Synthetic Biologics Inc.is developing an oral, statin-based candidate for chronic use that it thinks can get at the root cause of constipation-predominant irritable bowel syndrome – the overgrowth of a particular type of intestinal bacteria called methanogens.

During an investor briefing on Sept. 16, the company said that it has developed a plan that should enable it to have Phase II data by Autumn 2015 for SYN-010, a new candidate for IBS-C that the company is planning to develop through FDA’s 505(b)(2) pathway.

The company did not release the specifics on the drug, aside to say that it was statin-based – there was a suggestion during the briefing that it could include a combination of two statins – and that they could qualify for additional patent protection.

IBS, which is further characterized by whether constipation or diarrhea is the dominant symptom, is a common condition. Synthetic Biologics estimates that 10% to 15% of the U.S. population is affected, or 40 million people; about one-third have the constipation-predominant form of IBS. Treatment has typically consisted of laxatives, and market research has suggested there is demand for new therapies (IBS-D has a different set of treatments) Also see "Market Snapshot: Taking Constipation Seriously – Linaclotide Success Raises Hopes For Market Resurgence" - Pink Sheet, 4 July, 2011..

Yet, while IBS can be painful and interfere with life, it isn’t life-threatening, so the safety bar for approvals of new drugs at FDA has been high.

Synthetic Biologics is trying a new approach that it says will target the cause of the condition – and do so very safely. The approach is based on patents and pending patent applications for gastrointestinal indications – IBS-C, obesity and diabetes – in-licensed and optioned from Cedars-Sinai Medical School in December 2013. Pioneered by Mark Pimentel, director of the GI motility program and laboratory at Cedars-Sinai, the research highlights the role of targeting methanogens that produce methane gas in the intestines in order to cure certain digestive diseases. Pimentel now heads the company’s clinical advisory board.

Specifically, the candidate will target the Methanobrevibacter smithii organism. During the investor briefing, Pimentel maintained that extensive literature is available on the link between methanogens and digestive disease, though the theory has taken some time to catch on. A breath test showing elevated methane could be used as a biomarker for efficacy.

The particular statin or statins have not been named, but in an article in the American Journal of Gastroenterology in 2012 called Methanogens in Human Health and Disease, Pimentel cited lovastatin (Merck & Co. Inc.’s Mevacor) and mevastatin (an early statin that never reached the market) as drugs that have proven effective.

In response to questions about what would keep physicians from prescribing statins generically, execs explained the value of the company’s special formulation. Statins are designed to be absorbed quickly into the bloodstream to produce cardiovascular and cholesterol lowering effects, whereas Synthetic Biologics plans to take the opposite approach to ensure that the drug stays in the gut to work on methane gas. The goal is to prevent methane production, but not to kill methanogens.

“Could you do it off the shelf generically? You could try, but it’s not going to work as well – if at all – because our formulation is to keep it in the gut, to keep it in the area where the bugs are for as long as possible,” CEO Jeffrey Riley said in an interview.

Following Salix’s Lead

Research by Pimentel/Cedars Sinai is also supporting development of Salix Pharmaceuticals Ltd.’s gut-specific antibiotic Xifaxan (rifaxamin) in IBS; Pimentel developed the theory that IBS-D was caused by the buildup of bacteria in the small intestine (SIBO, or small intestine bacterial overgrowth) and could be targeted with an antibiotic like Xifaxan. Initially approved in 2004 for traveler’s diarrhea, Salix has been attempting to add an indication for IBS-D Also see "Irritable Bowel Drugs From Salix, Actavis Await FDA Action In 2015" - Pink Sheet, 3 September, 2014.. A lactulose breath test may be used to test for bacteria in the intestines.

Publication of pivotal Phase III studies by Pimentel and colleagues in the New England Journal of Medicine in 2011 had a high profile and appears to have helped to generate off-label sales in IBS.

Salix failed in its first attempt to get the new indication in IBS-D approved by FDA, amid fears of development of antibiotic resistance and concerns about the need for data on retreatment Also see "Salix Tumbles With Expected "Complete Response" Letter On Xifaxan In IBS" - Pink Sheet, 24 February, 2011.. However, market analysts believe that off-label use in IBS-D has been boosting sales, which rose from $371.6 million in 2011 to $514.5 million in 2012 and $645.6 million in 2013. The company has resubmitted a supplemental sNDA filing for Xifaxan in IBS-D that includes positive results from a new Phase III retreatment study (TARGET-3).

