icon-folder.gif   Conference Reports for NATAP  
  42nd ICAAC Meeting
San Diego, Sept 27-31, 2002
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Integrase Inhibitors Advancing: S-1360 & metabolic abormalities
Reported by Jules Levin
  At the final day's oral symposium on New Antiretroviral Drugs, not much new was presented. But new information was presented by GlaxoSmithKline in a poster today on their newly developed integrase inhibitor and this is described below. The symposium was mostly a review of information reported for the first time to the public at the Retroviral Conference and this Summer's Intl Confernce at Barcelona and the Resistance Workshop. Daria Hazuda reviewed the integrase inhibitor Merck is developing today and at the Resistance Workshop. Hazuda is leading the research effort at Merck to develop this brand new drug. This program has been ongoing for years at Merck and it has been a struggle for years to finally come up with a clinical candidate. At the Resistance Workshop Hazuda talked about the pre-clinical research of L-870812. Currently, a sister drug L-870810 is being studied in healthy volunteers. As David Margolis, MD, said in his report for NATAP from the Workshop: "Ending 2 years of troubling silence since this group first described the antiretroviral activity of diketobutanoic acids (DKAs) that specifically and potently inhibit the critical strand transfer step of the integration of the HIV provirus into the human genome, Hazuda and Young drew back the curtain at the Resistance Workshop with an impressive presentation to reveal oral integrase inhibitors ready for Phase I human study". This Fall Merck expects to begin a 10 day study of 810 in 20 HIV-infected patients. It appears as though 810 will likely be taken twice a day in humans. Here are links to reports on S-1360 from the Resistance Workshop.
Brand New Drugs for HIV: L-870812, integrase inhibitor
L-870812 and Resistance by David Margolis, MD
In "Differential Effects Between HIV-integrase Inhibitor S-1360 and HIV Protease Inhibitors on Fat Metabolism an Retinoid Signaling in Vitro" (abstract H-191p), Glaxo researchers today reported test tube results from a study to determine the effects of S-1360 on fat metabolism and retinoid signaling in vitro.
Mouse cells were treated in the test tube with indinavir, nelfinavir, and S-1360 to see the effects on fat metabolism, triglyceride signaling, retinoid signaling, and key metabolic genes. It's important to bear in mind that test tube studies do not necessarily predict the outcome in humans or HIV+ persons.
Glaxo researchers reported that S-1360 had no impact on in vitro adipogenesis. The mouse cells were cultured in the presence of S-1360 or nelfinavir under conditions to promote adipogenesis. Measurement of fat produced after 7 days in culture showed that nelfinavir totally inhibited fat accumulation whereas S-1360 had no effect during adipogenesis.
The mouse cells were cultured for 7 days under conditions that promote adipogenesis in order to form mature fat cells. Treatment of these cells with nelfinavir increased liipolysis (fat breakdown) in mature fat cells by 54% while treatment woth S-1360 had no effect.
S-1360 had no impact on gene expression involved in fat metabolism but nelfinavir did. Previously it was reported by Glaxo that indinavir was the only PI to stimulate the activity of a retinoic acid responsive gene. S-1360 had no effect on this gene.Nelfinavir increased triglycerides synthesis but S-1360 had no significant effect on liver triglyceride synthesis.
Glaxo researchers said the data presented here from pre-clinical studies in vitro show that while select HIV-protease inhibitors affected fat metabolism, retinoid signaling, adipocyte gene expression, and hepatic triglyceride synthesis, the HIV integrase inhibitor did not. In particular, decreased adipogenesis and increased fat catabolism, thought to contribute to liodystrophy, were not caused by S-1360. They said the lack of S1360 effect on triglyceride synthesis suggests a reduced potential for elevated lipids. And they added that the lack of S1360 effect on retinoid regulated osteoblast-specific alkaline phosphatase suggests a reduced potential for bone disorders. The researchers also added, appropriately, that it is difficult to predict the outcome in patients based on these test tube studies. But they feel the data suggests that S1360 has the potential for a reduced effect of metabolic abnormalities compared to certain protease inhibitors.
I think that in vitro or test tube studies performed pre-clinically on HIV drugs in use now, have often not accurately predicted the response in patients. But these types of studies ought to be conducted in the drug development process.