Hello, I'm James Stamos. I don't think the micro's working. There we go. Yeah, it's good. Hello everyone. I'm James D. Stamos, representing Maury Raycroft, one of the biotech analysts here at Jefferies. I'm happy to introduce and welcome Charlie Gayer, CEO of BioCryst. This is a fireside chat format. Thank you for joining us today. Thanks for having us. For those new to the story, can you please provide a one-minute introduction to BioCryst? Yeah. BioCryst is a company that focuses on rare disease commercialization. We've got a product, ORLADEYO, in the market for HAE, a prophylactic therapy, that did $602 million in revenue last year. That's partly because of the product itself. It's a differentiated product. It's the only oral prophy drug in its space. It's also just how we do the commercialization. We think we have a differentiated way of doing it, very patient-focused. It shows up in the results in the market. We also have a late-stage asset also in HAE with navenibart, which has the potential to be a best-in-class HAE prophy therapy itself, as in every three and six-month dosing profile. That is in phase III trials right now, getting ready for BLA filing at the end of 2027. We have an early-stage rare disease molecule in our pipeline for Netherton syndrome, BCX17725. Great, thanks for that. Let's just start off with ORLADEYO. You maintain the full year revenue guidance of $625 million-$645 million for ORLADEYO. 1Q came in at the lower end of $148.3 million due to typical insurance dynamics, what are you seeing in 2Q so far that gives you confidence in achieving the midpoint for the full year? Q1 was right in line with our expectations. ORLADEYO's in the sixth year on the market right now, and we're at a stage where it's all about consistent new patient demand, and we saw that in the first part of this year. We're in year six, and we're seeing last year we actually had more new starts than we had in the first year of the launch. That's going well, and then it's about helping patients get reimbursed. We finished last year at 82% of our patients are getting reimbursed. Every year we're making progress on that. That was a lot of what we were focused on in Q1. Basically everything's going according to expectations. Any comments on likelihood of having to adjust guidance for 2Q, and what reasons for that could be? No, like I said, we're right in line with where we expect to be, and we're on a longer-term path of growth for ORLADEYO, and eventually have a whole portfolio here of HAE products that in the 2030s could be in the $1.5 billion-$2 billion range. We're on track. You've maintained the $1 billion peak sales guidance for ORLADEYO, which includes pediatric sales and excludes EU sales. With the HAE landscape evolving, what are some of the key assumptions to support the $1 billion peak sales estimate? Yeah, for us to get there, we need to average about 150 net new patients in the U.S. per year. Over the last several years, we've been above 200 patients. As you mentioned, we're adding the pediatric indication. Kids age two to under 12 have never had access to an oral prophy therapy before. It's a market that we think can grow in terms of diagnosis, in terms of patients switching to oral prophy, and frankly, using more prophylaxis in that population. That's not the biggest driver of our growth, but it is an important driver in the next few years. What's your latest view on the total addressable market for the oral prophy opportunity, and how much market expansion is driven by newly diagnosed patients or newly treated patients versus market shift from competitors driving growth? What we see in the HAE market is, for a rare disease, the patients are blessed with a lot of treatment options. There are 10 branded products in the market right now. Where things have moved is there's a segment of patients who really prefer oral prophylaxis, and then there are patients who've been on injectable prophylaxis for a long time, and that's the right thing for them. For ORLADEYO launch to date, a little less than half the patients have come from switches from injectable prophy, they would prefer to do it with oral, and the other, just over half, has come from new patient starts and patients stepping up to prophylaxis from treating their attacks on demand only. Gross to net has historically tracked in the 15%-20% range. Do you foresee any pressure on gross to net as you negotiate broader formulary access to counter new injectable entrants? Have you seen any material changes in payer mix rebates or paid rate? No, actually, our payer mix, just to level set on that, is about 60% commercial, 20% Medicare Part D, and the last 20% is mostly Medicaid, some other government, some truly uninsured patients. That's been really consistent since launch. Gross to net 15%-20%. Last year, we actually tightened it a little bit more. It was closer to 15% for the whole year, as we're at the point in launch where we have the ability to really