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spk08: Good day. Thank you for standing by. Welcome to Travier Therapeutics' fourth quarter and full year 2021 financial results and corporate update. At this time, all participants' lines are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star 0. I would now like to hand the conference over to your speaker today, Mr. Chris Klein. Thank you. Please go ahead.
spk05: Thank you, Buena. Good afternoon, and welcome to Travere Therapeutics' fourth quarter and full year 2021 financial results and corporate update call. Thank you all for joining us. Today's call will be led by our Chief Executive Officer, Dr. Eric Duvet. Eric will be joined for the prepared remarks by Dr. Jule Inrig, our Chief Medical Officer, Peter Herma, our Chief Commercial Officer, and our Chief Financial Officer, Laura Clegg. Dr. Bill Rote, Senior Vice President of Research, will join us for the Q&A session. Before we begin, I'd like to remind everyone that statements major in this call regarding matters that are not historical facts are forward-looking statements within the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not guarantees of performance. They involve known and unknown risks, uncertainties, and assumptions that may cause actual results, performance, and achievements to differ materially from those expressed or implied by the statement. Please see the forward-looking statement disclaimer on the company's press release issued earlier today as well as the risk factor section in our Forms 10-Q and 10-K file with the SEC. In addition, any forward-looking statements represent our view only as of the date such statements are made, February 24, 2022. And Travere specifically disclaims any obligation to update such statements to reflect future information, events, or circumstances. Let me now turn the call over to Eric.
spk04: Eric? Thank you, Chris, and good afternoon, everyone. 2021 was an outstanding year for Travere. Our pipeline of potential first-in-class rare disease treatments delivered three positive top-line readouts from our ongoing studies. We made significant regulatory progress and established pathways to potential accelerated approvals for our lead candidates, sparsentin, in both IgA nephropathy and focal segmental glomerular sclerosis, or FSGS. We delivered 6% growth in net product sales from our commercial products, despite the ongoing challenges from COVID, and a generic entrant for thiola. And we continue to strengthen our ability to successfully deliver our treatments to the rare disease community in the future. I'll touch on each of these areas briefly. First, regarding the pipeline, we are incredibly pleased with the outcomes from both of our Phase III studies of sparsentin, duplex in FSGS and protect in IJ nephropathy. With positive top-line interim readouts from both studies, sparsentin has established a robust body of evidence around its ability to reduce proteinuria in patients with rare kidney diseases. Importantly, the sparsentin readouts have positioned us for three potential regulatory submissions this year. I am pleased to report that we remain on track to submit an application for accelerated approval under subpart H for IgA nephropathy during this quarter. If that application is accepted and granted priority review, we would anticipate a PDUFA date for sparsentin and IgA nephropathy towards the end of this year. We are also on track to submit to the FDA additional EGFR data from the ongoing duplex study in the first half of this year. If at that time the data further strengthen the prediction of long-term benefits in the study as we should expect they should, We anticipate submitting an MDA for accelerated approval for FSGS around the middle of this year. Together with our European partner, V4 Pharma, we also remain on track to submit a combined IgA nephropathy and FSGS MAA submission for conditional approval for sparsentin in Europe, pending additional support of EGFR data from Duplex. As you can see, we have a very exciting year ahead for sparsentin. Also from the pipeline, in December, we reported positive top line data from the ongoing phase one, two composed study of PEG-2-batinase in classical homocysteineuria, or HCU, a rare and devastating metabolic disorder. We believe these data support the potential for PEG-2-batinase to become the first therapy targeting the underlying cause of HCU for the more than 7,000 people in the US and Europe who are not able to adequately control their HCU with the available treatment options today. Having achieved this milestone also reinforces confidence in our strategy of bringing in external programs to further address the unmet needs of rare disease patients while diversifying and building our growth potential. This year, we look forward to engaging with regulators to establish next steps for a pivotal development program while we also gain experience with formulation enhancements and further explore the dose-response curve in the final plan cohort of the study. On the commercial side of the business, we continued our track record of strong execution. Our results in 2021 marked the sixth straight year of organic growth. We believe this illustrates the strength of our commercial capabilities and our ability to identify, treat, and support patients living with rare kidney and liver conditions. For 2022, we currently expect to see continued growth of our bile acid products, but we do expect pressure on the Fiola business. As a result, our consecutive growth streak in total net product sales is not likely to continue this year. But with the potential for Sparsentin to launch as early as the end of this year, we look forward to returning to growth again in the future. Importantly, our business planning has been accounting for this. Peter and his team are continuing to build upon our commercial strengths to translate our experience and establish relationships for successful launches of sparsentin in the U.S. Finally, I'd like to introduce Dr. Jule Enrich, our new chief medical officer. Jule joined us in January and has taken over for NOAA following his planned transition. Jule is a nephrologist who brings to Travere more than 15 years of expertise in drug development, clinical trial planning and execution, global regulatory engagement, and medical oversight. She has a clear passion for championing positive change for patients and a deep history of advancing new treatment options for rare diseases, specifically in rare nephrology. She joins our team at an exciting time as we approach the next inflection point on the path to bringing innovation to patients living with IgA nephropathy and FSGS. With that, let me turn the call over to Jula for the clinical update. Jula?
