Great. Welcome. Good morning, everyone. My name's Jess Fye. I'm a biotech analyst at JPMorgan. We're so glad to have you here at the 44th Annual JPMorgan Healthcare Conference. We're continuing the conference with BioCryst. And first, you're going to hear a presentation from the management team. Then we're going to go into some Q&A. If you're here in the room, you can just raise your hand to ask a question. You can also submit them via the portal, and I can read them off the iPad up here. But with that, let me pass it over to the company CEO, Charlie Gayer.
Thank you. Good morning. Thanks, Jess. Thanks to the JPMorgan team for inviting us here this year. I'm here with Babar Ghias, our CFO, and Dr. Bill Sheridan, our Chief Development Officer, and this is a really exciting time to be taking over this year as CEO of BioCryst. Because if you've been following BioCryst over the years, I think you'll see that it's not the same BioCryst that you've seen before. We have some really exciting things going on. Before I get started, my team and I will be making some forward-looking statements. Those statements have risks. You can read about them on Slide 2 or our website, and then we also will be using some non-GAAP financial measures in this, as we talk about last year's preliminary results and guidance for this year. 2025 was a really transformative year for BioCryst. We accomplished a lot.
First and foremost, ORLADEYO growth. 2025, we saw the most new patient prescriptions in the United States since the first year of the launch. This was in year five, which you don't normally see in a rare disease launch. We made great progress on paid rate improvement in the United States for ORLADEYO, ending Q1 at 84% and the year at 81%. And this compares to our long-term goal that I'll touch on more later of 85%. We sold our European business. The business was going great, but as one product in Europe, it was not profitable for us. And we sold it to Neopharmed Gentili for $250 million in cash upfront.
And that helped us not only streamline our business, but pivot directly into a business development strategy where we turned around and got into the proposed acquisition of Astria Therapeutics that we expect to close in the next couple of weeks. And that gives us another late-stage rare disease HAE asset in navenibart that we're really excited about. We also achieved profitability for the first time in BioCryst history. And now that we've done that, we don't intend to go back. We expect to be profitable from here on out. And then finally, right at the end of the year in December, we got approval for ORLADEYO for kids, allowing us to bring oral preventative therapy for HAE kids down to as young as age two, which we think will be transformative for the HAE community. So really big year for BioCryst.
Preliminary results for the year: $601 million in ORLADEYO revenue, beating our latest guidance of $590 million-$600 million that we announced after Q3, and what's really important here for everyone to look at is the next line: $563 million in our ongoing business, so this excludes the European business, so this is the baseline to measure our progress going forward. Ended the year with great cash position, nearly $340 million, and that sets us up for 2026, where we are anticipating ORLADEYO revenue of $625 million-$645 million. Total revenue, once you include RAPIVAB, of $635 million-$660 million, and then on our base business, prior to the Astria acquisition, because of the removal of our European business and other efficiencies, our base operating expenses on a non-GAAP basis will be $380 million-$390 million.
And then adding $70 million-$80 million once we close the Astria deal to continue the operations there, moving towards completion of the navenibart clinical trial. So strong year for prescriptions, 1,600 patients on therapy in the U.S., despite the competition in the HAE space. So this sets us up to have three very strong pillars for our growth strategy, starting with ORLADEYO, a commercial product that is on track for $1 billion at peak that we expect to hit in 2029. We're getting towards a greater than 80% contribution margin on that business. Once we add navenibart, this is going to be north of 90% contribution margin on the commercialization. And then very importantly, a really long runway with ORLADEYO. We have composition of matter protection out to May of 2040.
So as we hit peak in 2029, we have over a decade of significant cash generation on that business. BioCryst in the past was all about our internal R&D and will continue to do that in a very disciplined way with allocation of capital there. But we have some programs that we're really excited about, led by our Netherton Syndrome program that I'll talk a little bit more about. This is a high-need rare disease, and we have the potential to be the first truly transformative drug in a condition where there's no therapy for these patients right now. And then external opportunities.
