Good day, and welcome to the BioCryst First Quarter 2025 Earnings Conference Call. All participants will be in listen-only mode. After today's presentation, there will be an opportunity to ask questions. Please note that this event is being recorded. I would now like to turn the conference over to John Bluth with Investor Relations with BioCryst. Please go ahead.

Thank you. Good morning, and welcome to BioCryst's First Quarter 2025 Corporate Update and Financial Results Conference Call. Today's press release and accompanying slides are available on our website. Participating with me today are CEO, Jon Stonehouse; Chief Commercial Officer, Charlie Gayer; and Chief R&D Officer, Dr. Helen Thackray. Following our remarks, we will answer your questions. Today's conference call will contain forward-looking statements, including those statements regarding future results, unaudited and forward-looking financial information, as well as the company's future performance and/or achievements. These statements are subject to known and unknown risks and uncertainties, which may cause our actual results, performance or achievements to be materially different from any future results or performance expressed or implied in this presentation. You should not place undue reliance on these forward-looking statements. For additional information, including a detailed discussion of our risk factors, please refer to the company's documents filed with the Securities and Exchange Commission, which can be accessed on our website. In addition, today's conference call includes non-GAAP financial measures. For a reconciliation of these non-GAAP measures against the most directly comparable GAAP financial measure, please refer to the earnings press release posted in the press release in section of our Investor Relations website at www.biocryst.com. I'd now like to turn the call over to Jon Stonehouse.

Thank you, John. We've started 2025 with another quarter of outstanding performance. As you will hear from Charlie in more detail, the U.S. commercial team made tremendous progress in moving patients on ORLADEYO from free drug to paid at a much faster rate than we expected. The result is quarterly revenue of $134 million. This improvement in the paid rate impacts revenue performance in Q1, but also through the rest of the year, leading us to raise annual revenue guidance for ORLADEYO to between $580 million and $600 million, which is 33% to 37% growth over last year. Our improved revenue growth significantly increases our margins and has also accelerated our cash flow and profitability goal by a year. We now expect to be profitable on a full-year basis this year. This increased financial strength and the positive cash flow it generates enabled us to pay down $75 million of our debt in April, while continuing to invest in and advance our pipeline. In addition, we are now moving into ORLADEYO revenue levels where we no longer pay a royalty on sales above $550 million and we're getting closer to our peak sales for ORLADEYO of $1 million. In the current environment of uncertainty, having a company with growing sustainable revenue, an advancing pipeline and financial strength to be profitable, pay down debt and be independent of the markets is hard to find in our industry, but that's exactly what we have at BioCryst. With that, I'll turn it over to Charlie to discuss our fantastic first quarter results.

Thanks, Jon. The launch trajectory for ORLADEYO has been consistently strong for the past four years, but the first quarter of 2025 was our best yet because of the combination of great demand generation and amazing progress helping patients gain access to therapy. As we described previously, U.S. patient demand in 2024 matched the first year of the launch. Our team continued this momentum as first-quarter new prescriptions slightly exceeded our best quarter from last year. In addition, our latest patient survey showed that regardless of their current treatment status, the percentage of U.S. HAE patients who strongly prefer oral prophylaxis grew to 70%, up from 51% in 2023, as you can see on Slide 7 in today's presentation. And HAE treaters are increasingly convinced that ORLADEYO is very effective and convenient for patients based on their individual experience and the rapidly expanding body of real-world evidence that they have seen. ORLADEYO is becoming their treatment of choice. What really drove Q1 performance though was a 10 percentage point jump in the rate of paid patients in the U.S. Over where we ended 2024. We expected that level of improvement to take three years. We did it in four months. The Inflation Reduction Act drove about two-thirds of the improvement because the IRA is achieving its intent of helping Medicare patients afford their prescription co-payments. Medicare patients were not only able to afford their ORLADEYO prescriptions, but they were able to do so earlier in the quarter than expected. And we also continue to make great progress among the roughly 60% of ORLADEYO patients who have commercial insurance. The paid rate in that segment increased to 84% as we further improved our ability to convert patients from long-term free product to paid product. By the end of April, we were nearly through the reauthorization season and approximately 84% of all established patients on ORLADEYO were receiving paid therapy. That's close to our long-term goal of 85% on the past $800 million in U.S. revenue, a rate we forecasted would take at least three years to hit. This acceleration in paid rate improvement means a lot more revenue this year, allowing us to increase guidance significantly, as Jon noted. But it also positions us to capture more ORLADEYO revenue over the next several years as our patient base continues to grow. In other words, we're still on a path to $1 billion in global revenue in 2029 and the path is now even more profitable. As we look to the second quarter, our very strong first quarter means that the typical jump in Q2 will still be the largest quarterly increase for the year, but less pronounced than in prior years, in the range of $10 million to $12 million. Slide 5 shows visually how we expect this year to look different. We anticipate this pattern shift because we captured more revenue opportunity per patient in Q1. So the Q2 increase will move closer to the underlying patient growth trend. I'll provide a bit more color to explain. As I mentioned earlier, patients moved to paid status more quickly than expected in Q1, which means we gave away less free product. Our team also continued to improve gross to net, which in Q1 allowed us to keep it closer to the lower end of our typical range of 15% to 20%, when in prior years it was closer to 20% in the first quarter. We expect gross to net to improve throughout the rest of the year, but more gradually so that the full-year average will be right around 15%. Our great execution to start the year and accelerated ORLADEYO outlook for the rest of 2025 come at an exciting time because our clinical pipeline is nearing important early milestones. The path to another differentiated rare disease product like ORLADEYO could soon be increasingly clear. I'll turn it over to Helen to describe our progress.

