We have established a portfolio of programs by selecting disease targets based on a number of criteria, including high unmet medical need, advantages of CRISPR/Cas9 relative to alternative approaches, technical feasibility and the time required to advance the product candidate into and through clinical trials. We have initiated programs in four primary areas: (i) ex vivo programs involving gene editing of hematopoietic cells, (ii) ex vivo programs in immuno-oncology, (iii) in vivo programs targeting the liver and (iv) additional in vivo programs targeting other organ systems, such as muscle and lung. The following table summarizes the current status of our product development pipeline:
CRISPR Therapeutics is developing CTX001 for the treatment of both sickle cell disease and β-thalassemia. These diseases are caused by genetic mutations in the β-globin gene, which codes for a subunit of hemoglobin, the oxygen carrying component of red blood cells. In these diseases, hemoglobin is missing or defective, which results in devastating medical problems. Our approach is designed to mimic the presence of fetal hemoglobin (HbF) in newborn babies. HbF is a form of hemoglobin that is quickly replaced by adult hemoglobin. However, in rare cases where HbF persists in adults, it provides a protective effect for those who have sickle cell disease and β-thalassemia. (Powars, et al. Blood 1984; Musallam, et al. Blood 2012)
CTX001 is an ex vivo therapy in which autologous, or self-donated, cells are harvested directly from the patient. CRISPR then applies its gene-editing technology to the cells outside of the body to make a single genetic change that is designed to increase fetal hemoglobin levels in a patient’s own blood cells. The edited cells are then reinfused and are expected to produce red blood cells that contain fetal hemoglobin in the patient’s body, thereby overcoming the hemoglobin deficiencies caused by these diseases.
CRISPR, together with its partner, Vertex, has obtained approvals of Clinical Trial Applications (CTA) in multiple countries for both β-thalassemia and sickle cell disease (SCD) and remain on track to initiate a Phase 1/2 trial to assess the safety and efficacy of CTX001 in patients with transfusion dependent β-thalassemia later this year.
CRISPR believes that the precision and efficiency of multiplexed editing with CRISPR/Cas9 enable the rapid creation of CAR-T cell therapies that may have distinct advantages over the current generation of autologous CAR-T products. These potential advantages include: better access due to the “off-the-shelf” nature of allogeneic products, and greater efficacy and safety due to the consistency of the product. CRISPR is developing a portfolio of allogeneic CAR-T cell therapies based on its gene-editing technology.
The lead program in CRISPR’s immuno-oncology portfolio, CTX110, is an allogeneic CAR-T product in development targeted towards CD19+ malignancies that has several potential advantages over other CD19 cell therapies. First, the anti-CD19 chimeric antigen receptor, or CAR, is inserted into a specifically chosen locus rather than the random insertion common in current-generation products. Second, the T cell receptor (TCR) is eliminated to enable off-the-shelf use of a single batch of product in many different patients. Finally, the class 1 major histocompatibility complex (MHC I) is eliminated to improve durability of the CAR-T cells in the off-the-shelf setting. CTX110 is based on healthy donor cells that are edited ex vivo using CRISPR/Cas9, a process that the company has optimized and successfully transitioned to a GMP-capable CMO.
Process development and manufacturing activities have been initiated for CTX110 and preclinical studies have begun. CRISPR remains on track to file an IND for CTX110 by the end of this year and will provide an update upon approval of the IND by the FDA.
CRISPR is also advancing two additional allogeneic CAR-T candidates, targeting BCMA for multiple myeloma and CD70 for both hematologic malignancies and solid tumors. These programs are in preclinical development.