Meredith Kaya - IR Peter Hecht - CEO Tom McCourt - CCO Mark Currie - CSO Tom Graney - CFO.

Anupam Rama - JPMorgan Gary Nachman - Goldman Sachs Ravi Mehrotra - Credit Suisse Irina Koffler - Cantor Fitzgerald David Maris - BMO Capital Markets Boris Peaker - Cowen Mario Corso - Mizuho.

Good day, ladies and gentlemen, and welcome to the Ironwood Pharmaceuticals’ Fourth Quarter 2014 Investor Update Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time. As a reminder, this conference call is being recorded.

I would now like to turn the call over to your host Meredith Kaya. Please go ahead..

Good afternoon, and thanks for joining us for our fourth quarter 2014 investor update. By now, you should have a copy of our press release, which crossed the wire earlier this afternoon. If you need a copy of the press release, you can go to our Web site, www.ironwoodpharma.com, to find an electronic copy.

Some of the information discussed in today's call is based on information as of today, Thursday, February 12, 2015, 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 and on the current slide with the heading, Safe Harbor Statement, as well as the risks under the heading Risk Factors in our quarterly report on Form 10-Q for the quarter ended, September 30, 2014, and any of our future SEC filings.

Joining me for today's call are Peter Hecht, Chief Executive Officer, who will provide introductory remarks; Tom McCourt, Chief Commercial Officer, who will give an update on LINZESS; Mark Currie, Chief Scientific Officer, who will review our pipeline efforts; and Tom Graney, Chief Financial Officer, who will discuss our financial performance and guidance and then open it up for the question-and-answer portion of the call.

Our speakers will be referring to slides available via the webcast. For those of you dialing in, it may be helpful for you to go to the Events section of our Web site to access the webcast slides, if you haven't done so already. I would now like to turn the call over to Peter..

Thank you, Meredith, and snowy good afternoon to all of you from Cambridge. We made great strides delivering on our strategy in 2014. LINZESS continued on a strong growth trend, and in the fourth quarter we reported our first net profit for the U.S. collaboration, a critical inflection point for LINZESS.

That, over the coming years, will provide the opportunity for substantial operating leverage and increasing cash flows to the Company into at least 2031.

We also generated great momentum across our innovative R&D efforts with the initiation of five new clinical studies, including two on Ironwood programs and three linaclotide studies with our partners.

2015, we anticipate nine ongoing clinical studies with four data readouts expected during the year, including the positive IW-3718 Phase IIa data that we reported last week. 2014 was a really exciting and productive year for us, and sets us up for a big 2015.

I want to thank all of our Ironwood team members and our Board members, our shareholders, partners, physicians and the millions of patients we hope to benefit with our medicines, for your continued commitment and support.

It has been fundamental to our efforts over the past year and we look forward to working with all you going forward as we continue to advance our mission. With that, I’ll turn it over to Tom McCourt to provide an update on LINZESS..

Thanks Peter and good afternoon everyone. LINZESS demonstrated strong commercial performance during the fourth quarter of 2014 with solid growth in prescription demand supported by an increase in physician prescribing, good payer access and reimbursement and most importantly an ability to provide symptomatic release to patients.

All of which, driven by effective collaboration and execution in all fronts. More than 440,000 LINZESS prescriptions were filled during the fourth quarter, a 12% increase quarter-over-quarter and a 108% increase year-over-year. Since launch, there have been over 2 million prescriptions filled by more than 530,000 patients.

And importantly, in mid-December we surpassed Zelnorm in launch line weekly prescriptions for the first time, a remarkable achievement when you consider that Zelnorm launched more than 10 years earlier into a far more favorable marketplace.

We believe the growth we’ve seen over the past several months is driven by our strong product offering, the outstanding efforts of our integrated selling effort with Actavis and the multichannel direct to consumer campaign that we launched in April 2014.

