Background Hydrogen sulfide (H2S) is an endogenous signaling molecule that exerts powerful anti-inflammatory and cytoprotective effects. Linking an H2S-releasing moiety to an NSAID greatly reduces the gastrointestinal (GI) damaging effects of the NSAID, as demonstrated in extensive pre-clinical testing in animal models (mouse, rat, dog). ATB-346 is an H2S-releasing derivative of naproxen; the latter is considered the most cardiovascular-safe of all NSAIDs. In addition to the a profound reduction in GI toxicity with ATB-346 (significant decreases in ulceration and bleeding throughout the GI tract), plasma levels of ATB-346-derived naproxen in rats and dogs remained elevated much longer after administration of ATB-346 when compared to equimolar doses of naproxen. ATB-346 suppresses COX-1 and COX-2 in vivo and in vitro with similar potency to naproxen, and is effective in reducing inflammation in various animal models. We now report on the first human trial of ATB-346.
Methods ATB-346 was orally administered at a range of doses to healthy volunteers, both as a single dose, and as a daily (or twice-daily) dose for 14 days. Each cohort consisted of 8 subjects, with 6 receiving ATB-346 and 2 receiving placebo. A total of 8 cohorts were studied in the single-dose study (25 mg to 2000 mg), and 3 cohorts in the multiple-dose study (250 and 750 once daily, and 750 mg bid). All adverse events were recorded, and blood samples were drawn prior to and for at least 72 h after drug administration for measurement of ATB-346-derived naproxen levels. Routine cardiovascular, renal, hepatic and hematological biomarkers were monitored, along with clinical signs. Multiple ascending dose studies examined ATB-346 at doses of 250 and 750 mg once daily, and 750 mg twice daily.
Results ATB-346 treatment did not produce any serious adverse events across the dose-ranges and treatment paradigms studied, nor were there any significant gastrointestinal, cardiovascular renal, or hematological findings associated with administration of this drug. As in animals, ATB-346 administration to humans resulted in a marked prolongation of therapeutically relevant levels of naproxen in the blood, supporting the possibility of once daily dosing for chronic conditions.
Conclusions ATB-346 was very well tolerated and shown to be safe at all administered dose levels. These studies suggest a high level of safety of this drug, and support progression of testing to a relevant patient population in Phase 2 trials.
Disclosure of Interest J. Wallace Shareholder of: Antibe Therapeutics Inc., Employee of: Antibe Therapeutics Inc.