Good morning, everyone. My name is Gena Wang. I'm senior biotech analyst at Barclays. Welcome to our annual Global H ealthcare Conference in Miami. It is my great pleasure to introduce our next presenting company, BioCryst. With us today, we have a Jon Stonehouse, President and CEO of BioCryst. We also have a Charlie Gayer, Chief Commercial Officer. Before I dive into specific questions, maybe, Jon, you wanted to give a brief overview about BioCryst. Sure. Well, first off, thank you for inviting us to your conference this year. It's good to be here in Miami. Charlie and I are both gonna be making some forward-looking statements. Those statements have risks, and you can find our risk factors on our website. Yeah, you know, I think we're in a unique position as a biotech company, especially in a pretty challenging environment. You know, we have a product on the market that's been off to a spectacular start in terms of the launch. We're now in our third year. You know, we expect no less than $320 million in revenue this year on our way to $1 billion at peak. That's a position of strength, we believe, and it puts us in a really solid financial position. We have a discovery platform where we believe we can repeat this and bring another drug forward, like ORLADEYO, to a population of patients suffering from rare diseases. We think it can be as big or bigger. We don't think we got lucky with ORLADEYO. We think that it's a part of our scientific platform and our capability, and we expect that we'll do it again, and we believe we have the money to get there, so. That's very good. Maybe start with your guidance, less than $320 million this year. Maybe if you can elaborate a little bit underlying assumption and what could be, you know, the upside opportunity there? Sure. Yeah. The no less than 320 is a number we're very, very confident in, first off. That confidence stems from a few things. Number 1 is the very steady pace of new patient starts, the steady demand that we've seen quarter after quarter, really since the start of the launch, and no sign of that slowing down thus far. The other thing that gives us a lot of confidence is that patient retention, now that we're 2+ years into the launch, we think we really see the steady state pattern of patient retention. Once we get patients to about 6 to 12 months on therapy, we lose very, very few of them. All of this means that we're growing month after month, quarter after quarter and, you know, based on what we see in front of us, that's what gives us the confidence for this year and then, you know, draw a line through what we've done the first 2 years in the 320, and this gets us out to $1 billion at peak. Okay. Then 1Q, I think you got it to be flat, maybe a little bit reason on the seasonality there. Absolutely. What we said was that we expect first quarter to be flat to possibly slightly down, not because our patients aren't growing, but because of just the headwinds of the insurance reauthorization process. We have a lot more patients on therapy this year than last year, not all of those, but the majority of those have to go through a reauthorization. What that means is, for some of these patients, they temporarily step back to free product. That's the biggest driver of the flat to down. The other kind of pieces of that is that co-payment assistance for commercial insurance. We have the largest hit of that in Q1 as well as the medicare donut hole. That's why we're setting that expectation. It's, you know, again, confidence in the no less than $320 for the year. Okay. You mentioned that you maintained the retention rate, and then you started when the patient on beyond 6... once they reach 6 to 12 months. Yeah. they stay on very. The compliance rate you maintain at a 90%, right? Yes. Yeah. you know, what would be the, I think retention when we look at since the launch until now, we have some deterioration compared initial was in the 70s, now it's around 60. What lead to that, you know? Yeah. decrease in terms of the retention rate? Yeah. I think time gave us a better understanding of the pattern. Mm-hmm. In the early days, it was just too early to see the settling out. We didn't have patients on for, you know, a year. Now we have patients on for two years or more in some cases. What we see now after two years is a really settling out and stabilization of the pattern. The pattern is what you described, the, if 50% of the patients that discontinue- Mm-hmm. Discontinue in the first two or three months. Mm-hmm. There's less between 3 months and 6 months, and then after 6 months, a lot less, and then after 12 months, next to none. It's not, it's not like we have patients on for, 2 years and all of a sudden we're losing a bunch of those patients. Mm-hmm. That's very, very rare. Mm-hmm. basically, once we've had a patient on for more 6 or 12 months. Mm-hmm. They're on for a long period of time.O kay. Okay. That's very helpful. You know, what is the% of a current patient on free drug, and then how do you see this change for the remaining of 2023? Yeah. First of all, by strategy, we put in a pretty generous free drug program because we wanted to make sure that patients had a chance to experience ORLADEYO. We didn't want the insurance process to be a barrier to that. That's worked very well. What it's meant is that by the end of last year, close to 30% of patients were on longer-term free drug. Now, most of that 30% actually has insurance, and in fact, most of it is commercial insurance. We believe that a lot of those patients we can convert over to paid therapy. It's really the reasons they're being denied, the main reasons are because the prior authorization was incomplete. The physicians hadn't provided all the information required, whether it's lab tests or a very complete patient history and justification. What we're doing is we're really