Targeting the SHIP1 Pathway Fails to Show Treatment Benefit in Interstitial Cystitis/Bladder Pain Syndrome: Lessons Learned from Evaluating Potentially Effective Therapies in This Enigmatic Syndrome

No AccessJournal of UrologyAdult Urology1 Aug 2019Targeting the SHIP1 Pathway Fails to Show Treatment Benefit in Interstitial Cystitis/Bladder Pain Syndrome: Lessons Learned from Evaluating Potentially Effective Therapies in This Enigmatic SyndromeThis article is commented on by the following:Editorial Comment J. Curtis Nickel, Robert Moldwin, Philip Hanno, Roger Dmochowski, Kenneth M. Peters, Christopher Payne, and Alan Wein J. Curtis NickelJ. Curtis Nickel *Correspondence: Department of Urology, Queen's University, Kingston General Hospital, 76 Stuart St., Kingston, Ontario , Canada, K7L 2V7 telephone: 613-548-2497; E-mail Address: [email protected] Queen's University, Kingston, Ontario, Canada More articles by this author , Robert MoldwinRobert Moldwin Zucker School of Medicine at Hofstra-Northwell, Lake Success, New York Financial interest and/or other relationship with Aquinox Pharmaceuticals. More articles by this author , Philip HannoPhilip Hanno Stanford University, Stanford, California More articles by this author , Roger DmochowskiRoger Dmochowski Vanderbilt University, Nashville, Tennessee More articles by this author , Kenneth M. PetersKenneth M. Peters Oakland University William Beaumont School of Medicine, Royal Oak, Michigan More articles by this author , Christopher PayneChristopher Payne Vista Urology, Stanford, California More articles by this author , and Alan WeinAlan Wein University of Pennsylvania, Philadelphia, Pennsylvania More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000192AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: In this 12-week, randomized, double-blind, placebo controlled, multicenter, 3-arm, parallel group, phase 3 trial we assessed the effects of a novel SHIP1 activator on bladder pain and urinary symptoms in patients with interstitial cystitis/bladder pain syndrome. Materials and Methods: Subjects with interstitial cystitis/bladder pain syndrome and a mean pain score of 5 or greater on an 11-point scale despite treatment were randomized to 100 or 200 mg of an oral SHIP1 activator or placebo once daily for 12 weeks. Maximum pain scores and urinary frequency were recorded in an e-diary. The ICSI (O'Leary-Sant Interstitial Cystitis Symptom Index) and BPIC-SS (Bladder Pain Interstitial Cystitis Symptom Score) questionnaires were administered. Safety was monitored through 12 weeks of treatment. Results: A total of 298 female subjects with moderate to severe symptoms of interstitial cystitis/bladder pain syndrome were treated with 100 or 200 mg SHIP1 activator orally once daily for 12 weeks. Treatment demonstrated no difference in maximum daily bladder pain compared to placebo. There was no treatment benefit over that of placebo in the secondary end points of urinary voiding frequency, the BPIC-SS, the ICSI and a global response assessment. Exploratory analysis in 87 male subjects yielded a similar result, that is no difference from placebo. Treatment was generally well tolerated at both doses. Conclusions: SHIP1 activation is a safe but ineffective therapeutic approach to interstitial cystitis/bladder pain syndrome. Although this was a negative trial, the important lessons learned from this study in respect to inflammatory phenotype differentiation, including the potential importance of cystoscopy based classification, will improve current treatment in patients with interstitial cystitis/bladder pain syndrome and allow for better future trial design in those with this difficult urological chronic pain syndrome. References 1. : Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol 2015; 193: 1545. Link, Google Scholar 2. : Incontinence, 6th ed. Edited by . Bristol, United Kingdom: International Continence Society 2017; vol. 2. Google Scholar 3. : Clinical and psychological parameters associated with pain pattern phenotypes in women with interstitial cystitis/bladder pain syndrome (IC/BPS). International Interstitial Cystitis Research Group. J Urol 2015; 193: 138. Link, Google Scholar 4. : Interstitial cystitis: cost, treatment and co-morbidities in an employed population. Pharmacoeconomics 2006; 24: 55. Google Scholar 5. : Contemporary management of the painful bladder: a systematic review. Eur Urol 2012; 61: 29. Google Scholar 6. : Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br J Pharmacol 2013; 168: 1506. Google Scholar 7. : Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 2. Efficacy studies in allergic and pulmonary inflammation models in vivo. Br J Pharmacol 2013; 168: 1519. Google Scholar 8. : A phase II study of efficacy and safety of a novel, oral SHIP1 activator, AQX-1125, in subjects with moderate to severe interstitial cystitis/bladder pain syndrome (IC/BPS). J Urol 2016; 196: 747. Link, Google Scholar 9. : The bladder pain/interstitial cystitis symptom score: development, validation, and identification of a cut score. Eur Urol 2012; 61: 271. Google