Travere Therapeutics, Inc.

Ladies and gentlemen, and welcome to the Travere Therapeutics second quarter 2021 financial results and corporate update call. At this time, all participants are in a listen-only mode. Later, we will conduct question and answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star, then zero on your touchtone telephone. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Mr. Chris Klein. Please go ahead.

Great. Thank you, Jerome. Good afternoon, everyone, and welcome to Travere Therapeutics' second quarter 2021 financial results and corporate update call. Thank you for joining us. Today's call will be led by our Chief Executive Officer, Dr. Eric Dubé. Eric will be joined for the prepared remarks by our Chief Medical Officer, Dr. Noah Rosenberg, Peter Herrmann, our Chief Commercial Officer, and our Chief Financial Officer, Laura Clay. Dr. Bill Rote, Senior Vice President of Research and Development, will join us for the Q&A session. Before we begin, I would like to remind everyone that statements made during 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 statements. We 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 views only as of the date such statements are made, July 29, 2021. And Travere specifically disclaims any obligation to update such statements to reflect future information, events, or circumstances. With that, I'll now turn the call over to Eric. Eric?

Thank you, Chris, and good afternoon. At the outset of the year, we highlighted the progression of our pipeline as a key priority in order to strengthen our position in the rare disease community. At the heart of this priority is an organization-wide focus on positioning sparsentin to potentially become a new treatment standard for FSGS and IgA nephropathy if approved. People living with FSGS and IgA nephropathy have gone decades without adequate treatment options and limited innovation. As a result, each year thousands of patients with these disorders are advancing to kidney transplant or dialysis. It is a collective understanding of this significant unmet need that drives our organization every day to help pave the way for new therapeutic options for these patients. Being at the forefront of these efforts can come with both achieving significant milestones as well as challenges that must be overcome. This was evident in the first half of 2021 where we generated positive results from the interim proteinuria assessment of our pivotal duplex study of sparsentin and FSGS, but subsequently heard from FDA that the interim data were not adequate to support an accelerated approval submission this year. Despite this, we remain undeterred in our commitment to ultimately deliver sparsentin as a potential new treatment standard for FSGS. We remain confident in the interim data generated by the duplex study, the largest controlled interventional study in FSGS to date. These data build upon the strong proof of concept from the Phase II duet study and provide a consistent data package to further inform sparsentin's profile. At our upcoming scheduled Type A meeting this quarter, we look forward to continuing our constructive dialogue with FDA in an effort to pursue accelerated approval submission in the U.S. next year. Outside of the U.S., I am pleased to share that we have made progress on our ongoing regulatory discussions with the EMA. Based upon our latest interactions, we anticipate submitting an application for conditional marketing authorization of sparsentin for the treatment of FSGS in Europe by the end of this year. NOAA will go into a bit more detail shortly, but we believe that if we continue to progress according to plan, sparsentin could be approvable for FSGS in Europe by during the first half of 2023. We also remain excited about the potential for sparsentin to become an important new treatment option for patients with IgG nephropathy. IgG nephropathy is the most common cause of primary glomerular nephritis and a leading cause of end-stage kidney disease. If ultimately approved, we believe there to be between 75,000 and 120,000 addressable patients at launch in the US and Europe. with room for greater patient identification through increased awareness and diagnosis over time. Our phase three PROTECT study evaluating sparsentin in patients with IgA nephropathy is progressing well. And we remain on track for top line data from the 36 week interim proteinuria assessment next month. The interim assessment is designed to support potential accelerated approval submissions in the US and Europe. which could result in the first approval for IgA nephropathy as early as next year. Finally, in the pipeline, we are encouraged by progress made with the PEG-debatinase program, where we remain on track to see preliminary data from the Phase I-II study later this year. We will also be working to lay the foundation for our regulatory pathway in HCU by leveraging both data from the Phase I-II study and the ongoing natural history study. Lastly, I'd like to touch on our commercial portfolio. As we have talked about for the last several years, we believe our commercialization capabilities in the U.S. are a strategic strength for Travere's ability to deliver our current product candidates if approved. We have demonstrated a consistent ability to identify and treat new patients living with rare kidney and liver conditions. The second quarter is another example of our team's resilience. as evidenced by the rebound in performance following the impact of the pandemic in the first quarter. We experienced year-over-year growth across all of our products, which speaks to the continued important role they play for patients. Looking ahead, we continue to expect underlying demand for our products, but we do anticipate that the recently announced generic version of the original formulation of Fiola will have an unfavorable impact on our net product sales growth in the second half of the year. At this time, we are not in a position to reliably estimate what that impact will be, but we plan to provide updates as we learn more about the evolution of the market. This is a scenario that has been part of our business planning for some time, and we remain committed to the Cystinuria community. It also does not change our confidence in or plans to continue identifying and treating patients. and building upon our commercialization capabilities to successfully deliver sparsentin if approved. Let me now turn the call over to Noah for updates from the pipeline. Noah?

