Synthetic Biologics Inc. - Special Call
Dec 10 2013, 16:24
Executives
Jeffrey Riley - President and CEO
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Kris Maly - VP of Corporate Communications
Analysts
Rahul Jasuja - Noble Financial Capital Markets
Jason Kolbert - Maxim Group
Synthetic Biologics Inc. (SYN) Special Call December 9, 2013 9:00 AM ET
Operator
Good morning, and welcome to Synthetic Biologics Conference Call. All participants will be in listen-only mode. (Operator Instructions). After today's presentation, there will be an opportunity to ask questions. Please note that this event is being recorded.
At this time, I would like to turn the call over to Kris Maly, Vice President, Corporate Communications of Synthetic Biologics. Ms. Maly?
Kris Maly - VP of Corporate Communications
Thank you, Keith, and good morning everyone. In addition to the phone line, we are streaming this call live over the internet with slides today. After the formal portion of the call, we will offer the opportunity for Q&A. The webcast replay with slides will be archived on our website for 30 days.
During this call, there may be forward-looking statements regarding our current expectations and projections about future events. Generally, the forward-looking statements can be identified by terminologies such as may, should, expects, anticipates, intends, plans, believes and similar expressions. These statements are based upon current beliefs, expectations and assumptions and are subject to a number of risks and uncertainties, many of which are difficult to predict.
No forward-looking statements can be guaranteed, and actual results may differ materially from such statements. The information in this conference call is provided only as of the date of this call, and there is no obligation to update any forward-looking statements.
Now I'd like to turn the call over to our CEO, Jeff Riley. Jeff?
Jeffrey Riley - President and CEO
Thanks Kris and good morning everyone. Over the weekend, we announced that we have entered into a worldwide license and option agreement with Cedars-Sinai Medical Center for the development of new treatment approaches to target non-bacterial intestinal microorganism life forms known as archaea, that are associated with intestinal methane production and chronic diseases such as irritable bowel syndrome, obesity and Type 2 diabetes, through our newly formed subsidiary, Synthetic Biomics, Inc.
Cedars-Sinai investigators have discovered that eradicating archaea and inhibiting intestinal methane production may treat the underlying cause of major diseases, not typically considered forms of infectious disease. These efforts are being led by Dr. Mark Pimentel, Director of the Gastrointestinal Motility Program at Cedars-Sinai Medical Center, who is credited with discovering that IBS, is a form of infectious disease, in which gut microflora that should normally be confined to the large intestine inappropriately colonize the small intestine. We are pleased to have Dr. Pimentel with us today to present his work that he has compiled in this area.
And with that, it's my pleasure to introduce Dr. Mark Pimentel.
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Thank you Jeff and Kris, and it's a great pleasure to have the opportunity to speak to you all today. The title of my talk is Methanogens and Methane: Implications in Therapeutic Opportunities For Major Disease. The outline of what I am going to speak to is -- and I am going to talk a little bit about the microbiome. Of course, you'd have to be in a cave for the last 10 years, if you didn't know that the microbiome was a great area of inspirational research and opportunity for the future, as even microbiome is being investigated very aggressively this last decade.
Methane and Methanogens are a specific component of that, that are often overlooked, and I will show you why that is. We will talk a little bit about irritable bowel syndrome of various types, leading all the way to the archaea and what their role might be.
Some data we have on obesity, metabolic syndrome, a brief look at the market evaluation and a timeline of where we could be in a couple of years.
Many of you may have or may not have seen slides like this, but literally, there are 100 times more bacterial cells in the human body than there are human cells in the human body, and some of them quip that, bacteria have been around a lot longer than we have and maybe we have all been the vehicle for them. But they didn't expect us to come up with pharmaceuticals and other processes that can alter their presence. But they do both help us in terms of health and hurt us in terms of disease, and the understanding of this relationship is, I think we're just beginning to understand.
In this slide I really want to talk about -- there are really three domains of life. We have Eukaryota, which is basically -- when you say you are here, that means humans are in that category. Then there is a group called bacteria, and then there is a group called archaea. It used to be that archaea were under the category bacteria, but they are so unique, in fact archaea are so ancient that their DNA is not DNA like we, you and I know it. There are four parts to the DNA; the A, T, C, and G that we're conventionally used to knowing about. They don't have those, there are different structures. So they are quite ancient, but it also means that they are more evolved than any others, because they've been around such a long time.
And the archaea are composed of a number of different organisms, one of which are the methanogens, which we'll speak to in a few minutes. But the specific targets that we're looking at are the archaeal species.
Now, if we go back to the human microbiome project which I was referring. The human microbiome project has essentially studied bacteria and the bacterial colonization of the human body; and while there are some studies looking at archaea, there is little still known about what their role is in the human body.
What I want to focus on, and you'll see some slides later validating this, is that there is a particular methane producing organism in the digestive tract called Methanobrevibacter smithii, and this is really the predominant organism in the human digestive tract. To-date, there really is no drug development plans by any company that I am aware of for this organism and this organism appears to be very important to health and disease, and I'll demonstrate that in the next few slides.