look at potential savings in all places. There's not contracting pressure on us so much, particularly now that ORLADEYO has 1,600+ patients on therapy. What payers recognize is this is the number 2 prophylaxis product, most prescribed product in the marketplace. We're in a much stronger position than when we were during launch. For the pediatric launch, you had a delay due to batch specific manufacturing issue. Is there a status update, and when do you expect to resolve the issue? Yeah, we think we have identified the root cause. As we said a few weeks back, we thought that this was an isolated incident. It is, just with the quality of one batch, so it's not a safety issue. We've isolated the root cause, so we'll be manufacturing again soon. We'll update our customers and the rest of the community when we have product in the pharmacy ready to ship. We think it will be in the relatively near future. You noted you received prescriptions for all four strengths of the pediatric pellets shortly after launch. How much of a backlog is currently building, and what's the expected contribution towards 2026 revenue? As we've said before, we were conservative in how we forecasted the pediatric portion for this year because we knew long term the demand is really high for this group. We just didn't know how quickly it would come in. Early prescriptions have been ahead of our expectations, we've got a little bit of a warehousing of that when product is available, we actually think we'll be on or ahead of plan for our pediatric indication for the year because of that. Yeah, the point about all four strengths, the ORLADEYO pellets are weight-based dosing, so weight being obviously correlated with children's age. The fact that we're actually getting prescriptions from the lowest as well as the highest just shows that this particular population is ripe for a treatment paradigm shift towards prophylaxis. We're enthusiastic about the opportunity over the next few years. A key oral competitor for Pharvaris's extended-release phase III prophy data is in 3Q. Can you walk us through scenarios for how the readout could ultimately impact ORLADEYO's commercial opportunity? What's your base case assumptions for what Pharvaris will show? Yeah. One thing we do, and we've done this since launch, is we do a lot of market research around the potential impact of current and future competitors. In the case of future competitors, we like to take the conservative view for BioCryst and ORLADEYO. We always assume that until we have a phase III profile or a final label profile, we will give competitors the best case. We build in really good data for deucrictibant from their phase II, and we assume that that's what they're going to get in phase III. Even with that, we still expect to get to $1 billion in peak sales because patients who do well on ORLADEYO tend to stay on ORLADEYO. The patients who don't get the efficacy that they're looking for, they move off to another product, and that may be one of the opportunities for deucrictibant demand. But we're looking forward to seeing their data. We think it'll be a very approvable product, and we're ready for that product in the marketplace. Intellia recently reported phase III data for their gene editing program. Based on what they showed, how much traction or impact do you think this program could have? We think that there will be interest from some patients. Our view, based on talking to the patient community, doctors doing research on this, is it'll fill a niche for patients who have maybe tried other options, and those options just haven't worked for them. HAE, like a lot of rare diseases, can be tricky. Not every drug works for every patient, that may be a good opportunity for the Intellia product. We don't see a groundswell of patients going toward that. What has been the feedback from your field team on the broader adoption of oral on-demand Ekterly impacting or potentially impacting ORLADEYO? What we've not seen is it affecting ORLADEYO in any negative way. We do have patients on ORLADEYO who, as we'd expected, are also taking Ekterly to treat breakthrough attacks, but it hasn't changed the trajectory of ORLADEYO. We think it's a good option for a lot of patients. We've also not seen it necessarily improving the trajectory of ORLADEYO, just no change at this point. Okay. Let's move on to the navenibart strategy. Walk us through how you see the current injectable market dynamics, what share of prophylaxis patients prefer subcutaneous options over oral, and why, and how do you see this evolving once navenibart enters the market? As I said up front, there's about 5,000 patients in the U.S. market who are already on injectable prophy. It's not a straight preference kind of thing. It's really more, what are they used to? Just the way the market has evolved, Takhzyro came into the market almost 10 years ago. It's a really good drug, and naturally, a lot of patients ended up going onto that and