Q4 2019 Earnings Call

Eric Dube: This demonstrates our ability to understand patients and their needs, to execute a launch plan, and to identify new patients, including by reengaging those who have previously discontinued therapy. Additionally, it gives us a high degree of confidence that we have a robust foundation in nephrology to launch Sparsentin if approved, and that we will be able to maximize its potential for patient success. We also continue to have solid execution with COBOL, where our goal is to help patients manage their bile acid synthesis disorders or liver disease from Zellweger Spectrum Disorder. Our efforts with specialists, including pediatric geneticists and hepatologists, are resulting in the identification and treatment of new patients with these ultra-rare conditions. Keenadal also continues to grow, and we recently initiated clinical development that may ultimately lead to an NDA to support a label for CTX. Noah will talk a bit more about that shortly. Our final priority is to evaluate opportunities to diversify our growth potential through business development. We continue to look opportunistically within the rare and ultra-rare spaces. Importantly, we will remain disciplined to only act on transitions where we believe we can leverage our current expertise to create meaningful value.

Noah: Let me now turn the call over to Noah for a clinical update. Okay, Noah?

Noah: Thanks Eric and good afternoon. Sporcentan has the potential to be a first-in-class therapy and shape the treatment paradigm for patients with FSGS and IgA nephropathy. The goal of our ongoing pivotal duplex and protect studies is to ultimately deliver Sporcentan as the first medicine approved for these rare kidney disorders. As Eric mentioned, awareness and enthusiasm for these programs continue to rise, which is in part due to broad support for proteinuria and ETFR measurements serving as clinical endpoints in glomerular diseases like FSGS and IGAN. We also hear from investigators and thought leaders in the space that Sparsantan has a well-understood mechanism with an established safety database of more than 500 subjects and that our Phase II duet study, one of the largest FSGS trials conducted to date, provides confidence in Sparsantan's potential to impact disease progression. In a duet study, the overall Sparsantan Treatment Group demonstrated a significant reduction in proteinuria and a clinically meaningful response in the FSGS Partial Remission of Proteinuria Endpoint, or FPRE.

Noah: This is the 36-week endpoint in duplex to support potential FDA and EMA submissions next year. After 8 weeks in the duet study, we also saw that 28% of Aspartame-treated patients achieved the FPRE endpoint, a three-fold increase when compared to Orvastatin. Importantly, we saw an increasing proportion of patients achieving FPRE during the 84-week open-label period, including nearly 50% of Sparsantia-intrusive patients qualifying as responders at 36 weeks. These components, along with an efficient network of sites and scientific engagement, have fueled the momentum in both of our pivotal studies to end 2019 and begin the new year. As you have just heard, both our duplex and protect studies are enrolling well, and we are maintaining high-quality study conduct. This is a testament to the collective hard work of our entire organization and partners.

Noah: Enrollment in our LEAD Pivotal Study Duplex in FSGS continues to benefit from a heightened sense of awareness and engagement among a broad global network of open sites. We have designed Duplex to recruit a similar patient population to our duet study, and thus far, the baseline characteristics of the enrolled population remain consistent with our expectations and how the study was powered. Our most recent months have produced some of the strongest screening and enrollment trends yet.

Noah: This gives us confidence in reaching 190 patients enrolled in duplex in the next two months and keeps us on track to report top-line results from the 36-week protein re-analysis in the first half of next year. The protonary analysis will measure the proportion of responders that reach FPRE after being randomized to either Sparcentin or Orbitz-Sartin for 36 weeks. Importantly, if Sparcentin shows a statistically significant improvement in response rate and duplex, we would expect to then file a new drug application under the subpart H accelerated approval pathway in the U.S. and for conditional marketing authorization consideration in Europe. To ensure we're in a position to file for approval after receiving top-line data, our teams are conducting regulatory submission planning in parallel.

