Merck has announced results of a pivotal phase 3 clinical trial evaluating the safety and efficacy of doravirine (MK-1439), an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI). The study met its primary efficacy endpoint of the proportion of participants achieving levels of HIV-1RNA less than 50 copies/mL after 48 weeks of treatment, demonstrating the non-inferiority of once-daily doravirine (DOR) to once-daily ritonavir-boosted darunavir (DRV+r), each administered with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC), in previously untreated (treatment-naïve) adults with HIV-1 infection. In addition, a secondary endpoint showed that the DOR-treated group had statistically significant lower levels of fasting low density lipoprotein cholesterol (LDL-C), versus the DRV+r group. Findings from the ongoing ‘DRIVE-FORWARD’ Phase 3 trial following 48 weeks of treatment were presented as a late-breaking abstract at the annual Conference on Retroviruses and Opportunistic Infections (CROI) being held in Seattle from Feb. 13-16, 2017.
“Improved understanding of the biology of HIV and growing clinical evidence from current therapies are advancing the management of HIV infection,” said Dr. Kathleen Squires, professor and director of infectious diseases, Thomas Jefferson University, Philadelphia. “The results of this study provide solid evidence of the efficacy and safety profile of doravirine as a potential treatment option for treatment-naïve HIV-1 patients.”
In the trial, after 48 weeks of treatment, the proportion of participants achieving levels of HIV-1 RNA less than 50 copies/mL following once-daily DOR (100 mg) or once-daily DRV+r (800 mg and 100 mg respectively), each in combination with either TDF/FTC or ABC/3TC, was 83.8 percent (321/383) and 79.9 percent (306/383), respectively; with a treatment difference (95 per cent confidence interval) of 3.9 [-1.6, 9.4]. Increases in mean CD4+ T-cell counts from baseline were similar for the DOR and DRV+r treatment groups: 193 and 186 cells/mm3, respectively.
In addition, comparable efficacy was observed for participants with baseline levels of HIV-1 RNA greater than 100,000 copies/mL: 81.0 percent (64/79) for DOR and 76.4 percent (55/72) for DRV+r; with a treatment difference (95% confidence interval) of 3.0 [-11.2, 17.1]. One out of 383 participants developed phenotypic and genotypic resistance in the DOR arm (the patient came off study at Week 24 because of non-adherence). None of the 383 participants receiving DRV+r developed phenotypic and genotypic resistance.
The rates of reported adverse drug reactions were 31 percent (117/383) for DOR and 32 percent (123/383) for DRV+r. Discontinuations due to adverse events for the DOR and DRV+r treatment groups were 2 percent (6/383) and 3 percent (12/383), respectively. The most common adverse events for DOR and DRV+r (occurring in greater than or equal to 10 percent of participants) were: diarrhea (14% vs. 22%); headache (14% vs. 11%); nausea (11% vs. 12%) and nasopharyngitis (8% vs. 10 %), respectively.
Analysis of fasting serum blood lipids for the DOR and DRV+r treated groups showed a statistically significant difference (p<0.0001) in mean changes from baseline in the levels of LDL-C (-4.5 mg/dL vs. +9.9 mg/dL) and non-high density lipoprotein cholesterol (non-HDL-C) (-5.3 mg/dL vs. +13.8 mg/dL), respectively. Mean changes from baseline in total cholesterol, high density lipoprotein cholesterol (HDL-C) and triglycerides for the DOR- treated group and the DRV+r- treated group were -1.4 mg/dL, +3.9 mg/dL, and -3.1 mg/dL vs. +17.9 mg/dL, +4.2 mg/dL, and +22 mg/dL, respectively.
“Merck has been at the forefront of research into HIV for three decades,” said Dr. George Hanna, associate vice president, clinical research, Merck Research Laboratories. “We are encouraged by these results, which provide additional insights into the efficacy and safety of doravirine.”