Thank you, Eric, and good afternoon, everyone. We remain focused on developing sparsentin as a potential new treatment option for people living with FSGS and IG nephropathy, and I'm pleased to report that our ongoing pivotal Phase III duplex and protect studies continue to progress as planned. During the second quarter, the Independent Data Monitoring Committee, or the DMC, completed its sixth scheduled meeting to assess safety in both duplex and protect. The DMC recommended both studies proceed as planned based upon their safety review. Looking first at FHDS, Duplex is continuing in a blinded manner to the study's confirmatory endpoint, which will measure changes in EGFR after 108 weeks of treatment, and we continue to be pleased with its high-quality conduct. As many of you will recall, in February, we announced that the duplex study achieved its interim protein era endpoint. The data showed that treatment with sparsentan resulted in a 60% greater relative likelihood of achieving the FSGS partial remission of proteinuria endpoint, or FPRE, when compared to erbisartan. And overall, the safety and tolerability profile between treatment groups in the study at the time of the analysis were generally comparable, which is very encouraging. We are working collaboratively with both FDA and EMA on the independent submission pathways to ultimately deliver sparsentin. In the U.S., Preparations are progressing well for our upcoming Type A meeting. Our objective for the meeting is to further our dialogue from the pre-NDA meeting held earlier this year. We will look to align with the agency on providing additional EGFR data from the ongoing study with the goal of enabling an accelerated approval submission for FSGS in the U.S. next year. We look forward to continuing our constructive dialogue and providing an update in the coming months. During the second quarter, we had a productive interaction with our assigned rapporteur and co-rapporteur representing the EMA for the Sparsentin conditional marketing authorization process in Europe. As a result of that interaction, we are continuing to move ahead with our plans to submit a CMA application by the end of this year. Based upon these discussions, we are planning for a standard review time in Europe. We expect the standard review to allow us to utilize a planned clock stop to supplement our submission with the same EGFR data that we're proposing to generate in the first half of 2022 for the potential U.S. regulatory submission. As you know, the EMA review process is different from the U.S., but we anticipate this could result in a potential approval in the first half of 2023. our teams are working diligently to complete the CMA application by year end. In parallel, we are also making meaningful progress on initiating enabling studies to support the CMA submission and potential pediatric approval in Europe. Consistent with our pediatric investigation plan that was agreed to by EMA earlier this year, we expect to initiate our open label epic study of sparsantan in children between the ages of one and 18 in the third quarter. Moving to IgA nephropathy, during the second quarter, we achieved completion of patient enrollment in our phase three PROTECT study of sparsantia. Achieving this milestone ahead of schedule speaks to the execution of our clinical teams and significant unmet need in this population. There are currently no approved medicines indicated for IgA nephropathy. and non-immunosuppressive steroid-sparing treatment options are desperately needed, given the long-term tolerability concerns amongst nephrologists and patients. Our Phase III PROTECT study is designed to determine the effect of sparsantan on proteinuria and renal function as compared to orbisortan, an angiotensin receptor blocker, and a current standard of care in patients with IgA nephropathy. Proteinuria reduction in IgG nephropathy is well established as the primary treatment goal by nephrologists, and data generation in the field continues to be consistent with the recognized literature. It clearly supports the utility of proteinuria reduction and its tie to clinically meaningful outcomes for kidney function. The interim assessment in PROTECT will evaluate the pre-specified primary endpoint, which is the ratio of of geometric mean reduction of proteinuria from baseline to 36 weeks of treatment between sparsentan and erbisartan. Our goal for sparsentan is to demonstrate a statistically significant and clinically meaningful response on proteinuria reduction compared to erbisartan. Ultimately, we are optimistic that this interim assessment will generate a data package that will support regulatory submissions in the U.S. and Europe. Similar to our interactions with the regulators on the DUPLEX study, we anticipate that FDA and EMA will be looking at all available data, including EGFR, when determining the ability to submit for accelerated approval. There are some differences between the study designs that lead us to believe that should the PROTECT study meet its primary endpoint in interim analysis, there may be a more developed data package compared to DUPLEX to potentially support an accelerated approval submission. Of note, we anticipate a significant number of patients to have at least one year of EGFR data at the time of the interim assessment. Also, the PROTECT study requires all patients come into the trial on maximal tolerated dose of ACE ARV therapy for at least 12 weeks prior to randomization, and there is no washout period. As Eric mentioned, we remain on track for top-line data from the interim assessment for PROTECT next month, and we look forward to providing an update for you and the nephrology community. We do expect a limited data disclosure as patients will be continuing on a blinded basis out to two years, and we have a need to maintain integrity in this study through completion. We anticipate providing the outcome on the interim assessment of the primary endpoint of proteinuria reduction from baseline but we do not anticipate being able to provide EGFR values. Lastly, from the pipeline, our PEG to Batenase program achieved enrollment of the last patient in the highest currently planned dosing cohort. We look forward to gaining a more comprehensive understanding of the safety and tolerability profile of PEG to Batenase and to determine if we have reached the appropriate dose to advance into a pivotal study or if the program would gain from an additional cohort to maximize potential benefit. We anticipate providing either a qualitative or a quantitative update before year-end. Overall, I remain pleased with our development progress. We generated strong interim data supporting the profile of sparsantan for the treatment of FSGS, and we have an excellent opportunity to further establish sparsantan's utility with the PROTECT study top-line readout next month. I'll now turn the call over to Peter for the commercial update. Peter?

