All right. So thanks again, everybody, for joining us this morning at the Citizens JMP Life Science Conference. Excited to be joined now by the management team from Ironwood Pharmaceuticals. Ironwood is a company that has demonstrated substantial success in GI medicine, both in terms of commercializing their lead product, Linzess, as well as advancing an exciting pipeline, including apraglutide, which I know we'll spend some time. We've got Tom McCourt, Company CEO. We also have a couple of other members. You know what? I'll pass it over to you, Tom, to introduce the team, and we'll start from there.
Sravan Emany, who's our Chief Financial Officer, and Mike Shetzline, who's our Chief Medical Officer.
Great. So Tom, maybe just give us a quick 30-second overview of Ironwood and your core priorities today.
Yeah. I think we transformed the company about five years ago, as you know, Jason, from a company that was kind of struggling with what it wanted to be. We were roughly losing $200 million a year. We really restructured the company. A few of us really focused on what we knew we were good at, which is GI diseases. We brought in Mike, who's certainly one of the best GI developers in the industry. We really focused on kind of three core priorities. One, how do we maximize the value of Linzess? How do we expand our GI portfolio? How do we generate cash and generate profits? With Linzess , we've continued to drive its growth. It's the market-leading brand, blockbuster brand that continues to thrive. Even in year 10, 11, 12, we don't see the growth slowing down.
It's still growing at about 10% a year as far as demand growth. And we continue to evolve the marketing mix. As you know, there's always this balance of at what point do we start harvesting the brand and dropping greater profits? But there's two pieces to that. One is we want to make sure we have very broad payer access, which obviously we got to pay attention to with regard to the pricing pressures, but also what's the right level of commercial support. And I think we're in a very, very good position where it's become a very profitable brand, and it's going to get more profitable. So we have IP out to 2029. So we have a nice long runway. I don't see an emerging competitor. We have over 50% of the market at this point and an increase in the market share.
So I think Linzess is in very good shape. And of course, around that, we have built a lot of really key GI capabilities with regard to the commercial and the development team. And we've been out looking to expand the clinical pipeline. And we came across apraglutide, which Mike has been familiar with for 10 years. We saw it as a differentiated brand. We thought it had a very high probability of approval when we looked at the profile and knew the molecule. And as we've released our phase three data, which was positive in February, the more we've dug into the data, it's clearly a differentiated molecule. It's going to be an exciting week this week. We have Digestive Disease Week, which is kind of the big tent for GI. We were granted a late-breaking oral presentation, which never happens, in the big tent.
So we'll have the opportunity to share a lot more data around apraglutide for the use in short bowel syndrome with intestinal failure. Mike can talk a bit more about that. I think we're certainly looking at launching the drug in 2025. We're really moving the company ahead. I think the last thing to mention, a couple of things to mention before we kind of get into it more deeply, is certainly CNP-104. CNP-104, again, in the GI hepatology space for primary biliary cholangitis. The unique thing here is it looks like it could be a disease-modifying agent. It's the first treatment ever for PBC that actually treats the underlying cause, the root cause of the disease, which is this destruction of bile ducts. Mike can certainly get into that in greater detail.
But I think the last thing we're always conscious of is creating value to shareholders. So we have an eye on making sure that we're delivering healthy profits to the bottom line, that we can continue to flourish as an organization. So this year and next year are going to be very exciting years for us. And I couldn't be happier with where the company is right now.
Great. Obviously, want to spend some time on Linzess , but really wanted to start on apraglutide. It's almost exactly a year today that you announced the acquisition. Obviously, we now have the positive phase three results. But maybe if we just rewind, what was it that attracted you to the asset in the first place and made you go out there and also take the risk of buying the asset before the phase three results?
Sure. I mean, Sravan kind of led the charge on that. So Sravan, why don't you share your thoughts?
