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spk10: Thank you for standing by. My name is Cath and I will be your conference operator today. At this time, I would like to welcome everyone to the Ironwood Pharmaceuticals first quarter 2024 investor update call. All lines have been placed on mute to prevent any background noise. 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 followed by the number one on your telephone keypad. If you would like to withdraw your question, press star one again. I would now like to turn the call over to Matt Roach, Director of Industrial Relations. Please go ahead.
spk04: Thank you, Cass. Good morning and thanks for joining us for our first quarter 2024 investor update. Our press release issued this morning can be found on our website. Today's call and accompanying slides include four looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements involve risks and uncertainties and 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 31, 2023, and in our subsequent SEC filings. All four looking statements speak as of the date of this presentation. We undertake no obligation to update such statements. Also included are non-GAAP financial measures, which should be considered only as a supplement and not a substitute for or superior to GATT 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 GATT measures. During today's call, Tom McCourt, our Chief Executive Officer, began with a brief overview. Mike Schetzlein, our Chief Medical Officer, will discuss our pipeline, and Shravan Imani, our Chief Financial Officer, will provide a commercial update and review our financial results and guidance. Today's webcast includes slides. So for those of you dialing in, please go to the events section on our website to access the accompanying slides separately. With that, I'll turn the call over to Tom.
spk00: Thanks, Matt. Good morning, everyone, and thanks for joining us. We're pleased to be here to discuss our significant advancements that we've made across our portfolio so far this year and our mission to become the leading GI healthcare company. I always like to start with the three strategic priorities, which are maximize LINZUS, advance our GI pipeline, and deliver sustained profits and cash flow. In the first quarter of 2024, LINZUS maintained its strong demand momentum with prescription volume increasing 10% year-over-year, supported by robust new-to-brand prescription growth of 18% versus the prior year, marking the fifth consecutive quarter of double-digit new-to-brand growth. As you may have seen in our press release this morning, based on information provided by Abby, we recorded an adjustment to the first quarter collaborative arrangement revenue as a result of a gross net change in estimate for LINZUS related to the year ended December 31, 23, which led to our revised full year 24 outlook. Trevor will provide more detail on the impact of this one-time adjustment later on the call. Moving to our pipeline. We made important progress across our development programs in the quarter. Most notably, we believe we have transformed our company with the positive top-line results in February from the Phase III STARS trial, evaluating the efficacy and safety of apraglitide in patients with short bowel syndrome with intestinal failure. These positive Phase III results demonstrate the potential of preglutide as the first and only weekly GLP-2 therapy for the treatment of adults with short bowel syndrome who are dependent on parental support if approved. Following the top-line results shared in late February, we have continued to analyze the robust data set of the STARS Phase III. and new data was submitted as a late-breaking abstract and selected for an oral presentation at the upcoming digestive disease meeting. These data further strengthened the clinical profile of Priglitide, which we're eager to share with the broader GI medical and scientific community. Based on the combination of demonstrated efficacy, tolerability, and once-weekly dosing, we are confident that Priglitide has a high probability of approval. We believe these three distinguishing factors will drive uptake, compliance, and improvement in quality of life for patients, reinforcing our belief that apricotide has the potential to achieve a billion dollars in peak net sales. We are now focused on ensuring a successful path forward to commercialization, an area where we have significant expertise and a track record of success. We are working swiftly and plan to file the NDA as soon as possible with a label focused on adult SPS patients who are dependent on parental support and continue to expect a commercial launch in 2025. We estimate that there's approximately 17,000 adult patients across the United States and Europe who suffer from short bowel syndrome with intestinal failure, with a significant portion of these patients still untreated by GLP-2s. We have the commercial infrastructure already in place and expect only incremental investments needed to launch Apraglitide successfully. We are well on our way with the launch planning and believe we are equipped to commercialize Apraglitide if approved, with a strong sales presence already established in the offices of GI specialists across the United States. We are confident The positive results from the STARS trial, coupled with our proven track record of effective commercial execution, position us uniquely in the market. We're excited to leverage our expertise to maximize the potential for a preglutide and drive meaningful, impactful outcomes for patients with short bowel syndrome who are dependent on parenteral support. So to wrap up, we are poised for future growth. for the following reasons. First, Lizus continues to deliver robust demand growth and is driving meaningful cash flows for Ironwood, which we expect to continue until generic entry in 2029. Second, we believe we have transformed our company with the positive phase-through results from the STARS trial, which reinforce our conviction in a pragmatized high probability of approval and long-term revenue and profit growth potential. Finally, We're excited to see the Phase II top-line results from CMP104 later this year. We believe CMP104 has the potential to be a disease-modifying therapy for the treatment of primary biliary cholangitis. With that, I'll hand it over to Mike to discuss apraglutide and our pipeline in more detail. Mike?