But before I do that, I do want to talk about irritable bowel syndrome, so what disease are we actually talking about? Irritable bowel syndrome, as many of you might know, is a complex, symptom complex of diarrhea and constipation, also characterized by abdominal discomfort and bloating. And while people often look at it as a lifestyle disease, it is not a lifestyle disease, it is actually a very severe condition, in fact likened to heart disease, diabetes and others, in terms of the crippling nature it has on the quality of life of these patients. So these patients are severely affected.
The other thing that's unique about irritable bowel syndrome; for example, in heart disease, it happens to people in their retirement or at an older age, whereas irritable bowel syndrome really affects young people, as well as people of all ages. So it doesn't discriminate by age, and therefore affects people often in their productive years of life and making them less productive, and that's been shown in workplace studies, where it's affected workplace productivity and other factors of work, really did the impairment.
But the statistics are, irritable bowel syndrome is a major disorder, is probably the most common chronic disease and certainly the most common disease in gastroenterology. 10% to 15% of the entire global population suffers from various degrees or severity of irritable bowel syndrome, based on epidemiological studies.
In the United States, based on the AGA [Burden Wellness Document], now 10 years old, but probably applies equally today, it's the most expensive disease in GI because these patients undergo numerous investigations that always turn up nothing, because there isn't anything to see on endoscopy or colonoscopy; and so they undergo such expensive and invasive tests, only to come up empty handed and numerous pharmaceutical agents given to them, again with, mostly, futility.
One of the challenges we've had in irritable bowel syndrome is that we have been treating IBS symptomatically. So for example if you have constipation, you give them a laxative. If you have diarrhea, you give something to slow the bowel down; and we've suffered with not understanding what the cause was, and therefore not being able to direct therapy.
We've been involved, and I particularly have been involved in the development of Rifaximin, which is a product made by Salix Pharmaceuticals, in an attempt to get that to market for irritable bowel syndrome. It is not yet indicated for irritable bowel syndrome, but I'll show you some of that data here in a moment also. But it's the only therapy that treats a causative factor, and this is used for the diarrhea form of irritable bowel syndrome. There is no treatment for a causative factor on the constipation side, and that's where we get into the details here today.
But again, let's start on the non-constipation side, just to show you where we were and let me go straight to the next slide, which talks about where we were before 1999. Before 1999, IBS was though of as a physiologically associated disease. The problem with medicine is, and I put examples here is that; in the 1970s, stress was the cause of heart disease. So if you were the CEO of a company and you had a heart attack, you should resign and you should grow a garden in your backyard, because otherwise you will have another heart attack. But we soon learned at shortly thereafter that, yes stress is an important part of health and disease, but cholesterol, hypertension genetics were far more important in terms of the ideology of that.
Stress ulcers, ulcers in the stomach were often thought of as stress related. Now we know they are related to H. pylori, which was a bacteria; and many other diseases [suffer] from that example of when we don't know what's going on in medicine, we often attribute it to stress.
Well circa 1999 and before, that was the approach. IBS was characterized by this constellation of abdominal pain and bowel dysfunction and bloating. It was associated with psychological diseases and even alluded to in the DSM-IV and DSM-III and was treated with anti-depressants. So it was an all-in-your-head approach for irritable bowel syndrome.
Then our paper came out in 2000, where we discovered that bacteria could be important in irritable bowel syndrome. I got to tell you, the day we did this, it was kind of chaotic because the media was very excited about this concept that bacteria could cause IBS. But the introduction of the media caused a flurry of excitement around this, but the people who were studying irritable bowel syndrome at the time, found that it was too big a space shift in thinking overnight, and it was controversial initially, because it was one study. But it was an inflection point, and it took many-many years. In fact I have pretty much dedicated the last 15 years of my life to move this concept forward.
There are so many millions of patients that suffer from this disease in the United States and its my passion to try and legitimize their disease, and the thing that makes me most proud is when I receive so many emails and correspondence from these patients, thanking me for moving the field away from the psychological component to a more objective and treatable condition, and I'll show you that in a moment or two.
But the inflection point in 2000, I think in some ways, we are at the front of the wave of microbiome related disease. We were starting to say that gut microflora are related to irritable bowel syndrome in a very-very specific way. This is the slide showing microbiome publications, and you can see that the year 2000 was kind of the start of this new wave of concepts that gut microflora and microflora of the human body are really important and we should study and you can see the number of publications growing exponentially after the year 2000.
So what were we trying to look at? Well, we eventually proved this, and I'll show you in the next three slides, four slides, exactly how we prove this. But is the concept of small intestinal bacterial growth overgrowth. Unlike ruminating animals, humans, the small intestine which is in the middle of your screen, normally contains very few bacteria. The colon contains 1011 bacteria per milliliter, in fact half the weight of stool is bacteria and not just the residual of food.
