Good day, welcome to the Ironwood Pharmaceuticals Q4 and full year 2022 investor update conference call. Today's call is being recorded. All lines have been placed on mute to prevent any background noise, and after the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star one on your telephone keypad. If you would like to withdraw your question, please press star one again. Thank you. I would now like to turn the conference over to Matt Roache, Director of Investor Relations. Please go ahead. Thank you, Savanna. Good morning, and thanks for joining us for our fourth quarter and full year 2022 investor update. Our press release issued this morning can be found on our website. Today's call and accompanying slides include forward-looking statements. Such statements involve risks and uncertainties that may cause actual results to differ materially. A discussion of these statements and risk factors is available on the current safe harbor statement slide, as well as under the heading Risk Factors in our annual report on Form 10-K for the year ended December 31st, 2021 and in our future SEC filings. All forward-looking statements speak as of the day of this presentation, and we undertake no obligation to update such statements. Also included are non-GAAP financial measures, which should be considered only as a supplement to and not a substitute for or superior to GAAP measures. To the extent applicable, please refer to the tables at the end of our press release for reconciliations of these measures to the most directly comparable GAAP measures. During today's call, Tom McCourt, our CEO, will review our strategic priorities and provide an update on the commercial performance of LINZESS. Michael Shetzline, our Chief Medical Officer, will discuss our pipeline, and Sravan Emany, our Chief Financial Officer, will review our financial results and guidance. Today's webcast includes slides. For those of you dialing in, please go to the Events section of our website to access the accompanying slides separately. With that, I'll turn the call over to Thomas McCourt. Thanks, Matt Roache. Good morning, everyone, and thanks for joining us today. As we begin 2023, our commitment to developing and advancing innovative solutions in the area of high unmet need in GI is as strong as ever. Looking back in the past year, we've made important progress in advancing the treatment of GI diseases while redefining standard of care for patients. I'm very proud of the Ironwood team, and thanks to their hard work and dedication, we closed 2022 with a lot to be proud of. You've heard us talk about our focused approach based on three strategic priorities, where we seek to maximize LINZESS, strengthen and progress our innovative GI portfolio and deliver sustained profits and generate cash flow. I'm delighted to say that we continue to drive strong LINZESS prescription demand growth, delivered on our full-year Adjusted EBITDA guidance, and we made strides across all three of our key strategic pillars. I remain confident in our strategy and believe we are well positioned for even greater success in 2023. Let's begin on slide 6 with a quick overview of some of the key achievements against our strategic priorities for 2022 and what we expect in 2023. First, maximize LINZESS. LINZESS continues to see strong prescription demand growth, profitability, and widespread acceptance among healthcare practitioners as a leading branded prescription treatment for adults with IBS-C and chronic idiopathic constipation. In 2022, prescription demand increased more than 9% year-over-year. The brand continued to demonstrate market leadership by achieving an all-time high in new patient starts, which is a lead indicator for future growth potential and growing TRX market share, which reached an all-time high of 45% as of the end of December. We announced earlier this week, we are pleased that the FDA granted priority review of our sNDA for functional constipation in pediatric patients ages six to 17 and assigned a PDUFA date of June 14, 2023. We're particularly excited about the potential to expand the clinical utility of LINZESS to this underserved patient population, and we plan to leverage a focused investment to drive growth and improve brand margins over time. Strengthen and progress our innovative GI portfolio, starting with CNP-104, the potential disease-modifying treatment for primary biliary cholangitis. In 2022, Cour Pharmaceuticals initiated a proof of concept study in PBC, which will assess the safety, tolerability, pharmacodynamic effect, and efficacy. We also kicked off study start activities at the end of 2022 for IW-3300, Ironwood's wholly owned GC-C agonist for the potential treatment of visceral pain conditions such as interstitial cystitis and bladder pain syndrome. We anticipate several exciting opportunities to advance our the value potential of our pipeline this year. First, we expect early data in the second half of the year from patients enrolled into the clinical study for CNP-104. Second, we expect to begin patient dosing for a proof of concept study in interstitial cystitis and bladder pain syndrome for IW-3300 in the near term. We continue to actively evaluate opportunities to strengthen our portfolio, and we see