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spk11: Welcome to the Biochrist 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, with 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 Biochrist.
spk12: Thanks very much, Vanessa. Good morning and welcome to Biocris 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 John Stonehouse, CFO Anthony Doyle, Chief Commercial Officer Charlie Geyer, Chief Medical Officer Dr. Bill Sheridan, and Chief R&D Officer Dr. Helen Thackeray. 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 John Stonehouse.
spk00: Thanks, John. The Orla Dale 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 Orladeo 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 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 Orladeo 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 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. Orla Deo'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 leverage 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 Orlodeo 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 Orladeo. The steady and consistent revenue growth, discipline and objective decision making on capital allocation and alternative financing sources like the additional debt from Ethereum we recently drew down. are the things that give us confidence we can repeat the Orlodeo 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 Orlodeo. Charlie?
spk04: Thanks, John. The consistent pattern of patient growth that we've 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 Orladeo 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 Orladeo 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. Sixty percent of those Tier 1 physicians have now prescribed Orlodeo, 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 percent of the HAE market opportunity. And they prescribed 32 percent of the new Orlodeo 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 Orlodeo 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 Orlodeo. We made more progress toward the globalization of Orlodeo 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 Orlaneo will reach at least $200 million at peak. The prescribing dynamics and the patient trends that we saw in Q2 confirmed to us that we were still in the early stages of the Orlodeo launch trajectory. The trends that we see tell us that Orlodeo is on track not only for between $255 and $265 million in sales in 2022, but also future market leadership and a billion dollars in peak sales. Now I'd like to turn the call over to Anthony.
spk14: Thanks, Charlie. All of their 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 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 Orlodeo. We had around $2.2 million of non-repeating reimbursement-related accrual releases in the quarter, and so Orlodeo 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 $90.4 million. This was lower than we previously forecasted as the team worked hard to manage costs during the 99-30 enrollment hole period. With the program now moving forward, we've lowered our OPEX forecast for 2022 to $390 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 Ethereum, 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 P&H. 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 Orladeo. 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 Orlodeo and will continue to guide us in all of the programs that we have going forward. Now I'll pass it over to Hala.
spk10: Thanks, Anthony.
spk09: As we announced today, the FDA has lifted their partial clinical hold on the BCX-9930 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 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 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 non-clinical 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 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 keys to avoiding risk of adverse kidney effect 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 milligrams twice daily. When C5 inhibitor naive patients were taking this dose, 400 milligrams, in the Phase I 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 PKPD 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 one. 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 reopen the studies to enrollment. To do this, we will proceed with regulatory submissions for the amended protocols in the redeemed clinical trials. We've included simple hydration instructions for all patients. And for new patients, we've included a revised regimen to get to the 400 milligram dose level with a short initial step-up in dose. We are also amending the renewed 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 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'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 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 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. 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 John.
spk00: Thanks, Helen. Let me conclude by summarizing where we are. The Orladeo 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 Orladeo. If not, we move on to the rest of our pipeline to find the next Orladeo. 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.
spk11: Thank you. We will now begin our question and answer session. If you have a question, please press 0, then 1 on your touchtone phone. If you wish to be removed from the queue, please press 0, then 2. If you're using a speakerphone, please pick up the handset first before pressing the numbers. So that is star, then 1 to queue up with a question. We have our first question from Stacy Kuh with Cowan & Company.
spk10: Hi all. Thanks so much for taking our questions and congratulations on a rate or lady out quarter. So we have a few questions. First on the 99 30 update, can you speak about the patients that have stayed on the reading trials? Are there any safety measures that are being monitored? Any updates there? Sounds like they are on 500 milligrams and that will be adjusted to 400. So 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 for the street, so any details would be appreciated there. Thank you.
spk00: So, Helen, you want to take the first one. I'll take the second one.
spk09: 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 derive benefit. They continue on drug. Their results have supported that, and we're reducing the dose in all patients.
spk00: 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 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.
spk10: All right.
spk11: That's very helpful. Thank you. Thank you. We have our next question from John Wallen with JMP Securities.
spk05: 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 could talk about, you know, the potential of this cropping up over time in some patients as they stay on 9930 long term.
spk00: 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 that same small group of patients. So I think we get the benefit from both patterns with this early group of patients.