Pimentel explained during the Synthetic Biologics investor call that the theory of the original cause – bacterial overgrowth – is the same for IBS that mainly manifests in diarrhea symptoms as it is for constipation. The basic idea is that food poisoning causes damage to the gut, which in turn causes bacteria to accumulate in the intestines. But there are important differences. The type or types of bugs produced determines whether a patient gets IBS-D or IBS-C, he said. And the cures are therefore different as well. Whereas rifaximin is effective in diarrhea, research suggests its effects don’t last long enough to treat constipation, he explained.

Growing Support For Bacterial Intervention?

The bacterial overgrowth theory was initially controversial in IBS-D, but it has come into the mainstream.

“It is generally accepted that some change in bacterial flora of bacterial function in the colon or in the small intestine causes IBS symptoms in a subgroup of IBS patients. This theory is much less controversial than it was a few years ago,” commented University of Michigan GI specialist Philip Schoenfeld, an advisory board member at Synthetic Biologics.

Targeting methane in IBS-C is promising, but the Synthetic Biologics drug is still in a very early stage of development, with no Phase I data available yet, Schoenfeld noted. However, the theory makes sense in his view. One of the most difficult IBS symptoms to treat is bloating, which is related to gas formation in the colon. One of the most effective ways currently to manage gas is through the “FODMAP” restricted diet, which essentially starves bacteria to minimize gas production, he said.

As to whether GI docs will buy into the methanogen theory in IBS-C, Schoenfeld said that he believes most would accept the idea that targeting methane production could have a beneficial effect on symptoms.

Brian Lacy, chief of gastroenterology and hepatology at the Dartmouth-Hitchcock Medical Center, agrees that there is more recognition now of the connection between intestinal bacteria and IBS. Pimentel “deserves a huge amount of credit” for making clinicians and scientists think about the etiology and pathology in a different light, he said in an interview.

However, Lacy said that it’s still unclear whether in IBS-D the issue is bacteria is in the small intestine or the colon. One of the main obstacles is lack of faith in the lactulose breath test used to test for bacteria in the small intestine – it can result in false positives and is difficult to reproduce. In the pivotal trials of Xifaxan, breath testing was not done in all patients and the positive results do not prove the SIBO theory; the symptoms of bacteria in the small intestine and colon are identical and it’s unclear why Xifaxan works, he said. The gold standard of taking jejunal cultures is invasive and hard to perform – some researchers who have used this technique have not shown that people with IBS have SIBO, Lacy suggested.

“I think the idea of SIBO causing IBS in a majority of patients is still controversial. What’s less controversial is the concept that changes in the gut microflora could produce symptoms of IBS, in particular gas, bloating, distension and even abdominal pain. I think most people are on board with that concept. The controversy (or debate) is whether IBS symptoms arise due to SIBO or colonic dysbiosis. I think most clinicians would say it is not SIBO but rather colonic dysbiosis. Based on emerging data, I believe that this makes more sense,” Lacy said.

Pimentel has had “fascinating” research about the complex association between methane gas production, colonic transit and symptoms of constipation, with some beneficial effects demonstrated through treatment with the antibiotic neomycin, Lacy said. The idea is gaining traction in the medical community and the next question is whether statins work as well. “There’s starting to be kind of a nice story here,” he said.

Testing for methane levels in the small intestine and colon is pretty simple and accurate, Lacy said. Performing a trial in this setting could be tricky, however, because you would presumably want to take only patients who have high methane, he said.

Synthetic Biologics has not disclosed details about trial design.

Where SYN-010 Fits

The IBS-C space is very safety conscious, having been damaged by some early scares. Novartis AG’ 5-HT4 agonist Zelnorm (tegaserod) was once popular in IBS-C but was withdrawn from the market in 2007 due to cardiovascular safety concerns. Safety issues have created demand for therapies that act specifically in the gut, minimizing systemic exposure as much as possible.