spk05: Thanks, Tom. And good morning, everyone. We're pleased with the progress we made across our pipeline programs in the first quarter. I'll begin with epiglutide for short bowel syndrome in patients dependent on parenteral support. We're very proud of the positive results from the Pivotal Global Phase 3 STARS study, which is the largest ever GLP-2 trial in short bowel syndrome with intestinal failure, generating a robust data set across 68 sites and 18 countries. An important aspect of the STARS Phase 3 study design was the rigorous optimization of parenteral support volumes prior to treatment. That resulted in a low placebo rate, which in turn generated a robust treatment effect for apraglutide in this patient population. Apraglutide is the only once-weekly GLP-2 to meet its primary endpoint of relative change from baseline in actual weekly parenteral support volume at week 24, with a two-times treatment effect relative to placebo, driven by both stoma and colon incontinuity populations. As a clinician myself, I'm thrilled about Apragutide's strong profile, including the convenience of once-weekly administration and its potential to benefit a patient community in need of new treatment options. Summarized on slide 9, I'm excited by the demonstrated efficacy in the primary endpoint in both stoma and colon incontinuity patient populations at 24 weeks. With further analysis of the data, we're also excited by the rapid onset of treatment effect observed at week eight and onward throughout the study. The fact that some patients in both stoma and colon and continuity populations reached enteral autonomy or a complete weaning off of parenteral sport. And the low prevalence of reported injection site reactions and abdominal distension, which are in line with placebo. Overall, we believe apraglutide's differentiated profile including its demonstrated efficacy and tolerability and convenience of once-weekly dosing support our belief in apraglutide's high probability of approval and potential to improve the standard of care for patients with short bowel syndrome who are dependent on parenteral support. We're very much looking forward to the upcoming DDW meeting and presenting data which we believe further supports and enhances the clinical profile of apraglutide. We also look forward to continuing to evaluate the robust data set from the largest ever GLP-2 study in short bowel syndrome with intestinal failure, and plan to disclose further findings at additional meetings later this year. In addition to the positive Phase III results from apraglutide in short bowel syndrome with intestinal failure, we also announced positive results from our exploratory Stargaze trial of apraglutide in patients with steroid refractory, gastrointestinal, acute graft-versus-host disease. The primary objective of the trial was to evaluate the safety and tolerability of once-weekly apraglutide in steroid refractory acute GVHD patients treated with standard of care. Results up to day 91 showed that apraglutide in acute GVHD was well tolerated with an acceptable safety profile, the study's primary objective. In addition to evaluating safety, secondary endpoints assessed efficacy via lower GI and all organ responses. The majority of patients responded to treatment by day 28 and day 56. All lower GI responders at day 28 maintained their response through day 56 and 91. We're encouraged by the data on safety, tolerability, and maintenance of response and expect to present additional data at a future medical congress. The Stargrave study will continue through its two-year endpoint when aproglutide will be evaluated for safety and efficacy. Moving to CMP104 on slide 10, in the first quarter, CORE completed patient enrollment for the Phase 2 proof of concept study in patients with PBC and are on track to report top-line results in the third quarter of this year. The CMP-104 Phase II study is a 42-patient placebo-controlled study evaluating the safety, tolerability, pharmacodynamics, and efficacy of CMP-104 in patients with PBC who are unresponsive to UDCA and or Ocalva. Top prime results will be based on data through day 120 of treatment. The strong immunology underpinning the CMP program is focused on targeting the specific PDCE2 antigen responsible for the T-cell-driven pathology of PBC. Last year, we saw early data showing favorable PDCE2-specific T-cell responses in patients treated with CMP104. In the top-line results anticipated in the third quarter, we're looking for a demonstrated T-cell response. which we believe is a leading indicator of clinical benefit. The study will also evaluate several markers of liver function. A positive signal on liver function markers, in addition to the T cell response, would further support the potential for CMP104. We believe CMP104 has the potential to be the first disease-modifying therapy for patients suffering with PBC, as there are no therapies on the market today that address the root cause of the T cell-driven immune destruction of the liver bile ducts. With that, I'll turn it over to Shravan.
