Travere Therapeutics, Inc. Q3 FY2021 Earnings Call

Good day and thank you for joining us for Travere Therapeutics' Third Quarter 2021 Financial Results and Corporate Update Call. All participants are currently in listen-only mode, and this call is being recorded. I would now like to turn the conference over to Mr. Chris Cline, Senior Vice President of Investor Relations and Corporate Communication. Please proceed.

Thank you, Justin. Good afternoon and welcome to Travere Therapeutics third quarter 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 Dube. Eric will be joined for the prepared remarks by our Dr. Noah Rosenberg, Chief Medical Officer; Peter Heerma, our Chief Commercial Officer; and our Chief Financial Officer, Laura Clague. Dr. Bill Rote, Senior Vice President of Research & 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 statement. Please see the forward-looking statement disclaimer on the company’s press release issued earlier today, as well as the risk factors section in our Forms 10-Q and 10-K filed with the SEC. In addition, any forward-looking statements represent our views only as of the date such statements are made, October 28, 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 by the way, Happy Birthday today. Good afternoon everyone. I am proud of the progress made across all facets of our business during the third quarter. First, I am pleased to report that we achieved several significant milestones related to our goal of positioning sparsentan to ultimately become the new treatment standard for IgA nephropathy and FSGS if approved. In August, we reported that our pivotal Phase 3 PROTECT study of sparsentan in IgA nephropathy achieved its primary proteinuria endpoint with statistical significance in its prespecified interim analysis. The results exceeded our expectations by demonstrating a greater than three-fold reduction in proteinuria from baseline compared to those patients receiving the active control irbesartan. And at the time of the interim assessments, sparsentan was generally well-tolerated and consistent with the observed safety profile to date. This is the first time a single non-immunosuppressive agent has demonstrated this magnitude of effect on proteinuria reduction in a large well-controlled study. And we know from our engagement with the nephrology community that a treatment with these attributes is precisely what physicians are seeking to help prevent progression to end-stage kidney disease. I'm very pleased to report today that we've completed our pre-NDA interactions with the FDA for sparsentan in IgA nephropathy. Notably, the FDA agreed that the interim analysis from the PROTECT study supports submission of an application for accelerated approval under subpart H. Based upon the agency's feedback and alignment on our structure of the planned NDA, we expect to submit our application for accelerated approval in the U.S. in the first quarter of next year. We also made meaningful progress on our sparsentan program for FSGS during the quarter. Most importantly, we gained alignment with the FDA on our plan to provide the agency with additional eGFR data from the ongoing DUPLEX study in the first half of 2022, which enables us to continue on the accelerated approval pathway for FSGS. If the additional eGFR data further strengthen the prediction of long-term benefit in the study, as we expect they should, we anticipate submitting an NDA for accelerated approval for FSGS in the middle of next year. We are pleased that we now have a clear regulatory path to potential accelerated approval for both IgA nephropathy and FSGS in the U.S. And we look forward to achieving those submissions next year. I'm also pleased to share that we have formalized our plan to pursue a combined IgA nephropathy and FSGS submission for sparsentan in Europe. This strategic decision will allow us to pursue the most expedited path to making sparsentan available for both IgA nephropathy and FSGS in Europe, and we believe it will increase the probability of success for achieving optimal market access across regions. Additionally, this option allows us to potentially request accelerated assessment for the review process. We will continue our engagements with the EMA and expect the MA application to be submitted mid next year. Once the planned additional eGFR data from the DUPLEX study can be incorporated if supported. Also, as it relates to Europe, we were very pleased to recently enter into a joint collaboration and licensing agreement with Vifor Pharma for the commercialization of sparsentan in Europe, Australia, and New Zealand. This collaboration aligned the strength of two leaders in rare nephrology with a shared mission to make sparsentan the new treatment standard for IgA nephropathy and FSGS if approved. And it significantly increases our probability of success across all launches, as it will allow us to have the dedicated focus needed for successful launches in these substantial markets. The collaboration also recognizes the value sparsentan can bring in Europe and strengthens our financial foundation with potential milestone payments totaling up to $845 million and royalties on sales in these regions up to 40%. We look forward to working closely with Vifor as they integrate sparsentan into their portfolio and prepare for potential launches in Europe, Australia, and New Zealand beginning in 2023. Beyond sparsentan, we continue to be encouraged by the potential for our novel pegtibatinase program in classical homocystinuria or HCU. We believe that it has the potential to become the first disease-modifying therapy for the more than 7,000 people in the U.S. and Europe who are not adequately responding to current treatment options. We remain on track for a preliminary assessment from the ongoing Phase 1/2 trial now named the COMPOSE study before year end. And we look forward to establishing next steps for the program if the data are encouraging as we expect. Lastly, I'd like to highlight the performance of our commercial organization in the third quarter. Our execution led to another quarter of year-over-year growth across all approved products, despite the ongoing challenging environment created by the COVID-19 pandemic. This performance underscores our confidence in the ability to successfully deliver sparsentan and pegtibatinase if approved. Let me now turn the call over to Noah for the clinical update. Noah?