spk11: Thank you, Eric, and good afternoon. I'm honored to be here and partnering with our team members at Travere to advance new therapies for people living with rare disease. Over the course of my career, I've experienced the challenges that patients and their families have encountered as a result of having few options available to slow the progression of their kidney disorders toward end-stage kidney disease. That has shaped my own personal mission to help the nephrology field advance new treatments that may be able to delay the time to transplant or dialysis. This has taken the form of working with FDA, EMA, and community leaders to further establish proteinuria as an acceptable regulatory endpoint for clinical trials in nephrology. And it has taken the form of helping strategize and execute nearly 50 clinical trials in the space. I was incredibly motivated to join the Travere team because of the patient-inspired leadership that has been established over the last several years and the exciting potential to continue working at the forefront of advancements in rare nephrology, ultimately by helping physicians understand the foundational role sparsentan may be able to play for their patients if approved. To that end, I am pleased with the continued progression of the sparsentan programs. Both the duplex study in FSGS and the PROTECT study in IgA nephropathy are progressing according to expectations and are well positioned for their confirmatory EGFR endpoint readouts next year. To date, sparsentin has consistently shown the ability to meaningfully reduce proteinuria versus the current standard of care. And proteinuria is a key measure by which nephrologists determine treatment for patients with proteinuric kidney diseases. In the combined treatment group in the Phase II duet study in FSGS, sparsentan more than doubled the reduction of proteinuria compared to the active control, erbisartan. In the top-line interim results from the Phase III duplex study in FSGS, treatment with sparsentan resulted in a 60% greater relative likelihood of achieving the clinically relevant FSGS partial remission of proteinuria endpoint, or FPRE, when compared to the active control erbisartan. And in the Phase III PROTECT study in IgA nephropathy, sparsentan demonstrated a greater than three-fold reduction in proteinuria from baseline compared to the active control erbisartan. The first time a single non-immunosuppressive therapy demonstrated this magnitude of effect on proteinuria reduction in a large, well-controlled study in IgA nephropathy. These results are exciting for the nephrology community and are providing great motivation for our medical teams. As Eric outlined earlier, we are on track for all of our regulatory milestones planned for this year. Of note, we were encouraged to see FDA recently grant the first accelerated approval based on proteinary reduction in IgA nephropathy. This precedent is in clear alignment with our approach. For IgA nephropathy, we anticipate submitting our application for accelerated approval in the US before the end of this quarter. We would anticipate hearing a response on that application in the second quarter with a potential PDUFA date as early as the fourth quarter if accepted for priority review. And for FSGS, we are on track to provide the FDA with additional EGFR data from the ongoing duplex study in the first half of this year. As many of you will recall, at the time of the interim assessment for duplex, a high proportion of the available EGFR data were weighted to early study visits. This is the period in which acute reductions in EGFR are likely to be most prominent from RAS and ETA blockade. Following our pre-NDA interactions for FSGS last year, we aligned with the FDA on a plan to provide the agency with additional EGFR data from the ongoing duplex study to provide a more mature data set and enable us to continue on the accelerated approval pathway for FSGS. At the time of the planned EGFR data cut later this year, all patients in the duplex study will have completed at least one year of treatment, and approximately 50% of patients will have completed two years of treatment. Based upon our understanding of sparsentan and its mechanism of action, we believe at this time point in the duplex study, the data will have sufficiently matured to strengthen the prediction for long-term EGFR benefit. If the EGFR data continues to progress as planned, we expect to submit for accelerated approval in the U.S. mid this year. Finally, I'll touch on our PEG to Batinase program, which reported positive top-line results from the ongoing Phase I-II COMPOSE study in December. From a safety perspective, we were pleased to see that PEG to Batinase has been generally well-tolerated to date in the study. From an efficacy perspective, PEG to Batinase demonstrated dose-dependent reductions in total homocysteine during the 12 weeks of treatment. And we were very pleased to see that in the highest dose cohort to date of 1.5 milligrams per kilogram, dosed twice weekly, treatment with PEGtobatinase resulted in rapid and sustained reductions in total homocysteine beginning at week two and continuing through 12 weeks of treatment, resulting in a 55.1% reduction from baseline and maintenance of total homocysteine below a clinically meaningful threshold of 100 micromoles. Additionally, the data demonstrated