spk06: Thanks, Mike, and good morning, everyone. I'll begin on slide 12. As Tom mentioned earlier, Linzess carried the positive demand momentum into the first quarter. This is now the 12th year on market for Linzess, and as you can see, prescription demand remains remarkably strong. Linzess volume rose 10% year-over-year in the first quarter, while new-to-brand prescriptions increased 18% with the first quarter of 2023. reinforcing that patients and healthcare professionals continue to choose LINZ-S. We believe the strong demand momentum and success of LINZ-S will continue as a result of high treatment satisfaction with both patients and healthcare professionals, combined with increased utility from the pediatric syndication, class-leading formulary access, guideline recommendations, focused commercial execution, and new patient start acceleration. I'd like to take a moment to provide additional details on the LINZES gross to net change, an estimate that was reflected in the first quarter of 2024 on slide 13. In the first quarter, AbbVie reported U.S. net sales of $257 million, an increase of 3% year-over-year. Based on information subsequently provided by AbbVie, Ironwood estimates a $60 million adjustment to LINZES U.S. net sales representing the difference between AbbVie's gross to net estimates made in 2023 and actual subsequent payments made. As a result of this change in estimate, Ironwood recorded a $30 million reduction to collaborative arrangements revenue. With this adjustment, total Ironwood revenue in the first quarter was approximately $75 million, down 28% year-over-year. Turning to our first quarter financial performance slide on slide 14. Q1 LINZES U.S. net sales, as reported by AbbVie, were $257 million, an increase of 3% year-over-year. LINZES commercial margin, excluding the gross to net change in estimate, was 71% in the first quarter of 2024, compared to 73% in the first quarter of 2023. As I noted a few moments ago, Ironwood revenue was $75 million, driven primarily by U.S.-LINZES collaboration revenue of $72 million. Revenues in Q1 were lower year over year, primarily due to the $30 million change in estimate recorded to collaborative arrangements revenue. As a result, gap net loss was $4 million and adjusted EBITDA was $13 million. In the first quarter, Ironwood generated approximately $45 million in cash flow from operations and ended the quarter with $122 million in cash and cash equivalents. after repaying $25 million of the outstanding principal balance on our revolving credit facility in cash. As of the end of March, the outstanding drawn balance on the revolver was $275 million. In the near term, we continue to expect to settle our 2024 convertible notes that mature on June 15th through a combination of cash on hand and undrawn revolver capacity. Regarding capital allocation, We are in a fortunate position with meaningful cash flow generation from Linzess, which we believe will be sufficient to fund all ongoing operations, and we do not anticipate the need to access the capital markets for incremental funding to support the potential Afroglutide launch and further progress our development programs. Next, I'll review our updated 2024 guidance on slide 15. As a result of Linzess' gross to net change in estimate in the first quarter, For full year 2024, we now expect a Linzess U.S. net sales decline in the mid-single digits percent, Ironwood revenue of between $405 and $425 million, and adjusted EBITDA of greater than $120 million. To wrap up, we've made significant advancements across our portfolio in the first quarter. We look forward to sharing additional detail from the Afroglutide STARS Phase 3 study at Digestive Disease Week. later this month, which we believe will further enhance the clinical profile of apraglutide. With the positive STARS data readout, we believe we are well on our way to diversifying our portfolio and extending our growth horizon beyond Linzess. Looking ahead, we are focused on moving quickly to get apraglutide approved and to patients with SPS who are dependent on parental support as soon as possible. executing across our strategic priorities by advancing our other GI pipeline assets, driving robust Linzess demand growth and delivering sustained profits and cash flow. I want to close by thanking all of our employees, patients, caregivers, and advocates for their shared dedication to advancing and supporting therapies for GI diseases. Operator, you may now open up the line for questions.