getting really good efficacy injecting every two weeks. Where navenibart's going to fit in is it's a known mechanism of action as a kallikrein inhibitor. It has the advantage of a formulation that doesn't have citric acid, so it's not painful. There's no injection site pain. It's got the three and six-month dosing, and what we've seen in the phase II data, is that efficacy for both three and six months is very equal across the doses and very durable. The patients are getting down to a mean attack rate of 0.16 per month in that open label phase II, which is less than two attacks a year. When patients and doctors look at this profile, they say, "Oh, I get it. That's kind of a better version of what I'm already familiar with." The big segment will be these 5,000 patients, most of them who we expect to still be on Takhzyro, switching towards something that they feel is going to give them at least equal efficacy to what they expect, and a much more favorable dosing profile. Are you still on track to complete enrollment of the ALPHA-ORBIT phase III trial by the end of June 2026? What more can you say about the types of patients you're enrolling? Are you observing trends in subjects transitioning from injectable therapies like Takhzyro, or are these largely treatment-naive patients? Yeah. We are absolutely on track. You can rarely say something like this, I can guarantee that the last patient will enroll this month based on the screening period. The last patients are in screening. We will be finished, it could be in the next few days, it will definitely be by the end of June. What that means is the final patients will be through the 12-month blinded period by the end of June 2027. What that means is we've agreed with the FDA that we're going to keep that blinded because of the six-month dosing profile. The six-month patients need to have that second dose. We'll keep it blinded through then, and we'll have top-line data for both six and 12 months at some point in Q3 of next year. That puts us on track to file the BLA by the end of 2027. navenibart's key selling strategy is the every three months and every six months dosing frequency compared to Takhzyro, which is biweekly, and then Andembry, that's as monthly. How representative are the navenibart phase I-B/II results with 84% to 92% mean attack rate reduction as it relates to what you expect in the pivotal? Are there potential variables in the phase III that strengthen confidence or could add some risk on efficacy/safety? Just maybe to update on the data from phase II, the longer-term phase II data that we presented at AAAAI back in February is the 92% reduction from baseline in a mean of 12 months for the three-month dosing, and a 90% reduction for the six-month dosing. Again, the six-month dosing is twice the three-month dose. The commercial presentation will be a two-milliliter auto-injector, either one every three months or two every six months. That's open label, but that gives us confidence in the durability of the product, and we would expect to see comparable efficacy in the pivotal study. Does the BLA filing hinge on having the 12-month safety follow-up data? Well, the good thing about the design is when that last patient finishes next June, as I described, this is actually the largest pivotal study ever done for HAE, and it enrolled really quickly, which I think is largely because of the profile of this product. At that point, we will have sufficient number of patients, not only through 12 months of efficacy, but 12 months of safety as well. Where does navenibart stand relative to the competition based on the data to date for other attributes like injection site reactions, immunogenicity, attack control, safety? Yeah. I did mention the injection site reactions, the fact that it doesn't have citric acid. We've seen this in the phase I and phase II studies that there's been essentially 0% report of injection site pain, which is the real thing. Naturally, there will always be some minor injection site reactions reported, as you'll have with any injection. To be able to launch with an auto-injector, it's a really simple and attractive profile. From an immunogenicity standpoint, you are always going to see these things in monoclonal antibodies. The key is your long-term data durable? That's where we're really pleased with this long-term phase II data. It's showing patients are getting similar efficacy from both doses, and it's been very durable. All the other safety aspects that you look at have looked very in line with what you would expect. Assuming approval in late 2027 or early 2028, how are you thinking about pricing and reimbursement for navenibart? Will you position it at parity with existing injectables like Takhzyro or premium, given the dosing convenience? Just to correct so we don't get ahead of ourselves. It'd be great to launch that soon, but we'll file by the end of 2027, so most likely launch scenario is in the latter part of 2028. This profile