Okay, good morning. We're gonna get started. Hi, this is David Amsellem from the pharma team at Piper Sandler. Welcome to day 2 of the 35th annual Piper Sandler Healthcare Conference. We're gonna start off, at least my portion of the day, with Ironwood, and very pleased to have the team here. Tom McCourt, CEO, Sravan Emany, CFO, Mike Shetzline, Chief Medical Officer. Did I get all the titles right?
You did.
Okay, excellent.
Spot on.
I always like when I do that. So, let's get started. Lots to talk about here. So I'm gonna ask a high-level question, just post-acquisition of VectivBio. Just talk about the current state of the capital structure, and where leverage ratios are going to be or should be once apraglutide launches. I guess that's a question for sure.
Yeah. Great.
Okay.
First of all, David, thank you for inviting us. We always appreciate being here at the Piper Conference. So I'll start by saying, you know, we're really excited about where we stand today, post-acquisition. From a balance sheet perspective, I think one of the attractive things about Ironwood was the untapped potential with its cash flow and, from LINZESS, and the potential it generates, from a acquisition capacity. And so we don't think that's necessarily unchecked. At the moment, we've got about $325 million of bank debt. We borrowed $400 million in a revolving credit facility to help acquire the VectivBio company. That also included using $600 million of our balance sheet cash at the same time.
So we've got $325 million of bank debt. We've got about $400 million in convertibles spread across two tranches, one maturing next June, one maturing in June 2026. You know, from our perspective, we're generating meaningful cash flow from LINZESS. We've already paid down $75 million of debt, and then I think we're gonna continue to pay down debt really rapidly here over the next few years before launch. And I think, you know, we'll exit 2025, around the time we launch apraglutide, with less than 2x net leverage, inclusive of the converts. So I think we'll be in a place where we're gonna reload very rapidly to continue to be acquisitive in GI.
I think the other piece that, too, is the core business on LINZESS continues to be extremely healthy.
Mm-hmm.
The demand growth has never been any better than it is right now. And it's throwing off, to Sravan's point, it's throwing off a lot of cash. And we just don't see an emerging competitor, so we don't see a major threat there.
Yeah.
So I think we like where we're at right now.
Excellent. So let's dive into apraglutide. I know everyone wants to talk about that.
Sure.
So I wanted to start and just have a higher level discussion about short bowel syndrome with intestinal failure. Just give us a lay of the land on the size of the population, and also where these patients are coming from. Is it mostly inflammatory bowel disease patients? Then also talk to the mix between what's called colon in continuity and stoma patients.
Yeah, I'll handle it. Maybe we start with kind of how we got here.
Yeah, sure.
And as you know, you know, Ironwood's gone through quite a, you know, evolution over the last five or six years, and we decided to really, you know, really focus on GI diseases. And, you know, when I took over as CEO, you know, we brought in Mike, you know, who is an expert in GI, and we really started to nurture that group. And we looked at a lot of different assets in GI. And, you know, Mike was very familiar, you know, with the asset, with apraglutide from years ago, and we really liked the profile. We could see it as a great fit with our existing development capabilities as well as the commercial capabilities.
And then I think when we move as we move forward, we've learned a lot more about what this market looks like, what does the terrain look like? What do we think we're gonna need to do as far as our go-to-market strategy?
Yeah.
Maybe, Sravan, if you can talk a little bit about how you saw the, you know, the patient population. Maybe Mike can talk a bit more about-
Yeah.
That'd be helpful.
Yeah, sure. So as Tom said, I think one of the... We've been on a long journey here, and since you've started picking up coverage, we talked about being an acquirer of an asset, given the fact that we had this LOE in 2029 with LINZESS. And one of the things that we liked about the VectivBio opportunity was the ability to control the commercial launch, as opposed to inheriting somebody else's market development. And so with the launch in 2025, we here, we have the opportunity to spend the next few years, you know, building and arraying our assets in the right way to attack this market and make sure we maximize the potential of the drug.
Mm.
Right now, you know, one of the things that we have is, with our sales force at LINZESS, we're 90 sales reps, which would be the largest number of reps ever applied to treatment of the, you know-
Mm-hmm
... coverage of SBS-IF. And they're all across the United States, and they cover the large GI super groups. They cover all the meaningful people that would be prescribing apraglutide already. And so from our perspective, you know, we know where these patients are, and we can track these patients. Overall, as a disease state, to answer your question more specifically-
Mm-hmm
... you know, we think there are about 17,000 patients in the United States and Europe, with another 1,000 patients in Japan, so 18,000 patients in total.