Thank you, Charlie. Good morning. Today, I'm pleased to share an update on recent significant milestones for our pipeline programs. First, we've submitted our pediatric NDA for ORLADEYO to the FDA, introducing an oral granule formulation for patients aged two to 11 with additional filings in Europe, Japan and Canada also this year. This would be a significant advance in the treatment of children with HAE as it would be the first targeted oral prophylactic therapy for this age group. Next, I'm pleased to report that we received authorization to initiate patient enrollment for both pipeline programs following ORLADEYO, BCX17725 in Netherton syndrome and avoralstat in diabetic macular edema, which is an important step on our path to having initial clinical data in patients for both programs by the end of the year. Today, I'll focus on the Netherton syndrome program in detail and provide more information about the trial design, what we're looking for and what to expect by the end of the year. First, I'll describe why we're so excited about the potential for 17725 as a transformative treatment for people living with Netherton syndrome. This is a devastating illness. Its consequences are very serious and lead to lifelong impacts on health and well-being. We've heard from patients that the lack of treatment leads them to withdraw from medical care. We recently heard exactly the same feedback from our clinical site investigators. Just as it's been for other rare diseases like HAE, we expect that introducing a new potential treatment that could revolutionize care will attract patients back into the care system and into clinical trials. We designed 17725 to address the fundamental pathology that causes Netherton syndrome, every aspect of which is ultimately caused by a genetically determined lack of an essential skin protein called SPINK5, also known as LEKTI. Normally, this protein stops cells in the outer layer of the skin from prematurely separating from the cells below. It achieves this by controlling the activity of key kallikrein, KLK5, which digests bridging proteins that glue the outer layer skin cells together. In Netherton syndrome, there is no breaking mechanism for this, because KLK5 is continuously on. And so skin cells quickly separate and are lost. What that causes is a massive disruption of the essential barrier functions of the skin, which normally keeps warmth and moisture inside and microorganisms outside, but not in Netherton syndrome. And in addition, KLK5 directly activates the rest of the kallikrein cascade in the skin via KLK7 and KLK14. Through cascading, pathologic inflammatory and allergic pathways, the effect is magnified down into the deeper skin and tissue layers, ultimately also resulting in systemic inflammatory and atopic effects like asthma and food allergies. All this stems from one faulty gene, leading to the lack of one protein SPINK5, the regulator for KLK5. This means KLK5 is the key pharmacologic target in this disease, because it's the pinnacle protein, the one at the very top of the cascade that drives the whole process as we see in Slide 13 in today's presentation. Our scientists engineered 17725 to replace the function of that missing protein in its control of KLK5. So we have tremendous confidence in the target and the pharmacologic approach we are taking based on significant experience of our scientists and many others who have published their clinical and preclinical work. A big challenge with a protein therapeutic in this disease is to get enough drug into the epidermis and have it stay put. The epidermis or the outer layer of the skin is where it needs to act. So to give us the best chance of success, our scientists designed this molecule with far greater potency compared to the natural inhibitor and very high affinity or stickiness for KLK5. These features give us the best chance to minimize the dose necessary and make every molecule that finds the target count by binding tightly and blocking KLK5. Today, we're reporting that the IND has cleared in the U.S. for enrolling patients with Netherton syndrome into our Phase 1 trial. This clinical trial is set up to tell us quickly whether we've met our objectives and design of the drug. The trial plan is outlined on Slide 14. We're currently dosing healthy volunteers to evaluate basic information on exposure and safety, and we're now identifying sites in both the U.S. and Australia for the patient arm of the study. Patients will be given four weeks of treatment and about two months of continuing evaluation beyond that. Building on this, we also plan to expand the trial later in the year to evaluate a longer 12-week course of treatment as we learn more about the drug. Cohort size will be small as we expect to gain a significant amount of information from just a handful of patients and perhaps from every patient. To best inform the design of future trials and to provide early insights into the therapeutic potential of 17725, we need to understand how the drug behaves in patients living with Netherton syndrome. To do this, we'll be looking at drug levels in the epidermis, both by using adhesive tape to collect skin epidermal cell samples and with small skin biopsies. We would be thrilled to see the presence of 17725 in those samples and normal levels of skin kallikrein enzymatic activity achieved in patients who have Netherton syndrome, which would provide a strong signal of the potential for clinical efficacy. In addition, we'll be looking at clinical impact. If we don't see clinical benefit at a study dose level and dosing is safe, we intend to progress to higher doses. If we do see clinical benefit as indicated by improvement in measures such as itch score and physician global assessment of severity, we'll have excellent information to inform dose selection for a future pivotal program and even higher confidence in the opportunity for 17725 to be a truly disease-modifying therapy for people living with Netherton syndrome. Although it's always a challenge to conduct clinical trials in rare diseases, we have plenty of experience with this and we're very encouraged by the clear enthusiasm for our trial that we heard during our recent clinical site visits. We look forward to sharing our initial Phase 1 trial data in patients with Netherton syndrome by year-end. And now, I'll hand the call back to John for a financial review.

