SummaryBackground
ONO‐2952 is a novel and selective inhibitor of translocator protein 18 kDa that reduces stress‐induced defecation and visceral hyperalgesia in rat models.AimTo evaluate the efficacy and safety of ONO‐2952 in females with irritable bowel syndrome with diarrhoea in an exploratory proof‐of‐concept study.MethodsA randomised, double‐blind, placebo‐controlled study was conducted at 49 US centres. Two hundred subjects with irritable bowel syndrome with diarrhoea (Rome III criteria) were randomised to ONO‐2952 20 mg, or 60 mg, or placebo. Subjects recorded irritable bowel syndrome symptoms daily during a 2‐week baseline period, the 4‐week treatment period and for 4 weeks post‐treatment. The co‐primary endpoints were change from baseline to week 4 in abdominal pain, stool consistency and stool frequency.ResultsImprovements in irritable bowel syndrome symptoms were seen with ONO‐2952 over placebo in per‐protocol analyses for all three co‐primary endpoints, but these did not reach statistical significance at the 5% level. The largest improvement was seen with ONO‐2952 60 mg. ONO‐2952 was well tolerated with a safety profile similar to that of placebo. Most adverse events were mild or moderate in severity and not treatment related.Conclusion
ONO‐2952 showed evidence of clinical efficacy in reducing irritable bowel syndrome‐related symptoms in female subjects with irritable bowel syndrome with diarrhoea, and further evaluation is, therefore, warranted to assess its potential as a treatment for irritable bowel syndrome with diarrhoea (NCT01844180).
Attenuation of EAR, LAR, and airway inflammation is consistent with cysLT blockade. Whether dual cysLT antagonism offers additional benefit for treatment of asthma requires further study.
In healthy adults ONO-4232 was generally well tolerated in the dose range of 0.001 to 0.27 ng/kg/min. There were dose-related changes in systolic blood pressure and heart rate. Infusion site erythema, which was likely associated with a venodilatory effect and possible evidence for the pharmacologic effects of ONO-4232, occurred increasingly with increasing dose. Pharmacokinetic parameters appeared to be dose-proportional. The study results support further evaluation of the cardiovascular effects of this first-in-class selective left ventricular lusitropic and venodilatory drug in patients with acutely decompensated heart failure.
2. Mitsui K. Effects of ono-2925, a novel translocator protein 18 kDa antagonist, on stress-induced rectal hyperalgesia and defecation in rats. We thank Drs Nee and Lembo 1 for their editorial commenting on our article. 2 We would like to respond by pointing out the need for a treatment for irritable bowel syndrome with diarrhoea (IBS-D) that addresses the increased frequency of loose, watery stools and the increased pain caused by stress. Stress-induced diarrhoea and pain are regarded as key factors in IBS, although they are not much discussed. They are targets for the treatment of IBS with behavioural approaches that focus on the use of paced respiration and relaxation training to regulate stress, and a recent review of these techniques was published in the stress chapter of the Rome IV project.3 Unfortunately, these behavioural techniques are time-consuming, and are not widely available. A new drug such as ONO-2952, 1 if confirmed in subsequent studies, would make it possible for this aspect of IBS to be addressed by primary care practitioners. We look forward to follow-up studies which would make it possible to select patients who are uniquely responsive to this category of drug. In animal studies, rats were selected who were selectively trained to avoid fear-producing shocks, and these subjects were uniquely responsive to the drug; however, in the human study reported to date, no such selection of subjects was done to minimise recruitment problems. New studies could include patients who are selected for their responsiveness to the effects of anxiety.Future studies should also test higher doses of ONO-2952 to identify whether the drug is uniquely associated with actions in the brain or has peripheral effects as well. To date, there is no reason to expect the highest dose of the study drug to be 60 mg/day, but more data are needed on higher doses. Thus, there is considerable room for future research to expand on this unique preliminary study.
ACKNOWLEDGEMENT
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