several potential attractive opportunities in the market that could benefit from Ironwood's expertise in GI. Our third strategic priority is to deliver sustained profits and generate cash flow. We delivered on our guidance of over $250 million in Adjusted EBITDA. Ended the year with $656 million in cash and cash equivalents on the balance sheet. After deploying nearly $250 million in 2022 by completing our share repurchase program and repaying the principal on our 2022 convertible notes. We are in a fortunate position of being a profitable biopharma company with a highly skilled and experienced team in the management of gastrointestinal diseases and a strong and growing cash balance. We believe we're well-positioned to execute on our strategy as we strive to become the leading GI healthcare company in the US Let's talk a bit more about the performance of LINZESS in slide seven. As you can see on the left side of slide seven, the performance of LINZESS has been remarkable as we continue to see a robust linear growth trajectory. Over time, the strong prescription demand growth for LINZESS has been supported by a combination of high treatment satisfaction, updated clinical guideline support, and class-leading formulary access. We continue to see an acceleration of appropriate new adult patient starts and anticipate this will be augmented in the future should the FDA approve an indication for functional constipation in patients ages six to 17. We believe the pediatric opportunity, if approved, could expand the market potential for LINZESS as functional constipation affects roughly 6 million six to 17-year-old children and adolescents in the US This is incremental to the need that still exists amongst approximately 40 million adults in the US that suffer from IBS and chronic constipation. LINZESS is well-positioned to be the branded market leader across both its current and potential future indication. Looking ahead, we're confident in our strategy and in our future. We believe the investments we're making in the brand and in our pipeline position our company for long-term growth. I would like to say a very big thank you to all the Ironwood employees who have laid the groundwork for continued momentum and strong execution against our strategic priorities as we continue to make meaningful impact on patients' lives. I would now like to turn the call over to Michael Shetzline to discuss our pipeline. Michael Shetzline? Thanks, Thomas McCourt. Good morning, everyone. We continue to make progress across our three pipeline programs. I'll begin with our linaclotide pediatric program on slide nine. As Thomas McCourt mentioned, we're thrilled that the FDA granted priority review for the LINZESS sNDA for functional constipation in children and adolescents six to 17 years of age, which could potentially lead to a commercial launch in June. If approved, LINZESS would be the first and only prescription therapy to treat this patient population. A new pediatric indication would further reinforce the strong clinical profile of LINZESS. I'm proud of the team's accomplishments as we continue to seek opportunities to broaden the clinical utility of LINZESS and redefine the standard of care for this patient group. We look forward to presenting the phase three data at the Digestive Disease Week meeting in May of this year. CNP-104 next for the potential treatment of PBC, which affects an estimated 130,000 people in the U.S. As we've discussed previously, the strong immunology underpinning the CNP program is focused on targeting the specific PDC-E2 antigen responsible for the pathology of PBC. Therefore, there is an opportunity to assess PDC-E2 specific T-cell responses, which should be a lead indicator of clinical benefit. We expect to assess T-cell responses in patients dosed with CNP-104 in the second half of 2023. This early T-cell data will inform the timing of top line and potential option exercise. We're excited about the CNP-104 because it is truly precision medicine. It introduces a potentially new game-changing asset for PBC patients, as there are no therapies on the market today that address the root cause of the autoimmune destruction of the bile ducts in PBC. We'll provide updates on the program progress throughout this year. Moving on to IW-3300, a wholly owned Ironwood asset for the potential treatment of interstitial cystitis and bladder pain syndrome. There's a significant unmet medical need in the area of IC/BPS, as it affects an estimated 4-12 million Americans, yet there are very few treatment options currently on the market or in development. In 2022, we successfully completed dosing studies in healthy volunteers. We kicked off study start activities for the phase 2 proof of concept study. We're prepared to begin dosing patients in the near term. This study has been thoughtfully designed to evaluate the potential impact of IW-3300 on visceral pain in patients with interstitial cystitis and bladder pain syndrome. This trial will enroll patients with moderate to severe pain in a randomized, double-blind, placebo-controlled study over 12 weeks. Patients will receive IW-3300 administered once daily. Efficacy will be assessed based on change from baseline in the worst abdominal pain using an 11-point