Thank you, Eric. I remain very pleased with the progression of our pipeline of potential first-in-class therapies for people living with rare diseases. In the third quarter, we took meaningful steps towards advancing sparsentan towards potential approvals in both IgA nephropathy and FSGS. Most notably during the quarter, were the positive topline interim results from the ongoing pivotal Phase 3 PROTECT study of sparsentan in IgA nephropathy. After 36 weeks of treatment, patients receiving sparsentan achieved a mean reduction of proteinuria from baseline of 49.8% compared to a mean reduction of proteinuria from baseline of 15.1% for irbesartan treated patients. This result was clinically meaningful and statistically significant with a P-value of less than 0.0001. Preliminary eGFR data available at the top end of the interim analysis were consistent with our powering and indicative of a potentially clinically meaningful treatment effect after two years of treatment. And from a safety perspective, we continue to be encouraged; at the time of the interim assessment, sparsentan appeared to be generally well-tolerated and it appeared consistent with a previously observed safety profile. These data build upon a robust data path and have helped shape sparsentan's safety profile and demonstrated the potential for clinically meaningful proteinuria reductions across nearly 500 patients with IgA nephropathy and FSGS, including several patients that have been on therapy for more than seven years in the open-label extension of the Phase 2 DUET study. This further supports our confidence that sparsentan has the potential to meet the clear need for a new therapeutic option to meaningfully reduce proteinuria over and above widely used ACE inhibitor and ARB treatments and to do so, while avoiding the long-term safety challenges associated with immune suppression. As Eric mentioned earlier, we recently completed our pre-NDA interactions for IgA nephropathy and we are very pleased with the successful outcome. The FDA's agreement that the interim analysis from the PROTECT study supports the submission of an application for accelerated approval under Subpart H was clear. With this feedback and alignment on the content and organization of our application, we will be continuing our NDA preparations with the expectation of submitting in the first quarter of next year. Our FSGS program also continued its forward momentum with a recent Type A interaction, where we gained alignment with the FDA on our plan to provide the agency with additional eGFR data in the first half of next year to support a potential application for accelerated approval. At the time of the planned eGFR data cut, all patients remaining 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. We believe at this time point, the data will have sufficient maturity to strengthen the prediction for long-term benefit. If the data meet these expectations, we anticipate submitting an NDA mid-next year for accelerated approval of sparsentan for FSGS in the U.S. In parallel, we'll be working on the combined IgA nephropathy and FSGS MAA application for conditional marketing authorization of sparsentan in Europe, with the expectation of a submission mid-next year as well. Both the PROTECT and the DUPLEX studies continue to advance and based upon the progression of this study data, they are well-positioned to meet confirmatory endpoints in 2023. Lastly, on the pipeline, our optimism for the pegtibatinase program remains high as it continues to advance through the Phase 1/2 COMPOSE study. COMPOSE is a dose escalation study designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical effects of pegtibatinase in patients with HCU. Patients in this study are being followed for up to 12 weeks in a blinded fashion in each cohort before entering an open-label extension, and we are anticipating a preliminary assessment from the study before year-end. When we evaluate the preliminary data, we'll be examining a few factors. First, as you would expect with any early study of this nature is safety; we'll be looking for any signals of interest, including immune response. Next is early evidence of efficacy. We know that for those patients who are B6 non-responsive, treating physicians typically target patients below 100 micromolars of total homocysteine. If pegtibatinase can bring patients below this level, we believe it could have the potential to become a clinically meaningful new treatment option. When we provide our update later this year, we'll look to provide insight into some of these areas of focus. I'll now turn the call over to Peter for the commercial update. Peter?

