Safety and Efficacy of GSK2248761, a Next-Generation Nonnucleoside Reverse Transcriptase Inhibitor, in Treatment-Naive HIV-1-Infected Subjects

Abstract

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-], and concentration at the end of the dosing interval [C ]) 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 (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.

Unexpected Finding of Delayed-Onset Seizures in HIV-Positive, Treatment-Experienced Subjects in the Phase Iib Evaluation of Fosdevirine (Gsk2248761)

“…Although antiviral activity was observed in patients in the intent-to-treat exposed population, the short time on randomized FDV limited the ability to evaluate the standard HIV efficacy parameters for FDV. FDV was absorbed rapidly following oral dose administration, with a median time to maximum concentration of approximately 4 h in most subjects at either dose with exposures consistent with earlier predictive data [4]. There was a moderate to high degree of variability observed for most of the key PK parameters.…”

“…A series of subsequent Phase I drug interaction studies up to 21 days in duration failed to reveal any treatment-emergent toxicities in HIV-1 seronegative adults [3]. In a 7-day Phase I/IIa study, FDV monotherapy demonstrated short-term safety and efficacy at doses of 100 to 800 mg in treatment-naive subjects with HIV-1 [4]. Prior to Phase IIb, 187 human subjects had received up to 1,200 mg of FDV for 21 days or less without treatment-emergent serious adverse events (AEs), grade 3 or 4 drug-related AEs, or any AE trend compared with placebo.…”

Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations

“…In addition, we also evaluated the IQ values against WT virus for NNRTIs that were licensed or under clinical development. EFV exhibited the highest IQ, 178, and RPV displayed the lowest IQ, 4.5, followed by IDX899, with an IQ of 5.5 (20). Those NNRTIs all achieved efficacy in the clinic setting at these trough concentrations.…”

Non‐nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability

“…GSK 2248761 GSK 2248761 (formerly IDX 899) is an aryl phosphinate-indole with a 50% effective concentration (EC 50 ) of 36.9 ng/mL and activity against EFV-resistant strains [98]. GSK 2248761 is a weak CYP3A4 and CYP2D6 inhibitor [112].…”