a substantial reduction in methionine and increase in cystothionine in a dose-dependent manner following treatment with PEG to Batenase, which supports our mechanistic approach. These data provide proof of concept, supporting the potential for PEG to Batenase to become the first disease-modifying therapy for HCU and give us confidence in moving toward aligning with regulators on a pivotal program. As we do that, the program this year will be focused on three areas. The first is engaging with regulators to align on total homocysteine as a biomarker endpoint, and with that, a Phase III program design that can support approvals in the U.S. and abroad. The second is completing the sixth cohort in the COMPOSE study to further build our knowledge of the dose treatment response of pectobatinase and to explore potential formulation advancements. Enrollment activities here are already underway. The third is working through the global supply constraints suppliers in the industry are currently facing to scale CMC and manufacturing for the pivotal phase of development and commercial access. Overall, I have inherited a great set of programs with real potential to make a meaningful difference in patients' lives and an extremely talented team to help advance them We are well positioned to deliver sparsentan if approved as the first non-immunosuppressive therapy for the treatment of IgA nephropathy and to continue the advancement of our other programs this year. Let me now turn the call over to Peter for the commercial update. Peter?
spk09: Thank you, Joelle. As Eric talked about earlier, the commercial organization continues to execute incredibly well under challenging conditions in 2021. Despite fewer patients seeing their physicians as a result of COVID and a generic entrance for the original formulation of Viola, we identified and treated new patients with all of our commercial products and achieved our targets for the year. In the fourth quarter specifically, net product sales grew by 7%. This was driven by organic year-over-year growth across Viola and the bile acid products. We finished the year with approximately $211 million in net product sales, a more than 6% organic increase over 2020. As we look to 2022, we are expecting continued growth of our bio-acid products, with increasing pressure on our Sciola business as a result of generic competition. This has been factored into our business planning for some time and allows a natural pivot to our preparation for launching Sparcentum. The results from this past year further bolster my confidence in our team's commercial execution and their established relationships in the rare nephrology community. We are building upon this established infrastructure and expertise as we prepare our organization to position Sparcentum as the new treatment standard for IGI nephropathy, if approved. We are currently doing this by focusing on three areas. The first is further educating the scientific community by leveraging the deep understanding and long-held belief in the utility of proteinuria reduction amongst nephrologists. And that sparsenton, if approved, may substantially lower proteinuria for their patients. We know from syndicated market research that nephrologists consider the emerging product profile of sparsenton as one of the most desirable programs in development. So we are building and educating upon that. The second is furthering our work to instill a strong understanding of the burden of disease amongst payers, the value that Spar Center may be able to provide, and progressing our strategy that will allow for broad access to become a new treatment standard if approved. Many of you will recall the 2019 publication of the Kidney Health Initiative project team, where proteinuria was identified as the most widely recognized and well-studied risk factor for the progression to end-stage kidney disease in IgA nephropathy. Following this risk prediction analysis, the patient-level risk assessment was presented, describing that a 30% reduction in proteinuria could result in a greater than 10-year delay in dialysis for IgA nephropathy patients. With the proteinuria reduction demonstrated in the recent PROTECT data, we have a strong foundation to build upon. Lastly, now that we have line of sight of the regulatory path this year, we have plans to expand our commercial organization for launch readiness. This includes adding to our field force to reach more nephrologists, building upon our best practices for virtual engagement with healthcare providers, and readying the distribution and patient support services infrastructure, all ahead of launch, so we can hit the ground running if approved. With an anticipated addressable US IgA nephropathy patient population of 30 to 50,000 people at launch, we recognize the significant potential for this market if Sparcentum is approved. We have started early and are investing and building appropriately to position ourselves for success. Most importantly, we are doing this from a differentiated position of strengths. We are not starting from scratch, but instead, building upon a team that has leadership experience in rare nephrology and has demonstrated for more than six years that it can successfully identify, treat, and support patients living with rare diseases. Let me now turn the call over to Laura for the financial updates. Laura?
