Back HIV/AIDS HIV/AIDS Topics HIV Treatment More Promising Data on GSK572 Integrase Inhibitor, Phase 3 Studies to Begin Soon

More Promising Data on GSK572 Integrase Inhibitor, Phase 3 Studies to Begin Soon

S/GSK1349572 (better known as GSK572), the second-generation integrase inhibitor being developed jointly by Shionogi and ViiV Healthcare, continues to show potent antiviral activity with good tolerability, according to 2 studies presented at the XVIII International AIDS Conference (AIDS 2010) this week in Vienna. GSK572 worked against HIV with some raltegravir resistance mutations and has a high genetic barrier to resistance itself. Based on these findings, the companies announced the drug would soon enter Phase 3 trials.

GSK572 is an oral integrase inhibitor that can be taken once-daily without a booster. As previously reported, it demonstrated good bioavailability, potent antiviral activity, and little potential for drug interactions in laboratory and early clinical studies.

SPRING-1 Study

As described in a late-breaker presentation on Thursday, SPRING-1 is an ongoing Phase 2b trial comparing GSK572 versus efavirenz (Sustiva) in 205 treatment-naive patients. Most participants were men, 80% were white, the median age was 37 years, and the median baseline CD4 cell count was 324 cells/mm3.

Participants were randomly assigned (1:1) to receive GSK572 at doses of 10, 25, or 50 mg, or else 600 mg efavirenz once-daily. In addition, 67% also took tenofovir/emtricitabine (Truvada) and 33% took abacavir/lamivudine (Epzicom) as an NRTI backbone.


  • In a planned interim analysis at 16 weeks, GSK572 demonstrated "rapid and robust" antiviral activity greater than that of efavirenz:
    • GSK572 10 mg: 96% with HIV RNA < 50 copies/mL;
    • GSK572 25 mg: 92%;
    • GSK572 50 mg: 90%;
    • Efavirenz: 60%.
  • Patients taking GSK572 had a significantly shorter time to reach undetectable viral load compared with efavirenz recipients.
  • 2 participants taking GSK572 had confirmed virological failure at week 16.
  • CD4 cell gains ranged from 153 to 176 cells/mm3 in the GSK572 arms, compared with 116 cells/mm3 in the efavirenz arm.
  • GSK572 was generally well-tolerated.
  • 4%-8% of participants in the GSK572 arms experienced at least moderate drug-related adverse events, compared with 18% in the efavirenz arm.
  • No drug-related serious adverse events were observed in the GSK572 arms (1 suicide was considered possibly related to efavirenz).

Based on these findings, the researchers concluded, "S/GSK1349572 administered once-weekly without a [pharmacokinetic] booster was generally well tolerated, with potent antiviral activity at all doses tested."

These data, they added, "fully support progression of S/GSK1349572 into Phase 3 evaluation."

Coinciding with the presentations, Shionogi and ViiV Healthcare announced that it is commitment to a Phase 3 development program for the drug. The 50 mg dose has been selected for further testing in Phase 3 trials.

"There remains a significant need for additional medicines that can help address the complex treatment issues for HIV, and also help simplify treatment regimens for patients," said ViiV Healthcare Chief Scientific and Medical Officer John Pottage. "As a once-daily, unboosted integrase inhibitor, '572 could provide an important therapy for patients living with HIV. We look forward to confirming the safety and efficacy of this compound in Phase 3 studies, which are expected to begin by the end of the year."


VIKING was a smaller single-arm Phase 2b evaluating the safety and efficacy of GSK572 in treatment-experienced patients with pre-existing resistance to raltegravir (Isentress) -- the sole approved integrase inhibitor -- as well as any 3 antiretroviral drug classes.

This study enrolled 27 patients. Most were men and the average age was 48 years. Compared with SPRING-1, this group had more advanced HIV disease, with a median CD4 cell count of 110 cells/mm3; 26% had < 50 cells/mm3 and 59% had been diagnosed with AIDS. They had been on antiretroviral therapy for a median of 14 years and had taken a median 17 drugs.

