GSK's second integrase inhibitor looks potent and well-tolerated in early study

The experimental integrase inhibitor S/GSK1265744, which is being developed as a backup to S/GSK1349572 (GSK-572), also demonstrated high potency and good tolerability in early studies, researchers reported this week at the 49^th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.

At the International AIDS Society meeting this past July, researchers from GlaxoSmithKline and Shionogi reported the first data from their joint integrase inhibitor development programme. They presented findings from several laboratory studies and early clinical trials of GSK-572, which was characterised as having "unprecedented" anti-HIV activity.

This week, the team introduced another next-generation integrase inhibitor, GSK-744. Laboratory studies indicated that GSK-744 has many similarities to GSK-572 in terms of pharmacological properties, antiviral activity, and susceptibility to resistance.

Sherene Min presented results from the first clinical trial of GSK-744, which included both healthy HIV-negative and HIV-positive individuals. In this complex Phase I/IIa study, 18 HIV-negative volunteers (two of them women) were first randomly assigned to receive single escalating doses (5, 10, 25 and 50 mg) of GSK-744, or placebo. In the next part, 30 HIV-negative participants (one woman) took multiple escalating doses (5, 10, and 25) of GSK-744, or placebo, once-daily for 14 days. These participants received the drug as an oral suspension formulation.

The third part of the trial, conducted after a review of pharmacokinetic and safety findings, included eleven HIV-positive participants (all men) with a median CD4 count of approximately 390 cells/mm³. They could be either antiretroviral treatment-naive or treatment-experienced but off therapy for at least three months. Participants were randomly assigned to receive 30 mg GSK-744 monotherapy, or placebo, once-daily for ten days, followed by three days of no treatment then 14 days of combination antiretroviral therapy. These participants used a tablet formulation.

GSK-744 was generally well tolerated. Adverse events (including headache) were common, but most were mild to moderate and they occurred with similar frequency in the active drug and placebo groups. The researchers did not see any clinically significant trends in laboratory values or electrocardiograms (ECGs), a test of heart function.

Pharmacokinetic analysis showed that GSK-744 has an unusually long half-life in the body of 30 hours - nearly twice as long as GSK-572 - which might mean it could be taken less often.

GSK-744 demonstrated potent antiviral activity. Amongst the HIV-positive patients receiving 30 mg GSK-744 monotherapy, viral load fell by a median 2.6 log₁₀ copies/ml - similar to the 2.5 log₁₀ copies/ml drop seen with GSK-572 - versus 0.3 log₁₀ copies/ml in the placebo arm. Furthermore, antiviral activity extended beyond the dosing period. By Day 14, all but one participant (88%) achieved a viral level below 50 copies/ml.

In this short study, the researchers identified no emerging mutations that reduced HIV susceptibility to GSK-744, or that conferred resistance to raltegravir (Isentress), the sole approved integrase inhibitor, or to elvitegravir, another candidate further along in development.

The researchers concluded that, "S/GSK1265744 was well tolerated in healthy and HIV-infected subjects. The [pharmacokinetic] profile indicated that once-daily tablet doses of ≤ 30 mg would achieve target therapeutic concentrations. Potent short-term antiviral efficacy was shown with 30 mg once daily dosing."

During a conference call following the presentation, Dr Min said that researchers expect GSK-744 and GSK-572 to have similar types of drug interactions. Posters presented at the meeting indicated that GSK-572 does not have clinically relevant interactions with other antiretroviral drugs tested. It does interact with metals - found in certain antacids and vitamin/mineral supplements - but this can be overcome by taking GSK-572 two hours before or six hours after these products.