But as you ascend the small intestine there really is no bacteria in the duodenum, or there shouldn't be. And in patients with IBS, we were finding that they had a plethora of colon type bacteria, and that is this was abnormal and that this shouldn't happen and because of this, the patients were developing bloating, pain and altered bowel function.
Obviously the paper in 2000 which first suggested this, was controversial, but now 10 years later in the year 2010, a summary or meta-analysis of all the age and sex match studies, not just by our group, but by many groups throughout the world; clearly showed that using the breath test technology that's been around for quite some time, that the odds ratio of having an abnormal breath test in IBS was 10, as compared to healthy controls. So clearly, the breath test was picking up an abnormal fermentation in the gut that validated that paper we published in 2000, that there was a problem with the gut flora in IBS. Of course this has now gone molecular. This is a culture study. There are two large scale culture studies that show that IBS patients, when you take samples from the duodenum or the small bowel, they have too many bacteria, and this was a study from Sweden.
In another study that we've been involved with from Greece, we show that 60% of diarrhea predominant IBS patients have too many colon bacteria in their small intestine.
Jumping to the next, which is PCR, which is a very accurate technique for determining bacteria, because we can't culture all the bacteria, because we don't know how to; a lot of them are very-very unique. But using PCR which is a molecular technique, we pick up all the bacteria that are there and we see that some specific players, in particular E. Coli and klebsiella are the dominant players or overpopulators in the irritable bowel syndrome and probably accounting for the bulk of the symptoms.
And not to be left out, this is the more advanced technique; this is the latest. This is now deep sequencing. Many of you have heard of deep sequencing. This is basically sequencing everything that's in the sample. And I want to point to the left hand side of your screen, because I want you to see the scale. So IBS is on top, the peak is how many bacteria are present. So these are deep sequencing of the small bowel.
Let me digress for just a moment a lot of microbiome work that has been published in the last decade is focused on stool; and I can tell you that the stool microbiome, if you want to look at human health and disease, it's a good place to start because the stool is easy, it's easy to get, it's harder to access small bowel.
However, it's kind of like looking in the trash bin outside somebody's house to figure out who is living in the house, because there is a lot of dead bacteria in there that get amplified and there is a lot of trash. So when you look at the stool, there is a lot of noise and contamination.
But when you look at the small valve, we actually correlated that we we're picking up is live bacteria, because the PCRs correlate with live culture. So what we get is we're actually characterizing live bacteria.
But nevertheless, what we did with this deep sequencing, is we show that IBS patients, again, looking at the Y-axis, a tremendous amount of bacteria, very high peak of bacteria. But the width of the column or the width of that peak is very narrow and unhealthy, the width is wide and there is multi-peaks.
What this shows you is that there is great diversity in healthy people. There is less diversity of bacteria in IBS, but there is a heck of a lot more bacteria in IBS in the small bowel.
So what do we do with all this information? So in the year 2002 in fact, we already had the idea that we didn't have deep sequencing then, we didn't have these technologies. Where do we go from our initial observations that IBS could be microbial and the answer was, well, let's try antibiotics. I did a lot of homework on antibiotics at the time, and I was trying to be responsible to the issues of bacterial resistance, the issues of, are we really going to give an antibiotic to a large swath of a population. We had to have an antibiotic that was clean, that didn't get absorbed, that wouldn't compromise treating a urine infection or a lung infection; and Rifaximin was the ideal choice and Rifaximin was selected and I approached Salix Pharmaceuticals about doing a trial for this.
Rifaximin is a rifamycin derivative, it has been developed more than 20 years ago. So it was a reformulation of Rifaximin that was brought to the U.S. and marketed by Salix Pharmaceuticals, now in the U.S. and Canada and is the principal drug for Salix; and it's been approved for hepatic encephalopathy and traveler's diarrhea, and their irritable bowel syndrome studies are continuing with the anticipation of an FDA approval some time in the near future for irritable bowel syndrome.
But the first study that was approved or that was undertaken was this trial. I approached Salix Pharmaceuticals to see could we try and study in irritable bowel syndrome using their product and they approved the study and this became the Annals of Internal Medicine paper that you see here.
The Annals of Internal Medicine paper, it's interesting; because I submitted this paper a very long winded paper and talking about CIBS and dIBS. But the bottom line was, they wanted this figure and this figure is, they have never seen a drug where you take it for 10 days; and for 10 weeks the patients are better; and that's what we saw in this trial is that the percent of global improvement was statically greater after Rifaximin was completed, and it was maintained for 10 weeks. So we must have treated a cause for IBS in order for this to occur.
Now we moved on to Phase III trials and the Target 1 and Target 2 trials are listed here, and then the combined data. So if you look down is this column, Target 1, Target 2 and then combined for the primary endpoint, were statistically significant. Key secondary for bloating, abdominal pain and stool consistency all were statistically better. So it's one of the first products for irritable bowel syndrome that made the diarrhea better, the [global] better, the bloating better and the stool consistency. So everything was uniquely improved.