Mm-hmm.
Gattex, which is the on-market drug today, which is marketed by Takeda, has treated about 3,500 patients-
Mm-hmm
... or in aggregate, about 20% of the overall patient population. And so part of the issues that, you know, for them, is that they've never been able to penetrate beyond the stoma population and to the CIC patient population, and Mike can go into the differences between the disease states and why that's true.
... But we think we have the potential with our product to expand the utility of it beyond stoma, if the, you know, if we hit our primary endpoint here with the trial. Yeah.
Yeah. So I mean, SBS, or short bowel syndrome, with intestinal failure, is actually a pretty morbid condition. Most patients, if not all, have had an abdominal catastrophe oftentimes. That could be progressive inflammatory bowel disease, that could be ischemia or mesenteric ischemia, where they literally lose a part of their bowel. It dies from lack of blood flow. There are some other conditions, but the bulk of it really comes down to oftentimes, advanced IBD or ischemic events. And it's very morbid from a standpoint that, you know, not too many decades ago, these people would have a very poor outcome. But then, with the advent of parenteral support, we can keep those people alive and functioning by giving them nutrition through the night.
The sad reality of that is that can often require 10-15 liters of parenteral support, often every day or seven days a week. Now, there's a whole range of outcomes, and it really depends on how much of your bowel gets hit, so to speak. And that does determine sort of your prognosis, and that's where we get into stoma-
Yeah.
and colon discontinuity. And the reality is the current landscape, meaning NPS and Gattex, which did a great job, they really highlighted the disorder, really helped a lot of patients. But really called out the fact that a lot of patients have a need for just volume. They can eat, these people can eat, but they can't eat enough or drink enough to actually keep their hydration status adequate, so many have a volume need. The interesting feature of that is that most of those patients fall into the stoma group. They're the group who their bowel ends at an ostomy site on their abdominal wall, and it empties into a bag. They're the stoma population.
But the other half of that is if you have some colon left and you can connect that part of the bowel to the colon, then you have a better chance to reabsorb fluid, and you can often sometimes do better. The downside of that is that in the clinical experience with GLP-2s, much of the outcome has been focused on the stoma group because the outcome has always been about parenteral support volume reduction, so the volume of fluid, right? And a lot of times, the colon continuity group has taken a backseat.
Mm-hmm.
That's what we liked about the apraglutide program, is it actually takes into account, kind of get better outcomes in the colon in continuity patient population. Because the stoma patients, as I said, could need 10-15 liters a day. Oftentimes, the colon in continuity patients need just a couple, 4 or 6 liters a day. You can see just by those numbers, it's hard to show a clinically meaningful impact.
Right.
In a study design focused on volume reduction, right? But the advantage with the approach we're taking with apraglutide is we now have an opportunity for those colon continuity patients to participate in the endpoint, even if they don't meet 10% or greater urine output. And we think that, and the reason that was real important to build in is because we have such a different differentiated PK profile from a long half-life, right?
Right.
It's going to be weekly dosing. We really think that prolonged exposure is going to give optimal pharmacodynamic outcomes for patients, and we want to make sure that colon in continuity patients have a chance to improve as well. And that's why we also have their endpoint more around 48 weeks than the traditional 24 weeks-
Mm-hmm.
-that the stoma population has been looked at for both Gattex and glepaglutide, right? The primary endpoint is a 24-week endpoint.
Mm-hmm.
We have also built in a 48-week endpoint to look at the colon in continuity outcomes. The reason that's important is because most of the best outcomes happen in colon in continuity patients. They're actually the group that can oftentimes be weaned completely off their parenteral support. In other words, go from not needing any parenteral nutrition anymore. And that's really a finding that came out of a lot of post-marketing work, which was done initially with Gattex. So we think there's a nice opportunity there as well-
Mm-hmm.
because the colon-in-continuity patients now can participate in the endpoint and also push potentially better outcomes.
So I wanted... That's all, that's very helpful and actually answered a few of my questions, subsequent questions. So that's great. One of the things I wanted to come back to was dosing. So it's once weekly. And, you know, I don't want to downplay that we know that Gattex is a daily injection, but I wanted, for you, if you could-
Yeah.
to frame the value proposition of dosing convenience in and of itself. Maybe talk about some of the challenges of administering Gattex and also just the injection and infusion burden for patients on parenteral support and what that is like for that population.