expanding our help for those physician practices to help them get patients over to paid therapy. That's part of our plan for this year. It's a smaller part of the no less than 320. Over the long term, we expect to get that free drug percentage down into the teens and maybe closer to 10% over the next few years. Usually how long, you know, when patient on free drugs, usually how long they will be on free drug before you are able to convert it to commercial? For a new patient starting, actually, the average patient would be on free drug for only about a month- Okay. Before we get them over to paid therapy. If they are denied by the insurance company, though, that's where some of these patients end up on the longer-term free drug. The majority of them do get paid. As I was describing, we've got kind of this- Yeah. -this backlog of patients that we think that we can really improve that percentage over time. That 30% is a long-term patient on free drug or? Correct. Okay. Yes. Like, you know, kind of thinking like a, you did mention how that converted to the teams. Yeah. What actual steps do you need to do? Like communicating with the- How do we fix it? Yeah. Yeah. Yeah. Yeah. Yeah. The real steps, the most important steps are kind of what I was describing. Mm-hmm. which is having a very clear clinical justification of why this patient needs to be on ORLADEYO. Mm-hmm. You know, some of these patients are denied simply because all the lab tests have not been provided. Sometimes physicians get frustrated with that because it's a genetic disease, and the lab tests don't change over time. Insurance companies still require that on a frequent basis. They require updated tests. That's the number one thing. Number two then is writing a very comprehensive letter that describes the patient's history, describes, if they've been on ORLADEYO, how they're benefiting from ORLADEYO, and then resubmitting that to the insurance company. Sometimes it requires getting a peer-to-peer review or consultation to explain why this actually is necessary. It's doing that hard work. Mm-hmm. A lot of physicians, they're very busy. They don't always have staff to help them with this. We've added to our team to be able to help them get patients onto paid therapy. Okay. Good. Like, how frequently you interact with those like patient on free drug with their doctors, like from BioCryst perspective? Mm-hmm. You know, helping them? Very, very frequently. We have kind of three different touch points. Mm-hmm. With our specialty pharmacy, the care coordinators are interacting with patients on at least a monthly basis. We have two teams on the BioCryst side. We have our market access team that is out there in the field, and they're working with the physician practices. In the last year, we've also added a patient access specialist team, and they work very closely with the patients and to some extent with the practices. It's making sure that all of this is pulled together so that the insurance companies get what they require to get. to get to the paid therapy. Okay. You know, we discussed, you know, all different data points. What would be the important data point that you gauge the long-term growth potential? Also what data point change can change the, say, 2023 guidance? I think. To the upside. The data point this year to look for is revenue. Particularly the no less than $320 at the end of the year. Yeah. Plus what we say, you know, about the consistency of demand. If we keep seeing what we've seen over the last couple of years, this consistent demand, the good stable patient retention that we're talking about, that's what's gonna get us there. Things that could change this, I think there's one piece of this launch that hasn't been where we haven't had quite the same drive that we thought, which is coming from patients. Most of the prescriptions now, the doctors are driving the conversation. If we can get more patients aware and asking about ORLADEYO, the doctors are already prepared and ready. I think that's something that could add more of a tailwind to this launch. Okay. The main driver will be the more new patients come to. That's right. Yeah. What is your estimate of penetration rate for the prophy market? We think in the, in the U.S. at this point, based on our research, that at least 70% of patients are on prophylaxis. That's grown from about 60% at the time of the ORLADEYO launch. It's been part of a long-term trend that was already there prior to our launch, and then I think ORLADEYO's accelerated it. We see that in the U.S. growing to 80%, maybe even to 90% of patients. Out of the 7,500 diagnosed and treated patients in the U.S., we would expect that at least 80% of them, possibly more, will ultimately be on prophylaxis. Was your question what%? Of those will be. Yeah. On ORLADEYO? Well, at peak, we would expect 25-30% of all patients, so not just of prophy. Okay. You know, that's when we get to the $1 billion, which would be $800 million in the U.S., $200 million outside the U.S. That would equal about 2,000 patients on long-term stable therapy with ORLADEYO. That's what would get us to $800 million. Pretty simple and achievable from a share perspective. In the fourth quarter, in our promotional material, we said that, in the US, 1,500 patients have tried ORLADEYO. Yeah. That gives you some sense as well. About 20% of the market has already tried. Mm-hmm. Okay, good. Now Europe launch update. Yeah. All signs that we see in Europe gives us confidence in this $200 million at peak for ex-US sales. We haven't broken it out yet. We may do that. Well, we will do that at some point when revenue reaches about 10% on a, of ex-US reaches 10% on a steady state basis. We've launched in Germany, we've launched in the UK, we've launched in France, the Nordic countries. The uptake that we're seeing looks really good. There's a trend in Europe more towards prophylaxis like in the US. Probably won't ever reach that 80% rate, but we see it growing north of 50% in Europe. ORLADEYO is contributing to that. What is the price in Europe in average? I know each country will be different. Yeah. relative to U.S. The best way to think about it is it'll take about 3 to 4 ex-U.S. European patients to add up to 1 U.S. patient. It's 25%-30%. 