Noah: We have also made noteworthy progress recently with our PROTECT study in IgA nephropathy. We continue to leverage the established nephrology footprint built by the duplex study, the heightened awareness of IgA nephropathy, and the larger overall patient population to accelerate recruitment. We have maintained momentum in the study, including through the holiday period, which has resulted in some of the highest recruitment months to date. As a result, we are very confident in our ability to meet the enrollment milestone of 280 patients in PROTECT by early 2021 and to report top-line results from the 36-week protein analysis in the first half of 2022. The Protein Area Analysis and Protect will be the percent reduction in protein area after being randomized to either Sporcentan or Orbisartan for 36 weeks. It has been widely established that protein exposure over time is one of the strongest predictors of rate of renal function decline in IgA nephropathy.

Noah: Thus, if we are successful in demonstrating a meaningful difference in protein area reduction between Sparsantan and Erbisartan after 36 weeks in the PROTECT study, we would expect to then file an NDA under the Club Part H Accelerated Approval Pathway in the U.S. and for CMA consideration in Europe. As we move through 2020, we will channel the momentum in our two PIBLUH programs to continue our pioneering efforts, with the goal of potentially delivering the First Medicine Approved for FSGS and IgA nephropathy. Our focus will remain on completing enrollment in both studies and preparing for our subsequent FDA and EMA filings. Last, before I turn the call over to Laura for the financials, I would like to point out that we recently initiated a small pivotal study evaluating the efficacy and safety of our approved product, Kynadol, for the treatment of CTX, or Cerebral Tendinous Xanthomatosis.

Noah: As many of you may know, Kenanol is not labeled for the treatment of CTX, and we do not promote the product. However, over time, we have been working towards a path that will potentially allow us to gain an updated label. Our hope is that this study will ultimately lead to a CTX indication and allow us to support greater identification and earlier treatment efforts for this ultra-rare progressive neurological disorder. I will now turn the call over to Laura for the financial update. Laura?

Laura: Thank you, Noah. During the fourth quarter, net product sales from our commercial portfolio grew to $46.7 million, a 7% increase over the same period in 2018. For the full year 2019, we reported $175.3 million in net product sales. This achieved our guidance and represents our fifth consecutive year of organic growth.

Laura: We reported a gap net loss of $30.3 million for the fourth quarter and $146.4 million for the full year 2019. After adjusting for non-cash expenses and income tax, we reported a non-GAAP net loss of $11.2 million for the fourth quarter and $89.9 million for the full year 2019. On a gap basis, R&D expenses were $36.4 million for the fourth quarter and $141 million for the full year 2019. The increase over 2018 is largely attributable to higher expenses to support our clinical and product development efforts. On an adjusted basis, R&D expenses were $34.5 million for the fourth quarter and $132.9 million for the full year 2019. Relevant non-cash expenses for the fourth quarter included $1.9 million of stock-based compensation and amortization.

Laura: On a gap basis, selling general and administrative expenses for the fourth quarter were $27.5 million, and $129 million for the full year 2019. The increase over 2018 is largely attributable to increased compensation expense and higher professional fees. On an adjusted basis, SG&A expenses for the fourth quarter were $19.6 million, and $95.5 million for the full year 2019. Significant non-cash adjustments for the quarter consisted of $7.9 million in stock-based compensation and depreciation and amortization. Looking ahead for the year, we anticipate that our net product sales will continue to grow in the mid-single-digit range, similar to what we experienced in 2019. As has been typical for us in years past, we anticipate seasonality in net product sales, including higher growth in net discounts, during the first quarter of the year.

Laura: We do expect that to normalize throughout the balance of 2020. We anticipate that our operating expenses for the full year 2020 will be similar to what we reported for the full year 2019. This includes ongoing disciplined investments to achieve our enrollment and development milestones for our Phase III studies. We enter the new year with a solid financial foundation and $398.5 million of cash and cash equivalents as of December 31, 2019. Importantly, we believe that we have sufficient cash on hand to fund our operations beyond our Phase 3 data readout. Let me now turn the call back to Eric for his closing remarks. Eric?

Eric Dube: Thank you, Laura. The outlook for our organization is clear, and as a result of our dedicated team members' hard work and accomplishments, we are in a great position to build upon our momentum in 2020. We are fortunate to hear directly from the communities we aim to serve, including in the case of a renal pathologist who is living with IJ nephropathy. He recently shared with us that he has been hoping and waiting for a medicine that could meaningfully improve treatment options for rare kidney disorders for many years. For him, it is not just about his patience; it's also personal.