We have seen a strong response from our DTC efforts that resulted in greater than 20% increase in weekly TRx above our pre-DTC trend, making this one of the strongest DTC campaigns in the industry over the last couple of years.

Our DTC efforts are delivering a strong return on investment and we’ve continued to gain important insight into patient responses, which we are leveraging to develop a new DTC campaign that we expect to launch this spring.

Patient persistency is strong which in our view is the key indicator for patient satisfaction and we encouraged with the LINZESS continuing to perform approximately 40% to 60% better on launch aligned basis compared to Zelnorm and Amitiza.

From a physician standpoint we continue to expand our broad prescriber base with over an 110,000 practitioners having written in LINZESS prescription as of early January 2015. Lastly, payers are recognizing the clinical and economic value of LINZESS.

As of December 2014, over 70% of commercial or Medicare Part D patients had unrestricted access to LINZESS which created a 75% of commercial insurance patients having access to LINZESS for a co-pay of $30 or less per month through either formulary coverage or the LINZESS Instant Savings Program.

We continue to grow the entire category prescription treatment options for adults of IBS-C in chronic constipation, while capturing meaningful market-share within the category which in turn is generating significant growth in total LINZESS prescription.

Total prescription volume for the category during the fourth quarter of this year was up nearly 12% compares to the same period last year and in addition to growing the market, LINZESS continues to build significant market-share within the category.

Since initiating our DTC efforts 10 months ago total prescription share for LINZESS has grown over 50%. As you can see on the pie chart in left, if you dollarize both the prescription and OTC Laxative treatment at a current lax price of LINZESS, this market could be over $9 billion.

OTC Laxative represents the greatest potential and we are very pleased to see that the majority of LINZESS growth is coming directly from the OTC Laxative market. Looking ahead, we feel great of the response we’re seeing in our patient awareness efforts and field force promotion.

As we’ve seen in the past is fairly standard in the industry to see some softening and update in the early part of the year as people transition to new plans or work through their deductible, but we expect to acceleration as the year progresses supported by the initiation of our new DTC campaigning the strength.

With more than 16 years of expected path life remaining and an estimated 40 million adult IBS-Sales in chronic constipation suffers in U.S., we believe we’ve only scratch the surface. We have the opportunity to bring this important treatment option to millions of additional patients generating great value to the brand.

Before I turn it over to Mark, I want to quickly highlight our excitement around the recent reported top-line Phase IIA data with IW-3718 in Refractory GERD. There are several people here dying with working in the current space for many years and fully recognized the significant unmet need in this refractory population.

Refractory GERD is a highly prevalent disorder with a limited number of treatment options available. Millions of GERD suffer find relief from PPI such as Prilosec, as we’ve learnt firsthand that are more effective heartburn relief can build huge brand.

As you can see in this slide illustrating the growth of Prilosec overtime and there exist an estimated 8 million American still suffering from frequent bothersome symptom despite treatment of API that could benefit from better heartburn release.

We have more work to do as we continue to advance this program, but believe that represents a huge opportunity to -- opportunity potential and for new treatment options of millions of suffering patients and this opportunity is very well aligned with our scientific and commercial expertise. With that, I’ll turn it over to Mark..

Before Mark speaks, it’s Peter. For those of you who are trying to follow along with the presentation, we’re having a little bit of audio visual challenges, I think some of the slides are working and some of them aren’t.

The slides are already up on our website, so you can follow along directly yourself and will be available after the call as well, we apologize if it's frustrating, and we’re doing the best we can..

Thanks Peter. We generated great momentum in 2014 across our R&D efforts with the initiation of five new clinical studies in GI. This year we anticipate a total of nine clinical studies ongoing with four data readout expected including our recent Phase IIA data for IW-3718. In addition, we expect several more data readout next year.

Let me begin with IW-3718, as you're aware reported top-line data from our Phase IIA Refractory GERD study last week. Preliminary data from this study indicate 3718 improved heartburn and certain other symptoms associated with Refractory GERD.

