Sickle Cell Disease Gene-Editing Therapy Trial Voluntarily Paused Following Serious Adverse Event


The first patient dosed in the study experienced a case of prolonged pancytopenia that has required ongoing transfusion and growth factor support.

Graphite Bio has voluntarily paused the phase 1/2 CEDAR clinical trial (NCT04819841) of nulabeglogene autogedtemcel (nula-cel; formerly known as GPH101), an autologous CD34+ hematopoietic stem cell (HSC) gene-editing therapy intended to correct the mutation that causes sickle cell disease (SCD), following an unexpected serious adverse event (SAE) deemed likely to be related to the treatment.1,2

The first patient dosed in the study experienced a case of prolonged pancytopenia that required ongoing transfusion and growth factor support. Graphite Bio reported the SAE to the FDA, and while the company was not required to stop the study, the decision was made to voluntarily pause the trial "based on evolving clinical data.” It was additionally noted that the patient achieved neutrophil engraftment according to the study’s criteria, no indication of myelodysplasia was observed in the patient, and the study’s investigators and the Safety Monitoring Committee supported the company’s decision to pause the trial. Graphite Bio announced that it is performing a comprehensive assessment of the SAE and associated risk factors, as well as investigating modifications to the therapy’s manufacturing process as a potential mitigation strategy. 

“The safety of every patient who participates in our clinical studies and is treated with our therapies is our absolute highest priority,” Josh Lehrer, MD, chief executive officer of Graphite Bio, said in a statement regarding the announcement.1 “We thank the patients enrolled in our study, especially our first patient, for trusting us with their treatment and care. We are committed to working closely with our scientific and clinical experts to fully assess this event and identify a potential path to resume the CEDAR study. We are grateful for the partnership with the sickle cell community, our clinical investigators, our founders and scientific experts, and the FDA as we determine next steps for our nula-cel program in sickle cell disease.”

It was originally announced that the first patient had been enrolled in the CEDAR trial in January of 2022, and the announcement of the first patient’s dosing came in August.2,3 The open-label, multicenter trial aimed to enroll around 15 participants aged 12 to 40 years with severe SCD. Nula-cel previously received FDA fast track designation in May 2022 and FDA orphan drug designation in late 2021.

In addition to nula-cel, Graphite Bio is developing GPH102, a gene-replacement therapy intended to treat beta-thalassemia.1,4 Although Graphite Bio previously intended to file an investigational new drug application for GPH102 by the middle of 2024, the company no longer expects to hold to this timeline in light of activities related to the nula-cel program. The company also has preclinical research programs in the discovery validation phase, including a program for the treatment of alpha-1 antitrypsin (AAT) deficiency via targeted gene insertion, and a program to develop non-genotoxic HSC targeted conditioning regimens.

In April 2022, Lehrer spoke with CGTLive in an interview to share details about the CEDAR trial as well as Graphite Bio’s other pipeline targets, which can be viewed below:

1. Graphite Bio announces voluntary pause of phase 1/2 CEDAR study of nulabeglogene autogedtemcel (nula-cel) for sickle cell disease. News release. Graphite Bio, Inc. January 5, 2023.
2. Graphite Bio enrolls first patient in phase 1/2 clinical trial of GPH101 for sickle cell disease. News release. Graphite Bio. November 17, 2021.
3. Graphite Bio doses first patient with investigational gene editing therapy GPH101 for sickle cell disease. News release. Graphite Bio, Inc. August 11, 2022.
4. Graphite Bio. Pipeline. Website Accessed January 3, 2023.
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