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SPD754: new NRTI, early study results
Reported by Jules Levin
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The conference is ending now, it's enough already. There's no fat free milk in France to have with your coffee. And the Chinese restaurants don't have hot mustard. At the Late Breaker oral session which is the last session before the closing ceremony ongoing now, the first results were reported from a study in patients with this new NRTI. Pedro Cahn from Buenos Aires reported on this 10-day monotherapy study. SPD754, from Shire Pharmaceuticals, is a cytidine analogue NRTI: (-) enamtiomer. Preclinical studies demonstrate activity against HIV-1 isolates resistant to 3TC, AZT and other NRTIs. Cahn reported that in vitro the drug has not shown mitochondrial toxicity. The drug selects for the K65R mutation, which is associated with tenofovir.
This study is a double-blind placebo controlled trial of 4 different doses, and two different regimens (twice and once daily). Sixty treatment-naive patients are studied. CD4 counts were >250, HIV viral load 5,000 to 100,000 copies/ml. Regimens were: 800 mg twice daily, 600 mg twice daily or 1200 mg once daily, 400 mg twice daily or 800 mg once daily, and 200 mg twice daily.
62 patients completed the study. 11-13 patients were in each dose regimen. 46-70% male, viral load 4.2 to 4.5 log. CD4 count was 400-500 cells. The placebo group showed no reduction in viral load, but the patients receiving SPD754 had about a -1.14 to -1.65 log reduction in viral load after 10 days on the drug. There was a trend towards increasing viral load reduction with increasing dose. Placebo patients had no viral load reduction. Using the low dose of 400 mg twice daily 64% of patients had >1.0 log viral load reduction after 10 days. 75-90% of patients receiving the other doses achieved >1 log reduction in viral load after 10 days on the drug. CD4 counts did not change but 10 days on drug is not much.
Some patients had increases in creatinine and lipase. A few patients had increases in ALT and AST. The most common adverse event reported was headache. Cahn said all doses were well tolerated. No deaths, serious adverse events, nor withdrawals were due to adverse events. All adverse events were mild. And he said that in general there was no apparent relationship between adverse events and treatment.
In sum, Cahn concluded SPD754 is highly potent in 10 days monotherapy with up to 1.65 log reduction in viral load. All doses showed >1.0 log viral load reductions. The drug is well tolerated with no dose limiting adverse events. Over 10 days of therapy the drug did not select for NAMS resistance.
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