Thanks, Helen. We are exiting the first quarter in a great financial position with stronger than expected revenue growth, increasing full-year revenue guidance, accelerating full-year profitability to this year, and last month we've reduced our outstanding debt. While you can find our detailed first quarter financials in today's press release, I'd like to draw your attention to a few items. Total revenue for the quarter came in at $145.5 million, $134.2 million of which came from ORLADEYO. Of that ORLADEYO total revenue, $120.2 million or 89.5% is coming from the U.S. Operating expenses excluding stock-based compensation were $102.9 million for the quarter, up from $93.6 million in the same quarter last year. This was primarily driven by an increase in commercial expense to support our growing ORLADEYO revenue, our newly launched regions like Spain and Italy, and expanded international operations, including global commercial support activities across finance, HR, IT, and supply chain. Operating profit for the first quarter of 2025 was $21.2 million and net income was slightly positive. Cash at the end of the quarter was $317 million. As a result of the significant and durable improvements to revenue that Charlie discussed, we are revising our revenue guidance by $45 million to $50 million above our prior guidance, and which represents, as I mentioned before, a 33% to 37% growth over last year. We now expect non-GAAP operating expense for the year to be $440 million to $450 million, a $15 million increase over our prior guidance, driven by expenses supporting our commercial growth and an increase in COGS as sales of RAPIVAB increased. The result of this strong revenue performance combined with our continued focus on disciplined capital allocation is that we now expect to be profitable for the full year on a net income and positive cash flow basis this year. This is one year earlier than we previously planned. Further, based on this improved financial strength in April, we made a paydown of $75 million on our debt with Pharmakon and reduced our outstanding debt to $249 million. As a result, we expect to save approximately $23 million in interest payments over the life of the debt net of the early prepayment penalty. I am immensely proud of the continued focus of our employees who are delivering meaningful improvements in patients' lives both today and in the future. Our commercial and support teams are driving access and usage of ORLADEYO and our R&D team is advancing our pipeline to address challenges in new disease areas where patients are underserved. Financially, we are driving revenue growth and well on our way to $1 billion at peak, efficiently allocating capital and R&D to create sustainable and long-term revenue growth, accelerating our profitability, and reducing our outstanding debt. We have never been in a stronger financial position, and I am excited for how this sets us up for a very bright future. Operator, we are now ready for your questions.

Thank you. We will now begin the question-and-answer session. Our first question comes from Steven Seedhouse from Cantor. Please go ahead.

Good morning. Thanks so much for taking the question. Just looking ahead to another potential tailwind for ORLADEYO, which is the pediatric launch. Do you have a sense of how many pediatric HAE patients are on TAKHZYRO today in the U.S.? And do you think you'll mainly be switching children from TAKHZYRO, or can you sort of quantify how many patients maybe just don't want a needle, but would be new starts opportunities for ORLADEYO prophylaxis altogether?

Charlie, you want to take that one?

We do expect pediatrics to be a beneficial factor for us. Any future revenues for pediatrics are not included in our $800 million in the US or $1 billion global peak sales. I don't know the exact number of patients on TAKHZYRO, but we estimate that there are about 500 pediatric patients in the US, with at least 200 potentially suitable for prophylactic therapy. Once an oral option becomes available, we believe that number could increase. Our patient base will likely include those transitioning from injectable therapies like TAKHZYRO, and we anticipate that the overall treatment landscape for children under 12 will evolve, allowing more kids to start prophylaxis at a younger age to prevent attacks and significantly improve their quality of life with this condition. An oral therapy is key to facilitating that, as there is hardly any preference for injectables among children. We believe we will be well positioned in this market, and we are excited about the prospects.

Yes, I would add that when you consider that you can just sprinkle our medicine, the granules, onto some soft food or into a glass of water versus the trauma of sticking a needle into a toddler, we should be the market leader. There's no doubt in our minds that that's going to be the case. And I think the other thing that Charlie's referenced in the past is this halo effect. We still have some top HAE physicians that haven't started switching patients, and we know they have pediatric patients, and there's no reason for them to not start using our drug for pediatric patients. And when they see how well it works, our expectation is that, that's going to expand their usage. So we're really excited about this. We haven't put any hard numbers on it yet publicly, but we're really excited about it.

