Merck Moves Doravirine Into Phase 3 Clinical Trials
Earlier this month, at the 21st Conference on Retroviruses and Opportunistic Infections (CROI), Merck indicated plans to initiate a Phase 3 clinical trial program for doravirine in combination with ARV therapy in the second half of 2014.
"Building on our long-standing commitment to the HIV community, Merck continues to evaluate new candidates we believe have the potential to make a meaningful difference in the lives of HIV patients," said Daria Hazuda, Ph.D., vice president, Infectious Diseases, Merck Research Laboratories. "We look forward to advancing doravirine into Phase 3 clinical trials in the second half of 2014."
The announcement came after the company, known as MSD outside of the U.S. and Canada, presented data from the dose-ranging portion of an ongoing Phase 2B clinical trial of doravirine, the company's investigational next-generation, non-nucleoside reverse transcriptase inhibitor (NNRTI).
The interim data demonstrated potent antiretroviral (ARV) activity for four doses (25, 50, 100 and 200 mg) of once-daily, oral doravirine in combination with tenofovir/emtricitabine in treatment-na�ve, HIV-1 infected adults after 24 weeks of treatment.
This randomized, double-blind clinical trial examined the safety, tolerability and efficacy of once-daily doravirine (25, 50, 100 and 200 mg) in combination with once-daily tenofovir/emtricitabine versus efavirenz (600 mg), in treatment-na�ve, HIV-1 infected patients. The primary efficacy analysis was percentage of patients achieving virologic response (< 40 copies/mL).
At 24 weeks, doravirine doses of 25, 50, 100, and 200 mg showed virologic response rates consistent with those observed for efavirenz at a dose of 600 mg. All treatment groups showed increased CD4 cell counts.
The incidence of drug-related adverse events was comparable among the doravirine-treated groups. And the overall incidence of drug-related adverse events was lower in the doravirine-treated groups (n=166) than the efavirenz-treated group (n=42), 35 percent and 57 percent, respectively.
The most common central nervous system (CNS) adverse events at week eight -- the primary time point for evaluation of CNS adverse experiences - included dizziness, nightmares, abnormal dreams and insomnia. The incidences of these adverse events were much higher with efavirenz than with doravirine.
Based on the 24-week data from this dose-finding study, a single dose of 100 mg doravirine was chosen to be studied for the remainder of this study, up to 96 weeks.
Doravirine, also known as MK-1439, is an investigational next-generation, NNRTI being evaluated by Merck for the treatment of HIV-1 infection. In preclinical studies, doravirine demonstrated potent antiviral activity against HIV-1 with a characteristic profile of resistance mutations selected in vitro compared with currently available NNRTIs.
In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and did not show a significant food effect.
In AIDSMap.com, Liz Highleyman reported that at CROI 2014, Javier Morales-Ramirez from Clinical Research Puerto Rico shared his late-breaking findings from a phase 2b study evaluating the safety and efficacy of various doses of doravirine versus efavirenz (Sustiva) for initial antiretroviral therapy including 208 treatment-niave people.
Early studies at 24 weeks indicated that Morales-Ramirez found patients tolerated doravirine more than efavirenz, discovering that they had more favorable lipid profiles and less frequent liver enzyme elevations with doravirine. The drug was shown to have potent antiretroviral activity with fewer drug-related adverse events than efavirenz.