Importantly, approximately two-thirds of the patients who were tested for bile reflux tested positive, validating on a high positives that some patients with Refractory GERD reflect biohazard.

In this sub group of patients who tested positive for bile reflux and were treated in this study with 3718, we have very encouraging improvement in the relief of heartburn the certain other upper GI symptom often associated with Refractory GERD, when compared to patient receiving placebo.

A few highlight from the bile reflux positive sub group data include a full one point drop in heartburn severity at week four relative to placebo. Heartburn severity was measured on a 10 points scale with the base line of 3.5 in the overall study population.

In terms of heartburn frequency study patients were heartburn free approximately one day per week. Following 3718 treatment heartburn free days increased to approximately 3.5 day total per week for week four. In comparison placebo increased to a total of approximately 2.3 heartburn-free days per week.

And lastly 56.3% of IW-3718 treated patients were responders regarding degree of release of overall GERD symptom versus 29.4 for the placebo treated group. Further 3718 were generally well tolerated across patient group with constant patient being the most common adverse event.

We continue to analyze the comprehensive set of data from this trial and planned to present the full data at an upcoming science medical meeting. We are excited by this opportunity and have a lot of work to do.

Since IW-3718 at minimally absorbed in the formulation is unable to bridge with pharmacokinetic study we planned to focus on further formulation development to efficiently support advancement towards the final commercial product before entering into a Phase IIb trial for dose optimization.

Turning to rest of our pipeline, I will begin with linaclotide. We and Actavis initiated two clinical studies during the fourth quarter of 2014. In October, we initiated a Phase II clinical study evaluating linaclotide for the treatment adult suffering opioid-induced constipation or OIC.

This study is designed to provide with data on whether linaclotide can increase bowel movement frequency and impact other symptoms in adult OIC patient. With an estimated 8 million patients in the U.S. suffering from OIC we believe that if approved by the FDA linaclotide could be a potentially important treatment option.

Enrollment is ongoing with data expected in the second half of 2015. In November, we initiated a Phase III clinical trial of a 72 microgram dose of linaclotide which we at Actavis are exploring for adult CIC patients.

If improve this will be an additional dose option that could provide a broader range of treatment option for a physician in a million of adult patients in the U.S. suffering from CIC. Further accelerating the expansion of LINZESS used with this indication. Enrollment is ongoing with data from this trial expected in 2016.

We and Actavis had made very good progress in developing the commercial formulation of linaclotide colonic release. We expect to initiate a Phase IIb clinical trial our colonic formulation of linaclotide in adult IBS-C patient in mid-2015.

By separating out the aspect of the pharmacology of linaclotide, we believe we have the opportunity to further enhance relief of the lower abdominal pain in IBS-C patient and we planned to continue to pioneer this space by potentially expanding our linaclotide colonic release development efforts into additional GI disorder with severe lower abdominal pain as a predominant symptom such as other forms of IBS, ulcerative colitis and diverticulitis.

Our global partners continue to make progress in advancing linaclotide worldwide. Astellas initiated a Phase III clinical for linaclotide in adult IBS-C patients in Japan. In addition, we and AstraZeneca recently completed enrollment in our Phase III trial of linaclotide and IBS-C for China. Data from this trial are expected in the second half of 2015.

Moving on to our non-linaclotide R&D efforts, in addition to the results of our Phase IIa trial with 3718 described earlier. We initiated a Phase IIs clinical study evaluating the ability of IW-9179 to provide relief of diabetic gastroparesis symptoms.

Like the 3718 Phase IIa study, this is an exploratory study evaluating a range of symptoms rather than specifying a primary endpoint and as expected to inform the path for further development. Enrollment is ongoing with data expected in the first half of 2016.

We also initiated a Phase I clinical study with IW-1973, our first sGC candidate with patient enrollment expected to begin in the coming weeks. We are evaluating 1973 for the potential treatment of cardiovascular diseases. Data from this study are expected in the second half of 2015.

