Randomised clinical trial: exploratory phase 2 study of <scp>ONO</scp>‐2952 in diarrhoea‐predominant irritable bowel syndrome

Duffy, Kevin J.; Sharpe, John C.; Nabata, Toshiya; Bruce, Mark

doi:10.1111/apt.13839

Cited by 18 publications

(13 citation statements)

References 39 publications

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“…Taken together, the results show that a minimal therapeutic dose of ONO-2952, as well as its optimal dose level for clinical use, could be estimated using a human PET study by targeting a brain occupancy of 50% rather than using this compound's pharmokinetic profile. More recently, we have published a study showing that ONO-2952 exhibits clinical efficacy in patients with irritable bowel syndrome at whole-brain occupancy level of 77.4% (Whitehead et al, 2017). As we did not investigate here the relationship between the antistress effect of ONO-2952 and its TSPO occupancy in the monkey brain, the reason why higher whole-brain occupancy is needed in this POC study compared with rats studies remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography

Mitsui

Morimoto

Niwa

et al. 2016

J Pharmacol Exp Ther

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We have previously shown that ONO-2952, a novel 18-kDa translocator protein (TSPO) antagonist, inhibits stress-induced accumulation of neurosteroids and noradrenaline release in the rat brain and alleviates the subsequent symptomatic responses with a brain TSPO occupancy of 50% or more. In this study, we measured ONO-2952 brain TSPO occupancy in conscious rhesus monkeys using positron emission tomography (PET) with C-PBR28 as ligand for translational research to clinical application. PET scans were performed after single and repeated oral administration of ONO-2952 at several dose levels for each animal, with sequential arterial blood sampling. In vitro binding studies showed that ONO-2952 potently binds to brain TSPO in monkeys with an affinity equivalent to that in rats. ONO-2952, given orally before PET scans, dose dependently decreasedC-PBR28 uptake without marked brain region specificity. Results of the quantitative analysis using arterial input function revealed that TSPO occupancy after ONO-2952 single and repeated oral administration tended to increase in parallel with its plasma concentration, reaching the highest level of 100%. These findings indicate that ONO-2952 has sufficient brain distribution in primates and that ONO-2952 TSPO occupancy in humans can also be determined using PET.

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Section: Discussionmentioning

confidence: 99%

Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography

Mitsui

Morimoto

Niwa

et al. 2016

J Pharmacol Exp Ther

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“…[32] In a 4-week study in IBS-D with approximately 65 patients per arm, ONO-2952 (60 mg) tended to improve stool consistency and diarrhea, but effects were not statistically significant versus placebo. [33]…”

Section: Diarrhea and Diarrhea-predominant Ibs (Ibs-d)mentioning

confidence: 99%

Existing and emerging therapies for managing constipation and diarrhea

Bharucha

Wouters

Tack

2017

Current Opinion in Pharmacology

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Functional bowel disorders (i.e., constipation and diarrhea) are characterized by abdominal pain, bloating, distention, and/or bowel habit abnormalities in the absence of obvious anatomic or physiologic abnormalities on routine diagnostic tests. These symptoms are attributable to gastrointestinal sensorimotor dysfunctions resulting from peripheral and/or central mechanisms. Available drugs target the underlying bowel disturbance (ie, constipation, diarrhea, or both), supplemented when necessary by management of pain. Osmotic and stimulant laxatives, secretagogues, and serotonin 5-HT4 receptor agonists are approved for treating constipation. Loperamide, anticholinergic agents, rifaximin, bile-acid binding agents, eluxadoline, and clonidine are used to treat diarrhea. Several exciting new compounds, some of which have been evaluated in humans, are currently under development.

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“…The authors' declarations of personal and financial interests are unchanged from those in the original article …”

Section: Acknowledgementmentioning

confidence: 99%

“…We thank Drs Nee and Lembo for their editorial commenting on our article . 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.…”

mentioning

confidence: 99%

Editorial: ONO‐2952 in irritable bowel syndrome with diarrhoea – authors’ reply

Whitehead

Duffy

Sharpe

et al. 2017

Aliment Pharmacol Ther

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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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Randomised clinical trial: exploratory phase 2 study of ONO‐2952 in diarrhoea‐predominant irritable bowel syndrome

Cited by 18 publications

References 39 publications

Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography

Quantification of ONO-2952 Occupancy of 18-kDaTranslocator Protein in Conscious Monkey Brains using Positron Emission Tomography

Existing and emerging therapies for managing constipation and diarrhea

Editorial: ONO‐2952 in irritable bowel syndrome with diarrhoea – authors’ reply

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