MedicalResearch.com Interview with:
Mark Pimentel, MD
Associate Professor, Medicine
Director, GI Motility Program
Director, GI Motility Laboratory
IBS-C Clinical Advisory Board (Chair) at Synthetic Biologics
Los Angeles, CA
MedicalResearch.com: What is the background for this study?
Dr. Pimentel: The SYN-010 program is based on research from my group at Cedars-Sinai Medical Center, and other researchers and collaborators worldwide, investigating the role of intestinal methane production in functional gastrointestinal disorders. Low levels of intestinal methane are a ubiquitous by-product of normal intestinal microbial digestion; however, elevated intestinal methane levels are correlated with decreased intestinal motility and increased symptom severity in patients with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC).
Methane in humans is produced almost exclusively by the intestinal microorganism Methanobrevibacter smithii (M. smithii). Highest levels of M. smithii are found in the colon; however, overgrowth of M. smithii into the small intestine has also been observed. Previous work from my laboratory demonstrated that methane production by M. smithii in stool samples from IBS-C patients is inhibited by the lactone form of lovastatin. Lovastatin lactone does not appear to eradicate microbial species in the intestine, which should reduce the risk of intestinal dysbiosis and/or the development of microbial resistance.
SYN-010 is a proprietary, modified-release, oral formulation of lovastatin lactone, designed to protect lovastatin lactone from the stomach and release the active ingredient in two different locations of the intestinal tract where the M. smithii reside. SYN-010 exerts its therapeutic effect at the level of the intestinal microbiome and does not require absorption into the systemic circulation or conversion of the active ingredient (lovastatin lactone) to the cholesterol lowering β-hydroxyacid form.
MedicalResearch.com: What are the main findings?
Dr. Pimentel: SYN-010 was evaluated in two consecutive Phase 2 clinical trials enrolling IBS-C patients who tested positive for breath methane levels greater than ten parts per million (ppm) at screening. A statistically significant reduction from baseline in breath methane area under curve (AUC) was observed at Week 1 in patients treated with high dose SYN-010 and at Weeks 1 and 4 for both the low and high dose arms of SYN-010. Mean breath methane AUC was further reduced in patients transferred from Placebo or low dose strength SYN-010 in Study 1 to high dose strength SYN-010 in Study 2. Analysis of the combined data from all patients who completed Study 2 and received at least 8 weeks of treatment with high dose SYN-010 demonstrated a statistically-significant reduction in breath methane AUC from baseline to Week 12 and an inverse correlation between breath methane AUC and the weekly number of spontaneous bowel movements (SBMs) was observed. A similar inverse correlation was observed between breath methane AUC and the weekly number of complete spontaneous bowel movements (CSBMs).
Data from both Phase 2 studies highlighted additional outcomes of potential clinical significance if they are confirmed in larger scale clinical trials. For example, patients in both the low and high dose treatment arms in Study 1 used 60% less rescue medication than Placebo-treated patients. In addition, patients who completed Study 2 had statistically significant improvements from baseline in IBS Symptom Severity Scores (IBS-SSS). Of particular note, there was a dose-dependent improvement in the percentage of patients who reported a ≥30% decrease in the weekly average bloating score during Study 1 that further improved throughout Study 2. Patients routinely identify bloating as the most irksome symptom in IBS-C, so improvements in bloating are a highly desirable therapeutic outcome.
SYN-010 was well tolerated in both Study 1 and Study 2 and no severe adverse events were reported. The few reported adverse events observed were mild to moderate in intensity and balanced between groups. Significantly, only one incidence of diarrhea was reported during both studies and was identified as mild and unrelated to SYN-010.
MedicalResearch.com: What should readers take away from your report?
Dr. Pimentel: SYN-010 action in IBS-C patients is distinct from statin action used to lower cholesterol. Specifically, intestinal methane production by M. smithii is inhibited by the lactone form of lovastatin, while the cholesterol lowering β-hydroxyacid form of lovastatin (and other statins) proved ineffective against methane production in human stool.
The two Phase 2a studies demonstrated that a microbiome-targeted, methane-reducing therapy can improve constipation, abdominal pain and bloating in IBS-C patients. In addition, SYN-010 is the first IBS-C therapeutic in development to target a direct cause of constipation and associated symptoms, specifically, elevated intestinal methane. In this regard, SYN-010 is very different from OTC, prescription laxatives and therapies currently in clinical development that simply move the stool mass and can “flip the needle” from constipation to diarrhea. Assuming that SYN-010 efficacy is affirmed in Phase 3 clinical testing, SYN-010 may be considered a chronic medication – taken daily by IBS-C patients to normalize bowel habits – rather than a rescue medication taken sporadically in moments of constipation crisis.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Pimentel: Phase 3 clinical trials will need to evaluate the effects of SYN-010 in a larger IBS-C patient population over a longer treatment period (typically 12 weeks). Detailed in vitro studies to confirm the proposed mechanism-of-action of lovastatin lactone as an inhibitor of methane production will also be beneficial. Finally, development of a more sensitive and, ideally, less variable non-invasive test to routinely and reliably estimate intestinal methane levels is warranted.
MedicalResearch.com: Is there anything else you would like to add?
Dr. Pimentel: IBS-C is one of 4 IBS subtypes (the other being diarrhea, mixed, or unsubtyped). It is estimated that 15% of the world population suffers from IBS (30-40 million people in the US alone), but IBS remains an expensive and under diagnosed gastrointestinal disease. These patients suffer in silence and have tremendous abdominal discomfort. IBS is socially isolating. Patients need answers that are based on biology and pathophysiology, not just another laxative.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
- Gottlieb K, Wacher V, Sliman J, Coughlin O, McFall H, Rezaie A, Pimentel M (2016) [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(4, Suppl 1): S496–S497.
- Gottlieb K, Wacher V, Kokai-Kun J, Sliman J, Pimentel M, Muskal SM (2016) [Mo1319] Syn-010, a proprietary modified-release formulation of lovastatin lactone, may improve constipation by inhibiting enzymes in the archaeal methanogenesis pathway: results of computational M. Smithii enzyme-ligand docking experiments. Gastroenterology 150(4, Suppl 1): S696–S697.
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