spk12: Thank you, Peter. For the fourth quarter of 2021, we reported net product sales of 54.6 million from our commercial portfolio compared to 51 million for the same period in 2020. For the full year 2021, we reported 210.8 million in net product sales. Total revenue for the full year 2021 was 227.5 million, consisting of 210.8 million in net product sales and 16.7 million in licensing and collaboration revenue from our European partnership with V4 Pharma. We reported a gap net loss of 51.6 million for the fourth quarter of 2021. For the full year 2021, gap net loss was 180.1 million. After adjusting for non-cash expenses and income tax, we reported a non-gap net loss of $37.6 million for the fourth quarter and $100 million for the full year 2021. On a gap basis, R&D expenses were $62.2 million for the fourth quarter and $210.3 million for the full year 2021. The increase compared to 2020 is largely attributable to increased patient enrollment in the ongoing studies of sparsetin as well as advancement of the PEG2Batinase program in HCU. On an adjusted basis, R&D expenses were $57.7 million for the fourth quarter and $196.2 million for the full year 2021. Relevant non-cash expenses for the fourth quarter included $4.4 million of stock-based compensation and amortization. On a GAAP basis, selling general and administrative expenses for the fourth quarter were $42.1 million and $149.9 million for the full year 2021. The increase compared to 2020 is largely attributable to increased headcount and professional fees as a result of the company's operational growth as we prepare for potential commercial launches. On an adjusted basis, SG&A expenses for the fourth quarter were $30.9 million and $106.6 million for the full year 2021. Significant non-cash adjustments for the quarter consisted of $11.2 million in stock-based compensation and depreciation and amortization. As we look ahead to 2022, we are not providing specific net product sales guidance as this is a transitional year with the expected impact on Sciola sales from generic competition and the potential launch of Sparsentin in the fourth quarter. As has been typical for us in years past, we do anticipate higher growth to net discounts in the first quarter, driven by insurance coverage changes in the beginning of the new year. From an OPEX perspective, we anticipate that our R&D expenses will continue to run at a rate slightly higher than in the fourth quarter. This is representative of the ongoing Duplex and Protect studies that will continue into 2023. as well as the ongoing COMPOSE study of PEG to Batinase and foundational work, including scaling CMC, to prepare for a pivotal program. We also expect meaningful increases in FG&A, particularly in the second half of this year, as we look to continue the commercial build-out, including additions to our field team for the potential sparsetin launch in IgA nephropathy. Importantly, we continue to be in a strong financial position to execute in 2022 and beyond. We ended the year with $552.9 million in cash and cash equivalents. This balance includes $30.8 million in net proceeds from our at-the-market facility during the fourth quarter. Taking into account the potential impact of a more genericized Biola market, but not yet factoring in the full pivotal program for peg to bat nature, We anticipate this cash balance will support our planned operations through 2023. Let me now hand the call back over to Eric for his closing comments.
spk04: Eric? Thank you, Laura. Our execution in 2021 has enabled us to enter this new year with great momentum and an incredibly bright outlook. Our priorities for 2022 are clear. We will remain focused on positioning sparsentin to become a new treatment standard for IJ nephropathy and FSGS if approved. This includes achieving on-time and high-quality regulatory submissions, the first of which could enable an approval of sparsentin for IJ nephropathy by the end of this year. We will also focus on continuing to advance our PEG-debatinase program following the exciting proof of concept data in HCU reported in December. And in parallel to focusing on the advancement of our pipeline, we will further prepare our organization for the potential upcoming launches of sparsentin by building upon our proven commercialization capabilities in rare nephrology. Let me now turn the call over to Chris for Q&A. Chris?
