Benefits of gene-editing therapy OTQ923 seen in small Phase 1 trial

OTQ923 led to sustained fetal hemoglobin production in 3 severe SCD patients

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by Steve Bryson, PhD |

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Treatment with the investigational gene-editing therapy OTQ923 led to the sustained production of fetal hemoglobin and prevented vaso-occlusive crises (VOCs) in three adults with severe sickle cell disease (SCD), according to data from a Phase 1 study.

The treatment involved collecting red blood cell precursors, called hematopoietic stem cells (HSCs), from a patient and modifying them with the CRISPR-Cas9 gene editing tool to stimulate the production of fetal hemoglobin. Modified stem cells were then infused back into the same patient in the form of a stem cell transplant.

“The biggest take-home message is that there are now more potentially curative therapies for sickle cell disease than ever before that lie outside of using someone else’s stem cells, which can bring a host of other complications,” James LaBelle, MD, PhD, the study’s senior author and director of the pediatric stem cell and cellular therapy program at the University of Chicago Medicine, in Illinois, said in a university news story.

Details of the trial were reported in a study, “CRISPR-Cas9 Editing of the HBG1 and HBG2 Promoters to Treat Sickle Cell Disease,” published in the New England Journal of Medicine.

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Gene editing emerging as potential treatment for genetic diseases

SCD is caused by mutations in the HBB gene, leading to the production of a defective version of adult hemoglobin, which is the protein that transports oxygen throughout the body. This abnormal version of hemoglobin can form clumps, causing red blood cells to acquire a sickle-like shape and to become rigid and more fragile. Because of this, sickled red blood cells are prone to die prematurely and obstruct blood vessels, giving rise to a wide range of complications.

Gene editing is emerging as a potential treatment approach for diseases with a known genetic cause. Several such therapies are currently being investigated in SCD patients.

“Especially in the last 10 years, we’ve learned about what to do and what not to do when treating these patients,” LaBelle said. “There’s been a great deal of effort towards offering patients different types of transplants with decreased toxicities, and now gene therapy rounds out the set of available treatments, so every patient with sickle cell disease can get some sort of curative therapy if needed.”

OTQ923 is one such experimental therapy for SCD that uses the CRISPR-Cas9 gene-editing tool to modify specific genes in a way to promote the production of fetal hemoglobin (HbF). Compared with adult hemoglobin, the fetal version of the protein is more efficient at transporting oxygen and has the potential to be used therapeutically in SCD.

This study, sponsored by Novartis Pharmaceuticals, reported on the ability of OTQ923 to enhance the production of fetal hemoglobin in cells. It also described the results of a Phase 1/2 trial (NCT04443907) that tested the therapy in three SCD patients.

Initial experiments showed that gene editing in HSCs obtained from four healthy donors resulted in the production of fetal hemoglobin in 60.5% of red blood cell precursors (erythroblasts). Similar results were seen in HSCs collected from three SCD patients, where 65.4% of red blood cell precursors produced HbF. Likewise, fetal hemoglobin protein levels significantly increased after gene-editing treatment in cells from healthy individuals, as well as in those from SCD patients.

The biggest take-home message is that there are now more potentially curative therapies for sickle cell disease than ever before that lie outside of using someone else’s stem cells.

3 patients received OTQ923 treatment in Phase 1/2 trial

As of March 27, three SCD patients had received OTQ923 as part of the Phase 1/2 trial.

Participant 1 was a 22-year-old man with SCD. He had been receiving hydroxyurea and regular red blood cell transfusions for six years due to recurrent episodes of VOCs, a painful SCD complication caused by sickled red blood cells blocking blood flow to certain parts of the body.

He discontinued hydroxyurea two months before HSC collection, while continuing to receive blood transfusions for about one month after gene-editing treatment.

Before OTQ923, his total hemoglobin level was 10.0 g per deciliter (g/dL), with 0.4% HbF and 4.0% erythroblast cells producing HbF. Between 12 and 18 months after infusion, total hemoglobin level was maintained at 10.3-11.9 g/dL, with 25.0%-26.8% HbF and 78.1%-87.8% erythroblasts producing HbF.

During follow-up, he had one VOC episode that progressed to acute chest syndrome, an SCD complication marked by fever, chest pain, and breathing difficulties, at 17 months after treatment. He also experienced recurrent intermittent priapism (persistent and painful erections and mild hemolysis, or red blood cell destruction).

Participant 2 was a 21-year-old man who had multiple VOCs while receiving hydroxyurea. He stopped hydroxyurea before HSC collection and was given red blood cell transfusions until about two weeks after gene-editing treatment. Before the therapy, his total hemoglobin level was 7.6 g/dL, with 4.2% HbF and 20.4% HbF-producing erythroblasts.

Between six and 12 months after OTQ923 infusion, his total hemoglobin level was maintained at 10.1-11.5 g/dL, with 23.0%-25.3% HbF and 80.4%-86.8% erythroblasts generating HbF.

One VOC episode occurred at 12 months after infusion, with no acute chest syndrome, stroke, or priapism, but with continued mild hemolysis.

Participant 3 was a 24-year-old woman who had had frequent VOCs resulting in hospitalization, as well as a loss of blood supply to the hips and iron overload. She discontinued hydroxyurea eight months before HSC collection, while continuing to receive monthly blood transfusions.

Four to six months after her infusion, her total hemoglobin level rose from 8.3 to about 10.5 g/dL. Her HbF levels increased from 1.4% up to 23.4%, as did the percentage of HbF-producing erythroblasts, rising from 6.2% up to 85.6%.

Like the other two participants, she had one VOC episode nine months after infusion, with continued mild hemolysis.

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No treatment-related adverse events reported during trial

Overall, none of the adverse events experienced by all three participants during the trial were considered related to OTQ923 by the investigators.

“Although the long-term durability of the response and the safety of this genetically modified product continue to be evaluated, our data suggest that this approach offers a safe and potentially disease-attenuating option for patients with severe sickle cell disease,” the researchers wrote.

LaBelle added: “At UChicago Medicine, we’ve built infrastructure to support new approaches to sickle cell disease treatment and to bring additional gene therapies for other diseases. The data from this trial supports bringing on similar gene therapies for sickle cell disease and for other bone marrow-derived diseases. If we didn’t have this data, those wouldn’t move forward.”