numeric rating scale along with monitoring of urinary symptoms and other weekly and monthly assessments. We're excited to begin patient dosing, and we look forward to providing updates as this study continues to advance. This is the first time the crosstalk hypothesis will be tested in humans, and we're proud to be at the forefront of clinical development in this area. With that, I'll turn the call over to Sravan Emany. Thanks, Michael Shetzline. Good morning, everyone. I'll start with an update on LINZESS performance. LINZESS US net sales were $260 million in the fourth quarter of 2022. A decrease of 7% compared to the fourth quarter of 2021. Strong prescription demand growth of 9% was more than offset by price and inventory channel fluctuation. For full year 2022, as shown on slide 11, LINZESS US net sales were $1.002 billion, a slight decrease as compared to full year 2021. While full year net sales growth came in lower than our expectations for 2022, primarily due to inventory fluctuations in the retail channel, we remain confident in the long-term growth potential of LINZESS based on the strong prescription demand that we continue to see. Turning to LINZESS brand profitability. Commercial margins in the fourth quarter of 2022 were 74% compared to 76% in the fourth quarter of 2021. For full year 2022, commercial margins were 73% versus 74% for full year 2021. Moving to Ironwood revenues. In Q4, Ironwood revenues were $107 million, driven primarily by US LINZESS collaboration revenues of $105 million. For the full year, Ironwood revenues were $411 million, with LINZESS U.S. collaboration revenues of $399 million. In the fourth quarter, for the full year, Ironwood recorded $23 million and $77 million of income tax expense, respectively. The majority of which was non-cash. GAAP net income was $49 million in the fourth quarter and $175 million for the full year. Adjusted EBITDA was $69 million in Q4 and $252 million for the full year. Throughout the year, we remained focused on our commitment to deliver strong profits and cash flows by driving continued robust LINZESS prescription demand and demonstrating disciplined expense management. As a result, I'm pleased that we were able to achieve our initial Adjusted EBITDA guidance of greater than $250 million that we issued at the beginning of 2022. Next, cash and capital allocation. In the fourth quarter of 2022, we generated $79 million in cash flow from operations and $274 million for full year. We ended 2022 with $656 million in cash and cash equivalents after deploying nearly $250 million during the year by completing our share repurchase program and repaying the principal amount on our 2022 convertible notes. We believe we are positioning our company for future success by maximizing LINZESS growth and actively pursuing innovative, highly differentiated GI assets to bolster our portfolio. We continue to take a balanced and disciplined approach to capital deployment and remain focused on identifying and investing in opportunities that we believe will create value for our patients and shareholders over the long term. Turning to our 2023 guidance on slide 12. As previously stated in January, we expect LINZESS US net sales growth of between 3% and 5%, driven by high single-digit% prescription demand growth. We expect to maintain our class-leading payer access with mid-single-digit price erosion. We expect Ironwood revenue of between $420 million and $435 million and Adjusted EBITDA of greater than $250 million, which includes increased investment to advance our pipeline programs CNP-104 and IW-3300. To wrap up, we believe Ironwood is well-positioned for continued growth, we remain focused on advancing our three strategic priorities of maximizing LINZESS, strengthening and progressing our innovative GI portfolio, and delivering sustained profits and generating cash flow. We have a blockbuster brand in LINZESS that continues to deliver impressive demand growth with the potential to expand the market with a pediatric functional constipation indication beginning this year, if approved. An emerging pipeline with anticipated exciting milestones ahead. A strong balance sheet with over $650 million of cash and cash equivalents. An accomplished management team with strong GI, commercial, drug development, and M&A expertise. We are excited about the work ahead of us as we strive to make a difference for patients living with GI diseases and to deliver shareholder value. Operator, you may now open up the line for questions. Thank you. As a reminder, it is star one if you would like to ask a question. Our 1st question will come from David Amsellem with Piper Sandler. Please go ahead. Thanks. I just had a few. First, with the guidance in mind, can you talk about your level of confidence that you'll see a more stable trajectory for net realized price per Rx? Just talk about the dynamics that are driving more stability, or less in the way of erosion, in 2023 versus 2022. That's number one. Secondly, can you talk about your work on LINZESS regarding children under the age of two or two and under, and just how you're thinking about making progress towards the eventual removal of the box warning? That's my second question. Just lastly, how do you frame up