Welcome to the BioCryst second quarter 2022 earnings conference call. My name is Vanessa, and I will be your operator for today's call. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session. During the question and answer session, to ask your question, you can enter the queue by pressing zero then one. I will now turn the call over to your host, Mr. John Bluth at BioCryst. Thanks very much, Vanessa. Good morning and welcome to BioCryst's second quarter 2022 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, CFO, Anthony Doyle, Chief Commercial Officer, Charlie Gayer, Chief Medical Officer, Dr. Bill Sheridan, and Chief R&D Officer, Dr. Helen Thackray. Following our remarks, we'll answer your questions. Before we begin, please note that 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. I'd now like to turn the call over to Jon Stonehouse. Thanks, John. The ORLADEYO launch continues to be very strong. Revenue is on track to exceed $250 million this year. New patient starts remain consistently strong now for six quarters in a row. The prescriber base is expanding and deepening. The 96-week data we've begun promoting is resonating with our customers, and the switch data shows ORLADEYO is maintaining disease control while decreasing disease burden. While the vast majority of our revenue is still from the U.S., sales from Europe are starting to grow, and all of this is good news for HAE patients. This is even more exciting when you realize there's so much more opportunity ahead of us, which leads us to refine our guidance for this year to between $255 million and $265 million and continue to track toward $1 billion at peak. Why is this important? Having a meaningful product in the market growing quarter after quarter with very long IP creates an amazing base to build on. In this challenging financial environment, having significant and steady revenue growth is rare and critically important to creating greater value. Our plan is to repeat this ORLADEYO success with our pipeline molecules for other patients suffering from rare diseases. A few companies can get one successful product to market, but if you're able to do it again and again, you can compound value. Key elements to getting there are having a strategy to bring therapies forward that patients truly want and being disciplined by following the data and insights gathered objectively to make informed business decisions about when to invest and when not to. ORLADEYO's success is a great example of this. Wouldn't it have been nice back in the early days of the program if clinical trials and market research pointed to a clear and straight path to success? That's not how it played out. There were clear challenges and things that went differently than planned along the way, and we were disciplined in objectively following the data, studying the switch market carefully and quickly leveraged those insights to make the investment decisions that ultimately are paying off today with our successful launch. We use this approach in all our capital allocation decisions, including our pipeline. This disciplined approach is especially important in the current environment. We see the complement area and the ability to bring oral drugs to fill large unmet needs for these rare disease patients as a massive opportunity that includes factor D and extends even more broadly to include other targets. Our immediate decision is to allocate capital in the REDEEM and RENEW studies to see if we're able to achieve our goal of finding a safe and effective dose with BCX9930. If the data from the first small group of patients enrolled supports this goal, we'll continue to allocate capital to the 9930 program. If not, we'll stop its development, but still pursue factor D inhibitors as we've already invested in next-generation backups and molecules that we hope will be improvements. With the partial clinical hold now removed, preparations to restart enrollment have begun, and Helen will share more with you on what we know now and how we plan to proceed. We have a successful rare disease launch with ORLADEYO growing into a global blockbuster. We have an exciting pipeline of compounds, some you know about and some you don't yet. Lastly, we have substantial capital to make thoughtful capital allocation decisions. This is a unique and very good spot to be in the current environment, and that brings me back to where I started, the tremendous market success of ORLADEYO. The steady and consistent revenue growth, discipline and objective decision-making on capital allocation and alternative financing sources like the additional debt from Athyrium we recently drew down are the things that give us confidence we can repeat the ORLADEYO success with other molecules and create much greater value in the process. Now I'll turn the call over to Charlie to share additional details on another strong quarter of growth of ORLADEYO. Charlie? Thanks, Jon. The consistent pattern of patient growth that we have seen since launch continued without interruption in the second quarter. New patient prescriptions in Q2 were the best since the first quarter of the launch, driven by continued broadening and deepening of the ORLADEYO prescriber base. There is no sign this launch is slowing. Our market research with HAE treaters predicted this expansion, and the 96-week data that we started promoting late last year is convincing physicians to prescribe. When they see the sustained median monthly attack rate of zero, they know that their patients can expect great efficacy. When they see patients doing really well on ORLADEYO in the real world, in particular, those patients who switched after being controlled on injectable prophylaxis, they were encouraged to increase prescribing. Our prescriber data in Q2 reflect this pattern. We added the most first-time prescribers since the third quarter of last year, and we also had an identical number of repeat prescribers. We saw an uptick in prescribing among the top 500 physicians that treat 50% of HAE patients. 