spk10: Thank you. We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, press star 1 again. If you are called upon to ask your question and listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not in mute when asking your question. Again, press star 1 to join the queue. Your first question comes from the line of David Amsalem with Piper Sandler. Your line is open.
spk01: Hey, thanks. So a couple questions here. I know you've got the data coming at DDW, but I just wanted to get some additional color on what you mean about efficacy across both stoma and colon in continuity patients. And I guess what I'm getting at is, just within the CIC subgroup, is there statistical separation? I know what you had shown at 48 weeks, but is there statistical separation, say, at earlier time points, say 24 weeks or 12 weeks? So just help us understand that, and if you can't answer it, that's fine, but I thought I'd ask the question anyway. And then secondly, on 104, what do you have to see in order to move forward? Help us understand how you're thinking about the bar for continued advancement. I'll leave it there. Thanks.
spk05: Thanks for the question, David. So we're very excited about the data from apraglutide, and a lot has been discussed around CIC versus stoma. It's just critical to remember that the primary endpoint included both stoma and colon incontinuity patients. So we clearly think we have a high probability of approval for the whole population, stoma and CNC, based on the fact that colon and continuity patients contributed to the primary endpoint. That was quite distinct from what happened with the regulatory precedent that GATx set, where they really didn't see a meaningful contribution for the colon and continuity patients. So we continue to believe that the potency of the asset is well established now with this Phase III data, and that that's given us the opportunity for once-weekly therapy. And what you'll see at DDW is a further rollout of the colon and continuity-specific data which certainly gives us even more confidence in the efficacy in colon and continuity patients. And we certainly fully support the submission we're going to do for the whole population and have a high probability of success for approval in colon and continuity and stoma patients. In addition, there'll be a fair amount of tolerability data which will further support the differentiation of apraglutide from other GLP-2 therapies in the class. We've really learned a lot from the pivotal trial data in terms of the safety and tolerability. And you'll see details on events and numbers at DDW, which really support a very safe and well-tolerated profile. And in principle, most all events were actually in line with placebo. So we think it's a very good profile for commercial success. The next question you asked was on CMP, okay? What we hope to see in CMP as we discuss the real strength of the CNC program is the science behind the immunology and what we know about the pathology of PBC. It's a PDCE2-driven disease, and we can test the T cells that destroy the bile ducts with PDCE2 to determine if treatment with CMP104 modulates or reprograms those T cells. So we're really looking for a demonstrated T cell effect that shows that those T cells are no longer pathologic, no longer prone to destroying bile ducts. And in combination with that, we're looking for a meaningful clinical outcome, and that's why we have a number of liver function assessments in the trial as well. And this 120-day assessment gives the opportunity to look at that demonstrated T cell response and the potential opportunity to improve a liver function assessment.
spk01: Thank you.
spk10: Your next question... Your next question comes from the line of Chase Meeker-Bucker with Craig Hallam. Your line is open.
