Long-acting integrase inhibitor S/GSK1265744 active against multiple HIV subtypes

Published: 17 September 2012

The integrase inhibitor S/GSK1265744 exhibited potent and prolonged activity against a broad range of HIV subtypes, was active against clones with resistance to raltegravir (Isentress) and elvitegravir, and appears to have a high barrier to resistance, according to a presentation at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this week in San Francisco.

Integrase inhibitors work by preventing HIV from inserting its genetic material into a host cell's chromosomes, a necessary step in viral replication. Researchers at Shionogi and ViiV Healthcare set out to discover integrase inhibitors that had a better resistance profile than earlier drugs in the class, could be administered once daily and were suitable for inclusion in a single-tablet regimen.

Their lead compound, dolutegravir (formerly S/GSK1349572), is now in phase III development and has demonstrated good efficacy and tolerability in both treatment-naive and treatment-experienced people with HIV.

They also found a promising 'back-up' compound, S/GSK1265744 (or S/GSK744 for short). In a previous phase I study, orally administered S/GSK744 exhibited robust antiviral activity, with a 30mg once-daily monotherapy dose suppressing HIV RNA by about 2.5 log10 copies/mL after eleven days.

Researchers also determined that an injectable formulation of the drug binds strongly to human proteins, enabling it to remain active in the body much longer than dolutegravir.

At the 19th International AIDS Conference (AIDS 2012) this July, investigators reported that a nano-suspension of S/GSK744 was generally safe and well tolerated in healthy HIV-negative volunteers and had a half-life of 21 to 50 days after a single injection, suggesting once-monthly dosing might be possible.

At ICAAC, Tomokazu Yoshinaga from Shionogi presented data on S/GSK744's in vitro anti-HIV activity and resistance profile.

In this laboratory study, researchers looked at how well S/GSK744 works against HIV-1 and HIV-2 in cell cultures, as well as the effect of human serum proteins. To assess cross-resistance, they tested S/GSK744 against clones containing mutations confer resistance to other integrase inhibitors.

S/GSK744 showed antiviral activity against a range of HIV clinical isolates from patients including HIV-1 subtypes A to G and from Group M, HIV-1 Group O and HIV-2.

When tested in human peripheral blood mononuclear cells, S/GSK744 had a 50% inhibitory concentration (IC50) – the amount needed to inhibit HIV replication by half – of 0.22 nanomolar (nM).

When exposed to human serum, the estimated protein-adjusted IC50 was 102 nM, compared to 38 nM for dolutegravir, 20 for the experimental integrase inhibitor elvitegravir, and 5.6 for the sole approved integrase inhibitor raltegravir.

Exposing MT-2 cells (a laboratory cell line commonly used in retrovirus research) infected with HIV-1 IIIB to S/GSK744 for up to 112 days did not produce any highly resistant mutations.

Bioengineered site-directed mutant clones containing single signature mutations that confer resistance to raltegravir or elvitegravir generally showed less than a two-fold change in susceptibility to S/GSK744.

The notable exceptions were the Q148K and Q148R mutations, with about a five-fold change. Susceptibility to S/GSK744 was further reduced in clones containing double mutations, but even these showed less than a twelve-fold change.

The researchers concluded that S/GSK744 demonstrated "low nM activity against a broad range of HIV-1 subtypes and HIV-2", shows "limited cross-resistance to both raltegravir and elvitegravir", and has "a high barrier to resistance in vitro".

"These encouraging antiviral data and demonstrated human pharmacokinetics, suggest S/GSK744 may have a favourable profile for both HIV treatment and PrEP [pre-exposure prophylaxis]," they added. 

A phase IIb trial of the S/GSK744 nano-suspension in combination with a long-acting injectable formulation of the NRTI rilpivirine (Edurant) is currently underway.

Reference

Yoshinaga T et al. Antiviral characteristics of S/GSK1265744, an HIV integrase inhibitor (INI) dosed by oral or long-acting parenteral injection. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract H-550, 2012. View the abstract on the conference website.

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