60% of those tier one physicians have now prescribed ORLADEYO, and they accounted for two-thirds of new prescriptions in the quarter. Our source of business is also very balanced with overall patient potential. There are roughly 120 physicians in the top three deciles, accounting for 30% of the HAE market opportunity, and they prescribed 32% of the new ORLADEYO prescriptions in Q2. Roughly 1,400 physicians represent the next 40% of the opportunity, and that group accounted for 48% of prescriptions. We also saw an improvement in patient retention. Although it is too soon to call this a trend, we had the fewest number of discontinuations since Q3 of last year, even as the overall number of patients on ORLADEYO has grown substantially. Our metrics on access and reimbursement, which were already good, also continued to improve. The median time to shipment of reimbursed product for a new prescription is now under three weeks as our team helps patients move quickly through the prior authorizations. Healthcare providers worry about the burdens of the access process for HAE treatments, so the success of our patient service model adds to their confidence in prescribing ORLADEYO. We made more progress toward the globalization of ORLADEYO in Q2 with regulatory approvals in Canada and Switzerland and final price agreements in Germany, France, as well as Switzerland. We also entered a commercial distribution agreement with Pint Pharma for Latin America, and we expect to file for market authorization in multiple Latin American countries before the end of 2022. While the ex-U.S. contribution to 2022 sales will be small, the progress we are seeing in Europe and other regions gives us confidence that ex-U.S. sales for ORLADEYO will reach at least $200 million at peak. The prescribing dynamics and the patient trends that we saw in Q2 confirm to us that we are still in the early stages of the ORLADEYO launch trajectory. The trends that we see tell us that ORLADEYO is on track, not only for between $255 million and $265 million in sales in 2022, but also future market leadership and $1 billion in peak sales. Now I'd like to turn the call over to Anthony. Thanks, Charlie. ORLADEYO revenue performance for Q2 was really strong and takes our trailing 12 month revenue to just short of $200 million. With the consistency of new patient growth in the U.S. and continued expansion globally, we're really well-positioned to achieve our updated revenue guidance of $255 million-$265 million for 2022, and on from there to peak sales of $1 billion. You can find our detailed second quarter financials in today's earnings press release, and I'd like to call your attention to a few items. Revenue for the quarter was $65.5 million, of which $65.2 million came from net sales of ORLADEYO. We had around $2.2 million of non-repeating reimbursement-related accrual releases in the quarter, and so ORLADEYO net revenue specifically related to Q2 was $63 million. Having seen Q1 gross to net impacted by reauthorizations, copay assistance, resets, and the government donut hole, Q2 reimbursement rates and gross to net adjustments have normalized and should continue at current rates through year-end. Operating expenses, not including non-cash stock compensation for the quarter, were $90 million. This was lower than we previously forecasted as the team worked hard to manage costs during the 99 30 enrollment hold period. With the program now moving forward, we've lowered our OpEx forecast for 2022 to $390 million-$400 million. Cash at the end of the quarter was at $419 million. Having achieved and maintained the required revenue thresholds to draw the additional $75 million debt tranches from Athyrium, pro forma cash is at approximately $492 million. We have always been and will continue to be responsible and disciplined allocators of capital. This is especially true as we recommence enrollment in the 9930 program. We have taken into consideration the delay to the program, applied a reduced probability of success, and reduced our assumptions for peak penetration. Despite that, there's still significant value potential to support investment in the program. There are numerous markets that we can go into with 9930, not just PNH. These markets are big, especially in renal indications, and this is a drug that patients want. All of that results in a revenue potential for 9930 that is larger than that of ORLADEYO. Our intent is to progress as quickly as possible, limit the additional investment, and get to the point where we have confidence that we have a safe and effective drug. If we can achieve this, then we will continue to invest in moving the program forward. If we cannot, then we will terminate the program and allocate capital elsewhere. This data-driven, objective, unemotional approach has been a key factor in the successful launch of ORLADEYO and will continue to guide us in all of the programs that we have going forward. Now I'll pass it over to Helen. Thanks, Anthony. As we announced today, the FDA has lifted their partial clinical hold on the BCX9930 program, and our pivotal trials in PNH can resume enrollment, along with our proof of concept trial in renal indications. This is an important step forward toward our goal of bringing a safe and effective factor D inhibitor to patients with PNH and complement-mediated renal diseases. We will reinitiate enrollment using a step-up approach and a dose level of 400 mg twice daily, together with encouraging hydration and more frequent safety testing for the first few months in each patient. After review of the data and investigating the elevations in serum creatinine we reported in April, we have arrived at a hypothesis for the mechanism contributing to these observations and our proposal for how to address it. The hypothesis is that crystals are forming in