Sure. So first of all, I would say that the most important thing is we got a great deal. I mean, being able to buy an asset in biopharma for one-time peak sales, it's pretty rare. And I think we got a great asset for a great price. Two, I think that it leverages our existing capabilities very well. So as a GI-focused health care company, it was an opportunity to launch a drug in the mid part of this decade. And having launched Linzess and having the team here that knows how to market and launch a drug felt great about that, leveraged our existing sales force capabilities, felt really strongly about that. So just great opportunity to leverage our existing infrastructure.
Third, about the asset itself, I mean, I think we felt really strongly about, given Mike's prior knowledge, as Tom mentioned, about its mechanism of action, its efficacy or potential for efficacy, as demonstrated by the phase two results, the once-weekly dosing, and then overall product profile, we felt like it would be the best-in-class asset. And based on the phase three results, we feel like that's still true. And then lastly, just as we go forward, I think the opportunity to continue to lean into what Ironwood does really well, which is market and sell in detail GI-related drugs. So I think all of that felt like it was and financially viable, again, as I said, start.
Great. So before we jump into the phase three results in detail, can you maybe just give us a couple more insights into what about the product profile you view as attractive? I think we've said we think it's best-in-class relative to the standard of care today.
Yeah. I'll start. And then maybe, Mike, if you've got I'd say, first of all, the efficacy, the fact that patients will see benefit. I think the phase three results clearly demonstrated by meeting the primary endpoint with a level of statistical significance not seen in the other competitive trials about being twice the placebo, I think just shows that patients will receive benefit, having met the first two secondary endpoints. So I think this will really help the underlying patients that suffer from short bowel disease that are dependent on parenteral nutrition. Two, I think which you'll see more, I guess, at DDW is the tolerability data on top of that, which I think is differentiating. Three, the once-weekly mechanism, the dosing regimen of once weekly is truly differentiated for these patients. I don't know, Mike, if there's anything you want to add.
Yeah. And I think a key feature behind all that is really the pharmacokinetics and the pharmacodynamics. I mean, what originally attracted us to the molecule was its potency and its PK/PD parameters. Because in reality, what Sravan's alluded to, the opportunity for better efficacy, the opportunity for broader efficacy, we've seen efficacy in the stoma and CIC patient populations, as well as the tolerability probably really rests in that PK/PD part. Because there was always a question with GATTEX about a daily injection each day for a week. You get peaks and troughs. But is the real mechanism the AUC and sort of trough-related? And now we've sort of shown with our trial, with once weekly, that we really drive substantial efficacy with the weekly, which is probably more AUC and trough-related, but also then that can translate into better safety and tolerability. We're seeing a profile adverse event-wise.
It's really in line with placebo. We'll see that all more granularly at DDW. But we think they're the parameters that really give us the opportunity to be best in class.
Right. So the core, I think, facet of the disease here, short bowel syndrome, is a patient's inability to absorb nutrients. And so you've got to replace that somehow. We know that the mechanism is validated from at least one approved drug. And so as you think about the phase three design, what are the aspects of the design that you really wanted to focus on to show that differentiated product profile?
Yeah. I think the underlying features you're alluding to is it's trophic hormone. So it's growing the intestinal epithelium. The phase two data that was present when we did the acquisition really showed that the pharmacodynamics were there from an intestinal growth perspective. And that's maintained. And with the opportunity for once weekly, we think adherence and actual exposure for the duration of the week will be much better managed with the weekly therapy. And that should provide an opportunity, and we believe it does, for a best-in-class approach. So as that translates into clinical trial outcomes, it really has translated from our perspective or from the patient's perspective. Because in our primary endpoint, we see efficacy coming from not just the stoma population, but the colon-in-continuity population. And that wasn't present in the Gattex phase three data.
If you look at Gattex 's data, they didn't show any efficacy in the colon-in-continuity subgroup. Neither study is powered for the individual subgroups. But if you look at the subgroup analysis, colon-in-continuity contributes to our primary endpoint. That's why we strongly believe that we're going to get a label for both populations or all SBS-IF patients, both stoma and colon-in-continuity, because of that enhanced potency and that driving efficacy in CIC. You'll see more of that at DDW. We know there have been some questions on the CIC patient population based on the third and fourth key secondary endpoints, which were the first time 48-week endpoints were ever tested in this population. But the data we have clearly supports efficacy in the colon-in-continuity patient population.
