Thanks for joining us for day two of the Jefferies New York Healthcare Conference. I hope everyone's still hanging in there. I'm Amy. I'm the Biotech Analyst at Jefferies. I have the pleasure of hosting the Ironwood team. We have Tom McCourt, Chief Executive Officer, and Tammi Gaskins, the Chief Commercial Officer. Awesome. I will turn it over to them for opening remarks.
Well, first of all, I want to thank Amy for having us. We're having a very productive day here. I think where we are right now with Ironwood is this is really going to turn around year for us. As you know, we ran into some headwinds due to some legislative issues on pricing, that we made a very bold move with our WAC strategy that really has had a huge impact on our revenues, we're looking at probably a $300 million swing in net sales as far as growth. We're continuing to make great progress with LINZESS to broaden the clinical utility, strengthen the clinical profile. I think the second piece obviously was Apra. Obviously, we were disappointed when the FDA requested a confirmatory trial. They've been very reasonable to work with. They like the data.
I mean, apraglutide clearly has demonstrated efficacy and placebo-like tolerability, and they really wanted a reasonable confirmatory trial, which we've worked closely with them on to create really a much smaller trial and a shorter trial. I think we feel good and we'll be initiating sites literally this month.
As I think about the year, it's continuing to maximize the value creation with LINZESS. Second is get apraglutide up and running and enrolling as rapidly as possible. Third, certainly free cash flows, which is going to enable us to reduce our debt load. We'll pay off $200 million in the convertible notes that we have this month, and we hope to finish the year with roughly about $300 million of debt, which is equivalent to basically where we are with our EBITDA. I think it's been a challenging couple of years, but I think we really like where we're at right now.
Awesome. That's super helpful. Let's actually start with apraglutide. A few days ago, you saw the Lilly deal, right? It seems like there's strategic interest, especially in the GI space. I think the deal value is around $1.3 billion. We talked about this Hanmi asset before. I believe it's quite long-acting. What is kind of the read-across to you from the deal, both in terms of the deal value and then in terms of the interest in this SBS-IF or beyond space?
Maybe I'll start and I'll have Tammi, as she's certainly the expert in this category. I think, one, it's brought tremendous new life to the GLP-2 mechanism, which obviously we're getting a lot of inbound questions saying, "What's going on? Where is everybody going?" Clearly this is looking more and more like a platform opportunity.
where it's going to be beyond just Short Bowel Syndrome. Clearly, Lilly kind of communicated that indirectly as far as where I'm not exactly sure where they're heading, but it's certainly beyond SBS. We're looking at those opportunities as well. Things like should you combine it with a GLP-1 to manage muscle wasting? Do you combine it with a biologic for inflammatory bowel disease? I think there's a number of options as far as a life cycle management play that we're still really understanding.
That being said, it's very early on for that asset. They really don't have any human efficacy data that has been reported. When you have a drug that long-acting, if you got a tolerability issue, you got a real problem. I think the thing that we see with our molecule is, yes, it's much longer-acting than GATTEX, but it's got placebo-like tolerability, which is the piece that the FDA got very comfortable with when they allowed us to do a 24-week trial rather than a 52-week trial. I think it's spurring a lot of interest. We're getting a lot of inbound questions about where we are, what do we like about apraglutide , which is exciting.
Awesome. Then Tammi, yes.
Yeah, if I could just add, Amy, we're certainly as excited about apraglutide and the differentiated clinical profile that we believe it will have if approved. We have already had positive phase III data, to your point, in SBS-IF. Right now we're certainly further advanced. We're working on initiating this month, the second confirmatory trial to eventually move forward with an NDA in SBS-IF. As you were saying, the Hanmi asset has been in phase II since 2021 and still doesn't have any human efficacy data. We're certainly ahead there, but again, it also makes us, as we've already been excited about the GLP-2 mechanism and platform, we believe there is more potential there to explore beyond SBS-IF alone.
Awesome. When would you start potentially looking at indications beyond SBS-IF, and can you go over a couple ones that are on your shortlist?