the pediatric opportunity, the six to 17, and particularly what I'm getting at is what's your view on the extent to which that could drive accelerated growth in volumes post-approval? Thank you. Yes. Well, good morning, David Amsellem. Thank you for the questions. Look, I'll start with your first question on price. The second question regarding the children under the age of 2, I'll hand to Michael Shetzline, and then we can we may have you restate the third question, which I think Thomas McCourt will answer. Okay. With respect to 2023, as you know, LINZESS is a high volume and value prescription brand. We are really excited that we're in the 11th year of the drug's life cycle, and we're still growing high single digits with the drug. We've made significant investments over the course of the last several years with payers to establish and maintain the class-leading payer access that we have. In 2023, we did not need to make the same level of investment to maintain that access as we did in 2022. You know, as you know, we continually evaluate price and volume trade-offs. We strive to maximize performance of LINZESS, and try to generate profits for the company and for the brand. As a reminder, LINZESS is preferred on 10 out of 10 of the top commercial programs or commercial plans and covered on, like, 7 out of the 7 top Medicare Part D plans. A s we've entered the negotiations over the past year, I think 2022 came in line from a price perspective where we thought we were going to be based on expectations. We have in, you know, visibility just based on the volumes and our negotiations with payers. Just where we sit today, we feel pretty good about that mid-single-digit erosion for 2023. I think the bottom line in that, Trevor, is, you know, we have great visibility into the contracts. We saw that last year. We predicted high single-digit, and we came in within probably 0.5% of what we expected. I think we have similar confidence here, you know, where, you know, we didn't see as much aggressive price erosion in the contracting process, so, you know, we're projecting mid-single-digit. I think we do have fairly good. Anything, you know, things can happen, but I think we have reasonable confidence that, you know, we're going to be in the mid-single-digits. Michael Shetzline? Yeah, sure. In regards to the question you had about the younger kids, including the less than 2, but also around the box in general, it's good to recall that the original institution of the label when the drug was originally launched, that box warning was due really to the theoretical risk of adverse events in kids under the age of 18. We worked with the agency with the post-marketing requirements in our clinical studies to put together a plan to generate that data. As you saw in 2021, we had a significant box revision which took the warning from 18 and below, pretty much encompassing all the populations, down to just 2 and below which is where it currently is. That's just because we've had the opportunity to generate data in those pediatric populations. You can see that's actually what got the six-17-year-old sNDA that we submitted at the end of last year and the priority review we just talked about during the call. We have a very robust data set in pedes. To your point directly, we're continuing additional pede studies. We have an additional study going on in two-five-year-olds that's part of our working with the agency, and we're also planning a study in less than two-year-olds, from six months to zero's, with our partners, AbbVie. I mean, we certainly believe with the generation of further clinical data, we have a path in discussions with the agency to continue to have the label manifest a real clinical profile of LINZESS, which to date has been very safe and well-tolerated. Maybe I'll take the. This is Thomas McCourt. I'll take the pediatric opportunity. Obviously, to Michael Shetzline 's point, we have great confidence in the safety and tolerability of this drug and it. You know, the clinical data on the pediatric, out of the pediatric phase three program is really remarkable. You know, one, it clearly demonstrates efficacy, but what was striking was how well the drug was tolerated, which is a real challenge with currently available therapeutic options. You know, when I look at the pediatric opportunity, we talk about the 6 million patients that are suffering chronically from functional constipation. You know, one of the things to keep in mind, which is different from kids from adults, is the seeking care behavior. You know, if you got a kid that's really suffering, you're going to go see a doctor. The% of care-seeking patients is a much, much higher%, and they generally present multiple times a year, not just one or two times. It's a very available population. We also know that, you know, while there's a lot of pediatricians out there, it's a pretty concentrated prescriber base. You know, we think that we can get to a lot of the top prescribers with our existing selling efforts. We talk about this concentrated promotional effort 'cause we really want to first understand how promotionally sensitive the drug will be in the marketplace, which will then inform further investment. We're not just looking at, you