Yeah, yeah, I think it's a great question. So, I mean, Gattex, in its current form, right, is an injection that patients have to prepare it. They have to give it sub-Q on a daily basis. That can-
They have to reconstitute it, right?
They have to reconstitute it, yeah.
Yeah.
It's reconstituted lyophilized powder in a vial. That, they do that every day. And so even though they have already a pretty significant burden with their nighttime parenteral support administration, now they have to give a drug, you know, sub-Q every day. And so depending on how they view the clinical benefit, you know, the ability to maintain that every day, you know, could be burdensome for them. And it's also relevant because what we know about the GLP-2 mechanism action is you need to take it all the time, or you have to have drug exposure all the time to get the downstream benefit, so your gut can regrow to a degree that you get the advantage of the reabsorption, which decreases your parenteral support needs. So if you miss a day or two, you could miss a big chunk of the potential.
Obviously, that translates into-
Sure
... poorer outcomes, and then it translates into lack of compliance and less persistence and all those things. That's where the once a weekly can really add a lot of value because you just have to worry about that one day a week. Take it, you're sort of covered for the week, and then you could potentially, because of that week-long exposure, get the maximum pharmacodynamic response and hopefully the maximum clinical outcome.
... Okay, that's helpful. So let's talk about clinical outcomes. In general, what kind of reduction in parenteral support volume is considered by clinicians to be clinically compelling?
Yeah. So, it's a good question, and as a physician-scientist, I kinda like these questions because I always like to say, you know, we like to always take care of patients and meet the patient's needs. In the end, it comes down to a regulatory decision on what the approved label is gonna be and what the indication is.
Sure.
Gattex, like I said, doing what they did very well with NPS and the GLP-2s to break into this therapy, really had the same conundrum. You know, what is meaningful to patients? So they focused on the parenteral support volumes, which then, as we talked about before, made the stoma population more relevant. But the critical thing was the agency didn't know. The whole point of the Gattex advisory committee was actually trying to get an understanding from the advisors and the patient, the open patient forum, about what's clinically meaningful. And they kinda settled on this 20% reduction in parenteral support volume being clinically meaningful. Why?
If you ask some of the investigators at the time, they tell you because as they talked about it, they figured that if you're on parenteral support 5-7 days a week or something, you get a 20% reduction. That potentially frees up 1 day a week. And that 1 day a week being off parenteral support is extremely meaningful to patients, 'cause-
Mm-hmm.
Patients can now take a weekend off. They could go somewhere and not have to worry about taking all their parenteral support equipment, having to do all that in a hotel room or-
Mm-hmm.
-with their relatives and stuff like that, and was very meaningful. And in fact, at the Gattex Advisory Committee, there's 21 patients showed up, literally support this idea that that one day or that 20% was extremely meaningful to them.
Yeah.
I think that's kind of the metric.
Yep.
We're set to continue that if you're looking at sort of what glepaglutide has done for the primary. But we're also looking beyond that-
Sure.
Because we have... We do think we have an opportunity for better outcomes, including, like I said, the enteral autonomy piece, and that does resonate a lot with patients. Clearly, to be able to be completely off parenteral support is a really big win.
Yeah. So let's talk about the Phase 2 STARS Nutrition study. So you had some recent updated data, I think, out to 52 weeks. I guess, what can we glean from that 52-week data relative to the previous update, say, at 24 weeks?
Yeah. Well, I think the 24 weeks was more or less in line, obviously, with a lot... Not obviously, but consistently with a lot of stuff that happened with the 24-week endpoint for Gattex and Glepa. Right? Now, the nuance here, though, was just in colon continuity. So and if you remember, for both Gattex and Glepa, they hit the primary endpoint, which is an aggregate endpoint for stoma and colon continuity patients, but all of the efficacy came from the stoma population. So this was the first time we saw 24-week data, where the colon continuity patients were meeting the PS or the parenteral support volume reductions that could participate in a primary endpoint like we've designed it in the Apra program. So that was the really a nuance for the 24-week data. It showed that that can be achieved in colon continuity.
The update is the 52-week data, which actually shows that persists. So now, again, we're taking a weekly administration. We're showing that we potentially get outcomes in a patient population like colon in continuity, which wasn't present for some of the other products, and now showing that is maintained out to 52 weeks.
Mm-hmm.