In addition, we expect to advance our second sGC candidate 1701 into a Phase I clinical study in the second half of this year. So as you see, we made a lot of progress during the past year and we look forward to an exciting and productive year ahead as our pipeline continues to build and progress.

With that I will now hand it over to Tom Graney to discuss our financial results for the quarter. .

Thanks Mark, really exciting developments in R&D. And thank you everyone for joining us this afternoon. I will be walking through some key financial highlights for the quarter. Please refer to our press release for the detailed financials from the fourth quarter and the full year.

As Peter mentioned, we achieved an important milestone which I will discuss in detail in a minute in the fourth quarter the U.S. LINZESS collaboration with Actavis is profitable in just its eight full quarter of launch.

We entered 2014 with a strong balance sheet with $248 million in total cash and investments and we used $23 million in cash from operations for the fourth quarter, down from $39 million in the third quarter.

While there will be fluctuations on a quarterly basis due to factors such as the $15 million milestone payment we received from Astellas in the fourth quarter, we expect cash used to continue to decline over time primarily due to revenue growth from LINZESS and disciplined expense management.

We continued to see strong uptake for LINZESS which resulted in $93.8 million in net sales for the fourth quarter, up approximately 18% quarter-over-quarter and $297 million in net sales for the full year resulting in year-over-year growth of approximately 150%.

Wholesaler inventory levels were higher at the end of the fourth quarter compared with the end of the third quarter. But we’re within the expected to two to three week range.

Moving to gross to net adjustments for the fourth quarter, we did see an increase compared to the third quarter to the mid-30% range driven primarily by successful pull through from important commercial contracts as well as a price increase taken early in 2015 that resulted in increased reserves at the end of 2014.

So both competitive and commercial reason we and Actavis do not plan to provide specific inventory levels or gross to net details going forward. We will continue the point to total prescriptions and prescription growth as key performance indicators of the end user demand for LINZESS.

Subsequent to the end of the fourth quarter effective January 5th, we and Actavis increased the price of LINZESS by approximately 9.5% to its current list price of $9.24 per capsule. Importantly, as I mentioned previously and as you can see on the right side of slide 13, we and Actavis achieved profitability for the U.S.

collaboration in just the eight full quarters of launch. Now turning to Ironwood’s financial highlights for the quarter, GAAP revenue for the fourth quarter was $38.1 million including $23.9 million in collaboration revenue with LINZESS commercialization activities with Actavis in the U.S.

Cost of revenue for the fourth quarter was $13.1 million compared with none in the third quarter. During the fourth quarter, Almirall lowered its inventory demand forecast in Europe due to increased commercial challenges in this territory.

As a result of this forecast reduction and the fact that we have better insight into the launch trajectories outside of the U.S. we wrote down 11.4 million of inventory to an estimated net realizable value of 5 million. This write down represents the primary driver of the increasing cost of revenue in the fourth quarter.

Lastly, we ended the year within our guided expense ranges for 2014 total operating expenses which consisted of both R&D and SG&A expenses and 2014 combined marketing and sales expenses for LINZESS. We look forward to 2015 in which we expect our total operating expenses to be in the range of 220 million to 250 million.

This consists of 105 million to 120 million in R&D expenses and 115 million to 130 million in SG&A expenses. We also expect the combined Ironwood and Actavis total 2015 marketing and sales expense for LINZESS to be in the range of 230 million to 260 million.

As we have discussed, we achieved a critical inflection point in the fourth quarter when the U.S. collaboration achieved profitability. Now with the continued growth of LINZESS and prudent management of operating expenses as reflected in our 2015 guidance we anticipate delivering increased operating leverage going forward. Thank you.

And with that, I will turn it back over to Patrick to begin the Q&A portion of the call..

(Operator Instructions) Our first question comes from Anupam Rama with JPMorgan. Your line is open..