spk05: Great. Thank you, Eric. Buena, can we please go ahead and open up the lines for Q&A?
spk08: Absolutely. As a reminder, to ask a question, please press the star, then the number one on your telephone. To withdraw a question, press the . Your first question is from Greg Harrison of Bank of America. Your line is open.
spk02: Hey, good afternoon, and thanks for taking our questions. On FSGS, what would you consider to be supportive EGFR data, in your opinion? And if that were not considered to be sufficient for filing, What would be required for a filing? Would you have to complete the entire study, or could there be another interim analysis performed?
spk04: Greg, thanks so much for the question. Bill, why don't you speak to the regulatory expectations with the FSGS data? And, Jule, perhaps you can speak a bit to what might be supportive from a nephrologist perspective. Bill?
spk07: Certainly, I'll start. With the construct of the trial, the primary endpoint for approval under subpart H accelerated approval is proteinuria. And we've met that milestone with a very robust superiority of sparsentin over erbosartan. But in that accelerated approval rubric for the FDA, their criteria is that the totality of the data are, you know, generally supportive or reasonably likely to support or to predict success at the two-year endpoint. So, in that case, the agency is going to be looking to see are the trends there that are consistent with the hypothesis that this level of proteinuria reduction should yield a preservation of renal function. And in this case, that would be shown by a separation in the EGFR slopes at two years. I'll hand over to Jula for the nephrologist's viewpoint.
spk11: Certainly. Thanks. Well, recall in Duet that there was an early acute EGFR decline and then a flattening with sparsentan, and this is consistent with the nephroprotective agents such as SGLT2 inhibitors and RAS inhibitors. And the key is to understand the nature of the curve, as a reduction in proteinuria should flatten the EGFR curve and then provide long-term nephroprotection. So for duplex, it will be a matter of having enough EGFR data that is mature enough to predict the two-year EGFR slope endpoint.
spk04: Thank you, Bill and Julie. And, Greg, just to complete out the last part of your question around, you know, if FDA does not deem the additional EGFR data sufficient for subpart H submission, what next? Well, I think we first believe that the profile sparsentin will, you know, if behaving like we expect, it should support the, you know, longer-term two-year difference that we expect. And we are committed to completing this trial out to the two years. So if for some reason FDA says, you know, we wouldn't support a subpart H, we would evaluate but our plan certainly would be to complete the trial and then submit for full approval at that point. And just a reminder, we would expect the last patient last visit for the two-year endpoint to occur in the first half of next year.
spk02: Great. That's helpful. Thanks again, and congrats on the progress. It's exciting to see you guys getting close to the finish line. Indeed. Thank you, Greg.
spk08: Your next question is from Carter Gould of Barclays. Your line is open.
spk06: Yeah, hey, this is Justin. I'm for Carter. Congrats on all the progress this year. Another one on the interim readout for Duplex, sort of how long after discussing those data with FDA do you expect to be ready to file for approval? And then sort of related to that, do you expect to file the combo MAA in Europe you know, around the same time as the NDA, or is one of those going to precede the other?
spk04: Yeah, so great questions, Justin. Thank you for them. Bill, would you like to talk about the timing? Just as a reminder, overall we would expect those filings, assuming, you know, the regulators are supportive of the additional EGFR data, we'd look to do that in the middle of this year. Bill perhaps can provide a little bit more color on the timing and sequence.
spk07: Yeah, I think the preparation is well underway, Justin, working on those filings now so that once we do have that supplemental look at the EGFR data, we can tuck those additional data in and submit very quickly. So we've guided mid-year for both of those filings. They're going to be very close to one another because they're both essentially waiting for that additional data to be available, and then we'll have the conversation with the agency. And in the scenario where they are, as we expect, supportive, that will be the last elements to drop in so that we're ready to file quickly. Awesome. Thanks so much.
spk08: Thanks, Joseph. Your next question is from Joseph Swartrip, SVB Learing. Your line is open.
spk03: Hi, thanks very much. To what extent will you be scrutinizing the merit of the protein area and EGFR effects in the next look at the duplex data in order to determine whether it makes sense to show to the FDA? In other words, is there a scenario where you would not submit the data to the FDA if it were not supportive, however remote? And if If so, how much would the data have to worsen beyond what you've already seen in order to lead you not to submit the data to the FDA?