And then also, literally, it's a small study. It's an open-label study, but we literally, based on your prior question about what's a meaningful reduction at 20% responder, we had 100% of patients achieve that 20% reduction in that study.
Yeah.
Again, open label included, so every patient met the responder definition by the end of the study.
I wanted to come back to the 48-week endpoints as for the colon in continuity patients. This is in the STARS Phase 3. Just make sure that I understand this. So the idea here is that the CIC patients have a lower parenteral support burden relative to stoma patients. So the idea is that by evaluating them out to 48 weeks, having a 48-week endpoint, you're essentially it's going to take longer to potentially drive a statistically meaningful response in those patients relative to stoma patients. Is that the right way to think about it?
I mean, you could call it a statistically meaningful response, but the reality is that-
Yeah
... the physiology of this colon in continuity population just demands more time.
Sure.
They come in at a lower volume need, but that consequently means you can't make a big, deep reduction in the volume early. You've got to take a more slower and pragmatic approach to the volume reductions as well.
Okay.
To the same point, they don't have the same high urine outputs-
Mm-hmm
Because they have lower volume needs. So oftentimes, they're less eligible for a parenteral support reduction because of the volume needs. But in our phase 3 program, even if they don't achieve the 10% threshold for parenteral support volume reduction, they, in their colon in continuity patients, they still can have a parenteral support volume reduction if their nutritional status, their body weight, their oral intake, their nutrition, their urine output-
Mm-hmm
stool, and all that meet criteria, they can still have their parenteral support volume reduced, and that gives them a more time to do that, with the 48-week endpoint. That was critical as well. We learned a lot with the post-marketing experience with the other GLP-2s.
Mm-hmm
that it takes a little longer to get there, and that's why the 48-week is in there. This is the first trial really to add that 48-week point and really make a focus of it. It's included as key secondary endpoints, so they're statistically accounted for. If we hit those, there's certainly an opportunity there.
Can you comment at all on the powering of the STARS Phase 3?
...Well, right now, we're gonna have 164 patients, even in its original form, with 140 is very well-powered.
Right.
Very well-powered study. And it's all, we know the history now, obviously, not just with the phase III program for Gattex, but with the recent experience with glepaglutide. So we kinda know roughly the outcomes. We have the phase II program with apraglutide as well. So it's a very well-powered study, and we're really looking forward to the outcome.
Okay, so wanna move on to other aspects of the pipeline and maybe fit in a couple of minutes on, you know, the actual product that generates cash flow. But we'll get there, I promise. So first, on just moving on to apraglutide and graft versus host. I guess the question here is I know that that's you're running that study. Any thoughts on, you know, the extent to which you move it forward if there's an efficacy signal, given that it's outside of your core GI focus? How are you thinking about that? And I know that that wasn't core to the acquisition-
Mm-hmm.
you know, the study is happening. So-
Yeah.
Help us understand your thinking.
So I'll start. I think just to put a finer point on what you just said.
Yeah.
It wasn't the reason we bought-
Sure
-the company.
Yeah.
But I think we saw there was an interim look at it in the summer, and I think from our perspective, there was enough to continue till the end of the trial.
Mm-hmm
which will happen in early first quarter.
Mm-hmm.
So I think from our perspective, we'll evaluate depending on the data. We're always gonna be opportunistic. I think if there's something meaningful there, we'll take a look. I think our focus has been with apraglutide on the SBS-IF. I don't know, Mike?
Yeah. Well, I think the other, the other piece of this is, one, it's gonna come down to the data.
Sure.
If the data is really promising, of course, we're gonna pursue it. It's absolutely the right thing to do. And you're talking about... When you're talking about commercial coverage, it's a fraction of what we do, for instance, on LINZESS. So you know, would be, if the drug really does work here and we're encouraged by it, it certainly, you know, certainly would not be a big reach for us to be able to commercialize it-
Sure
in this space, and we'd take a look at that. But I think maybe, Mike, you can talk more specifically about, you know, the outcomes that you'd hope to see.
No, I mean, I think it's, it looks, there's still a huge medical need. There's a lot of activity from a medical therapy perspective in the space. The actual path forward that Vectiv took, and we're pushing forward as well, came from actually GVHD physicians.
Mm-hmm.
You know, they were looking with the GLP-2s. They were trying it in patients, and they thought there was a huge opportunity there. That's what got the interest in the phase II trial for GVHD. There's certainly a lot of preclinical evidence to support that.
Yeah.
I think there's, you know, we're looking forward to the outcome. It's a hard endpoint, right?