30% of the U.S. price is about the average net price for Europe. Will you share US, ex-US revenue breakdown at some point? We definitely will. That could happen this year, but once we hit about that 10% of- Okay. -of all global revenue, we'll break it out as ex-US versus US. Okay. The pediatric patient, DNA, in an update maybe? Our trial is underway. It's a relatively small trial that we need to have, so about 20 patients, open-label. We've developed for pediatrics kind of a, it's a granules formulation, so it's easier for kids to take. You can just put it in yogurt or other soft food, makes it very easy for them to take. You know, it's a few years off before we have the SNDA, but we know that patients and particularly their parents are really looking forward to having an oral option for the kids because doing injectables for kids... Fortunately, most children with HAE aren't as symptomatic, but when they are, they really need prophylaxis. To be able to do it with an oral will be a huge benefit for them. Yeah, we're really excited about this because talk about unmet need. I mean, if you've ever had a child that you've had to give, to have an injection given, and think about that every 2 weeks or every 4 weeks, you know, it's pretty traumatic. To have something that's so easy to take, I mean, families are really excited about this. It's a patient for life that we get with this formulation. It's a hereditary disease, so the carryover effect to possibly other members of the family, we think could be great. The best part is it's a high unmet need. Maybe one last question on ORLADEYO regarding the, you know, $1 billion peak revenue assumption and giving all the competitive landscape, new therapy comes in or less frequent dosing, subcu and oral possibility and maybe in the future, you know, genetic once and done, how do you see the ORLADEYO, you know, the regarding reaching the peak revenue and maintaining or like what certain market share can maintain? Yeah. I'll go back to what Charlie said earlier, that we need about 2,000 patients in the U.S. to stay on drug. Mm-hmm. -to get to 80% of that $1 billion, and then the rest comes from outside- Mm. the U.S. That's not crazy market share, right? That's 25%-30% market share, and we think it's very doable. In terms of the competition, it's really interesting, right? The real competition with orals is in acute or on-demand therapy. If you have a breakthrough attack on ORLADEYO and you can take an oral, that, I think that's a really interesting option. That's not a threat. That might even be a help. I think on the injectable side, you know, what we're excited about is if those companies start talking about convenient dosing and less frequent dosing, we're gonna say, "What's more convenient than a once-a-day capsule? Right? Try ORLADEYO before you try these others." That could break through some of these docs where they're like, "Oh, this patient's controlled. I don't wanna switch them. They're all pretty far off. You know, the first injectable, next injectable comes late next year, and the rest of them are many years out. That gives Charlie and his team a lot of time to get patients to try our drug. Okay, good. We switch gear to your oral Factor D program. Maybe, you know, are you able to disclose, you know, what were the dose-related finding in non-clinical chronic, tox study? Yeah. Let me be clear on what we've seen. Right. Mm-hmm. It's observations in the ongoing chronic toxicity study. Okay. It's a study that's not completed. Mm-hmm. We're continuing to run the study. We'll run the study. We'll do the work to figure out what the answers are with regard to what we find in that study. It's observations in a chronic study. Mm-hmm. What's perplexing to us, and makes it more challenging to understand is that we also did a 13-week study in the same species at a similar dose. In this chronic study, in a timeframe within the 13 weeks, we're seeing this observation where we didn't see it in the 13-week study. In the earlier study, we didn't see it. In this study, we did in the same time period. That could be law of small numbers, but-. Mm-hmm. That's unusual, in toxicology studies. It's not something like the longer we study it, the more we see these issues. I see. Yeah. That's an important distinction. Which species is that? We haven't said, but you know. Yeah. You need two species in chronic tox, six to nine months. We haven't gotten into that detail. Okay. It's an ongoing study. Okay. We'd like to know more about. Usually is rodent. One is rodent, like mi-. Rodent and one large animal. Yeah. Yeah. Yeah. We haven't gotten into which species that is. You saw in the same species and in two different studies, same period, the first one you didn't see and second one you saw. Correct. Yeah. Okay. Correct. Which makes it more complicated. Mm-hmm. Our view is we've got enough out of the SAD and MAD healthy volunteer study to get an idea of where we could start on. Mm-hmm. do dose-ranging. Mm-hmm. At the end of the day, clinical data trumps non-clinical data with regulators. Being able to go in and study this in patients where the benefit risk is probably, you know, more important, is really the strategy to move forward. We expect that we'll go into a study like PNH in a country where there aren't a lot of options. Mm-hmm. -for other therapies and be able to dose slowly upwards. The key to our disclosure was all around the speed at which we can get to