spk09: And 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.
spk05: That's helpful. And then 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 and redeem and renew? And then 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?
spk00: Yeah, so maybe on that second one, the stopping rule, and the first one's pretty straightforward.
spk09: Yeah, so 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. So this is an incremental approach. First is get to the readiness for startup, then get to enrollment, 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 for patients 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.
spk00: 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? So it's pretty straightforward. And on the first point, we're going to go as fast as we can, right? You know, it's hard to predict how quickly that will happen, but we're going to go as fast as we can.
spk05: I'll jump back in the queue. Thanks for taking the questions. Yep.
spk11: We have our next question from Chris Raymond with Piper Sandler.
spk13: Yeah, thanks. 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, you know, what specifically you submitted to FDA in terms of, you know, what patients need to do. Is it more of the hydration protocol? or the lower dose, I guess, that 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 Orlodeo, you know, we've done some KOL checks recently, 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? Thanks.
spk00: So you want to take the first one on hydration?
spk09: Yep. 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.
spk00: Great. Charlie, you want to take that Orla Deo?
spk04: Hey, Chris. Thanks for the question. So first of all, overall, 50%, about 50% of the patients that are on Orla Deo 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 switchers, prophy switchers, are coming from TaxIRO, then Haygarda, 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. Thank you.
spk11: We have our next question from Jessica Fye with J.P. Morgan.
spk08: Hey, guys. Good morning. Thanks for taking my questions. So 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? And then second, how do you define a small number of patients Is that a dozen, a couple dozen? I'm just trying to figure out when investors will have more clarity here.
spk00: Yeah, 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 or we are. And 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've got to go to the regulatory authorities. And then, you know, 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'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. So. I hope that gives you a little bit more frame. It's really hard to predict, Jess, 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.
spk08: 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?
spk00: 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 ClinPharm and what we saw in laboratory tests and some recent animal studies. And so we believe it's a threshold effect that causes the 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, you know, 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, you know, the small number of patients in the early phase of the study will give us much more confidence. Eleanor, Bill? Anything else you want to say?
spk09: I would only add that the findings in that first group of patients 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 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. Thank you.
spk04: I would only add that it gives you confidence to complete enrollment in the studies.
spk00: Yeah, that's right.
spk11: Thank you. Our next question is from Maury Raycroft with Jefferies.
spk02: Hi. Thanks for taking my question. For Orladeo, can you elaborate more on what the ideal patient is to switch and the ideal patient to benefit from Orladeo? I guess are there some observations that you're seeing from the front line on that that you can talk about?
spk04: Yeah, hey, 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 Orladeo. 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 the trend of switching continuing and maybe even increasing. And, Charlie, when you say low attack rate coming in, you mean on their prophytherapy? On their, exactly, on their existing prophytherapy. And then they switch and keep the same low attack rate on Orlaneo.
spk02: Got it. And thanks for providing all of the detail on 9930 as well. I'm just wondering for the actual molecule itself, Do you have an understanding of why it's crystallizing? Is that something that is relevant as to why the molecule is actually crystallizing? So Helen, you or Bill?
spk09: Yeah, 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 analysis. as a result of the molecule's chemistry. So there's nothing really special about it. But now that we know that, we know what to look for.
spk02: Got it. Okay. Thanks for taking my questions.
spk11: 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 Gina Wang at Barclays.
spk01: Thank you very much for taking my questions. I have a few regarding the Olodeo. And so I hope I did not miss it. Just wondering, have you mentioned the patient retention rate? Were they still maintained at a 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, you know, the price compared to the U.S. price? And I'm sorry, one last question. Regarding Factor D, how much initial capital allocation will you put for that program?
spk04: Yeah, go ahead, Sharon. Great. Hi, Jana. 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 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 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 Orlodeo as their first drug. Yeah, Charlie, I think part of her question was retention in those folks. It's actually better in those folks. Oh, sorry. Yeah, right. That was the other part. And I've mentioned this in previous calls, that the retention of people switching from injectable prophy at six months for Taxiro, Haygarda, Synrise is in the high 70%. And that's based on the fact that they were well-controlled before, and most of those patients stay well-controlled on Orladeo. And then you had a question about EU pricing. So our German list price is about €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 WAC pricing is $499,000.
