Good morning, everyone. My name is Liisa Bayko, Biotech Analyst at Evercore ISI, and I'm really pleased to be joined by my two friends by the same name, John and Jon, but spelled differently, from BioCryst. BioCryst is a name that I've been covering for some time, and of course, they're making waves in HAE, but they've got a pipeline behind it, and I know they're really excited to talk about that. So we're gonna dig into all of this, but I'm gonna turn it over to Jon, without the H, CEO of BioCryst, to give us an overview of the company. Sure. So first off, John and I will probably both be making some forward-looking statements, and they have risks, and our risk factors can be found on our website. But you know, it's an interesting time in biotech. You know, horrible market, and you know, having capital and applying capital wisely is paramount right now, and so having revenue is certainly important to creating value. And so we have that with ORLADEYO. You know, it's an oral, once-daily prophylactic for HAE, and you know, we're making really steady progress. This year will be, you know, less than $320 million in revenue, and you know, we've laid out a path to $1 billion, and we're real confident that we can get there. Behind that, as you said, is a pipeline we've been working on for a bit and unveiled it a few weeks ago, and we're really excited, and the goal there is to bring another drug forward, like ORLADEYO or better. So we're focusing on rare diseases, complement and non-complement mediated rare diseases, and we're shooting for best-in-class or first-in-class. Yeah, we're very excited. You've talked about $1 billion a couple of times, and I thought you did a really nice job on your earnings call, which happened right before your, your kind of pipeline reveal day, in laying out some of the assumptions to get there. And one of them that really struck me was this consistent add of, like, 200 patients a year, and that's something I just like... How can we feel secure about that? Where does that come from? How do we know there's gonna be 200 patients per year? 'Cause that, that's kind of like, the rest of the assumptions I totally agree with, but that's the one thing I just struggle to gain as much confidence as you. Just because it seems like, you know, at the beginning, it would be easier to find those 200 patients, right? You'd get kind of the low-hanging fruit, patients who aren't on treatment yet, patients who are dissatisfied with their current treatment. But if you've stuck on, you know, kind of alternative treatments for that long, does it become harder to find those next 200 patients? Yeah. I'm curious about how you kind of come to that. Yeah, I think one thing that maybe makes that different is this... There's no analogue for what we're experiencing in HAE. I mean, there's seven drugs in a rare disease. We're the eighth. Right. It's, it's incredible- Right, so that's- If you think about it. So that's, that's unheard of, right? So, so throw out all your analogues 'cause they don't apply here. And, the other piece is that these other drugs work really well, and so does ORLADEYO. And so patients aren't going to see their doctor as often, and they're pretty satisfied. So you've gotta be able to convince them and their doctor that there's a reason, that there's a bigger benefit for them to try our drug or any other drug. And, so it's... You know, one of the things that you see in that graph that we showed at our earnings call is the steady adds over time, and we're adding, I think Charlie said in May- Three hundred ... of last year, the trailing twelve months was 300, so we're above 200 right now. At some point we'll be below 200, but over the course of that period from now to, I think it was 2029, we expect on average about 200 patients a year. And I think the other piece is there's still a lot more to get. You know, 7,500 patients in the United States, and we've got about 1,000 patients on therapy now, so there's a lot more to get. How many patients have tried ORLADEYO thus far? We've gotten to about 25%, roughly, of the 7,500 so far. So, you know, like I said, there's a lot more to get. Okay, good. And where is ORLADEYO being used? Like, if you're a newly diagnosed patient or a patient who just for the first time decides I wanted to try prophylaxis, are you kind of, like, first? I mean, it would seem that it would make sense. It's oral. Yeah. It makes sense. Yeah, that's- Do payers prioritize anything? Yeah. Or do some payers just say, "You gotta kind of step through and weigh ORLADEYO before you go to something else?" Or how does... Where are you in the- Very few payers, you know, maybe some of the smaller ones- Okay ask for step through, and- Okay ... even with that, you can write a medical exception letter and, and get through that. So, so the payers are making it a very even playing field, which- Okay ... which is great, and I think patients and physicians appreciate that as well. Where are we getting them from? There are very few newly