know, personal promotion. We're also looking at other communication channels in which we can educate these physicians on a better choice, you know, for managing their patients. Everything we've seen in market research looks very encouraging with regard to the target product profile and the clinical profile of the drug and the willingness to try. As I look at the upside over time, obviously we hope to get the indication in June. There could be some upside in 2023 as we really evaluate the promotional response. The real value creation, we believe, will start in 24 and 25. I think we all believe that based on the size of the population, the unmet medical need, and the clinical profile of the drug, that LINZESS will be well-positioned to help an awful lot of kids. Okay. Very helpful. Thanks, guys. Thank you, Thomas McCourt. Our next question will come from Daniel Wolle, Daniel Wolle with JPMorgan. Please go ahead. Morning, guys. Two questions from me. One on CNP-104, can you clarify for us what you will see versus what the street will see when early data reads out in the second half of 2023? Is it an internal readout where you'll announce the opt-in assuming positive data on T-cell response, or will you be able to release the data to the street? Second question is, if we are going to see some data, will it just be on T-cell response, or is there potential to include changes in serum alkaline phosphatase levels? I guess my question is it possible to see serum alkaline phosphatase level changes data this year? Yeah, I can address that. Thanks. Thanks for the opportunity to clarify. Just to be clear too, as reported in ClinicalTrials.gov, you know, the trial was always planned to extend in 2024, till 2024. What we're trying to do is we're trying to add clarity by acknowledging the opportunity to get data in the second half of 2023 that will inform us on the timing for the full study readout of the top-line data. In addition, our objective in any of the clinical programs is to use all the data we can to inform business decisions as early as possible. In the second half of 2023, we expect to see the early data focused on T-cell responses from enrolled patients. Based on the strong science around CNP-104, we really think that the T-cell response is potentially a lead indicator for clinical responses. You mentioned specifically ALP. You know, ALP is a liver biomarker, right? Again, it is still a biomarker. For products approved with ALP, they often have to do post-marketing commitments to actually show that the ALP provides a meaningful, you know, benefit to patients. We actually think the underlying pathology of PBC driven by the PDC-E2 to antigen is more specifically addressed by looking at the autoreactive T cells. That's what we're really trying to focus on in the second half of 2023. As I mentioned in the prepared marks, we really expect to see early data on the T-cell responses in the second half of 2023, and it'll inform us on the timing. At that point, we'll give you an update on the status of the program. Okay. Just to clarify, is this an internal readout, or will you be able to release that T-cell response data to the street? Yeah. Again, we're going to make an early assessment as a small group, in a very controlled fashion just to make internal business decisions. When we see the data and we understand the relevance at that point, we'll make a decision to update the program further and decide what to do. Great. Thank you very much. Our next question will come from Tim Chiang with Capital One. Please go ahead. All right. Thanks. Michael Shetzline, I wanted to follow up on some of the comments on CNP-104. I think in prior discussions we've had, you've made the comment that, I guess, in preclinicals, there's been, what? About a 90% reduction in T cells, T cell response that you've seen. Is that right? I mean, obviously, there's some preclinical data out there on CNP-104 and, you know, I wanted to ask you know, what leads you to think that this should have a very, very positive reduction in T cells counts here? Yeah. That's a good question. There is preclinical data. There's an animal model for PBC, which Cour has interrogated that does show that with the treatment with CNP-104, you get a reduction in this autoreactive T cells in that animal model. The 90% number you refer to is a number you've heard me say in regards to the proof of technology study in celiac disease that was run by Takeda, actually. That uses the Cour platform and the nanoparticles there encapsulate gluten, and then it gets degraded to deaminated gliadin peptides. That's the autoantigen in celiac. In celiac patients, and this is published in Gastroenterology in June of 2021. The celiac patients, the two-week, two treatments over an eight-day period in celiac patients saw a 90% reduction in the autoreactive T cells in celiac patients. That also translated into a meaningful improvement in gut epithelial structure, the histology. Again, that's the sort of downstream effect of reducing those autoreactive T cells. As we said, and you might have heard me say before, too, you know, if we see a similar response, you know, in PBC, that would be quite impressive and potentially, you know, game-changing for the opportunity to help patients