spk00: Anthony, you want to take the capital allocation question?
spk14: Yes, sir. 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 to 400 million for the year. So that in combination with the revenue increase in the guidance means from a net cash burn perspective, you know, we're definitely in a better spot now than we were previously. So 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.
spk11: Thank you very much. We have our next question from Brian Abrams with RBC Capital Markets.
spk03: Good morning. Thanks for taking my questions, and congratulations on the continued stronger of the day launch. A few from 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 expanded out. And then lastly, on Orlodeo, 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 US-XUS 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.
spk00: So, Helen, you want to take the 9930, and then Charlotte can take the Orlodeo.
spk09: Yeah. 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 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. 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 a rise in creatinine in patients being dosed at 400 milligrams, then 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.
spk00: Yeah, and his question, too, was around the FDA and efficacy. There were no requirements by the FDA. 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. But from an efficacy perspective, you know, if we have breakthrough hemolysis, you know, we'll see that. And we're evaluating whether the DMC can look at the blinded data or unblinded data as well from an efficacy perspective. So, you know, we're concerned about both, Brian, and those, you know, we said before the goal is a safe and effective drug.
spk04: Brian, as far as the billion dollars, Nothing significant has changed. 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 Orladeo 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.
spk00: Yeah, 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. You know, our confidence goes up every single quarter. There is no sign of slowing down.
spk03: It's really helpful. Thank you, guys.
spk11: We have our next question. Our next question comes from Serge Belage with Needham & Company.
spk06: 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 oral Adeo, a couple for Charlie. Can you talk about where you are with market share now and in terms of new patient ad cadence, how it progressed in the second quarter, and maybe whether you expect summer seasonality impacts on that cadence. Thank you.
spk00: So I'll take the backup one, Charlie, and then you take the Orladeo new patients. Yeah, we're always working on backups, and we didn't slow down. We've always put a full court advance on it. 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. I think the other piece is we work to have improved molecules as well, and you saw that with the move from Mavorlstat to Orladeo. And so, 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.
spk04: 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, the survey showed Orladeo share of about 12%. That was probably a little ahead of where we actually were in the market at the time, but then we've grown since then. And physicians 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 billion dollars 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, six 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. You're welcome.
spk11: Thank you. And thank you. We have our final question from Lisa Baco with Evercore ISI.
spk07: 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 I know you saw it in 15 patients. If you see one case, is that enough to stop? What's your threshold for seeing cases as you go into this next phase now?
spk09: So I can take the questions. 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, 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. 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.
spk00: And then the stopping rule and, you know, what's the – I think that's important for people to know.
spk09: Yeah, so – and the question is, 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 what's happening with the 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 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.
spk07: Okay. So it's three cases. Okay. And then just this notion of inferring, so like what makes you believe that 400 is sort of below that threshold?
spk09: 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 one went through the 400 milligram stage of dosing.
spk00: And 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.
spk10: Okay.
spk00: Yeah.
spk07: Okay. And then, sorry, I may have missed it, but did you break down sales like U.S., Japan, rest of the world, or could you do that?
spk04: We have not broken that out yet, Lisa.
spk00: Yeah, and the reason we haven't 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 Europe 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. So over time, you know, we will break it out. But at this point, it's vast, vast majority is U.S.
spk07: Okay. And then one quick question. I've been getting questions from clients, you know, lately about the types of patients who stay on Orla Dale for longer than six 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, you know, related question on severity and response to Orladeo. Thanks.
spk04: 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 Orladeo and remain well-controlled. And so The fact that they were on prophylaxis prior suggested they needed their attacks controlled, and then they maintained that same rate on Orlodea.
spk00: Yeah, this idea of attack severity or frequency of attack, people control their disease now, so 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 will continue to grow, and we'll get more and more share of that.
spk07: All right.
spk11: Thanks.
spk00: You're welcome.
spk11: Thank you. This concludes our question and answer session. I will now turn the call over to Mr. Stonehouse for closing remarks.
spk00: 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 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 Biochrist. 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 Orla Deo 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, but 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.
spk11: Thank you. Ladies and gentlemen, this concludes our conference. Thank you for participating. You may now disconnect.
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