But when I pan to the next slide, it's going to look the same, but the heading at the top is going to say this lasted three months, and the study's duration was three months. So in diarrhea IBS, which is what these studies were, Rifaximin had a very durable benefit. You took it once and they stayed better for a protracted period of time.
Now what did this do? Obviously, this had an impact, because in 2002 when I first approached Salix and then subsequently the publication in 2006 of the Annals of Internal Medicine paper, the Rifaximin sales have gone from a very small number to over $600 million a year in sales, and Salix's market cap between 2006 and 2013 has risen to over $5 billion as a company. And you can see the line item where the top line results from the Phase III trials I just presented were released to the stock market on September 14, 2009, and the company, on the back of Rifaximin, for not just the irritable bowel syndrome since it's off-label, but for further approvals with hepatic encephalopathy, has been very impactful for the company.
Now going to constipation IBS, this was the part that was confusing, because in tradition in medicine, bacterial overgrowth which I have been presenting all through this, has been on the differential diagnosis of diarrhea. So when people think of diarrhea and they can't figure out what the cause of bacterial overgrowth, as sometimes thought of. But in fact, we found in that paper in 2000 and subsequently in the paper one year later, that it can also cause constipation and in fact, this may be even more interesting, as you'll see in the next few slides.
We knew that hydrogen producers were the major gas producers from bacteria in the gut. These organisms produced a tremendous amount of hydrogen and we've picked that up on breathe testing, because it's unique to bacteria, humans don't produce hydrogen. But it turns out this hydrogen is being used by another set of organisms, the archaea organisms that we started with in this presentation called methanogens. And when methane is being produced by methanogens, it eats up all the hydrogen in the environment.
And you can see that there is a red curve on the second graph on the right, and you can see that there is a flat line below it, that's hydrogen. So the methane is using up the hydrogen to produce methane. Now this becomes very important when we talk about obesity later, because these methanogens are helping the hydrogen producers get rid of their hydrogen from the environment. But in turn, this methane is impairing the gut and I'll show you.
So when we looked at the breath tests we were doing, and this was a very large study. When methane was present on the breath test, every single patient nearly was constipation predominant IBS. So it's very few times in medicine that you see a black and white finding, where one thing is so dramatically associated with another. But in fact that was the case here. When methane was seen on the breath test, almost all these patients were constipated. So we explored this in a number of ways, but it led down to the final issue, which is the next slide, is that when we infused methane gas into a live animal model, the gut slowed down by nearly -- between 60% and 70%. So we could slow the gut just by putting methane in there. And so we realized that it's a methane gas that's slowing the gut and probably causing the constipation, or at least that was our hypothesis.
Now, fast forward on this idea, because this was now back in 2006; fast forward to 2011, looking at all the studies that have ever been done in humans, where you study the methane on the human's breath and if methane is present, patients were constipated, and this study proves that through the years, this has been noticed and this meta analysis confirms that methane is associated with constipation.
Well how associated is it? So we did a blinded study where we took constipation IBS patients and doctors were asked to talk to them and find out if they are constipation or diarrhea, meaning not CIBS. But what I want to point out to is in this study, out of 24 CIBS patients, 22 were methane positive. So 91% of CIBS patients appear to be methane positive. So this is a biomarker and a biomarker for a gas that's from bacteria or from archaea or ancient type of organisms, that could be treatable; because the methane is causing constipation.
We then moved on to discover that this bacteria that I presented way in the beginning of the conference call, Methanobrevibacter smithii is the cause; because it was associated -- the amount of bacteria was related to the degree of constipation and the degree of bloating and also the degree of methane production on the breath. So Methanobrevibacter smithii is the organism that's the culprit in the CIBS patients.
So let's talk about CIBS therapy for just a minute, because one of the problems with CIBS therapy, and we'll touch on this a little bit further later, there is no biomarker for treatment of constipation IBS previously. We now have methane as a biomarker. Treatment was not based on cause, we were treating constipation with laxatives. Now there may be a cause. Current therapies are laxatives. Now, this is a non-laxative based approach that we're going to be embarking on. Antibiotic approach is temporary as I'll show you, may need a long-term strategy and methanogens are not bacteria. And so we need a better approach to inhibit these organisms.
Let me just point to one thing here, and this is what I will just speak to for a second is, when we look at treatments for irritable bowel syndrome based on a laxative approach for constipation and a diarrheagenic approach -- sorry on a constipating approach for the diarrhea IBS. We're not really treating IBS, so let me give you an example for Alosetron which was a treatment on the market and now is under an FDA program for limited access because of side-effects. When Alosetron improved IBS, that's the green bar by 13%; and also 17% detriment in constipation. So 17% more people on Alosetron got constipated severely as compared to the placebo group. Basically, so what you are doing, is you are taking diarrhea IBS and making them constipation IBS.
