Ironwood Pharmaceuticals, Inc. (IRWD) Q1 2012 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to the Ironwood Pharmaceuticals First Quarter 2012 Investor Update Conference Call. [Operator Instructions] As a reminder, today's call is being recorded. I would now like to turn the conference over to your host, Meredith Kaya. Ma'am you may begin.

Good morning, and thank you for joining us for our investor update for the first quarter of fiscal year 2012. Joining me for today's call are Michael Higgins, our Chief Operating Officer and Chief Financial Officer; Mark Currie, our Chief Scientific Officer; and Tom McCourt, our Chief Commercial Officer. We also have Peter Hecht, our Chief Executive Officer; and Jim DeTore, our Vice President of Finance, available for the question-and-answer portion of the call. By now, you should have a copy of our press release which crossed the wire earlier this morning. If you need a copy of the press release, you can go to our website, www.ironwoodpharma.com, to find an electronic copy. Some of the information discussed in today's call, particularly the information related to linaclotide, is based on information as of today, May 1, 2012, and contains forward-looking statements that involve risks and uncertainties. Actual results may differ materially from those set forth in such statements. We do not undertake any obligation to update any forward-looking statements made during this call or contained in the accompanying slides, as a result of new information, future events or otherwise. For a discussion of these risks and uncertainties, you should review the forward-looking statements disclosure, as well as the risks under the heading Risk Factors, in our annual report on Form 10-K for year-ended December 31, 2011, and any of our future SEC filings. I would now like to turn the call over to Michael.

Thanks, Meredith. This morning I'd like to provide some brief highlights and then, I'm going to turn the call over to Mark, who will discuss linaclotide and our broader pipeline. Lastly, as we've done in previous calls, Tom will then discuss our view of the linaclotide opportunity. First, a few highlights. As you know, our NDA for linaclotide is presently under review at the FDA. As we announced last week, the FDA notified us and our U.S. partner, Forest Laboratories, that they will extending the review period of our NDA for 3 months. The PDUFA date for linaclotide is now September 2012. Additionally, in February, we were notified by the FDA that an advisory committee meeting, in connection with its review of the NDA, was not necessary. We, and Forest, continue to work with the FDA to address its questions during the review process. Back in September of 2011, our European partner, Almirall, submitted a marketing authorization application to the EMA for linaclotide for the treatment of irritable bowel syndrome with constipation. Almirall continues to work with EMA so address their questions during the MAA review process. Commercial preparations continue throughout the organization. The commercial and manufacturing operations teams here at Ironwood, and at our commercial partners, Forest and Almirall, as well as our supply-chain partners are all working together closely across the global network, to prepare for the launch and commercialization of linaclotide. In addition to our linaclotide partnerships with Forest and Almirall and Astellas, we're also exploring alternatives in the rest of the world. There continues to be a great deal of interest and we're excited about the potential opportunities. We'll keep you updated as those discussions progress. Now shifting to some corporate financial updates. We ended the first quarter of 2012 with approximately $202 million in cash, which includes $85 million in net proceeds raised back in February. As we have mentioned in the past, we have several remaining potential pre-commercial milestones for linaclotide from our commercial partners. These milestones include $85 million from Forest upon NDA approval, and up to $20 million from Almirall upon commercialization in the 5 primary countries in Europe. One final comment before I turn the call over to Mark. As Ironwood continues to grow, we will eventually need to move in to a larger facility. Therefore, we are currently exploring our options. Our lease here in Cambridge expires in 2016 and, therefore, there will be minimal impact on our cash for the next 4 years as we explore our options. With that, now let me turn it over to Mark.

