Updated: Sickle cell gene editing startup halts trial after flagging serious side effect in first patient

The first-ever patient to be treated with a new, gene-edited stem cell therapy being developed for sickle cell disease experienced a serious side effect, forcing the drugmaker to halt the trial.

Graphite Bio said it voluntarily paused further dosing in the Phase I/II CEDAR trial after concluding that the serious adverse event is likely related to its therapy, nulabeglogene autogedtemcel (nula-cel). It also reported the event to the FDA.

Specifically, the patient, who was dosed in August, saw prolonged low blood cell counts, or pancytopenia, “requiring ongoing transfusion and growth factor support.”

“The patient remains enrolled in the CEDAR study and continues to receive care and close monitoring from the clinical investigator and study staff,” a spokesperson wrote in response to an Endpoints News inquiry. “We are in close contact with the clinical site and are monitoring the patient’s status. Out of consideration for the patient’s privacy, additional details about the patient cannot be disclosed at this time.”

While the trial is on hold, Graphite Bio said it is taking a thorough look at the adverse event, analyzing risk factors and mitigation strategies — with modifications to the nula-cel manufacturing process also on the table.

Phil Nadeau

“The company’s initial investigation has ruled out common causes of post-transplant pancytopenia such as a viral infection and autoimmunity, leading to the conclusion that it is likely due to treatment with nula-cel itself,” Cowen analyst Phil Nadeau wrote after talking to the execs.

Several other companies have set out to treat sickle cell disease — which is caused by defective red blood cells and marked by painful episodes — via the same approach of editing genes in stem cells and then putting them back into the patient. But while Vertex/CRISPR and Editas seek to fix the problem by activating a fetal hemoglobin gene in cells, Graphite Bio’s idea is to correct the mutated adult hemoglobin using its own set of CRISPR-inspired tools, coming from academic pioneers such as Maria Grazia Roncarolo and Matthew Porteus.

“At the DNA level, we’re making stem cells normal again,” was how CEO Josh Lehrer described the approach back in 2021.

Mani Foroohar

Mani Foroohar of SVB Securities wrote that the company is now investigating whether that fundamental approach could’ve caused the side effect. Other hypotheses include “the quality of the patients’ underlying bone marrow,” Graphite’s technology and its use of AAV6 as a delivery vector.

“Given this number of degrees of freedom in any evaluation, determining the proper remedy with a high enough degree of confidence to drive a return to treating patients will be a prolonged and uncertain process,” he wrote.

While the company had previously hoped to deliver proof-of-concept data from 15 patients in mid-2023, it’s now pushing back that timeline.

Editor’s note: Updated to include comment from Graphite Bio.

fda