With all the cash generation from ORLADEYO, eventually from navenibart, we will continue to look for late-stage rare disease assets where we can plug that into our commercialization engine and really leverage the infrastructure that we built and the skills that we have in commercialization to drive future value in rare disease. So again, this starts with ORLADEYO, a molecule that we developed ourselves, was first approved in 2020, is now entering its sixth year of launch and still growing. As you can see from the right side of the slide, about 50% of the patients who have tried ORLADEYO in the U.S. are still on therapy after five years, and the growth continues. And the reason they're still on therapy is because ORLADEYO is a drug that either works fantastically well for you or it doesn't, in which case you move on.
And we knew this going back to our Phase III pivotal trial, APeX-2, when we looked at the long-term two-year data from this trial. And the patients who stayed on ORLADEYO 150 milligrams had a 91% reduction in attacks versus their baseline. And so in the real world, that's what physicians and patients are discovering is you should expect great efficacy from ORLADEYO. And if you don't get it, that's okay. You have many other options that you can try. And what this translates to is when a patient starts, patients start on ORLADEYO, 60% of them make it to a year. And then after a year, because they're doing well, very few drop off therapy. So ORLADEYO is not only the most differentiated product as the only oral prophylaxis product in the market, it's also highly competitive on an efficacy perspective.
So what this sets up for the next several years in ORLADEYO is we believe 15% roughly year-over-year CAGR in revenue growth out to 2029, where we expect to hit $1 billion. If you look at the chart on the right, this is very achievable. All we need to do to get, we've got 1,600, a little more than 1,600 patients today, an average net of 150 net patients per year over four years gets us to where we need to go in the United States. A little bit of improvement in our paid rate going from 81% at the end of last year to 85%. We continue to make progress year-over-year in this, modest price increases, and then contribution from our businesses in Japan, Canada, and the rest of the world.
This is a very achievable path to $1 billion. And then that sets up what we expect to be coming in a couple of weeks with the acquisition of Astria. We're really pleased with this deal. We were purchasing Astria for $700 million in total enterprise value. And it starts with a strategic fit. We have shown that we're really good at commercializing differentiated products in the HAE space. And this navenibart fits right into that strategy, right into our core area of expertise. Navenibart is a very differentiated product. It has the potential to be an every three- to six-month injectable dose. And when patients and doctors hear about that three- to six-month profile, they get excited. This is something that makes them think about switching from existing injectable products. And it's very simple for them to understand because kallikrein inhibition is a mechanism that they already know well.
So you put these two things together in one team. As ORLADEYO hits peak, we won't need to spend as much marketing dollars on ORLADEYO. But it's the exact same team that will be commercializing. So we don't need more people to commercialize navenibart. And so that just strengthens our cash flow position and sets up the opportunity to do more in the rare disease space. So what's the opportunity for these two products where you've got the only oral prophy product right now in ORLADEYO, and then you're adding in a differentiated injectable product? What we see is that the U.S. HAE population on prophylaxis has been growing steadily at about 3%-5% a year. And we expect that to continue as more patients are diagnosed and as more patients continue to move over to prophylaxis.
ORLADEYO has at least another two years where it is the only oral prophy product on the market. We'll continue to grow with ORLADEYO. Then as I explained, if the patients are already doing well on one pill once a day, why would they switch to anything else? From an injectable population, there's about 5,000 patients and growing who are on some type of injectable prophy. Navenibart comes in there with the most patient-friendly every three- to six-month dosing profile. The majority of the opportunity there is to switch patients from other prophys. Two very complementary prophylaxis products that meet the needs of the market.
We're going to do this with a team that has great rare disease commercialization experience, has been doing it in a very dedicated and differentiated way using a sole-source specialty pharmacy that allows us to generate evidence, evidence that we use to help our commercialization efforts on a day-to-day basis, and then evidence that helps us build more into the clinical literature and teaches physicians, in this case, about ORLADEYO, in the future about navenibart, and in the future about other products, perhaps like 17725. So as I said, navenibart is highly differentiated. Early proof of concept data from Phase Ib shows that it's got a very competitive efficacy profile, regardless of whether it's the three or the six-month dosing. Very importantly, it's a small injection. Three months will be a 2 mL injection. Every six months will be double that in auto injectors.
