545. Rational Design of Doravirine (DOR): A Review of Development From Bench to Patients

Abstract

Background. First-generation NNRTIs with nucleoside reverse transcriptase inhibitors are efective in sustaining HIV-1 suppression but development of resistant mutants is often seen in patients whose regimens fail. Tese NNRTIs are also associated with safety/tolerability issues, such as CNS and rash. Despite intensive eforts in developing NNRTIs with improved resistance and safety profles, only two next-generation NNRTIs were successfully developed over the last decade, etravirine (ETR) and rilpivirine (RPV). RPV is less efcacious in patients with high viral load and ETR is only approved for treating experienced patients. Lessons from the limitations of approved NNRTIs and past development failures informed a rational approach to the development of DOR. Methods. Tis review describes the development of DOR, which applied resistance selection and crystallography studies to improve resistance profles, qEEG studies to evaluate CNS efects, and animal studies to optimize pharmacokinetic profles, with confrmation in clinical trials. Results. DOR demonstrated potent in vitro activity against wild-type virus and mutant viruses containing common NNRTI resistance mutations (K103N, Y181C, G190A, E138K, and K103N/Y181C), and selection studies suggested a unique resistance profle characterized by the emergence of a mutation at position 106 (V106A/M) with additional substitutions, such as F227C, required for high-level resistance. Related analogs were devoid of qEEG efects in rats and nonhuman primates. The metabolic profle was devoid of induction potential, suggesting a benign drug interaction pro-fle. In the ongoing clinical studies, resistance rates were lower than frst-generation NNRTIs, with no clinically meaningful drug interactions, and DOR has been generally well tolerated with favorable safety, neuropsychiatric, and lipid profles. Conclusion. Current clinical experience confrmed the preclinical profle of DOR. DOR is a unique NNRTI, distinguished by its low risk of resistance and excellent tolerability. DOR demonstrated a superior neuropsychiatric profle compared with EFV, a superior lipid profle vs. DRV+r and EFV, and a favorable drug-drug interaction profle comparable to integrase strand transfer inhibitors.