The biotech team, and I'm here with my colleague, Visha . We're really happy to be hosting BioCryst today. With us today, we have Charlie Gayer, CEO.
Sorry.
Babar Ghias, CFO, Nick Wilder, head of IR. Now that we're in the sixth year of launch, maybe just start with some opening remarks on the recent earnings performance.
Sure. Thanks, Stacy, and great to be here again. Before I start, I will be making forward-looking statements. Those statements have risks. You can learn about them on our website. For those who have looked at BioCryst before, you may have in the past, and we've been around for a while, this is a new BioCryst. Last year, we hit $601 million in revenue with ORLADEYO, $563 million after you exclude the fact that we sold our European business in October. We had $214 million in non-GAAP operating profits. We're a profitable company and growing, and we just completed the acquisition of Astria Therapeutics, which brings a late-stage asset to our portfolio in navenibart. Very different companies set up really well for the future.
Okay. By the way, last but not least, [Anurag Mehta]. Can't miss you. Sorry. Let's get into the launch dynamics. Before we dig in, obviously, you gave us a nice broad overview, of what we view as a very impressive launch for ORLADEYO. We did notice during your earnings call, you made this comment on ORLADEYO super-responders, which again does mirror some of the KOL feedback that we hear from folks. Maybe help us understand, now that we're a couple years, more than a couple years into the launch, something that continues to get underappreciated in our investor conversations, how is the team communicating this dynamic for super-responders when it comes to grabbing patient share?
We use the term super-responders, like you said. That was a new term, but it's not a new concept for ORLADEYO. This is something that we've been communicating to physicians for many years now. Once we had the two-year data from our clinical trial, and we started promoting on that back, you know, in the second year of the launch, what that two-year data showed is, of people who started on ORLADEYO in the clinical trial, just over 50% of them made it to two years, and that 50% had a 91% reduction in attacks versus baseline. The whole point is ORLADEYO is a great drug for many people.
It's not just a pill, it's not just convenient, but patients either get great efficacy and then they stay on, or they don't, and they move off. In the real world, what we see is that 60% of patients who try make it to a year, and then most of them stay on after that. We just wanna show that there is this population that responds really well, otherwise they move on to another drug.
They're essentially getting injectable-like efficacy.
Exactly.
Again, as we think about 2026, still really early days, but we get a lot of questions around your guidance range, and how we should all be thinking about grabbing patient share. How you all will be grabbing patient share. Maybe help us understand the different dynamics. We get questions on the impact of other injectables coming to the market, maybe potentially growing the market, but maybe leading to some other additional churn. Just help us understand what you're seeing there as it relates to the current, let's say, new changes to the prophylactic marketplace.
Yeah. What we're seeing is what we've seen over the last many years, which is ORLADEYO is still the most differentiated product on the market 'cause it's the only oral prophy on the market today. That's something that a lot of patients really want. Launch to date, and this continues to be true, close to half the patients who start ORLADEYO are switching from an injectable prophy because they'd prefer to do it with an oral option. Then the other half is coming new to prophy. Some are newly diagnosed patients, some are switching from acute only. That is what we expected to continue even with the launches of new injectables because of the differentiation of ORLADEYO, and that's what we're seeing.
Okay. We're going kinda big picture first and then getting into some, maybe some of the more narrow dynamics, as we think about this year. You've talked in the past, recently updated the 200 patient adds per year to 150. One dynamic we've seen in the last few years has been continued, new prescribers that have also kind of driven this patient growth. How do we think about that? Obviously not sustainable, what kind of dynamics are you seeing on both sides?
Yeah. It's really interesting. Through the end of five years, we're still seeing a lot of new prescribers coming on board with ORLADEYO. One of the reasons for that is I always say that you know, the majority of HAE treaters are allergist immunologists, but actually the majority of allergist immunologists don't treat HAE.
I was at the AAA AI conference, I'll give you an example of this, AAA AI conference this past weekend, and I was talking with a big KOL in the HAE space, and she said, "You know, so there's an Allergy Partners practice nearby, and those doctors are actually starting to keep their HAE patients right now because they're realizing it's not that complicated with the options that they have available." The number of prescribers is expanding and the work that we do in data analytics has been one of our secrets to our success in the launch of ORLADEYO. We have a lot of tools that we use to find potential prescribers out there, and then our field team goes and gets them. And we think that's really been a competitive advantage for us.