Thanks, Michael. And thanks for joining us on the call today. I would like to briefly touch on some recent updates with respect to linaclotide, as well as highlight our continued progress with the rest of our pipeline. As you know, we and Forest were recently notified by the FDA that it has extended the review period for linaclotide by 3 months, to complete its full review of the data supporting our NDA. This extension came as the result of a digital analysis of existing data, which had been recently requested by the FDA to further characterize the relative effects of the 2 doses that were studied in Phase III chronic constipation clinical trial. As previously disclosed, the 2 doses were tested and chronic constipation clinical trials showing both doses to be significantly better than placebo. Because the requested information was provided within 3 months of the original PDUFA date, the regulation provides for a 3-month extension for full review of the submission. Therefore, the PDUFA date for linaclotide will now be September 2012. We and Forest are continuing to plan for a 2012 launch. We will work -- we will continue to work closely with the FDA as they move forward in their review of the NDA. Additionally, we are looking forward to our participation in Digestive Disease Week 2012 later this month, in San Diego, where we will have 15 poster presentations and one oral presentation. We will provide more detail on the specific topics and timing of these presentations in the coming weeks, however, it's worth noting that the data being presented will be focused primarily on linaclotide's impact on reducing abdominal pains. We also continue to accept lifecycle management opportunities in order to ensure that we are maximizing the potential value of linaclotide. While it is difficult to assess what -- either the scope or timing of these activities, based on our preliminary effort to date, we anticipate that these activities will include the exploration of the potential for linaclotide in the pediatric population, as well as in other indications. And while our focus remains largely on linaclotide, our broader pipeline, which is comprised of discovery research efforts and early development candidates in multiple therapeutic areas, including GI, CNS, pulmonary and cardiovascular diseases, continue to advance as well. This includes 9179, our second generation GC-C agonists, discovered by Ironwood scientists. That is in early development for the treatment of painful disorders of the small intestine. We expect to initiate Phase II clinical studies on 9179 later this year in functional dyspepsia patients. Our pipeline also includes IW-2143, a novel early development candidate being developed for the treatment of anxiety, that we in-license from Bionomics Limited in Australia. Data from several preclinical studies indicate 2143 has anti-anxiety activity without the sedative side effects of the typical of the benzodiazepine, a class of drug currently used to treat anxiety. In total, we anticipate spending approximately $60 million to $70 million in 2012, on our non-linaclotide-related R&D effort. With that in mind, I will now turn the call over to Tom.