that I'm describing really has the potential to be best in class. Probably too early to talk about what we'll do from pricing, but at least I think parity will be very supported from a value proposition. Back to something I said earlier about how we go about working with payers, how we generate evidence in the real world to support use of our products. We think we have the best model to get patients quickly to reimburse therapy, and that's going to be a key part of the launch. What market share do you expect to capture in years one, three, and five post-launch? We haven't talked specifically about a forecast. We've kind of echoed some of the analyst consensus for navenibart because we generally agree there's significant opportunity. Given our position in the market, our experience, it's all the same customers. It's going to be our same team going to the same customers to launch navenibart. That plus the profile of the product, we think that this can have a faster ramp. We will certainly be shooting for a faster ramp than ORLADEYO, which has been more of a consistent growth story over the years, as first the customers got familiar with BioCryst and increasingly familiar with ORLADEYO. Great. Let's move on to Netherton syndrome. For the upcoming phase I, Part 4 readout at year-end, you'll evaluate preliminary safety, systemic exposure, and early efficacy signals, such as itch reduction and skin healing. What specific magnitude of improvement would you consider a home run situation? Well, I think, first of all, this is an incredibly high need disease. These are patients who have no approved targeted therapies, and so they manage mostly with over-the-counter stuff. They frankly stop seeking care from physicians because the doctors have nothing to offer, and it's a horrible disease. The skin barrier is affected. They have atopic conditions, asthma, food allergies, all sorts of things. Really high need. What we'd be looking for, a home run would be, we're going to have 12 patients of data by the end of the year, patients treated through three months. If we see very consistent effect across the patients, I think that would be the first part of the home run. The second part of the home run would be meaningful clinical improvement, and that doesn't need to be healing completely because, again, there's nothing out there. For example, if there was sort of an average improvement of 40% or so in the global assessment of skin, and we saw consistent effect across the patients, and if we got some sense that we're narrowing in on the right dose, that would be the home run. We don't have to have a home run, but this is the kind of product we will be looking for, something that clearly instructs us how to go to a pivotal study that we clearly have a drug. If it's not clear, we'll move on and look for other opportunities. For the healthy volunteer data, confirm that the BCX17725 successfully distributed to the epidermis, how tightly do you expect this target engagement to correlate with observable clinical healing once administered to patients with actively compromised skin barriers? It was kind of a surprise, and very interesting for us, and certainly interesting for the investigators to see that the drug got to the epidermis in healthy volunteers. We didn't fully expect that. There's every reason to believe that the drug will get there at least as effectively in Netherton patients. There's a possibility it could even be better in Netherton patients, but we have to wait and see on that, but it's certainly an encouraging signal for the drug, and importantly to the investigators. They've seen some failed therapies in this area, but that one gave them a lot of encouragement. Jumping ahead, what do you expect the pivotal trial design and regulatory timeline could look like for Netherton? Do you see potential path to accelerated approval? Yeah, it's probably too early to overly speculate. There are lots of options in rare derm conditions. We've seen drugs having pivotal designs that are open label and certainly more accelerated. It probably gets back to some of that what uniformity of effect do we see. Our baseline assumption is we'd love to do a placebo control just because it's gold standard that way. We'll do that assessment when we see the totality of our data at the end of the year. What are your latest thoughts on the competitive landscape? Are there competitor updates you're tracking or expecting soon, and what have you learned from some of the other players out there? Certainly there's a company that folks may be familiar with called Quoin, with a Q, that has a topical kind of pan-serine protease inhibitor applied twice a day. They put a little bit of data out. I think they're gearing up to potentially file an NDA in the first part of next year. We're watching for that because, again, patients need options here, and we think that could be a meaningful option for patients. We also know from HAE and other rare conditions