All participants first received GSK572 at a dose of 50 mg once-daily as "functional monotherapy" (meaning it was the only active drug in their regimen) for 10 days. At day 11, background regimens were optimized and treatment continued through week 24.

Based on previous studies including the BENCHMRK trials, participants were categorized into 2 groups depending on pattern of raltegravir resistance mutations:

Q148 pathway mutation plus at least 1 secondary mutation -- increased fold-change, or reduced susceptibility, to GSK572;

Q148 mutation alone, or N155 or Y143 pathway mutations -- minimal change in GSK572 susceptibility (no one in this study actual had an isolated Q148 mutation).


  • 78% of participants overall achieved viral load < 400 copies/mL by day 11 or >0.7 log drop in HIV RNA (mean decrease 1.45 log).
  • Response rates differed, however, based on pre-existing resistance pattern:
    • Q148 + secondary mutations: 33% with virological response (mean HIV RNA decrease 0.72 log);
    • N155 and Y143 mutations: 100% response (mean decrease 1.82 log).
  • GSK572 was generally well-tolerated with no serious drug-related adverse events.
Few new integrase resistance mutations emerged and only minimal changes in GSK572 susceptibility occurred during the functional monotherapy phase.

"A strong correlation was observed between change from baseline in plasma HIV-1 RNA and baseline fold change susceptibility to S/GSK1349572," the investigators concluded. "S/GSK1349572 was generally well tolerated in this advanced HIV-1 infected population."

Investigator affiliations:

VIKING: University of North Carolina School of Medicine, AIDS Research Clinical Care, Chapel Hill, NC; Hôpital l'Archet, Nice, France; Hôpital Sainte Marguerite, Marseille, France; Hôpital Gui de Chauliac, Montpellier, France; Instituto de Salud Carlos III, Madrid, Spain; Georgetown University, Washington, DC; Fort Lauderdale, FL; Hôpital Paul Brousse, Villejuif, France; Shionogi & Co., Ltd., Osaka, Japan; GlaxoSmithKline, London, UK; GlaxoSmithKline, Research Triangle Park, NC.

SPRING: Hospital La Paz, IdiPAZ, Madrid, Spain; Vita-Salute San Raffaele University, Milan, Italy; University Hospital, Nantes, France; Botkin Hospital of Infectious Diseases, St. Petersburg, Russian Federation; Broward Health, Ft. Lauderdale, FL: University of Bonn, Bonn, Germany; University Medical Center, Hamburg-Eppendorf, Germany; Rocky Mountain CARES/DIDC, Denver, CO; Health Connections International, Amsterdam, Netherlands; GlaxoSmithKline, Oakville, Canada; GlaxoSmithKline, Research Triangle Park, NC.



J Eron, J Durant, I Poizot-Martin, and others. Activity of a next generation integrase inhibitor (INI), S/GSK1349572, in subjects with HIV exhibiting raltegravir resistance: initial results of VIKING study (ING112961). XVIII International AIDS Conference. Vienna, July 18-23, 2010. Abstract MOAB0105.

J Arribas A Lazzarin, F Raffi, and others. Once-daily S/GSK1349572 as part of combination therapy in antiretroviral naïve adults: rapid and potent antiviral responses in the interim 16-week analysis from SPRING-1 (ING112276). XVIII International AIDS Conference. Vienna, July 18-23, 2010. Abstract THLBB205.

Other Sources

Shionogi-ViiV Healthcare LLC. Shionogi-ViiV Healthcare LLC Presents Positive Data on Investigational Once-Daily Integrase Inhibitor at International AIDS Conference. Press release. July 22, 2010.

Shionogi-ViiV Healthcare LLC. Shionogi-ViiV Healthcare Announces Commitment to Phase III Development Programme for Investigational Once-Daily HIV Integrase Inhibitor. Press release. July 21, 2010.