with PBC. That's where we see the data. The preclinical evidence is in PBC directly. The clinical evidence you hear about the 90% is from a celiac study done by that's published by another company. Michael Shetzline, you've Yeah, I've heard you say in the past that if we do see, you know, a dramatic reduction in T cells, it's clearly a strong indicator of what you would expect to see as far as overall clinical response with regard to probably the impact on ALP and bile salt or bile duct destruction. Yeah, exactly. We really think, based on the science, that this approach, CNP-104, and targeting the specific autoantigen of PBC, which is the PDC-E2 antigen, that that is targeting the root cause of the pathology of PBC, which is the bile duct destruction. The T cells, the autoreactive T cells, destroy the bile ducts. If we can decrease those T cells, then we should reduce or potentially eliminate the bile duct destruction in PBC patients. Again, the celiac data in proof of technology and proof of concept in patients actually showed that their decrease in autoreactive T cells, in celiac patients did improve gut epithelial histology. No, that's helpful, Michael Shetzline. Maybe just one follow-up then. The dosing in the celiac study, is that comparable in the dosing that you're running in the PBC study? I mean, is there anything comparable there? I think it's a great question, and that's why we're studying two doses in the current PBC patients. I think clearly there's a reason to make the association, but I do think it's also fair that different diseases may have a different pharmacodynamic response, you know, to doses. We're clearly open-minded in terms of as we do this study to be cognizant that we want to find, you know, the right dose in PBC patients. Similarly I'm sure with what's happening in the celiac space as well. Okay, great. Thanks a lot, Michael Shetzline. As a reminder, that is star one if you would like to ask a question. Our next question will come from Boris Peaker with Cowen. Please go ahead. Great. Thanks for taking my question. One question on CNP-104. You mentioned that the market is about 130,000 patients, if I heard you correctly. Can you break that down based on disease severity and if there is any particular subgroup that 104 will be targeting? Yeah. I think it's a good question. I think as with most liver diseases, this aspect of disease severity is important. And in fact, you probably know that with ursodeoxycholic acid, the label is indicated around aspects of liver disease severity in terms of not being advised in patients with cirrhosis or decompensated liver disease. Our program, because it's obviously innovative and new in patient populations, is starting with more early liver disease patients with PBC. The reality is the underlying mechanism should be broadly applicable to all patients with PBC because, again, we're targeting the immunology behind the bile duct destruction. In using semisynthetic bile acids and other approaches, you could see a reason, and as demonstrated with some of the semisynthetic bile acid labeling, that there might be a reason to have concern with some more severe liver disease patients. If the science plays out and we're able to reduce those autoreactive T-cells, that should be applicable to the broad population of patients. Now, again, we're in proof of concept study. We got a long way to go getting data. Again, that's why we like the program because it's really grounded in the science of the real root cause of PBC. Great. My second question is maybe you could comment on your thoughts on the impact of Inflation Reduction Act on LINZESS? Sure. Hey, Boris Peaker, this is Sravan Emany, and I'll take that. Look, as with any proposed legislation, we'll follow the developments closely here. We're working with our partner, AbbVie, to assess any potential impact on our business. At this stage, just so, I think a wide number of unknowns around certain aspects of this legislation. In thinking about the potential impact here to LINZESS, it's important to note we've been working with Medicare Part D for years. For many years, as a core aspect to our strategy, it has been to ensure broad coverage and patient access. From a negotiation standpoint, from a discounting standpoint, none of this is new to us. I think we'll come back to you when we have a better sense of what that looks like. Right now I think that's what we can say. I think we're reasonably confident. I mean, we're providing very significant discounts currently to Medicare. I mean, which is a reason why, you know, we're seeing some price erosion here because, you know, we are working closely with the Medicare payers as well as the commercial payers to ensure very broad payer access. You know, could it have some impact? Yeah. I think of all the brands that are out there that they're gonna be focusing on, you know, we're already in the game and actively, you know, negotiating, you know, with the major payers. You know, we'll have to wait and see, but I think we feel pretty good about the position we're in. Great. Thanks for taking my question. Yeah, of course. With no further questions, we will conclude today's conference. Thank you for your participation, and you may now disconnect.