On the flipside, looking at constipation IBS, we have drugs like Amitiza and Linaclotide, and these products make the constipation patient have diarrhea. MiraLAX, Dulcolax and laxatives make patients have diarrhea. So I'm not sure that constipation patients necessarily want to have diarrhea, they want to have a normal bowel movement. Whereas Rifaximin on the diarrhea side, it made people have a normal bowel movement. And so there was no adverse effect on the opposite direction.
So what about Rifaximin; what about Rifaximin for constipation IBS and specifically methane? So we've just completed a double-blind randomized control trial, small trial just over 30 patients, with about 16, 17 patients per arm and this was presented literally just a few weeks ago at the ACG meeting, so these are the figures from that meeting, it's in the public domain. And this is the first randomized control trial treating methane positive constipation IBS patients. The primary endpoint is on this slide of constipation severity.
Now it compared neomycin with placebo, because we had previous data suggesting neomycin might be effective, and we then looked at neomycin plus Rifaximin, and this was superior. So Neomycin and Rifaximin together made CIBS better. It made the bloating better as well. And then, after you stop the drug or the drugs, the patients stay better. But unlike Rifaximin in diarrhea IBS, Rifaximin in diarrhea IBS, you take it once and they stayed better for months.
In this case it looks like after only a few weeks, these organisms start to return and the statistical significance starts to diminish. So while it maybe a great acute approach, it may not be a long-term approach like it is for the diarrhea side.
And this is bloating with the same kind of effect and then abdominal pain, doesn't show significance too much throughout relative study, because the power is low. But again, at the end of the trial, after four weeks, things start to diminish in terms of their discrepancy.
But it comes down to this slide, which is the most important thing to know. If you received Rifaximin and Neomycin in this trial, and you made the methane go away, that's the person who got better. So the study basically shows a proof-of-concept that methane is important in constipation, get rid of it and the patients gets better. Now we need something that can treat it and keep it away, because it looks like it comes back quite quickly.
Now what I'm going to do is, I've talked to you a little bit about IBS; I'm going to frame some data on obesity and metabolic syndrome, because this is very interesting and really important and will be part of the overall plan here. If you look at the obesity epidemic in the United States, these are maps starting in 1999 in the left upper corner progressing to 2010 and in 2013, the CDC estimates that currently there are -- that 35.7% of the entire U.S. population is now officially obese or with a BMI greater than 30.
So this is a serious progression of an ailment that's going to lead to a lot of health burden in the future. And the question is, what's causing this? Well obviously, we don't know all the causes, but up to 50% of the population is some states are obese. It leads to metabolic syndrome, the future is heart disease stroke and cancer from this scourge and the cause is unclear.
The recent intention has focused on gut microbiology. In fact, there is a lot of papers looking at bacteria and obesity. And so we have this slide, where we know obesity is not just caused by bacteria, it's caused by a lot of different factors and a lot of different things in different people. But bacteria play a role in some people and I will point to what -- methanogens or the role they may play in this.
I already showed you this slide, showing that methane slows transit. While there is another issue when methane slows transit, when methane slows transit you have more time. If you have more time, you absorb more calories. And so, we believe that methane or we hypothesized a number of years ago that if that happened, may be methane was -- could contribute to obesity.
There is another thing that methane does, and I briefly alluded to it previously. If you don't have methane organisms in your gut, the hydrogen organisms are the ones that are digesting the food, and when they do, they release some of that food for you. For example if you ate lettuce, humans can't digest lettuce. The lettuce are digested by a bacteria, the bacteria release products, we absorb that, we get a few extra calories from the lettuce because of that process. But once the bacteria produce hydrogen, it pickles them, they get intoxicated and they reduce their ability to convert food.
When methane organisms are around on the right panel, the methane is taking all the hydrogen away, cleaning the environment and the hydrogen producers are firing through that lettuce much faster, releasing more energy and that's the second aspect of why methanogens help liberate energy, and then that energy translates into more calories from the meal, than what's on the outside of a box of what you're eating, if you have methane.
So we examined this in a study of obese patients. This is a study by Dr. Mathur here at Cedars-Sinai Medical Center published in 2012, where we looked that just obese people. These are all -- people are all greater than 30 BMI; and what we found was, if we looked at their breath, if they had methane on their breath, they were 299 pounds on average and that's 60 pounds higher than people who did not have methane on their breath and the BMI and body weight were both statistically higher.
What about the general population? So in a general population study published earlier this year, 792 patients if the methane and hydrogen are present on the breath test, these patients had a greater BMI, and this was after controlling for age, sex, diabetes, antidepressants and other confounding variables. So this was probably most dominant, at least in this cohort, the dominant factor associated with obesity.