Thank you, Noah. We are very pleased with the performance from our commercial organization in the second quarter, which resulted in approximately 13% organic growth over the same period last year. The underlying strengths of our business provided for us to make up some lost ground from the first quarter, and ended the first half of the year with approximately 6% organic growth, in line with our expectations. During the second quarter, we continued to see demand and strong patient compliance across all approved products. We also experienced the normalization of our gross to net deductions, which normally occur at the beginning of each year with insurance resets. Regarding our Fiola products, During the quarter, we continue to see new patient initiate therapy and further demand for our Fiola EC. We experienced minimal impact from the generic version of the original formulation that entered the market during this quarter. And as I mentioned earlier, we anticipate there will be an unfavorable impact on Fiola revenues in the second half of the year. Despite this, We currently anticipate being able to continue identifying and treating new patients for the foreseeable future. Bioassay portfolio is providing an important treatment choice for pediatric hepatologists, and we continue to expect growth through the balance of the year. Within the pediatric hepatology space, we were pleased to see the recent approval of Alvareos Milvain, the first approved treatment of pruritus in all subtypes of PFAC. As part of our limited co-promotion agreement with Albareo, we look forward to leveraging our established expertise to help deliver its much needed new treatment options for people living with this rare, hepatic condition. We are also optimistic that our work on this launch will provide additional opportunities to engage with those specialists that treat with Colbon. Overall, I am proud of our commercial progress in the first half of the year. We have maintained a focus on identifying and treating new patients and further strengthening our capabilities. We continue to ready our organization by building upon the foundational pre-commercialization work to support Parcentum in both FFTS and IGA nephropathy with the goal of a successful first launch in the U.S. as early as next year. I'd like to turn the call over to Laura now for the financial update. Laura?

For the second quarter of 2021, we reported net product sales of 54.6 million from our commercial portfolio compared to 48.4 million for the same period in 2020. We reported a gap net loss of 39 million for the second quarter of 2021. After adjusting for non-cash expenses and income tax, we reported a non-GAAP net loss of $23.3 million for the second quarter of 2021. On a GAAP basis, R&D expenses were $51.8 million for the second quarter of 2021. The increase compared to 2020 is largely attributable to increased patient enrollment in the ongoing studies of sparsentin, as well as advancement of the PEG to BAT and ACE program and classical HCU. On an adjusted basis, R&D expenses were $48.7 million for the second quarter of 2021. Relevant non-cash expenses for the second quarter included $3.1 million of stock-based compensation and amortization. On a GAAP basis, selling general and administrative expenses for the second quarter were $35 million. and is comparable to the same period in 2020. On an adjusted basis, SG&A expenses for the second quarter were $24 million. Significant non-cash adjustments for the quarter consisted of $11 million in stock-based compensation and depreciation and amortization. For the balance of the year, we expect gradual and modest increases in our operating expenses primarily driven by continued clinical development of programs and activity to support potential launches of Barsentin. Our financial foundation to support this activity remains strong. For the second quarter, we were nearly neutral on cash use as a result of receiving final tax refunds related to the CARES Act, which offset our operating cash use. Not including additional business developments, Our total cash balance of $522.8 million at the end of the quarter is expected to support our current operations into 2023. This takes into consideration potential impact of the generic version of Sciola, as well as investments in Sparsentin pre-launch and early launch activities and advancing the PEG to BATINACE program. I will now hand the call back over to Eric for his closing comments.

Eric? Thank you, Laura. In the first half of this year, we generated further evidence to support the value that sparsentin can bring to patients and to our organization. I'm incredibly proud of our team's continued execution of our landmark studies in FSGS and IJ nephropathy and remain excited about our path ahead. We remain confident that we will ultimately be in a position to deliver sparsentin as a potential new treatment standard for patients with FSGS in the U.S. And we look forward to continuing our path for patients in Europe by submitting our CMA application by the end of this year. Furthermore, we have an exciting opportunity ahead of us with the PROTECT results coming next month, which have the potential to build upon the growing evidence supporting sparsentin as the first non-immunosuppressive innovation in decades for patients living with IgA nephropathy. Through the balance of this year, we will remain focused on the priorities that will enable us to deliver sparsentin and the rest of our pipeline to patients who desperately need new treatment options. Let me now turn the call over to Chris for Q&A.

Chris? Great. Thanks, Eric. Jerome, can we please go ahead and open up the line for Q&A, please?

Ladies and gentlemen, if you have a question at this time, please press the star and then the number one key on your touchstone 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 Joseph Schwartz with SVB Learn. Your line is open.

