GSK-Shionogi researchers presented data
for GSK-572, which the company considers its lead integrase inhibitor compound,
at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment
and Prevention (IAS 2009) in July.
ICAAC, they presented further data in a series of posters
describing studies of GSK-572 interactions with other antiretroviral drugs (expected
to be clinically insignificant) and metal cations found in certain antacids and
vitamin/mineral supplements (which can be overcome by taking GSK-572 either 2
hours before or 6 hours after these products).
research team also introduced the company's "backup" integrase inhibitor
candidate, GSK-744. In laboratory and animal studies, GSK-744 was shown to have
good pharmacokinetic (PK) properties, potent antiviral activity, and a favorable
Min presented data from the first clinical trial of GSK-744 in humans. In Part
A of this Phase I/IIa study, 18 HIV negative volunteers (including 2 women) were
randomly assigned to receive single escalating doses (5, 10, 25, and 50 mg) of
GSK-744, or else placebo. In Part B, 30 HIV negative individuals (including 1
woman) received multiple escalating doses (5, 10, and 25) of GSK-744, or placebo,
once-daily for 14 days. In Parts A and B, participants used an oral suspension
formulation of GSK-744.
Part C, 11 HIV positive participants (all men) were randomly assigned to receive
30 mg GSK-744 monotherapy, or placebo, once-daily for 10 days, followed by 3 days
off treatment, then 14 days of combination antiretroviral therapy (ART). These
participants used a tablet formulation of the drug. In this cohort, the median
CD4 count was approximately 390 cells/mm3. Participants could be either antiretroviral
treatment-naive or treatment experienced but off therapy for at least 3 months.
pharmacokinetic properties were dose-proportional over the dosage range studied
in HIV negative participants.|
drug did not require boosting and could be administered with or without food.|
was generally well tolerated in both the HIV negative and HIV positive cohorts.|
events were mostly mild-to-moderate and occurred at similar rates in the GSK-744
and placebo arms.|
was the most commonly reported adverse event (7% in GSK-744 arm, 15% in placebo
were no clinically significant changes in laboratory markers or electrocardiogram
(ECG) heart rhythm tests.|
had a half-life of about 30 hours.|
exhibited potent antiviral activity similar to that of GSK-572.|
HIV positive patients receiving GSK-744 monotherapy, viral load fell by a median
2.6 log copies/mL.|
activity extended beyond the 10-day dosing period, with viral suppression maintained
through day 14. |
day 14, all but 1 patient (88%) had HIV RNA below 50 copies/mL.|
detected no mutations known to confer resistance to the sole approved integrase
(Isentress), or to Gilead's investigational integrase inhibitor elvitegravir.|
new GSK-744 resistance mutations emerged during the study period.|
on these findings, the researchers concluded, "S/GSK1265744 was well tolerated
in healthy and HIV-infected subjects. The PK 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."
a conference call following the presentation, Min said that many characteristics
of GSK-744 and GSK-572 were similar, but GSK-744 has a much longer half-life,
nearly double that of GSK-572. She also indicated that the 2 compounds are expected
to have similar interactions with other drugs.
Research Triangle Park, NC; ITZ111451 Investigators, Research Triangle Park, NC;
Shionogi & Co, Ltd, Osaka, Japan.
Min, E DeJesus, L McCurdy, and others. Pharmacokinetics (PK) and Safety in Healthy
and HIV-Infected Subjects and Short-Term Antiviral Efficacy of S/GSK1265744, a
Next Generation Once Daily HIV Integrase Inhibitor. 49th Interscience Conference
on Antimicrobial Agents and Chemotherapy (ICAAC 2009). San Francisco. September
12-15, 2009. Abstract H-1228.
A Sato, T Seki, M Kobayashi, and others.
In vitro passage of drug resistant HIV-1 against a next generation integrase inhibitor,
S/GSK1349572. ICAAC 2009. Abstract H-932.
Song, S Min, J Borland and others. Lack of Interaction between the HIV Integrase
Inhibitor, S/GSK1349572, and Tenofovir Disoproxil Fumarate (TDF) in Healthy Subjects.
ICAAC 2009. Abstract A1-1303.
Song, S Min, J Borland and others. The Effect of Ritonavir-Boosted Protease Inhibitors
(Pis) on the HIV Integrase Inhibitor, S/GSK1349572, in Healthy Subjects. ICAAC
2009. Abstract A1-1304.
Song, A Patel, S Min, and others. Evaluation of Antacid and Multivitamin (MVI)
Effects on S/GSK1349572 Pharmacokinetics (PK) in Healthy Subjects. ICAAC 2009.