Thank you, Noah, and good afternoon. We continue to be very pleased with our commercial organization's performance, especially in this environment where virtual ATP interactions remain commonplace, and we still see that fewer patients are visiting their physicians compared to pre-pandemic times. In the third quarter, our execution resulted in 6% organic growth in net product sales over the same period last year. This was driven by underlying demand and strong patient compliance across all products. For our Thiola products, we continue to see new patients initiate treatments. And to date, we have experienced limited impact from the generic version of the original formulation that entered the market in the prior quarter. Despite the limited impact so far, we do still anticipate an adverse impact on Thiola sales in the quarters ahead. Our focus will remain on identifying new patients, ensuring access to therapy, and providing the important service and support that many patients need to potentially be stone-free. The bile acid portfolio also continues to perform in line with our expectations. As a result of the strong performance from the commercial portfolio over the last two quarters, we anticipate ending the year with low to mid-single-digit growth in net product sales over 2020. Given the COVID-19 pandemic and evolving dynamics, this would be a meaningful achievement and further bolster confidence in our team's abilities going into a critical period of anticipated launches for sparsentan. We are planning for launches of sparsentan in both IgA nephropathy and FSGS in the U.S. We anticipate the first launch to now be in IgA nephropathy, and we have an incredibly exciting opportunity in front of us. In the U.S. alone, we believe there are between 30,000 and 50,000 patients living with IgA nephropathy that would be good candidates for sparsentan if launched and if approved. And we believe that opportunity is likely to increase meaningfully over time with greater awareness and diagnosis. We are well-positioned to embark on our journey to reach these patients. We will be growing our organization from a position of strength by scaling our proven infrastructure in rare nephropathy to extend our core points and provide the services and support we know are critical for patients living with rare diseases. And in market research studies with nephrologists, prior to the PROTECT data readouts, we learned that sparsentan has an emerging product profile that rises to the top of the most desirable programs in development. Given the strength of the interim data from PROTECT and the positive feedback that we have received from the nephrology community since our topline announcement, we are confident that if approved, we will be in a strong position to ultimately establish sparsentan as the new treatment standard for IgA nephropathy. Overall, I have great confidence in our team's ability to add sparsentan to our multi-year track record of delivering life-changing therapies to people living with rare diseases. And I look forward to sharing more about our progress as we continue to prepare the organization for potential upcoming launches. Let me now turn the call over to Laura for the financial update. Laura?

Thank you, Peter. For the third quarter of 2021, we reported net product sales of $54.2 million from our commercial portfolio compared to $51.1 million for the same period in 2020. We reported a GAAP net loss of $35.6 million for the third quarter of 2021. After adjusting for non-cash expenses and income tax, we reported a non-GAAP net loss of $7.9 million for the third quarter of 2021. On a GAAP basis, R&D expenses were $48.4 million for the third quarter of 2021. The increase compared to 2020 is largely attributable to increased patient involvement in the ongoing studies of sparsentan as well as the advancement of the pegtibatinase program in HCU. On an adjusted basis, R&D expenses were $45.2 million for the third quarter of 2021. Relevant non-cash expenses for the third quarter included $3.2 million in stock-based compensation and amortization. On a GAAP basis, selling, general, and administrative expenses for the third quarter were $36.1 million. The increase compared to 2020 is largely attributable to increased headcount due to the company's operations growth and professional fees. On an adjusted basis, SG&A expenses for the third quarter were $25.5 million. Significant non-cash adjustments for the quarter consisted of $10.6 million in stock-based compensation and depreciation and amortization. We ended the quarter in a strong financial position with $551.2 million in cash and cash equivalents. This balance includes the $55 million upfront payments we received as part of the joint collaboration licensing agreement with Vifor Pharma that was entered into during the quarter. For the balance of this year, we expect modest increases in our operating expenses. As we look further out, we anticipate significant investments throughout next year as we prepare for multiple potential product launches, continue to support the ongoing studies of sparsentan, and advance our pegtibatinase program. Taking into account the potential impact of generic Thiola, but not including additional business development, we anticipate this cash balance will support our planned operations into 2023. I'll now hand the call back over to Eric for his closing comments. Eric?