Hi, everyone. Thanks so much. I was hoping to gain a better understanding about your expectation for an unfavorable impact on the Theola franchise from the recent approval of a generic for the first gen formulation. Is the unfavorable impact that you expect just from a decrease in sales of your branded first-generation formulation, or do you expect that patients will actually switch back from Theola EC to the generic, to the first gen, and how much of your Theola franchise has already converted to EC? And do you have any color commentary that you can offer that could help us model Theola revenue over the next 12 months on any changes in prescription patterns that you've detected so far? Thank you.

Joe, thanks so much for the questions. I'll start out by saying that at this time it's just really difficult for us to project reliably what erosion might take place given that there's been very little time and we've actually seen very little uptick of the generic since it's been available. That said, we do believe that things will evolve and I'll ask Peter to talk a little bit about how that might evolve and impact our business as well as your question around the split between FIOA and FIOA EC.

Yeah, thanks, Eric. And Joe, thanks for your question. I mean, we knew that at a certain time we could be facing generic competition. So in that respect, we have been planning for this scenario. In the first half of the year, we have been very pleased with our continued performance both in identifying new patients as well as allowing services for those patients that are in treatment already and to retain those patients. So to Eric's point, we have seen limited impact so far. That doesn't mean that there won't be an impact in the second half of the year, but it's early days. So I think we have to better understand how the dynamics may play out. Also, with regards to your question, with regards to the original formulation and the fail that we see, right now we have less than 20% of the patients that are still in the original formulation. But like I said, we have to get a better understanding on the dynamics with regards to formulary and how formulary will be adopting the new generic version. But we remain rather confident in our ability in the infrastructure that we have built over the last seven years, most in identifying new patients as well as in providing support for those patients that are on the product. So it's yet to be seen, and we will be closely monitoring the impact, and at a later time point, additional perspective what the impact may be.

Thank you very much. That's super helpful. And I was wondering also if you could talk about how you're preparing for your upcoming Type A meeting with the FDA in order to make your interactions as persuasive as possible, and has this meeting been scheduled yet? Will you update investors after it occurs, or you receive the minutes?

Sorry about that. I was on mute. So, Joe, yes. We do have the meeting scheduled and it has not yet occurred. So I'll ask Bill to talk a bit about the preparation. What I can say is that we certainly reinforce and we believe FDA understands the high unmet need within this space. So very much Bill will talk about what our goals are and how they're preparing.

Certainly, Eric. The process of preparation begins with submission of a briefing book and outlining our positions going into the meeting and providing the agency with detailed information about our plans moving forward. Coming out of the pre-NDA discussions, one of the specific asks from the agency was around just give us the specifics of your proposal for a second look at EGFR in the first half of next year. How would that work specifically? Give us the details. around the statistical analysis and efforts made and how are you preserving the integrity of the study, given that this is an ongoing study that runs out to two years for each of the patients. So that's been the bulk of the preparation, and we look forward to having those discussions with the agency this quarter.

Thanks, Bill. And just to close out on the other part of your question, Joe, We will plan to provide a public disclosure on these regulatory interactions once we receive written minutes, just to make sure that we're in full alignment and understand the FDA's thinking after the meeting.

Excellent. Thanks again, and best wishes. Thank you.

And your next question comes from Carter Gold with Barclays for Lines Open.

Yeah, hi, this is Justin Arthur Carter. Thanks for taking our question. First one on PROTECT, just sort of understanding that you need to maintain the integrity of the study, but given that you're going to have a substantial amount of patients with a year's worth of EGFR data when it reads out next month, can you characterize how much freedom you're going to have to potentially give qualitative messaging around those EGFR trends and sort of if you're thinking there has changed at all with your ongoing discussions with FDA? Yeah.

Sure. So, Justin, thanks so much for the question. I'd say that we are aiming to be as consistent as possible with the disclosure from the duplex interim. And since then, though, we've learned quite a bit from the FDA and our interactions on duplex and believe that we may be able to provide some type of qualitative update on what we're seeing that may be helpful to understand the status of the trial But ultimately, that's going to be based on the data as well as any guidance that FDA provides on our disclosure practice just to make sure that we're in alignment with how they view the maintenance of integrity of the ongoing trial.

Okay, awesome. Thank you. And then one quick one on duplex, just given that you'll be filing in the EU first. Is that sort of you know, was there any additional information that was shared or that you plan to share with them ahead of that filing, or was that decision based a lot around the sort of mid-review stoppage meeting that should be occurring next year?

So I will turn that question over to Bill.

Yeah, so the EMA saw the same interim data package that we provided to the FDA in And additionally, we made them aware of the progress of our discussions with the FDA and the plans to share additional EGFR data in the first half of next year. The EMA was interested in also seeing that EGFR data. And as you alluded to, there's a clock stoppage period that times out appropriately where we Procedurally, we can add those information or those data, that information, to the review at that point in time.

Great. Thanks so much, and congrats on all the progress. Thank you.

Your next question comes from Lisa Baco with Evercore ISI Airlines Open.