diagnosed patients. That's another difference in this rare disease market. You know, 7,500 are diagnosed and treated. There's, you know, maybe a few hundred every year that get newly diagnosed, but that's a tiny percentage. We should get those. Those, we should be first in line for that, and it appears from the data that we got that we are, but it's a small percentage. The bigger percentage is switching, and it comes from either somebody that wants to go on prophylaxis, and they've been waiting for an oral, and... Or they realize now, "Hey, maybe if I go on an oral instead of an injectable for prophylaxis, that'd be a better deal," or they're switching from injectable prophylaxis. But that's, that's typically the best success rate we have, is those that switch from or injectable prophylaxis. I see. So there's a wave of, if you can believe it or not, 'cause there's already eight approved compounds, as you mentioned, but there's a wave of innovation coming, right? So we have another oral therapy, at least one that I'm really just focused on one, but maybe you can comment on kind of, you know, what that could do to your market. Yeah. Yeah, the second part of the question is, there's these kind of injectable products that are just dosed incredibly infrequently, actually. So there's some innovation in the short term, but longer term, we're gonna see products that maybe are dosed every three months, you know, once a quarter, every six months. I think there was eyes on once a year, but I think that might be a stretch now, but every three or six months. How does that kind of factor into sort of the longer term vision? Yeah, we, we spend a bit of time on that every year. And Jinky Rosselli was on our earnings call, and she does the data analytics and market research, and she described the once yearly, you know, 100—I think it's 175 docs and over 100 patients market research that we do, and we do a conjoint analysis. So we basically lay out the profiles and the timing, and we're, we're pretty favorable to all the people behind us in terms of when and, and what, what it'd look like. And what we see is injectables will take from injectables if they're, you know, less frequent. And the oral, if you're controlled on our drug, you're not gonna switch to another oral 'cause it's once a day. So they're gonna take from other injectables. And so what you'll see is the injectables on the market now are gonna decrease over time. So, yeah, we pay a very close attention to that, but I... You know, we're really just- Can I throw in one more? Yeah, yeah. What about a one-and-done cure? 'Cause I, you know, I do cover Intellia. They're working on a gene edit approach. Yeah. I think what we hear is that the risk-benefit there is scary for patients and for physicians. The unknown of editing your genome, and what it does, and what are the long-term consequences, when in effect, with either the injectables or ORLADEYO, you've got a functional cure. If you're controlled, you know, you basically have a completely different life than you had before, right? So, I think there's a place for that. You know, it's not surprising that they're going to countries where there isn't a lot of therapies available because, you know, that'd be a great place for them to go, and I think for those patients that don't respond to the other drugs, makes sense for, you know, something like a higher risk, but big benefit. Jon, what's going on kind of ex-U.S.? Because I know when you were launching ORLADEYO, there weren't a lot of treatment options in Europe, and so that would seem to be, like, a very ripe market for an oral treatment, and then also Japan. Those are two key other markets. Can you maybe just kind of give us what's kind of the latest going on that you have boots on the ground in those areas? Yeah. But slightly twist your, what you said about Europe a little bit. Okay. There were injectable prophys that made the market. Okay. Okay. In some countries, they didn't get approved because of pricing. That makes sense with Japan. Yeah. Okay, okay. Japan, there was no- Oh, great. Okay, okay, okay. But let me, let me take Europe first, because that's probably the... Not probably, it is the biggest contributor in the ex US, which is at about 10% right now, and we expect ex US will grow to 20% at peak. You know, country by country, I think we're doing a great job. It's a, it's more of a volume than price. The price is pretty sig- Right ... significantly different. But- Can you give us any kind of view on that? Yeah. Can you help us with the price? We've said it. It probably takes four patients in Europe- Okay ... to make one patient- Okay ... of value in the U.S. Is that the same thing for Japan? No- Okay ... we, we have a better price there. That's closer to 2 to 1. Okay. But, but back to Europe, we've made great progress in the U.K. We've made great progress in Germany, France, the Nordics. We're launching in Spain. We're gonna be launching in Italy next year. You saw we just got, or, or we're about to get approvals in Latin America, and so, you know, we're making great, great progress on that front, and... But remember, the U.S. is 80% of the market. And then, with Japan, that's going slower, I think, than we expected. Yeah, we were. I think we had about a year head start, but, you know, it's a completely different market where it's find the patients. There's only 700 identified or diagnosed in a population that should have close to 3,000. So there's a consortium of companies that are working to identify patients. Are you still the only game in town there? Is that- No, no, no. Okay. So, Takhzyro's approved there- Okay ... as well. Firazyr is available, so- Part of it is the market hasn't been developed, right? Yeah. 