Great. Just also on DME programs, it looks like you're guiding forward data this year. I'd be just curious if you could frame what you would view as a successful outcome for that first readout, given the precedent data, given obviously the novel delivery method, just what are you hoping to see there in the first group of patients?

Yes. So we'll have our first patients on drug. As I said, we have authorization to proceed with enrolling patients in that trial. And what we're looking for is the obvious safety and tolerability, but more importantly to your question, we're looking for the effect on the thickness of the retina, the edema in the retina. So we'll be able to, in those first patients, watch over several months of exposure to assess that retinal thickness and whether that is changing. We do expect it will take a little bit of time to change, but not very long. And I point to some of our preclinical data that shows that in a VEGF-dependent model, the use of oral stat as a plasma kallikrein inhibitor has a result on leakage of the vessels very quickly within six days. So just to say that a readout that we'll be watching this year will be that retinal edema, retinal thickness, and will be observing in the first few patients by the end of the year.

Yes, normally we don't get super excited about SAD studies, but this is in patients. And what we've seen in rabbits is that when you give a single dose, you still have a really high concentration out to six months. So a single dose of this drug in DME patients could tell us a lot and so we're excited to see what we see at the end of the year.

Thanks so much.

You’re welcome.

Thank you. Our next question comes from the line of Maury Raycroft from Jefferies. Please go ahead.

Hi. Good morning. Congrats on the update today, and thanks for taking my questions. I'm wondering if you could just talk more about getting patients onto paid drug and what you did there that worked better than expected and should we expect the rate to be maintained or improved upon going forward or what are some of the drivers you're focused on that could cause the rate to decrease again over time?

Sure, Maury. The number one thing that we did, and we've talked about this before, is we've, over the last couple of years, made investments in our team to make sure that we're really prepared and really expert in this reauthorization process. And we've gotten better every year, and we knew that there was this potential tailwind with Medicare this year. We also knew there was more space that we could improve in the very important commercial segment. And so, I would just say that the team has just reached a level of excellence that allowed them to execute this year. And we're looking forward to further improvements going forward. What we would expect the rest of this year is that, the rate will stay about the same, maybe decrease a little bit because the rest of the year our paid rate is driven more by new prescriptions as opposed to reauthorizations. But where we ended Q1, where we ended April becomes the floor for what I would expect in the future. And I'm very confident we'll reach our 85% goal. We'll reach it ahead of when we expected to originally. And we'll be looking to exceed it if we can.

Yes, the other thing I'd say is, you should take a look at that slide that Charlie referred to around the pattern of revenue this year, it's different, right? So we pulled forward revenue that would usually be a big bump from first quarter to second quarter into the first quarter, so you're going to see less of a bump. I think the other thing, though, that's exciting is that the underlying growth continues to be really strong. And so, that's where we're going to see incremental improvement over the course of the year, and we're really excited to share that with you.

Got it. That's helpful. And maybe just as a follow-up, if you could just provide more specifics on what you did to improve gross to net in the first quarter and what you're doing to better improve that over the course of the year as well.

Yes. So a couple things, Maury. One big, big impact was just the fact that we got so many more Medicare patients paid, and that changed the overall gross to net mix. The other thing is, the team's just been really focused at every little detail that can make a difference, such as how much co-payment assistance do we give to commercial patients? And we've made some adjustments there that have improved gross to net. So the team is being very disciplined, not just about getting patients to pay, helping new patients come on board, but the team is very focused on maximizing the opportunity in all segments. And so, I'm really pleased that we made that kind of progress in the first quarter, and I think that will be durable through the rest of the year.

Got it. Okay, thanks for taking my questions.

Thank you. Your next question comes from Jessica Fye from JP Morgan. Please go ahead.

Hey, guys. Good morning. Thanks for taking the question. I was curious, more specific to the guidance bump for ORLADEYO, can you quantify how much of that increase is related to Part D redesign and a higher proportion of paid patients through that kind of mechanism versus higher than expected demand, versus just execution dealing with the coverage re-offs at the start of the year? And second question, just with profitability pulled forward here, how does that impact how you think about investing in the business? And I guess, more specifically, could that allow you to accelerate any development plans for your earlier stage pipeline? Thank you.

I can take the first part of that. As I mentioned in my remarks, of the 10% improvement in paid rate, about two-thirds of that was related to the IRA helping patients afford their co-pay. So that's great. But what I'm really excited about is, how much progress we made in the 60% of patients who are in commercial insurance, where we improved by close to 5% over where we ended last year, ending up at 84%. So that was the other third of that improvement. Clearly, in terms of raising our guidance for the year, that increase in paid rate overall was the number one factor. But we have an underlying patient growth year-over-year, close to 20%. And as I mentioned, we had one of our best years ever last year, and in the first quarter we were a little bit better than that. And so, that underlying demand is what's going to drive this brand going forward. And then John, do you want to talk about that?