In the Phase Ib, no injection site pain, which is something that a lot of patients experience on the market leader today, lanadelumab. As I mentioned, you put these two together, we're addressing both segments of the market. There is growing preference for oral prophylaxis, and we're addressing that with ORLADEYO. In fact, we're building that preference. For those patients already doing well on an injectable, there's sometimes reluctance to switch to anything else unless the benefit is very clear to them. That's where we think that navenibart is going to step in and be a very clear you can go from every two weeks or every four weeks to every three months or every six months. That's going to be the value proposition without giving up any efficacy.
You put these two products together in one portfolio, and this is what it could look like. You've got ORLADEYO growing at mid-teens revenue CAGR through 2029 and hitting peak in 2029 as we do expect additional competition. But that's right when we'll have the first full year of navenibart revenue kicking in. So $1 billion late this decade, and then navenibart keeps us growing at double digits, mid-teens revenue into the 2030s. And all of this is on a very steady base of operating expense. So we expect our OPEX over this time to grow at about 4% or 5%, mid-single digits. And what do you get for that? You get the team that's commercializing both of these products. Again, we don't need to grow it because we have the expertise. We have enough sales reps. We have the marketers. We have the marketing dollars.
We just need to redeploy the focus between ORLADEYO and navenibart. You get the G&A function that supports all of this, and you get the finance team. You get the HR team, pharmacovigilance. All of that is built into this, and then you also get our R&D, and so drugs like 17725, the cost of developing that and taking it forward is included in this chart. What is not included is the potential revenue from something like 17725, and so that becomes upside, so we're going to be really disciplined on our operating expenses, growing revenue from HAE and beyond, and then it gives us the ability, with we see $1 billion in cash in 2029, to redeploy and look for other late-stage assets that our team can commercialize, so let's turn quickly to our pipeline.
The real thing to focus on here is BCX17725 for Netherton Syndrome. It's about to enter initial proof of concept trial in Netherton patients. We have other undisclosed targets that we're excited about, and we hope to bring forward in the future. Right now, let's focus on 17725. Netherton Syndrome is a really horrible disease. You can see from the picture of the kid on this page; it's a genetic disorder that causes uncontrolled skin turnover. Not only does that obviously affect the skin, but for patients, this leads to increased infections, increase of atopic conditions, asthma, food allergies. What we hear from patients is patients with Netherton spend their whole day thinking about how they're going to deal with this disease. There are no approved therapies for this condition right now.
We've done initial work showing that there are about 1,600 patients looking in claims data in the U.S. I'll tell you about some additional work that we're doing that suggests it could be even larger. So it's a classic rare disease, no treatments available right now. And our therapy is going to be replacing the missing protein and controlling KLK5 that is the uncontrolled bad actor in this case. And we have the potential to be the first targeted therapy and the first systemic targeted therapy. So as I'm sure everyone's familiar, in rare disease, you often see this where the prevalence, the incidence goes up once there are therapies. And it makes sense because doctors don't tend to look for things that they can't treat. And we think we've seen this in HAE.
We have people on our team who launched CINRYZE back in the day, and they thought there were 2,000 or 3,000 HAE patients. Now we know there are over 10,000 in the U.S. We think the same thing will happen in Netherton's. We're in the middle of doing a lot of really deep analytical work. That's a part of our commercial strategy and success. We're doing that work in Netherton's. We're using natural language processing models right now, digging into EMR data. It's suggesting that the population could be 3,000+ in the U.S. alone for this high need disease. More to come on that, but we're excited about the opportunity. 17725 inhibits KLK5, which, again, because of the natural genetic defect, the control of KLK5 is what's missing.
That is at the top of a cascade of proteases and ultimately cytokines that cause the skin to turnover, cause patients to have itch, cause redness, and many other problems. We believe that inhibiting KLK5 really significantly, and that's what 17725 does, can control this cascade and has the potential to restore normal skin turnover and everything downstream from there. So where are we in this program right now? We're through healthy volunteers. And our healthy volunteer work showed two important things. Number one, this drug appears to be safe in multi-doses. So that's super important. And then number two, you can see from this slide, the drug is getting to the epidermis. That's where it needs to go. So you look at the right side here, we used a phosphorescence tag on the antibody.
