Earnings Call Transcript - BCRX Q2 2022

Operator, Operator

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, I will now turn the call over to your host, Mr. John Bluth at BioCryst.

John Bluth, Host

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.

Jon Stonehouse, CEO

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 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 a very long intellectual property 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 path to success? But 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. And lastly, we have substantial capital to make thoughtful capital allocation decisions. This is a unique and very good spot to be in, 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, disciplined and objective decision-making on capital allocation and alternative financing sources like the additional debt from Athyrium recently drawn 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.

Charles Gayer, Chief Commercial Officer

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. Sixty percent of those Tier 1 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. Health care 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.

Anthony Doyle, CFO

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 non-repeating 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 non-cash stock compensation for the quarter was approximately $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 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.

Helen Thackray, Chief R&D Officer

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 solubility is lowered over the typical pH range of human urine, and recent nonclinical studies have also demonstrated dose-related crystal deposition in the renal tract in 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 the 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 milligrams. It could further explain why it is happening only in some patients and at the 500-milligram dose level, when intrarenal drug levels exceed a threshold for crystal formation. This mechanism of injury is avoidable. We believe that the key to avoiding risk of adverse kidney effects is 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 milligrams twice daily. When C5 inhibitor-naive patients were taking this dose 400 milligrams 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 milligrams 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 milligrams twice daily will achieve similar efficacy results to those we saw in Phase I. So 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 reopened 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. And for new patients, we've included a revised regimen to get the 400-milligram 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-milligram 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 milligrams support continuing to invest through the 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'll proceed. If the data are not supportive, we will discontinue the 9930 program and redirect our efforts and investment elsewhere in our pipeline. So how will we know this? As we resume enrollment at 400 milligrams, we'll look for absence of the early rise in serum creatinine in new patients enrolling in the study. You will recall that over the first few months of enrollment in REDEEM-1 and REDEEM-2 and in about one-third of the first 15 patients, we saw a rapid rise in serum creatinine at 500 milligrams. As we enroll patients at 400 milligrams, this will give us a good basis for comparison to inform our next step. Let's 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 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.

Jon Stonehouse, CEO

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 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, Operator

We have our first question from Stacy Ku with Cowen and Company.

Stacy Ku, Analyst

Congratulations on a strong 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 readthrough? Kind of it's clearly an overhang to the street. So any details would be appreciated there.

Jon Stonehouse, CEO

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

Helen Thackray, Chief R&D Officer

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.

Jon Stonehouse, CEO

And then on the FDA question, we said the end of the 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.

Operator, Operator

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

Jonathan Wolleben, Analyst

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 could talk about the potential of this cropping up over time in some patients as they stay on 9930 long term.

Jon Stonehouse, CEO

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.

Helen Thackray, Chief R&D Officer

I can address another point regarding the early rise and the gradual trend. We believe this is a threshold effect related to the drug concentration in the urine, which could account for both the initial rise and the subsequent slow findings. We anticipate that we will be able to address each of these questions with the first small group of patients who were enrolled.

Jonathan Wolleben, Analyst

That's helpful. I have a couple of follow-up questions. Helen, you mentioned several procedural steps for onboarding new patients. When do you anticipate starting to treat new patients in REDEEM and RENEW? Additionally, regarding the early evaluation, what is the acceptable threshold? Is it necessary to observe a complete absence of serum creatinine, or have you discussed with the FDA what outcomes might be considered tolerable versus intolerable?

Jon Stonehouse, CEO

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

Helen Thackray, Chief R&D Officer

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 tracked patients, we will have the opportunity to see data. So this is an incremental approach. First is to 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.

Jon Stonehouse, CEO

Yes. If we have 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.

Operator, Operator

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

Christopher Raymond, Analyst

I have two questions. First, could you provide more details about the hydration protocol you mentioned? I want to understand what you submitted to the FDA regarding what patients need to do. Is it primarily about hydration or the lower dose that you believe can address this issue? Additionally, could you explain how this might work in practice if the hydration protocol is approved and patients are required to hydrate?

Jon Stonehouse, CEO

Do you want to take the first one on hydration?

Helen Thackray, Chief R&D Officer

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 taking your medicine with a glass of water. And so we think that this is very achievable.

Jon Stonehouse, CEO

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

Charles Gayer, Chief Commercial Officer

Thanks for the question, Chris. To start, around half of the patients currently using ORLADEYO have transitioned from another prophylaxis treatment, which aligns with our understanding of market share. Approximately half of these transitions are from products like Takhzyro and Haegarda. Regarding our prescriber base, we have a large number of prescribers, and we believe we are still in the early stages of helping key opinion leaders fully grasp this. We anticipate that in the future, they will switch more patients. Overall, there has been significant switching in the market, and as more doctors become familiar with our data and witness the real-world effectiveness experienced by those who switch to our treatment, I expect this trend to persist.