Great. As we look forward to TDW, can you just talk to us about you've had the data for several months now? What has been the feedback from health care providers, from KOLs, about the data so far?
Yeah. We've had it for two months, which is several or two. But it's still been the team has really done a great job diving in deep. We have a lot of data. These trials are data heavy. There's a lot of metrics from volumes perspective. So there's a lot to work on. And as we look at it, we continue to be excited about the outcomes. Like I said, we're seeing a lot. You'll see this at DDW. But we're seeing a lot more data supporting the primary endpoint. We hit the primary endpoint in a very robust manner. We run the largest SBS-IF trial ever run. And we have a very robust data set with the lowest placebo response, 12.5%. Our placebo response was half that of Gattex or glepa. And our treatment effect was double placebo.
No other entity has doubled their placebo in their treatment effect, and we have. We also hit the first key secondary endpoint, which is the clinically meaningful endpoint. You may know that the first key secondary is the reduction in one day per week across the population of both stoma and colon-in-continuity. We hit that endpoint. That's the clinically meaningful outcome. That's the outcome that really was the driver for Gattex 's advisory committee over a decade ago. Because the FDA really wanted to know what's clinically meaningful. One day a week off of parenteral support was determined clinically meaningful. So that's real robust. So at DDW, you'll see more data, especially in the CIC population, the colon-in-continuity population, further supporting that efficacy. You'll see time to response showing you a real early treatment effect, which we think bodes well for adherence and patient outcomes.
Because patients will see and feel that benefit earlier. As I mentioned, safety and tolerability. You'll see details on how much the safety and tolerability profile is strengthened, the numbers there, and how much it aligns with placebo. And all that will come together at DDW, supporting the once weekly approach where we think we have an opportunity to be best in class.
I think, Jason, one of the things, as you can imagine, I spent the last couple of months going around talking to investigators and key opinion leaders to kind of get the real live feedback. It's been striking to go in. Because these patients are high-need patients. These clinicians and investigators are really passionate about making sure the patients are taken care of. I was even at UCLA a couple of weeks ago and met with the lead investigator and his nurse, who was the largest enroller in the trial. They were concerned that we would stop therapy, that all these patients got rolled into an extension. Literally, what, 98% of the patients that were in the trial went on to the extension.
They were just so excited that they had already had two patients that already had complete enteral autonomy, which is, you think about how that changes somebody's life. So I think that's the thing that's been so kind of exciting for me to see, can we really make a difference in patients' lives?
Got it. Yeah. And a final DDW point is we'll see the enteral autonomy data there as well. We actually see enteral autonomy at 24 weeks, which is another thing speaking to the potency of the asset.
Got it. One more question just on short bowel. It's a big question. But I want to save time for other things. When you think about the path and the steps from now through to launch, obviously, the regulatory submission, it seems like that's although I don't want to try to minimize this, it's a pretty straightforward process to get there. There's no other studies you're waiting to read out. Talk to us a little bit about manufacturing and your readiness there. And then, I guess, most importantly, what you're doing on the medical education and the commercialization side to get ready for a launch next year.
Yeah. So I'll start on the first two pieces. I think you're simplifying the process, obviously. But we are planning on to submit, hopefully, by the end of this year, still charting at 2025, end of 2025 commercial launch. From a CMC perspective, we're a third-party manufacturer, spending time with them to make sure we're commercially ready with a commercial kit. So it's more about commercial readiness on the CMC side. But that work has been in progress since we acquired. I think one of the key things to one of the things I probably ellipsed at the beginning about why we bought the asset when we did ahead of phase three was to launch a drug in 2025. The work really began in 2023.
