Graphite Bio Drops Lead Sickle Cell Gene-Edited Cell Therapy

Graphite Bio is discontinuing development of its lead program, the sickle cell disease (SCD) gene therapy nulabeglogene autogedtemcel (nula-cel; formerly known as GPH-101), and will instead seek a partnership agreement for external development of the therapy.¹

“We believe that gene correction is the optimal way to treat SCD and many other genetic diseases. However, after an extensive assessment of the nula-cel program, we made the difficult decision to discontinue nula-cel development based on the time and resources needed to resume the CEDAR study and the evolving treatment landscape for sickle cell disease,” Josh Lehrer, MD, chief executive officer, Graphite Bio, said in a statement.¹ “We remain deeply grateful to the patients, investigators and study staff for their participation in CEDAR, to the sickle cell community for their partnership and to our entire Graphite Bio team for their commitment and dedication to our company.”

Nula-cel is gene-edited, autologous hematopoietic stem cell therapy designed to precisely correct the SCD-causing beta-globin gene mutation and suppress the production of sickle hemoglobin while restoring levels of healthy adult hemoglobin. The therapy is being evaluated in the phase 1/2 CEDAR clinical trial (NCT04819841). CEDAR had enrolled 15 participants with SCD and the first patient was dosed in August 2022.²

The discontinuation announcement comes less than 2 months after Graphite Bio voluntarily paused the CEDAR trial after the first patient dosed experienced an unexpected serious adverse event (SAE) of prolonged pancytopenia deemed likely to be related to the treatment, although the FDA did not elect to halt the trial based on the SAE.³ This patient required ongoing transfusion and growth factor support although they did achieve neutrophil engraftment with no signs of myelodysplasia.

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“The safety of every patient who participates in our clinical studies and is treated with our therapies is our absolute highest priority,” Lehrer said in a statement at that time.³ “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.”

Graphite also announced a corporate restructuring program that, along with other initiatives, will roughly cut its workforce in half “to reduce cash burn”.¹ The company has not yet detailed plans for other therapies in its pipeline as part of its strategic realignment. These therapies include the gene replacement therapy GPH-102 for beta-thalassemia in investigational new drug application-enabling studies and its gene insertion candidate for alpha-1 antitrypsin deficiency in discovery studies. Graphite did state that it will continue research for its discovery-stage non-genotoxic conditioning program for hematopoietic stem cell transplantation, which has potential applications in cell therapy treatments.

REFERENCES

1. Graphite Bio announces process to explore strategic alternatives and corporate restructuring. News release Graphite Bio. Februrary 22, 2023. https://www.biospace.com/article/releases/graphite-bio-announces-process-to-explore-strategic-alternatives-and-corporate-restructuring/?keywords=Graphite+Bio
2. Graphite Bio doses first patient with investigational gene editing therapy GPH101 for sickle cell disease. News release. Graphite Bio, Inc. August 11, 2022. https://ir.graphitebio.com/press-releases/detail/76/graphite-bio-doses-first-patient-with-investigational-gene
3. Graphite Bio announces voluntary pause of phase 1/2 CEDAR study of nulabeglogeneautogedtemcel (nula-cel) for sickle cell disease. News release. Graphite Bio, Inc. January 5, 2023. https://ir.graphitebio.com/press-releases/detail/84/graphite-bio-announces-voluntary-pause-of-phase-12-cedar