finding a dose at this point in time. Okay. We'll have to go a bit slower. Okay. Jon, if we take one step back, you know, the modification that the next gen BCX10013 versus the previous BCX9930, what are the exact modification that, you know, if we're just talking about once daily dosing versus twice daily dosing, I think that that's not sufficient? It should be something also more safe. Like, the efficacy part also should have a opportunity there. Can you share a little bit more color? I know the technical detail never share, like, but what would make us confident this next gen will not face the same issue, safety that actually preventing the first gen to be able to dose higher to show better efficacy? Like, how will we be confident this next gen will not have the same issue? Yeah. It's same backbone but very different molecule. Mm-hmm. I mean, you said it. You know, 9930. Yeah. Had a dose of almost a gram and was dosed twice a day. This is ten zero thirteen. You know, we're looking in the hundreds... Mm-hmm. of, you know, low hundreds of milligrams, you know, maybe 100 and something. Once a day dosing. Clearly different pharmacokinetics, in terms of the two drugs. There are absolute differences. I think, you know, what we should all have confidence on including BioCryst, is can we find a safe and effective dose? It's not good enough, as you said, to have once daily dosing if you don't have an effective drug. That's not what we're shooting for. Mm-hmm. We're shooting for... Yeah. similar or better efficacy with a once daily dose. We think that is a differentiated molecule and option for patients. If we get there, then it'll be a huge success. If we don't, we'll move on to something else. Mm-hmm. When we say similar to better, we mean similar to what else is out there, not similar to BCX9930. Yeah. Like Novartis, right? Correct. Exactly. They're setting the bar now. Yeah. Yeah. Yeah. We were hampered by how high we could go in the. Mm-hmm. We were already at a, you know, 400 milligrams twice a day. Mm-hmm. We don't have the same issue with BCX10013, but we still... It's an early program and there's still risk- Mm. associated with that program. Okay. With this animal finding, like how long do you think that will resolve? Like what kind of data points do you want to collect to make comfortable-? Yeah, I think- That you can move forward? Completing the tox study is an important piece of. Mm-hmm. of figuring out what's going on. I also think that the clinical data I referred to earlier, getting into patients and seeing if we can get to a safe and effective once daily dose. Mm. is more important. Mm. I think if you're looking for what are the next key steps, it's our ability to get into that study and announce that we've started dosing patients for perhaps in PNH with BCX10013. Mm. That'll be an important step, and then the data coming out of that'll be an even more important step. For that 13-week data, we're thinking what dose is that? If we translate that to clinical relevant dose, is it much higher than the therapeutic? Like within the therapeutic but much higher dose? observation that we have is dose-dependent, you can imagine. I see. at higher doses than at the lowest dose. Mm-hmm. You know, we haven't gotten into the specifics around the, you know, human equivalent. You can imagine that's why it's important to do the dose ranging in patients, is to find out what dose is effective and safe. Mm-hmm. That, that's why that's the next step. Okay. Maybe I will ask a differently. Like, what kind of data or condition you would discontinue 10013? Yeah. If we believe we can't get to a safe and effective once-daily dosage, we'll kill the program. Okay. It's that simple. That would be based on the animal data, or you will still try to go back to the human-? I think going into patients is the key. Right. If something goes south in the non-clinical study, beyond what we've seen so far, that could be a reason to stop. I think right now we believe that getting data in patients is the most important next step. Okay, good. Maybe one last question. Cash runway and maybe. Yeah. I'm glad you don't have exposure, now it's all fine. Yeah, yeah. Yeah. There's a No Silicon Valley Bank exposure, just to make everybody comfortable. Yeah. Mm-hmm. We have $440 million in the bank as of the end of the year, last year. You know, we're generating less than $320 million in revenue, our expenses, operating expenses are flat. The cash use is shrinking every year, and it's only gonna get better as we keep increasing the revenue and stabilizing the expense. Can't predict when we'll get to profitability, but we're in a much stronger position than most companies. I think there's some investor, you know, thoughts on profitability part. You know, why focusing on the oral Factor D when we have actually strong competitors out there? You are a little bit behind. Why not focusing on turning company into profit, profitable? Like, what would be your thoughts on the vision for the company in the future? Yeah, we wanna be really profitable, right? You can do that when you have more than one molecule. Mm-hmm. I think we've shown the discipline around, you know, stopping programs when we don't think we have a competitive profile. Mm-hmm. We'll be very focused and careful in the spend. You know, I think our dependence on the capital markets is decreasing every year, so we feel really good about it. Orladeyo, you know, by itself is profitable as we speak. It was profitable last year. You know, it's just gonna keep getting better each year, and we'll be very thoughtful about where we invest that can create another Orladeyo. Mm-hmm. Okay, that makes sense. Great. Well, I think we are running out of time. Well, thank you very much. Yeah. Yeah. Look forward to the update later this year. Thank you for having us. Thank you. Thanks, Gena.