Yes, I'll discuss profitability. We are entering a new territory and are very enthusiastic about it. The programs are fully funded and we are ready to move as quickly as possible. The teams have done an excellent job figuring out how to expedite the programs. Regarding our reinvestments, we recently made a payment of $75 million on the Pharmakon debt. This helps clean up the balance sheet, and by reducing interest payments over time, we will continue to focus on this as cash flow increases for the company.

Operator, I think we can go to the next question.

Yes, thank you. The next question comes from the line of Brian Abrahams from RBC Capital Markets. Please go ahead.

Hi, everyone. This is Nevin for Brian. Congrats on the quarter and thanks for taking our questions. So just a following up from some of the prior questions. So given that you're on around 84% paid drugs and also that you're on the lower end of your growth in net range for the year. Does this potentially indicate that there was a dip in the total patients that were on ORLADEYO and how do you see that kind of evolving into the rest of the year?

Well, I can tell you there wasn't a dip in patients on ORLADEYO. So I'm maybe not quite understanding your question, Nevin. We've had extremely consistent demand. So, again, last year we had as many new patient starts as we did in the first year of the launch, and then we did a little bit better than that in the first quarter. The retention rate of patients has also been extremely consistent the last couple of years, where anybody who starts on ORLADEYO, we get about 60% of those patients to stay on therapy through the first year, and then very few drop off after that. So what we're seeing in patient demand is as strong, if not stronger than we've ever seen it. And then you add on top the paid rate and the improved gross to net. It just means that we're more profitable. And so, we still see reaching $1 billion in 2029, but the path to get there every year with that underlying demand is just going to be more profitable than we previously expected. So it's a great position to be in.

Yes, I think, Nevin, that I don't know if you're referring to that slide of the pattern of sales, which because of the fast change in free drug to paid, the pattern is different than previous years, and it'll probably go back to the same pattern as previous years next year, but there is nothing that is slowing down. And we're really excited about the underlying demand and continuing. And there's more patients to get, quite frankly. I mean, I think the last update Charlie said is around 3,000 patients.

3,000 at the end of last year.

Yes, and there's 10,000 available, so there's plenty more to get. So no signs of slowing down. Just a change in pattern.

Got it. And then I guess on the uptick in patients that you're seeing for a preference for oral prophylactics, what do you think is kind of driving that underlying dynamic there? Have rates of maybe needle phobia changed or is it just a convenience factor that's being appreciated more as they kind of see the more maturing launch of ORLADEYO and the convenience that that offers?

Thanks for the question. From the time we launched, it has been clear that most patients prefer oral therapy over injections. However, what truly matters to them is regaining control over their HAE attacks, meaning they would never choose convenience over effectiveness. Now, more than four years after the launch, patients are recognizing that with ORLADEYO, they can achieve both. They are experiencing strong efficacy alongside convenience. The patient community is very interconnected, and they are hearing positive feedback from peers. Additionally, healthcare providers are increasingly confident in the medication, which is crucial since physician confidence plays a key role. When you combine these insights with our sales and marketing efforts, it’s understandable that patient preferences are emerging more prominently, which is reflected in the approximately 20% growth we've seen over the past couple of years. I wouldn't be surprised if this growth continues.

I think it was around a year ago we told you, Charlie told you that there was a momentum change and that there was a confidence build-up. And that was because more and more physicians were having positive experiences with their patients. Patients talk and doctors talk about other patients to their patients saying, I have a patient that does really well on ORLADEYO, you might want to consider trying it. And so, it's that confidence in the product that I think is reflected in the market research.

Great. Thank you all so much, and congrats again on the quarter.

Thank you.

Thank you. Our next question comes from Stacy Ku from TD Cowen. Please go ahead.

Thanks so much for taking your questions and congratulations on the really impressive quarter. So first, as we think about these additional patient additions and strong patient demand, you've previously added around 60 prescribers per quarter. What are your expectations for this year? And then some follow-ups on Netherton. Are you able to make any disclosures on the Phase 1 early SAD-MAD results? Are you able to disclose anything at this point in time? Or can you narrow the timelines for any updates in Netherton? And then I have a follow-up on Netherton.

Okay, I'll start with the healthcare providers. Good memory, Stacy. Last year we actually averaged 61 new healthcare prescribers for ORLADEYO per quarter. It was 62 in 2023. And in Q1 we had 59. So it's incredible consistency at this stage in the launch that we're still convincing new prescribers. Our team will always go out and find new prescribers. The other thing though is, and John touched on this earlier, but we've made progress in the Tier 1 physicians. So 81% of those doctors have now prescribed and we're seeing more and more physicians become repeat prescribers and even some returning who prescribed some years ago now returning, now that they better understand the product. So the physician dynamics are excellent along with the overall patient dynamics.