Eric Dube: Hearing stories like this gives us a deep understanding of the unmet need and provides an incredible sense of urgency for all of us at Retrofit. We will channel this urgency throughout the year to remain focused on the execution and advancement of our pivotal duplex and protect studies so that we deliver top-line data and potential FDA and EMA filings next year. In parallel, we will continue to deliver our commercial products and build upon our commercial capabilities so that, if approved, we are in a position to quickly reach the greatest number of patients with Sparsenta. I will now turn the call back over to Chris to open it up for questions.

Christopher Cline: Chris Great. Thanks, Eric. Angela, can we go ahead and open up the lines for Q&A, please? Yes, of course. Ladies and gentlemen, if you have a question at this time, please press the star and the number one key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. And your first question comes from the line of Joseph Schwartz with SVB. Please go ahead.

Joseph Patrick Schwartz: Great. Thanks so much for taking my question and congrats on the progress. Several sessions at ASN during the fourth quarter highlighted a significant amount of interest.

Eric Dube: New treatments for glomerular disease are being discussed amongst the treatment community. So I was wondering if you could just summarize your main takeaways from the sessions and if you have any new insights on where SPARS and PAN could fit in.

Eric Dube: Thanks, Joe, for the question. Let me start and then I'll ask Noah to weigh in. I think important what we saw at the most recent ASN was a growing body of evidence to support the link between proteinuria and EGFR, particularly within IgA nephropathy and rare renal diseases, which gives us great confidence in how we have designed our studies.

Noah: Yeah, I think, Eric, I would just support your statement about the emphasis on protoneurine. I think that's probably, Joe, what's really spurred a lot of interest in the area. The nice thing about where we are at this stage is that, in FSGS, in particular, we're in phase three. There are no other programs in phase three, and we're pretty far ahead of the pack. I think we've got an established database from a safety standpoint. The drug is well-accepted and well-understood. I think the other advantage that we have is that we're non-ISP, meaning that we're not an immune-suppressive therapy. As you probably noticed, quite a bit of interest in the area is in areas of complement, in different immune suppression, steroid-sparing approaches. But many of these approaches have not yet been proven safe from a safety standpoint.

Noah: And while, of course, we hope that they are successful in bringing new cures to patients because they direly need them, number one, they still have to be proven in terms of both efficacy and safety. And number two, I would say that there really wasn't anything out there, Joe, that I could see that we really couldn't necessarily be complementary to, given the way the drug works. So I think it further supplements the arguments that, you know, there's a role for Sparsenta and not just when we get there, which is probably first, but also when some of these other therapies potentially get there as well and work together.

Noah: That's very helpful, thanks. And then, as a follow-up, I was wondering if you could talk about the requirement for patients on duplex to wash out of any RAS blockers other than herbicartan before entering the study. Has this been an impediment for any patients or investigators who might prefer a different RAS blocker than herbicartan? And is this being handled the same way in PROTECT? It seems like it could be different based on the protocol I see online.

Noah: Noah, do you want to take this one?

Noah: Sure, to answer your first question, in terms of the way that duplex is designed, these patients do go through a washout period. I would say the majority of the patients that are coming in are on RAS blockade because, as we know, those patients are often treated with that therapy. We saw that in Duet, about 85% of patients are on RAS. I think that, you know, we talked frequently with sites and investigators. They've told us from the beginning that this is a very recruitable protocol.

Noah: That specifically was not raised to us as a particular concern, and I think the reason for that, Joe, is that, recall that Sparcentan is a dual blocker. So we've got not only an endothelin blocking component but an angiotensin blocking component as well. So essentially, it's kind of, in a sense, two drugs in one. The patients who aren't going to be randomized onto Spar go onto, as you know, Herbisartan. So either way, they're going to get an ARB, and frankly, when you look at the data, it's not really clear that one ARB is necessarily superior to another. They're generally thought of as, you know, a class effect. These drugs tend to work pretty uniformly, so I think that's kind of how I would answer that.

