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New Integrase Inhibitor, S-1360
Reported by Jules Levin
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We all know there is a pressing need for new classes of anti-HIV drugs with no cross-resistance and that target new steps in the viral reproduction process. HIV produces reverse transcriptase enzymes (AZT, d4T, 3TC, abavacir, efavrirenz, etc target this enzyme), protease enzyme (Kaletra, indinavir, nelfinavir, etc), and integrase enzyme. Merck has been researching integrase inhibitors for 10 years and announced at the Resistance Workshop in Seville July 2 results from a study of their drug in monkeys and plans to test the drug in HIV-infected in the Fall 2002. S-1360 is an HIV integrase inhibitor being jointly developed by Shionogi and GlaxoSmithKline.
A number of entry inhibitors are in development. T-20 is the entry inhibitor furthest along in development and is in large phase III studies. These study results were presented at this conference and were very positive. You can read them on the NATAP website in the conference highlights. As a result T-20 is expected to be approved by the FDA in early 2003. An expanded access program is expected to be started by Roche & Trimeris in the Fall 2002. T-20 is administered twice daily by subcutaneous injection, and does not appear so far to have major side effects except for injection site reactions.
In the test tube S-1360 appears to be potent (EC50 of 63 ng/mL). At the Conference researchers reported results from a study of oral administration of S-1360 in healthy volunteers. In this study subjects received escalating multiple doses under fed conditions. Several doses were given to study subjects including 500 mg every 12 hours, 1000 mg every 12 hours, 2000 mg every 12 hours, or a placebo. 24 subjects were enrolled in this study with 18 receiving S-1360 and 6 receiving placebo.
Investigators reported S-1360 was readily absorbed with an average time to peak blood drug levels of 2.25 to 3 hours following repeat dosing. Repeat dosing did not result in significant accumulation meaning elimination was ok. An approximate proportionate increase (dose response) was observed for AUC (total drug blood levels during dosing period) and Cmax(peak drug blood level) between the 1000 and 2000 mg dose groups. S-1360 plasma protein binding ranged from 98.23 to 99.98% in vivo.
Investigators reported the drug was generally well tolerated following administration of a single dose up to 2000 mg and twice daily dosing up to 2000 mg for 11 days. Where adverse events were reported they were of mild to moderate severity and resolved spontaneously. Headache was the most frequently reported adverse event.
They are planning to move ahead and test this drug in HIV+ individuals. GSK has a development program for integrase inhibitors so if this particular drug is not successful others are in development.
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