Ironwood Pharmaceuticals Inc (IRWD) 2012 Q1 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Ironwood Pharmaceuticals first quarter 2012 investor update conference call. At this time, all participants are in a listen-only mode. Later we will conduct a question-and-answer session and instructions will be given at that time. (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 in our press release, as well 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'd now like to turn the call over to Michael.

Thanks, Meredith. This morning I'd like to provide some brief highlights, then I'm going to turn the call over to Mark, who will discuss linaclotide in a 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 US partner Forest Laboratories that it will be extending the review period of our NDA for three months. The PDUFA date for linaclotide is now September 2012.

Additionally, in February, we were notified by the FDA that in 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 linaclotide for the treatment of irritable bowel syndrome with constipation. Almirall continues to work with EMA to address their questions during the MAA review process. The commercial preparations continued 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 are excited about the potential opportunities. We'll keep you updated as those discussions progress.

Now shifting to some corporate and 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 on NDA approval, and up to $20 million from Almirall upon commercialization in the five 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 into 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 four 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'd like to briefly touch on some retail update 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 had extended the review period for linaclotide by three months to complete its full review of the data supporting our NDA. This extension came as a result of a digital analysis of existing data, which had been recently requested by the FDA to further characterize the relative effects of the two doses that were studied in Phase 3 chronic constipation clinical trial.

As previously disclosed, the two doses were tested in chronic constipation clinical trials showing both doses to be significantly better than placebo. Because the requested information was provided within three months of the original PDUFA date, the regulation provides for a three-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 16 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 pain.

We also continue to [access] life cycle management opportunities in order to ensure that we are maximizing the potential value of linaclotide. While it is difficult to assess 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 include 9179, our second generation GC-C agonist discovered by Ironwood scientists that is in early development for the treatment of painful disorders of the small intestine. We expect to initiate Phase 2 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-licensed from Bionomics Limited in Australia.

Data from several preclinical studies indicate 2143 has anti-anxiety activity without the sedative side effects that is 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 efforts.

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 the potential commercial opportunity for linaclotide. We have a number of new 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 seem to be applicable, as Ironwood and our global commercial partners prepare to hopefully launch linaclotide.

The IBC or IBS-C and chronic constipation patient population has experienced 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 described these 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 medications 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 patient 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 is an additional 12 million to 15 million patients not currently seeking care that are struggling to self manage their symptoms and are not satisfied with their current treatment option.

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 profile of linaclotide looks 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 3 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 four Phase 3 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 discontinued the trial due to diarrhea and no serious adverse events reported as diarrhea. Overall patient satisfaction is the 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 reported 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 five-point scale, but directionally is very encouraging.

In an independent third-party research study, where patients and 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 the 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 is generally a higher cost associated with specialty drugs. This -- thus sales uptake curves tend to be steeper and plateau faster, as opposed to primary care drugs.

We have previously mentioned that proton pump inhibitors in gastroesophageal reflux disease, or GERD, appears to be a reasonable analogue as we chart the linaclotide launch. GERD, IBS-C and chronic constipation are generally not considered to be serious disorders. However, they're extremely problematic for patients. The prevalence of GERD, the frequency in bothersomeness of 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 the 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 patient's 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 US.

Prilosec and Zelnorm serve as reasonable, but not perfect analog for linaclotide and the GCCA category. As you can see, they both experienced steady and comparable growth over the first 12 months to 18 months. For Prilosec, growth was driven by stability 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 [relative esophagitis] in refractory GERD. The results are 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 a 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 is 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 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 these 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 a positive treatment [result], it often lead 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 option, 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 linaclotide is approved.

In order to successfully build the brand over time, it's critical to educate the full prescriber base. Therefore, the combined force in Ironwood selling effort will call on 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 would drive the initial growth of linaclotide. This effort will require somewhere between 1,200 to 1,400 sales specialists to ensure that we are able to reach these key physicians.