Noah: And then, with regard to the two studies, while there is a two-week washout in duplex, it's a small nuance, but we actually do have, in the PROTECT study, the ability to go directly in and switch over to Spar or Herbisartan without the washout effect there. There's certainly always debate in these studies, and we've had many, many discussions about what's right and what's the best approach Frankly, it probably doesn't matter that much because for the two weeks, once they get into the study, they're just going to switch over anyway. So it doesn't have much of an impact on the overall data set.

Maurice Thomas Raycroft: That makes sense. Very helpful. And your next question is from the line of Maurice Raycroft with Jeffries. Please go ahead, sir.

Unknown Speaker: Hi everyone. Congratulations.

Eric Dube: Congratulations on the progress, and thanks for taking my questions. I was wondering whether, for phase three duplex, the confirmatory endpoint is changing.

Unknown Speaker: Transcribed by https://otter.ai If you can, I'm wondering if you can remind me.

Unknown Speaker: Remind me what exactly is the confirmatory endpoint in Phase 3 PROTECT? And then, for both studies, how important will the results be after the four-week drug cessation at the end of the study?

Unknown Speaker: Transcription by CastingWords

Eric Dube: Thanks, Maury, for the questions. Why don't I take the first part around the confirmatory endpoint, and then I'll have Noah talk about the end of treatment measurement. So for both duplex and protect The confirmatory endpoint is EGFR slope, with an interim analysis on proteinuria. And we're confident in Sparsentin's ability to have efficacy both for proteinuria and EGFR. With regard to this approach for both diseases, it's very much aligned with the nephrology community and the wide belief in the utility and the link between proteinuria and EGFR. And this is supported by the literature and, in fact, a growing body of evidence that supports the link between proteinuria and EGFR. And it remains a focal point for future use in clinical studies, as we've seen both at ASN this past year as we've just talked about, but also, we think from a regulatory standpoint that there is growing confidence and acceptance of this approach, which we're seeing now reflected in more and more studies using this methodology of proteinuria and EGFR in rare renal trials.

Eric Dube: For us, it's critical to demonstrate that link in a trial, and we've designed our studies to have some flexibility. As is common in studies like this, we have planned a sample size reassessment procedure that would allow us to further de-risk the EGFR endpoint if we think it would be helpful. Importantly, if the decision is made to do this, we believe it would not impact the timelines for our proteinuria analysis or subsequent NDA and EMA filings of the proteinuria data. So, Maury, overall, that confirmatory endpoint of EGFR, we think, is well established. And for our clinical trials, everything is aligned to make sure that we are successful. And so, we've got a high degree of confidence in that confirmatory endpoint. I'll ask Noah to add anything else and also address your question around the cessation of treatment at the end of the trial.

Eric Dube: Thank you, Eric. So, Maury, it's a great question.

Noah: If you look across, it essentially is a regulatory requirement to stop the drug and then measure four weeks off. Frankly, if you look at Bardoxilone and some of the other programs, the ADPKD drug from Otsuka, you know, they were required to do this as well. My sense is that what they're looking for is to ensure that there are no significant, number one, safety concerns and any changes in EGFR after drugs. You know, once you stop drugs, there are no dramatic changes there. That probably doesn't apply as much to our therapy, but I think it's a standardization technique that they're probably applying. Again, I'm just intuiting here across programs so they can sort of look from one to the other. But for us, it's probably not a huge, relevant piece.

Noah: Great! That's very helpful.

Noah: And then I had a question about the Shenandoah Phase III and TTX trials. Just wondering if FDA recommended that trial or is Ritrofen proactively running it? And then I see the primary endpoint is change in urinary flow.

Noah: Bio-Alcohols Week 4 and 16. I guess, can you walk through the crossover design for the study? Yeah, so I'll give a brief overview, and then I'll ask Bill to mention it. You know, the Ketadol program is quite unique, and I think it's important to just remind everyone that this is a medicine that has been available for some time and is not approved for CTX, but is commonly used for this ultra-rare condition. And we believe that it was the right thing to do to study this and to get approval for this, and to have a label that would help in guiding our discussions with clinicians about how to use Ketadol in these patients. Bill, do you want to talk about the design of the trial?

Bill: Certainly, the trial is a placebo-controlled, randomized, crossover design.

