545. Rational Design of Doravirine (DOR): A Review of Development From Bench to Patients (pts)
Session: Poster Abstract Session: HIV: Antiretroviral Therapy
Thursday, October 4, 2018
Room: S Poster Hall
Posters
  • 18-1315 MRPHI18305 IDWeek Rationale Design_FINAL.pdf (1.0 MB)
  • Background: First-generation NNRTIs with nucleoside reverse transcriptase inhibitors are effective in sustaining HIV-1 suppression but development of resistant mutants is often seen in pts 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 2 next-generation NNRTIs were successfully developed over the last decade, etravirine (ETR) and rilpivirine (RPV). RPV is less efficacious in pts with high viral load and ETR is only approved for treating experienced pts. Lessons from the limitations of approved NNRTIs and past development failures informed a rational approach to the development of DOR.

    Methods: 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.

    Results: DOR demonstrated potent in vitro activity against wildtype 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.

    Conclusion: 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 versus DRV+r and EFV, and a favorable drug-drug interaction profile comparable to integrase strand transfer inhibitors.

    Carey Hwang, MD, PhD, Ming-Tain Lai, PhD and Daria Hazuda, PhD, Merck & Co., Inc., Kenilworth, NJ

    Disclosures:

    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 .

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 3rd with the exception of research findings presented at the IDWeek press conferences.