The highly effective Forest sales force will provide great access and to effectively educate and prepare a primary care physician 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 demonstrates the clinical profile linaclotide. The patient play -- 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, there are -- these suffering patients are actively seeking information, particularly online. This presents an efficient means to educate patients on the importance of actively describing all their symptoms as well as their treatment histories to their physicians, 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 US as soon as possible. As Mark commented earlier, we and Forest continue to plan for 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 manner.

Our internal effort 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 a successful launch of linaclotide if approved.

At this point, I'll open it up for questions.

(Operator Instructions) Matthew Harrison, UBS.

Good morning. So, I have two questions. First, on costs, can you give us a sense of the run rate for R&D, the run rate we should be looking at or were there some one-time items?

Hi, it's Jim DeTore. There was one-time 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 been -- in previous calls, you've talked about sort of 100 days you used to get DDMAC approval and then be able to launch. So that was [pretty short of in] December. Is that still what you are thinking, or maybe you could go through the timeline more specifically? Thanks.

Yes. I think -- I think, you -- hi, this is Tom. Yes, I think that that's very close. We said 90 to 100 days. Of course, this is 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.

Understood. Thanks very much.

Okay.

Thank you. Catherine Arnold, Credit Suisse.

Thanks a lot, and good morning. I have two questions. One, I wondered, Tom, if you can 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, some upfronts? And how much flexibility do you have and wide swings in your production forecast, obviously that could be important in the first 12 months to 24 months? Thanks.

Tom wants to take --

Look -- yes. So, 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 Resource did that was published a few months ago. I think that the kind of the key walkaways that we're hearing is, one, our payers know they have a problem with this patient population. They recognized that they're suffering. They know they don't have particularly effective therapies. So they are responding well to the profile of the drug. I think 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 is 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 the reimbursement.

And Catherine, it's Michael. Let me take the manufacturing question, I'll answer it in two different categories. One is, let me address API and drug product separately.

API, we have significant flexibility in that -- the manufacturing production -- or production of commercial quantities. We have -- as we've discussed previously, there's two different companies, three 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, and 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 US, Forest is the primary source of drug product manufacturing. They have significant excess capacity in terms of their ability to produce what we all 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 online shortly after. So we'll have additional redundancy there. But we have no questions with regard to capacity either in the US or in Europe. Almirall is primarily 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 US 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 upon where we are right now, we're feeling quite good about being able to meet the demands regardless of how they swing.

Super. Thank you.

Thank you. David Friedman, Morgan Stanley.

Hi, thanks for taking my question. It's just regarding and I'm sure there's only so much you can talk about [given your actions of] 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 two that you submitted, or was it more related to finding subtle differences between the two doses that otherwise look pretty similar that you did test?

Hi, David, this is Mark Currie. Thanks for the question. Yes, there is no discussion around lower doses and really the discussion, I think, is all around how to best use the two doses and with patient population, the best use of relative to the chronic constipation and what would be the scenario, how you would use the two doses. Clearly, we believe both doses offer relief for patients. We see a clear activity and efficacy with both compounds. We think the risk benefit is, again, consistent with the compound and it's just really trying to just 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 sub analyses or more sort of detailed datasets that reveal larger differences than we have seen with between the two doses, because in the sort of top line datasets, they look fairly similar?

Well, we thought that the top line, I think, the comprehensive data that we have, again, indicate that there is -- dose trends -- for the two 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 IIb study and then also go across the combining the two studies or looking at them independently, I think overall the data supports that 290 offered greater relief. And then I think as you indicated, of course, there's a large number of sub analyses that get done across the population, gender, age, and on down the list. And again, we feel that the data continued to warrant that 290 offered patients a greater efficacy with very little difference in the risk benefit analysis relative to the tolerability.

Great. Thanks a lot.

Welcome.

Thank you. Geoff Meacham, J.P. Morgan.

Hi, this is [John Shiane] for Geoff Meacham. Just a follow-up question to the sub-group analysis that was submitted to the FDA. Yes, I see that there possibly is some differences in age and sex. But the -- I guess the question is, 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 on other clinical study section of the label? And the second follow-up question to that is, have you already discussed the label with the FDA? Thank you.

