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, [Operator Instructions] 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 will 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 6 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 of 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 towards $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. 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 gain 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…

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 0, 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 are 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 1 physicians have now prescribed ORLADEYO, and they accounted for 2/3 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 3 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…

Thanks, Charlie. ORLADEYO revenue performance for Q2 was really strong and takes our trailing 12-month revenue to 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 to $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 nonrepeating reimbursement-related accrual releases in the quarter and saw ORLADEYO net revenue specifically related to Q2 was $63 million. Having seen Q1 gross to net impacted by reauthorizations, co-pay 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 noncash stock compensation for the quarter was [ $90 million. ] This was lower than we previously forecasted as the team worked hard to manage cost during the 9930 enrollment hold period. With the program now moving forward, we've lowered our OpEx forecast for 2022 to $390 million to $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 the reduced probability of success and reduce their 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 milligrams 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've arrived at the 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 milligrams twice daily to 400 milligrams 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-milligram 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…

Thanks, Helen. Let me conclude by summarizing where we are. The ORLADEYO launch through 6 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 9930 that we believe we can answer in relatively short order. And if 400 milligrams 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.

[Operator Instructions] We have our first question from Stacy Ku with Cowen and Company.

Congratulations on a ORLADEYO quarter. So we have a few questions. First, on the 9930 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? It sounds like they are on 500 milligrams and that will be adjusted to 400 milligrams. That's the first question, those patients. And then for the second, can you talk about kind of that FDA decision a little bit earlier than expected. So should we look into that as any read through? Kind of it's clearly an overhang to the street. So any details would be appreciated there.

So Helen, do you want to take the first one, I'll take the second one?

Sure. Thanks for the question. So 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 drive benefits. They continue on drug. Their results have supported that, and we're reducing the dose in all patients.

And 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. And when we send 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.

We have our next question from Jon Wolleben with JMP Securities.

Thanks for all the color on the 9930 update. Just wanted to ask, previously, you discussed 2 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 could talk about 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. So 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 going to give us a sense of the first pattern, which was that acute rise. And those same patients we're going to continue to track over time, and we'll get a sense of what happens over time with the same small group of patients. So I think we get the benefit from both patterns with this early group of patients.

And I can answer on the -- another point on the early rise and the slow trend. We think this is a threshold effect. We think it's 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 were enrolled.

That's helpful. And then maybe a couple of follow-ups. Helen, you discussed a few different procedural steps to get -- take new patients in. Wondering, when do you think you could start dosing new patients in REDEEM and RENEW. And then also when you're thinking about this early evaluation, what is the bar that's acceptable? Do you have to see a complete absence of serum creatinine, or is there any discussion with FDA about what can you see that's tolerable and what is intolerable here?

So maybe on that second one, the stopping rule and on the first one's pretty straightforward.

Yes. So we have some work to do initially, which is to get the protocols up and running. We have to submit 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 [ track ] patients will have the opportunity to see data. So this is an incremental approach. First is get to the readiness for start-up, then get to enrollment and then get to the data. And 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. And so what we're looking for is the patient to be dosed at the 400-milligram dose level and for us to be seeing in those new patients that we're not observing these findings.

Yes. If we have serum creatine major increases in serum creatinine, then we don't have a drug that's safe and effective, right? So it's pretty straightforward. And on the first point, we're going to go as fast as we can, right? It's hard to predict how quickly that will happen, but we're going to go as fast as we can.

We have our next question from Chris Raymond with Piper Sandler.

Two questions. I guess, first on 9930. 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 what specifically you're -- you submitted to FDA in terms of that -- what patients need to do. Is it more the hydration or the lower dose, I guess, that you're hypothesizing can alleviate this issue. And maybe just give us a sense of how this sort of translates into the real world, if in fact, you keep going with this hydration protocol and it's approved and then there's this requirement for patients to hydrate. And then the second question on ORLADEYO. We've done some KOL checks. I'm kind of 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 bolus of use is like 80% or more of new patients, at least from one of our KOLs. So I guess I'm just kind of curious, what are you seeing in the broader market? And if you're seeing a similar sort of proportion there, what kind of lag do you anticipate before this really starts to accelerate total share?

Do you want to take the first one on hydration?

Yes. So 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. And so we think that this is very achievable.

Great. Charlie, do you want to take the ORLADEYO?

Chris, thanks for the question. So 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. So about half of those switches -- prophy switches are coming from Takhzyro, Haegarda and so on. As 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. And I think in the future, they will switch more patients. But across the overall market, there's been a lot of switching. And 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.

We have our next question from Jessica Fye with JPMorgan.

So a couple more for you on 9930. When you talk about a reasonable time frame and a relatively small number of patients needed to find a safe and effective dose, can you just elaborate on how you define 2 things? First, is a reasonable time frame, the 3 months you talked about in the prepared remarks? And is that 3 months from today? Or is that once you get 3 months of follow-up on a small number of patients, and it could take a few months to spool up enrollment again? And then second, how do you define a small number of patients? Is that a dozen, a couple of dozen? I'm just trying to figure out when investors will have more clarity here.