Maybe a quick question for Mark on IW-3718 incurred what are you doing from physicians about a potential primary endpoint in the Phase IIb trial, would you be looking at an individual endpoint such as heartburn-free or more of a global symptom responder type of scale?.

We certainly are very excited about the trial, we build -- as mentioned we have a lot of work to do, we will focus with experts -- with the experts on the data that we have, there is a lot of data we’re still reviewing and specifically we’re excited that we were -- that we did have positive impact on the GERD symptom, obviously the GERD symptoms have been used previously for getting drug approvals in this space.

So we think there is a pass that’s a little more straight forward and at this time that’s about as far as we can go..

Our next question comes from Gary Nachman with Goldman Sachs. Your line is open..

Hi, good afternoon.

I know you guys aren’t giving these metrics going forward, but how much that inventory build contribute in the quarter going to the higher end of two to three weeks and the growth to net in the mid-30s will say roughly at that level is that a good proxy?.

First the question Gary going forward as you heard, we’re not going to be in a position to provide sales on inventory gross net, but what I can tell you is along with [activist] we work with wholesalers to ensure that we have high service levels and believe that the two to three week range as the wholesale little level on average satisfies that requirement.

We do work with our partners throughout the supply chain to ensure that is that a not inventory in the channel to satisfy patient needs.

As far as growth to net, the view access as an important commercial strategy for us and always have some launch, we want to ensure that patients get access to the drug, we view investment behind access as part of our marketing mix and we look at those investments where we think that we’re going to get the best return..

And then so we should assume that there is a pretty good proxy going forward issued time being?.

Gross net is a function of -- a number of different element including our less price but also our patient assistance program which as I said, we’re going to launch where we think we can create the most value and ensure patient access..

And then just a couple of more, what’s the non-Linaclotide R&D expense expected to be in 2015 out of a 105 times of 20 million total R&D as given that in the past? And then the write-down of the API of 11 million, I mean what’s exactly is going in Europe, why has it been such a struggle, are you guys satisfied with the partnership with Astellas anything you could do there maybe to improve that? Thanks..

Gary, we did provide guidance in 2014 on the split between Ironwood-only R&D and total R&D going forward for 2015 we just provided overall guidance for total R&D..

Gary, its Peter here.

With expect to Europe, I think the situation hasn’t changes dramatically accept that we continue to see negative input from Germany in terms of ability to launch the product and -- our partner Almirall is working very hard on the launching now in 10 different countries, they are having success in a number of those countries, but while Europe has been challenging I would say overall you see the same demographics in Europe with respect to on that need and IBS-C, we have a terrific label for the product with Almirall in Europe.

As first George indicated for IBS of any kind of in Europe and it described as visceral analgesic on the label.

So, we’re very pleased with the label, it is a new category that said and we knew and will take time to build awareness both with divisions and patients and importantly in Europe the Almirall and other one or two companies don’t have ability to do interactive patient education the way that we can here.

You can see what an important level that is in the marketing -- in the U.S. So, we always knew with the new indication, new category like DTC it would be a longer slower ramp, we do think ultimately there is a big opportunity in Europe, but a big patient need, no question Germany was surprise and something that we and Almirall are wrestling with..

Thank you. (Operator Instructions) Our next question comes from Ravi Mehrotra with Credit Suisse. Your line is open,.

Hey, good afternoon guys. Thanks for taking my question; one on the 3718, can you just remind us of the intellectual property protection for that molecule? And secondly you talked about your new DTC campaign in spring, can you just walk us through how you're going to adapt that DTC campaign versus the one you just had? Thank you..

So, as you know 3718 is a very innovative formulation where what we are trying to do is target a gastric retentive bile acid sequestrant for that, we keep the bile acid sequestrant in the stomach and prevent bile acid from refluxing into the esophagus.

So it’s a novel approach we have a number of filings in this area relative to that formulation and we will continue to have patent filings in the future all around the innovation that we are doing. .

This is Tom; I will take the DTC ad question.