Operator, Operator

We have our next question from Jessica Fye with JPMorgan.

Jessica Fye, Analyst

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 two things? First, is a reasonable time frame, the three months you talked about in the 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? 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.

Jon Stonehouse, CEO

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 a 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've got to go to the regulatory authorities. And then it took about two 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 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.

Jessica Fye, Analyst

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?

Jon Stonehouse, CEO

Yes. I'll begin, and then you and Bill can add your thoughts. The hypothesis is based on the data we've collected so far, which includes both clinical data at 400 milligrams and 500 milligrams, as well as insights from our clinical pharmacology, laboratory tests, and recent animal studies. We believe there is a threshold effect that may cause the drug to precipitate and clog these tubules. Therefore, if we do not observe these elevations, we do not expect this issue to persist over time. This drug does not accumulate, so it is not a matter of prolonged exposure; it is about the threshold. That is why we think the limited number of patients in the early phase of the study will provide us with greater confidence. Helen or Bill, do you have anything else to add?

Helen Thackray, Chief R&D Officer

I would only add that the findings in that first group of patients, for which we paused enrollment, were quite definitive and came early on. If we don't observe similar results in this next group, which is about the same size as the first, it would boost our confidence. This will be an incremental process; we need to see the first step, and then we'll continue monitoring and adding more patients.

William Sheridan, Chief Medical Officer

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

Operator, Operator

Our next question is from Maury Raycroft with Jefferies.

Maurice Raycroft, Analyst

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?

Charles Gayer, Chief Commercial Officer

Yes, Maury, that's a great question. We are gathering more evidence regarding the ideal patient profile. It seems that the best candidates are those who were already well-managed on another prophylactic medication. If they had a very low attack rate when they started, they tend to maintain that low rate while using ORLADEYO. As more physicians recognize this and as more patients experience these results, we anticipate an ongoing and possibly increasing trend of switching to our treatment.

Jon Stonehouse, CEO

And Charlie, when you say low attack rate coming in, you mean on their prophylactic therapy?

Charles Gayer, Chief Commercial Officer

Exactly. On their existing prophylactic therapy, and then they switch and keep the same low attack rate on ORLADEYO.

Jon Stonehouse, CEO

Got it. 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 Thackray, Chief R&D Officer

Yes, I can respond to that. Since making these observations, we've conducted additional laboratory work, and we've determined the solubility level at the pH range found in urine. The crystal formation is simply a result of the molecule's chemistry. There's nothing particularly unique about it. But now that we have this information, we know where to focus our attention.

Operator, Operator

We have our next question from Gena Wang at Barclays.

Huidong Wang, Analyst

I have a few questions regarding ORLADEYO. I hope I didn't miss it. Can you provide the patient retention rate? Is it still at 70%? Additionally, what is the percentage of new patients who switched from other prophylaxis? Is that still around 50%? Lastly, concerning the pricing, I know you have finalized it in Germany, France, and Switzerland. How does that price compare to the U.S. price? One more question regarding Factor D: what initial capital allocation are you planning for that program?

Jon Stonehouse, CEO

Yes, go ahead, Charlie.

Charles Gayer, Chief Commercial Officer

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, about 50% of the patients have switched from other prophylaxis, 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.

Jon Stonehouse, CEO

Yes, Charlie, part of your question was about the retention of those individuals. The retention rate is actually in the high 70% range for patients who switched from injectable prophylaxis at six months for Takhzyro, Haegarda, and Cinryze, based on the fact that they were well controlled before and most of those patients remain well controlled on ORLADEYO.

Charles Gayer, Chief Commercial Officer

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 the U.S. where our WAC pricing is $499,000.

Jon Stonehouse, CEO

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

Anthony Doyle, CFO

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.

Operator, Operator

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

Brian Abrahams, Analyst

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?

Jon Stonehouse, CEO

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

Helen Thackray, Chief R&D Officer

Yes. So the first question was, is there any mechanistic difference in the patients with different diseases. And we don't think so. And the hypothesis says crystals form 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 a 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.