Are you seeing with the new prescribers, more coming more from the community side of things? Were they seeing one or two HAE patients? Is that part of the dynamic when it comes to now a fairly mature launch, but really continued clinician adds?
That's exactly right. It is much more the community allergists. We finished last year over 1,500 prescribers of ORLADEYO, and that number is still growing. It's not coming from the academic centers in terms of the number of prescribers. It's coming from out there in the field. We're getting deeper penetration on both within the academic centers and the community.
Okay. One question we also get, is the pediatric launch, which you all had the approval in December and should slowly come on board. What are the current offerings as it relates to some of these young HAE patients, and what kind of early dynamics to the extent that you can comment.
Yep.
You're seeing?
Sure. The current offerings for kids and what we believe about the pediatric population is HAE is number one, is probably 50% underdiagnosed. There are 500 kids. There should be more like 1,100-1,200 kids diagnosed based on the epidemiology. Then it's undertreated. Of those 500, only 40% are treated with prophy. Their options before ORLADEYO were C1 inhibitor down to age six, and then a year or so ago, Takhzyro got the indication for ages two and up. I'll give you another example from a doctor told me this weekend.
He said, "I actually just realized that lanadelumab Takhzyro shots hurt," the reason he should have realized that before, but the reason he realized that is because parents were coming and saying, "My kid's doing well on Takhzyro, but I have to chase them around the house once a month to do the injection." Now to have ORLADEYO pellets available for kids age two and up, it's gonna be a real advance. A lot of excitement. We just formally launched at AAA AI, with, you know, all of the community there, and we'll have product in our pharmacy by about the end of this month, early April, so we're starting to take prescriptions now and there's a lot of excitement.
Okay. Would you expect the adoption in pediatrics to be more of a steady trajectory? Help us understand your views as it relates to the value propositions you just outlined.
What we are forecasting for 2026 is relatively conservative because while there's all the excitement, there's the value proposition I just described, we don't know exactly how fast the parents will bring their kids in, how fast, you know, we've got to get the physicians aware of this, all of that. For the moment, we're being conservative, and then as the prescriptions start to come, you know, we can see if any of that changes. Long term, though, this is a meaningful value driver for ORLADEYO.
Okay. remind us, is this the same prescriber base as adult HAE, or should we be thinking about a new segment that you all have to go after?
No, it's really the same prescriber base. Our team has done a lot of the profiling leading up to the launch. We've got all the analytics, so we don't need any more people in the field. It's the same customers.
Okay. Any peer dynamics we should be thinking about as well?
This is one of the neat things, which is ORLADEYO pellets will slot right into all of our existing contracts, it'll be treated as ORLADEYO, so there's no medical exception or anything else. We do plan to launch the product at flat pricing to ORLADEYO capsules. One dose is one dose of ORLADEYO no matter what.
We're obviously going in the order of different investor questions and controversies.
Yeah.
And one that we do get, is the view that 26 guidance does seem to be somewhat conservative, especially for the U.S. growth that we've seen historically. Just, obviously cannot be carried forward, but just help us understand what are the different factors you all are thinking about. Remind us potentially how we should be thinking about the seasonality for Q1 as well.
Sure. The first thing is what I said up front, which is we sold our European business on October 1st, and that was, you know, roughly $50 million of annualized revenue. The thing that you gotta compare 2026 to is $563 million from last year, stripping everything out. The midpoint of our guidance, $625 million-$645 million, is about a 13% growth over last year. Are we being conservative? We call it like we see it at the beginning of the year. The other thing we don't have compared to last year is last year we had a really big tailwind on the payer side in the Medicare space. As the Inflation Reduction Act rolled in, it made ORLADEYO and other drugs affordable from a co-payment perspective for patients.
Our paid rate in Medicare, which is 20% of our patients, went from about 50% to close to 90% kind of overnight. We don't have that this year. This year it's more steady patient growth and then chipping away, at the paid rate.
Okay. Babar Ghias and his team put together a very clear historical breakdown of ORLADEYO sales for the U.S., E.U., and rest of world. As we look forward, are you willing to give us some guidance around the rough split for U.S., ex-U.S., or rest of world specifically?