spk07: Good morning, guys. Thanks for taking the questions. Maybe just digging in a little bit on the growth to net. adjustment from last year. Can you just talk to us about kind of what that was specifically as far as, you know, probably, you know, by pair channel or just however you think it's best to break that down, just a little bit more detail around exactly what that $60 million adjustment was that was not accounted for by AbbVie?
spk06: Yeah. So first of all, Chase, thank you for your question. Good morning. I'd say that, zooming out first, I would say that fluctuations in gross to net relating to shift in channel mix are common and their normal occurrence within this industry, as you know. It's something that happens on a periodic basis for us. Rarely is it this material. I think the change in estimate for us was based on information that AbbVie provided subsequent to their reporting, and it was the difference between the grossed investments during the year and the actual invoices they got, and it was primarily associated with government and contractual rebates. I think that's the, you know, the coloring probably can give you in terms of where we were.
spk07: That's helpful. Maybe one for Mike. Can you just talk around kind of next steps with the APRA NDA? You know, certainly looking forward to the data, just maybe specifically on the filing. Have you had your Type B meeting or is that, you know, scheduled for soon? And then, you know, kind of talk a little about what's left to be done with all the data work that you've been doing in the background to prepare the submission?
spk05: Yeah, sure. That's a good question, and clearly that's our key priority. Our number one, two, and three priorities is the APRA submission, so it's all hands on deck for that. We clearly continue to look at the data. That's what resulted in the DDW oral abstract acceptance, so we're very excited about that. That's going to support, obviously, getting the data out, but also all that data is part and parcel to the submission. and aligns with everything we're trying to do to get the submission in and on track. So we're currently now planning the pre-NDA meeting, which we will do as well, and we're really looking forward to moving the submission forward as expeditiously as possible. We're still targeting a potential launch in 2025, and as we get more granular on the submission timelines, we'll certainly make that available.
spk07: Okay, and then just last for me on CNP 104. Um, just to confirm for investors, when we get that data in 3Q, um, that will be, you know, both T cell response and we will also be able to see that liver function data. Is that right, Mike?
spk05: Yeah, we plan to talk about the T cell, the demonstrated T cell effects to obviously prove the point of the program, which is the reprogramming and the immunology around the PDCE2 specific antigens. So we plan to share that as well as a liver function, um, outcomes as well. Remember, it's a 120-day study. It's a phase two study. It's the first in human study for CMP104. And so that is a sort of early timeframe. You may know that things like abetacolic acid and Sinabay and those products went out to a year. But we clearly think based on the science and the technology and why we did the deal, that we have an opportunity to see real early a clinical endpoint in those liver function assessments.
spk07: Great. And just last, Ravan, to come back to you, just on guidance, I mean, looking at it, you know, it certainly seems that really the only material changes to your guys' expectations was this $30 million adjustment. Is that fair to say, you know, as far as, you know, the Medicaid changes on the rebate cap this year, everything else is the same as far as your expectation goes on, you know, your revenue expectations in 2024 from one test?
spk06: Yes. So I would say that our guidance now is reflective of the one-time adjustment. As you can see, based on AbbVie's reporting, I think our performance of the brand continues to be really strong with double-digit demand growth. The pricing headwinds that we would have faced or we anticipated having of high single-digit price erosion and low single-digit revenue growth were kind of there outside of the one-time out-of-period adjustment.
spk00: I think the only other comment that I would make on this is, as you can see, the demand is really remarkable with regard to what kind of growth we're seeing in year 11, year 12 for the brand, which we obviously want to continue to nurture. And what we do know is there's really kind of three things that are driving that. Certainly the high treatment satisfaction, no question. But I think the other piece is payer access, which is part of the marketing mix. Now, what we'll be doing moving forward is, is really working with our partner to continue to evolve that marketing mix so we can really optimize the value that Linzess can create. So, you know, we have been doing this from day one. As we've evolved the marketing mix, we've reduced the investment and increased the profit of the brand. As we move forward, I think we're seeing very durable growth in brand demand. And what we really want to focus on now is what is the right appropriate marketing mix and investment to continue to drive profits to the bottom line.