Yes. So I think it's important to look at what we saw in the study that caused us to stop, right? So it was about 15 patients roughly in enrollment in the REDEEM studies that we saw this effect. And so we think similar number is roughly what will give us confidence that we're not seeing the effect where we are. And the time frame for that, as Helen said, it could take some months to get the revised protocols. These are major amendments. And so you got to go to the regulatory authorities. And then it took about 2 months to see the effect in these patients. So once we got it up and running and we're enrolling patients, it will be a couple of months before we see -- we feel like we're in a position where we know what we're seeing. So I hope that gives you a little bit more frame. It's really hard to predict, just because it takes time to get these things approved and then start enrollment. But we're going to work as fast as we can, and we'll keep you updated along the way.

Got it. And I appreciate the kind of deliberate approach here. And 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?

Yes. Maybe I'll start and then you and Bill can jump in. 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 milligrams ] and what we saw at [ 500 milligrams ] and then what we saw in [ Clinfarm ] and what we saw in laboratory tests and some recent animal studies. And so we believe it's a threshold effect that causes the drug to go out of solution and causes a clogging of these tubules. And so we think that if we don't see these elevations, we won't -- it's not something that will linger on over time. right? It's not -- this drug doesn't accumulate, so it's not something that will happen over time. It's not an exposure issue. It's a threshold issue. So that's why we think the small number of patients in the early phase of the study will give us much more confidence. Helen or Bill, anything else you want to say?

I would only add that the findings in that first group of patients that -- 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, it's about the same size, as you said, it would give us increasing confidence. This is going to 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.

Yes. I would only add that it gives you confidence to complete enrollment in the studies.

Yes. That's right.

Our next question is from Maury Raycroft with Jefferies.

For ORLADEYO, can you elaborate more on what the ideal patient is to switch and the ideal patient to benefit from ORLADEYO? I guess there are some observations that you're seeing from the front line on that, that you can talk about?

Yes. Maury, good question. And, 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. And so I think as more and more physicians start seeing that and as more and more patients start experiencing that, that's where we're going to see more -- the trend of switching continuing and maybe even increasing.

And 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. And -- any -- and 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? And is that something that is relevant as to why the molecule is actually crystallizing?

Helen, you or Bill?

Yes, I can take that. So we have -- since making these observations, as I 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 molecules chemistry. So there's nothing really special about it. But now that we know that, we know where to look for.

[Operator Instructions] We have our next question from Gena Wang at Barclays.

I have a few regarding the ORLADEYO. And so I hope I did not miss it. Just wondering, have you mentioned the patient retention rate, would they still maintain at 70%? And regarding the new patient percentage of patients that switched from other prophy, what was the number there? Was that still like 50%? And then quickly on the pricing. I know you finalized in Germany, France and Switzerland. What are the comparison -- the price compared to the U.S. price? And sorry, one last question regarding Factor D, how much initial capital allocation will you put for that program?

Yes, go ahead, Charlie.

Great Gena. So on patient retention, what I did note is that we had a decrease in discontinuations in Q2. So retention, it's too soon to call 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. And 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.

Yes, Charlie, I think part of your question was retention and those folks, it's actually better in the...

Yes. Sorry, yes, right. That was the other part. Yes. So -- and I've mentioned this in previous calls that the retention of people switching from injectable prophy at 6 months for Takhzyro, Haegarda, Cinryze is in the high 70%, and that's based on the fact that they were well controlled before and they stay -- most of those patients stay well controlled on ORLADEYO. And then you had a question about EU pricing. So our German list price is about EUR 156,000. The Swiss price is a little bit higher than that. So you get a sense for how that compares to U.S. where our WAC pricing is $499,000.

And then, Anthony, you want to take the capital allocation question?

Yes, sure. So from a capital allocation perspective, it will 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 to $400 million for the year. So 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. So 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.

We have our next question from Brian Abrahams with RBC Capital Markets.

Congratulations on the continued strong ORLADEYO launch. A few for me. I guess, on 9930, are there 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 going to 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 extended out? And then lastly, on ORLADEYO, it sounds like you're reiterating your $1 billion 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?

So Helen, do you want to take the 9930 and then Charlie can take the ORLADEYO?

Yes. So the first question was, is there any mechanistic difference in this -- in the patients with different diseases. And we don't think so. And the hypothesis says crystals forming when there's a high concentration of the drug excreted in the urine. That is a drug that's independent of disease. So 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 rise in creatinine in patients being dosed at 400 milligrams, and we'll know that we're seeing it, if we're not, then we won't be. And that's the extent of the interim view.

