Efficacy and Safety of SYN-010 in IBS-C

Summary

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) syndrome characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. The symptoms of IBS not only adversely affect a patient's health-related quality of life (QoL), but also place a significant financial burden on society due to reduced work productivity and increased use of healthcare-related resources. Patients with IBS frequently complain of abdominal bloating and increased gas production in the form of flatulence or belching. The prevalence in North America and Europe is approximately 10-15%. Irritable bowel syndrome affects all ages and genders however there is a 2:1 female predominance in North America. Irritable bowel syndrome is classified into 4 subtypes based on stool pattern: IBS with constipation (IBS-C), IBS with diarrhea, mixed IBS, and un-subtyped IBS. Irritable bowel syndrome with constipation is defined as the presence of hard or lumpy stools with ≥ 25 percent of bowel movements and loose or watery stools with \< 25% of bowel movements. SYN-010 is a modified release, oral formulation of lovastatin being developed for the treatment of IBS-C. The SYN-010 program is based predominantly on research by Dr. Mark Pimentel and collaborators hypothesizing that reduction in intestinal methane (methane) production can reverse constipation and improve global symptoms in IBS-C. Methane production in humans is due to methanogenic archaea in the intestine, predominantly Methanobrevibacter smithii (M. smithii). Methane, the key product of anaerobic respiration of methanogens, had been perceived to produce no ill effects in humans aside from gaseous distention. However, several research groups worldwide have shown that a significant percentage of patients with IBS-C excrete methane, and elevated methane production by methanogens correlates with constipation and related symptoms in both IBS-C and chronic idiopathic constipation. A direct causative role for methane in IBS-C was demonstrated in a recent case report, wherein a woman undergoing fecal microbiota transplantation (FMT) for C. difficile infection unknowingly received stool containing a high concentration of methanogens. The FMT recipient rapidly developed severe symptoms of IBS-C that were subsequently reversed by ablation of methane production.

