Clinical Trials

Date: 2017-05-27

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 9th International Conference on HIV Science (IAS 2017)

Company: Merck&Co (USA - NJ)

Product: doravirine (MK-1439)

Action mechanism:

• non-nucleoside reverse transcriptase inhibitor (NNRTI). Doravirine is an investigational non-nucleoside reverse transcriptase inhibitor being evaluated for the treatment of HIV-1 infection. In early clinical studies, doravirine demonstrated a pharmacokinetic profile supportive of once-daily dosing and the ability to be dosed with or without food.

Disease: HIV-1 infection

Therapeutic area: Infectious diseases

Country: Australia, Belgium, Canada, Chile, Colombia, Denmark, Germany, Guatemala, Honduras, Israel, Mexico, The Netherlands, New Zealand, Peru, Portugal, Puerto Rico, Russian Federation, South Africa, Spain, Switzerland, Taiwan, Thailand, UK, USA

Trial details:

• DRIVE-AHEAD is an ongoing Phase 3 multicenter, double-blind, randomized, active comparator-controlled clinical trial evaluating the safety and efficacy of a once-daily, single-tablet, fixed-dose combination containing doravirine 100 mg, lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg versus a once-daily, single-tablet, fixed-dose combination containing efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg in treatment-naïve HIV-1 infected adults. The primary endpoint of the clinical trial was the proportion of participants with levels of HIV-1 RNA <50 copies/mL at Week 48. The primary safety endpoint was the proportion of participants with neuropsychiatric adverse events through Week 48 in the following pre-specified categories: dizziness, sleep disorders and disturbances, and the inability to think clearly or concentrate. The trial consists of a 96-week double-blind treatment period (base study) and an open label extension after participants complete the base study.(NCT02403674)

Latest news:

• • On July 25, 2017, Merck&Co announced the presentation of results from the DRIVE-AHEAD study at the 9th International Conference on HIV Science (IAS 2017) taking place in Paris, France, from July 23-26, 2017. Merck&Co plans to Submit New Drug Applications with the FDA in Q4 2017.
• DRIVE-AHEAD is the second of two pivotal Phase 3 clinical trials evaluating the efficacy and safety of doravirine 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.
• After 48 weeks of treatment, 84 percent 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 percent (95 percent 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 percent 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 percent versus 37.1 percent); sleep disorders and disturbances (12.1 percent versus 25.5 percent); and inability to think clearly or concentrate (4.4 percent versus 8.2 percent). 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.
• 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 percent; 229/364), representing a -31.9 percent treatment difference (95 percent 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 percent vs. 12 percent); diarrhea (11 percent vs. 14 percent); nasopharyngitis (11 percent vs. 9 percent); dizziness (9 percent vs. 37 percent); nausea (8 percent vs. 11 percent); abnormal dreams (5 percent vs. 12 percent) and, rash (5 percent vs. 12 percent), 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.

       

Is general: Yes