Merck, known as MSD outside the United States and Canada, has announced the presentation of results from the DRIVE-AHEAD study, the second of two pivotal phase 3 clinical trials evaluating the efficacy and safety of doravirine, the company’s investigational, non-nucleoside reverse transcriptase inhibitor (NNRTI), for the treatment of HIV-1 infection. At 48 weeks, the study showed that a once-daily single tablet, fixed-dose combination of doravirine (DOR), lamivudine (3TC), and tenofovir disoproxil fumarate (TDF) met its primary efficacy endpoint of non-inferiority based on the proportion of participants achieving levels of HIV-1 RNA less than 50 copies/mL at 48 weeks of treatment, compared to a fixed-dose combination of efavirenz (EFV), emtricitabine (FTC), and TDF, in treatment-naïve adults infected with HIV-1.

In addition, through 48 weeks, statistically significantly fewer patients taking DOR/3TC/TDF reported pre-specified categories of neuropsychiatric events (dizziness, sleep disorders and disturbances, and inability to think clearly or concentrate) than patients receiving the EFV/FTC/TDF regimen. Treatment with DOR/3TC/TDF also showed a statistically significant lower change from baseline in fasting low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) compared to EFV/FTC/TDF at Week 48. Findings from the ongoing DRIVE-AHEAD phase 3 trial were featured as part of a late-breaking oral presentation session at the 9th International Conference on HIV Science (IAS 2017) taking place in Paris, France, from July 23-26, 2017.

“Data from DRIVE-AHEAD at 48 weeks show that a fixed-dose combination tablet containing doravirine achieved viral suppression in HIV-1 infected treatment-naïve adults, comparable to a fixed-dose combination containing efavirenz,” said Dr. Kathleen Squires, professor and director of infectious diseases, Thomas Jefferson University, Philadelphia, PA, a study investigator. “The results for doravirine are encouraging, as it may offer appropriate patients a new single-tablet treatment option.”

After 48 weeks of treatment, 84 per cent of the 364 treatment-naïve patients taking once-daily DOR/3TC/TDF achieved levels of HIV-1 RNA <50 copies/mL compared to 81 percent of the 364 patients taking once-daily EFV/FTC/TDF, with an estimated treatment difference of 3.5 per cent (95 per cent confidence interval; -2.0, 9.0). Increases in mean CD4+ T-cell counts from baseline for the DOR/3TC/TDF and EFV/FTC/TDF groups were 198 and 188 cells/mm3, respectively, with an estimated treatment difference of 10.1 (95 per cent confidence interval; -16.1, 36.3). In addition, comparable efficacy was observed across both treatment groups among individuals with high viral load (HIV-1 RNA >100,000 copies/mL) at baseline, which consisted of 69 patients in the DOR/3TC/TDF group and 73 patients in the EFV/FTC/TDF group (Observed Failure approach). Of those patients with a high viral load (HIV-1 RNA >100,000 copies/mL) at baseline, 81 percent in the DOR/3TC/TDF group and 81 percent in the EFV/FTC/TDF group achieved the study’s primary endpoint of <50 copies/mL of HIV-1 RNA, with a treatment difference of 1.0 percent (95 percent confidence interval; -12.4, 14.3).

The study also met its primary safety endpoint, showing that treatment with DOR/3TC/TDF resulted in fewer patients reporting events of several pre-specified neuropsychiatric adverse events compared to EFV/FTC/TDF by Week 48, including dizziness (8.8 per cent versus 37.1 per cent); sleep disorders and disturbances (12.1 percent versus 25.5 per cent); and inability to think clearly or concentrate (4.4 per cent versus 8.2 per cent). The 2-sided p-values for treatment differences with respect to these three pre-specified categories were p<0.001, p<0.001, and p=0.033, respectively.

Furthermore, the reported rates of drug-related adverse events were lower in the group taking DOR/3TC/TDF (31 percent; 113/364) versus the group taking EFV/FTC/TDF (63 per cent; 229/364), representing a -31.9 per cent treatment difference (95 per cent confidence

interval, -38.6, -24.8). Treatment discontinuations due to adverse events for DOR/3TC/TDF and EFV/FTC/TDF were 3 percent (11/364) and 7 percent (24/364), respectively.

The most commonly reported adverse events occurring in =10 percent of patients in the DOR/3TC/TDF group compared to the EFV/FTC/TDF group were: headache (13 per cent vs. 12 per cent); diarrhea (11 per cent vs. 14 per cent); nasopharyngitis (11 per cent vs. 9 per cent); dizziness (9 per cent vs. 37 per cent); nausea (8 per cent vs. 11 per cent); abnormal dreams (5 per cent vs. 12 per cent) and, rash (5 per cent vs. 12 per cent), respectively.

Treatment-emergent viral mutations leading to any drug-associated resistance was detected in 1.6 percent of patients in the group receiving DOR/3TC/TDF, and 3.3 percent of those in the EFV/FTC/TDF group, respectively, through Week 48.

An analysis of fasting lipid levels showed a statistically significant treatment difference in mean changes from baseline in fasting LDL-C and non-HDL-C between the two treatment groups (p<0.0001 for both cholesterol types). The mean changes from baseline in levels of fasting LDL-C and non-HDL-C among the group taking DOR/3TC/TDF was -1.6 mg/dL and -3.8 mg/dL, respectively; compared to the group taking EFV/FTC/TDF which was +8.7 mg/dL and +13.3 mg/dL, respectively.

“For more than 30 years, Merck has been at the forefront of HIV research and the development of new treatments that make a difference for people living with HIV,” said Dr. George Hanna, associate vice president, clinical research, Merck Research Laboratories. “The development of doravirine is the result of a decade of Merck research. Based on our encouraging phase 3 study findings, we plan to file regulatory applications in Q4 2017.”