the kidney when the concentration of the drug is highest in the urine, and that this can be mitigated by lowering drug levels in the urine. We will test this by lowering the dose from 500 mg twice daily to 400 mg twice daily and encouraging adequate fluid intake to achieve dilution of the drug as it is excreted in the kidney. If we are correct in our hypothesis and these steps successfully address the problem, this will mitigate the risk of elevated serum creatinine in patients receiving BCX9930. The evidence in support of this hypothesis comes from clinical observations and laboratory studies. As we shared in May, the clinical evidence suggested that the serum creatinine elevations occurred only at the 500 mg dose level and were likely dose-related. In addition, our recent clinical pharmacology studies have shown that a large fraction of the administered dose of BCX9930 is excreted by the kidney. Importantly, new laboratory studies have found BCX9930 drug solubility is lowered over the typical pH range of human urine. Recent nonclinical studies have also demonstrated dose-related crystal deposition in the renal tract and kidneys in animals. Understanding that suggests a mechanism contributing to the rise in serum creatinine. It is likely to be a physical one, where crystals form in the urine, in the kidney when urine concentration of the drug reaches a threshold level. The crystals cause an inflammatory response with resulting damage to the kidney cells. This would explain how kidney function is affected and why a rise in serum creatinine is observed with BCX9930 at 500 mg. It could further explain why it is happening only in some patients and at the 500 mg dose level when intra-renal drug levels exceed a threshold for crystal formation. This mechanism of injury is avoidable. We believe that the keys to avoiding risk of adverse kidney effects are to reduce the load of drug excretion by lowering the dose and to maintain more dilute urine to further lower the concentration of excreted drug by encouraging adequate fluid intake, especially at the time of drug administration. That dose reduction, together with the dilution effect of hydration, is designed to maintain adequate levels of the drug circulating in the blood for efficacy while reducing the concentration on elimination in the kidney to avoid crystal formation. Of course, we also need to maintain strong clinical efficacy. As a reminder, the data from our phase I PNH program supports studying 400 mg twice daily. When C5 inhibitor-naive patients were taking this dose, 400 mg in the phase I program, the hemoglobin rose from baseline by a robust amount, a mean of 4.3 grams per deciliter, and no transfusions were required. This clinical observation was consistent with our PK/PD work, showing that 400 mg twice daily provided plasma levels above the exposure needed to achieve near complete inhibition of the alternative pathway of complement. Given that evidence, we believe that 400 mg twice daily will achieve similar efficacy results to those we saw in phase I. What comes next? If we are correct in our hypothesis, and if the steps we are taking are the right ones to resolve the elevation in serum creatinine while maintaining strong clinical efficacy, we will be able to confirm this in the clinic. Our next steps are to lower the dose for patients already on study, while in parallel, we reopen the studies to enrollment. To do this, we will proceed with regulatory submissions for the amended protocols in the REDEEM clinical trials. We've included simple hydration instructions for all patients. For new patients, we've included a revised regimen to get to the 400 mg dose level with a short initial step-up in dose. We are also amending the RENEW trial with similar measures and initiating the steps to reopen to enrollment at the 400 mg dose in that trial. In terms of testing our hypothesis, we will assess patients in the first months of reopening enrollment in the REDEEM and RENEW trials, and we will observe patient outcomes closely to determine if the data on safety at 400 mg supports continuing to invest through to completion of the pivotal studies. Provided we can recruit patients in a timely manner and the initial data are supportive of safety and efficacy, we will proceed. If the data are not supportive, we will discontinue the BCX9930 program and redirect our efforts and investment elsewhere in our pipeline. How will we know this? As we resume enrollment at 400 mg, we'll look for an absence of the early rise in serum creatinine in new patients enrolling in the study. You'll recall that over the first few months of enrollment in REDEEM-1 and REDEEM-2, and in about 1/3 of the first 15 patients, we saw a rapid rise in serum creatinine at 500 mg. As we enroll patients at 400 mg, this will give us a good basis for comparison to inform our next step. Look at it like this. If about the same small number of patients are treated without similar observations, this will build confidence that the hypothesis is correct and the protocol adjustments are sufficient to address it. By monitoring for serum creatinine at more frequent intervals in the first three months, we will gather the information we need to determine if our hypothesis is correct and if our revised amendments sufficiently resolve the problem. On an individual patient level, more frequent monitoring will allow us to identify any changes in the near term and react swiftly if warranted, both for each individual's safety on trial and for any appropriate decision on continuing the program. It's clear to us that the need for better treatment options in these diseases is significant. Throughout our investigation, we have received unwavering encouragement from our investigators and patient organizations in both the hematology and nephrology communities to find a path forward for BCX9930 if there is one. We are pleased that the FDA has removed the partial