Thanks, Mark. As we've mentioned in previous calls, we will continue to share our highlights on potential commercial opportunities for linaclotide. We have a number of the participants on the call today, so I'll briefly review how we think about the patient, the customer and the market, as well as highlight some primary care launch analogs and relative learning that seems to be applicable, as Ironwood and our global commercial partners prepare to, hopefully, launch linaclotide. The IBS-C and chronic constipation patient populations experience a continuum of symptoms, with all patients experiencing difficult and infrequent bowel movements and over 30 million patients suffering from a variety of additional bothersome abdominal symptoms, such as pain, discomfort, bloating and fullness. Patients typically experience at least one symptom over 100 days annually, with over 70% experiencing some symptom every day. The majority of patients describe their symptoms as extremely to very bothersome, with pain as the primary reason they seek care. Patients take a variety of medications to manage both abdominal and constipation symptoms. Laxatives are the mainstay for treatment and are generally used as rescue medication when straining gets quite difficult, but can often exacerbate abdominal pain, bloating and cramping. Therefore, it's not surprising that over 70% of patients are not completely satisfied with these treatments. Yet, due to a lack of treatment options, patients still take laxatives, 90 to 100 days each year. This slide identifies the patients that we'll be focusing on at launch. Currently, there are about 15 million patients suffering from both abdominal and constipation symptoms who are actively seeking care and treated. More than 10 million of these patients are not satisfied with their treatment and have a significant need for effective alternatives. It's also important to mention that in addition to these 10 million patients actively seeking care, we estimate that there's an additional 12 million to 15 million patients not currently seeking care. They are struggling to self-manage their symptoms and are not satisfied with their current treatment options. This high-need population will be a secondary target for us to educate and help. Based on the clinical profile -- clinical program results to date, the emerging a profile of linaclotide was very promising. Linaclotide is the first-in-class, local-acting, minimally absorbed peptide, that acts on both pain sensing nerves and intestinal fluid to improve abdominal pain, bowel symptoms and patient satisfaction. It's also important to note that in our Phase III IBS-C and CC clinical trials, symptoms returned within a week of patients discontinuing treatment. Diarrhea was the most common adverse event reported in about 20% of patients. These data are from the 26-week IBS-C trial and are representative of all 4 Phase III trials. 90% of patients experiencing diarrhea, reported the episode as mild to moderate, with 50% of reported events occurring within the first week of treatment. It's also important to note that 4% of patients discontinue the trial due to diarrhea, and no serious adverse events reported as diarrhea. Overall patient satisfaction is a key indicator of the clinical performance, and often reflects the real-life discussion between patients and physicians, as they assess treatment response. Over 50% of patients receiving linaclotide reported to be very to quite satisfied. This is quite comparable to the level of satisfaction report with other patients experiencing significant symptomatic relief, such as heartburn sufferers, taking proton pump inhibitors. It's important to note that this comparison is across studies, and is using a slightly different 5-point scale but, directionally, is very encouraging. In an independent third-party research study, where patients -- physicians were exposed to a clinical profile similar to linaclotide, about 20% to 25% of gastroenterologists and PCPs reported they would prescribe linaclotide, if approved, immediately after launch. With another 50% to 60% of physicians expressing a willingness to prescribe linaclotide, once they're comfortable with the post-marketing safety profile. In a separate research study conducted by Ironwood, physicians were asked, what percent of IBS-C and CC patients they would prescribe this agent for, having a similar, when it's a similar profile to linaclotide? These physicians reported, they would potentially prescribe linaclotide to 40% to 50% of IBS-C and chronic constipation patients, and 60% to 65% of their patients who were not fully satisfied with current treatment. Now we must acknowledge that these estimates are often overstated, based on historical correlation between market research, stated intent and actual physician prescribing behavior. But the intent to prescribe, again, looks very promising. Now I want to remind you of our current thinking around possible adoption and uptake analogs for launch. It's important to note that primary care and specialty product launches are quite different. First, the population of patients for primary care products tend to be much larger and managed by far more physicians. Second, there are generally far more components in the primary care treatment process to progress from physician treatment decision to chronic management of patients. For the most part, these patients need to go to a retail pharmacy each time they need their drug, often facing significant co-pay, which can impact treatment adherence. This is in sharp contrast to the specialty drug market, where there are generally far fewer patients, seeing fewer physicians, often getting their drug in the office, which tends to be scheduled and actively monitored. Finally, there's generally a higher cost associated with specialty drugs. This -- thus, sales uptakers tend to be steeper and plateau faster, as opposed to primary care drugs. We have previously mentioned that proton pump inhibitors and gastroesophageal reflux disease, or GERD, appears to be reasonable analogue, as we chart the linaclotide launch. GERD, IBS-C and chronic constipation are generally not considered to be serious disorders, however, they are extremely problematic for patients. The problems with the GERD, the frequency and bothersome of the symptoms and the level of poor satisfaction with pre-existing treatment, are all quite comparable to IBS-C and chronic constipation. Prilosec, like linaclotide, was a first-in-class innovation in a market that needed to be developed, in terms of patient and physician awareness of the level of suffering. And most important, provided the opportunity to improve patients' lives. Prilosec provides us a real-life example, demonstrating the benefit of focusing and improving physician and patient communications. The simplicity of owning, relieving and