THU0464 PHASE 2 CLINICAL TRIAL OF THE GI SAFETY OF A HYDROGEN SULFIDE-RELEASING ANTI-INFLAMMATORY DRUG (ATB-346)
Authors: John Wallace, Andre Buret, Peter Nagy, Marcelo Muscara, Gilberto de Nucci
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Hydrogen sulfide (H<sub>2</sub>S) is a naturally occurring gaseous mediator produced by intestinal bacteria and various eukaryotic cells. H<sub>2</sub>S exerts anti-inflammatory, pro-resolution and cytoprotective effects <i>in vivo</i>. ATB-346 is an H<sub>2</sub>S-releasing derivative of naproxen, which in animals was shown to produce negligible gastrointestinal (GI) damage and bleeding. In human studies, ATB-346 was found to be much more potent and long-lasting than naproxen. A phase 2 open-label efficacy study demonstrated that ATB-346 (250 mg daily) significantly reduced pain in patients with osteoarthritis of the knee, and markedly suppressed cyclooxygenase (COX) activity. The aim of the present study was to determine if ATB-346 would induce less gastroduodenal ulceration than standard dose naproxen. <h3>Objectives:</h3> To determine if healthy subjects taking ATB-346 for 14 days would develop significantly less gastroduodenal ulcers (≥3 mm diameter with depth) than subjects taking an equi-effective dose of naproxen. <h3>Methods:</h3> This was a double-blind, active control, endoscopic study. 244 healthy volunteers completed the study. Upper GI endoscopy was performed prior to and on day 14 after commencing 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 thromboxane synthesis was measured on days 0, 7 and 14. Plasma H<sub>2</sub>S levels were also measured. <h3>Results:</h3> 53 subjects taking naproxen (42.2%) developed at least one ulcer, while only 3 subjects (2.5%) treated with ATB-346 developed at least one ulcer (p&lt;0.0001). The two drugs suppressed COX activity to the same extent (&gt;95%). Affected subjects in the naproxen group developed more ulcers (an average of 4 per subject) than in the ATB-346 group (an average of 1.3), and there was a much greater incidence of larger ulcers (≥5 mm diameter) in the naproxen group than in the ATB-346 group (125 vs 0, respectively). The incidence of gastro-esophageal reflux, abdominal pain and nausea was lower with ATB-346 than with naproxen. Plasma H<sub>2</sub>S levels were significantly elevated (by ∼50%; p&lt;0.001) in the ATB-346 group. <h3>Conclusion:</h3> Consistent with the pre-clinical studies, this phase 2 clinical trial demonstrated a dramatic reduction of upper GI ulcer formation in subjects treated with equi-effective doses of ATB-346 versus naproxen. The COX inhibition observed in this trial was consistent with a previous phase 2A trial that demonstrated significant pain relief with ATB-346 in patients with osteoarthritis of the knee. ATB-346 appears to be an effective and much safer alternative to existing NSAIDs. <h3><b>Disclosure of Interests:</b>&nbsp;:</h3> John Wallace: None declared, Andre Buret Shareholder of: Antibe Therapeutics, Peter Nagy: None declared, Marcelo Muscara Grant/research support from: Antibe Therapeutics, Gilberto de Nucci Shareholder of: Antibe Therapeutics, Employee of: BioLab Brasil&nbsp;