Mm-hmm.
So I think we do have an opportunity to really interpret that and see how it plays out. But if there's certainly a reason it's gonna benefit patients, we're certainly gonna look hard at it and see a path forward.
Yep. And then real quick on CNP-104 and primary biliary cholangitis. So you've been talking about T-cell responses, and I wanted to get more color from you on, you know, what you're seeing here and, you know, why those T-cell responses are important.
Yeah. So the reason we did the deal, the CNP deal, was because of the opportunity, obviously, to look at T-cell responses.
Mm-hmm.
I mean, you probably know from the history with obeticholic acid and some other products in the space, it can take a long time to figure out whether drugs work in PBC. Now, a lot of that reason is because those products are focusing on endpoints like pruritus or lab changes that can take a lot more time. So, PBC is still a huge medical need. Even today, the therapies more adjust the symptoms of the disease rather than the root cause.
Sure.
But this opportunity, based on the proof of concept in celiac and other autoimmune disease, really showed an opportunity for us to sort of look at PBC patients, and maybe be able to identify if we're in the right direction by looking at early T-cell responses. That way, we can just get an early read on, is this something we really want to stay in and not wait five years for an outcome? So we did that, a little bit while back, and certainly saw favorable T-cell responses, meaning there's an antigen-specific change in the T-cell populations, which could bode well from a clinical outcomes perspective. Now, that will only be defined when we get those clinical outcomes, which are coming in quarter three.
Mm-hmm.
But also, remember, this is an early look, right?
Sure.
If you look at what happened in celiac, we often get challenged. Well, celiac, they know the percent, they know the population. That came much later in that development program, after phase I and phase II, with a combined of a lot of data, but also with the end result, clinical outcomes available at that time as well. Again, we were looking at this as an early opportunity to get a read in for our business planning for 2024 and 2025. So we're very happy to see the favorable T-cell response.
Mike, maybe you can comment on why the T-cells are so, so important?
Yeah. I mean, the T-cells are important because the whole disease is based on T-cells.
Sure.
The T-cells are the entity that destroys the bile ducts, and that's what gives you the cholestasis or the cholangitis.
Sure
-in primary biliary cholangitis. It is honestly all about the T-cells.
Yeah.
And if the T-cells work, we should potentially see clinically meaningful impact on that. And the nice part of PBC is, PBC is driven by one antigen.
Mm-hmm.
The PDC-E2 antigen. That's why we can look at these antigen-specific T-cell responses. So the science is just super strong, and I really mean that. You know, you could diagnose PBC based on the presence of an anti-mitochondrial antibody. That antibody is in response to the PDC-E2 antigen.
Yep.
We're giving a therapy directly to the inciting antigen. That's the root cause of the disease that causes T-cell destruction.
Okay, well, we got about a minute left-
Great.
So I wanna make sure we talk a little bit about LINZESS. So you have the pediatric label expansion. So just talk generally about the extent to which that could drive some degree of acceleration and volumes.
Sure.
I mean, volumes have been, volume growth has been pretty consistent. I'd say remarkably consistent.
Yeah.
What does the expansion do for volumes going forward?
Yeah, I think remarkable is a good word. I have, you know, I've been in multiple GI products throughout my career, and I haven't seen a drug with this kind of linear growth probably since Prilosec.
Mm.
You're still seeing, you know, high single-digit volume growth on, you know, 4-4.5 million prescription base. So it's really remarkable. And right now, the new-to-brand volume is increasing even faster than it has in the last 4 years. And a lot of that's coming from the lower dose, the 72-microgram dose, which, you know, is the indication for pediatric constipation. You know, and this is the first drug ever approved for pediatric constipation. And right now, what we've been doing is, you know, piloting a number of promotional efforts to really understand how promotionally sensitive this is and what are we gonna do next as far as an adjustment of our marketing mix.
Mm-hmm.
I don't see us increasing our investment in the marketing side dramatically, but I think we may call on slightly different docs. For instance, we'll maybe call in the large GI pediatric practices, et cetera. But there's no question, it looks like it's very promotionally responsive.
Mm-hmm.
We probably won't see the benefit from that until probably towards the end of this year or next year.
Mm-hmm
With regard to the upside, but there's no question, it's driving part of the growth of the product right now.
Great. Well, wish we had more time.
Yeah.
Thanks.
We're out of time. Thanks, thanks, gentlemen, and thanks everyone in the audience.