In past years, because of the successful growth in Europe ex- U.S. was about 10-12% of revenue in any given quarter in kind of recent quarters. You strip out Europe, though, Europe was the big chunk of it. Now U.S. is way over 90% of our revenue. Still growing in Canada, Japan, and some of our distributor markets, and that still contributes to our view of a billion dollars in 2029, U.S. is really where it's at now.
Okay. Clearly the paid rate you've all really executed on in the last few years, but just remind us what does that represent in terms of sales? For every 1% that's converted, what does that mean for your bottom line?
Yeah. If you look out to what we think ORLADEYO will look like in 2029, we ended last year with just over 1,600 patients on therapy. We expect to have about 2,200 at the end of 2029. Each 1% there of those patients in 2029 is gonna be worth about $12 million in annualized revenue. That improvement from 81% to 85%, roughly $50 million in annualized revenue. Of course, we'll try to do better than that if we can, but that, hopefully, that puts it in perspective.
Yeah. Incredibly helpful. We've talked about this in the beginning, with the super-responders for ORLADEYO, and we'll talk about it again, because again, this is something that we do think is very much underappreciated. For this retention rate, you've talked about the five-year, 50%. You've exited the year about a 1,600 patients in the U.S., obviously 3,500 then tried since launch. Just help us understand what's underappreciated about this metric, especially as it relates to the Pharvaris data that were expected in Q3 and that type of overhang that we get from investors.
I think what's underappreciated about it is patients could care less what a reduction in attacks is versus placebo. That's not how they measure their lives. They care about me. You know, what is it? You know, how am I doing? They care about the type of administration that they wanna have. So for patients who want oral prophylaxis, take one pill once a day, if you get down to a very low rate of attacks, and by the way, this is important too, the attacks that patients have on ORLADEYO or any other prophy for that matter, tend to be less severe. Sometimes they don't even need to be treated with a rescue medicine. If you're having infrequent mild attacks, you're very low burden of treatment, patients aren't looking for something else.
These patients that are in that, these super responders, we believe they're gonna be very sticky going forward. They're not gonna be looking for what's next. The, you know, 2,000 plus patients over time who've tried ORLADEYO and moved because they weren't super responders, they might look for another oral, but the patients doing well long term on ORLADEYO won't be, in our view.
Is there anything else as we think about kind of the upcoming data, any additional nuance that we should be thinking about?
I think the other nuance for the Pharvaris data is, we think it's a good drug. We anticipate it's gonna be a good drug. That's how we build it into our future forecasts. In their phase 2, the placebo patients actually got worse, and that's never happened in a phase 3 trial for prophy in this space. Placebo patients, there's always a strong placebo patient response, around 20% in most studies. The number could look different even if the drug performs just as well. Again, we think it's a good drug, it's gonna reach the market, and we build that into our future views.
Of course, the 50% of the patients that have tried ORLADEYO found out it's not working for them, that's.
That's a great option.
That's a great option.
That's a great option.
For Pharvaris. Okay.
We may have another great option too, which I'm sure we'll talk about.
We are speeding through ORLADEYO because we wanna make sure we have enough time to talk about navenibart. We obviously share your enthusiasm with the acquisition of Astria. Just help us understand, what do you think is, at this point, underappreciated about the asset, especially as we think about, get a lot of questions here, the three-month and the six-month, administration times and the importance of really both. Just help us understand from you all why you're so excited.
Yeah. First of all, we bought Astria obviously because of navenibart, but we didn't want navenibart to replace ORLADEYO. Everything I just described about ORLADEYO, we think that's a very durable patient base. It's gonna continue to grow. We're gonna have the pediatric indication by ourselves for a long period of time. That's one big segment of the market. The other big segment of the market is 5,000 plus patients who are doing great on an injectable prophylaxis therapy, usually every two weeks or every four weeks today. navenibart is gonna give those patients the opportunity to continue to have the same great efficacy, but to inject just two or four times a year in a very easy autoinjector, it doesn't hurt. There's zero incidence of injection site pain, which is actually a good differentiator versus the market leader.
