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IDX899, a novel HIV-1 NNRTI with high barrier to resistance, provides suppression of HIV viral load in treatment-naïve HIV-1-infected subjects
Abstract Content:
Background: IDX899, a second generation NNRTI, has potent antiviral activity against wild-type and NNRTI-resistant HIV-1 viruses in vitro and a high barrier to resistance. Favorable clinical safety and pharmacokinetics in healthy volunteers supported the current study which assessed antiviral activity, safety and pharmacokinetics of daily (QD) IDX899 in treatment-naïve HIV-1-infected subjects.
Methods: Thirty treatment-naïve patients with HIV-1 RNA ³ 5,000 copies/mL and CD4+ cell count ³ 200 cells/mm3 were enrolled and each consecutive cohort was randomized (8:2) to receive IDX899 (800, 400 or 200 mg) or placebo QD for 7 days. HIV-1 RNA levels were measured using the HIV-1 Roche COBAS Amplicor® 1.5 assay. IDX899 plasma levels were quantitated using a validated LC/MS-MS method.
Results: The protocol enrolled 30 patients (27 men and 3 women) with mean baseline CD4+ of 486.8 cells/mL and baseline viral load of 4.68 log10 copies/mL. Patients were infected with HIV-1 clades B or B/F. The mean log10 decreases in HIV-1 plasma RNA from baseline to Day 8 were 1.78, 1.78 and 1.83 in the 800, 400 and 200 mg cohorts, respectively. The placebo group showed a 0.05 log10 increase. Mean CD4+ count increased by 66.3, 65.5 and 67.4 cells/µL in the 800, 400 and 200 mg cohorts, respectively, while a mean decrease of 83.7 cells/µL was observed in the placebo cohort. All three doses achieved IDX899 trough levels which exceeded the protein binding-adjusted EC90 by more than 5- to 20-fold, consistent with the observed lack of PK/PD relationship. There were no treatment discontinuations, treatment emergent SAEs or dose-limiting toxicities. No discernable patterns in adverse events or laboratory abnormalities were observed.
Conclusions: Once daily oral IDX899 was well tolerated and demonstrated potent HIV-1 antiviral activity at all tested doses. The protocol was amended to add a 100 mg cohort which has been initiated.
Methods: Thirty treatment-naïve patients with HIV-1 RNA ³ 5,000 copies/mL and CD4+ cell count ³ 200 cells/mm3 were enrolled and each consecutive cohort was randomized (8:2) to receive IDX899 (800, 400 or 200 mg) or placebo QD for 7 days. HIV-1 RNA levels were measured using the HIV-1 Roche COBAS Amplicor® 1.5 assay. IDX899 plasma levels were quantitated using a validated LC/MS-MS method.
Results: The protocol enrolled 30 patients (27 men and 3 women) with mean baseline CD4+ of 486.8 cells/mL and baseline viral load of 4.68 log10 copies/mL. Patients were infected with HIV-1 clades B or B/F. The mean log10 decreases in HIV-1 plasma RNA from baseline to Day 8 were 1.78, 1.78 and 1.83 in the 800, 400 and 200 mg cohorts, respectively. The placebo group showed a 0.05 log10 increase. Mean CD4+ count increased by 66.3, 65.5 and 67.4 cells/µL in the 800, 400 and 200 mg cohorts, respectively, while a mean decrease of 83.7 cells/µL was observed in the placebo cohort. All three doses achieved IDX899 trough levels which exceeded the protein binding-adjusted EC90 by more than 5- to 20-fold, consistent with the observed lack of PK/PD relationship. There were no treatment discontinuations, treatment emergent SAEs or dose-limiting toxicities. No discernable patterns in adverse events or laboratory abnormalities were observed.
Conclusions: Once daily oral IDX899 was well tolerated and demonstrated potent HIV-1 antiviral activity at all tested doses. The protocol was amended to add a 100 mg cohort which has been initiated.