Thank you, Laura. I couldn't be more pleased with our organization's execution in the third quarter. We delivered impressive results from the pivotal Phase 3 PROTECT study. We made considerable regulatory progress across our sparsentan programs, entered into a collaboration agreement with a global leader in nephrology to maximize the value of sparsentan in Europe, Australia, and New Zealand, and we continue to effectively deliver our approved products to patients in need. With the regulatory pathways for IgA nephropathy and FSGS now set, we will be working in earnest to prepare three high-quality NDA and MAA applications to be submitted next year. And we will continue our steps to prepare our organization to execute successful launches of sparsentan if approved. Lastly, a few weeks ago, we announced the planned transition for Noah to an Executive Advisor role at the end of this year. I'd like to take this opportunity to thank him for all of his contributions in getting us to this strong position. We look forward to working closely with Noah to ensure a smooth transition in the coming months in his new role next year as we continue to advance our clinical studies and prepare our NDA and MAA applications. Thank you, Noah. Let me now turn the call over to Chris for Q&A. Chris?

Great. Thank you, Eric. Justin, can we go ahead and open up the line for Q&A please?

Thank you. Our first question is from Maury Raycroft from Jefferies. Your line is now open.

Hi everyone. Congrats on the update and happy birthday, Chris. My first question is if you can talk more about the IgA nephropathy pre-NDA meeting and say if it was the more mature eGFR data relative to FSGS that enabled the FDA to concur that the interim analyses were adequate for submission? And can we assume that because of this IgA nephropathy regulatory update, we can have more confidence that FSGS data will mature similarly?

Maury, thanks so much for the questions. I'll turn that one over to Bill.

Yes, thanks for the question, Maury. The eGFR picture for the PROTECT study does represent a more mature dataset. That comes from a couple of things. Predominantly, the enrollment dynamics were very different. Recall that the PROTECT study began about six months behind the DUPLEX study. So, the work building the infrastructure was done on the DUPLEX study, and the PROTECT study drafted in behind. So, with a much more linear enrollment dynamic, we had a much greater fraction of the dataset that was out in the later time points. And that was in stark contrast to what we saw with the PROTECT study. To your other question regarding confidence building for FSGS, when we look across the program, sparsentan has been in three efficacy studies in two diseases and has performed very consistently across those studies. So, when you allow the picture to mature in DUPLEX, our expectation is that it's going to come in line and we'll meet our expectations. We'll have the data cut in the spring, and that will give us that answer.

Great. I mean, maybe one follow-up. If you just remind us what your expectations are for their review period for both programs for FSGS and IgA nephropathy?

For the PROTECT study, we will be asking for a priority review. If we submit in the first quarter and receive that priority review, which we believe the disease and this drug merit based on the data, we would receive an answer from the agency with a PDUFA date before the end of 2022. For FSGS, we plan to submit that in the middle of next year after discussing the eGFR cut with the FDA, and if the data allows for filing, that would occur mid-year 2022. A priority review would position that in the first half of 2023, while a standard review would place it early in the second half of 2022.

Great. Okay. Congrats again, and thanks for taking my questions.

Sure. Thank you.

Thank you, Maury.

And thank you. And our next question comes from Greg Harrison from Bank of America. Your line is now open.

Good afternoon, guys. Thanks for taking our questions. First one is on pegtibatinase. What is the extent of the data that we could expect to see in the coming readout? And what would you consider to be clinically meaningful there? And then assuming it is, what would be the next steps for this program if the data are supportive of moving forward?