We presented some data at AAA AI showing exactly what we expected, which is really durable response at both doses. The patients in the phase 1b/2 who've all been out to about 12 months on average now, three-month dosing had a 92% reduction versus their baseline, and the six-month dosing had a 90% reduction. What we think this profile is gonna be, you can kinda get the same efficacy and dose it the way you want, either one injection every three months or two injections every six months. When patients and doctors see this profile, they say, "Okay, it's a kallikrein inhibitor, monoclonal antibody. I get that. I'm very familiar with that," and this dosing profile is very exciting. It's what's known with a big advance, and we think that will lead to a lot of these injectable prophy patients to switch over when that, when that product launches.
Of course, you need to de-risk as a phase 2 asset, just given the fact they've shown repeat dosing in their open-label.
I mean, this is.
Yeah.
That's the other appealing thing about this acquisition for us is as de-risked as you can possibly have for a phase 3 asset. The only risk now is just execution, and we feel like the Astria team was doing a great job, and we're picking that up and continuing right from where they left off.
Maybe talk about the phase 3 potential for data disclosures, timing, help us understand that dynamic in 27.
The real key near term timing thing is when do we enroll the last patient in the pivotal study, because that's when you can really start the clock, and it's getting close. It'll be sometime around the middle of this year. Call it the middle of this year, then it's six months from then until the last patient reaches six months, and six months from that point until they reach 12 months. The 12-month endpoint is really important because, number 1, the FDA always wants to see 12 months of safety data on a 100+ patients. This is gonna be there'll be 135 adults in this study, so that's covered.
The other thing is it's a six-month dosing is one of the arms, that 12-month is important as well. That puts us in position to file with the FDA by the end of next year. We haven't decided yet what we're gonna announce and when in 2027, but the real key is getting the full enrollment this year, because then the clock to filing will be very clear.
Okay. One interesting aspect, for their phase 3 open-label extension trial is they're allowing to interrogate the patient preferences. Do you wanna talk about that unique design as well?
Yeah. I think what's really gonna be important about the design of the trial, but ultimately it's gonna be in the label. The important thing is to be able to show that you have a three-month dosing and a six-month, like I said earlier, that have very comparable efficacy. The drug that a patient gets in a year is gonna be the same. What we're hearing from patients and physicians is there are different preferences depending on, you know, how they wanna manage their lives. They're gonna have options, and they're very clear, like, this is not gonna be complicated for us.
Okay. We also get some questions on the competitive landscape for navenibart. Clearly when you thought about doing the acquisition, I'm sure you also did some work in the private space. Just help us understand in general what your view is there. We'll give you ours first before we ask, which is obviously BioCryst has a presence in HAE, with a lot of, I would say, patient loyalty. Just help understand how that's gonna help.
Yeah. I think that's a very important point that, you know, we feel like we can launch whatever product we happen to pick up, we could launch it very successfully. The things that we did assess other options, the reason we number 1, why we chose navenibart is what I mentioned earlier, which is it's a very known mechanism, and so the built-in idea of like, "Hey, this is gonna work. It's what I know. It's gonna be safe," that's really important to patients and doctors. It comes with that halo up front. Very importantly is execution. Where were the relative companies on the clinical trial pathway? We just saw that Astria was doing all the right things. They were well ahead. Launching the first product with up to six-month dosing is really important, and then doing it within the BioCryst portfolio, we think gives us a great advantage.
We hear from folks that the HAE landscape is crowded, but what we've grown to appreciate in the last few years is the number of patients that are really coming out of the woodwork. Just remind us the epi work you all have done. How much conviction do you have in the 1,100 patients? Just remind us all the different metrics around the diagnosis, treatment, prophylaxis rate.
Yeah. Going back to before we launched ORLADEYO, we've done a lot of deep work on claims data, looking at the epi, because obviously we knew that was gonna dictate a lot of what our opportunity was, and then we've done it repeatedly over time. We've seen the number of diagnosed patients in the HAE space growing about 3% a year. As Stacy, as you said, there are patients still coming out of the woodwork, both type one and two patients, the classic HAE, but also HAE with normal C1 inhibitor, which has been a big growth area for us. It's about a third of the patients on ORLADEYO, and we've been generating data showing how well those patients are responding. They're super responders there as well. That's been a big part of our growth.