I think right now we have to focus on getting SBS-IF up and running and e nrolling very fast. That's going to be absolutely number one, two, and three priority. We certainly will begin looking at probably animal models, et cetera, as far as additional areas of interest. I think IBD could be one of those areas. We'll certainly start examining that. I think right now, we really need to get our clinical trial, our confirmatory trial run.
Okay, great. Then, since you reported the STARS, now, I guess STARS 1 trial, you've given out a couple of additional cuts on enteral autonomy, long-term durability. Can you go over, one, the physician reception, and then two, the key learnings as you look at people on extended duration of apraglutide? Was there anything that was surprising, or was there anything that was interesting?
Tammi, why don't you.
Yeah, sure. We continue to hear very positive feedback from KOLs, from our investigators, from physicians and market research about the data from our initial STARS trial. You're calling it STARS 1. We called it 007. As well as we have an ongoing long-term extension study called STARS Extend. If I just go back to the original phase III positive primary endpoint, double the rate of placebo, significant p- value, 0.001. Really impressive results in terms of reducing relative change from baseline and weekly parenteral support volume, which can be really burdensome for patients. Many are on for 10 hours a day, five to seven days a week. It's a big burden for these patients. What we're even more excited about is in our STARS Extend trial. The longer patients are on apraglutide, the more improvement and benefit we see.
One of our key data cuts, as you mentioned, analyses, was looking at one in five patients actually achieving enteral autonomy, and that's the ultimate goal, to have complete weaning. We continue to see the benefit together with the only one to show once-weekly administration and achieve these results, but also with a good tolerability profile that we know those three things together are going to be key to not only differentiating apraglutide, but really growing comfort and use of the class and improving persistency levels along the way.
Awesome. You talked about differentiation, right? I think now, there is probably more of a need to differentiate more than ever because it looks like there could be GATTEX generics. Let's please update us if you heard anything new coming this year or next year. You have glepaglutide, and for now, it looks like Zealand's still committed to running that trial. Can you talk to us about physician feedback on what the differentiation factors are? I think you mentioned safety, and the ability to reach enteral autonomy, especially in a real-world setting. Just what is mostly resonating in your discussions?
I think maybe it starts with what's the unmet medical need, right? When you look at GATTEX, whether it's the branded product or generic, the challenge is they can't keep patients on the drug. 50% of these patients discontinue within the first 12 months, that's mainly due to the fact that they can't adhere to therapy, because of the short-acting nature of the drug, if you miss a couple doses, it really can mess up the parenteral support equation, right? There's a fair bit of gastric distress, patients just don't tolerate the drug. They can't really realize the full benefit of the GLP-2 mechanism where with apraglutide , because it's so well-tolerated and it's so convenient to use, once a week subcutaneous injection, patients adhere to therapy. They do realize the first benefit. The generic doesn't solve the problem.
The problem is managing the patient more effectively, and maybe you can comment on what we're hearing back from not just the patients, but the caregivers.
You said it absolutely right, Tom. In terms of a lot People understand the GLP-2 mechanism is helpful for these patients, they also have to be motivated to want to start because they believe that in doing so, they're going to see a benefit. They're going to be able to take the therapy and tolerate it and stay with it, that's really correct. It's the combined profile of the ease of administration, the efficacy that we're seeing with days off therapy really being the North Star together with the tolerability that's going to help set apraglutide apart in the class, and is really critical to grow the utilization of the class overall, too. You mentioned generics. Our projections, our commercial forecast, of course, does assume that there's a generic GATTEX on the market as well as glepaglutide from a competitive company.
With that, we still believe that apraglutide will drive to class-leading share because of that profile.
Okay. Are you aware of any updates from the generic front?
From a U.S. perspective, the only thing that's been disclosed publicly, which was later last year, was from Cipla that they anticipate launching a generic in the 2026 to 2027 timeframe. We haven't received any further or heard publicly any further updates on that this year. It was possible for a generic to come into the market since 2023, but that hasn't happened. Based on research and just precedent in the rare disease space, we think it's unlikely this would be a multi-source generic market because it takes a lot of patient support not just from a reimbursement, but also from a clinical management perspective to support these patients, because as they're starting GLP-2 therapy, they also have to have their parenteral support adjusted and managed throughout the process. It's pretty complex, and so that's why we believe that it's not going to be a multi-source generic market.