Hi. Thanks for taking the questions and a good quarter. Can you comment on the possibility of a generic Fiola EC and what implications are there if you do get any patents for that? Can you walk us through that scenario?

Sure. Why don't I take that one, Lisa? There is a possibility that there is a generic for Fiola EC. It's something that we will continue to monitor, but we're not aware of. of such activity imminently, but again, it certainly is a possibility. We continue to be in the process of engaging with the Patent Office for a FIOLA EC patent, and if that is granted, then certainly that may allow for continued exclusivity of that newer formulation. At this point, given that that has not yet been granted, I would suggest considering any type of patent coverage as an upside to that existing business.

Okay, great. Thanks. And then for Protect, I'm really excited to see the data coming up. And I just wanted to ask, I understand the point about having, like, a period of maximum tolerated standard of care, you know, 12 weeks ahead of time and how that will help. study, and granted it's an FSGS, you know, there was sort of something that was a proxy for that in my view, which is there was an eight-week treatment period for the people on placebo then crossed over. So what are we to make of that? Because there was actually a pretty lengthy dip in EGFR, which looked like it took about 40 weeks to recover. Can you maybe talk about sort of how you think about that observation vis-a-vis the run-in period?

Sure, and I think, Lisa, just to make sure that I'm clear on the question, you're referring on that eight-week crossover and the EGFR acute dip is from the DUET study?

Yes.

Yeah, okay, great. So, Noah, do you want to take this question?

Sure. It's a great question, Lisa. Just reminding that DUET design was different in the sense that we had three doses, so we started at 200, 400, 800 doses. So some of those patients coming across with the lower doses may have impacted that dip. And, you know, here I think, you know, having maximally tolerated, you know, ACE-ARB and then going right into, again, right into the erbosartan, we believe may provide, you know, the ability to show in a more clear way addition of ERA on top of angiotensin. blockade. So it's a slightly different design, to answer your question.

Sorry, how does the dose relate? I didn't quite make the link.

Well, it was, remember, yeah, so in duet, it's not just a matter of going from sparsantan, sorry, from angiotensin blockade to erbisartan. It was going from dose, let's say, of 200 sparsantan or 400 up to higher doses when they went into the crossover period. So you're saying there's an impact there of change of dose of sparsentin in addition to, right?

Yeah, so I think, Noah, what you're saying is the variability of patients coming into the DUET study as well as the variability across the different dose levels, you're going to have, you know, introduce more variability in looking at what purely sparsentin and the endothelin blockade can do on top of max tolerated

And as I remember, the doses were like you started at 200 and then you might have gone to 400 and 800, so I guess that took some time and that probably lengthened out that hemodynamic effect, right? The acute hemodynamic effect.

Yeah, I think that's what I'm saying, exactly.

Okay, good.

And then just last question from me. For 058, what are you looking for in the data? Because that's a product we don't think about as much, but, you know, you kind of mentioned you're going to be looking for the highest dose to determine if you can get another dose cohort. What exactly are you going to be looking at? If you could just give us an understanding there. Thanks.

Sure. Thanks, Lisa, for that question, because we are really excited about this program as well. And I'll ask Bill to talk a bit about what we're planning to evaluate in that Phase I-II.

Certainly. With any Phase I-II study, and this is the first in human study for this molecule, we Primary is, of course, safety and tolerability. Beyond that, we're also looking, and I think the heart of your question is really looking at, from an efficacy readout on the biochemical markers, what are you seeing changing on a dose-dependent basis within these patients over time in response to repeated administrations of PEG-2-batinases? foremost in those measurements, and there are many, is certainly homocysteine concentration in the plasma. These patients are troubled by very high homocysteine and very low methionine, and so normalizing that mix in that patient population is, you know, to what degree can we lower these very high levels of homocysteine in their plasma is part of what we're looking at, as well as the the variability in the response between patients and within patients, and the durability of the response over time. Ultimately, in future studies, one of the things that's going to be an important piece for us is looking at the ability to predict clinical benefit for these individuals in the long term, but also in the short term. Is there enough of a lowering of plasma homocysteine that there's some liberalization that might be allowed in their diet. These patients are forced to eat a very low-protein, methionine-poor diet that is quite unpalatable and very difficult to adhere to, regardless whether they're children or adults. And if we're able to lower homocysteine to the point where that can be ameliorated, even in part, that would be huge from the patient perspective and quality of life aspect.

Okay, great. That's really helpful. Thanks a lot for answering my question.

Certainly helpful.

Your next question comes from Team Lugo with William Blair. Your line is open.

Thanks for taking the question. And I guess following up on the homocysteine drops, expected in the pectobatinase data by year end. How much of a drop is going to kind of lead to the cognitive function and maybe some of the ocular health endpoints you're looking at? Can you just give us a sense of what the natural history data maybe suggests?