Yes. So thanks so much Greg for the questions. I'll take the first one on what we can expect. And then I'll ask Bill to share a little bit more around the next steps. So as Noah mentioned, we are really looking at a couple of key areas with this analysis from the COMPOSE study. First and foremost, this is the first study in humans. So we want to have a particular eye on safety. The second aspect is to really understand the dose response in this trial, given that we are studying different dose cohorts. And then the third, and I think particularly around your question of what would be considered clinically meaningful, is to assess whether patients are able to get below 100 micromolars for total homocystine, and whether they're able to stay below those levels. That is considered the treatment goal in the guidelines and by clinicians and patients with homocystinuria. And so we're going to be particularly looking at that threshold. And we will obviously continue to assess that. But those are the major areas of focus as we go into that analysis. And I'll turn it over to Bill to talk about next steps.

Thanks, Eric. Yes, the first step will be to analyze the data from the interim analysis, and we expect to share that at least to some degree. The next immediate step is really to use that dataset and engage with regulators. And that'll be the results from the interim analysis of the COMPOSE study, as well as the current data from the Natural History Study. We'll then take their input and do our own feasibility analyses and work toward developing a plan for the next clinical study. In parallel to that we'll be working on manufacturing scale-up and process development. The goal is ultimately going to be to move downstream from the COMPOSE study into a pivotal study, and that next phase of development, and we'll be able to share more about that once we've had those engagements with the agencies.

Great. That's helpful. And then if I can sneak in one more. As far as the IgAN program, would you expect that there would be an AdCom needed there?

No. One of the questions we asked in our pre-NDA interactions was their perspective on whether or not we will have an AdCom. The agency said that based on the data they've seen thus far, they don't anticipate calling for an Advisory Committee. We're not surprised with that given the data from the interim analysis; can we see that as a positive? That said, these things can change and we'll be prepared should an AdCom be called. But at this point, we don't expect to have one.

Great. Very helpful. Thanks again, and congrats again on all the progress.

Thank you.

Thank you, Greg.

And thank you. And our next question comes from Joseph Schwartz from SVB Leerink. Your line is now open.

Hi. Thanks very much. I was wondering if you will be reporting any more data to investors at the time that you perform your next interim analysis of the DUPLEX study in the first half of 2022? Or will all of the information just be for the FDA? And likewise, will we hear whether the FDA has any feedback for the company on your plan to file as occurred when you perform your first interim analysis?

Joe, thanks so much for the questions. So as part of our interactions and plans for that additional eGFR cut, we're going to be working with the FDA on any disclosure plans. I would say, it's probably safe to assume that we would not be providing any additional data given that the trial is ongoing. And we continue to be very focused on maintaining the blind and the trial integrity. Really, what we're going to be focusing on in large part is to communicate following the meeting, once we receive minutes, or once we have submitted or accepted by the FDA the NDA. And so that really is going to be our focus as we look at those additional data. But as I've mentioned, we're going to be working with the FDA to see what they are comfortable with us disclosing at that point.

Great. Thanks for the color. And then how would you rate the awareness and appreciation of proteinuria lowering as an important treatment goal in the community of physicians who see the most FSGS and IgA nephropathy patients? How ready is the market to adopt a proteinuria lowering agent like sparsentan? And how much education do you still need to undertake in order to encourage strong uptake in the real world?

Yes. Thanks for that question. I'll have both Peter and Noah answer that. Given that Peter’s team is working very much on a lot of the market research with the broader nephrology community. Noah and his team with some of the top nephrologists, and they can provide a bit of feedback on what they are hearing. Peter, you want to start?

Yes. Thanks, Eric. And thanks, Joe, for the question. Well, what we have learned from the market research, as well as the thought leaders that we are speaking with, is that proteinuria is often the marker that results in treatment initiation and monitoring of patients and how well they're doing, which makes sense because proteinuria is also the strongest predictor of progression of disease. So I think there is a well-established understanding of proteinuria and its relation to progression of disease, particularly in patients at higher risk for dialysis. Noah, I don't know if you want to build upon that.