You can see not only does 17725 flood the dermis, which is great, but it gets into that outer layer, which is the epidermis. That's where KLK5 acts. That's where the drug needs to be. So this doesn't prove everything, but it was an important de-risking of the program. And we'll see how the drug behaves in patients. So we're done. We've got a Phase I study that studied healthy volunteers and now is moving into patients. We're finished with the healthy volunteers. We're moving into both parts three and four of this. Part three is expected to be one to three patients, and it's a one-month dosing period, three doses over one month. And then part four is dosing for three months every two weeks in up to a dozen patients. That's what you really want to focus on.
We are highly confident by the end of this year, we will have up to about a dozen patients who have gone through three months with follow-up. And we'll be looking to see not only the safety and exposure, is it getting to the skin, but importantly, is it changing the clinical picture? Is it improving skin turnover? Is itch going away for patients? And that's the information we're looking for to design our Phase III program, go to the regulators next year, and begin a pivotal study for this high need disease. So upcoming milestones, key milestones in about two weeks from today, we should be through the Astria acquisition. All that remains is a shareholder vote from the Astria shareholders. Then by the end of next year, and it could be sooner depending on the size of effect that we see, 17725 proof of concept in Netherton's.
And then early next year, Netherton's top line, sorry, navenibart top line result for HAE, which is obviously a critical stage towards moving towards filing and approval. This is on top of quarterly revenue growth in both ages 12 and up and the pediatric indication and more and more cash generation for the company. So again, I'm excited for what we have going on at BioCryst right now. It's going to be a big year, and we have a lot of opportunity in front of us. So with that, I will turn it over to Jess.
Great. Thank you. And as a reminder, if you have a question in the room, just raise your hand. And if you have a question on the webcast, you can send me them on the iPad here. So great. So we've had some competitive entrants in HAE prophylaxis recently.
Can you just expand a little bit on how you've seen that landscape evolve over the past year, just kind of what you're seeing with the new entrants?
Sure. Yes. HAE for a rare disease is very competitive. I think there's 10 or 11 products approved right now, which is fantastic for patients. The most recent approvals have been an oral acute therapy and then two injectable prophy therapies. And so as I was describing, we have the most differentiated prophy therapy as the only oral prophy on the market. And for many patients, that's what they're looking for. And so that's a segment that we really own. Overall, the market keeps going more and more towards preventing attacks with prophylaxis, which is the right thing to do. So it's probably around 80% of patients in the U.S. are on prophylaxis. And we see that continuing to grow. And then having the opportunity to treat the occasional breakthrough attack with an oral acute therapy is a great opportunity for patients.
We see that as a potential benefit for patients. If they can be on ORLADEYO plus an oral acute, it's great. But the oral, or sorry, the injectable prophy products moving from every two weeks to once a month is a nice to have for patients, but it's not changing the trajectory for ORLADEYO because of our differentiation. We've seen all through 2025, even as new products came on, continued strong demand for ORLADEYO.
With the European ORLADEYO rights divested, can you also just talk through in a little more detail how ORLADEYO still gets to a billion peak sales without that region? How much of that growth is coming from market expansion versus market share?
Sure. Sure. Several years ago, we announced that we saw ORLADEYO getting to $1 billion. That was with a 12 and up indication, as Jess was suggesting. That also included our European business. So when we sold off our European business, we looked at our current U.S. business. We also looked at the upcoming opportunity in treating kids down to age two. And based on the pace of growth in the U.S., the addition of the pediatric population, which is both underdiagnosed and undertreated from a prophylaxis standpoint, and then modest growth from other regions, we see ourselves still getting to $1 billion because of that product differentiation. Capsules for 12 and up, oral pellets for kids in a market where they only have injectable opportunities right now. You put all that together.
So we'll get most of that $1 billion in the U.S. and then contributions from Japan, Canada, and other regions.
How do you think you want to develop avoralstat in the coming years, in the coming months or something?
Can you repeat that?
Yes. The question was about avoralstat, which is I didn't mention this, but it's on our pipeline slide, which is avoralstat is being developed for diabetic macular edema. We're in the middle of a Phase I proof of concept study in DME patients. And we decided in the second half of last year to finish this Phase I study, but this is not a rare disease. So this is not core to our strategy. So what we're going to do is finish that program, and we're going to be looking for partners to spin it out, to out-license it. We think that having a kallikrein inhibitor dosed via suprachoroidal injection, so it's at the back of the eye, has the potential to be there for many months to inhibit kallikrein, is a great opportunity for patients. But we're going to finish that Phase I, see what we have.
