Background Nonsteroidal anti-inflammatory drugs (NSAIDs) remain a mainstay of therapy for osteoarthritis, but their use is limited by their propensity to cause significant gastrointestinal (GI) bleeding and ulceration. Hydrogen sulfide (H2S) is an endogenous signaling molecule that has been shown to exert protective and pro-healing effects in the GI tract. We developed a series of H2S-releasing NSAIDs, and have now tested the lead drug (ATB-346) in a phase 2a clinical trial in patients with osteoarthritis. ATB-346 is a derivative of naproxen, the most cardiovascular-safe of the NSAID family. Data from a phase 1 clinical trial suggested that ATB-346 was significantly more potent and long-lasting than naproxen in terms of suppressing cyclooxygenase (COX) activity.
Objectives An open-label phase 2a trial was performed to determine if a low dose of ATB-346 (250 mg; equimolar to 160 mg naproxen), given once daily, would provide significant pain relief in patients with osteoarthritis. To be admitted to the trial, patients had to exhibit a ≥10 point increase in the WOMAC Visual Analog Score between their screening visit and the baseline study entry visit.
Methods 12 patients with osteoarthritis of the knee who met the inclusion criteria were recruited for the trial (diagnosis of OA ≥2 years; age 40–75; BMI ≤40). The WOMAC subscale pain score (0–20) was the primary endpoint. The patients were off anti-inflammatory medication for 5 days prior to starting this study. After recording the initial WOMAC subscale pain score, they began once daily oral treatment with ATB-346 (250 mg). Pain scores were recorded on the day prior to starting ATB-346 treatment (“day -1”), and on days 4 and 10 of treatment. Blood samples were collected for measurement of COX activity on days -1, 1, 4 and 10.
Results ATB-346 was safe and well tolerated. The mean WOMAC subscale pain score the day prior to initiation of treatment was 14.0 + 0.7. A significant decrease in the WOMAC subscale pain score was observed on day 4 (-4.3±1.0; p<0.01), with an even greater decrease on day 7 (-7.6±1.5; p<0.001). Whole blood COX activity was suppressed by more than 80% (p<0.01) on the first day of treatment, and continued to be suppressed throughout the study.
Conclusions The results of this study demonstrate that a low dose of ATB-346, given only once daily, produces a clinically and statistically significant reduction of pain in patients with osteoarthritis, that may exceed what can be achieved with standard doses of napoxen or celecoxib (1,2). The observed suppression of COX activity was consistent with the pain reduction data, supporting the conclusion that ATB-346 is considerably more potent and long-acting than naproxen. Extensive pre-clinical studies have demonstrated that ATB-346 has greatly improved GI safety as compared to naproxen and other commonly used NSAIDs.
Wittenberg et al. Arth Res Therap 2006; 8: R35 (doi: 10.1186/ar1854.
Disclosure of Interest J. Wallace Shareholder of: Antibe Therapeutics Inc, Employee of: Antibe Therapeutics Inc, D. Vaughan: None declared