Bill: with blinded withdrawal that happens twice during the study. So the way that works is, patients who are already on Kenadol, once randomized, go into their first period of blinded withdrawal, and their medication is changed, and the patient and the physician don't know whether it's being changed to placebo or whether they remain on Kenadol. And there are observations for clinical symptoms on the part of the patient and the physician. There are also biomarkers that are being assayed, and you mentioned urinary bile alcohols, to see if there are biochemical changes that are evident with cessation of treatment.

Bill: By having two periods, we repeat the process and just flip the treatment collection. That way, each patient serves as their own control. And so by using a short window of time for withdrawing the medicine from the patient, we're able to maintain a study that's safe and ethical and, hopefully, enrollable, that patients will accept, that physicians will accept, but will give us the data that allows us to demonstrate the utility and support an ultimate regulatory filing to get CTX on the label for Kenan-Isaac.

Unknown Speaker: Got it. Thank you very much. And your next question is from the line of Gina Wang with Barclays. Please go ahead. Hi, this is David from GINA. I thank you for taking my questions.

David: My first question is regarding the Duplex and Protex trial. Can you remind us the powering assumptions for the trial? And then, to follow-up on Maurice's question, you know, you said that you were planning to do a sample size assessment. Can you just help us understand whether the sample size assessment would actually affect the powering of the trial?

Noah: Thanks, David. Noah, why don't you take these questions around powering and then how it samplifies might affect us?

Noah: Sure, thanks, sir. So let's start with the duplex. For the protonary analysis of 190 patients, the analysis will evaluate the proportion of patients achieving FPRE at week 36. So with 190 patients, that gives us power at approximately greater than 90% with a two-sided alpha of 0.05. You know, this assumes that the treatment difference in FTRE response at 36 weeks is consistent with the observed difference at week eight, so the end of double-blind treatment, which was 28.1% for sparsantan and 9.4% for ERB from the sparsantan phase two duet study. For the EGFR endpoint, we'll be looking at EGFR slope, and that is the confirmatory endpoint to week 108. And the projected treatment difference between slopes was obtained by modeling the relationship between EGFR and FPRE using DUET and the Neptune databases. Importantly, what has been observed is that even what appears to be small differences in EGFR slope, such as like, we use 0.8 to 1.52, that range, that small range around one, has been considered to be clinically meaningful. So that's kind of how it worked, or works for duplex.

Noah: For PROTECT, the primary endpoint, remember, is slightly different, and duplex is FPRE, and PROTECT, it's percent change from baseline, and that's because they utilize separate databases to derive these cut points. And that is the last, so for PROTECT, the percent change from baseline, the last pretreatment value available before the first dose of study medication. In UPCR, based on a 24-hour urine collection at week 36, so they have a similar time point and similar measure, just a different percent versus absolute. PROTECT has been powered to detect a 30% difference in proteinuria between spore and placebo, and this is based on two large IGAN registries in Leicester and Glasgow. And basically, you know, it would show in these registries that a greater than one gram per deciliter change, or patients who had greater than one change to achieve a 30% reduction at nine months with RasBlockade, had decreased long-term EGFR decline.

Noah: And consistent with findings from the NKF workshop based on the KHA white paper, a 30% reduction at nine months is also predicted to reflect the treatment effect on outcomes. So you can see we've incorporated multiple ways in these two studies of assessing these endpoints, and they are consistent with the data and literature that's out there. So that was the first question on powering, right? And the second question was... Sample size. Okay.

Noah: You can see how that might affect power. Right?

Noah: So, in terms of how sample size might affect powering, you know, It's hard to put a specific likelihood on either study, you know, whether, you know, it would affect the overall endpoint, but remember that this reassessment, which is a de-risking piece, right, which allows us to recalibrate, really is designed to affect the confirmatory endpoint and not the initial proteinuria endpoint. So we don't expect that to impact our primary endpoint, our 190 patients in the timeline. We don't have visibility into whether that reassessment will or will not occur. We'll just continue to monitor the data and monitor our data and externally what's out there. And as we mentioned earlier, if the reassessments result in any change, it would not be expected to impact the timelines for proteinuria, so the timelines that we've been speaking about.

