Promising Data on GSK572 Integrase Inhibitor, Phase 3 Studies to Begin
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.
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.
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.
a planned interim analysis at 16 weeks, GSK572 demonstrated "rapid
and robust" antiviral activity greater than that of efavirenz:
10 mg: 96% with HIV RNA < 50 copies/mL;
25 mg: 92%;
50 mg: 90%;
taking GSK572 had a significantly shorter time to reach undetectable
viral load compared with efavirenz recipients.
participants taking GSK572 had confirmed virological failure at
cell gains ranged from 153 to 176 cells/mm3 in the GSK572 arms,
compared with 116 cells/mm3 in the efavirenz arm.
was generally well-tolerated.
of participants in the GSK572 arms experienced at least moderate
drug-related adverse events, compared with 18% in the efavirenz
drug-related serious adverse events were observed in the GSK572
arms (1 suicide was considered possibly related to efavirenz).
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."
data, they added, "fully support progression of S/GSK1349572 into
Phase 3 evaluation."
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.
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
(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:
pathway mutation plus at least 1 secondary mutation -- increased
fold-change, or reduced susceptibility, to GSK572;
mutation alone, or N155 or Y143 pathway mutations -- minimal change
in GSK572 susceptibility (no one in this study actual had an isolated
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).
rates differed, however, based on pre-existing resistance pattern:
+ secondary mutations: 33% with virological response (mean
HIV RNA decrease 0.72 log);
and Y143 mutations: 100% response (mean decrease 1.82 log).
was generally well-tolerated with no serious drug-related adverse
new integrase resistance mutations emerged and only minimal changes
in GSK572 susceptibility occurred during the functional monotherapy
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."
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,
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
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.
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.