A proof‐of‐concept, Phase 2 clinical trial of the gastrointestinal safety of a hydrogen sulfide‐releasing anti‐inflammatory drug

Abstract

Background and Purpose ATB‐346 is a hydrogen sulfide (H2S)‐releasing anti‐inflammatory and analgesic drug. Animal studies demonstrated negligible gastrointestinal (GI) damage despite marked inhibition of COX activity and significant analgesic and anti‐inflammatory effects. In humans, ATB‐346 (250 mg once daily) was found to inhibit COX to the same extent as naproxen (550 mg twice daily). Experimental Approach Two hundred forty‐four healthy volunteers completed a 2‐week, double‐blind study, taking either ATB‐346 (250 mg once daily) or naproxen (550 mg twice daily), with upper GI ulceration being examined endoscopically. Key Results Forty‐two per cent of the subjects taking naproxen developed at least one ulcer (≥3‐mm diameter), while only 3% of the subjects taking ATB‐346 developed at least one ulcer. The two drugs produced comparable and substantial (>94%) suppression of COX activity. Subjects in the naproxen group developed more ulcers per subject than ATB‐346‐treated subjects and a greater incidence of larger ulcers (≥5‐mm diameter). The incidence of dyspepsia, abdominal pain, gastro‐oesophageal reflux, and nausea was lower with ATB‐346 than with naproxen. Subjects treated with ATB‐346 had significantly higher plasma levels of H2S than those treated with naproxen. Conclusions and Implications This Phase 2B study provides unequivocal evidence for a marked reduction of GI toxicity of the H2S‐releasing analgesic/anti‐inflammatory drug, ATB‐346, as compared to the conventional dose of naproxen that produced equivalent suppression of COX. Linked Articles This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc

Hydrogen Sulfide as Potential Regulatory Gasotransmitter in Arthritic Diseases

“…In animal models, NSAIDs conjugated to H 2 S, i.e., naproxen and celecoxib, demonstrated a strong protective effect on gastrointestinal epithelium compared to the toxic effect of the parent drug [102]. For example, the H 2 S-releasing naproxen, called ATB-346, which releases H 2 S via a hydrolytic mechanism [102], was demonstrated to have a greater anti-inflammatory and chondro-protective effect on osteoarthritic joints in animal models, reducing leukocyte migration and reducing TNF-α and NF-κB expression, and less gastrointestinal toxicity [102,140,141]. Recently, a phase II clinical trial investigating 244 healthy subjects demonstrated a drastic reduction of gastric ulcer investigated with endoscopy when treated with ATB-346 (42.2% vs. 2.5% ulcer development with naproxen and ATB-346, respectively).…”

“…Recently, a phase II clinical trial investigating 244 healthy subjects demonstrated a drastic reduction of gastric ulcer investigated with endoscopy when treated with ATB-346 (42.2% vs. 2.5% ulcer development with naproxen and ATB-346, respectively). This effect was associated with an increased suppression of COX activity [141]. The efficacy of ATB-346 was recently evaluated in patients with OA, demonstrating that ATB-346 can reduce joint pain, possibly to a greater extent than other standard NSAIDs, such as naproxen or celecoxib [142].…”

Synergisms, Discrepancies and Interactions between Hydrogen Sulfide and Carbon Monoxide in the Gastrointestinal and Digestive System Physiology, Pathophysiology and Pharmacology

“…However, novel CO-releasing prodrugs were developed recently and further studies will hopefully reveal their clinical potential [86]. It is worth to highlight, that H 2 S-releasing derivative of naproxen, ATB-346 with its reduced gastrotoxicity passed successfully the Phase 2 of clinical trial [24]. Taken together, there are still many missing aspects to be answered and extensively investigated in the context of CO and H 2 S-related physiology and pharmacology of GI digestive system.…”

“…Moreover, H 2 S-releasing NaHS has been shown to accelerate ulcer healing and to attenuate non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrotoxicity [22,23]. Interestingly, H 2 S-releasing derivative of naproxen (ATB-346) which successfully completed phase 2 clinical trial, offers a promising safer alternative for conventional native form of this NSAID not only in improvement of pain relief but also in GI-safety manifested by the reduction of upper GI tract damage formation in subjects treated with equimolar effective doses of ATB-346 versus naproxen [24]. Similarly GYY4137, slow H 2 S-releasing compound has been shown to exert anti-inflammatory activity [25] and to decrease the area of ischemia/reperfusion-induced gastric damage in rats [23].…”

“…It is also worth mentioning that natural sources of sulfur compounds, such as garlic-derived compounds including diallyl sulfide (DAS) disulfide, diallyl disulfide (DADS), diallyl trisulfide (DATS) and allicin were described as H 2 S releasing molecules [27]. Numerous studies have shown beneficial therapeutic and protective effects of these compounds in cancer development [24][25][26]. Cell cultures and animal models, as well as epidemiology data have revealed the chemopreventive activity of these H 2 S donors, especially in gastric and colorectal cancers [28][29][30].…”