Eric Dube: Thanks, Noah. I think, you know, just to take a step back, David, from the detailed description that NOAA has provided. If we were to adjust the sample size for either trial, it would be for EGFR to ensure that we have sufficient power and thus de-risk the trial in demonstrating the confirmatory endpoints. And again, if we do that, it has no bearing on, or is unlikely to have any bearing on, our timing for proteinuria and certainly would not impact the power assumptions for that endpoint.

Eric Dube: And just Eric, if I may add one more thing, it is a technique that's commonly used in the area, and there are, you know, examples out there of companies that have used this in renal rare diseases.

Unknown Speaker: Very helpful; thank you, guys.

Christopher Amorai: And your next question comes from the line of Christopher Amorai with Nomura Instant. Please go ahead. Hello, this is Jackson Harvey on behalf of Christopher Mirai.

Jackson Harvey: Now that you have quite a few patients in the duplex study, I was just curious if you could provide some early color around the proportion of patients that have had to reduce their dose due to tolerability, and maybe there are reasons for doing so. And my second question is, if the 36-week proteinuria measurement is not statistically significant but is trending in the right direction, will you continue to run the trial for the EGFR endpoint? Thank you.

Noah: Thanks, Jackson. Noah, why don't you take these questions?

Noah: Sure, let me start with the duplex. I think specifically you're asking about the progress of the study and dosing and how many patients. And just to reflect back, you know, for those of you who don't know, the DUET study and duplex were slightly differently designed. Duplex had, DUET did not have a titration step, so everyone started at 200, 400, or 800, and there were a number of patients that the 800 didn't tolerate it and had it back down. We designed a duplex study with a 400 to 800 titration step to allow patients to acclimate to the dose and hopefully reduce any safety concerns. While, you know, it's an ongoing study and I, you know, we can't reveal the number, we do track that, and I can say that we're not seeing any significant safety concerns or safety issues. The drug does appear to be well tolerated and, you know, as you know, we had a recent data monitoring committee meeting, which we mentioned on the last call, that gave us the ability to continue to move forward with the study. And I think that's probably as much as I can say.

Eric Dube: Yeah, no, I think the only other thing I would add before you go to the 36-week proteinuria study is that in the duet study, we did see that there was a significant efficacy difference between the patients that were on 400 or on 800. So, Jackson, while the team has designed the duplex study to minimize those early-onset RAS blockade associated adverse events that we saw, if those patients do down-titrate, we don't believe that that would impact efficacy.

Noah: Yeah, can you just repeat the 36-week question for me, the proteinuria question?

Jackson Harvey: Sure, I'm just curious if that endpoint misses at 36 weeks, but it's close and trending in the right direction, will you continue the trial to the EGFR endpoint?

Noah: Yeah, that's a really great question. You know, I would say this, that when we get the data in the first half of next year, when we have that data set, we will look at it, and we'll look at the totality of the evidence at that time. So, you know, there could be some circumstances where you might imagine where, you know, a particular subgroup while we might not hit significance overall, perhaps you might see a subgroup that shows a significant difference. So, you know, we try to prepare for all scenarios, but of course, when you get the data, you get the data, and you look at it. And for me, as a clinician, having, you know, done many of these studies, it really comes down to do you have clinically meaningful data that can help patients in the long run?

Noah: If you look out there in the renal rare space, I mean, you have therapies that haven't necessarily even improved their end point, and specifically in rare diseases as well, but they're out there, and even some therapies that are approved within select populations. So, I don't want to speculate on what that might look like, but we internally are always evaluating and looking at these different potential scenarios, and we'll certainly update you at that time, and hopefully, you know, we won't have to cross that bridge, and we'll have significance.

Jackson Harvey: Great, and if I could squeeze in one more question. You said the duplex demographics are similar to duets. So does that include the percentage of African American patients? Thank you.

Noah: Yeah, thank you, Eric. We haven't disclosed those numbers, and I will tell you that we've screened quite a number of patients in the study, including African American patients, and we've made every effort to include as many patients as we can, and that's really as much as I can say.

Liisa Ann Bayko: Thanks, operator. Can we go to the next question please? And your next question is from the line of Liisa Bayko with JMP Securities. Please go ahead. Hi, I also wanted to say congratulations on the progress and just a couple questions for me. One follow up: for this adjustment, is there a particular time frame where you'll be doing that? And is that something you'll communicate to us, you know, just letting us know that, you know, you've increased the size or that you're proceeding as? With no adjustment or not, I'm curious on that point.