And then Helen, you might want to talk about how we're thinking about packaging all the data towards the end of the year.

In terms of the results from the SAD-MAD trial, we have been monitoring it closely. We have initial safety and pharmacokinetic data that gives us confidence to start dosing in patients. This should be viewed as an indication of what we are experiencing. Most importantly, we are focused on the skin outcomes in patients. We will compile all the information together by the end of the year, which will include updates from the healthy volunteer data and, more significantly, the patient outcomes, as well as whether we have reached the dose that promotes skin healing.

Yes, in healthy volunteers, no news is good news.

Okay, wonderful. Well, I guess that leads to my then follow-up about the Netherton. You talked about kind of the early interactions of investigators in the activations of sites, but maybe nuance Part 4 of the Phase 1 study. It sounds like you're getting at least some sense of safety. Could you broaden the POC in the younger patients or are you mainly staying into adults? Thank you.

Part 4 involves extending treatment to serve more patients. We are receiving positive feedback from the sites, with enthusiasm regarding a powerful KLK5 inhibitor that could effectively target the initial stages of the cascade, which physicians are eager to utilize for their patients with Netherton syndrome. The initial patients will be those from Part 3, and we will proceed to open Part 4 to expand enrollment for longer-term exposure. It’s important to view these parts as interconnected rather than separate. By the end of the year, we anticipate having patients in both sections, allowing for long-term follow-up on those who participated in Part 3, as well as more recent follow-up for those in Part 4.

I think one other thing, Stacy, that I'm certainly learning as we learn more about this community and both the physicians and the patients is, there are some significant differences from HAE, right? There's no therapies in place. The organization for advocacy isn't nearly as advanced as HAE was. So those are challenges in finding patients. But the flip side is, the hope we're offering these patients is off the charts, right? They were hopeless, or they have been hopeless, and coping because they have nothing to treat the underlying cause of their disease. And when we start talking to patients and tell them what we're trying to work on, I mean, it brings them to tears. And so that's powerful. And so if we can find these patients, and I'm confident we will, and this drug gets to the skin, we've got something really powerful to help them and give them hope.

Wonderful. Thanks so much.

You're welcome.

Thank you. The next question comes from Gena Wang from Barclays. Please go ahead.

Thank you for taking my questions. I have two questions. I think I joined a bit late, so if these have already been discussed, I apologize. Your paid rate is quite impressive, showing over a 10% increase from last quarter, moving from 73.5% to 84%. You mentioned this during your previous answers, but could you help us understand what led to such a significant improvement in such a short time? Can you explain the process that enabled this remarkable increase in the pay rate? My second question is about the DME. You will have patient data later this year. Can you provide some benchmarks that you will consider encouraging enough to proceed?

Yes. Hey Charlie, maybe I'll start first on this first one and then you can answer the rest. I want to remind everybody that when the Medicare negative thing happened, it snapped the other direction very quickly, like within a quarter. So this is a snap back, but I'll let Charlie explain it in more detail.

Sure. So, to reiterate, a significant portion of the improvement we've seen can be attributed to Medicare. As John mentioned, there was a rapid recovery, which was possible due to our team's preparation. Medicare plans approve ORLADEYO at the highest rate compared to other insurers, and the main challenge for patients was affordability. It's encouraging to see that the IRA is helping patients with costs. Currently, the approval rate among the 20% of our patients on Medicare is 89%, which highlights its status as the leading segment for approvals. On the commercial side, our team has also done extensive preparation. We've gathered long-term real-world evidence, and our understanding of the drug's efficacy has evolved significantly over the past four years. This data enables the team to engage more effectively with payers, convincing them of the drug's effectiveness, leading to more approvals for patients. I believe there is still room for improvement, but it relies on data, preparation, and the positive implications of the IRA being realized.

The other thing before I turn it over to Helen on the DME is, back when patients were struggling to make their copay, we made a very conscious decision to give them free drug. And we kept patients and we actually gained patients as a result of that strategy. So then when the affordability got back to normal, those patients snapped back quickly. And I think strategically that was in hindsight a good move to me. Helen, you want to talk about DME?

Yes. So because we have authorization now to dose in patients, this is a big milestone for this program. We are looking this year to have exposure and experience with a few patients with that single dose. As John mentioned earlier, this is a drug with long durability of exposure. And we're looking for that the outcome, the retinal edema lessening, reduction in the size of the retinal thickness. We're looking for that, and we'll be looking for that for the end of the year. In terms of what then is the benchmark to move forward, we're looking for a really big effect. We're looking for a clear and uncontroversial reduction in edema that would then tell us that we have a dose level that's got the exposure necessary to have that effect. If we don't see that, we will increase the dose. So we'll either see a very significant reduction in edema and know that we have a dose we can take forward, or we'll not have to achieve that yet, and we'll expect to increase the dose until we do.

