CROI 2017: New NNRTI Doravirine Shows Good Efficacy in Phase 3 Study

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Doravirine, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) from Merck, reduced HIV viral load as well as boosted darunavir in a Phase 3 clinical trial of people starting antiretroviral therapy (ART) for the first time, but it had a better lipid profile, according to a late-breaking presentation at the Conference on Retroviruses and Opportunistic Infections last week in Seattle.

Current first-line ART regimens are safe and highly effective, but having multiple potent and well-tolerated drugs available in multiple antiretroviral classes offers more options for constructing optimized regimens.

Doravirine (formerly MK-1439) is active against HIV with common NNRTI-resistance mutations including K103N. It can be taken once-daily with or without food and has low potential for drug-drug interactions. As previously reported, a Phase 2 trial showed that doravirine suppressed viral load as well as efavirenz (Sustiva), but with fewer neuropsychiatric side effects.

At CROI Kathleen Squires from Thomas Jefferson University in Philadelphiapresented results from DRIVE-FORWARD, a Phase 3 trial comparing doravirine against ritonavir-boosted darunavir for first-line therapy.

The study analysis included 769 previously untreated adults with HIV. Most (84%) were men, nearly 80% were white, and the average age was 35 years.At baseline the mean CD4 T-cell count was approximately 420 cells/mm3 and the mean viral load was 4.4 log copies/mL; 20% had high viral load above 100,000 copies/mL. At baseline they had no genotypic resistance to any study drugs.

Participants in this double-blind study were randomly assigned (1:1) to take either 100 mg doravirine or 800 mg darunavir (Prezista) plus 100 mg ritonavir. In addition they received 2 nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), either tenofovir DF/emtricitabine (Truvada; 87%) or abacavir/lamivudine (Epzicom; 13%). In each arm patients received matching placebos for the drug not assigned, so they all took 4 pills a day.

Treatment continued for 96 weeks. The primary endpoint was the proportion of people with HIV RNA below 50 copies/mLat week 48.

Results

"Doravirine is a novel once-daily NNRTI for first-line treatment with consistent efficacy regardless of baseline viral load and very good tolerability," the researchers concluded. The major advantage of doravirine over darunavir/ritonavir was its favorable effect on lipid levels.

While rates of discontinuation due to adverse events were low, most people who did not complete the study were either lost to follow-up or voluntarily withdrew consent -- 7% in the doravirine arm and 9% in the darunavir/ritonavir arm. Squires said that the large pill burden was commonly mentioned as a reason for withdrawal.

In order to be competitive in today's market, antiretrovirals must be easy to take as well as safe and effective, as a majority of people starting first-line treatment can now take 1 pill once daily.

Merck has developed a fixed-dose coformulation of doravirine, tenofovir DF, and lamivudine, which is being evaluated in ongoing studies. The Phase 3 DRIVE-AHEAD trial is comparing doravirine/tenofovir DF/lamivudine to efavirenz/tenofovir DF/emtricitabine (Atripla) for initial treatment, while DRIVE-SHIFT is evaluating a switch from another suppressive regimen to the doravirine coformulation, according to a Merck press release.

2/20/17

Sources

JM Molina, K Squires, PE Sax, et al.Doravirine is non-inferior to darunavir/r in phase 3 treatment-naive trial at week 48.Conference on Retroviruses and Opportunistic Infections. Seattle, February 13-16, 2017. Abstract 45LB.

Merck. Merck’s Doravirine, an Investigational Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for the Treatment of HIV-1 Infection, Met Primary Efficacy Endpoint in Pivotal Phase 3 Trial. Press release. February 14, 2017.