Okay, awesome. Just going to your STARS 2 trial, I will say we were going into, we were hoping for potentially a smaller trial, shorter trial, a bridging trial. It looks to be more almost like a full confirmatory trial, and you committed to using the same dose. I think there were some differences. You might not go for the CIC subset, which, we've talked about before, wasn't even necessarily required by the FDA, right?
Yeah.
Can you talk to us about your trial design and what you think you could do differently this time? You are going for a slightly lower than planned dose, but similar to what your STARS 1 trial showed. It's a very variable indication. What is the kind of comfort level that you can replicate what you saw in STARS 1?
I think we're very confident we'll replicate. I think we believe, based on all the work we've done, while there was a lower dose that was actually delivered to the patient- . Across the board. Clearly we saw sound efficacy as well as very good tolerability. I think this is very similar to the first trial. The primary endpoint is basically the same. I think that it will only be a 24-week trial, as I mentioned, as opposed to a 40, 42, or 52-week trial, which glepaglutide is going to be required to do. I think the real opportunity here for us is how can we accelerate enrollment.
For us, we certainly have all the current centers up and running from STARS Extend, but we're going to increase the number of sites, particularly in the U.S., because keep in mind, VectivBio was a European-based company. Most of their sites were in Europe. We think there's clearly a very significant opportunity in the U.S. to expand the sites. Also with, certainly the concentration of electronic records as well as AI, I think we can identify and enroll patients faster than we did before.
Awesome. I think you've talked, in terms of timelines, you said you would file before year-end 2029, right? It looks like from ClinicalTrials.gov, it says late 2028. You're saying maybe that's a placeholder. Is there an ability to accelerate timelines before that year-end 2029 timeframe? How do you think you'll enter relative to glepa?
Well, we'll see how the recruitment goes, right? I think we do see a real opportunity to accelerate enrollment by identifying patients faster and getting them to the study centers, which we've dramatically expanded. I think this is really about execution. That's all we're focused on right now.
Yeah, just to add, Amy, because of the fact that we do have the experience, we have the largest trial to date in SBS-IF. We had 164 patients, 68 sites. We certainly have the foundation and the experience in that. Because the STARS Extend trial's ongoing and clinicians know these patients are seeing positive results, we do expect there's going to be enthusiasm for enrolling in an apraglutide trial, and all those things are going to be critical to getting this done as quickly as possible and ultimately out there for patients.
Awesome. Super helpful. We've talked about this before, because you've done some kind of dose relationship from your current data, also from the earlier phase, like the phase II as well. Do you think you're leaving efficacy on the table by going for a slightly lower dose that replicates STARS 1? Why don't you just run a higher dose trial?
Well, I think first of all, number one is we want the strongest benefit-risk profile I can possibly have when I go in and talk to the FDA. Right. We have a very good benefit-risk profile right now. The last thing I want to do is compromise that. Are we leaving efficacy on the table? Possibly. Will we explore that? Absolutely. I also want to be careful that something doesn't pop up on the safety side that I can't explain w ith the higher dose. That's always going to be the risk.
Well, you guys tested the 5 mg dose in the phase II, right?
Yeah.
The open label phase II, and then even earlier than that, there was an option of a 10 mg versus 5 mg
Agreed.
I guess, what are the safety risks that you can think of?
Well, I look at the other GLP-2s, right? You got fluid overload, which appeared to be a problem with some of the GLP-2s. You had gastric distress which is a significant problem. The question is, those were small numbers.
Right? There was a dose ranging study done, but those were relatively small doses, and I think 5 mg probably was the right dose to use at the time. I want to be able to leverage safety of database of the 3.5 mg. We'll be exploring a dose escalation study. For instance, we have over 150 patients in STARS Extend. Those people that are partial responders, should we escalate the dose? I think those are things we'll be talking to the FDA on, to say, "Can we get there faster with an existing population that's currently on a lower dose?
