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ICAAC 2012: Long-acting Integrase Inhibitor S/GSK1265744 Active Against HIV Subtypes


The experimental 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 2012) 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 3 development and has demonstrated good efficacy and tolerability in both treatment-naive and treatment-experienced patients.

Researchers also found apromising back-up compound, S/GSK1265744 (or S/GSK744 for short). A previous Phase I study showed that orally administered S/GSK744 exhibited robust antiviral activity, with a 30 mg once-daily monotherapy dose suppressing HIV RNA by about 2.5 log after 11 days.

They 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 -- or pretty much any other antiretroviral currently available or under development.

At the XIX International AIDS Conference this past 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 may be possible.

At ICAAC, Tomokazu Yoshinaga, PhD, presented data on S/GSK1265744's in vitro anti-HIV activity and resistance profile. In this laboratory study, researchers looked at how well S/GSK744 works against subtypes of 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 that confer resistance to other integrase inhibitors.


  • S/GSK744 showed antiviral activity against a broad range of HIV clinical isolates from patients including HIV-1 subtypes A through G 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 protein-adjusted IC50 estimate 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 infected with HIV-1 IIIB to S/GSK744 for up to 112 days did not produce any highly resistant mutations (maximum 8.4-fold resistance).
  • Bioengineered site-directed mutant clones containing single signature mutations that confer resistance to raltegravir or elvitegravir generally showed less than a 2 fold-change in susceptibility to S/GSK744.
  • The notable exceptions were the Q148K and Q148R mutations, with about a 5-fold change.
  • Susceptibility to S/GSK744 was further reduced in clones containing double mutations, but even these showed less than a 12-fold change.

The researchers concluded thatS/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 2b trial of the S/GSK744 nano-suspension in combination with a long-acting injectable formulation of the NRTI rilpivirine (Edurant) as maintenance therapy after participants achieve viral suppression using a traditional 3-drug antiretroviral regimen is currently underway.



T Yoshinaga, M Kobayashi, T Seki, 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 (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract H-550.

Other Source Dose Ranging Study of GSK1265744 Plus Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus-1 (HIV-1) Virologic Suppression Followed by Virologic Suppression Maintenance by GSK1265744 Plus Rilpivirine. Last Updated on July 12, 2012.