preventing heartburn drove the success of Prilosec. Prilosec, which was the market leader for over 10 years, experienced steady growth and built the GERD category in excess of $12 billion in sales. Prilosec alone exceeded $30 billion in accumulative sales, just in the U.S. Prilosec and Zelnorm serve as reasonable, but not a perfect analogs for linaclotide and the GCCA category. As you can see, they are both experience steady and comparable growth over the first 12 to 18 months. For Prilosec, growth was driven by its ability to relieve heartburn, thus capturing patient share. These patients tended to adhere well to treatment, which further accelerated growth. However, Prilosec was hampered by initial safety concern, including a boxed warning. In addition, it had a very narrow indication for [indiscernible] esophagitis and refractory GERD. There is also a limitation on the duration of therapy and a very poor understanding of GERD. And early on, managed-care restrictions were heavy. The initial growth of Zelnorm was fueled by a highly visible, outspoken patient population actively seeking care and asking for effective relief of their symptoms. But the growth of Zelnorm slowed at 18 months, following a Dear Doctor Letter communicating the safety risk. The growth was further hampered by a narrow indication, which was for women with IBS-C under the age of 65. A limitation was also in place for the length of therapy. There was early safety concerns and, importantly, there was relatively low adherence likely due to the very marginal improvement in abdominal symptoms. Yet Zelnorm was still on track to exceed $1 billion in sales. Now we believe, if approved, the profile of linaclotide will look quite different. First, we believe linaclotide should be indicated for both IBS-C and chronic constipation, at launch. Having demonstrated statistically significant reduction in abdominal pain while improving constipation symptoms in clinical studies. It also appears that symptoms returned within the first week of discontinuation, indicating that we could see a higher adherence rate and chronic use. And finally, physicians can easily identify patients and clearly recognize the need for effective treatment. In addition to Prilosec and Zelnorm, we examined all primary care launches since 2005. The uptake and success of the launches varied widely. The more successful launches appear to have some significant similarities, including the existence of a significant unmet medical need, often highly symptomatic. The level of -- and the level of product differentiation could be clearly identified and soundly justified. As a result, physicians tended to more easily identify and recognize the need for better treatment, and exhibited a greater urgency to switch, once convinced the new drug provided an incremental improvement with minimal hassle to their office staff or to patients. Patients were generally actively involved in the treatment process. They were either highly symptomatic or concerned about their health care disorder. And when they experienced the positive treatment result, it often led to better adherence to therapy. Third, payers tended to provide more reasonable access and reimbursement once convinced the patient was truly suffering and struggling with current treatment options. And that the new drug provided clear benefit at a reasonable price. We and our partners are completely focused on the launch of linaclotide. We have aligned on one global brand strategy and, together, we'll be collaborating on the implementation of the brand message and tactical plans, assuming when linaclotide is approved. In order to successfully build a brand, over time, it's critical to educate the full prescriber base, therefore, the combined force in Ironwood selling effort will call and 70,000 to 80,000 physicians to maximize linaclotide's growth. We will concentrate our efforts, particularly, on the top 20,000 to 25,000 high-potential early adopters, as well as other physicians who are likely to move quickly. This will drive the initial growth of linaclotide. This effort will require somewhere between 1,200 and 1,400 sales specialties to ensure they we are able to reach these key physicians. The highly effective Forest sales force will provide great access, and to effectively educate and prepare primary care physicians to prescribe linaclotide, as they are already calling on the vast majority of potential linaclotide prescribers. Ironwood will create a GI specialty sales force that will complement the Forest selling effort. A robust physician education effort will be implemented to ensure a comprehensive understanding of the disease, patient and linaclotide. Sales force and educational programs will help physicians identify appropriate patients and demonstrate the clinical profile of linaclotide. The patient plays a really critical role in the overall management of these disorders, and their communication with physicians is core to adequate care. Based on our research, these suffering patients are actively seeking information, particularly, online. This presents an efficient means to educate patients on the importance of accurately describing all their symptoms, as well as their treatment histories, to the physician so the physicians can determine if linaclotide is appropriate treatment. Finally, the payer team will focus on establishing a strong value proposition to various public and private payers based on the burden of illness, the unmet medical need, the benefits of linaclotide and associated costs. In summary, linaclotide looks promising and we have very much to do. Assuming that the NDA does get approved, we and Forest plan to launch linaclotide in the U.S., as soon as possible. As Mark commented earlier, we and Forest continued to plan for a 2012 launch. While it will ultimately be dependent on the timing of the potential approval, we will do our best to tighten the timeline, as much as we can, to accelerate launch. The timing hinges on a few key items. First, we need to pre-clear all of our promotional materials with the Office of Prescription Drug Products, formerly known as DDMAC. Second, we will need to stock all retail channels so that we have sufficient quantities of product. Finally, we will need to prepare and educate our sales force on how to effectively promote linaclotide in an efficient and compliant matter. Our internal efforts to prepare for a successful commercial launch are completely on track. Together with our partners, we have put together an incredibly strong sales and marketing leadership team with extensive experience and knowledge around implementing a launch of this nature. This group is functioning as a fully integrated and collaborative team to ensure that we are prepared for the successful launch of linaclotide, if approved. At this point, I'll open it up for questions.