We're making good progress on it, and then see if we can out-license that this year.
So for the ORLADEYO business, you've talked about that by 2029, when you reach steady state, the franchise just might not require the same level of resourcing. So how should investors think about the SG&A associated with ORLADEYO as it matures? And how should we think about kind of terminal operating margins for that franchise?
Sure. Maybe I'll start, and then Babar can add some comments to that, which is we have a small sales force. We have 40 rare disease specialists covering the market, and we think they cover the HAE space better than any other team. They are super excited about launching navenibart, and they can do ORLADEYO and navenibart at the same time. As ORLADEYO reaches peak, the markets can be very familiar with it. We don't need to spend as much promoting that. And so maybe that takes a second position to navenibart. We devote more of our efforts to navenibart, our marketing dollars to navenibart. So basically, same pool of money, same great team, just shifting the priorities around. So very similar OpEx. Babar, is there anything you want to add to that?
Yeah. And I think we disclosed this in our quarterly reports that at this point in time, we are not spending more dollars to buy revenues. The only expansion that you see in our S&M expense is primarily, let's say you're selling more, you're going to pay the specialty pharmacy fees more. So at this point in time, I think the expense structure for the base business is steady state. But even further, I think the overall business is reaching a point of equilibrium in the sense that as programs advance, or basically we are also very disciplined in terms of cutting programs that do not make the mark, we expect that the R&D expenses to remain fairly standard and going forward as well.
And then I guess just bigger picture, you've laid out very detailed long-term projections. What's the rationale behind kind of why you're providing such kind of specific long-term guidance for folks?
Let me start with the revenue, and then we can talk about the OpEx too, so we have launched to date, a big part of our success has been our ability to do deep market research and really predict what patients and doctors want, and we do very detailed models that predict the future in this space. It's been very predictive of where ORLADEYO has gone launch to date. Basically, five, six years ago, we predicted where we are, where we were in 2025. We're doing the same thing for navenibart, so we want to help investors see what we see from that standpoint.
Then from the operating expense, we really want to show how disciplined we are around our capital allocation right now and how we're balancing between those three priorities of driving the commercial growth, devoting what we should devote, but not going overboard on the internal R&D, and then allowing for cash generation for business development as the opportunities come up.
So then maybe related to kind of the R&D outlook, if the navenibart Phase III is going to be kind of ongoing in 2026 and wrapping up with data in 2027, what's the right way to think about kind of the near medium-term R&D trajectory?
You want to handle that one, Babar?
Yeah. So I think on the navenibart side, there's going to be an incredible amount of synergies from the Astria acquisition since we are not going to have the G&A overhead. So we are guiding to this morning that upon closing of the transaction, we'll have about $70-$80 million of additional burn. But that will essentially go down because that trial is in its Phase III enrollment. So we're doing the enrollment, we're preparing for pivotal CMC activities. So going forward, that expense will come down. But naturally, if 17725 is successful, then essentially we'll see some pivotal trial. But having said that, and this goes back to the point in terms of strategy, any rare disease trial that you're looking at, you're not looking at several hundred million dollars of expense.
Year on year, you'll see some expenses go up, others go down as trials complete. We're not looking at several hundred million dollars of R&D expense by nature of our business in terms of focus on rare diseases.
So you talked about the Netherton trial and I think talked about part four data by the end of 2026. What about part three? Do we get that kind of in between or?
So I'll start on that, then Bill can add some color. Both part three and part four are open label. Part three is only three doses over a month. Part four is six doses over three months and then follow-up. And the other key thing here is that part three is not a gate to part four. It's really about when the sites have the IRBs approved to go into part four. And so some patients will go straight into part four, and we may just have a couple of patients in part three. So what we're looking for is when the outcomes in patients are really significant, when we see clear signs of clinical improvement that allow us to declare that we have a drug that can move on to a Phase III pivotal trial. Bill, anything else to add?
Sure. What matters for us is seeing a big treatment effect in enough patients to give us the confidence to invest in a pivotal study. So 12 weeks of opportunity of dosing and with follow-up gives us more of an opportunity to see that. We're measuring, as you would expect, symptoms of pain, itch, redness, well-being, general health. And if the drug gets into the skin in sufficient quantity, I'm confident it'll work. We've got the right target. So very exciting program. Can't wait to see the data. But you should focus on having sufficient numbers of patients through 12 weeks of dosing to give a realistic estimate of treatment effect size.
