Investigational New Drug (IND) Update

In August of this year, Editas obtained Rare Pediatric Disease Designation For EDIT-301 as a potentially best-in-class treatment for SCD in children from birth to 18 years.

ET-01: CRISPR-Engineered Stem Cell Therapy for Beta-Thalassemia

EdiGene, China is also developing an engineered cell therapy to increase HbF levels in red blood cells. The new ex vivo therapy, ET-01 is in development for the treatment of beta-thalassemia, a disease that shares some clinical overlap with SCD, but which is characterised by deficient rather than defective adult haemoglobin.

Beta-thalassemia arises from an imbalance in the beta globin chains of haemoglobin, which serve as the building blocks for mature and functional adult haemoglobin. Mutations in the beta globin (HBB) gene underly these imbalances, and given that there are at least 200 known disease-causing HBB mutations, most gene-editing strategies aim to increase HbF levels to compensate for the lack of haemoglobin rather than correct mutations in the HBB gene.

ET-01 is EdiGene’s most advanced pre-clinical candidate, and it is developed using CRISPR-Cas9 technology to disrupt and thereby reduce the activity of the B-cell lymphoma/leukaemia 11A (BCL11A) protein in patient-derived CD34+ cells. BCL11A is a negative regulator of HbF expression, thus its disruption increases HbF levels, and this is expected to lessen the clinical symptoms of beta-thalassemia.

EdiGene announced earlier this year that its IND application for ET-01 to the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) had been accepted for patients with transfusion-dependent beta-thalassaemia (TDT), and the company is now preparing to move ET-01 into clinical development.

FT819: An Off-The-Shelf CAR T-Cell Therapy for Acute Lymphoblastic Leukaemia

Californian biopharmaceutical company Fate Therapeutics has a pipeline of induced pluripotent stem cell (iSPC)-derived cellular immunotherapies for cancer and immune disorders. One of these is FT819, an off-the-shelf CAR T-cell cancer immunotherapy candidate for the treatment of acute lymphoblastic leukaemia (ALL). FT819 is CRISPR-engineered to express a novel 1XX CAR that targets the CD19 B cell-specific cell surface antigen that is expressed in all B cell lineage malignancies.

Fate Therapeutics announced that it had obtained IND clearance from the FDA in July of this year, allowing it to proceed with the clinical development of FT819 for treatment of CD19+ cancers. FT819 is the first-ever CAR T-cell therapy to be derived from a clonal master iPSC line engineered with several first-of-kind features that are designed to improve the safety and efficacy of CAR T-cell therapy.

In FT819, the 1XX CAR is inserted into the T cell receptor alpha constant (TRAC) locus, which disrupts the native T cell receptor (TCR) locus while simultaneously placing the CAR under the regulatory control of the endogenous TCR promoter. Inserting a CAR at this location has previously been demonstrated to improve T cell function and potency in mouse models of ALL.

At last year's American Hemotology Association Annual Meeting, Fate Therapeutics presented encouraging in vivo preclinical data demonstrating that FT819 exhibits durable tumour control and extended survival in xenograft mouse models of ALL.

This was our first update about pre-clinical stage therapies based on gene editing. If you want to learn more about the clinical development path, you can check out our earlier explainer piece that covers the path from IND filing right through to Phase IV (post-market surveillance).