagulation, or immunodeficiency disorder.
Patients will receive a single dose of nula-cel via intravenous infusion after a myeloablative conditioning regimen. The primary end points are the proportion of patients who attain neutrophil engraftment in 42 days, incidence rates of treatment-related mortality at 100 days and 12 months post-infusion, overall survival at 24 months, and frequency and severity of adverse events and serious adverse events. Secondary end points include time to neutrophil engraftment, time to platelet engraftment, and evaluations of gene correction levels in peripheral myeloid cells, HbA as a percentage of total hemoglobin (Hgb), and HbS as a percentage of total Hgb. Total Hgb without disease-indicated transfusion support, the change in annualized packed red blood cell transfusion requirements for SCD indications, the proportions of patients achieving complete resolution of severe VOCs and HbS levels of less than 50% for at least 3 months, and the incidence rate of severe VOCs will also be examined.
“We continue to make tremendous progress with the development of nula-cel, which in preclinical studies successfully corrected the sickle cell disease mutation, directly reducing sickle hemoglobin and restoring healthy adult hemoglobin to potentially curative levels,” Lehrer added to the statement.1 “We believe nula-cel could be a definitive cure for sickle cell disease, with the potential to address all complications associated with this life-threatening disease. We look forward to reporting initial proof-of-concept data from the CEDAR trial in mid-2023.”
Nula-cel previously received FDA fast track designation in May 2022 and FDA orphan drug designation in late 2021. The investigational therapy was developed using Graphite’s next-generation targeted gene integration platform, which relies on Cas9 technology and a non-integrating DNA template to correct the mutation in the β-globin gene through the homology-directed repair cellular pathway.
Earlier this year, Lehrer spoke with CGTLive to share more details about the CEDAR trial in SCD as well as Graphite’s other pipeline targets, including therapies for β-thalassemia and Gaucher disease. Click here to watch the interview.