Christopher Cline: Eric, would you like to answer?

Noah: Yeah, so Noah, why don't you take that one?

Noah: Okay. You know, Liisa, the reassessment is based on enrollment trends and DMC scheduling, so we really cannot provide a specific time frame there. As is common in these assessments, you know, any change will be done working with the DMC after reviewing the available data and with regulatory input. So, you know, I just want to reemphasize that if any of these reassessments occur, they're not likely to have an impact on the protonary end point. And of course, you know, once we are confident that if such a change were made, we would let you know.

Eric Dube: Yeah, I think important that if there was a change, we would make sure that we communicated anything around the timelines that we have committed to. And I think, you know, as Noah and I have mentioned, if we were to do this, it would be on the confirmatory endpoint, and we don't believe that it would have any impact on proteinuria and the timelines that we've committed to over the next year in terms of proteinuria readout and regulatory filings. But certainly, we make sure that we...

Unknown Speaker: Providing the update. Okay. And it's not a futility analysis; it's just a... It's just an interim check to see if things are trending in the right direction, you know, and then, you know, if any adjustments are needed to highlight those separations a little bit more, okay. And then,

Eric Dube: Yeah, that's absolutely right.

Liisa Ann Bayko: Okay, for CTX, can you talk about sort of the, you know, a little more specifically about the growth opportunity and doing the study. Maybe you can quantify it in some way in terms of maybe additional number of patients that you may be able to treat or some percentage growth that you might expect.

Eric Dube: Sure. Thanks, Liisa. The rationale for doing this study was to make sure that we have a label for this treatment that has been around for some time and is considered a very important treatment option for these patients. I'll ask Peter to talk a little bit about what he sees as the opportunity if and when we receive the approval.

Peter Heerma: Thanks, Eric, and thanks, Liisa, for the question. Based upon what we know today and the fact that CTX is an ultra-rare disease with kinadol currently available as the standard of care, we do not anticipate a material change in the market opportunity. We would, however, like to pursue additional investment in raising awareness and ultimately earlier diagnosis to help patients. We think it's appropriate to give the right guidance to our field force to physicians so they are in a good position to write a prescription for kinadal. Okay, I thought part of it was to maybe uncover, be able to kind of look for more patients, but I guess that's, is that sort of the unknown? Okay. Okay. Yeah, I certainly think it certainly is.

Unknown Speaker: [inaudible] Yeah, Liisa, thank you. Certainly, it would give us the opportunity, you know, as we've done over the last few years with our promoted products. You know, finding these rare and ultra-rare patients is not an easy task. And so, you know, with something like CTX, where we don't promote it, we think that, you know, we could help in identifying these patients. But I'd say right now that we're not in a position to say that it's going to have an inflection on any of the growth that we've seen with that product. But I think it's going to be, you know, as Peter says, an opportunity for us to continue to raise awareness, and hopefully, you know, for these patients to be able to get that diagnosis and connected to treatment even earlier. And, you know, once we get closer to completion of that trial and filing, we can talk more in detail about what that might look like.

Eric Dube: Okay, great. Thank you. And your next question is from the line of Tim Lugo with William Blair. Please go ahead.

Timothy Francis Lugo: Hey, this is Lachlan on the phone. Thanks for taking the questions.

Lachlan: You sounded pretty positive about protecting enrollment, so I was just wondering what you mentioned that leveraging your footprint and increasing awareness has helped with the enrollment there. Are there any other specific learnings you've been able to apply from duplex that have helped there? And are there any more that you're sort of in the process of implementing that could further speed up the rate of enrollment?

Noah: Thanks, Laughlin. Noah, why don't you take this one?

Noah: Yeah, number one, you know, I would say, to reemphasize the foundational sites. I think that's a key point. We continue to grow the site footprint, and I think it's really important that, you know, you have a global reach.