Yes, I think we've always said, we're looking for signals of activity and starting to get a sense around dose, and that's exactly what Helen said. When you have three patients per cohort, there's a limited amount of information that you can get, but I think if we can see some sort of effect and duration of effect that gives us encouragement, nobody else with a kallikrein inhibitor has done that yet, right? And so, that would be very exciting for the program.

Sorry, if I can follow up. So how many micron reduction you would consider clear and uncontroversial?

So I would use the, within the literature for what is generally accepted as something that's going to be predictive of likely response and visual acuity. I can't give you a number today, but I can tell you we're looking for an uncontroversial difference, so not something that's small.

Okay, thank you.

Thank you. Your next question comes from Laura Chico from Wedbush Securities. Please go ahead.

Good morning. Thanks very much for taking the questions. First one is just going back to the pediatric formulation for ORLADEYO. Can you just remind us on maybe some of the timelines after a pediatric launch arrives? Would there be a lag in deployment to the channel upon approval, just getting material out for supply? And then as we're thinking about the cadence of uptake in the pediatric population versus the adults, just kind of curious what dynamics we should be thinking about that might impact that uptake a little bit differently than what we've seen in the adults. And I have just one quick follow-up.

We will aim to keep the lag as minimal as possible. When we introduced capsules in 2020, it took just two weeks from approval to reach the market, which was impressive. While I can't guarantee we'll be that quick this time, we intend to launch as swiftly as possible. Additionally, we will get our team ready to start promotions immediately. This is crucial since it will take some time for children to see their doctors. As I mentioned earlier, the main difference is that prophylaxis hasn't typically been the standard treatment for children under 12. It has been commonly believed that children mainly show symptoms around puberty. However, our clinical trial revealed that this is not the case for many kids, with the average onset of symptoms being at age two. Shifting the treatment approach for children could significantly impact their lives by preventing attacks and alleviating fears for both patients and parents. This will likely be the most significant change. As Jon and I previously stated, we believe that an oral formulation will be the preferred option for initiating prophylaxis in children. We'll see how quickly we can move forward, but we're receiving a lot of positive feedback from healthcare providers and the patient community regarding these changes.

Yes. And Laura, I'd add one thing. One of the things we learn with adults is, it takes longer than you think. And so that's why we're not getting out over our skis here on giving you guidance on the uptake, because we just don't know yet. We're confident that we will be the market leader because we believe we have a formulation that is way more acceptable to little kids than injectable. But the pattern to get there, it's just too early to predict.

Understood. Okay, thank you for that one. And then one quick follow up on Netherton. Can you remind us the dosing range you're going to be starting with for 17725? And then I just wanted to clarify, I know you mentioned advancing later to 12-week dosing, but what is the actual trigger for that? Is it dependent on occurring sufficient four-week data in the initial cohorts? Any clarity there would be helpful.

Sure. In terms of the dosing range, we have experience with a fairly broad dosing range in healthy volunteers, and we'll be dosing patients in the middle of that range. The dose for patients in the initial part of Part 3 will be 8 milligrams. There isn't a specific trigger for Part 4 after 12 weeks; instead, we'll learn about the dose level and whether we observe initial effects quickly in Part 3. From that, we'll determine if we should maintain the same dose or increase it rapidly in Part 4. Essentially, we'll be dosing initially in Part 3, gathering insights as we move into Part 4, with both parts running concurrently while we continue to observe over time. It's more of a continuous set of two arms that operate together.

Yes, and if the drug works, we'll have an ability to keep patients on drugs.

I see. Okay. Thank you, guys. Congrats on the quarter.

Thank you.

Thank you. Your next question comes from Liisa Bayko from Evercore ISI. Please go ahead.

Hi there. Thanks for taking the question. Congratulations on a strong quarter. Two parts to my question. First is, I just want to make sure I understand that the paid rate improvement that you saw, you've talked about it kind of being like a switch that flips on. Is there any chance this flips back? Can you talk about the sustainability of this paid rate improvement as we head into next year and future years? And then part two is really, can you talk about the patients on treatment today? And then walk us through the kind of remaining pool of patients out there, at least in the U.S., who have not yet tried ORLADEYO and your plans to kind of increase utilization there. Thanks.

Thank you, Liisa. I believe the paid rate will remain very sustainable based on the evidence we've presented for ORLADEYO. It is truly transforming our discussions with payers, and I think that 84% will serve as our new baseline moving forward. As I mentioned earlier, by the end of last year, 3,000 patients in the U.S. had tried ORLADEYO out of approximately 10,000. So far, 52% of our patients have transitioned from other prophylactic treatments, while just over 30% have moved over from acute-only therapies, and the remaining 16% to 18% were previously naive to therapy. I find that last point particularly exciting as it indicates that this is a market still on the rise. We've always recognized the growth in the prophylaxis market, but we're discovering new patients who are now seeking prophylaxis. There are at least another 7,000 patients who have yet to experience ORLADEYO, many of whom will likely be suitable for prophylaxis. When you factor in the 70% preference for oral prophylaxis that we discussed today, alongside the increasing enthusiasm from healthcare providers and our high payment rates, it strengthens overall confidence and should continue to bolster ORLADEYO’s momentum moving forward.

