idx-899 and HIV-Infections

Antiretroviral drug resistance is one of the complications of highly active antiretroviral therapy (HAART). Second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) are being developed for use in patients infected with HIV-1 because of the enhanced activity of these inhibitors against viruses that are resistant to the first-generation NNRTIs. IDX-899 (GSK-2248761), under development by Idenix Pharmaceuticals Inc and ViiV Healthcare, is an aryl phosphinate-indole second-generation NNRTI that potently and selectively inhibits wild-type and NNRTI-resistant HIV-1 in vitro. Preclinical data for IDX-899 suggest a significantly greater barrier to resistance compared with that of the first-generation NNRTI efavirenz. Two pathways of resistance have been identified for IDX-899 in vitro that include Glu138Lys and Val90Ile/Tyr181Cys mutations. Pharmacokinetic studies demonstrated that IDX-899 exhibits linear, dose-proportional and food-dependent pharmacokinetics; Cmin concentrations achieved with this drug allow once-daily dosing. In phase I clinical trials, IDX-899 reduced HIV-1 RNA and increased CD4+ cell counts in treatment-naïve patients infected with HIV-1. At the time of publication, a phase II clinical trial of IDX-899 was being conducted.

Topics: Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Indoles; Phosphinic Acids; Reverse Transcriptase Inhibitors

HIV type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV infection. NNRTI-based HAART regimes effectively suppress viral reproduction, are not cytotoxic and show favourable pharmacokinetic properties. First-generation NNRTIs suffer the rapid selection of viral variants, hampering the binding of inhibitors into the reverse transcriptase (RT) non-nucleoside binding site (NNBS). Efforts to improve these first inhibitors led to the discovery of second-generation NNRTIs that proved to be effective against the drug-resistant mutant HIV-1 strains. The success of such agents launched a new season of NNRTI design and synthesis. This paper reviews the characteristics of second-generation NNRTIs, including etravirine, rilpivirine, RDEA-806, UK-453061, BIRL 355 BS, IDX 899, MK-4965 and HBY 097. In particular, the binding modes of these inhibitors into the NNBS of the HIV-1 RT and the most clinically relevant mutant RTs are analysed and discussed.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Binding Sites; Cell Line; Drug Design; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indoles; Models, Molecular; Molecular Conformation; Nitriles; Phosphinic Acids; Pyrazoles; Pyridazines; Pyridines; Pyrimidines; Quinoxalines; Reverse Transcriptase Inhibitors; Rilpivirine

Fosdevirine (GSK2248761) is a non-nucleoside reverse transcriptase inhibitor with HIV-1 activity against common efavirenz-resistant strains. Two partially blind, randomized, Phase IIb studies were initiated (1 in treatment-naive and 1 in treatment-experienced subjects with HIV) to select a once-daily dose of fosdevirine for Phase III trials.. In the SIGNET study, treatment-naive subjects were randomized 1:1:1 to receive once-daily fosdevirine 100 or 200 mg or efavirenz 600 mg, each along with tenofovir disoproxil fumarate/emtricitabine 300 mg/200 mg or abacavir/lamivudine 600 mg/300 mg. In the SONNET study, treatment-experienced subjects with non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 were randomized 1:1:1 to treatment with fosdevirine 100 or 200 mg once daily or etravirine 200 mg twice daily, each along with twice-daily darunavir/ritonavir 600/100 mg and raltegravir 400 mg. The primary efficacy end point was the proportion of subjects with HIV-1 RNA<50 copies/ml. Safety and pharmacokinetics were also addressed.. A total of 35 subjects were exposed to fosdevirine 100 or 200 mg. Trials were halted when 5 treatment-experienced subjects (1 receiving fosdevirine 100 mg, 4 receiving fosdevirine 200 mg) developed new-onset seizures after ≥4 weeks of exposure to fosdevirine. There was no clear association between seizures and fosdevirine plasma drug levels. Time to seizure onset ranged from 28 to 81 days, and all 5 subjects experienced ≥1 seizure after drug discontinuation.. The delayed onset of seizures after fosdevirine exposure and persistence after discontinuation is without precedent in antiretroviral drug development, leading to additional investigation and underscoring the need for careful subject monitoring.

Topics: Anti-HIV Agents; Drug Substitution; Female; HIV Infections; HIV-1; Humans; Indoles; Male; Phosphinic Acids; Reverse Transcriptase Inhibitors; Seizures; Time Factors; Treatment Outcome; Withholding Treatment

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

Topics: Adult; Alkynes; Anti-HIV Agents; Argentina; Benzoxazines; Cyclopropanes; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indoles; Male; Mutation; Phosphinic Acids; Placebos; Reverse Transcriptase Inhibitors; Viral Load

Topics: Clinical Trials as Topic; HIV Infections; Humans; Indoles; Phosphinic Acids; Placebos; Reverse Transcriptase Inhibitors