Whether that's preceding the market and preparing to go to market from a commercial perspective, whether it's KOLs, whether it's understanding where the patients are and identifying them to some of the CMC work and making sure you had a viable commercial-ready kit, I think all that stuff had been in progress. So we've been hard at work at it. So I think we feel pretty confident about that component of the process. I don't know if there's anything else you'd add on the commercial side.
Yeah. I think this is really about preparing for launch. What is your go-to-market strategy? And I mean, a big part of this is where are the patients? And I think now, with the new ICD-10 codes, I mean, these people are jumping out of all kinds of databases where we didn't see them. So I think we're spending a lot of time in these super large GI practices, as well as the academic centers of excellence, to say, who is the patient? Who is the first patient you're going to give this drug to? And so we have a time to really focus on some disease awareness and patient need messaging to a very selective group of physicians that we think we can start identifying patients well in advance of commercialization, which I think is going to be the gain.
It's really going to be about who's the patient and why this drug. I think the story is fairly compelling based on everything we're seeing.
Got it. OK. I want to move on to CNP-104. You talked about how excited you are about the program. Can you just give us a little bit of the background and then the initial data you've already seen? And then, most importantly, what we're looking forward to seeing later this year?
Yeah, Mike. Yeah. I think the thing that attracted us to CNP-104 is actually the science. There's just so much robust science about Primary Biliary Cholangitis and the mechanisms that give the pathology. And PBC is really a T-cell-driven disease. The T-cells chew up the bile ducts. And what's driving that pathology is an antigen expressed in mitochondria. It's a mitochondrial antigen called the PDC-E2 antigen. And that activates the T-cells to destroy the bile ducts. So it's very clear. And the core technology actually gives us the opportunity to present that antigen in a unique way to suppress the autoimmunity of PBC. So with treatment, you no longer get that T-cell response that you see with chewing up the bile ducts. And last year, we did an early look as part of that deal. What attracted you to the deal was we can objectively assess this.
So last year, we took some peripheral T-cells to see if the T-cell profile is changing from a pathologic state to a more accepting state, meaning no longer reacting to the antigen in the bile ducts. And we saw favorable responses then. Now, the key now in quarter three is to see how that translates. We're going to obviously relook at the T-cells in a broader population and over more time, but also look at the liver function changes as well to see if we can see liver functional improvement. But the key pathology is T-cells. We really think that T-cell responses will provide a clinically meaningful outcome downstream. Our endpoint is a phase two study. It's going to be 120 days. So a little earlier, you may know many of the PBC endpoints are at 12 months.
But that's only to say that we really still believe in the T-cell responses as an early indicator of how the clinical response could be. But we're going to have a lot of liver markers data as well. So real excited about it because it really is precision medicine. I mean, these patients have a PDC-E2-driven disease. You diagnose it with a positive antimitochondrial antibody. That's how PBC is diagnosed today. So everybody has a positive AMA, or at least 95% of the patient population. And then you give them a PDC-E2-driven therapy. That's the CNP-104. So we really think it has a chance, as Tom mentioned on the opening, to be disease-modifying in that patient population.
To that point, and maybe this is obvious, but that's a much more attractive approach than just suppressing or depleting T-cells on a chronic basis.
Yeah. Yeah. Because it would actually alter the T-cells. You're not really suppressing them. So your basic immunity should stay the same. It's just that these specific T-cells no longer chew up the liver.
Well, I think the other piece to that is when you look at current standard of care, it's really about increasing bile flow. You think about the synthetic bile acids. I mean, they just really don't fix the problem. They improve the symptoms. There's no question about that. But you still have this underlying pathology present that's still causing liver damage. So it's like this could be a real game changer for these patients.
Yeah. And maybe a final adverse, to Tom's point, because that's going to be a thing to recall as well. Because when you increase bile flow, one of the first responses you get is decreased Alk Phos. So Alk Phos has been the marker in this space with CymaBay and with obeticholic acid. We're going to track Alk Phos as well. But it's just a call out that we're not a bile acid mimetic. So we'll see how we're going to measure it and see how it plays out. But we've got liver and liver function markers as well, which will bode well for the pathology of PBC. So that's just a thing to keep on the radar about how Alk Phos may play out.
