Covalent drugs in development for immune-mediated diseases

The discovery and development of novel small molecule immune-mediated drugs has been a formidable challenge for the drug discovery community. For the treatment of chronic immune-mediated diseases, a successful covalent inhibitor, depending on protein target turnover, could have the potential to minimize drug exposure while maintaining high target coverage for efficacy. The development stories of five covalent inhibitors in clinical trials for immune-mediated diseases are highlighted in this book chapter. The preclinical assays to determine the selectivity and toxicology profile and any publicly available first-in-human pharmacokinetics and target occupancy Phase I data would be highlighted for these inhibitors. A slowly metabolized JAK3-TEC inhibitor ritlecitinib (PF-06651600) from Pfizer was developed which maintains coverage despite the rapid turnover of the JAK3 protein. Several covalent BTK inhibitors are currently in advanced clinical studies for immune-mediated diseases. Evobrutinib, a covalent BTK inhibitor developed by EMD Serono, is in phase 3 trials for relapsing multiple sclerosis. Another BTK inhibitor from BMS, branebrutinib (BMS-986195), is being studies in systemic lupus erythematosus, rheumatoid arthritis and primary Sjögren's syndrome (pSS). Remibrutinib (LOU-064) is another potent BTK covalent inhibitor that binds to the inactive conformation of BTK and is being evaluated in the clinic for urticaria, pSS and asthma. Finally, rilzabrutinib (PRN1008) is a reversible-covalent BTK inhibitor currently in phase 3 clinical trials for the treatment of pemphigus and immune thrombocytopenic purpura.