spk04: Joe, thank you for the question. I think first I'll just reinforce that our view is that sparsentin overall has performed very consistently throughout our clinical program, and so we do believe that if sparsentin does behave the way that it has and the way that we expect it, there will be you know, a continued improvement over time. But I'll ask Jula to comment on, you know, what type of assessment would you be looking with these and, you know, what's that limited kind of evaluation that will be done?
spk11: Certainly. So the only evaluation is EGFR. We've already seen the magnitude of the proteinuria reduction from the top line results. So we are just looking at EGFR and the additional maturity of the data. to be predictive of the long-term EGFR benefit. And we believe that the proteinary reduction is meaningful. And then really, as I said, it's just looking at the EGFR data at that point in time.
spk03: Okay, great. That's very helpful. Thank you. And then maybe another question, but this one relating to IgA nephropathy. Given there was a recent approval and pricing and launch of another therapy, I was wondering, I'm thinking of Tarpeo, and you mentioned you were doing some considerable work in terms of pharmacoeconomics. I was wondering, you know, how does the pricing for that agent compare with some of the work that you've been doing in preparation for determining a price for sparsantan and IgA nephropathy?
spk04: Yeah, Joe, thank you for the question. I think first, we were quite pleased now to see a precedent from a regulatory approval in the use of proteinuria with the approval of budesonide. And so, you know, we think it further bolsters our confidence. I'll ask Peter to talk a little bit about how we think about pricing and, as you say, the pharmacoeconomic evidence to support pricing and access for sparse antenna. Peter?
spk09: Yeah, certainly, Eric, and thank you for the question. So I think it's good to start with, like, what is your unmet need? And we know the unmet need, in particular in IGI nephropathy, but also in FSGS, is among the most difficult patients to treat for nephrologists. And in particular for the current standard of care, because patients are not being treated well to the targets that physicians want, with ACE inhibitors and ARBs. And that's where we see the sweet spot for sparsanthin. That's what we're hearing from patients as well as from nephrologists that they're very excited about the profile because they see this as a new standard of care potentially replacing ACE and ARBs without having the need to go to the steroid path. And so our work, our planning, our positioning will be to take that foundational position and our pricing will be will be consequently. With regards to the pricing you referenced, I think there is now multiple products in the rare nephrology space in the last year in particular, including Benettonite that you were referencing, and I think that allows us a certain level of flexibility, but again, we see SparCentral as a new potential of care and as a new standard of care, and we will be pricing accordingly.
spk03: Thanks for taking my questions.
spk15: Thank you, Jeff.
spk08: Your next question is from Maury Raycroft of Jefferies. Your line is open. Maury Raycroft, your line is open.
spk05: Bueno, maybe let's come back to Maury.
spk08: Your next question is from Michelle Gilson of Canaccord Genuity. Your line is open. Hi. Can you guys hear me?
spk04: Yes, we can. Hi, Michelle.
spk14: Hi. Thank you for taking my question. I guess a couple on pectobatinase. You indicated when you presented the data in December that you were planning to meet with the FDA in the first quarter of this year to get aligned on, you know, potential pivotal . I was just curious if, you know, if you guys have had that meeting. And then, you know, when it comes to total homelessness as a surrogate endpoint or as a biomarker, you know, Can you maybe discuss how established the link is with homocysteine and clinical outcomes in homocysteineuria? And just maybe if the FDA does ask you to run a trial with a clinical outcome endpoint, what kind of options do you have?
spk04: Michelle, thank you so much for the questions. Bill, would you like to take those?
spk07: Sure. I'd be happy to. And clearly, the GOG is a big fan of pegtivatinase. Oh, yes.
spk14: They're a very big fan.
