CRISPR Therapeutics (NASDAQ: CRSP) and Vertex Pharmaceuticals (NASDAQ: VRTX) report that recent progress in the clinical development programs for CTX001, an investigational autologous, CRISPR/Cas9 gene-edited hematopoietic stem cell therapy being evaluated for patients suffering from severe hemoglobinopathies. A brief TrialSite News Background:
What are Hemoglobinopathies?
A kind genetic defect that results in abnormal structure of one of the globinchains of the hemoglobin molecule. Hemoglobinopathies are inherited single-gene disorders; in most cases, they are inherited as autosomal co-dominant traits. Common hemoglobinopathies include sickle-cell disease. It is estimated that 7% of world’s population (420 million) are carriers, with 60% of total and 70% pathological being in Africa. Hemoglobinopathies are most common in populations from Africa, the Mediterranean basin and Southeast Asia.
Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. Thalassemias, in contrast, usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some hemoglobinopathies are also thalassemias, but most are not.
Either hemoglobinopathy or thalassemia, or both, may cause anemia. Some well-known hemoglobin variants such as sickle-cell anemia and congenital dyserythropoietic anemia are responsible for diseases, and are considered hemoglobinopathies. However, many hemoglobin variants do not cause pathology or anemia, and thus are often not classed as hemoglobinopathies, because they are not considered pathologies. Hemoglobin variants are a part of the normal embryonic and fetal development, but may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Other variants cause no detectable pathology, and are thus considered non-pathological variants.
CTX001 is an investigational 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 (HbF; hemoglobin F) in red blood cells. HbF 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.
CTX001 is being developed under a co-development and co-commercialization agreement between CRISPR Therapeutics and Vertex.
As reported in Sickle Cell Anemia news https://sicklecellanemianews.com/ctx001/ CTX001 is an investigational therapy that CRISPR Therapeutics is developing to treat inherited disorders of hemoglobin such as sickle cell anemia and beta-thalassemia.
How CTX001 works
Sickle cell anemia is caused by a mutation in the HBB gene that provides instructions to make the protein hemoglobin, a molecule inside red blood cells that is responsible for carrying oxygen. In sickle cell anemia, this mutation results in missing or deficient hemoglobin.
CTX001 uses gene editing technology to make a genetic change to increase the production of fetal hemoglobin in a patient’s red blood cells. Fetal hemoglobin is a form of hemoglobin that naturally exists in newborn babies and is later replaced by the adult form of hemoglobin. However, sometimes fetal hemoglobin persists in adults, providing protection for people with sickle cell anemia and β-thalassemia.
For the treatment, a patient’s hematopoietic stem cells, which are cells from the bone marrow that give rise to all the red and white cells that form the blood, are collected and then genetically modified in the laboratory so they are able to produce high levels of fetal hemoglobin. These manipulated cells are then reintroduced into the patient’s body, where they will produce large amounts of red blood cells containing fetal hemoglobin, overcoming the hemoglobin deficiencies caused by the disease.
CTX001 in clinical trials
The results of preclinical experiments with CTX001 were presented in December 2017 at the American Society of Hematology (ASH) Annual Meeting. CTX001 was able to efficiently edit the target gene in more than 90 percent of hematopoietic stem cells to achieve about 40 percent of fetal hemoglobin production, which investigators believe is sufficient to improve a patient’s symptoms.
Study results also showed that CTX001 affects only cells at the target site and that it has no off-target effects on hematopoietic stem cells, thereby appearing to be a safe potential treatment.
These positive results prompted CRISPR Therapeutics to start a collaboration with Vertex Pharmaceuticals to develop and commercialize CTX001 as a gene-editing treatment for inherited hemoglobin disorders, including sickle cell anemia and β-thalassemia. CRISPR and Vertex are planning to submit an investigational new drug (IND) application to the U.S. Food and Drug Administration to start a Phase 1/2 clinical trial in sickle cell anemia in the U.S. in 2018.
CRISPR Therapeutics also submitted a clinical trial application (CTA) for CTX001 to advance into a Phase 1/2 clinical trial in patients with β-thalassemia in Europe in 2018. This trial will evaluate the safety and effectiveness of CTX001 in adult patients with transfusion-dependent β-thalassemia.
About the Phase 1/2 Study in Beta Thalassemia
The Phase 1/2 open-label trial is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 18 to 35 with TDT, non-beta zero/beta zero subtypes. The first two patients in the trial will be treated sequentially and, pending data from these initial two patients, the trial will open for broader concurrent enrollment. The companies plan to target presentations of data at scientific conferences once there is enough data on multiple patients.
The study is currently being conducted at multiple clinical trial sites in Canada and Europe. In addition, CRISPR Therapeutics and Vertex expanded the U.S. Investigational New Drug Application (IND) for CTX001 to include beta thalassemia and plan to begin enrollment of the Phase 1/2 study at clinical trial sites in the U.S. this year.
About the Phase 1/2 Study in Sickle Cell Disease
The Phase 1/2 open-label trial is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 18 to 35 with severe SCD. Like the trial in beta thalassemia, the first two patients in the trial will be treated sequentially prior to broader concurrent enrollment. The companies plan to target presentations of data at scientific conferences once there is enough data on multiple patients.
The study is currently being conducted at clinical trial sites in the United States. CTX001 was granted Fast Track Designation by the U.S. Food and Drug Administration for the treatment of SCD in January of this year. In addition, CRISPR Therapeutics and Vertex have obtained approvals of Clinical Trial Applications (CTAs) for CTX001 for SCD in Canada and additional countries in Europe and plan to initiate the Phase 1/2 study at clinical trial sites outside the U.S. this year.
About the Gene-Editing Process in These Trials
Patients who enroll in these studies will have hematopoietic stem cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, CTX001, will then be infused back into the patient as part of a stem cell transplant. Patients will initially be monitored to determine when the edited cells begin to produce.