I could go on and on about obesity and metabolic syndrome. I am going to really point to one more slide, and that is that we noted in a previous presentation at a major meeting that if you have methane, your glucose metabolism is also altered, and you have higher (inaudible) of the peripheral glucose. And I will leave it at that for the obesity; but what I will say is, we have an ongoing trial currently funded by the American Diabetes Association and Dr. Mathur is the principal investigator on this trial. It's a small open label trial, but it is a first anti-methanogen treatment trial for metabolic syndrome and obesity and top line results of this are expected in 2014. We also have multiple ongoing animal trials and studies have already been published, where we actually infused this bug, this methanogen, and Methanobrevibacter smithii into animals, and we see the development of obesity. So this is going to become an important part of the future of obesity.
Just a few more slides and we're going to now divert to market analysis. I'm going to point to the top panel there, a very busy slide, but just so that you can understand, how many patients we're talking about here. When you break down irritable bowel syndrome, there is a CIBS which is constipation type and MIBS which is mixed IBS, and a dIBS which is diarrhea.
So breaking out the CIBS, which is really the group of interest. We now know that 91% of that chunk of patients is methane positive constipation predominantly irritable bowel syndrome, which amounts to 13.5 million people in the U.S. only. Of course, this is a worldwide condition, but in the U.S., only 13.5 million people.
In chronic constipation, when I go back to the meta-analysis that I showed you earlier in the presentation, there was a study by Attaluri, that showed that chronic idiopathic constipation or CIC also suffers from methane. In other words, a good proportion of patients with constipation in general, not just CIBS, are methane and therefore that biomarker is relevant for a treatment that could address that in 9 million U.S. citizens in addition to the 13 million above. So the potential is a cohort of people eligible for a methane therapy of 22.5 million people in the United States.
On the metabolic syndrome side of things, there are, I now believe to be, and I think even higher than this based on CDC data I presented to you, saying that 35.7% of the population. But suffice to say that about 100 million people suffer from obesity. We have estimated based on our breath testing studies, that 20% of these patients are methane positive, and that's a market in the United States of 20 million people.
So the therapeutics and candidates that we are exploring here in this relationship is that repurposing or intending to repurpose FDA approved oral drug substances found to inhibit meth antigens. We anticipate little or no impact on gut flora, by targeting pathways unique to meth antigens, and utilization of approved drug substances here, this will offer the fastest routes to treating patients.
Honestly, I have spent 15 years looking at this, these patients are in my clinic everyday I see over 200 patients a month with IBS. They suffer a tremendous amount of symptoms, and it's really quite an honor to have the fortune or the fortune to be able to discover some exciting new things that can help these patients. It is a passion of mine to try and discover these exciting therapies, because my patients suffer immensely.
The FDA has a special 505(b)(2) route for already indicated products and for approvals of new indications. There's a track record of these products having safety in humans and that reduces the development risk. And we have a broad multi-layered, seminal and new intellectual property in place which should help to protect this. Going to that, there are nine issued U.S. patents that are part of this portfolio, 26 issued worldwide patents and eight pending U.S. patents.
Looking at the anti-methanogen timeline for this relationship. In 2013, late 2013, which is just a handful of days ago, a license was obtained from the Cedars-Sinai Medical Center. We are expecting some top-line results from the metabolic syndrome study in February as I've declared already. Phase II trials would be expected to begin in mid-2014. These trials, because we have methane as a biomarker, unlike treating for example in the Linaclotide studies, treating just constipation IBS, means you are treating all the patients irrespective of the ideology of their CIBS. So you need larger numbers of the patients. But because we have methane as a biomarker, we are lasering in on the people who would respond to a therapy, and we think that the timeline is an accelerated timeline, because the biomarker allows us to pick the patients who would respond and we hope that the Phase II clinical trial could be completed either by late 2014 or early 2015 and then roll straight into two Phase III trials, leading to an NDA submission somewhere in 2016 -- and somewhere in 2016 early 2017, perhaps regulatory approval.
And my final slide is; again I keep saying the same thing and I don't want to be too emotional, but basically it has been an exciting journey for me, and some of the things that we are also discovering is that food poisoning starts this whole process. We know that acute gastroenteritis triggers irritable bowel syndrome and at Cedars-Sinai, we've actually discovered a lot of components of that pathway, and that IBS develops after a toxin exposure from acute gastroenteritis leading to autoimmunity, and this autoimmunity then leads to the damage to the nerves of the gut, the buildup of these bacteria, and if it's methane archaea that are part of this buildup, this can lead to all the sequelae that I've outlined in this lecture.
We now know some of the other targets in the autoimmune and antibody targets in this, and our goal is to eradicate and cure irritable bowel syndrome over the next decade or so; and so there's a lot of opportunity to help these patients, and I hope that they have a great deal of optimism that we're working very hard for their future.
Well thank you for your time, and I hope I didn't go too long over and I appreciate your attention.
Kris Maly - VP of Corporate Communications
Thank you so much Dr. Pimentel. We'd now like to open the line up for questions. Keith, would you please describe the procedure for asking questions for our listeners.
Question-and-Answer Session
Yes. Thank you. At this time we'll now begin the question-and-answer session. (Operator Instructions). Okay. The first question comes from Rahul Jasuja from Noble Capital Markets.