'Cause there wasn't kind of that basis already- Yeah ... with companies marketing. I actually think the more treatment options, the better in the market- It helps, yeah. ... because it's just more noise around finding patients. Right, and you differentiate on being oral and all that stuff. Yeah. Yeah. Yeah. Yeah. Okay. Let's get into your pipeline for a little bit. Kind of walk us through some of the highlights of your R&D Day, and what are you most excited about in the pipeline? Yeah, I mean, we had one, and now we have six. So that's a big difference, and pretty exciting. And you know, we've been working on these other compounds for a while, but they're at a point now where we have data, and we really feel we can stand behind- Yeah ... the statement of first-in-class or best-in-class. So having six programs to advance to get one or two more drugs on the market, I think the odds are pretty good. It's a diversified pipeline. We have protein therapeutics, like a KLK5 inhibitor, 1775 for Netherton, and the bispecific fusion protein for complement-mediated diseases. Big difference there is the off-target toxicity is basically non-existent with an antibody, right? And so different risk profile. You know, the big issue there is immunogenicity, and there are predictive models now that are very accurate at determining what is or isn't gonna be immunogenic. So we feel really, you know, excited about those programs. And then we've got oral drugs, like an oral C5 inhibitor, which I think could be an absolute game changer in diseases like myasthenia gravis. So, they're early. You know, it's gonna take us some time to advance them, but yeah, with our pipeline got a lot bigger. I know, you've said it, it kind of wouldn't cost very much, you know, it's pretty low spend. But can you give us a better sense, what is it gonna take? Like, how much spend will there be to get to proof of concept for these programs collectively? 'Cause I think that's the big thing, right? I think investors look at you, and they're like, "If you just focus on ORLADEYO, you'd become profitable pretty quickly." So how much spend to kind of get to proof of concept to know that you actually really do have a, like a, an asset? Yeah. I think in this market, you've gotta be really thoughtful and careful about how much you allocate, and you gotta be disciplined around investing in things that you believe really hit the bar of best-in-class or first-in-class. And so early on... I mean, these are preclinical assets, so toxicology, you know, not that expensive. Phase I study is not that expensive. Proof of concept, depending on the size, you know, much smaller compared to pivotal. Pivotal is where it gets really expensive. There's probably gonna be some attrition rate with these programs. Are all six gonna make it to the market? That would be wonderful, but, you know, I, I don't think the probability is that high that they all will, but some will. And, and if we're fortunate where many make it to pivotal studies, we'll find partners. I mean, I've said it before, I'll say it again, 'cause I'm even more confident now, we'll have people breaking down our door if we've got an oral C5 inhibitor that has proof of concept, right? Or we've got a bifunctional fusion protein that works in lupus nephritis or IgAN, or... I mean, there will be a line out the door for people that wanna help us. So we'll, you know, we wanna drive towards profitability, and the first step is to get the expense line and the revenue lines to cross, and, you know, we're getting close. So when do you think you'll reach profitability then? Yeah, I'm not ready to answer that, 'cause the variables are, how fast does ORLADEYO grow, and how much do we spend? But, you know, it's – I think in the next couple of years, the lines will cross, maybe even sooner. Okay. And give us a view on kind of when you expect to get proof of concept for some of these programs, so we can go through the kind of the individual programs- Yeah, I mean- Okay... the one that's nearest term is this proof of concept study we're running with 10-013 in PNH, and we expect that data by the middle of next year. So, you know, we're shooting for once a day, you know, with efficacy similar to the Factor B inhibitor, and safe, and enough safety data that regulators