clinical hold following their review of our data, our investigation findings, and our proposed protocol adjustments. Because of this high unmet need in PNH and other complement-mediated diseases, and because we believe making a limited additional investment now to test this hypothesis is warranted by the potential value if the program is successful, we continue to pursue our goal of bringing a safe and effective factor D inhibitor to the market for these patients. We are working hard to achieve this goal, and we will make the decisions on where to invest in our pipeline based on sound evidence and where we can create the most value. Now I'll hand the call back to Jon Stonehouse. Thanks, Helen. Let me conclude by summarizing where we are. The ORLADEYO launch through six quarters continues to be strong with no signs of slowing down, and we are on our way to global peak sales of $1 billion. We have a testable hypothesis with BCX9930 that we believe we can answer in relatively short order. If 400 mg BID is a safe and effective dose, we have an asset potentially more valuable than ORLADEYO. If not, we move on to the rest of our pipeline to find the next ORLADEYO. We have a very solid balance sheet, and when the capital markets are challenging like they have been for a while now, we can access other sources of capital. Add this all up and you can see we are creating meaningful value now, and we have the potential for much greater value in the future. That concludes our remarks, and we'll now open up the call to your questions. Thank you. We will now begin our question-and-answer session. If you have a question, please press zero then one on your touch-tone phone. If you wish to be removed from the queue, please press zero then two. If you're using a speakerphone, please pick up the handset first before pressing the numbers. That is star then one to queue up with a question. We have our first question from Stacy Ku with Cowen and Company. Hi, all. Thanks so much for taking our questions and congratulations on a great ORLADEYO quarter. We have a few questions. First, on the BCX9930 update, can you speak about the patients that have stayed on the REDEEM trials? Are there any safety measures that are being monitored? Any updates there? Sounds like they are on 500 mg, and that will be adjusted to 400. That's the first question, those patients. Then for the second, can you talk about kind of that FDA decision a little bit earlier than expected? Should we look into that as any read-through? Kind of it's clearly an overhang for the Street, so any details would be appreciated there. Thank you. Helen, you wanna take the first one? I'll take the second one. Sure. Thanks for the question. With regard to patients on the REDEEM trials, we have continued to monitor them. Patients who remain on drug are doing so because, per the partial clinical hold, they were continuing to derive benefit. They continue on drug. Their results have supported that. We're reducing the dose in all patients. Then on the FDA question, we said the end of third quarter because we didn't know how many rounds we'd go back and forth with the FDA. When we sent in the complete response to their hold, they reviewed it, and we got off clinical hold, so we got off faster than we originally planned. All right. That's very helpful. Thank you. Thank you. We have our next question from Jonathan Wolleben with JMP Securities. Hey, good morning, and thanks for all the color on the 9930 update. Just wanted to ask, previously you discussed two different patterns of the creatinine elevations, some patients seeing it early and then some developing over time. These mitigation steps seem to affect the latter, but wondering if you talk about, you know, the potential of this cropping up over time in some patients as they stay on 9930 long term. Let me start, and then you and Bill can jump in. I think the important thing is a small number of patients, like we saw in the early start of the enrollment of the REDEEM study, is gonna give us a sense of the first pattern, which was that acute rise, and those same patients we're gonna continue to track over time, and we'll get a sense of what happens over time with that same small group of patients. I think we get the benefit from both patterns with this early group of patients. I can answer on another point on the early rise and the slow trend. We think this is a threshold effect. We think it's a threshold of the drug concentration in the urine that could explain both the early rise findings and the slow later findings. We expect to be able to answer each of those questions in the first small group of patients who are enrolled. That's helpful. Maybe a couple follow-ups. Helen, you discussed a few different procedural steps to get new patients in. Wondering, when do you think you could start dosing new patients in REDEEM and RENEW? Also, when you're thinking about this early evaluation, you know, what is the bar that's acceptable? Do you have to see complete absence of serum creatinine, or is there any discussion with FDA about, you know, what can you see that's tolerable and what isn't tolerable here? Yeah. Maybe on that second one, the stopping rule, and on the first one's pretty straightforward. We have some work to do initially, which is to get the protocols up and running. We have to submit to countries and sites. That will take a few months, and then we will be enrolling from there. We expect that within the first few months of experience with the first patients, we'll have the opportunity to see data. This is an incremental approach. First is get to the readiness for startup, then get to enrollment, then get to the data. In terms of what we're looking for then, we think that this is a threshold effect, as I said. The goal is to avoid that. What we're looking for is the patients to be dosed at the 400 mg dose level and for us to be seeing in those new patients that