Article Text

THU0474 A Phase 1 Clinical Trial of ATB-346, A Gastrointestinal-Ssafe Nonsteroidal Anti-Inflammatory Drug
  1. J.L. Wallace
  1. Antibe Therapeutics Inc, Toronto, Canada


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.

Statistics from

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.