Rahul Jasuja - Noble Financial Capital Markets
Hi, good morning and congratulations Dr. Pimentel on your amazing work. This really could be a paradigm shift.
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Thank you.
Rahul Jasuja - Noble Financial Capital Markets
So a few questions, and sort of starting my education on this. So are these archaea bacteria -- is there a commensal or a synergistic or a mutualism based relationship between normal bacteria, gram-positive to gram-negatives and the archaea bacteria within -- are normal in gut flora is there not a relationship?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Well, what's interesting is that, I mean different parts of the gut have different archaeal colonization. So in normal people, these bugs are relegated to the left colon or the last part of the bowel. So it's very -- they are supposed to stay in one spot, they are not supposed to become overabundant and I think what we are seeing is a proliferation of these organisms, and they are commensal to each other. I mean, I am not saying archaea are bad, but they are not good when they are in excess.
Rahul Jasuja - Noble Financial Capital Markets
So is there any strategy that targets the archaea bacteria -- will then allow the balance of the archaea bacteria oppose the therapy to be reached, I guess?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Well exactly. And I think what you are saying exactly, the correct thing is that, they are out of balance and what we are proposing is to try and recorrect that balance.
Rahul Jasuja - Noble Financial Capital Markets
Okay. And so looking at methane as a potential biomarker; so where do you see the hiccups and the issues with the FDA? How far has that gone, is that being a (inaudible) of the biomarker in the eyes of the regulators?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Well I mean, if you actually look -- this is a brief presentation. I could probably give you a two hour lecture on the details and data on methane and it's potential. But I can tell you from my -- I have a fairly extensive experience with the FDA having gone there a number of times with Rifaximin. The FDA loves biomarkers, because it limits the population exposure. What we end up doing with a lot of drugs, is we're giving it in a swath of patients, and we obviously know that not all those patients are going to respond to -- with a particular therapy, and if you have something that hones in on a population using a biomarker. It's golden because the FDA, they can understand that better. The physicians who are treating can understand that better and they know exactly who to give the therapy to. So that's a very important thing to have.
Rahul Jasuja - Noble Financial Capital Markets
Okay great. And then finally, you didn't really talk about the mechanism of how you're going to tackle this. You did mention that you're going to use an approach that is distinct an antibiotic or the sort of antibacterial approaches. So can you provide some inkling as to what is the mechanism of this agent that you would be taking to clinical trials?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Jeff, do you want to take that? Jeff? Go ahead. Sorry.
Jeffrey Riley - President and CEO
Rahul, this is Jeff, how are you?
Rahul Jasuja - Noble Financial Capital Markets
Hi Jeff.
Jeffrey Riley - President and CEO
I believe for simplicity sake, what we're trying to do is the way that the compound that Dr. Pimentel is using today, is we believe that the mechanism is disruption of the hydrogen take up by archaea during their energy cycle. So rather than creating methane gas, we are interrupting that particular cycle.
Rahul Jasuja - Noble Financial Capital Markets
Alright and then clearly, you guys did mention a 505(b)(2). So obviously, this is an approved agent that you could pass-through a 505(b)(2) strategy I guess?
Jeffrey Riley - President and CEO
Well, we are looking at both approved agents, as well as new novel agents, correct.
Rahul Jasuja - Noble Financial Capital Markets
Okay, very good. That was a great call. Thank you.
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Thank you.
Operator
Thank you. And the next question comes from Jason Kolbert with Maxim Group.
Jason Kolbert - Maxim Group
Yeah, similar questions. Thank you very much, really informative. But just trying to understand specifically, how you could target the disruption of the hydrogen uptake and are there any positive attributes that these agents contribute to the gut and the intestinal flora?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Well I mean, I am not exactly sure if I understand your question. Can you just restate? I mean, are you saying there are other flora or you --
Jason Kolbert - Maxim Group
Two different questions, one is mechanistically, if we are talking about disrupting the hydrogen synthesis of these organisms, that seems like a very complex way to attack a very small segment of the overall flora. Is that possible and have you done any work in that area? And then the second question is, if you take these bacteria out, if you kill them, is there a cost that you pay? Is there some other positive attribute that they have in terms of their presence in the flora?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
What we know is, what we're embarking on and we have a lot of good targets, is trying to affect the metabolism of the methanogen. By doing so, downstream, we see an impact on patients' symptoms. So, I mean that's about all I could say it for the time being.
Jason Kolbert - Maxim Group
Okay. And Jeff I wondered if there, can you expand a little bit on kind of what the next steps are for you in terms of -- now that you have this license, how do you proceed? Are you going to identify a product candidate? Do you have to do preclinical work? Help us understand what the sequence of events should be?
Jeffrey Riley - President and CEO
Well, it's a little bit of all the above Jason. We just signed a deal late last night to be honest with you, and we've done roughly six months worth of diligence working into this. I think it's a combination of steps going forward. One of those being actual clinical development, which is what Dr. Pimentel is working on and what the graph showed as far as what we're doing in 2014, which are a substantial number of targeted clinical trials.