Yes. I think that's right, Peter. I think physicians and nephrologists specifically are acutely aware of the toxic effects of proteinuria. We speak of it all the time, and they're aware of the concern that proteinuria will drive worsening outcomes and ultimately lead to dialysis and the need for immunosuppressive therapy. I think where the education comes in is now that we have additional therapy and a potential therapy; it's around targets, educating around those targets, where they can realistically go, because it really has had such limited options until now. Specifically in IgAN, for instance, your choices are very limited. ACE inhibitors, ARBs we know often fail and immunosuppressants are very limited in that they can create concerns around their short-term treatments, and they often don't work. So I think awareness around sparsentan and the mechanism of how it works, and the safety data set is really important. We need to get the message out there that realistically with a drug like sparsentan, there's a better chance for clinicians to achieve some of these targets that have been set out by the guidelines. So, I think that that's certainly an area that we're focused on.

Sounds good. Thanks for taking my questions and best wishes to Noah.

Thanks, Joe.

Thank you. And our next question comes from Michelle Gilson from Canaccord Genuity. Your line is now open.

Hi. Thank you for taking my question. I was wondering if you could provide a little bit more color around your pre-NDA meeting. And what the FDA was most focused on? And I guess more specifically, what eGFR analyses were done and presented to the agency for IgAN, and I know we discussed in the past that there are different ways that you can evaluate changes in the eGFR slope. And I also I think that I heard you earlier allude to priority review timelines for IgAN. I was just curious if that was discussed during your pre-NDA meeting?

Sure. I think I've got them all jotted down. As far as what was presented to the agency for the pre-NDA interactions, the briefing book presented a comprehensive summary of the interim analysis. So, it was proteinuria measured in multiple different ways or expressed in different ways, eGFR versus time split by groups at a summary level, both observed and then the MMRM, which is the primary analysis endpoint. Additionally, there was some review of safety and adverse events. So that was how the analyses were presented. Your question around priority review, we certainly believe that this is an ideal case for priority review. But that's not something that gets granted at this stage of the game. We intend to request it, and we see this as an ideal case for it. But we won't know the answer to that question until after we've submitted the NDA in the first quarter.

Okay. If I could ask about that niche, you're currently assessing various dose levels and have mentioned the possibility of evaluating an additional dose level. I'm curious whether you plan to explore different dose intervals at that level or if you're simply looking at higher doses.

Yes. We have said that, within this study, we're looking both at dose regimen and dose levels. We will make the decision on what we're going to do with the next cohort when we see the data in December. So it could be either of those or it could be staying at the same level of dose and increasing the amount of experience at the current level. So it's going to be a data-driven decision once we're unblinded at the interim in later this year.

Okay. If I could just a follow-up, are there any issues with going up in volume here? I know it is a subcutaneous dose. If you do evaluate a higher dose?

There are limits to how much is tolerable on an individual subcutaneous injection. As you increase in dose, depending on the solubility of the agent that you are working with, there can be limits there. It becomes a balance between patient need and what's acceptable to patients. But one of the easy ways to deal with that is to split the injection, if you are going to higher doses or higher volumes into multiple subcutaneous injections, and that tends to ameliorate the issue.

Okay. Thank you guys so much for taking my questions.

Certainly, Michelle.

And thank you. And our next question comes from Liisa Bayko from Evercore ISI. Your line is now open.

Hi. I guess congratulations are in order for both Chris and Noah. So congratulations to you both. And I've been fielding a lot of questions on HCU. And we've been doing a bunch of work on it. And I think the main question I'm getting is just like how much information investors are going to get when you do kind of preview some data. So can you maybe just elaborate on expectations to set appropriately for what kind of information you're going to get, and how you know how much you can kind of communicate, what you're seeing in terms of response in patients?