We're confident that that 1,100 is gonna keep growing. Of the 1,100, about 8,500-9,000 are treated with an HAE specific therapy, and then sort of 7,500 or so are on Prophy. Each of these categories is growing on an annual basis, and we don't see that stopping.
A huge swing factor, for a lot of the HAE models. Okay. Just remind us the durability you all have when it comes to ORLADEYO, when it comes to navenibart, especially as we think about the work that investors are doing right now to try to really find a valuation floor for you all. Just help us understand that piece.
Yeah. We talked about the kind of the clinical durability, very stable ORLADEYO super-responder population, navenibart showing that it works just about for everyone. And these are gonna be two big segments of the market, not cannibalizing each other. Then our patent protection on both is fantastic. ORLADEYO, May of 2040, composition of matter, long runway there. Then even longer runway for navenibart, which is out to 2042 with composition of matter. What we're talking about is a portfolio that we see growing at mid-teens in revenue well into the 2030s, and then generating a lot of consistent cash, all with the same team because we do not need new sales reps, we don't need new marketers, et cetera, to launch navenibart. It's gonna be the same team launching both.
The operating leverage of that is phenomenal, and it's gonna give us a lot of other opportunities in the rare disease space as a company.
I know, in the past you've talked about your really broad pipeline behind the scenes, and we're obviously very keen to get an update at some point. We won't pin you on it. You do have yeah, your KLK5 inhibitor for Netherton's, and sounds like we're gonna have results by year-end or maybe potentially earlier. Just remind us what you've seen in the phase 1 SAD/MAD study that's given you conviction to move forward. We do get some questions around your decision to kind of parallel track some of the 12-week studies so that we could have a more fulsome update.
Sure. We put together a phase 1 study that started with healthy volunteers and then moves on to parts 3 and 4 in Netherton patients. We've completed 1 and 2, the SAD/MAD, and we found two important things in healthy volunteers. Number 1, what you would hope, it's safe, as best as you can measure in a MAD setting. We feel very good about that. Very importantly, we showed that the drug gets to the epidermis in healthy volunteers, which we actually didn't expect completely. It's something that has given the KOLs in this space a lot of excitement because KLK5 acts in the epidermis, so the drug has got to get there. The experts believe a systemic therapy is the way to go if you can deliver to the epidermis.
That was good. Then we've got part 3 of the study, which is dosing for a month. The reason we put the part 3 is when we started the study, we didn't have the nonclinical toxicology to dose for longer. Now we do. Part 3 is gonna be interesting, but we don't expect to solve whether or not we have a drug. Only expect a patient or two from the part 3. What's really important is part 4, which is gonna be up to 12 patients dosed every two weeks for three months. We're highly confident we'll have that information by the end of the year because of what we're hearing from the investigators, the sites that are enrolled, the sites that are about to enroll.
We've got sites opening up in Europe soon, and so we have high confidence we'll get to those 12 patients. We'll be looking to see if we have a drug and planning for a pivotal study.
As you're doing all of this really heavy legwork around enrollment, just are you finding the size of the market, getting an idea of the size of the market and opportunity? I know you've talked about the 1,600 claims analysis, and your view is that it could grow. Just help us understand that piece as well.
Yeah. The, the TAM on this is critical, obviously. Right now it looks like a very rare disease, but we've looked in claims. We've actually done another study using LLM models at this point where we think we've found 3,000 plus patients. There's no ICD-10 code, so this is a trick. We think that these patients are underdiagnosed because there's no treatment, and we hear from patients they stop asking their doctors. As soon as there's a treatment out there, though, we know from HAE, we know from all sorts of other rare diseases, the patients do come out of the woodwork because doctors have something to offer them. We're doing that work. If we discover that we have by the end of this year, everything looks good, we've got a drug, we'll turn on more of the market building and finding activities to get us ready for launch.
Wonderful. Well, we've always gotten a lot of inbounds on you all, but we are getting increased calls as we do believe it's trading close to a valuation floor. Our view is that others believe that as well. That suggests a very interesting setup as we get to the Pharvaris data in Q3, the Netherton's data potentially by year-end, and of course, navenibart in 2027. Again, the stickiness of ORLADEYO continues to be very much underappreciated. Looking forward to seeing the progress.
Thanks, Stacy.
Thank you. Thanks for listening in.