Trial of Gene Editing Therapy – Potential SCD Cure – Now Recruiting

GPH101, Graphite Bio’s investigational gene editing therapy, is able to correct the disease-causing mutation in blood stem cells of people with sickle cell disease (SCD), new preclinical data shows.

Graphite also announced it remains on track to start enrolling participants in a Phase 1/2 trial testing the gene editing therapy in SCD patients before the end of the year.

That will make GPH101 the first potentially curative treatment for SCD to be tested in such a trial, according to Graphite. The study is actively recruiting participants at study sites in California and Missouri.

The new early data demonstrating the therapy’s effectiveness was presented by the company at the 49th Annual Sickle Cell Disease Association of America (SCDAA) National Convention, held virtually Oct. 12–16. The poster presentation was titled “Preclinical Data in Support of CEDAR, a Phase 1/2 Study of Ex Vivo Autologous Gene Correction (HbS to HbA) in Hematopoietic Stem Cells to Treat Patients With Severe Sickle Cell Disease.”

“These positive preclinical data are foundational to our sickle cell disease program and support the evaluation of GPH101 in our Phase 1/2 CEDAR trial, for which we are on track to enroll our first patient before the end of the year,” Josh Lehrer, MD, CEO of Graphite, said in a press release.

SCD is caused by a genetic mutation that leads to the production of an abnormal version of hemoglobin — the protein that red blood cells use to transport oxygen through the body — known as hemoglobin S. This ultimately causes red blood cells to become misshapen and take on a sickle-like form, from which the disease gets its name.

The conceptual goal of GPH101 is quite straightforward: to “correct” the mutation in a patient’s blood cells in order to restore the production of a functional version of hemoglobin.

The therapy involves harvesting a person’s hematopoietic stem cells — those found in the bone marrow that can give rise to red blood cells and other types of blood cells. Harvested blood cell precursors undergo a process of gene editing using the CRISPR/Cas9 system, and are then returned to the patient via a stem cell transplant.

CRISPR/Cas9 is a technology that’s based on a naturally occurring system that bacteria use to fight off viral infections. In bacteria, the CRISPR/Cas9 system allows them to recognize the genetic sequence of certain viruses and to destroy the viral DNA containing those sequences. The system used in GPH101 is modified so that it will target the mutation leading to the production of hemoglobin S and remove it, thereby prompting other cellular mechanisms to repair that section of DNA with the correct sequence that codes for a normal version of the protein.

New preclinical data showed this system can effectively correct the disease-causing mutation in hematopoietic stem cells from people with SCD, with more than 60% of mutations corrected. Consistently, researchers observed that cells shifted from mainly producing hemoglobin S to making hemoglobin A, the normal version of the protein found in adults.

Additional tests found little evidence of changes to other parts of the cells’ genetic code caused by the gene editing process, showcasing the therapy’s high specificity and minimal off-target effects.

“These encouraging data reinforce our belief that GPH101 has the potential to directly correct the underlying disease-causing mutation to decrease production of sickle hemoglobin and restore the expression of normal adult hemoglobin with minimal off-target editing,” Lehrer said.

Notably, in mice experiments, modified stem cells were able to engraft, that is, get to their niche in the body and survive, for at least 16 weeks (about four months). The number of gene-corrected cells was higher than that expected to be curative for SCD, according to Graphite.

“Gene correction has been viewed as the optimal approach to potentially cure sickle cell disease, and the preclinical data we have generated indicate we can do this precisely and efficiently and at rates that are considered potentially curative,” Lehrer said.

According to Lehrer, those rates are based on “extensive data” from patients who have undergone stem cell transplants.

The company now is preparing to launch a Phase 1/2 trial called CEDAR (NCT04819841) to start testing GPH101 in people with SCD. The trial will be conducted at the Lucile Packard Children’s Hospital in Palo Alto, California, and at Washington University in Saint Louis, Missouri.

It is set to enroll approximately 15 participants: nine adults, ages 18–40, and six adolescents, ages 12–17.

In both age groups, the first three participants will be treated sequentially. That means the first patient will need to complete treatment and achieve engraftment — when the blood-forming cells received during transplant start making healthy blood cells — before the second patient can start the therapy.

Researchers will assess the effect of treatment on various measures of hemoglobin and red blood cell health, as well as SCD-relevant outcomes, such as the frequency of vaso-occlusive crisis and changes in organ function. Safety outcomes, including the frequency and severity of adverse events and lab abnormalities, also will be evaluated.

Earlier this year, Graphite raised $150 million to support the development of GPH101 and other gene editing therapies.