like the FDA say, "Yeah, you can go to a pivotal study." So, you know, we're driving, getting that thing enrolled, and hopefully, we'll have data in the not-too-distant future that'll allow us to make a decision of go or not go. Okay. And then the rest of them, you know, I think what you'll see is, you know, IND filings, you know, first in human studies, proof of concept studies, and, you know, they're early, so it's gonna take a few years to get there. Why... kind of what was the motivation to develop this pipeline, Jon? Because, you know, again, you could have kind of gotten to profitability pretty quickly without it. Why did you wanna go down this path? Is it, you know, so you can, I don't know, attract a buyer? I'm just asking, is it for investor interest? Is it 'cause you have great assets? Like, what, what was really kind of the driver, build a bigger company? What are some of the key motives? Yeah. I, I don't think it's about bigger, it's about more value, right? If, if you just look at—you've got ORLADEYO, and you look at the value curve of that over the life of the product, and then you add one or two more onto that, the value's dramatically different. And we believe that we didn't get lucky with ORLADEYO. We, we showed you on R&D Day exactly how we made it, right? SAR chemical, SAR by chemical SAR, how, how we saw the active site perhaps differently and in more in focus than others have, and that's why we're the only ones so far that's got an oral once-daily kallikrein inhibitor in the market. And, and so it's, it's all about creating value. And we think we can be very profitable with, you know, multiple products making it into market. Look at some of the companies that have multiple products, and what they've been able to do in terms of value or multiple indications. Why didn't you iterate on ORLADEYO and come up with kind of a next gen or... Yeah, I think we're constantly thinking about: Could we make improvements? I don't think it's the right time to say what we're thinking about- Okay ... or how we might do it, but yeah, if we could make that product better, we certainly will try. Do you think your balance sheet is... Not maybe your balance sheet, but the way you've structured your financing, you've tried to, I think, avoid the capital markets. You've done some royalty deals. Do you think that's made your story more complicated because you, you have a lot of these deals in the background, or do you think that's been a, you know, an advantageous way to, to kind of... Yeah, I- get access to capital? I think at a time when investors weren't super enthusiastic about ORLADEYO, Royalty Pharma stepped in, looked under the hood, and stepped up with, you know, cost of capital financing that was way more attractive than using our shares. And I think it's somewhat of a validation or endorsement, and then they came back a second time, right? So, we executed our plan, and they came back in for even more. And so, I think where it might be a little confusing to investors is, if you look at the way we report it, it's reported as debt, and so you should look at our earnings slide deck, and we've clearly delineated what is true royalty, and you only pay when you sell, and what is true debt. Okay. You know, it's $425 million of royalty funding, and it's $300 million of true debt. So that would be the only thing I would say is confusing, and we've tried to clear that up for people. Now, sort of talk about your cash runway. Do you have enough to get to profitability? Do you see the need to maybe access markets or some other royalty financing and to kind of develop your pipeline, or can you get there on what you've got now? Yeah, I'm pretty confident we don't have to go back to the capital markets. I'll never say never, but I've just, you know, based on the last time we tried to raise capital in the market and the current environment, no way. I mean, there's just no way, and I think we've been clever at other ways to do it, and we'll be thoughtful about how much we invest and continue to grow ORLADEYO. I think the big difference now is, you know, we're north of $300 million, on our way to $1 billion. You don't need to go back into the capital markets, even if you've got a pipeline that you could fund, so... Great. Okay, in the last minute, Jon, give us a sneak peek into 2024 for BioCryst. What can we look forward to? Yeah, I think continuing to show you that this pattern that we put on paper at our earnings call a few weeks ago continues, and that we are on this trajectory to $1 billion. So each quarter, continuing to gain confidence from investors on that, I think that's one. I think two, like I talked about before, the readout of our proof of concept study with 10-013 will be really important, and then the rest of the pipeline. And, you know, each step that we make getting it closer and closer to proof of concept data, I think is a sign of progress and success. So looking forward to keeping you updated on that. Great. Yeah. Thank you so much. Yeah, thank you.