By Liz Highleyman

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.

At 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).

The 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 toxicity profile.

Sherene 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.

In 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.

Results

	GSK-744 pharmacokinetic properties were dose-proportional over the dosage range studied in HIV negative participants.
	The drug did not require boosting and could be administered with or without food.
	GSK-744 was generally well tolerated in both the HIV negative and HIV positive cohorts.
	Adverse events were mostly mild-to-moderate and occurred at similar rates in the GSK-744 and placebo arms.
	Headache was the most commonly reported adverse event (7% in GSK-744 arm, 15% in placebo arm).
	There were no clinically significant changes in laboratory markers or electrocardiogram (ECG) heart rhythm tests.
	GSK-744 had a half-life of about 30 hours.
	GSK-744 exhibited potent antiviral activity similar to that of GSK-572.
	Among HIV positive patients receiving GSK-744 monotherapy, viral load fell by a median 2.6 log copies/mL.
	Antiviral activity extended beyond the 10-day dosing period, with viral suppression maintained through day 14.
	By day 14, all but 1 patient (88%) had HIV RNA below 50 copies/mL.
	Researchers detected no mutations known to confer resistance to the sole approved integrase inhibitor, raltegravir (Isentress), or to Gilead's investigational integrase inhibitor elvitegravir.
	No new GSK-744 resistance mutations emerged during the study period.

Based 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."

On 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.

GlaxoSmithKline, Research Triangle Park, NC; ITZ111451 Investigators, Research Triangle Park, NC; Shionogi & Co, Ltd, Osaka, Japan.

9/22/09

References

S 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.

I 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.

I 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.

I Song, A Patel, S Min, and others. Evaluation of Antacid and Multivitamin (MVI) Effects on S/GSK1349572 Pharmacokinetics (PK) in Healthy Subjects. ICAAC 2009. Abstract A1-1305.