we're not observing these findings. Yeah. If we have serum creatinine major increases, you know, in serum creatinine, then we don't have a drug that's safe and effective, right? It's pretty straightforward. On the first point, we're gonna go as fast as we can, right? You know, it's hard to predict how quickly that'll happen, but we're gonna go as fast as we can. I'll jump back in the queue. Thanks for taking the questions. Yep. We have our next question from Chris Raymond with Piper Sandler. Yeah, thanks. Two questions. I guess first on BCX9930, maybe could you provide a little bit more color on the sort of hydration protocol, I guess, you're describing? I'm just trying to understand, you know, what specifically you're you submitted to FDA in terms of, you know, the, what patients need to do. Is it more the hydration or the lower dose, I guess, that you know you're hypothesizing can alleviate this issue? And maybe just give us a sense of, you know, how this sort of translates into the real world, you know, if in fact you keep going with this hydration protocol and it's approved and, you know, then there's this requirement for patients to hydrate. And then the second question on ORLADEYO. You know, we've done some KOL checks. I'm kinda curious what you guys are seeing in the larger market. The feedback we've gotten is that overall prophy share is relatively growing steadily, but share of new patients is really where the, you know, the bolus of use is, like 80% or more of new patients, at least from one of our KOLs. I guess I'm just kinda curious, what are you seeing in the broader market? If you're seeing a similar sort of proportion there, what kind of lag do you anticipate, you know, before this really starts to accelerate total share? Thanks. You wanna take the first one on hydration? Yep, with 9930, the hydration protocol is actually really simple. It's simply to encourage hydration while on the drug. That could be as simple as taking the drug with a glass of water. We've not prescribed specifically what it should be, but it's encouraging hydration. The reasoning behind that is that we're taking a two-pronged approach to be able to get the urine concentration below the threshold for formation of any crystals, and that's both with the dose reduced within the effective dosing range and the addition of hydration in order to get to that sustained level below the threshold for crystal formation. In terms of where this would go in the sort of next, if you use this in the real world, it's really quite simple. This is as simple as take your medicine with a glass of water. We think that this is very achievable. Great. Charlie, you wanna take the ORLADEYO? Yeah. Yeah. Hey, Chris. Thanks for the question. First of all, overall, 50%, about 50% of the patients that are on ORLADEYO today have switched from another prophylaxis product, and that's really in proportion to what we think is the market share. About half of those switchers, prophy switchers are coming from TAKHZYRO, then HAEGARDA and so on. As you know, I talked about the prescriber base. We've got a really big prescriber base, and so I think we're still early in this process of getting all the different KOLs to fully understand this. I think in the future, they will switch more patients. Across the overall market, there's been a lot of switching. As more and more doctors get familiar with our data and see the real-world efficacy that those Prophy switchers are having, I expect that the trend will continue. Yep. Thank you. We have our next question from Jessica Fye with JP Morgan. Hey, guys. Good morning. Thanks for taking my questions. A couple more for you on 9930. When you talk about a reasonable timeframe and a relatively small number of patients needed to find a safe and effective dose, can you just elaborate on how you define two things? First, is a reasonable timeframe the three months you talked about in prepared remarks, and is that three months from today, or is that once you get three months of follow-up on a small number of patients and it could take a few months to spool up enrollment again? Second, how do you define a small number of patients? Is that a dozen? A couple dozen? Just trying to figure out when investors will have more clarity here. I think it's important to look at what we saw in the study that caused us to stop, right? It was about 15 patients roughly in enrollment in the REDEEM studies that we saw this effect. We think it, you know, a similar number is roughly what'll give us confidence that we're not seeing the effect or we are. The timeframe for that, as Helen said, you know, it could take some months to get the revised protocols. These are major amendments, and so you gotta go to the regulatory authorities. Then, you know, it took about two months to see the effect in these patients. Once we got it up and running and we're enrolling patients, it'll be, you know, a couple of months before we see. We feel like we're in the position where we know what we're seeing. I hope that gives you a little bit more frame. It's really hard to predict, Jess, because it you know, takes time to get these things approved and then start enrollment. Okay. We're gonna, you know, work as fast as we can, and, you know, we'll keep you updated along the way. Got it. I appreciate the kind of deliberate approach here. I can understand how a small number of patients can rule in a safety issue, but how do you get comfortable that a small number of patients can rule out a safety issue? Yeah, maybe I'll start, and then you and Bill can jump in. You know, the hypothesis is based on the data we've gathered to date, right? Which is a combination of the clinical data and what we saw at 400 and what we saw at 500, and then what we saw in clinical pharmacology and what we saw in laboratory tests and some recent animal studies. We believe it's a threshold effect that causes the drug to go out of solution and