spk07: You're great. Thanks, guys.
spk10: Your next question comes from the line of Amy Lee with Jeffries. Your line is open.
spk02: Hey, good morning, guys. Thanks so much for taking my question. On apriclutide, what is your current internal estimate on durability of treatment, and will we get any data at DBW to support potential differentiation on this over GADX? Additionally, can you give us any updates on how you're thinking about the addressable market for APRA post the ICD-10 codes being put in place late last year, and how many of these patients you have access to with your current sales force?
spk06: Well, why don't you start with the first one, and I'll answer the second.
spk05: So, thanks, Amy. So, in terms of durability, I suspect you mean the more longer term. I mean, clearly, as the only once weekly available We certainly think that phase three data supports the weekly administration and sort of the pharmacokinetics and pharmacodynamics really lend itself to that once-weekly dosing. So the data speaks for itself in that regard. It's a once-weekly therapy. I think in terms of longer term, right, the actual ideal goal for most patients is enteral autonomy, where they could come off all parenteral support. In that setting, they often would need continued GLP-2 therapy to maintain that intestinal growth. Then from that going forward, it'll be up to them, obviously, and their physician caretaker to understand how that long-term plays out, but the reality is In patients with short bowel who have limited bowel epithelium, they benefit from continued therapy from the GLP-2, because as we've seen with other GLP-2 therapies, when you come off it, you often revert back to a need for parenteral support.
spk06: And then on the question about the ICD-10 codes and our overall sales force, just taking a step back again, our level of access to the major GI practices across the United States It is probably unparalleled from our perspective. We've got over 90 sales reps calling on these practices and leading clinicians. Specifically with the ICD-10 codes, we're really excited about this development, honestly, Emily. Amy, I think the big thing for us is that these ICD-10 codes are starting to shed real light on how many patients there actually are. I think you've heard a little bit in some of the things you've hosted yourself. about differences in what the estimates are. You know, I think there have been 7,000 or so patients that have been identified already to date through the ICD-10 codes in just a few months. It just reinforces our estimates as more data comes to light about how many patients there are. And then I think given our presence across The United States, I think our ability to capture SHARE with our best-in-class product, you know, with our, you know, as an overall profile with apoglutide having, well, once a weekly administration, demonstrated real efficacy across both stoma and CIC patient populations. And then now, as you'll see in a few weeks, the safety and tolerability data being equivalent to placebo, I think that is, I think our ability to penetrate that and capture SHARE to be a a billion dollar brand is in sight. We feel confident about it.
spk02: Great. Thank you so much.
spk10: Your next question comes from the line of Jason Butler with Citizens J&B. Your line is open.
spk08: Hey, thanks for taking the question. First one is for Apra. Can you maybe talk about the work you're doing pre-commercial to build awareness in the brand and beyond just obviously presentation of data what work you're going to do this year to prepare the market for the drug. And then just secondly, on Lynn's ask, can you maybe speak to the contribution of the pediatric market to growth this quarter? I'm looking forward to 2024. Thanks.
spk06: Yeah. So, Tom, why don't you handle the first one, and then maybe I'll take the second part of the question, if that works.
spk00: I mean, remind me the first question was? The brand awareness, the activity. Oh, sure. So as far as as far as the pre launch activities, you know, we are just in the midst of launching a disease education program targeted primarily on the GI community. Which you know will will probably stretch into you know, a digital platform for patients and for patients to seek better understanding and options, so this is really about. increasing the awareness of who these patients are how debilitating this disease is and you know the need for more effective therapy and through that exercise a big objective here as far as overall impact on performance is identifying available patients within these large gi practices as well as the academic centers of excellence you know we've been very very encouraged by the feedback that we're getting from the key opinion leaders in the Center of Excellence as far as the response rate and the acceptance of Prigutide in the clinical trials. And they're all looking forward to working in a very collaborative way, not just as far as educating people, but also how do we really work with the patients to help them through the process to get better care. So, I think we're very well positioned to prepare our go-to-market strategy and, of course, that work has been ongoing and we're just in the early stages of implementing the Disease Awareness Program. Do you want to take the Linset's question? Yeah, I'll hopefully do that.