Yes, and if you think about it, if at the end of the fifth year since we got approval we're at about a third of the patients that have tried it and we're at $580 million to $600 million, we are definitely on our path to $1 billion.

You're welcome.

Thank you. Your next question comes from Serge Belanger from Needham & Company. Please go ahead.

Hi, good morning, and congrats on the next quarter. A couple of ORLADEYO questions for Charlie. Now that you've reached your target for the paid rate of 85%, should we expect continued improvements on that number? Is there more to do on the commercial or Medicare side? And then just to follow up on the patient add questions, sounds like 1Q was one of your best quarters ever in terms of new patient ads. Just curious if you're noticing a trend on where these patients are coming from. If it's still 50% pro-fee and 30% acute or is that mix changing with this new batch of new patient ads? Thanks.

Sure. Thanks, Serge. Yes, I think we're almost to our long-term goal of 85%, a little more room there. But what we'll do is, we'll probably up that number. We'll keep striving to get better. I mentioned just a minute ago that in the Medicare segment, that's 20% of our patients, the paid rate is now 89%. And so that shows that we can improve past the 85%. And we'll do everything we can to keep getting better. I don't expect another big tailwind like we had this year, but it's just now going to be incremental improvements. In the first quarter, yes, fundamentally the patient base was very similar to what we've seen since the beginning of launch. The other thing I'd add is, the mix of prescribers that I haven't completely discussed today, but in the first quarter, 55% of the prescriptions were from our top tier of doctors, those physicians that we know treat about 50% of all HAE patients. And then the other 45% came from everyone else. So really balanced across the board. I mentioned earlier, we had 59 new prescribers in the quarter. And so, we just keep capturing more opportunity and we keep capturing it from all the different segments, which gives us that extra confidence in the sustainability of this growth over the next several years.

Operator, we can go to the next question.

Perfect. Thank you. Your final question comes from Jon Wolleben from the Citizens. Please go ahead.

Hey, thanks for taking the questions. A couple on Netherton for me. Can you remind us of your preclinical tox work that you've completed so far? And then, Helen, when you talk about seeing a clinical impact, determining dosing higher, what metrics will you be looking at and what's your bar internally to determine whether or not you're in a sufficient spot in terms of efficacy?

Yeah, sure. So pre-clinical tox, so this is the biologic, it's a protein therapeutic. There's a fairly standard safety profile for protein therapeutics and we're seeing a very consistent profile with that. I think the other thing to look at with preclinical talks is, we have the authorization now to proceed not only in healthy volunteers but also in patients, and that includes authorization in the U.S. and Australia. So just indicative of the range of confidence coming from the preclinical tox data.

Yes, and Helen, I would add we have an open IND and we have the ability to dose in Part 3 up to four weeks and Part 4 up to 12 weeks. So that gives you some sense of the duration of tox and the like.

Right, so standard toxicology to support that. In terms of the clinical impact, so what we're looking for is really normalization of the skin. That means, we're assessing by how the patient feels about their skin. Is there itch still? And we want to see the itch really go away. We're looking also at a physician assessment of the skin and the severity index for thickening and scaling of the skin. And so, we're looking for that redness to go down and for the scaling to stop. I expect that we'll see some of that initially. I expect that it will probably improve over time. And if we need to dose up to get to healing, meaning, normal looking skin and patient not reporting itch, then we'll dose up to that.

How many patients per cohort? Can patients in Part 3 be included in Part 4? And then how do you think about the time-dependent nature of these improvements?

So Part 3 is smaller than Part 4. We could see what we need to see in single-digit patients, so it's going to be fewer than 10 in Part 3. Part 4 will be slightly larger, but it's still an ultra-rare disease and every patient will inform whether we're at the dose and seeing what we need. So it'll be larger, but not much larger in Part 4, maybe more than 10. In terms of the time dependency, we just don't know. We do know that we expect the skin turnover in Netherton syndrome to be about two weeks. We do know that we would expect healing to occur as the skin is turning over. So we may be seeing clinical signs as quickly as four or eight weeks in this. We also may be seeing continuing improvement and healing of the skin because the inflammatory components take a little bit longer to heal. But our goal is to see whether we are getting that initial quick result in the short term four or eight week timeframe after end of dosing and then observe over time as we continue to expand Part 4 and be able to dose patients for a longer period of time.

Super helpful. Thanks, Helen.

Thank you. This concludes our question-and-answer session. I would now like to turn the conference back over to Mr. Stonehouse for closing remarks.

Thank you. It was a great quarter, and I am immensely proud of the employees of BioCryst for achieving these results. We will continue to execute and won't rest on our laurels. There's much more to accomplish this year, and you can count on us to work hard to do that. Thank you for your interest, and we'll keep you updated along the way. Have a great day.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.