causes a clogging of these tubules. We think that if we don't see these elevations, we won't, you know, it's not something that'll linger on over time, right? It's not. This drug doesn't accumulate, so it's not something that'll happen over time. It's not an exposure issue, it's a threshold issue. That's why we think, you know, the small number of patients in the early phase of the study will give us much more confidence. Helen or Bill, anything else you wanna say? I would only add that the findings in that first group of patients that, you know, for which we paused enrollment, those were pretty definitive. They were pretty early, and I think if we don't see that in the first group that's about the same size as you said, it would give us increasing confidence. This is gonna be an incremental approach as well. We need that first step. We need to see that, and then we'll continue to follow them and add more patients. Thank you. Yeah. I would only add that it, you know, gives you confidence to complete enrollment in the studies. Yeah, that's right. Thank you. Our next question is from Maurice Raycroft with Jefferies. Hi. Thanks for taking my question. For ORLADEYO, can you elaborate more on what the ideal patient is to switch and the ideal patient to benefit from ORLADEYO? I guess are there some observations that you're seeing from the front line on that you can talk about? Yeah. Hey, Maury. Good question. Yes, we're starting to get an increasing amount of evidence about the ideal patient, and it really is patients who were already well controlled on another prophy drug. If they had a very low attack rate coming in, most of those patients tend to stay at the same low attack rate on ORLADEYO. As I think, as more and more physicians start seeing that and as more and more patients start experiencing that's where we're gonna see more of the trend of switching continuing and maybe even increasing. Charlie, when you say low attack rate coming in, you mean on their prophy therapy? Exactly. On their existing prophy therapy, and then they switch and keep the same low attack rate on ORLADEYO. Got it. Thanks for providing all of the detail on 9930 as well. I'm just wondering for the actual molecule, do you have an understanding of why it's crystallizing? Is that something that is relevant as to why the molecule is actually crystallizing? Helen, you or Bill? Yeah, I can take that. We have since making these observations, as said in the remarks, we've done further work in the laboratory, and we've been able to establish the solubility level at the pH range in the urine. It's simple crystal formation, as a result of the molecule's chemistry. There's nothing really special about it. Now that we know that, we know what to look for. Got it. Okay. Thanks for taking my questions. Thank you. As a reminder, if you have a question, please enter the queue by pressing zero then one. We have our next question from Gena Wang at Barclays. Thank you very much for taking my questions. I have a few regarding the ORLADEYO. I hope I did not miss it. Just wondering, have you mentioned the patient retention rate? Would they still maintain at a 70%? Regarding the new patient percentage of patients that switch from other prophy, what was the number there? Was that still like 50%? Quickly on the pricing, I know you finalized in Germany, France and Switzerland. What are the comparison, you know, the price compared to the U.S. price? Sorry, one last question. Regarding factor D, how much initial capital allocation will you put for that program? Yeah, go ahead, Charlie. Great. Hey, Gena. On patient retention, what I did note is that we had a decrease in discontinuations in Q2. Retention, it's too soon to call it a trend, but it appears to be getting better. It's been a real focus of the team, particularly in improving retention early in therapy so that patients don't give up too early. The overall retention rate since launch, I think I've said before, was in the mid-60% retention since launch. It's similar to that. But what's really important now is we see some signs that this is improving. As far as the overall switch rate, I think I just mentioned a minute ago, but about 50% of the patients have switched from other prophy and then the other 50% is mostly switching from acute only and then some patients who are naive to therapy starting ORLADEYO as their first drug. Yeah, Charlie, I think part of her question was retention in those folks. It's actually better in those. That was the other part. I've mentioned this in previous calls that the retention of people switching from injectable prophy at six months for TAKHZYRO, HAEGARDA, CINRYZE is in the high 70%. That's based on the fact that, you know, they were well controlled before and they stayed, most of those patients stay well controlled on ORLADEYO. Then you had a question about EU pricing. Our German list price is about EUR 156,000. The Swiss price is a little bit higher than that. You get a sense for how that compares to the U.S., where our WAC pricing is $499,000 Anthony, you wanna take the capital allocation question? Yeah, sure. From a capital allocation perspective, it's, you know, it'll depend on how quickly we can move through the trials. Our intent is to move as quickly as possible. Helen talked about it being incremental in terms of how we move forward with the program. One thing I will say is we've talked about it being a small number of patients that we need at the start. We've also said in the guidance that we've reduced our OpEx guidance down to $390 million-$400 million for the year. That in combination with the revenue increase in the guidance means from a net cash burn perspective, we're definitely in a better spot now than we were previously. Listen, we'll be absolutely responsible and smart in terms of how we invest that capital. It is the right investment in capital at this point in time, given the potential