Great. And then just the last question here. What are the key things we should look for in those phase two data? And then how do we think about the path to approval here? What's your confidence that the regulatory path is clear?
Yeah. I think it's a great question. So number one is the T-cell responses. We really think we should alter the T-cell responses in these patients. And we believe that should happen in a real-time fashion. I talked about the liver functional improvements may lag for months or something like that. But we should see changes in T-cells earlier. And how that bodes for the regulatory perspective, we really think we're going to have a unique approach. In the event of favorable or positive data in quarter three, we really think we have an opportunity for a good path to approval. And what I mean by that is you may know prior approvals around the Alk Phos got accelerated approval with a post-marketing commitment to do a study downstream, like obeticholic had to do, which, incidentally, they failed in to show some histologic or other liver functional improvement.
With the quantitative nature of the T-cell responses, as well as the clinical outcomes of liver function improvement, we really think we have a unique opportunity for a path to approval in this space as well.
Great. I know I only left a couple of minutes for Linzess . But I think the positive here is it's so clearly successful. I think one of the things that's really surprising is how it continues to grow and grow year on year. So why do you think that is, Tom? And you talked about the demand growth. Why do you think the demand growth remains so strong? Yeah.
I think it's three things. One, this is a very large population. We're talking about 40 million Americans, highly symptomatic diseases. And what we've learned over the years, you take people's pain away, they take the drug, and they stay on the drug. Because this is a chronic relapsing disease. So you stop your therapy, your symptoms come back. So I think that's the first. The second, the high level of treatment satisfaction. I mean, I can't tell you how many messages and stories and letters we get of patients saying, this drug changed my life. So I think that piece. I think the other piece, the third piece, is the marketing mix that we talked about. I mean, it needs to be easy to prescribe. I mean, people are not going to jump through hoops to do prior authorizations and step edits for constipation or IBS.
So we have very broad payer access, which is a significant investment. And I think the last thing is really the profitability of the brand. But I think the real strength over time is how we've strengthened the brand. This was a drug that didn't have some of the claims around bloating, discomfort. There were some real concerns about safety in kids, which hasn't turned out to be the case. In fact, as I mentioned earlier, it's the first drug ever, if you can believe this, to be indicated for kids or constipation, which is a huge population. And I think there are a couple of additional safety concerns that we're going to resolve in the next year or so. And then I think there's an OTC play. So I do think this is a very strong brand. I mean, think about having 50% of the market.
Your next competitor, branded competitor, has three or four. So I mean, the dominance that this product has had in the market, I just don't see it slowing down. Now it's really around how do we generate more profit over time.
As we wrap up here, last question here. You have that growth. You have that strong cash flow generation. Just how do you mentioned at the beginning, you're very actively managing the commercial investment as well. Just how do you think about over the remaining years before patent or brand exclusivity expires? How do you think about managing the overall funding of the company and how you choose to invest in both Linzess asset and the pipeline?
Maybe I'll take the first piece, and I'll hand it over to Sravan on the capital structure. But I think right now, I think we've got another couple of years where we're going to continue to drive brand really hard, drive demand really hard. Then I think you're getting close to harvesting mode, particularly as we bring apraglutide to market, because now I can have both products in the bag. But I think as far as overall capital structure, I think it'd be helpful for Sravan to kind of share your thoughts on that.
Yeah. So I think the most important thing is we don't need to raise capital. So the one thing that Linzess asset provides is this bridge to a future of being a company with two assets well into the early '40s, early 2040s, that have potential for $1.5 billion in peak sales in both CNP and apraglutide combined. And so the idea that we don't have to raise any additional capital or dilute shareholders in the interim, I think, is the benefit it provides from a cap structure perspective.
Great. Tom.