Gene-editing Trial of GPH101 to Start Dosing 1st Patient This Year

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by Steve Bryson, PhD |

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Dosing will soon start in a Phase 1/2 trial of GPH101, an experimental gene-editing therapy designed to correct the genetic mutation that causes sickle cell disease (SCD).

The first participant had been enrolled in the study late last year, but due to the recent surge of the SARS-CoV-2 Omicron variant, the virus that causes COVID-19, dosing was delayed. Graphite Bio, the therapy’s developer, now plans to dose the first patient in the second half of this year, with top-line proof-of-concept data anticipated in 2023.

The trial, called CEDAR (NCT04819841), is currently enrolling participants at Washington University, in Saint Louis, Missouri; the University of Alabama at Birmingham; and the Lucile Packard Children’s Hospital, in Palo Alto, California.

“2021 was a pivotal year in our company’s history as we established ourselves as a public company and initiated the clinical trial for our lead candidate, GPH101 for sickle cell disease,” Josh Lehrer, MD, CEO of Graphite Bio, said in a press release. “In 2022, we remain focused on advancing our research and development priorities, in particular the execution of our Phase 1/2 CEDAR clinical trial of GPH101.”

GPH101 uses the gene-editing tool CRISPR-Cas9 and a natural DNA repair mechanism to correct the SCD-causing mutation in a gene that provides instructions for making a subunit of hemoglobin — the protein that transports oxygen in the blood.

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As a first step, cells in the bone marrow called hematopoietic stem cells, which give rise to red blood cells, are collected from a patient. These cells are then modified with GPH101 and finally returned to the same patient in the form of a stem cell transplant.

GPH101 may potentially cure SCD by restoring the production of normal hemoglobin and preventing red blood cells from becoming misshapen, or sickled.

CEDAR aims to recruit about 15 people, ages 12–40, with severe SCD. To be eligible, participants must have had at least four vaso-occlusive crises — intense pain episodes caused by blood vessel blockage — and/or at least two episodes of acute chest syndrome, a serious lung condition characterized by fever, chest pain, and breathing difficulties, in the two years before study entry. In the case of patients experiencing acute chest syndrome, at least one of the episodes must have had occurred in the year prior to study entry.

The trial is not open to those who have undergone stem cell transplants or received gene therapies.

CEDAR’s primary goal is to determine the treatment’s safety, as well as the success of stem cell engraftment — the process by which investigators assess whether edited cells survive and grow after being returned to the patient. Efficacy-related measures will also be assessed, including hemoglobin levels, SCD complications like vaso-occlusive crises, and patient-reported outcomes.

“We continue to work toward demonstrating that our unique gene correction approach to reduce sickle hemoglobin production and restore adult hemoglobin expression [production] has the potential to achieve the ideal genetic outcome and provide a definitive cure for patients with sickle cell disease,” said Lehrer.