Interesting. Okay.
Which would be very doable.
Okay. Is there a possibility if you can build in some dose escalation into your open-label extension that you can talk to the FDA and potentially get that on label, given you already have existing phase II open-label data with that dose, right?
I can't speak for the FDA. I think, again, the data rules the day, right? If we see better efficacy and comparable tolerability, I think FDA would be leaning in on that because this is an enormously burdensome disease. If we can increase enteral autonomy or grab a couple more days a week off parenteral support, that's enormously beneficial to the patients. FDA recognized that, and they're very pleased with the safety profile.
The first principle being confirmatory, Amy. We have to confirm the positive results we saw, and it's the totality of those data sets that'll give us a comprehensive package to help us to get to market as quickly as possible, at a dose that we know can benefit patients.
Makes sense. I think another part of apraglutide's profile that stood out is the low rates of ISRs, right?
Yeah.
You're seeing with glepaglutide, they had almost multi-fold, much higher rates of ISRs than you guys. Which could be because of the ADAs and, you're seeing high rates of ADAs as well, but have you disclosed your rates of ADAs? If there's any kind of molecular differences between apraglutide and glepaglutide ?
The answer is we've disclosed everything that we have. Obviously the FDA's seen everything. There's a reason why we're running a 24-week study and they're not. They're running a 52-week study. Those are the facts that I know for sure. FDA has not pushed us on any front with regard to any kind of safety issues or tolerability issues.
Okay. Awesome. I guess looking at the market, I remember when we last talked a few years ago about the ICD-10 codes, that was I think recently instituted, and that was still kind of gathering patients, right? Then we talked about how these patients are generally interspersed, not necessarily even managed at academic centers, maybe even managed by home health nurses or a nutritionist. What is the most recent update on how many diagnosed patients there are with SBS-IF? Your $700 million number, I know Tammi, you talked about the split, but what does that imply in terms of how many players and then how much penetration or market share you're assigning for each?
Yeah. If I start with patient population and ICD-10 codes. They went into effect a little over two years ago. We are seeing them be utilized more. They're still not up to the levels that we would want them to be, but because of that, we are seeing, specifically in the U.S., increases just in the prevalence of SBS overall. Now, when we get to that $700 million, Amy, that's where we look at about 8,000 patients in the U.S. being what we would call GLP-2 eligible.
We define that as being on parenteral support three or more days a week. That's what the studies have done and the labeling of the currently available therapy. Of those patients, based on market research and then some claims data, we guess that at any given time, there's only about 2,000 patients on GATTEX, as I mentioned. For a variety of reasons. We definitely see not only with the differentiated profile of apraglutide, but also with share of voice out there, and even if we have more than one company selling a GLP-2, that's going to help increase awareness, connect those dots, to help identify patients. We do see class utilization growing as part of that forecast. We do see persistency improving with once-weekly administration and the tolerability profile over what we see with GATTEX today. As I mentioned, we expect to get to class leading share.
I'm not going to give you a specific percentage number, but we figure that in a market of having GATTEX/a generic GATTEX, glepaglutide, and apraglutide. Obviously, that only increases or improves if any of those things don't happen, any of those other products don't get to market.
Okay. Awesome. Makes sense. Maybe just going to LINZESS. Post the pricing reset, you're still seeing growth, right? Can you go over what segments you're seeing the most growth from in terms of indications and then maybe the payer channel or whatever relevant other metrics?
Absolutely. First, if I could start just with a little reminder that our first quarter results that we did report $272.5 million in U.S. net sales, which was a 97% increase year-on-year. I'll just start with that. To give a little context or foundation, for LINZESS, our largest books of business are Medicare Part D, followed by Commercial.
Through Q1, growth across all channels was in line with our expectations, including, as we reported in Q1, we had 5% demand growth year-on-year, which was slightly higher than what we guided to with low single-digit, but still in line with our expectations. Okay? This year, what really builds to our full year net sales guidance is a combination of improved net price and low single-digit growth.