Sure, Tim, I'll give a high level and then have Bill turn over. I mean, there's been some early data linking homocysteine levels and really trying to get what is considered under the threshold of 100 or 50 for these patients, which is incredibly challenging for many patients. But there is a link there. But I'll ask Bill to talk about the work that we're doing on the National History Study to really help in bolstering our understanding of that link.

Yeah, thanks for the question, Tim. And it's a really challenging question because what's out there in the literature are retrospective studies that look at essentially treated and untreated individuals. And the treated individuals don't see a huge drop in homocysteine, but they're certainly better off than those that are, you know, not diagnosed until they're older. In that comparison, you do see differences in cognitive development, in IQ scores, and in rates of thrombosis, in rates of lens dislocation, et cetera. The question I think that you're asking is how much homocysteine reduction do you need to see in order to prevent future clinical events? Because treating a patient today is not going to do anything about historical changes that have already occurred and cognitive changes that have already taken place are probably the most difficult to reverse. But that's part of the program going forward. And there's a certain element of clinical investigation here. We know that lower is better. And we know that the treatment guidelines in the past have been to try and get these patients below 100 micromolar. But normal is down in the teens. So are we able to drive it lower and keep it lower? And if so, what's the benefit from there? And we'll be working on that based on all the aspects of data, and one prime among them is the natural history study.

Okay, thank you for that. I guess going back to sparse sentence, following the interactions with EMA, can you just, I guess, broadly discuss a bit about was the data effectively the same as the data you took to the FDA? Was there any changes in the presentation, or is it merely just the kind of the clock stoppage, which, you know, occurs during an EMA submission, and the timing of the submission, you know, it seems like it would line up more with the interim look you'll take in 2022. Or is, I guess, is just the EMA looking at this differently than the FDA, or is it just merely more of a function of the timing of the filings? Bill, do you want to take this one?

Certainly. I think the first part of your question I can answer easily. They saw essentially the same data package. They both saw the full interim data cut, and it was presented the same way. But the different agencies have different processes, and so the filing process, the review process, they are different. And the EMA team had the advantage of knowing that the outcome of the discussions we had with the FDA. We made that known to them so that they were completely informed about our intentions or our proposal with the FDA to have the additional data in the first half of next year. And then so that shaped their thinking as well and made it feasible for us to align on a proposal where those data would be provided as supplementary information during a clock stop.

Okay. Understood. And can I, I guess, just quickly, you know, a how to protect. I'd love to hear your thoughts around kind of the competitive phase two data that we have seen, I guess, relatively recently from some of the larger players out there.

Sure, I'll ask Noah to give some thoughts on the other treatments being developed.

Yeah, I think what's exciting is there's a number of studies now ongoing in this field, and it really does validate. Sorry, there's a number of studies going on. Can you hear me now? I apologize.

Yeah, we can hear you.

Sorry, Tim. So there's a number of ongoing studies, as you pointed out. I think the key is two points. Number one, most of the work that's being done is currently in the immune-suppressive ISP camp, and even some of the lower-dose steroids are still within that realm. And so I think one of the strengths of sparsantan being a non-immune-suppressive therapy is I think there's still a huge opportunity there. for sparsantan and non-immune suppressive therapies, you know, because those steroid and immune suppressive treatments have the potential for tolerability concerns and long-term safety issues. So I think those mechanisms need to really be borne out from a safety standpoint long-term. I think sparsantan really has the ability with its efficacy and safety profile to really be a standard of care, you know, treatment. And I think the – so I think that's the main thrust. The other piece is that we don't see any reason why, and we've seen use of sparsentin. We've used it on top of immunosuppressive therapy and still seen an effect of sparsentin incrementally. So we don't see a reason why sparsentin could be used in a complementary manner as well on top of those treatments. So, you know, it doesn't really change our approach. We're really pretty far in the lead here. But, again, it's good for patients, and we think these different mechanisms – will ultimately hopefully be complementary to each other.

Understood. Thank you.

Thanks, Tim.

Your next question comes from Greg Harrison with Bank of America. Your line's open.

Hey, guys. Thanks for taking the question. Another one on peg to bat mace. Just wanted to get your thoughts on the commercial potential that you see for this asset. And if you can talk a little bit about how it fits into your portfolio and what considerations you would take into account when it comes to future BD activity. I know, you know, the focus is kind of sparse sentence now, but just wanted to get your sense of, you know, what may happen in the future as far as BD and, you know, what size of deals you'd consider.

