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Promising Mid-Stage Data Reported for HIV Drug Doravirine
Positive results were reported from a phase IIb clinical trial evaluating the safety and efficacy of once-daily oral doravirine (Merck), an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), plus tenofovir/emtricitabine (TDF/FTC) compared with efavirenz plus TDF/FTC in previously untreated patients with human immunodeficiency virus-1 (HIV-1) infection.
The new findings were presented at the 12th International Congress on HIV Drug Therapy, being held November 2–6 in Glasgow, United Kingdom.
The randomized, double-blind, dose-ranging trial evaluated the efficacy, safety, and tolerability of once-daily doravirine (25, 50, 100, and 200 mg) compared with once-daily efavirenz (600 mg), both in combination with TDF/FTC, in previously untreated HIV-1 infected patients.
In part 1 of the study (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. After dose selection, all doravirine-treated patients were switched to the selected dose (100 mg doravirine) for the expansion phase of the study (part 2).
In part 2, an additional 132 patients received doravirine 100 mg (n = 66) or efavirenz (n = 66), both in combination with TDF/FTC, to allow an assessment of the CNS safety and tolerability profile of doravirine.
The study’s planned total treatment duration was 96 weeks.
The primary safety analysis from the expansion phase of the trial compared the incidence of central nervous system (CNS) adverse events (AEs) by week 8 in patients who received doravirine 100 mg plus TDF/FTC (n = 108) compared with patients who received efavirenz with TDF/FTC (n = 108).
The results showed a significantly lower incidence of one or more of reported CNS AEs (all causality) among the doravirine-treated group compared with the efavirenz-treated group (22.2 % vs. 43.5 %, respectively; P < 0.001). The most common 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 study were presented in March 2014 at the 21st Conference on Retroviruses and Opportunistic Infections (CROI), held in Boston, Massachusetts.
Additional follow-up data through 48 weeks of treatment showed a 76% (n = 126/166) overall virologic response rate (HIV RNA < 40 c/mL) for all doravirine doses (25, 50, 100, and 200 mg), which was comparable to the 71% (n = 30/42) reported for patients treated with 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 demonstrated a lower overall incidence of treatment-related AEs (36.7%; n =166) than those who received efavirenz (57.1%; n = 42). The most commonly reported drug-related clinical AEs 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%), diarrhea (4.8% vs. 9.5%), and dizziness (3.0% vs. 23.8%). Doravirine-treated patients also had a lower incidence of laboratory abnormalities in routine clinical tests, including increased total cholesterol (6.8% for doravirine vs. 31.6% for efavirenz) and low-density lipoprotein (LDL) cholesterol (6.3% vs. 18.4%).
In preclinical studies, doravirine showed potent antiviral activity against HIV-1. In early clinical studies, the drug demonstrated a pharmacokinetic profile that supported a once-daily dosing schedule and did not show a significant food effect.
Source: Merck; November 3, 2014.