Merck Sharp & Dohme Ltd. MSD (known as Merck & Co., Inc. in the United States and Canada), has announced the presentation of results from a Phase 2b clinical trial evaluating the safety and efficacy of once daily oral doravirine, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), plus tenofovir/emtricitabine (TDF/FTC) compared to efavirenz plus TDF/FTC in previously untreated patients with HIV-1 infection. Results were presented as a poster (#0434) and oral presentation by Dr. Josep M. Gatell, Head, Infectious Diseases and AIDS Units-IDIBAPS, Hospital Clinic, Barcelona, at the 12th International Congress on HIV Drug Therapy being held in Glasgow, United Kingdom, Nov. 2-6.
The primary safety analysis from the expansion phase of the study compared the incidence of central nervous system (CNS) adverse events (AEs) in patients who received doravirine 100 mg plus TDF/FTC (n=108) for eight weeks versus patients who received efavirenz with TDF/FTC (n=108) for eight weeks. The results showed a significantly lower incidence of one or more of reported CNS AEs (all causality) among the doravirine-treated group compared to the efavirenz-treated group (22.2 % vs. 43.5 %, respectively; p<0.001). The most common (greater than 5 % incidence) CNS AEs in the doravirine- and efavirenz-treated groups, respectively, were dizziness (9.3 % vs. 27.8 %), insomnia (6.5 % vs. 2.8 %), abnormal dreams (5.6 % vs. 16.7 %), and nightmares (5.6 % vs. 8.3 %).
Interim results for this ongoing Phase 2b study, including the primary efficacy analysis for dose selection based on 24-week data from the dose-ranging cohort of the study, were previously presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI) in March 2014.
“This program underscores Merck’s ongoing commitment to the research and development of new therapeutic options for patients with HIV,” said Dr. Hedy Teppler, executive director, Infectious Diseases, Merck Research Laboratories. “We are encouraged by the antiviral activity and the overall tolerability profile of doravirine, and look forward to initiating Phase 3 studies.”
Additional follow-up data through 48 weeks of treatment showed a 76 percent (n=126/166) overall virologic response rate (HIV RNA <40 c/ml) for all doravirine doses (25, 50, 100 and 200 mg) that is comparable to 71 percent (n=30/42) reported for patients administered efavirenz (600 mg). In addition, all treatment groups showed increased CD4 cell counts relative to baseline, consistent with the 24-week findings. After 48 weeks of treatment, patients in the dose ranging part of the study who received doravirine continued to demonstrate a lower overall incidence of drug-related adverse events (36.7%; n=166) than those who received efavirenz (57.1%; n=42). The most commonly reported drug-related clinical adverse events in the doravirine and efavirenz groups respectively were abnormal dreams (10.2% vs. 9.5%); nausea (7.8% vs. 2.4%); fatigue (7.2% vs. 4.8%); diarrhoea (4.8% vs. 9.5%) and dizziness (3.0% vs. 23.8%). Doravirine-treated patients also had a lower incidence of graded laboratory abnormalities in routine clinical tests including increased total cholesterol (6.8% for doravirine vs. 31.6% for efavirenz) and LDL cholesterol (6.3% for doravirine vs. 18.4% for efavirenz).
MSD plans to initiate the first Phase 3 clinical trial of doravirine by the end of 2014. The study will enroll treatment-naïve patients and compare the efficacy, safety and tolerability of doravirine and ritonavir-boosted darunavir, both in combination with other anti-retroviral therapy.
About the Phase 2b Study
The Phase 2b randomized, double blind, dose-ranging clinical trial (NCT01632345) evaluated the efficacy, safety and tolerability of once-daily doravirine (25, 50, 100 and 200 mg) compared to once-daily efavirenz 600 mg, both in combination with TDF/FTC, in previously untreated HIV-1 infected patients. The study has two parts:
- In Part 1, the dose-ranging phase, patients received once daily doravirine (N=166) at one of four doses (25, 50, 100 or 200 mg) or efavirenz (N=42), both in combination with TDF/FTC. The doravirine dose to be used in Part 2 of the Phase 2b study and in Phase 3 was selected based on the Week 24 safety and efficacy data in doravirine-treated patients. After dose selection, all doravirine-treated patients were switched to the selected dose (100 mg doravirine) for the expansion phase of the study.
- In Part 2, the expansion phase, an additional 132 patients were enrolled to receive 100 mg doravirine (N=66) or efavirenz (N=66), both in combination with TDF/FTC, to enable an assessment of the CNS safety and tolerability profile of doravirine.
The planned total treatment duration in the Phase 2 study is 96 weeks.
Doravirine, also known as MK-1439, is an investigational next-generation, NNRTI being developed by MSD for the treatment of HIV-1 infection. In preclinical studies, doravirine showed potent antiviral activity against HIV-1. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of a once-daily dosing schedule and did not show a significant food effect.
Gatell, J. M. et al. 48-Week Efficacy and Safety and Early CNS Tolerability of Doravirine, a Novel NNRTI, with TDF/FTC in ART-Naive HIV-Infected Patients. Poster #0434, Monday 3 November 2014. Oral presentation, Thursday 6 November. HIV Glasgow, 2-6 November 2014, Glasgow, UK.