Sure, I'll take that one, Liisa. Our focus, again, is on those three areas of safety, dose response, and magnitude of effect on total homocysteine. There are, of course, other measures of efficacy that we're looking at, for example, serum homocysteine, which is a biomarker that is often assessed within HCU. So we're going to be looking at those aspects as well. I'd say the expectation is that we want to make sure that we provide clarity on each of those questions once we have that data readout. But we've not yet committed to whether how much data we're going to be disclosing at that time. Given that, one is a competitive space, and we want to make sure that we're not providing so much so as to lose the lead that we have in this space. But we also want to make sure that we really have a good understanding of what that dose, that dose and dose regimen is. We certainly wouldn't want to communicate efficacy if we believe that there's something more that we could be pursuing. So that's a little bit of how we're thinking about it. We said that at a minimum, we will provide a qualitative update on each of those three questions, but we very well could be in a position to provide more specific data as we go forward.

And any kind of additional color on timing?

Well, we're on track to be able to provide that update sometime later this year. But to be able to narrow that down even further, I would say, we're just not at that point to do so. But we're very near.

Okay. And then just finally, on the same program, kind of want to look at it, I think it could be at least as big of an opportunity as far as sparsentan. And in terms of its value, because it has a pretty long revenue tail, it actually could be pretty valuable as a, relative to sparsentan and more valuable actually. Can you maybe comment on how you're thinking about kind of the size of the opportunity and provide some benchmarks?

Well, we certainly are excited about the opportunity, given that there's a high unmet need here. The addressable population, if we start there, is 7,000 patients currently across the U.S. and Europe. But I think we recognize that there are a few areas that really can be improved, which we believe is typically the case within rare disease. One is that these patients are oftentimes undiagnosed; despite newborn screening, many of these patients still are not diagnosed early enough and go into adulthood before being effectively diagnosed. While there are other therapies like high-dose Vitamin B6, the literature states that there's a proportion of 50% that are responsive, and when we talk to experts in this area, they are very clear that is a very high estimate of B6 responsiveness. So we think that there's still opportunity there to better understand where the unmet need is and who is above that key threshold. So that's going to be a big part of what we're doing in parallel to clinical development at this time. I'd say that it's an enzyme replacement therapy, so we'll continue to assess what the benchmarks are for pricing and what value we bring there. But we do believe that this is a significant opportunity for us, and we are currently first in development, and we are really focused on ensuring that lead position.

Thank you very much.

Thanks, Liisa.

Thank you. And our next question comes from Carter Gould from Barclays. Your line is now open.

Hi, guys. This is Justin on Carter. Thanks for taking the question and congrats on all the progress this quarter. Just one quick wrap-up on for us on pegtibatinase. Understanding that you don't want to be sort of too revealing on what data you expect to show on the readout. But Eric, you mentioned earlier that duration of response is going to be sort of a key criterion in your moving forward decisions. And just wondering if you can tell us how much duration data we should expect in this first readout? How much that's going to impact your next steps with the program and sort of, you know, if you're going to be waiting on any more duration data going forward before you move out of the program.

Yes. So from a duration perspective, we'll have double-blind data from everybody in the interim up through 12 weeks, but then those patients go on to continue in open-label extension. So for many of the patients, we'll have significantly longer windows of time for that. As is often true in metabolic disease with biological or biochemical endpoints, there's a degree of variability. That is certainly aided by what you look with a longer window of ascertainment. So the trial design is very strong for that.

Awesome. Thank you very much.

Thanks, Justin.

Thank you. Our next question comes from Tim Lugo from William Blair. Your line is now open.

Hey, guys, this is Watson. Thanks for taking the question. So I just was wondering, Eric, if you could maybe provide a bit more color on the process behind choosing Vifor as your partner in Europe, what their infrastructure is, why that makes them the ideal partner for you, and then as well, on the EMA application, have you discussed with the EMA the idea of submitting the combined applications? And what's the feedback on that? Thanks.

