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

First-generation NNRTIs with nucleoside reverse transcriptase inhibitors are effective in sustaining HIV-1 suppression but development of resistant mutants is often seen in patients whose regimens fail. These NNRTIs are also associated with safety/tolerability issues, such as CNS and rash. Despite intensive efforts in developing NNRTIs with improved resistance and safety profiles, only two next-generation NNRTIs were successfully developed over the last decade, etravirine (ETR) and rilpivirine (RPV). RPV is less efficacious 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. This review describes the development of DOR, which applied resistance selection and crystallography studies to improve resistance profiles, qEEG studies to evaluate CNS effects, and animal studies to optimize pharmacokinetic profiles, with confirmation in clinical trials. 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 profile 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 effects in rats and nonhuman primates. The metabolic profile was devoid of induction potential, suggesting a benign drug interaction profile. In the ongoing clinical studies, resistance rates were lower than first-generation NNRTIs, with no clinically meaningful drug interactions, and DOR has been generally well tolerated with favorable safety, neuropsychiatric, and lipid profiles. Current clinical experience confirmed the preclinical profile of DOR. DOR is a unique NNRTI, distinguished by its low risk of resistance and excellent tolerability. DOR demonstrated a superior neuropsychiatric profile compared with EFV, a superior lipid profile vs. DRV+r and EFV, and a favorable drug–drug interaction profile comparable to integrase strand transfer inhibitors. C. Hwang, Merck & Co., Inc.: Employee and Shareholder, Salary. M. T. Lai, Merck & Co., Inc.: Employee and Shareholder, Salary. D. Hazuda, Merck & Co., Inc.: Employee and Shareholder, Salary.