returns. Thank you very much. We have our next question from Brian Abrahams with RBC Capital Markets. Good morning. Thanks for taking my questions and, congratulations on the continued strong ORLADEYO launch. A few from me, I guess on 9930. Are there, like, mechanistically different considerations with regards to this crystal formation for PNH patients versus those with underlying kidney disease? Secondly, on the interim assessment that you're gonna be doing, will efficacy be a part of that? And will the FDA have any requirements that they'll need to sign off on before the trial is expanded out? And then lastly, on ORLADEYO, it sounds like you're reiterating your billion-dollar peak sales estimate. I'm just wondering if there's any evolution in the parameters that form your confidence around that. It sounds like the U.S., ex-U.S. breakdown is similar to what you had expected before, but just wondering if the improving retention, new patient starts, degree of overall market growth, how those factors are evolving to continue to shape that goal? Thanks. Helen, you wanna take the 9930, and then Charlie can take the ORLADEYO. The first question was, is there any mechanistic difference in this, in the patients with different diseases? We don't think so. I mean, the hypothesis is crystals forming when there's a high concentration of the drug excreted in the urine. That is a drug that's independent of disease. Once we have solved this for a dose that is safe and effective in one disease, we would expect that to be relevant in all diseases. The second question was in terms of what we are assessing on an interim basis in the study. This is a simple safety assessment. It's simple observation. If we see continued episodes of a rise in creatinine in patients being dosed at 400 mg, then we'll know that we're seeing it. If we're not, then we won't be. That's the extent of the interim view. Yeah. His question two was around the FDA and efficacy. There were no requirements by the FDA. They, you know, they're always looking at a benefit risk, and clearly they see some benefit in keeping the patients on the study and us continuing the study. From an efficacy perspective, you know, if we have breakthrough hemolysis, you know, we'll see that. We're evaluating whether the DMC can look at the blinded data or unblinded data as well from an efficacy perspective. You know, we'll, we're concerned about both, Brian, and those, you know, we said before, the goal is a safe and effective drug. Brian, as far as the $1 billion, nothing significant has changed. We do, as you know, we do a lot of market research, a lot of planning. As we see the real-world evidence, the real-world results matching up what we expected, we gain even more confidence and reiterate. You know, what we're seeing in Europe, the early uptake, the pricing that we've been able to achieve is in line with our expectations. That gives us great confidence in the getting to at least $200 million in the rest of the world. The real-world evidence that I've talked about coming out of patients who are switching to ORLADEYO, in the U.S., and the fact that most of those patients are staying on drug and having a great experience gives us that much more confidence. What I said about our prescriber base expanding, all of this just gives us more confidence in where this drug is headed at peak. Yeah. Quarter after quarter, it keeps getting better, right? We're growing sales, we're expanding prescribing, we're getting more into the funnel in terms of new patients. It, you know, our confidence goes up every single quarter. There is no sign of slowing down. It's really helpful. Thank you, guys. We have our next question. Our next question comes from Serge Belanger with Needham & Company. Hi, good morning. I guess one on 9930 to start off. Did I hear correctly that you are evaluating some of the backup molecules to 9930? And if I did hear correctly, how close are they to being ready for clinical evaluation? And then on ORLADEYO, a couple for Charlie. Can you talk about where you are with market share now, and in terms of new patient add cadence, how it progressed in the second quarter, and maybe whether you expect summer seasonality impact on that cadence? Thank you. I'll take the backup one, Charlie Gayer, and then you take the ORLADEYO new patients. Yeah, we're always working on backups, and we didn't slow down. We've always put, you know, full court press on. I said in the remarks that we're investing fully in those. Can't tell you yet, you know, when it's ready to share more broadly, but, you know, there are multiple backups, and as we have more data, we'll share that with you. I think the other piece is, you know, we work to have improved molecules as well. You saw that with the move from avoralstat to ORLADEYO. You know, in this program, we're trying to do the same. You know, whether or not we'll be successful is to be determined, but full speed ahead on the backups. Serge, as far as market share, we've shared some of our market research in the past. I think most recently, some data from earlier this year, the survey showed ORLADEYO share of about 12%. That was probably a little ahead of where we actually were in the market at the time. We've grown since then. It's growing all the time. Physicians see in our market research this becoming their most prescribed drug in the future. As we've said before, you know, all we need is 25%-30% market share in the U.S. to get to about $750 million-$800 million towards that billion dollars of peak sales. We're doing well. Then as far as the new patient cadence, I mentioned in the remarks that we had the most new patient prescriptions in Q2 since the very first quarter of the launch. That's, you know, really significant now six quarters in, no signs of slowing down. As far as the summer slowdown, any differences there? You know, we'll see. We'll talk about that after Q3, but we ended Q2 in June