Timeline

Start

2018-12-24

Primary completion

2020-10-09

Completion

2020-10-09

Publications

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• Background Pimentel M, Gunsalus RP, Rao SSC, Zhang H. Methanogens in human health and disease. Am J Gastroenterol. 2012 Jul;1(1) Suppl:28-33.
• Background Pimentel M, Mayer AG, Park S, Chow EJ, Hasan A, Kong Y. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci. 2003 Jan;48(1):86-92. doi: 10.1023/a:1021738515885.
• Background Kunkel D, Basseri RJ, Makhani MD, Chong K, Chang C, Pimentel M. Methane on breath testing is associated with constipation: a systematic review and meta-analysis. Dig Dis Sci. 2011 Jun;56(6):1612-8. doi: 10.1007/s10620-011-1590-5. Epub 2011 Feb 1.
• Background Furnari M, Savarino E, Bruzzone L, Moscatelli A, Gemignani L, Giannini EG, Zentilin P, Dulbecco P, Savarino V. Reassessment of the role of methane production between irritable bowel syndrome and functional constipation. J Gastrointestin Liver Dis. 2012 Jun;21(2):157-63.
• Background Ghoshal U, Shukla R, Srivastava D, Ghoshal UC. Irritable Bowel Syndrome, Particularly the Constipation-Predominant Form, Involves an Increase in Methanobrevibacter smithii, Which Is Associated with Higher Methane Production. Gut Liver. 2016 Nov 15;10(6):932-938. doi: 10.5009/gnl15588.
• Background Lee KM, Paik CN, Chung WC, Yang JM, Choi MG. Breath methane positivity is more common and higher in patients with objectively proven delayed transit constipation. Eur J Gastroenterol Hepatol. 2013 Jun;25(6):726-32. doi: 10.1097/MEG.0b013e32835eb916.
• Background Suri J, Kataria R, Malik Z, Parkman HP, Schey R. Elevated methane levels in small intestinal bacterial overgrowth suggests delayed small bowel and colonic transit. Medicine (Baltimore). 2018 May;97(21):e10554. doi: 10.1097/MD.0000000000010554.
• Background Chang BW, Rezaie A. Irritable Bowel Syndrome-Like Symptoms Following Fecal Microbiota Transplantation: A Possible Donor-Dependent Complication. Am J Gastroenterol. 2017 Jan;112(1):186-187. doi: 10.1038/ajg.2016.472. No abstract available.
• Background Park YM, Lee YJ, Hussain Z, Lee YH, Park H. The effects and mechanism of action of methane on ileal motor function. Neurogastroenterol Motil. 2017 Sep;29(9). doi: 10.1111/nmo.13077. Epub 2017 Apr 18.
• Background Pimentel M, Lin HC, Enayati P, van den Burg B, Lee HR, Chen JH, Park S, Kong Y, Conklin J. Methane, a gas produced by enteric bacteria, slows intestinal transit and augments small intestinal contractile activity. Am J Physiol Gastrointest Liver Physiol. 2006 Jun;290(6):G1089-95. doi: 10.1152/ajpgi.00574.2004. Epub 2005 Nov 17.
• Background Jahng J, Jung IS, Choi EJ, Conklin JL, Park H. The effects of methane and hydrogen gases produced by enteric bacteria on ileal motility and colonic transit time. Neurogastroenterol Motil. 2012 Feb;24(2):185-90, e92. doi: 10.1111/j.1365-2982.2011.01819.x. Epub 2011 Nov 20.
• Background Mevacor® (lovastatin) tablets. Prescribing information, 2014. Merck & Co., Inc., Whitehouse Station, NJ 08889, USA.
• Background Duggan DE, Chen IW, Bayne WF, Halpin RA, Duncan CA, Schwartz MS, Stubbs RJ, Vickers S. The physiological disposition of lovastatin. Drug Metab Dispos. 1989 Mar-Apr;17(2):166-73.
• Background Marsh E, Morales W, Chua KS, Marsh Z, Weitsman S, Wacher V, Kim JH, Pimentel, M. (2015) [Abstract 1771] Lovastatin lactone inhibits methane production in human stool homogenates. Am J Gastroenterol. 110 (Suppl. 1): S753.
• Background Morales W, Marsh E, Yu A, Marsh Z, Weitsman S, Barlow GM, Rezaie A, Chang C, Wacher V, Pimentel, M. (2015) [Abstract Mo 2051] Lovastatin improves stool form in Methanobrevibacter smithii colonized rats with constipation. Gastroenterology 148 (Suppl. 1): S-779-80
• Background Gottlieb K, Wacher V, Sliman J, Coughlin O, McFall H, Rezaie A, Pimentel M. (2016) [Abstract Su1210] SYN-010, a proprietary modified-release formulation of lovastatin lactone, lowered breath methane and improved stool frequency in patients with IBS-C: results of a multi-center randomized double-blind, placebo-controlled Phase 2a trial. Gastroenterology 150 (Suppl. 1): S496-7.
• Background Wacher V, Gottlieb K, Sliman J, Coughlin O, Kokai-Kun, J, McFall H, Pimentel M (2016) [Abstract 562] SYN-010 modified-release lovastatin does not significantly alter lipid parameters at doses that reduce methane and alleviate symptoms in patients suffering irritable bowel syndrome with constipation (IBS-C). Am J Gastroenterol. 111 (Suppl. 1): S256.
• Background Hubert S, Chadwick A, Wacher V, Coughlin O, Kokai-Kun J, Bristol A. Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation. J Pharm Sci. 2018 Feb;107(2):662-671. doi: 10.1016/j.xphs.2017.09.028. Epub 2017 Oct 6.
• Background Muskal SM, Sliman J, Kokai-Kun J, Pimentel M, Wacher V, Gottlieb K. Lovastatin lactone may improve irritable bowel syndrome with constipation (IBS-C) by inhibiting enzymes in the archaeal methanogenesis pathway. F1000Res. 2016 Apr 8;5:606. doi: 10.12688/f1000research.8406.3. eCollection 2016.
• Background Camilleri M, Lembo AJ, Lavins BJ, MacDougall JE, Carson RT, Williams VS, Nelson LM, Shiff SJ, Currie MG, Kurtz CB, Johnston JM. Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C. United European Gastroenterol J. 2015 Feb;3(1):53-62. doi: 10.1177/2050640614555946.
• Background Passos MC, Lembo AJ, Conboy LA, Kaptchuk TJ, Kelly JM, Quilty MT, Kerr CE, Jacobson EE, Hu R, Friedlander E, Drossman DA. Adequate relief in a treatment trial with IBS patients: a prospective assessment. Am J Gastroenterol. 2009 Apr;104(4):912-9. doi: 10.1038/ajg.2009.13. Epub 2009 Mar 17.
• Villanueva-Millan MJ, Leite G, Wang J, Morales W, Parodi G, Pimentel ML, Barlow GM, Mathur R, Rezaie A, Sanchez M, Ayyad S, Cohrs D, Chang C, Rashid M, Hosseini A, Fiorentino A, Weitsman S, Chuang B, Chang B, Pichetshote N, Pimentel M. Methanogens and Hydrogen Sulfide Producing Bacteria Guide Distinct Gut Microbe Profiles and Irritable Bowel Syndrome Subtypes. Am J Gastroenterol. 2022 Dec 1;117(12):2055-2066. doi: 10.14309/ajg.0000000000001997. Epub 2022 Sep 6.

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