Sure. Greg, thanks so much for the question. With regard to the commercial potential in classical homocysteineuria, if we look at the U.S. and Europe, there's about 3,000, 3,500 patients that we believe are currently addressable. And we think that that underestimates the real opportunity to help these patients, given that many of them go undiagnosed for years, despite having homocysteine homocystinuria as part of the newborn screening in many states. And that's just because of the methodology that's used. Oftentimes these patients go undetected. And so we think through, you know, increased awareness and the availability of potential therapeutics and clinical trials that that will only increase. So there's a real opportunity in the U.S. and in Europe there. We think that it fits very nicely into our portfolio. It's a rare disease that is oftentimes, you know, these patients, if they are diagnosed early, are treated under the care of a pediatric geneticist and oftentimes across different specialties at tertiary care centers that focus on rare disease. And we have, through our Colbon business, a very strong team that has relationships and capabilities in navigating the diagnostic odyssey and helping clinicians treat and diagnose patients currently with bile acid disorders for Colbon, but we think that it's going to be very similar with the efforts around classical homocysteineuria if PEG-2-batinase is approved. And we think that that serves as a nice example of how we might think about business development where You know, we're going to continue to stay focused in rare disease, and within rare disease therapeutically, we're going to be looking at, you know, that rare renal, hepatic, or metabolic where we will be able to leverage our late-stage development commercialization footprint. In terms of size of deal, you know, that certainly can evolve over time. It's going to be something that we will continue to look at, you know, but it's not something that I'd be able to provide more specifics at this point.

Okay, that's helpful. Thanks.

Your next question comes from Michelle Gilson with Canaccord. Your line is open.

Hi. Thanks for taking my question. I guess one clarifying question. So from your discussion around your EMA interaction, it sounds like the key difference between, I guess, what was discussed with the FDA and the EMA, it was really in this, I guess, interim look that you guys, I guess, second interim look that you guys may take in the first half of next year. Am I gathering this correctly? Or is there some other, I guess, driver behind the image willingness to allow you to file like, I don't know, like greater reliance on proteinuria as a surrogate or you know, more comfort in the EAGFR data that you showed them or if it's the conditional, I guess, mechanism for approval that they have as an option. And then I do have a follow-up. Okay.

Bill, would you like to take that?

Certainly. You know, I think it's difficult to compare the two agencies and their responses because they're different processes and they go through different You know, independent review processes, ultimately they're performing the same function. But they did see the same data. They had the benefit of being aware of the strategy that we were taking or proposing to take with the agency and the supplementary EGFR data next year. And so that was really the biggest difference. And at that point it was, you know, around how do we work that into – the review process and how might that be done with the mechanics of what's permissible, when can you put in additional data, and under what types of reviews that's allowable. That was really the key difference there.

Got it. And, you know, on TPT-058, I know there's been a lot of interest in, or peg the gnat in it tonight. I just, you know, I'm wondering if you could clarify, you know, you seem to be confident that either this dose or the next dose are probably the effective dose or the go-forward dose. And, you know, is that really based on blinded data or is there some other factors? And then, I guess, would you expect, I guess, are you seeing anything in the safety that would really prevent you from going higher if you wanted to achieve the target product profile that you're looking for?

Thanks, Michelle.

Bill, why don't you take this?

Well, this is a blinded study, and we will have an interim look at the data at the completion of the current dose cohort. But we do look at the blinded study data in aggregate. At this point, there are no safety concerns that we're observing that look to be dose-limiting safety issues. Now, I say that from a position of not having full access to the data, so there's a qualifier on there, but that's really not where our limits lie. We do believe that it's likely to be this dose or the next dose, but that's going to be determined by the data and when we're able to analyze all the biochemical data going forward. So we should be able to give you at least a qualitative update later this year on how that looks going forward.

Can I dig into that just a little bit more? You know, why? I guess I'm trying to figure out, you know, if you could provide some perspective on why you're so confident that this dose or the next dose are probably going to be the go forward.

Well, I would say, you know, I wouldn't read it as confidence that it will be the dose. I think we're confident in the decision criteria that we're making. The design was well laid out. we now have that latest dose cohort fully enrolled. And I think, you know, on a blinded basis, as Bill mentioned, we're seeing what we would expect and hope. So I think, you know, for us, it's how do we make sure we continue to execute, make the right decision as we evaluate whether this is the right dose or if we want to go higher. So I think that's really the way that I would characterize our thinking on this. And everything that we see is very consistent with a lot of the preclinical data and the hypothesis that drove the development program.

Okay, thank you so much for taking my question. Congrats on the quarter. Thanks, Michelle.

Your next question comes from Maury Raycroft with Jefferies. Your line's open.

Hi, everyone. Congrats on the progress, and thanks for taking my question. I was wondering, for the IGAN Phase III, you're enrolling patients without washout for this study, and so they switched over to erbisartan or sparsentin from their optimized RAS inhibitor treatment. And so, can you talk more about if these patients have worsening UPCR when they are starting in the Phase III, or is their EGFR stable? And then separately, what are your latest expectations on how Urbisartan will perform in Protect based on Urbisartan outperforming in Duplex?

Maury, thanks so much for the questions. Noah, I'll pass this one over to you.

Yeah, so I think the first question, Maury, if I heard you correctly, was about the washout in Protect. And so when these patients come in, they're in PROTECT required to be on maximum tolerated dose of ACE or ARB treatment. And so the idea is they switch to Arbisartan. We're currently blinded, so we don't know what happens to those patients. But the presumption is that there's a potential with the lack of a washout and the maximum tolerated dose is to have, you know, an optimal ACE-ARB on board, which is, to then help us, you know, to really show the difference between the ERA inhibition on top of the angiotensin, whereas when you have non-optimally or not maximized doses, it's a bit of a confounder there, right, which may also be, you know, prodding things a little bit. So I think that's the first point around the washout. What was the second? Can you just repeat the second question again?