that patients don't just need one option, they need multiple options. What we hear from patients and physicians is a systemic KLK5 inhibitor that we have, if it works as I've described, that's what they would really consider best in class. We're rooting for patients to get any kind of option as soon as possible. What other indications or diseases could also be addressed by 17725? Really early on that one, too. We're excited about Netherton's. We've done a lot of epi work. There's no ICD-10 code, so this is a bit of a challenge, but we've done some deeper claims and electronic medical records work, and it's given us a high level of confidence that there's 3,000+ patients in the U.S. Like I said earlier, a lot of them just aren't seeking care. Once they have a therapy or two therapies out there, we think that this is a market that really has the potential to grow and is exciting in and of itself. If we have a drug, we'll look to see if there are any expansion possibilities, but this one would also be a very good standalone. Let's now talk about BD and financials. You've been active on the BD front with the Astria acquisition, EU ORLADEYO divestiture, and navenibart out-licensing deals. Are you open to further in-licensing assets? If so, what therapeutic areas or asset profiles, like small molecules, biologics, are you most interested in? We're absolutely active and open. With navenibart in the late-stage development right now, the next thing we do, we'd like to bring in something that is later stage, so not as much clinical regulatory risk. We're pretty agnostic at this point from a therapeutic area standpoint. We think we've got our HAE portfolio, so it's not that. It also doesn't have to be the same customer base. If we have success with Netherton's, we might look at rare derm. We might look at something completely different. The key is it's got to be a disease like HAE, where we can apply some of the same ways of commercializing, where we've been very successful and we think we can learn a new space and bring the same skills there. It's got to be a differentiated product, so oral or injectable, we're agnostic to that. Probably wouldn't do gene therapy, editing, cell therapy, those types of things. The other interesting thing for a company like us, we're profitable. We were profitable last year. We're going to be profitable this year. We're going to be more profitable next year. Our capacity is growing over time, and we don't need the next thing to be a blockbuster. It could be a $300 million peak sales opportunity that might be below the radar screen of others. For us, putting it through our commercialization engine, highly profitable, and we'd like something else that would contribute to revenue growth, ideally by the end of this decade. With 2026 non-GAAP OpEx guidance of $450 million-$470 million and revenue guidance of $635 million-$660 million, you're implying $165 million-$210 million in operating profit. Is that the right math, and is that sustainable as you invested in the navenibart phase III and prepare for launch? Yeah, that's absolutely the right math, and it's very sustainable because if you think about navenibart, we're in the later stages of the development there. Over the next couple of years, that's going to come down. Where we are right now as a company is we see that level of OPEX being the baseline we want to stick with. We don't need to grow G&A to do more commercialization. We don't need more sales and marketing to launch navenibart. It's going to be the same team, the same spend, and we just convert some of what we're doing on ORLADEYO as it's reaching maturity over to navenibart. The operating leverage there is growing significantly, and then that allows us to do BD or to gradually build a pipeline, maybe looking for earlier stages of assets. Again, we want to keep that profitability and keep the operating leverage growing. In the last few minutes in closing, what is your cash position, your runway, and what are key catalysts over the next six months that investors should be focused on? Our cash position pro forma at the end of Q1 after we licensed navenibart in early Q2, but pro forma back to the end of Q1 is $330 million. Like I was just alluding to, we are getting increasingly profitable. Things are actually growing. Our runway is in our control. It's not a cash runway thing. It's about what do we do with this cash as it's growing. Over the next six months, the things to look for, I've let the cat out of the bag on the full enrollment of navenibart, but that'll be done in the next few weeks. Obviously, we have quarter-over-quarter growth in ORLADEYO. Getting the peds indication, peds product out there in the very near future is something to look for. At the end of the year, by the end of this calendar year, we'll have those 12 patients of data in Nethertons to see if we have a product there. Great. Thank you so much for joining us today, Charlie. Thanks again for having us.