As you know we actually delighted with the performance of what we seen so far as far as patient’s reaction to the DTC campaign, and we have learned a tremendous amount with regard to which segment of patient were responding and not responding on a messaging prospect we are also creative perspective as the ad.

And so we are going to apply those learning’s to strengthen the ad obviously we want to broaden the appeal and the motivation to a broader patient base and we have also learned to good deal about the media in the media by and where we want to focus is geography as well as the various communication channel.

So again it’s been a tremendous success so far. We have learned a lot, we think it’s going to continue to push and certainly strengthen the impact of the DTC campaign moving forward. .

Our next question comes from Irina Koffler with Cantor Fitzgerald. Your line is open. .

For you API sales, should we assume that this is going to stay for somewhat this year since the China trial is wrapping up this year and the Europe still little bit soft, is the first question. Also wondering if maybe you can give us an update on the pediatric program.

And then finally what’s the difference between the two sGC cardiovascular programs thanks. .

I will take the API question. We haven’t provided revenue guidance at all but when it comes to API we do record sales to the our U.S. partner and we do not see it is being a material source of revenue for us next year. .

So with the pediatric program we continue to have interactions with the FDA to firm up the exact program that we will move forward and that development program and meet the PMR. Relative to the two sGC molecules they both have very interesting properties that where we think can be differentiating.

So we continue to advance both of them because we think they are potentially molecules that an go for two different types of indication. We haven’t disclosed all of that data yet but again we look forward to as we demonstrate that potentially in the clinic what we see in animal. .

Our next question comes from David Maris with BMO Capital Markets. Your line is open. .

On 3718, it was twice a day for four weeks, did you any improvement? Was it a linear improvement overtime that you saw improvement in week 2, week 3 and week 4 which might suggest that a longer study see a bigger gain from once a three days which is impressive result but maybe that you get the five days or was it too small to even see a trend maybe not statistically significant but even a trend of that and then separately this isn’t correct me if I am wrong this is not partnered with Actavis.

And so what’s you are thinking on that is that something that’s on the table now or will you wait so you get to the Phase II or will you just can’t take it all the way?.

Yeah, when we looked through the data we certainly see encouraging trends overtime and so we do think that help us confirm not only the our excitement for what we are seeing in a four week but what we are seeing in the earlier time point. .

And with respect to the question of intellectual property and ownership status, David it’s a question that intellectual property is I would develop -- we have a small license agreement with Diplomat with respect to the formulation and otherwise the writer we have very strong I see that we have developed in the house and continue to develop and will do so over the coming years.

And I think we feel very good about our ability here to continue to successfully develop and prosecute product and they commercialize it in the U.S. So we don’t have any partnering plans at this time. .

Our next question comes from Boris Peaker with Cowen. Your line is open..

Could you maybe expand a little bit to help us understand what fractions of patients are taking the drug chronically versus for short periods just think as periodically? And my question on 3718, do you have a sense if twice a day drug is required for efficacy or can patients take to address specific episodes..

So Boris this is Tom, I will take the first one.

With regard to what we are seeing in the clinics the overall we know physicians are directing patients to take the LINZESS chronically and what we’re seeing as far as the persistency rate certainly support that I mean certainly both Zelnorm and Amitiza are also being used to treat chronic diseases these are as you know very frequent, bothersome, and recurring rapidly recurring symptoms.

So, what we're seeing as far as chronicity of therapy looks very, very strong. And, again, I think that level persistency is probably the best indicator of the clinical performance of the drug which we’re very pleased with..

Mark can you take the question on SPT?.

On 3718 side, so we studied the drug in the refactoring patient for twice a day and that’s really the only data we currently have as the program move forward we will examine whether we will do once a day and what our dose ranging will be so at this point we can only comment that we got encouraging data with twice a day dosing pattern..

And I think the other thing I’d add there, Boris, is there is a substantial unmet need in the category and really beyond trying to adjust PPI usage or timing or use of PPI and so there is really nothing else out there to help these patients. So we think there is a very big opportunity to provide better solutions that are currently out there..

