Serious Side Effect Sidelines Gene-Edited Sickle Cell Therapy from Graphite Bio

Graphite Bio’s ambitions to use gene-editing to cure sickle cell disease have hit a setback. The first patient dosed with the experimental therapy has developed a serious blood complication, leading the company to pause the clinical trial.

The problem, which Graphite Bio characterized as a “serious and unexpected adverse event,” is pancytopenia, a decrease in blood cell counts. This complication required treatment with blood transfusions and growth factors to boost those counts. The FDA has been notified of the complication, which the company said is likely related to its experimental treatment. Even though the regulator has not placed a clinical hold on the study, South San Francisco-based Graphite Bio is stopping it for now as it continues to assess the adverse event.

“While the event did not meet study stopping requirements, based on evolving clinical data, Graphite Bio decided to voluntarily pause the study,” the company said in its announcement after Thursday’s market close.

Sickle cell disease stems from a genetic mutation that leads red blood cells to take on a crescent shape that slows or blocks blood flow and leads to anemia among other problems. Drugs are available to treat the disorder. Oxbryta, developed by Global Blood Therapeutics (acquired last year by Pfizer for $5.4 billion) addresses a root cause of the disease but this small molecule drug must be taken chronically. Graphite Bio is one of several biotech companies developing genetic medicines intended to be one-time treatments for sickle cell disease.

The Graphite Bio therapy, nulabeglogene autogedtemcel (nula-cel), is made by the ex vivo editing of a patient’s hematopoietic stem cells to correct the mutation that causes sickle cell disease. Those CRISPR-edited cells are then infused back into the patient. By replacing enough of a patient’s hematopoietic stem cells with these gene-corrected cells, this approach is hoped to lead to a cure of the blood disorder.

The Phase 1/2 study of nula-cel enrolled its first patient last August. Despite the reported blood complication in that patient, Graphite Bio pointed to some encouraging signs for its therapy. This patient achieved neutrophil engraftment, the production of new white blood cells that is an indication the procedure worked. The company also noted that there were no signs of myelodysplasia, a rare blood cancer.

However, the clinical trial pause means Graphite Bio will miss its mid-year target for providing initial human proof-of-concept data for nula-cel. The setback also affects another program in the company’s pipeline. Graphite Bio said it no longer expects to file an investigational new drug application in mid-2024 for GPH102, a gene-editing therapy for the rare blood disorder beta thalassemia.

Graphite Bio said it is working to “identify operational efficiencies” to extend its cash position at least until 2026, language that typically portends layoffs or a corporate restructuring. The company said it will provide a business update by the end of the current quarter. Graphite Bio’s stock price opened Friday at $1.62, down 47% from Thursday’s closing price. For context, the biotech’s $238 million IPO in 2021 was priced at $17 per share.

Photo by Flickr user Ed Uthman via a Creative Commons license