The very first patient treated with a new, gene-edited stem cell therapy developed for sickle cell disease suffered a serious side effect that forced the drugmaker to halt the study.
Graphite Bio said it voluntarily withheld further dosing in the Phase I/II CEDAR study after concluding that the serious adverse event was likely related to its therapy, Nula-Beglogene Autogedtemcel (Nula-Cel). It also reported the event to the FDA.
In particular, the patient who was dosed in August saw persistently low blood cell counts or pancytopenia “which required continuous transfusion and growth factor support.”
“The patient remains enrolled in the CEDAR study and will continue to be cared for and closely monitored by the clinical investigator and study staff,” a spokesperson wrote in response to a query from Endpoints News. “We are in close contact with the clinical site and are monitoring the patient’s condition. Out of respect for patient privacy, no further details about the patient can be released at this time.”
While the study is suspended, Graphite Bio is thoroughly investigating the adverse event, analyzing risk factors and mitigation strategies – with changes to the Nula-Cel manufacturing process also on the table.
“The company’s initial investigation ruled out common causes of post-transplant pancytopenia such as viral infection and autoimmunity, leading to the conclusion that it likely results from the Nula-Cel treatment itself,” wrote Cowen analyst Phil Nadeau after one Conversation with the manager
Several other companies have set out to treat sickle cell disease — which is caused by defective red blood cells and is characterized by painful episodes — using the same approach of editing genes in stem cells and then putting them back into the patient. But while Vertex/CRISPR and Editas try to solve the problem by activating a fetal hemoglobin gene in cells, Graphite Bio’s idea is to correct adult mutated hemoglobin with its own set of CRISPR-inspired tools developed by academic pioneers such as Maria Grazia Roncarolo and Matthäus Porteus.
“At the DNA level, we’re making stem cells normal again,” CEO Josh Lehrer described the approach back in 2021.
SVB Securities’ Mani Foroohar wrote that the company is now investigating whether this basic approach could have caused the side effect. Other hypotheses include “the quality of the patients’ underlying bone marrow,” Graphite’s technology, and the use of AAV6 as a delivery vector.
“Given this number of degrees of freedom in any assessment, determining the right remedy with a high enough degree of confidence to drive a patient’s return to treatment will be a lengthy and uncertain process,” he wrote.
While the company had previously hoped to have proof-of-concept data from 15 patients by mid-2023, it’s now pushing that schedule back.
Editor’s Note: Updated to include comment from Graphite Bio.