I can't go into any description around what was -- what our interacting with the FDA or in that manner. But, again, just the highlight. I think we view, when we look at our own data, we view that really that -- and as I said, I think both doses are often efficacy and have a really great risk benefit analysis. And so relative to using the two doses, we feel mostly it's directed on how would we best use these two dose, and not in a sense of restricted population of any sort. So, again, we think it's still the very broad chronic constipation that the two doses would be effective for both [with these] -- for that broad population, and then how would you advise the patient -- what would be the outcome of how you would advise the patient to use or the physician would advise the patient to use the drugs.

Thank you.

Thank you. Mario Corso, Caris & Company.

Yes, thank you. In terms of the R&D line, so for Bionomics, I think that's the $3 million upfront payment you are 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 past from there, I mean, 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 plan 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 math there. Thanks very much.

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

Yes, Mario, this is Tom. As far as the timeline, as I mentioned, there's kind of three 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 will 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 and why linaclotide make sense.

As far as the scientific launch versus the commercial launch, obviously, we're trying real hard to tighten up timelines and we are 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 are 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 it can move very quickly to push things into the marketplace, once we have approval. But it is the little fluid right now. Yes, FDA has extended the review time for 90 days, but he want to make sure that we are fully prepared if that decision comes sooner.

Thank you. Juan Sanchez, Ladenburg.

Good morning, guys. In the hypothetical case that the 145 dose [it's approval] chronic constipation and the 290 for IBS, what will be the commercial implications with these versus your prior expectation (inaudible)?

Yes, Juan, this is Tom. Well, I'm sorry.

And the second question is what about [cyclic] GMP? How much do you guys elevate cyclic GMP on (inaudible) cyclic GMP in the blood, the regulators might be concerned with (inaudible)?

Sure. So I'll take the first one, Juan, and Mark will follow-up. As far as the 145 and 290 for chronic constipations, and if 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 is 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 like IBS, that's a 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?

Yes, thank you very much.

Mark?

Great. Hi, Juan, this is Mark. So on the cyclic GMP, remember that this is a very -- in a sense of population of cells that are being turned on, a very limited number of cells that have cyclic -- guanylate cyclase (inaudible) turned on. And the cyclic GMP levels we see coming out of the cell is miniscule compared to the circulating cyclic GMP. There are a lot of pre-clinical studies that have shown that circulating cyclic GMP for the most part is driven by soluble guanylate cyclase which is throughout the endothelium, throughout the smooth muscle. So -- and many other cells. So, again, our little pool of cyclic GMP give great pharmacodynamic activity that we think in the [guts] and obviously regulating the very local nerve. But relative to the systemic exposure of cyclic GMP, again, we think that essentially none. We've looked at that a lot in the pre-clinical models, and there -- again, no change. So I think that's 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.

Perfect. Thank you, guys.

Thank you. (Operator Instructions) Ram Selvaraju, Aegis Capital.

Thanks very much for taking my questions. These pertain primarily to how we should be thinking about the European roll out of linaclotide. Could you give us some idea on how the trending of that might occur and how that compares to the US roll out?

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 four and six 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 UK as the most attractive markets and we're certainly going to more there 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 are looking at what are our strategic options of how to best approach those markets.

And then with respect to Almirall's 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 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? Thank you.

Yes, let's just -- Astellas, as you know, Japan, we have to redo the entire program. So, certainly are 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 intend 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 you of is that there would be a very strong commercial effort put forward across Europe. But the specifics to how many rough that is, how many calls that is, what additional products they may have in the bag, I really -- 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 West -- Far East?

Yes. So we're very excited about the progress that our partner Astellas is making with linaclotide. As I think you're probably aware of in the Far East and Japanese territory, you really -- as Tom indicated, you kind of thought over a little bit on your programs, going back and testing the agents in the Japanese population, even in Phase 1. That's been completed. We're very excited that our partners, again, are continuing to move the program forward. So we don't have exact dates when we would expect launch yet, but relative to the regulatory process -- progress and also the clinical development progress, we're quite excited about where they've been able to move the program.

Thank you.

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. Have a wonderful day.