spk06: So, Jason, good morning. So, I think on your question about the pediatric launch and its progress, I think we are purely, I think overall, I think since the launch has started, feel really positive about pediatric indication. We're still early in the launch, frankly, but to date we're really encouraged by the strong new-to-brand prescription volume growth. I think Tom mentioned earlier on the call that 18% new-to-brand growth, that's specifically a large portion of that growth in a year-over-year basis is in the 72-microgram dose, which is the approved dose for the 6- to 17-year-old patient group. So it's embedded in those numbers. And I think it's part of what's sustaining our long-term growth here for Linzess as we're in year 12.
spk10: Your next question comes from the line of Mohit Bensal with Wells Fargo.
spk03: Great. Thank you very much for taking my question. I have a couple of questions. So one on the guidance. Thanks for clarification, but one thing I wanted to ask was that typically this happens because you had a particular mix in the mind for government versus commercial and that mix changed subsequently because you don't know it until you get the receipts and all. Are you expecting similar mix, like the updated mix for 2024 as well? I'm asking because By our math, the impact that you are modeling is a little bit more than $60 million. So that's the first question. And the second question is on ALP with CNP-104. So if I look at drugs like Saldelpar, there was an impact on ALP by month one. And then at month three, it was more like stabilized. After that, it was not an incremental impact. Isn't 120-day enough to see benefit? I appreciate the mechanisms are different. So how should we think about benefit on endpoints like ASB there? Thank you.
spk06: Yeah, Mike, why don't you go first, and I'll answer the guidance.
spk05: Yeah, thanks, Reid. It's a good question, because as you know, the regulatory precedent is around ALKFAS. That's clearly how beta-chloric acid got approved and what CIMI-Base went through right now. So it clearly is an approved path for accelerated approval, which is not... full approval. You may know somebody's actually added puritis in that to sort of help balance that need. ALKFOS is a very non-specific sort of effect on liver function in a lot of ways because it really speaks to how the bile's moving through the liver. So it's very important to understand that if you give something like a beta-cholic acid, which is a bile acid mimetic, it actually increases bile flow. One of the early benefits you'll get from that is improved ALKFAS. It's also not necessarily part and parcel that that's aligning with liver function improvement. And that's why Obetacolic Acid had to have a post-marketing commitment to show a benefit in liver function more broadly with histology, which incidentally did not meet needs at the time. So it is important to understand what ALKFAS is there for. And as you highlighted, our mechanism is completely different. We're actually targeting the root cause of PBC, which is the T cell-driven bile duct destruction. So we clearly believe if we can affect the T cells and then reprogram those T cells so they no longer attack the bile ducts, we'll see clinical improvement. And then to your point, the timeline for that clinical improvement, we're going to learn. We clearly think we have an opportunity to see it early given the specificity of PDCE2 and the specificity of this therapy. That's why we have a 120-day look. But we're certainly going to learn from that. And that's why we have this combination of need, meaning to demonstrate a T cell response and the liver function improvement. So certainly the different mechanism is important to understand. And also it's very important to realize that we're actually going for a very disease-modifying approach, not just moving bile flow through the liver function. better, which is a biomarker for potential benefit for liver disease.