[Operator Instructions] Our first question comes from Matthew Harrison with UBS.

So I have 2 questions. First, on cost. Can you give us a sense if the run rate for R&D, is the run rate we should be looking at or were there some onetime items?

It's Jim DeTore. There was a onetime item in R&D related to our Bionomics deal, for our upfront payment. I think beyond that, the quarter proceeded as we expected.

Okay. Great. And then, just a question on timing. I know you said that you're going to try and accelerate the launch as soon as possible. I know you've -- in previous calls you talked about, sort of 100 days needed to get DDMAC approval and then be able to launch so that would put you sort of in December. Is that still what you're thinking? Or maybe you can go through the timeline more specifically?

Yes. This is Tom. Yes, I think that's very close. We've said 90 to 100 days. Of course, it's completely dependent on how quickly we get approval. Assuming that FDA takes the entire period of time and we see approval in September, we still think we can launch in 2012. However, we want to make sure we're prepared that, if that decision comes sooner, then we can move quickly.

Our next question comes from Catherine Arnold with Credit Suisse.

I have 2 questions. One, I wondered, Tom, if you could give us an update on what you're hearing on the payer front? And then, secondly, on manufacturing. Could you highlight to us what the standard deviation is, in your capabilities? So for instance, how much flexibility you have in wide swings in your production forecast? Obviously, that could be important in the first 12 to 24 months.

Catherine, why don't I take the first question on the payer and Michael will handle the manufacturing question. We've done a fair bit of blinded research with payers and, as you know, there was an independent assessment that Decision Resources did, that was published a few months ago. I think the kind of the key walk aways that we're hearing is, one, payers know they have a problem with this patient population, they recognize that they're suffering, they know they don't have particularly effective therapies, so they're responding well to profile of the drug. I think that the focus that we'll be really concentrating on, over the next couple of months, is what is the right price point to come in to really drive a strong value proposition. Because the last thing we want us to have unneeded barriers in the way, in between the product and the patient. So I think, overall, I think we're encouraged by what we're hearing and seeing. But obviously there's a lot of work to do, to be able to, one, come in and present the product in the best light, and also move acceptance as quickly as possible, to get to reimbursement.

And Catherine, it's Michael. Let me take the manufacturing question. I'll answer it in 2 different categories. One is, let me address API and drug products separately. API, we have significant flexibility in the manufacturing, production or production of commercial quantities. We have, as we discussed, previously, there's 2 different companies, 3 different sites, where we're manufacturing API. We've already built significant inventory that has got us nicely prepared for launch and we have the capacity to significantly expand that. The lead times are long, so we're not taking any chances and we are investing in advance, to be ready. So we're feeling great on the API side. From a drug product perspective, first, from a capacity point of view is the -- as you may recall, in the U.S., Forest is the primary source of drug product manufacturing, they have significant excess capacity, in terms of their ability to produce what we will need for launch and well beyond our launch needs and we have also, in terms of having redundancy in the supply chain. We've also been working to bring up a group called Almac, in Ireland. They won't come online at launch, they'll come on line shortly after. So we'll have additional redundancy there, but we no questions with regard to capacity either in the U.S. or in Europe. Almirall is primary responsible for drug product in Europe and again they have sufficient capacity. So we're feeling good about being able to deliver on whatever the commercial needs are for the product both in the U.S. and in Europe.

You could have wide swings in your base case forecast and be able to supply the market pretty easily from what your assessment is?

Yes. Based on where we are right now, we're feeling quite good about being able to meet the demands regardless of how they swing.

Our next question comes from David Friedman with Morgan Stanley.

It's just regarding -- and I'm sure there's only so much you can talk about your interactions with the FDA, but in terms of the dosing and the efficacy questions in chronic constipation, was there a discussion around the need to look at lower doses than the 2 that you submitted? Or was it more related to finding subtle differences between the 2 doses that otherwise look pretty similar that you did test?

David, this is Mark Currie. Yes, there's no discussion around lower doses. And really, the discussion I think is all-around how to best use the 2 doses in what the patient population the best to use them, relative to the chronic constipation and what would be the scenario of how you would use the 2 doses. Clearly we believe both doses offer relief for patients. We see clear activity and efficacy with both compounds. We think the risk benefit is, again, consistent for the compound. And it is just really trying to determine what the best population and use would be.