Our next question comes from Mario Corso with Mizuho. Your line is open..

A couple of things I wanted to ask about on LINZESS in terms of direct to consumer spend I know you don’t quantify things but is it a more targeted program this year I mean is the cost of DTC less in 2015 and 2014 and more similar on gross to net did I hear correctly was there a one-time affect in gross to net in the fourth quarter in that mid-30s which would lead me to believe maybe that’s not the kind of sustainable type of rate? And I guess also on the DTC spring I mean so we’re thinking early spring kind of late March early April I guess right around the same time of the program started last year? And then finally just one quick pipeline one SGC depending on which cardiovascular indication you’re looking at.

I mean are there -- is there any surrogate measure of efficacy in the Phase I studies or is it purely safety PK? Thanks very much..

Yes, so that’s going to be a good brain test for us. Four question Tom….

I have a few more too..

Tom can you take the two questions about DTC one about the investment in 2015 and the second about the timing?.

Yes, so first of all, the timing we’re roughly in the same area there is still a lot of work to do between now and early spring but you’re in the right range Mario.

With regard to the DTC spend we never given specific guidance on that what I will tell you is we have constant in market test going on to really try to optimize the investment in the marketplace and of course different ads performance differently.

We believe certainly the first commercial did very well I think we’ve gained a lot of insight to strengthen the commercial we’re going to go out and do the exact same work as far as the market investments. And depending on what we see we may invest more or less based on what the data guides us towards to really maximize the return on investment.

And like I said this market has been very responsive to this type of promotion and we’re very encouraged by what we’re seeing so far and what we think we’ll see this spring and throughout the year..

And pulling up just a level there Mario what we are seeing is we were 256 million in total sales and marketing investments in the launch year in 2013 we came in just over $250 million with a different marketing mix in 2014 and we’ve guided to roughly the same range in 2016.

And it’s not that we’re targeting that number, we think that following the data that that’s the way to optimize the marketing mix to benefit as many patients as possible and maximize the value of the brand. But we’re very pleased by the operating leverage we’re seeing behind that kind of investment. Tom the second question was about gross to net…..

Mario thanks for the question. We’re really pleased with the level of access that patients have to LINZESS as Tom McCourt mentioned in this presentation.

There was not an adjustment in the fourth quarter anytime you take a price increase which we did at the beginning of January you need to reserve for future rebates on sales at that higher price level. So, that was a component of the increase quarter-over-quarter but it was not the majority.

The majority of the increase was driven by again our successful pull through of newly signed contract from the second half of the year..

I’ll take the sGC Phase I study so certainly where the advantage of potentially looking in the type of cardiovascular studies in Phase I is we can look at and follow some of the key PD, pharmacodynamics measures not only the pharmacokinetic and safety tolerability.

So we currently will be looking at as an example blood pressure in several other cardiovascular endpoint..

Thank you. This ends the Q&A session for today. I’ll turn it back to management for closing remarks..

Thanks for your help Patrick. And thanks to all of you again for participating in this afternoon’s call. Just to summarize for you key points, LINZESS demand continues to be very strong with huge opportunity ahead for further growth of an asset that target millions of patients and which has IP through to at least 2031, so a very durable asset.

Second we’re making substantial progress against our R&D efforts and goals with nine clinical studies expected to be ongoing this year, four of which are expected to have data readout during the year including last week’s positive Phase IIA data with IW-3718.

For all of you who are targeting the reasons that affect millions of people and we’re very pleased by the success we had to-date. Finally, we’re prudently allocating shareholder capital within our key value drivers and same focus on our key goals for the year.

We’ll be around this evening and tomorrow, so contact Meredith if you like to follow-up with any additional questions. Please have a good evening and stay warm..

Ladies and gentlemen, thank you for participating in today’s program. This concludes the program. You may all disconnect..