nicotinamide + tetrahydrouridine + decitabine

This is an **oral triple combination therapy** comprising nicotinamide, tetrahydrouridine, and decitabine, under investigation primarily for the treatment of sickle cell disease. **Decitabine** is a small molecule cytidine analog and DNA methyltransferase 1 (DNMT1) inhibitor that acts as an epigenetic modulator by inducing DNA hypomethylation and consequently altering gene expression, notably reactivating fetal hemoglobin (HbF) in sickle cell disease. **Tetrahydrouridine** is a potent competitive inhibitor of cytidine deaminase (CDA), co-administered to block rapid decitabine metabolism, thereby enabling effective oral delivery and sufficient bioavailability of decitabine. **Nicotinamide** is a form of vitamin B3 and a histone deacetylase (HDAC) inhibitor, theorized to augment chromatin relaxation and potentiate fetal hemoglobin gene activation. The combination is designed for non-cytotoxic DNMT1 depletion and reactivation of fetal hemoglobin gene expression, with improved safety and oral dosing convenience compared to parenteral formulations. This combination has advanced to clinical trials in people with sickle cell disease who are at high risk or have failed benefit from hydroxyurea[1][4][5].