And just as a quick follow-up, since there wasn't a panel and we didn't sort of have access to the huge amount of filing data, are there subanalyses or more sort of detailed data sets that reveal larger differences then we have seen with -- between the 2 doses? Because in the sort of top line data set they look fairly similar.

With the top line, I think the comprehensive data that we have, again, indicate that there is -- dose trends for the 2 doses that 290 does offer greater efficacy than 145. Obviously these studies were not powered to be able to show significance in those but if you go back to the 2B study and then also go across the -- combining the 2 studies or looking at them independently, I think, overall, the data supports that 290 offers greater relief. And then I think, as you indicated, of course, there's a large number of subanalyses that get done across the population, gender, age and on down the list. And again, we feel that the data continues to warrant that 290 offers patients a greater efficacy with very little difference in the risk-benefit analysis relative to the taller building.

Our next question comes from Geoff Meacham with JPMorgan.

This is John Shiam [ph] for Geoff Meacham. Just a follow-up question to the subgroup analysis that were submitted to the FDA, yes, I see that there possibly is some differences in age and sex, but I guess, the question is, do you believe that this is going to have an impact on the overall indication or just the limitation of use or the specifics of the clinical studies section of the label. And second follow-up question to that is, have you already discussed the label with the FDA?

I can't go in to any description around what our interaction with the FDA or in that matter. But again, just to highlight, I think we view -- when we look at our own data, we view that, really, as I've said, I think both doses are off an efficacy and have a really great risk-benefit analysis. And so relative to using the 2 doses, we feel mostly it's directed on how would we best used these 2 doses and not in the sense of restricted population of any sort, so again, we think it's still the very broad chronic constipation that the 2 doses will be effective for both of these, for that broad comp population. And then how would you advise the patient? What would be the outcome of how you would advise the patients to use -- or the physician would advise the patient to use the drug?

Our next question comes from Mario Corso with Caris & Company.

In terms of the R&D line, so for Bionomics, I think that's the $3 million upfront payment you were talking about, just wanted to clarify. And then in terms of the logistics or tactical part of marketing, launching linaclotide. So if we assume FDA approval comes in September, when we think about the path from there, should we think about the drug then being available in pharmacies in a couple of weeks? So physicians obviously could begin writing it, if they chose to. And then is it still kind of planned for a scientific or launch with the label before you get the promotional materials approved? And again, all that's taking place before the end of the year. It sounds, so we're just looking for a little bit of a map there.

Mario, it's Jim. Yes, just to confirm that $3 million is the upfront on the Bionomics payment. Tom?

Mario, this is Tom. As far as the timeline, as I mentioned, yes, there's kind of 3 paths here, all of which are converging on that 90 days. But obviously the retail channel will be well stocked ahead of our active promotion. And certainly -- we'll push that out as quickly as we can. But I think the critical piece, really, as far as driving uptake is really getting into the physician's office and educating them on who is the appropriate patient is and why linaclotide makes sense. As far as the scientific launch versus the commercial launch, obviously we're trying really hard to tighten up timelines and we're certainly continuing to consider both options. But we just want to make sure that we are well prepared to really effectively present linaclotide in the most effective manner. So we're looking at all options right now. A lot of it's going to be dependent on where the approval lands with regard to timing. But I think we're in a position where we can move very quickly to push things into the marketplace, once we have approval. But it is a little fluid right now. Yes, FDA has extended the review time for 90 days, but we want to make sure that we are fully prepared if that decision comes sooner.

Our next question comes from Juan Sanchez with Ladenburg.

In the hypothetical case, that the 145 dose gets approved for chronic constipation and the 294 IBS, so what will be the commercial implications of these versus your prior expectations? And the second question is more about on cyclic GMP, how much do you guys elevate cyclic GMP and, if is there such thing as too much circulating cyclic GMP in the blood that the regulators might be concerned with?