Noah: I would also say that one thing that we've observed, and I think this may be why PROTECT is beneficial, beyond the fact that PROTECT is a little bit of a larger population, or LIGAND's a larger population, you know, when you recruit these studies, we have a pretty big overlap between the two studies, so PROTECT and DUPLEX, we have a substantial overlap there. And physicians, as investigators, what they'll typically do is enroll a patient, and they'll see how that patient does on therapy. In their hands, they want to make sure that the patient does well, they're comfortable, they're confident. Once they do that, then sometimes you'll actually see them enroll two or three patients. You know, they start to bring in more patients.

Noah: They want to make sure they're confident and comfortable, and I expect what's happened is, you know, for sites that are bringing in DUPLEX patients, they're getting comfortable and confident with Sporcentan, and now they're bringing in patients onto the PROTECT side. So I think it's kind of a hand-in-hand thing. It goes back to the well-understood mechanism; they understand how the drug works, they're comfortable with it, so I think that's a big part of it.

Noah: We continue to drive, you know, a number of strategic imperatives. I'll just add one that's going to be – that is key and important and helpful, and community key is we talked in the last call about the 9,000 nephrologists in the United States, 300 academic sites, and 8,700 sites that are community-based nephrologists, and we continue to extend the connectivity between the academic sites and the community-based sites. And there I'm specifically speaking about the U.S., which has done a pretty substantial amount of enrollment in DUPLEX and in PROTECT as well. So those are the kinds of things that we're doing. We will continue to drive those efforts to bridge and broaden that enrollment through Accelerate Recruiting.

Noah: Okay, and can you give a sense of whether the recent uptick is mostly coming from those centers that already have patients enrolled, or is that primarily driven by the addition of new centers?

Noah: Yeah, I would say it's a combination. We'll see sites that are recruiting and continue to recruit. But it's interesting, in this disease, we'll also see sites that haven't recruited in six months bring in a patient. So, you know, it really, it really depends on the site.

Noah: Mm-hmm.

Noah: So, and the other thing is, I mean, just remember, PROTECT is moving very well, trends continue, and, you know, we're pretty encouraged, we could reach our enrollment milestones early, potentially, and I think I just want to, I'll leave it there.

Lina Kaminsky: Great, thank you. And your final question comes from the line between Lina Kaminsky and Caine Kirkwood. Please go ahead. Hi guys. Thank you. So, it's Lina for Michelle. So, one of the things that were mentioned at ASN for the sonar study was the higher baseline UACR in non-responders versus responders. So, given the majority of FSGS patients have higher proteinuria, do you think this would be true for FSGS around the population that is most likely to respond? And I guess, have you done any analysis on this with respect to the duet population?

Noah: Yeah, I mean, I believe there is an analysis, there's a whisker plot in the duet paper that Lena, I think it's a great question that speaks directly to this. So I just, Chris can provide it, you know, after the call. But yeah, we've looked at the cut point of above and below; two or three was the cutoff there for, in this case, you know, UPC, or we're using UPC in this case. But yes, we've looked at that, and there appears to be an effect both above and below that quote unquote nephrotic range, proteinary level that you're getting at.

Lena: Got it. Thank you. And then just another one on Alport syndrome. Since you mentioned that earlier in the call, I was just wondering, since you seem like you're still looking into this. Can you maybe provide some color on kind of how the competitive landscape influences your decision to make progress on this disease, specifically since Bradoxone has a risk of fluid retention, and this may prevent the ability to dose it in combination with Prosenten?

Eric Dube: Yeah, Lena, thanks for that question. We are looking into that. And certainly, we want to make sure that we understand how the market and the treatment paradigm may evolve. But also, part of our assessment is looking at what the clinical and regulatory path would look like. We will continue to look at how other products may be developed and used, and we think that there could potentially be a role for Sparcenten. We're not in a position really to talk much in more detail about that or about the potential competitors in that space. But I will say that we will go into that if we believe that there is a clear role and a clear pathway for Sparcenten.

Lena: Got it. Thank you. This is super helpful. And congrats again on the quarter.

Operator: ..

Christopher Cline: And I'm showing no further questions at this time. I would now like to turn the conference back to Chris Cline for closing remarks. Great. Thank you, Angela. And thank you all for joining us today. This concludes our call. We look forward to seeing you in the next few weeks at the upcoming Investor Conference. Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and have a wonderful day. You may all disconnect.

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