Allergan PLC/Ironwood Pharmaceuticals Inc. capitalized on this need with their novel guanylate cyclase type C receptor agonist Linzess (linaclotide), which was approved for chronic constipation and IBS-C in August 2012.

Linzess is becoming widely accepted. In guidelines for managing IBS and chronic constipation published in August, the American College of Gastroenterology determined that the quality of evidence was high for Linzess and made a strong recommendation for use. Linzess had total sales of almost $120 million for 2013 and the sponsors embarked on a 12-month, national direct-to-consumer advertising campaign in April Also see "Ironwood/Forest Hoping To Change The Conversation About Constipation" - Pink Sheet, 16 April, 2014..

Zelnorm and Shire PLC’s 5HT4 agonist Resolor (prucalopride), approved in Europe and in Phase III in the U.S., have represented the gold standard for chronic constipation efficacy, but Linzess efficacy appears to “exceed that standard” without the CV signals that “sidelined” these two agents, Cowen analysts concluded in their 2014 Therapeutic Categories Outlook report. “Our clinical consultants believe linaclotide will be the best-in-class therapy for both chronic constipation and IBS-C given its strong efficacy on constipation and good evidence of efficacy against abdominal pain,” they wrote.

During the Synethetics Biologics investor briefing, Cedars-Sinai’s Pimentel explained the differences between SYN-010 and a range of available treatments. For both IBS-C and IBS-D, treatment has not been aimed at the cause, but at the symptoms, he said.

“It’s this patchwork of little Band-Aids for each of the symptoms, but nothing treating pathophysiology until rifaximin,” Pimentel said.

In constipation, one option is to increase secretion of water in the gut, through a variety of mechanisms, but this has the downside of inducing diarrhea, which then needs to be treated, he said. For example, he pointed out that in two published pivotal trials of Linzess, 19% and 19.7% of subjects got diarrhea.

“FDA’s endpoint is unidirectional and that’s another problem,” Pimentel said. “You have to move in the opposite direction of your symptom,” which runs the risk of triggering problems in the other direction.

Lacy counters, however, that for a patient who has been struggling with chronic constipation for many years, diarrhea is “not a side effect, [it’s] a sign of success.” It may be that the diarrhea could be addressed by adjusting the dose downward.

Furthermore, there are many factors behind constipation and methane gas production may only be part of the problem, so it may make more sense to give a drug that works on the symptoms, Lacy said. And, he added, patients may not care what the underlying cause is, they just want to feel better.

As for IBS-D, Actavis’ opioid receptor agonist/delta opioid receptor antagonist eluxadoline, acquired from Furiex Pharmaceuticals Inc., is the “new kid on the block,” but carries a risk for pancreatitis; five cases have been reported Also see "Furiex Makes Inroads In Tough-To-Treat IBS-d With Phase III Eluxadoline Data" - Pink Sheet, 19 February, 2014.. Eluxadoline is now under review at FDA.

“If I was the FDA I would view this very badly, because [pancreatitis can be] a potentially life-threating condition,” Pimentel commented.

Cowen analysts observed that eluxadoline’s efficacy was strong and that safety and tolerability were favorable in its two studies. As for the pancreatitis, three of the five cases were in patients with heavy alcohol consumption, so labeling might wind up including cautions for patients with liver dysfunction, but the sponsor has indicated this wouldn’t have much of a commercial impact.

Synthetic Biologics believes that SYN-010 will have a strong safety advantage because statins have been used in so many people. The statin the company plans to develop is supported by a “huge safety database,” Riley said.

The company hasn’t yet discussed plans with FDA for developing SYN-010, including whether the 505(b)(2) pathway would be appropriate for their modified-release formulation, but Riley noted that the company has had positive interactions with the agency regarding its Clostridium difficile prevention candidate SYN-004, which it is moving straight from preclinical testing into Phase II Also see "C Diff. Prevention Candidate Heads Into Clinic With Ambitious Timetable" - Pink Sheet, 3 September, 2014..

“It seems fairly straightforward. If you have a drug that is completely safe and has meaningful impact on a patient population I think they [FDA] are open-minded to it. The problem is most drugs don’t have that safety profile,” Riley said.

Synthetic Biologics Thinks Statins May Get At Root Of IBS-Constipation

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