And the one thing I'd add is we're seeing a lot of enthusiasm from there are not that many KOLs yet who focus on this disease, but the global KOLs, the U.S., Europe, Australia who see this disease are very enthusiastic about the profile of this product and of helping us complete this trial.
And you talked about a big treatment effect, and then you kind of outlined a number of clinical metrics. So have we moved beyond looking at biomarkers now that we're in patients?
This disease pathology starts in the epidermis. So there isn't really a plasma biomarker of use for estimating pharmacodynamic effect like there would be in a disease like HAE where you could use kallikrein inhibition as a tool. So this area lacks that. So we really have to focus on clinical outcomes. So it's all about the clinical outcomes here.
And then is the idea that you would go straight into some kind of pivotal study, or is there kind of like a Phase II step in between?
The ideal progression here is to see dramatic improvement in the skin and go straight into a pivotal. And given that there are no approved therapies, we're anticipating regulatory engagement both with the FDA and with international regulators to enable that to happen once we have the data from this study.
Can you give us a bit of a framework, maybe some epidemiology stats on just how to think about the opportunity in Netherton syndrome?
Sure. The first caution I would say is don't just look at the literature because like any really rare disease at this stage in the game, you look at the literature, you'll see numbers of case reports. And so what we've been doing is going deeper than that. There's no ICD-10 code for this disease. So we've done some work a year or so ago looking at mentions of bamboo hair in claims data. Bamboo hair is a feature that kind of is what it sounds like. You look at hair, particularly under a microscope, it looks like bamboo that is distinct to Netherton patients. And we found about 1,600 U.S. patients with mentions of bamboo hair. But we weren't satisfied with just that. So we're going deeper. As I mentioned, we're looking at EMR.
We're using NLM technology to look at EMR data, to look at other features of the disease, other diagnosis patterns, and we think that this is now likely a 3,000 patient plus market. At some point in the future, there'll probably be an ICD-10 code, but right now, it's really critical for us to do everything we can to determine the size, understand the size of this market, and we think it's a lot bigger than what you'll see in the literature.
And it sounds like highly symptomatic. So is this like a difficult diagnosis? Are these patients, I would think they would be kind of well identified? How do we kind of reconcile that with the idea that they may be underdiagnosed?
The simple story is what I said earlier, which is doctors don't look for things that they can't solve. And there's no diagnosis code, so they can't peg it there. Netherton syndrome is particularly acute and life-threatening for kids, for infants, because at young ages, children's skin turns over a lot faster, and kids are growing and maintaining a skin barrier is even that much more important. So it can lead to more diagnosis there, but some of these kids are missed. Then as patients get older, it becomes more of the chronic stage, which is still a really difficult disease. And as I mentioned, patients spend their whole day operating around this disease. They typically apply creams, over-the-counter creams across their whole body multiple times a day. They have other special things that they learn to deal with.
But what we hear from patients is because their doctors have nothing to offer them, they get frustrated and they stop going to ask anymore. So they kind of disappear into the woodwork of the healthcare system. And we think that having a targeted therapy is going to help them come back out. And we've seen this. We heard this story in HAE where patients would get misdiagnosed. They kind of bumble along on their own for the years. But now that there's therapy, they're with good doctors who know what they're doing, and it's completely changed in the last 15, 20 years.
Coming back around to avoralstat for DME, now that that's kind of in the bucket of kind of potential licensing opportunity, should we expect to hear about the initial data or only kind of when a deal materializes?
Most likely when a deal materializes. Let me tell you where we are right now. In the Phase I study, we've got three cohorts. We've completed the first cohort at a 100-microgram dose. That was by design. It's really a safety dose. So we did not expect to see much efficacy from that. The next cohort goes to 250 micrograms, and the third cohort goes to 500 micrograms. We just opened the IND in the U.S., so we're starting to enroll U.S. studies. Previously, it was just in Australia. And so we're confident that towards the middle of this year, we'll have a lot more data there. But you're likely to see the data more when we announce a deal.
So we're about out of time, so we'll leave it there. Thank you.
Great. Thanks, Jess.