Okay, sure. So Watson, thanks so much for the questions. I'll take the first one on really how our thinking evolved to select Vifor as our partner. And then I'll ask Bill to talk a little bit more about our engagements with the EMA. So as we set out to assess the value of partnering in Europe with sparsentan really it led us to think about who has an established presence within nephrology. And when we think about that, it's not just having the relationships with nephrologists, which Vifor clearly has; they have relationships not just with the majority of nephrology practices within Europe, but also with some of the top KOLs. They also have experience in working with regulators and with HTA bodies, not just nationally, but also regionally and in some countries at the hospital or local level, which countries like Spain are very important for ensuring optimal reimbursement and access. And that was very important when we thought about the launch of sparsentan. And then we thought about someone who's going to be a great partner for us, someone that's collaborative and is going to have the focus on making sparsentan the new treatment standard within Europe, and I think we certainly found that Vifor had all of what we were looking for. And so, we felt like it was also the right time for us to make that decision because there is quite a bit of work that needs to be done, not just to ensure filings from regulators, but dossiers for HTAs, and ensuring that we prepare the organization, the infrastructure, and educational outreach. And so that's what led us to making that decision. We think that we're in a really great place with Vifor. And I think what we have, as I alluded to in my prepared comments, is two organizations with exquisite focus in that same goal of making sparsentan the new kind of treatment foundation for IgA nephropathy and FSGS. And we think that that really does de-risk the executional risk that comes with any launch. So hopefully that answers your question. And Bill, I'll turn it over to you on how we've discussed that combined file with the EMA.

Yes, certainly. Thanks for the question. We have discussed this with the EMA and they're aligned with our approach for the combined decision. We're working at the current time to schedule a pre-MAA meeting to go through the interim analysis data and align on the content of the submission, but they are aware and align with the approach, and so we're good to go there.

Thank you. And our next question comes from Laura Chico from Wedbush Securities. Your line is now open.

Thanks very much for taking the question. And I apologize if I had missed or dropped off for a second. But I had a question just with regards to kind of contrasting the US versus the European regulatory strategies. So, if I'm understanding things correctly, IgAN could be submitted in the first quarter of 2022, if successful with the additional data from DUPLEX, FSGS could be submitted in the middle of 2022. I thought I heard you say, though that there was an advantage to filing these submissions together in the European case. I'm just curious why it might not make sense to file these together in the US settings?

Sure. So I'll ask Bill to talk about that. And really, it's what both regulatory agencies allow for pathways. And that's really what's driven our strategy, is how quickly can we get this out to as broad a population as possible. Bill?

Certainly, I mean, it's a logical question. From our standpoint, we have very strong interim trial results from PROTECT and a very clear pathway forward that leads to a filing in the first quarter of 2022 for IgA nephropathy in the U.S. We need to wait for the additional eGFR data, and then review that with the agency in order to support a similar filing for FSGS with the FDA. What we don't want to do is wait that extra period of months and hold back the IgA nephropathy submission. In the U.S., we can submit in parallel or slightly offset and have basically cross-reference between two active NDAs. Within the European system, there isn't a mechanism by which we can do that. So, to optimize the strategy there by combining the two, IgA nephropathy and FSGS, once the data are available, that allows us to get sparsentan to the most the largest number of patients, the quickest in that geography. If we didn't do it that way, we'd have to wait for one review to be completed before we can start the next or if we did parallel reviews, we'd end up with two different trainings, which isn't ideal either. So this is really two strategies with the same data that are optimized for the rules in their respective geographies.

Okay. That's helpful. And I can sneak in one quick follow-up. And again, I apologize if this has been asked. What is the risk to the U.S. submission being delayed? IgAN submission to sync up with FSGS? Is there potential for the agency to kind of change their position or kind of try to combine the reviews?

Sure. Bill?

Yes, at this point, I don't see that happening. Early in development, we asked about combining the two indications into one and one IND, which will lead to one NDA, and they preferred to keep the two separate, two separate indications, two INDs, two NDAs. Part of that is driven by the fact that their metrics and how they are able to justify resourcing comes down to how many reviews they do and how many NDAs. So, it doesn't help them in a fight for resources if they reduce the number of NDAs artificially, but it also decouples them from a timing perspective. I don't see based on all the discussions that we've had with them any indication that they would want to wait for subsequent data from FSGS.

That's very helpful. Thank you.

Thank you. And I'm showing no further questions. I would now like to turn the call back to Chris Cline for closing remarks.

Great, thank you, Justin. This concludes our third quarter update. Thank you all for joining us this afternoon to talk about our progress. We look forward to updating you further throughout the balance of the year. And I hope you all have a great evening.

Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.