Efficacyand safetyfromaphase 2b trialof sm04690, a novel, intra-articularwnt pathway inhibitor for the treatment of osteoarthritis of the knee

pleted the study.UpperGI endoscopywas performedprior to andonday14 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 (COX activity) and plasma hydrogen sulfide levels were also measured. Results: For the primary endpoint, incidence of ulcers≥3 mm in diameter, 53 subjects (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 comparable suppression of systemic COX activity. Subjects in the naproxen group developed 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), respectively. 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 H2S levels were significantly elevated 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 commonly used NSAIDs, naproxen. ATB-346 produced equivalent suppression of COX to naproxen, consistent with a previous Phase 2A clinical trial that demonstrated significant pain relief in patients with osteoarthritis of the knee. ATB-346 appear to be an effective and much safer alternative to existing NSAIDs.