spk06: So, on your guidance question, look, I think at a high level, I'd say, again, one, I think from our perspective, and it's the guidance we gave for 2024 counts were the mix we anticipate in 2024. It's our 2024 guidance. We expect to still see high single-digit prescription demand growth, and I think the decline is as stated based on our overall annual guidance. This is a one-time adjustment. We've been pretty good as a brand over the last several years in anticipating or with our estimates with respect to what the mix is in a channel. Channel mix is pretty fluid, and predicting Linzessnet sales can move in a positive or negative direction. This has always been true, but we've been pretty good about it over the years. And I think at this point, we're still expecting to deliver a mid-single-digit decline, as I said before, and that's predominantly driven by the one-time out-of-period adjustment. Outside of that, I think we would have been in line with guidance for the full year. Got it. Thank you.
spk10: Your next question comes from the line of Tim Chiang with Capital One.
spk09: Hey, thanks. Mike, you know, I'm just looking back at the secondary endpoints from the START study. Do you guys plan on showing, I guess, the earlier week data from the CIC patient population at DDW, especially with the secondary endpoints that you didn't meet statistical significance on?
spk05: Yeah, Tim, if you're referring to sort of specifically things like enteral autonomy or things you might see at 24 weeks versus The key secondaries of 48, the answer is yes, and we certainly think that that data further, you know, supports our conviction of good efficacy in both stoma and CIC patient populations. So, yeah, we plan to see that, have that at DDW, as well as sort of the decrease in parenteral support volume and the relative change from baseline in that capacity as well. The DDW planned oral presentation. It's obviously still ongoing. in development, but we have a lot done on it already. And it's very data heavy. I think you'll be very impressed with the amount of data. We're certainly clearly very excited by it because it clearly supports our conviction that the drug is approvable and works in both colon incontinuity and stoma patients. So we really are looking forward to sharing that more broadly with the community.
spk09: Mike, just one follow-up. You know, why is the placebo effect so high in these studies? Because I noticed on your third secondary endpoint, the placebo rate was almost 44%. Can you comment on that?
spk05: Yeah. I mean, I think the key to realize there is that the primary endpoint placebo response was 12.5%, right? And that's the key driver for the study's positivity statistically and the path to approval. So I think that's a key thing to keep aware of. The other thing to realize is the 48-week endpoints never had been tested in GLP-2 therapy before, and there can be a tendency for placebo response to change during a clinical trial. And it's also important to realize that what we're actually talking about here, placebo response, is different at 24 weeks on the primary endpoint, meaning it's the relative change from baseline versus the one day off, which is the third key secondary you alluded to, that's 44%. And then in addition, we instituted a new design in this trial, which is the weaning algorithm. So that's clearly played forward through the study. We're going to analyze that data real carefully to make sure we understand it. But there is a potential opportunity for the weaning algorithm, which would be in place for both placebo and drug-treated patients, could elevate the placebo response with later time points in the study. Because early in the study, it might be more volume-driven, whereas as people... wean, then you may fall under the urine output threshold of 10% and you may get exposed to the weaning out. We're still looking into that, but that's clearly one thing on the list to figure out if that's what made the 48-week endpoint placebo response so high. And one final point to realize, even though the placebo response was high at the third key endpoint on the CIC population, APRA was still numerically superior. So when we get to this sort of aspect of approvability, that fact that APRA still did numerically better will be a positive in terms of not looking at it like we're worse than placebo or things like that. That's not the case. And then given the things we talked about on the primary and the first key secondary being positive in the whole population, we clearly think that bodes well for a high probability of success for approval for both populations.
spk09: And maybe just one last follow-up, Mike. Are some of these items, do you think that you could get them on the label? Because I think, you know, I think those would be important, especially in the coronary incontinuity patient population.
spk05: Yeah, I think we're going to work to get everything in the label we can. We certainly think the drug works very well in both patient populations. One of the reasons we included those additional secondaries was for exactly that reason. However, that challenge is higher now, obviously, because they didn't meet statistical significance. But as I mentioned, both are numerically better, so we certainly have a strong confidence for approvability.
spk09: Okay, great. Thanks.
spk10: Ladies and gentlemen, that concludes our Q&A session and today's call. Thank you all for joining. You may now disconnect.
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