spk07: Yes. Remember, with respect to the FDA and the discussions around endpoints for Phase III, remember that we've made the comments in the past that this is an iterative process. There's multiple elements to that agreement around the assay, establishing the biomarker according to guidance, phase three clinical trial design. So it's more than just a one-step process. We've begun that process with the agency. We're not at a position where we can comment on it beyond the fact that we're pleased with the directions that it's going and we'll update as we get to a point of completion and we have more certainty around what that path looks like. The second part of your question was really, I believe, around the links between reductions in homocysteineuria and that linkage to clinical impacts. If you look at the guidance that is out there that suggests, that guides physicians to get total homocysteine below 100, That guidance was set based on looking at patients, their levels of homocysteine, and their incidence of clinical events, whether it's issues with eye, bone, thrombotic events, or cognitive issues. And the overall conclusion was that when they get below 120 micromolar, that those clinical events become very rare. They set the guidance at 100 micromolar because it gave them some breathing space and was easy to remember. So the retrospective data is there with the linkage between the clinical endpoints and the overall levels of homocysteine. What we also have is the natural history study data coming from the ongoing study that we have that fits and confirms that events are indeed linked to total homocysteine. So we'll be packaging that together in making our arguments.
spk04: I think the final piece of your question... It looks like... Can you hear me? It looks like we might have lost Bill's connection. So, Michelle, the last part of your question... Oh, and he's back. Bill, go ahead. We can hear you now.
spk07: To realize that we... we will be making clinical measurements. They just won't be primary endpoints. We will look at ocular.
spk04: Bill, I think we're having some audio difficulties. Maybe if I can frame, Michelle, the last part of your question, which is do we believe that there would be a need for clinical outcomes in a phase three program? And I think, you know, certainly as Bill had mentioned, we'll be looking at that as secondary measures, both for the ongoing phase one to composed study, as well as likely in any phase three, although we haven't yet reached agreement on what that trial design could look like. You know, homocystinuria is certainly one of those diseases that is heterogeneous, both in the presentation of the disease, as well as the the kind of time to onset of some of those. And so it's that heterogeneity that would make it very difficult to select a particular clinical outcome in a development program, which is why we're so focused on ensuring that total homocysteine or biomarker can be used for further development, given, again, that this is an ultra-rare condition that, you know, would be a challenge to have a Phase III with a So, more to come on that, and I think what's important is, you know, there is more engagement and work that will be done this year to ensure that we have that alignment with regulators and can move forward with the next phase of development. And, Bill, I'm not sure if we have you back. Okay. Michelle, hopefully that answers your question, and I think hopefully we'll have our resident expert back here soon.
spk14: All right. Sounds good. I can have Bear come back on. Thanks for taking my question.
spk04: Thank you, Michelle.
spk08: Your next question is from Lisa Mako of Evercore ISI. Your line is open.
spk13: Hi. Thanks for taking the question. I just wanted to see if you could give us a little color. Maybe you have talked about this before, but we just wanted to confirm. On the data that you're going to deliver to FDA on FSGS, is that like one-year estimated GFR? Is that what it is, that all the patients have been through one year? Could you just kind of give us some sense of that thing?
spk04: Sure. Jule, would you like to take that? And, Lisa, thank you very much for the question.
spk11: So the additional data, 50% of the patients – will be at two years, and 100% of the patients will be at one year for the EGFR data. And so it'll be a much more mature data set with regards to EGFR, and that's the data that we're gonna be providing.
spk13: Okay, great, thank you. Thank you, Lisa.
spk08: Your next question is from Morrie Raycroft of Jefferies. Your line is open.
spk01: Hi. Thanks for taking my question, and congrats on the progress. I was going to ask a question. Just based on the TARPAO launch, do you have an updated view on how you see the treatment paradigm shaping up? And if you have any feedback from payers on replacing traditional RAS inhibitors, or will you have to step through traditional RAS inhibitors? I guess, how are you guys thinking about that?
spk04: Mor, thanks so much for the questions. Jule, maybe I'll start with you. You can talk about how you might see the landscape evolving. And then, Peter, if you can add anything further as we think about commercialization and any feedback from payers.
spk11: Sure. Well, there remains a huge unmet need for patients with proteinuric kidney diseases. And we basically treat patients who have proteinuria above 0.75 grams per day or 0.5 with RAS inhibitors. And that's our foundation. And we envision barcentan to be the initial therapy or foundational therapy if approved. The utilization of steroid therapy historically and likely going forward is outlined in the KDGO guidelines, which we only use it in a subset of patients who are really at high risk of progression and those who have either a rapid decline in EGFR or very high proteinuria. I don't really envision that changing based on our guidelines and based on what we know and It's really a risk-benefit ratio that we do in patients and when we decide to use that therapy or pull that in.