really strongly. So I feel good about where we are. Thank you. You're welcome. Thank you. We have our final question from Liisa Bayko with Evercore ISI. Hi. Thanks for taking the question. I understand what you're saying about the threshold effect for 9930, yet you did have some patients that, you know, had these elevations and some that didn't. Any ability to decipher what that is, and what's your threshold? You know, I know you saw it in 15 patients. Like, if you see one case, is that enough to stop? You know, what's your threshold for, like, seeing cases, as you know, go into this next phase now? I can take the question. On the threshold, yes, we have seen this in some patients, not all. We do think this is a threshold effect. What that means is that in some patients, under some circumstances, crystals could be forming, and we're pretty close to the edge of that threshold with the 500 mg dose. That's what we infer. That means that with the two-pronged approach, and that's part of why we're taking that two-pronged approach of reducing the dose and hydration, we could see that we get below the threshold for all patients at all times. That's the goal, is to avoid this. This is, you know, this is hypothesis. We're still working on this. We need to observe in the clinical setting if we've addressed this with 400. That's why we think it's happening. It's sporadically occurring because we're close to the threshold some of the time, but not all the time. The stopping rule and you know, what's the, I think that's important for people to know. Yeah. The question is one case enough? What we think is that there are multiple things that can also occur in patients with these diseases that can cause rise in serum creatinine. We want to make sure that we are assessing any rise in serum creatinine in the context of what's happening with the patient, and if it is likely to be related to the drug or something else. We're assessing these. We will review them together with our DMC. We have a stopping rule in the studies that is if we see three events that are serious events and that are considered to be related to the drug, that's the point at which we would stop the study. Okay. It's three cases. Okay. Then, just this notion of inferring. Like, what makes you believe that 400 is sort of below that threshold? It's a hypothesis, and it's based on what we see at this point. In the data, we have not observed this at 400 mg, and we do have every patient in the phase one went through the 400 mg stage of dosing. Yeah. It's a drug concentration thing. If you have less drug and you have more hydration, less chance of having it go out of solution, right? Mm-hmm. There's logic there too. Okay. Sorry, I may have missed it, but did you break down sales like U.S., you know, Japan, rest of world, or could you do that? We have not broken that out yet, Liisa. Yeah. The reason we haven't is that, you know, the majority of it is U.S.. The other stuff isn't significant enough to report out. It is growing. I mean, what I said in the remarks, that it's nice to see it growing, and that's not surprising because now we've got pricing, now we've got promotion, now, you know, patients are getting on therapy. Over time, you know, we will break it out, but at this point it's vast majority is U.S.. Okay. One quick question. I've been getting questions from clients, you know, lately about the types of patients who stay on ORLADEYO for longer than six months. Is there any relationship between sort of severity of disease and response? If you could just kind of talk about the kind of patients who tend to be more sticky. You know, related question on severity and response to ORLADEYO. Thanks. Yeah. The type of patient that tends to be the most sticky are, again, those patients who were well controlled on another drug and then switched over to ORLADEYO and remain well controlled. You know, the fact that they were on prophylaxis prior suggested they, you know, they needed their attacks controlled. They maintain that same rate on ORLADEYO. Yeah. This idea of, you know, attack severity or frequency of attack, you know, people control their disease now, so that's like. That's an old way of looking at it. Now, the way you should look at it is where are we getting the business? We're getting it from people that are controlled on their injectable therapy but don't want the burden of therapy, the injectable therapy. Those are the people we're getting, and that'll continue to grow, and we'll get more and more share of that. All right. Thanks. You're welcome. Thank you. This concludes our question and answer session. I will now turn the call over to Mr. Stonehouse for closing remarks. Yeah. Thank you. Something I've learned, and I think we've learned as a company over many years of working on many, many projects, is the importance of objectivity and following the evidence and the data in our decision-making. You know, whether it's clinical data that we're looking at to advance a program or market data, do we have the right profile that'll be competitive in the marketplace? If you go into it wanting to see a certain thing, you're not gonna be objective, and you could make the wrong decision. We don't do that at BioCryst. We look at the evidence, and we make our decisions based on what we see. I think as a result of that, we're starting to create greater value and have more success. ORLADEYO is the case study for that. If you're not familiar with our thinking, we encourage you to get to know us better and we can share with you know. Listen, it's not the only part that's important in success. People, good science is also, but the decision-making on this stuff and the objectivity is critical, and we think it affects value tremendously. Thanks for your interest in our company and have a great day. Thank you. Ladies and gentlemen, this concludes our conference. Thank you for participating. You may now disconnect.