Yes. And his question too was around the FDA and efficacy. There were no requirements by the FDA. They they're always looking at a benefit risk. And clearly, they see some benefit in keeping the patients on the study and us continuing study. But from an efficacy perspective, if we have breakthrough hemolysis, we'll see that. And we're evaluating whether the DMC can look at the blinded data, our unblinded data as well from an efficacy perspective. So we're concerned about both, Brian. And those -- we said before, the goal is a safe and effective drug.

Brian, the -- 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. And as we see the real-world evidence, the real-world results matching up what we expected, we gain even more confidence and reiterate. So what we're seeing in Europe, the early uptake, the pricing that we've been able to achieve is in line with our expectations. And so that gives us great confidence in getting to at least $200 million in the rest of the world. And then 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. And then what I said about our prescriber base expanding. All of this just gives us more confidence in where this drug is headed in.

Yes, and 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. Our confidence goes up every single quarter. There is no sign of slowing down.

We have our next question. Our next question comes from Serge Belanger with Needham & Company.

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 it 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?

So I'll take the back up one, Charlie, and then you take the ORLADEYO new patient. Yes, we're always working on backups and we didn't slow down. We've always put full code advance -- I said in the remarks that we're investing fully in those. And so I can't tell you yet when it's ready to share more broadly. But there are multiple backups. And as we have more data, we'll share that with you. And I think the other piece is we're working to have improved molecules as well. And you saw that with the move from avoralstat to ORLADEYO. And so in this program, we're trying to do the same, whether or not we'll be successful is to be determined, but full speed ahead on the backups.

And then 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. We -- the survey showed ORLADEYO share of about 12%. That was probably a little ahead of where we actually were in the market at that time. But then we've grown since then. So it's -- and physicians see in our market research see this becoming their most prescribed drug in the future. And as we've said before, all we need is 25% to 30% market share in the U.S. to get to about $750 million, $800 million towards that $1 billion of peak sales. So it's growing all the time. We're doing well. And 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. And that's really significant now 6 quarters in. No signs of slowing down. And as far as the summer slowdown, any differences there? 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. We have our final question from Liisa Bayko with Evercore ISI.

I understand what you're saying about the threshold effect for 9930, yet you did have some patients that had these elevations and some that didn't any ability to decipher what that is? And what's your threshold I know you saw it in 15 patients. Like if you see one case, is that enough to stop what's your threshold for like seeing cases as you go into this next phase now?

So I can take the question. So 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-milligram dose. That's what we infer. And 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 all the time. And that's the goal is to avoid this. So this is a hypothesis. We're still working on this. We need to observe in the clinical setting if we've addressed this with 400 milligram. But 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.

And then the stopping rule. And then what's the -- I think that's important for people to know.

Yes. So -- and the question is one case enough. So 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 where -- what's happening with patient and if it is likely to be related to the drug or something else. So we're assessing these. We will review them together with our DMC. We have a stopping rule in the studies that if we see 3 events that are serious events and that are considered to be related to the drug, that's the point in which we would stop the study.

Okay. So it's 3 cases. Okay. And then just this notion of inferring. So like what makes you believe that $400 milligram is sort of below that threshold?

So 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 milligrams. And we do have every patient in the Phase I went through the 400-milligram stage of dosing.

Yes. 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? So there's logic there, too.

Okay. Okay. And then sorry, I may have missed it, but did you break down sales like U.S., Japan, rest of world? Or could you do that?

We have not broken that out yet, Liisa.

Yes. And the reason we have it is the majority of it is U.S. So the other stuff isn't significant enough to report out. But it is growing. I mean I said that in the remarks that it's nice to see you're growing, and that's not surprising because now we've got pricing, now we've got promotion, now patients are getting on therapy. So over time, we will break it out. But at this point, it's vast, vast majority is U.S.

Okay. And then one quick question. I've been getting questions from clients lately about the types of patients who stay on ORLADEYO for longer than 6 months. And is there any relationship between sort of severity of disease and response. So if you could just kind of talk about the kind of patients who tend to be more sticky -- and then related question on severity and response to ORLADEYO.

Yes. 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. And so the fact that they were on prophylaxis prior suggested they needed their attacks controlled and then they maintain that same rate on ORLADEYO.

Yes. This idea of attack severity or frequency of attack, people control their disease now. So that's like a -- that's a whole 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 will continue to grow, and we'll get more and more share of that.

This concludes our question-and-answer session. I will now turn the call over to Mr. Stonehouse for closing remarks.

Yes. 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, whether it's clinical data that we're looking at to advance a program or market data, do we have the right profile that will be competitive in the marketplace. If you go into it, wanting to see a certain thing, you're not going to 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. And I think as a result of that, we're starting to create greater value and have more success and ORLADEYO is the case study for that. So if you're not familiar with our thinking, we encourage you to get to know us better, and we can share with you -- and listen, it's not the only part that's important in success -- people, good science is also about the decision-making on this stuff and the objectivity is critical and we think it affects value tremendously. So 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.