Which we guided to with the expectation that with the WAC change and elimination of inflationary rebates across channels, that this could cause some channels like Medicaid to possibly make a shift in demand utilization versus prior year. We still remain confident in our guidance and always look at demand closely, but just to give a little context on that guidance, that gets us where demand fits in to get us to that full year guidance of between $1.125 billion and $1.175 billion.
Awesome. In terms of, I guess, the cadence for growth for the rest of the year, are you thinking about growth being consistent to what you saw from Q4 to Q1? Are there any seasonality aspects that we should think about? From a gross to net perspective, is there any changes in dynamics that we should be considering?
Yeah. From a sequential quarterly net sales perspective, we expect that there will be significantly reduced variability from quarter-to-quarter because of the change in net price and having more consistent net price across channels year-on-year. What that consistent net price does is help assure that you have less impact on a quarterly basis from shifts in mix of business relative to gross to net rebate reserve accruals versus actual units dispensed in a quarter. Less sequential variability. If any comes in, it'll be more from a year-on-year quarterly variability perspective because the differences in phasing of gross to net rate reserves year-on-year.
Okay. That's super helpful. Then just maybe about the growth that you're seeing, are these coming from, I guess, the benefit in pricing and then maybe insurance giving you guys more favorable coverage or reduction of either approval rates going higher, or are these coming from the fundamental population demand as well?
This is my favorite answer to give, and Tom, who launched the brand, can certainly add in. The good news is that with the price change, one of our key principles was to maintain access, which we have. We've had class leading access for LINZESS for a long time across both Commercial and Medicare Part D, and we have maintained that through this change. We know LINZESS is market leader, RX market leader. We're in our 14th year in the market. The clinical profile, the experience that physicians and patients have, it's really what continues to drive that. The IBS-C and CIC category continues to grow in the adult population because we do see an aging U.S. population.
More factors contributing to more patients presenting to their HCPs, coming out of the OTC category, looking for more relief from their symptoms. Tom, anything you want to add?
No, I think that's spot on. You rarely see a brand like this that is this kind of linear growth for 10, 12 years. I had the great good fortune to run Prilosec years ago, and I haven't seen a brand that looks anything like this. Which says a lot about how big the market is and how significant the unmet medical need is. I think this has become almost a tipping point, where we're at. Because it's so well understood. It's the knee-jerk go-to brand, and it's a great place to be. As a market leader, our number one job is to continue to grow the market and capture disproportionate share, and I think we've done that quite well. As you know, the margins get better over time.
We're really, I think, in a very good spot to finish the run. Now the focus really is on post-LOE strategies. Tammi and the team have spent a lot of time looking at how do we hang on to as much business as we can post-LOE, and certainly the OTC play, which is all on the table. I think now this is really about doing the work and making sure that we can hang on to those revenues as long as we can.
Awesome. When can we get an update? Have you talked to the FDA about it already? What type of studies do you need? I'm also assuming, given your pricing change there, you're probably seeing some sort of price elasticity as well, which kind of fits well into OTC, right? Any update there?
We continue to talk about and explore this with AbbVie, our collaboration partner on LINZESS, as you know, and look at this for the future. As we make more progress on that, we will be certain to provide updates at that time. Just know right now it is something we are working on very diligently.
Yeah, I think the path, obviously the first player here was MiraLAX that went over the counter. I think this trial design is very straightforward, if indeed we even need to do another trial for occasional constipation. It's generally a two-week trial. These patients can be recruited and enrolled very rapidly. I think because the safety profile is so strong in LINZESS, I think this will be a pretty reasonable move.
Okay. That makes a lot of sense. Maybe just finally, a financial question. You had $200 million debt tranche, right? It seems like you'll be fine for that. General de-levering. Maybe just from a management perspective, hiring for the new CFO, your plans for that and your vision.
Obviously losing Greg was unfortunate, but we're all cheering for him. He also left the team in very good shape. We have o ur interim CFO, who has been a 10-year veteran here, he was our controller, he's our chief accounting officer, and extremely capable. Right now, he's the acting CFO, and we'll evaluate that as it's come. I don't think we're missing a beat with regard to the CFO role.
Amazing. Well, thank you so much