The other half of the equation is obviously we need to build the preclinical package in addition to that, and that will be run primarily within Synthetic Biologics moving forward, in conjunction not only with what we are doing, but with some of our collaborators as well. So we have to build both sides of those equations, in addition to tweaking the diagnostics, but we do have a true (inaudible) approach to this. Dr. Pimentel has generated substantial amount of data, some of which you saw today, and there was significantly more behind that, which certainly does give us to cause believe that (inaudible) could be a combination approach. We can't really discuss at this point in time, with existing drugs in addition to the drugs that we're pursuing, specifically for this indication.
I'm sorry I can't be more specific than that, but until we get the intellectual property where we needed to be at this point in time, we are being somewhat vague at this point.
Jason Kolbert - Maxim Group
Jeff, can you just -- last question is, can you just help me understand what the impetus was that drove this deal? Was it a particular relationship that you had at Cedars? How did you come about doing this and just trying to understand what drove this decision?
Jeffrey Riley - President and CEO
It was two-fold. One it was the relationship that with Cedars-Sinai and Dr. Pimentel all over the last several months. In addition to that, it met sort of our criteria from a business development perspective, as we look at pathogen-specific strategies. As you know, our (inaudible) program is pathogen-specific -- acidaminobacter pathogen specific. Our CDIP program, though not pathogen-specific does have -- we have learned a lot about the microbiome and protection of that machinery in that commensal community that exists in our intestinal tract. This fit beautifully into that, because archaea again though not a bacterium, does fall into the category where it is -- or I believe it is a commensal. I believe it is necessary and part of human evolution that was created as part of the overall microbiome. But to Dr. Pimentel's point, sometimes they get in places where they shouldn't be for a variety of issues, and I think he elucidated on those well, and the question is can we mitigate that, in order to reduce methane, in order to reduce metabolic syndrome, which is associated with all these diseases.
So, it was two-fold Jason. One, it was the relationship, the knowledge base. We spent a lot of time with Dr. Pimentel on his research, and then the second piece was, it did fit into the overall paradigm that we've evolved into, which is a pathogen-specific approach to take it (inaudible) one-by-one.
Jason Kolbert - Maxim Group
Thanks Jeff. What a great call! This was really helpful. I appreciate it.
Operator
Thank you. (Operator Instructions). We have a follow-up from Rahul Jasuja from Noble Capital Markets.
Rahul Jasuja - Noble Financial Capital Markets
Hi there. Thank you again. Just quickly, just out of more curiosity here. Now Dr. Pimentel, so have you seen in your work, where the overproduction of methane in these patients by the methanobacteria leads to other changes in immune imbalance or are you seeing signs that there could be a Th1, Th2 shift that is involved in Crohn's disease or some of those kind of diseases?
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
So, I mean, yes, the answer is yes. We have for example, data going back to 2003 and we continue to explore cytokines and others, which I can't elucidate more on the call. But I can tell you that inflammatory bowel disease patients don't have methanogens, which is another issue altogether. The question what is the correct balance, what do you need? And so we are exploring a number of different pathways of what these methanogens and their importance is.
So the answer to your question is yes, but there is no final answer yet. These bugs are really important and really important especially if they go out of whack, and are overabundant as we clearly see in these slides. And as I pointed out earlier, I got three, four hours worth of slides on IBS, and indeed the data is thick and deep now, as to how all these organisms are playing a role here for the sake of a 30 minute conference call, we can only explore the key highlights.
Rahul Jasuja - Noble Financial Capital Markets
Great, thank you. I'd be happy to come to LA and sit down with you.
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
You might be bored.
Rahul Jasuja - Noble Financial Capital Markets
Thank you. And Jeff, great, great catch. Thanks.
Jeffrey Riley - President and CEO
Thank you, Rahul.
Operator
Thank you. And as there are no more questions at the present time, I would like to turn the conference back over to Jeff Riley for any closing remarks.
Jeffrey Riley - President and CEO
Well thank you again for everybody that could attend this meeting. Sorry we didn't put out enough -- give everybody enough time to really look at it, but obviously this will be available for the next 30 days, and you can go back through this presentation, and we are available for Q&A, if you guys want to call us. I think the majority of folks on the line have our number. We are pleased to initiate this exciting new approach to treat these major diseases. Again, it's a very pathogen-specific approach, which fits beautifully with the rest of our programs. It is a clinical stage program, we'll be generating lots of data next year, both pre-clinically and clinically, and we'll be moving forward. We look forward to update you guys as we go forward. And thanks again everyone for joining this morning.
Dr. Mark Pimentel - MD, FRCP(C), Director, GI Motility Program, Cedars-Sinai Medical Center
Thank you.
Operator
Thank you. That does conclude today's teleconference. You may all disconnect your phone lines. Thank you for participating. And have a nice day.