spk09: Yeah, and building on that, Maury, so the introduction of bedetanide is not changing the way we think about the introduction of sparsen and the potential it has to become a new standard of care. What we are hearing from our physicians as well as from patient societies is that they're feeling very comfortable on the position of sparsen to replace current standards of care, ACE inhibitors and ARBs. And so positioning it before the use of steroids and allowing that additional option later on in the pathway. So to your question, it doesn't change the way we are thinking about it. On your second part of the question with regards to payers, I think we are pleased with the interest that payers have. We're building the value proposition. We're building the burden of disease and the natural history of the disease to have a meaningful conversation with the payers. We are pleased where we are, and again, the introduction of Badesonite is not changing the way we position Sparcentum.
spk04: Yeah, and I think, you know, specifically, thank you, Peter, for that. Maybe just one other thing that I'll add, Maury, to your question around do we think that we need to step through an ACE or an ARB. I think given in hygiene nephropathy that the patients that are currently being treated, nearly all of them are on an ACE or an ARB. It's highly likely. that those patients would, if still having elevated proteinuria, would likely be stepped up to or switched to sparsentin. So whether it's, as Jula highlighted, that in the future patients may start on sparsentin or are on an ACE or an ARB and then are stepped up, we actually don't see that as an issue or a barrier for us, particularly given that so many of these patients still have elevated proteinuria and are at great risk of progression. So I think it underscores the role that we believe sparsenetum will play as becoming a foundational treatment within this disease.
spk05: Okay, now I think we can go ahead and move to the next question, please.
spk08: Your next question is from Laura Chico of Wedbush. Your line is open.
spk10: Hey, good afternoon, guys. Thanks for taking that question. I apologize because this is going to be a pretty naive one, but I wanted to ask on Duplex. I'm wondering if you could just kind of walk me through the communication strategy and essentially what level of detail should investors be anticipating with respect to the interim analysis here that's coming up? And I guess I'm asking because I'm not really clear. I just want to make sure. that we're all clear on terms of what data should be anticipated. I know you've been cautioned by the FDA on certain disclosures, so I'm just trying to understand what visibility we as investors will have with respect to the interim update.
spk04: Thanks. Laura, thank you very much for the question. Certainly not naive. It's a very important one as we can help provide as much clarity in the coming months. I think What's important is that we are on track for the additional data on EGFR that we will provide to FDA and EMA. Those data to date have not been extracted, but we're on track to do that in the first half of this year. And at that point, we really will not be commenting on any of the process or any of the data. You will hear from us once we've had the meetings with regulators and that we have that direction from FDA on the potential submission timing and process. But nothing incremental before that happens. And so we're going to remain quiet on that front. But you can expect to hear from us once we do have that agreement. And then, you know, of course, you know, related to Sparsentin, expect to hear from us on the submission of our IGAN NDA this quarter, as well as when we would receive an acceptance from FDA of that NDA. So there will be quite a bit of communication, but as you point out, we are going to remain very vigilant in the integrity of that trial and not disclosing anything on EGFR.
spk10: Thanks very much.
spk04: I believe that answers your question.
spk08: Yes, it does. Thanks, Eric.
spk04: Okay. Thank you, Laura.
spk08: Your next question is from Tim Luto of William Blair. Your line is open.
spk15: Hi, Tim. This is John on for Tim. Thanks so much for taking our question. Just wondering if you could give us any more details on what additional data from the COMPOSE study you're planning to share at a medical meeting, what meeting you might see that data at, and how we should be looking at, or is there anything that we should be looking for in that additional data? Thanks.
spk04: John, thank you so much for the question. Julie, would you like to take this one?
spk11: So we do expect to have additional details from Compose at a medical meeting this spring, and it'll be details from the first five cohorts. And as we do with participation in any medical meeting, we'll provide the details at an appropriate time.
spk15: Okay, thank you. Thank you, John.
spk08: No more questions. I would like to turn the call back to the presenters for the final remarks.
spk05: Great. Thank you, Blayna. And thank you all for joining us. This concludes our update for today. As you can tell, we have many exciting milestones ahead, and we look forward to keeping you updated throughout the year. Have a great rest of your evening.
spk08: This concludes today's conference call. Thank you for participating. You may now disconnect.
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