Scholar 10. : The interstitial cystitis symptom index and problem index. Urology, suppl., 1997; 49: 58. Google Scholar 11. : A randomized controlled trial of intravesical bacillus Calmette-Guerin for treatment refractory interstitial cystitis. J Urol 2005; 173: 1186. Link, Google Scholar 12. : Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 2005; 173: 1590. Link, Google Scholar 13. : A second multi-center, randomized, double-blind, parallel group evaluation of the effectiveness and safety of intravesical sodium chondroitin sulfate compared to inactive vehicle control in subjects with interstitial cystitis/bladder pain syndrome. Urology 2012; 79: 1220. Google Scholar 14. : Tanezumab reduces pain in women with interstitial cystitis/bladder pain syndrome and patients with nonurological associated somatic syndromes. J Urol 2016; 195: 942. Link, Google Scholar 15. : Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo-controlled study. J Urol 2015; 193: 857. Link, Google Scholar 16. : Effect of amitriptyline on symptoms of treatment-naive patients with interstitial cystitis/painful bladder syndrome. J Urol 2010; 183: 1853. Link, Google Scholar 17. : Investigation of a Ca2+ channel α2δ ligand for the treatment of interstitial cystitis: results of a randomized, double-blind, placebo controlled phase II trial. J Urol 2012; 188: 817. Link, Google Scholar 18. : Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned. J Urol 2011; 185: 901. Link, Google Scholar 19. : Clinical phenotyping does not differentiate Hunner's lesion subtype of interstitial cystitis/bladder pain syndrome (IC/BPS): a relook at the role of cystoscopy. J Urol 2016; 196: 1136. Link, Google Scholar 20. : Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies?J Clin Pathol 2018; 71: 840. Google Scholar 21. : Diurnal cortisol variations and symptoms in patients with interstitial cystitis. J Urol 2002; 167: 1338. Link, Google Scholar 22. : Alterations in resting state oscillations and connectivity in sensory and motor networks in women with interstitial cystitis/painful bladder syndrome. J Urol 2014; 192: 947. Link, Google Scholar 23. : Menstrual cycle affects bladder pain sensation in subjects with interstitial cystitis. J Urol 2005; 174: 1832. Link, Google Scholar 24. : A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology 2005; 128: 1953. Google Scholar 25. : Gynecological disorders in bladder pain syndrome/interstitial cystitis patients. Int J Urol, suppl., 2014; 21: 85. Google Scholar 26. : Depression and catastrophizing predict suicidal ideation in tertiary care patients with interstitial cystitis/bladder pain syndrome. Can Urol Assoc J 2016; 10: 383. Google Scholar 27. : Understanding Pain and coping in women with interstitial cystitis/bladder pain syndrome (IC/BPS). BJU Int 2017; 129: 286. Google Scholar 28. : Interstitial cystitis/painful bladder syndrome and associated medical conditions with emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol 2010; 184: 1358. Link, Google Scholar 29. : FDA BRUDAC 2018 criteria for interstitial cystitis/bladder pain syndrome clinical trials: future direction for research. J Urol 2018; 200: 39. Link, Google Scholar 30. : Phenotype-directed management of interstitial cystitis/bladder pain syndrome. Urol 2014; 84: 175. Google Scholar The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by Aquinox Pharmaceuticals. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. © 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited bySmith J (2019) This Month in Adult UrologyJournal of Urology, VOL. 202, NO. 2, (181-182), Online publication date: 1-Aug-2019.Related articlesJournal of Urology8 Jul 2019Editorial Comment Volume 202Issue 2August 2019Page: 301-308Supplementary Materials Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.Keywordscystitisinterstitialnegative resultsurinary bladderpatient reported outcome measurespelvic painMetricsAuthor Information J. Curtis Nickel Queen's University, Kingston, Ontario, Canada *Correspondence: Department of Urology, Queen's University, Kingston General Hospital, 76 Stuart St., Kingston, Ontario , Canada, K7L 2V7 telephone: 613-548-2497; E-mail Address: [email protected] More articles by this author Robert Moldwin Zucker School of Medicine at Hofstra-Northwell, Lake Success, New York Financial interest and/or other relationship with Aquinox Pharmaceuticals. More articles by this author Philip Hanno Stanford University, Stanford, California More articles by this author Roger Dmochowski Vanderbilt University, Nashville, Tennessee More articles by this author Kenneth M. Peters Oakland University William Beaumont School of Medicine, Royal Oak, Michigan More articles by this author Christopher Payne Vista Urology, Stanford, California More articles by this author Alan Wein University of Pennsylvania, Philadelphia, Pennsylvania More articles by this author Expand All The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. Supported by Aquinox Pharmaceuticals. No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article. 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