Rare Daily Staff

CRISPR Therapeutics and Vertex Pharmaceuticals reported positive results from the first two patients with severe blood disorders treated with the experimental CRISPR/Cas9 gene-editing therapy CTX001 in two ongoing phase 1/2 clinical trials.

One patient with transfusion-dependent beta thalassemia (TDT) received the treatment in the first quarter of 2019 while another patient with severe sickle cell disease (SCD) received the treatment in mid-2019. Patients will be followed for approximately two years following infusion and several additional patients have been enrolled.

“The data we announced today are remarkable and demonstrate that CTX001 has the potential to be a curative CRISPR/Cas9-based gene-editing therapy for people with sickle cell disease and beta thalassemia,” said Jeffrey Leiden, chairman, president and CEO of Vertex.

Transfusion-Dependent Beta Thalassemia (TDT) is an inherited blood disorder that reduces the production of hemoglobin, leading to a lack of oxygen in many parts of the body, and anemia, which lead to the need for chronic blood transfusions for survival and treatment for iron overload due to the transfusions.

The patient with TDT required 16.5 transfusions per year over the two years before enrolling in the clinical study. The patient achieved neutrophil engraftment 33 days after CTX001 infusion and platelet engraftment 37 days after infusion. Two serious adverse events occurred, but neither were considered related to CTX001 and both subsequently resolved. At nine months after CTX001 infusion, the patient was transfusion independent with total hemoglobin level of 11.9 g/dL and 10.1 g/dL fetal hemoglobin.

Sickle cell disease (SCD) is a debilitating inherited genetic blood disorder that affects the shape of the red blood cells and can make blood cells and blood vessels stickier than normal, leading them to stick together, cause damage to the blood vessels, and cause vaso-occlusive crises (VOCs) that are painful events that can lead to serious acute and chronic life-threatening complications and death. More than half of patients with SCD experience two or more VOCs a year.

The patient with SCD experienced seven vaso-occlusive crises (VOCs) per year over the past two years before enrolling in the clinical study. The patient achieved neutrophil and platelet engraftment 30 days after CTX001 infusion. Three serious adverse events occurred, but none were considered related to CTX001and all resolved. At four months after CTX001 infusion, the patient was free of VOCs and had total hemoglobin levels of 11.3 g/dL, 46.6 percent fetal hemoglobin, and 94.7 percent erythrocytes expressing fetal hemoglobin.

“We are very encouraged by these preliminary data, the first such data to be reported for patients with beta thalassemia and sickle cell disease treated with our CRISPR/Cas9 edited autologous hematopoietic stem cell candidate, CTX001,” said Samarth Kulkarni, CEO of CRISPR Therapeutics. “These data support our belief in the potential of our therapies to have meaningful benefit for patients following a one-time intervention. We continue to enroll these studies as we drive forward to develop CRISPR/Cas9 therapies as a new class of transformative medicines to treat serious diseases.”

Both studies are designed to assess the safety and efficacy of a single dose of CTX001 in adults with TDT or SCD, 45 patients enrolled to be enrolled in each study and followed for two years after infusion. 

CTX001 is an experimental ex vivo CRISPR gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD in which a patient’s hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin in red blood cells, is a form of the oxygen-carrying hemoglobin that is naturally present at birth and is then replaced by the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate transfusion requirements for TDT patients and painful and debilitating sickle crises for SCD patients.

Patients who enroll in these studies will have hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells are edited using the CRISPR/Cas9 technology, and the edited cells, are infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of CTX001. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of CTX001 on multiple measures of disease.

CTX001 is being developed under a co-development and co-commercialization agreement between CRISPR Therapeutics and Vertex that began in 2015 and focuses on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CTX001 is the first treatment to emerge from the joint research program.

Photo: Jeffrey Leiden, chairman, president and CEO of Vertex

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