Yeah, it's really hard. Sorry, go ahead.

Yeah, go ahead. Go ahead, Chris.

Sorry. Yeah, no, no, no. Sorry. I was just going to add, no, the question was around erbostartan. But before we go to that, I think the other aspect that's just important is the inclusion-exclusion criteria for PROTECT, which really does reflect that despite these patients being on max-tolerated ACE or ARB, they still are considered at risk. They're based on their UPC and presumably their EGFR. So these are patients that would not be considered well-controlled by treatment guidelines or by the nephrology community. So, you know, we would fully expect that there would be, you know, continued decline in their renal function over time, just as a background of what we understand about this disease. So, sorry, no, I thought that was an important point to mention, and then we can go on to Maury's question around what to expect in the herbicidin.

So, yeah, what's expected in herbicidin? So, on that front, I would say if you look at the literature, you know, across the studies, we're seeing in the teens up to 20% or 30% reduction in proteinuria with angiotensin blockade. But within a controlled setting, the most recent analog, it showed about a 5% difference. And so I think we've got – it's possible that we'll see something similar to 5% or somewhere between that and the other studies. But I think the important piece, again, is that we've got the maximally tolerated dose here, which is close to the, you know, the optimized or restarted dose. So we hope that we're thinking there will be less of a difference there and ultimately, you know, be able to really test the ERA on top of angiotensin II hypothesis ultimately. That's the goal.

Got it. That's helpful. Thanks for answering my question.

Yeah, and I'll say one more thing, Maureen. We've accounted for all those scenarios in our powering plans, and we have all that covered in our staff plans. Thank you.

Your next question comes from Laura Chico with Redfish Securities. Your line's open.

Hey, good afternoon. Thanks for taking the questions. I guess first one, we've gotten this one frequently from investors, so I just wanted to clarify this. It's around the disclosures you've provided so far around EGFR from duplex and contrasting that versus what we've learned from others like your competitor, Colititas. So I'm wondering what read-through you see from their filing and IGAN towards your own with respect to, I guess, FDA's commitment to surrogate endpoints, but then also kind of around the EGFR disclosure strategy. And then I have a quick follow-up.

Sure. Laura, thanks so much for the question. I'll take this one. I'd say, you know, first, the trial designs are different. And so while other companies have disclosed EGFR data from IGAN trials, those disclosure and those analyses are based on the completion of the treatment phase of the trial. you know, they are not ongoing blinded studies in the same way that Protect and Duplex are. And so there's just a slightly different way of managing the disclosure of data from an ongoing trial. And I think that that, you know, certainly has been informed by our continued engagement with regulators. Now, with regard to how you know, any potential read-through. I mean, first and foremost, it's great to see, you know, the innovation and the positive results within the space that have just been lacking for decades. Whether that's going to be incrementally confidence-building for the FDA or not, I'm not quite sure. You know, we certainly cannot speak for them. You know, reflecting the conversations that we've had with top nephrologists, you know, it certainly is incrementally confidence building all of the data that's come out in this space that continue to show that interventions that improve proteinuria are also improving EGFR over time. So that's certainly what we're hearing from the nephrology community. I think we're optimistic and we'll continue to work on, you know, data package that will demonstrate that with sparsentin with regulators. Hopefully that helps to answer your question.

It does, Eric. Thank you very much. And then I just have one follow-up, and this is perhaps a broader, higher-level strategic question on sparsentin, but would you still seek approval for FSGS if an accelerating filing cannot be completed? And I guess kind of related to that, you know, you're going to have a bit more understanding on where the agency stands following your type A meeting. Would you, I guess, look to pursue a similar strategy if you had to in IGAN if it didn't work out to have an accelerated filing right away after the interim assessment?

Yeah, thank you for the question. I think, you know, when I said that we're undeterred in, you know, whatever, you know, challenges we face, I think that certainly extends to the scenario that you just laid out. If for some reason we cannot gain alignment with the FDA in our type A meeting, we're gonna continue this trial out through the confirmatory endpoint. And we'll have the data on PROTECT next month. We're still blinded, but once we see the interim, we'll be able to see how clear that accelerated pathway is, or if we need to have similar types of conversations with them and the opportunity for accelerated approval. But we're committed to the space. I continue to hear from the patient community how important these programs are, and we're not going to let any of these aspects of the programs deter us.

Thank you so much, Eric. Appreciate it.

All right. Thank you, Laura.

I'm showing no further question at this time. I would now like to turn the conference back to Grace Klein.

Great. Thank you, Jerome. And thank you all for joining us today. We look forward to speaking with you again when we have top-line results from the Interim Protein Reassessment and Protect Study next month. I hope you all have a great rest of the week. Thank you.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and have a wonderful day. You may all disconnect.