A3 A PROOF-OF-CONCEPT, PHASE 2 CLINICAL TRIAL OF THE GI SAFETY OF A HYDROGEN SULFIDE-RELEASING ANTI-INFLAMMATORY DRUG (ATB-346)

Abstract

Objectives: Hydrogen sulfide (H?S) is a naturally occurring gaseous mediator produced by various eukaryotic cells and by intestinal bacteria. It can exert cytoprotective and analgesic effects. ATB-346 is an H?S-releasing derivative of naproxen that was found to be more potent and long-acting than naproxen. In animal studies, ATB-346 produced negligible gastrointestinal (GI) damage and bleeding, despite profound inhibition of cyclo-oxygenase (COX). A human efficacy study demonstrated that ATB-346 (250 mg daily) was very effective in reducing pain in patients with osteoarthritis of the knee, and inhibiting COX ac-tivity. This study tested the hypothesis that ATB-346 is GI safer than naproxen. Methods: This was a double-blind, active control study. 244 healthy volunteers com-pleted the study. Upper GI endoscopy was performed prior to and on day 14 after com-mencing treatment with naproxen (550 mg twice daily) or ATB-346 (250 mg once daily in the morning and placebo once daily in the evening). Whole blood thrombox-ane synthesis (COX activity) and plasma hydrogen sulfide levels were also measured. Results: For the primary endpoint, incidence of ulcers ≥3 mm in diameter, 53 sub-jects (42%) taking naproxen developed at least one ulcer, while only 3 subjects taking ATB-346 developed at least one ulcer (p<0.00001). The two drugs produced compa-rable suppression of systemic COX activity. Subjects in the naproxen group devel-oped more ulcers per subject (an average of 4) than in the ATB-346 group (1.3/subject), and a greater incidence of larger (≥5 mm diameter) ulcers (125 vs. 0), re-spectively. The incidence of abdominal pain, gastro-esophageal reflux and nausea were markedly lower with ATB-346 than with naproxen. Systemic COX activity was inhibited by 95% in both groups, and plasma H?S levels were signif icantly ele-vated in subjects treated with ATB-346 (by ~50%; p<0.001). Conclusions: As in pre-clinical studies, this phase 2 clinical trial demonstrated a dramatic increase in the GI safety of ATB-346 versus one of the most com-monly used NSAIDs, naproxen. ATB-346 produced equivalent suppression of COX to naproxen, consistent with a previous Phase 2A clinical trial that demon-strated significant pain relief in patients with osteoarthritis of the knee. ATB-346 appear to be an effective and much safer alternative to existing NSAIDs.