Jon Stonehouse, CEO

Yes. His question was also about the FDA and efficacy. There are no specific requirements from the FDA. They always consider the benefit-risk ratio. Clearly, they recognize some value in keeping patients in the study and allowing us to continue. From an efficacy standpoint, we will notice any breakthrough hemolysis. We are assessing whether the Data Monitoring Committee can review both the blinded and unblinded data in terms of efficacy. So we are concerned about both aspects, Brian. As we mentioned previously, the goal is to develop a safe and effective drug.

Charles Gayer, Chief Commercial Officer

Brian, regarding the $1 billion, there haven't been any significant changes. As you're aware, we conduct extensive market research and planning. We’re observing that real-world outcomes align with our expectations, which boosts our confidence. The initial uptake we’re seeing in Europe and the pricing we’ve achieved are in line with our forecasts, leading us to feel confident about reaching at least $200 million in other markets. Additionally, the real-world evidence I mentioned regarding patients switching to ORLADEYO in the U.S., with most remaining on the medication and having positive experiences, reinforces our confidence. Lastly, the expansion of our prescriber base further solidifies our optimism about the future of this drug.

Jon Stonehouse, CEO

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.

Operator, Operator

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

Serge Belanger, Analyst

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?

Jon Stonehouse, CEO

So I'll take the backup one, Charlie, and then you take the ORLADEYO new patient. Yes, we're always working on backups and we didn't slow down. I've 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.

Charles Gayer, Chief Commercial Officer

And then Serge, regarding market share, we've previously shared some of our market research, most recently earlier this year. The survey indicated that ORLADEYO held about 12% market share, which was likely a bit more than our actual market presence at that time. However, we've seen growth since then. Physicians in our market research anticipate that this will become their most prescribed medication in the future. As we've stated before, reaching a 25% to 30% market share in the U.S. would bring us to about $750 million to $800 million toward our goal of $1 billion in peak sales. The growth is consistent, and we are performing well. In terms of new patient acquisitions, I noted earlier that we recorded the highest number of new patient prescriptions in the second quarter since the launch. This is an important milestone six quarters in, with no indications of decline. Regarding the usual summer slowdown, we'll assess that after the third quarter, but we concluded the second quarter strongly. I feel optimistic about our position.

Operator, Operator

Thank you. We have our final question from Liisa Bayko with Evercore ISI.

Liisa Bayko, Analyst

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?

Helen Thackray, Chief R&D Officer

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 milligrams. 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.

Jon Stonehouse, CEO

And then the stopping rule is important for people to know.

Helen Thackray, Chief R&D Officer

Yes. The question is whether one case is enough. We believe there are several factors that can lead to an increase in serum creatinine levels in patients with these diseases. We aim to evaluate any rise in serum creatinine within the context of the patient’s overall condition to determine if it is likely related to the medication or other factors. We are currently assessing these situations and will review them with our Data Monitoring Committee. We have established a stopping rule in our studies: if we observe three serious events related to the drug, that will prompt us to halt the study.

Liisa Bayko, Analyst

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

Helen Thackray, Chief R&D Officer

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.

Jon Stonehouse, CEO

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.

Liisa Bayko, Analyst

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?

Charles Gayer, Chief Commercial Officer

We have not broken that out yet, Liisa.

Jon Stonehouse, CEO

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.

Liisa Bayko, Analyst

I've been receiving inquiries from clients recently about the types of patients who are on ORLADEYO for more than six months. Is there any correlation between the severity of the disease and the response? Could you please discuss the characteristics of patients who tend to remain on the medication, as well as the connection between severity and response to ORLADEYO?

Charles Gayer, Chief Commercial Officer

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.

Jon Stonehouse, CEO

Yes. The concept of attack severity or frequency of attack is that patients can now manage their condition. It's a different perspective to consider. Currently, we are attracting business from patients who are well-managed on their injectable therapy but are looking to reduce the burden associated with it. This segment is where our growth will continue, and we expect to capture a larger share of this market.

Operator, Operator

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

Jon Stonehouse, CEO

Thank you. Over the years, we have learned the significance of objectivity and relying on evidence and data when making decisions, whether it concerns clinical data to advance a program or market data to ensure our product profile is competitive. Approaching it with a predetermined view compromises objectivity and may lead to poor decisions. At BioCryst, we focus on the evidence and make decisions based on our findings. This approach is beginning to yield greater value and success, with ORLADEYO serving as a prime example. We encourage you to familiarize yourself with our philosophy, as it’s crucial to our success, alongside having the right people and good science. Objectivity is vital, and we believe it greatly impacts our value. Thank you for your interest in our company, and have a great day.

Operator, Operator

Thank you. Ladies and gentlemen, this concludes our conference. Thank you for participating. You may now disconnect.