Sure. I'll take the first one, Juan, and Mark will follow up. As far as the 145 and 290 for chronic constipation, and we just ended up with 145, what are the implications commercially? I think we've always assumed that there was that possibility, that we did, we don't get 290. I think we believe it should be included, but if it's not, we don't see any impact commercially as far as how the drug will be utilized. I think our initial thinking is that this primarily bowel-related symptom and probably more mild abdominal symptom, that's probably a 145 patient. If there is significant abdominal pain and bloating which tends to look a lot more IBS, that's the 290 patient. But as far as our pricing strategy, we'll have comparable pricing, so it's really up to the discretion of the physician, what's the appropriate dose for that patient, and as a result, we don't see that there's going to be a significant impact on our commercial performance. Does that help? Mark?

Juan, this is Mark. So on the cyclic GMP, remember that this is a very, in a sense of population itself that are being turned on, a very limited number of cells that have cyclic -- guanylate cyclase C being turned on. In the cyclic GMP levels that we see coming out of the cells is miniscule compared to this circulating cyclic GMP. There are a lot of preclinical studies that have shown that circulating cyclic GMP for the most part is driven by soluble guanylate cyclase which is throughout the endothelium and throughout the smooth muscle, so and many other cells. Again our little pool of cyclic GMP give great pharmacodynamic activity that we think in the gut and obviously regulating the very local nerve. But relative to the systemic exposure of cyclic GMP, that's again we think there's essentially none and we look at that a lot in the preclinical model and again no change. So I think that did set the expectation, we're in a very limited pool, in a very narrow area of the body and not having really any change in the broader cyclic GMP pool.

[Operator Instructions] Our next question comes from Ram Selvaraju with Aegis Capital.

This pertain primarily to how we should be thinking about the European rollout of linaclotide, can you give us some idea on how the timing of that might occur and how that compares to the U.S. rollout?

Yes, Ram, this is Tom. It's obvious we filed to the EMA later than we did the FDA so it will lag somewhere between 4 and 6 months from our launch. And of course, as you know, Europe is rapidly changing with regard to the payer model. I think we're currently in ongoing discussions with Almirall as to the appropriate sequence of approaching each one of the regional payers. But we still see Germany and U.K. as the most attractive markets, and we certainly going move there very quickly to secure reimbursement and then we're certainly -- we certainly see an opportunity in Spain, Italy and France. But as you know, those markets do tend to be more cost sensitive, so we're looking at what our strategic options of how to best approach those markets.

And then with respect to Almirall sales effort, can you give us an idea of how many sales people Almirall is going to be using to support the launch of linaclotide? And which in which additional products Almirall has that might be co-promoted at the same time, and then could you give us an idea again just like with the European launch timing, what the timing is for the potential commercialization of linaclotide in the Far East through your partner, Astellas?

Astellas as you know -- Japan, we have to redo the entire program, it's certainly is a ways off and maybe Mark can comment on the overall timeline there. So I'll turn that over to him. As far as disclosing what Almirall intends to put on the street, we certainly can't disclose that. What I can say is we have a joint commercial committee that oversees the commercialization across Europe and what I can assure of is that there will be a very strong commercial effort put forth across Europe but the specifics to how many reps that is, how many calls that is, what additional products they may have in their bag, we really are obligated to leave that up to Almirall to share with you. So I apologize, my intention is not to be dodgy but that's really all we can share at this point. So Mark, why don't you comment on the Far East.

So we are very excited about the progress that our partner Astellas with linaclotide. As I think, you're probably you're aware of, in this Far East and Japanese territories, you -- really, as Tom indicated, you kind of start over a little bit on your program, going back and testing the agents in the Japanese population even in Phase I, that's been completed. We're very excited that our partners again, are continuing to move the program forward so we don't have an exact date when we would expect launch yet, but relative to the regulatory process -- progress and also the clinical development progress we are quite excited about where they have been able to move the program.

Thank you, I'm showing no further questions at this time. I would now like to turn the conference back over to Michael Higgins for closing remarks.

All right, well thank you all for your time and your interest in Ironwood and we look forward to keeping you up-to-date as we progress forward. Thanks again and have a great day.

Ladies and gentlemen, this concludes today's conference. Thank you, for your participation and have a wonderful day.