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spk15: Hello, and welcome to the Travere Therapeutics first quarter financial results and corporate update. My name is Brandon, and I'll be your operator for today. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session, during which you may dial star 1 if you have a question. Please note this conference is being recorded, and I will now turn it over to Chris Klein. You may begin, sir.
spk02: Great. Thank you, Brandon. Good afternoon, and welcome to Travere Therapeutics first quarter 2021 financial results and corporate update call. Thank you for joining us. I hope you all remain well. Today's call will be led by our Chief Executive Officer, Dr. Eric Dube. Eric will be joined for the prepared remarks by our Chief Medical Officer, Dr. Noah Rosenberg, Peter Herma, our Chief Commercial Officer, and our Chief Financial Officer, Laura Clegg. 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 major in this call regarding matters that are not historical facts. are forward-looking statements within the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not guaranteed to performance. They involve known and unknown risks, uncertainties, and assumptions that may cause actual results, performance, and achievements to differ materially from those expressed or implied by the statement. Please see the forward-looking statement disclaimer on the company's press release issued earlier today, as well as the risk factor section in our Forms 10-Q and 10-K file with the SEC. In addition, any forward-looking statements represent our views as of the date such statements are made, May 6, 2021. Interviewee specifically disclaims any obligation to update such statements to reflect future information, events, or circumstances. Let me now turn the call over to Eric. Eric?
spk04: We remain dedicated... Sorry, technical difficulties. We remain dedicated to the key priorities that we believe will enable us to strengthen our position of leadership in the rare disease community. And the first quarter of this year was another example of our organization's ability to execute. For us, this centers on developing our pipeline for potential first-in-class programs targeting rare diseases that have significant unmet needs. Earlier this year, the Every Life Foundation published the National Economic Burden of Rare Disease Study. The study found that on average it takes approximately 6.3 years for a person living with a rare disease to find a diagnosis, and that patients typically see upwards of 17 specialists along their diagnostic journey. Overall, the study estimated that the direct medical cost associated with rare diseases in the US was more than $400 billion in 2019. This is especially relevant given the challenges the rare nephrology community faces due to the limited innovation over the past few decades for diseases like FSGS and IJ nephropathy. For example, FSGS is considered to have one of the worst prognoses amongst primary glomerular diseases. It is estimated that more than 50% of FSGS patients with persistent nephrotic proteinuria will reach end-stage kidney disease within 10 years. This translates to over 2,000 people each year reaching FSGS-related end-stage kidney disease in the U.S. Patients today have a long diagnostic journey, experience progressive loss of kidney function, and become dependent upon transplant and dialysis. This is why we have great urgency in pursuing our goal of developing sparsentin to become a new treatment standard for FSGS and IgA nephropathy if approved. We remain encouraged by the interim proteinuria data that we reported from the duplex study in February. The data showed that treatment with sparsentin resulted in a 60% greater relative likelihood of achieving FPRE when compared to erbosartan. The data also showed that sparsentin has been generally well tolerated. And overall, the safety profile between treatment groups in the study at the time of the analysis were generally comparable, which is encouraging. We are in the process of engaging with regulatory agencies to discuss potential accelerated approval submissions for FSGS. As such, we will not be in a position to provide a regulatory update today, but remain on track to do so as planned before the end of the first half of the year. In parallel, our PROTECT study of sparsensin in IJ nephropathy continues to advance and is nearing completion of enrollment. The study continues to receive broad support from the nephrology community and from patients and their families. Importantly, we remain on track for a top line readout from the interim proteinuria assessment in the third quarter of this year. And we look to the data from PROTECT. We remain encouraged by the consistency with which sparsentin has demonstrated its ability to meaningfully reduce proteinuria throughout its development. We also continue to see additional trial-level analyses published in the space, specifically in IG nephropathy, that clearly link the benefit of proteinuria reduction with beneficial outcomes in EGFR. Importantly, these are consistent with how we have designed our PROTECT study, and we are looking forward to those results coming up soon. We also continue to be excited about PEG-tobatinase, the new non-proprietary name for our TBT058 molecule in development for classical homocystinuria, or HCU. There are no approved treatments that specifically address the underlying genetic cause of HCU. The literature suggests that without control of HCU, approximately 25% of patients by age 16 and 50% of patients by age 29 have thromboembolism, which can lead to heart attack and stroke. Available treatments are often inadequate and patients also face challenges with compliance and adhering to a difficult, low-protein diet, especially as they age. So we believe that there is a meaningful opportunity to help the more than 7,000 patients estimated to be living with classical HCU in the U.S. and Europe and in need of an effective treatment option. Our team is working with investigators and patients to advance the ongoing Phase I-II study. And we continue to be encouraged by the potential to ultimately make pegtobatinase the first disease-modifying therapy for classical homocystinuria. We look forward to providing additional updates on the program later this year. Our leadership position in the rare disease community is also built upon our ability to consistently deliver our approved therapies to patients. In the first quarter, we experienced some challenges in new patient referrals from the ongoing pandemic. but our commercial organization continued to deliver, and the underlying strength of our business remains. Importantly, we have maintained consistent access and support for our approved treatments through the challenges over the last year. And while we had a slower than anticipated month for new patient starts in January and February as a result of the resurgence of COVID in the fall, we did see new patient referrals meaningfully increase in March and through April. This provides us with the confidence that we can achieve our full-year guidance of mid-single-digit growth and ultimately draw upon our expertise and resilience to be successful in delivering sparsentin if approved. Let me now turn the call over to Noah for updates from the pipeline. Noah?
spk05: Thank you, Art, and good afternoon, everyone. We continue to be encouraged by our engagement with the nephrology community as we work towards the goal of developing spursentin as a new treatment standard for FSCS and IgA nephropathy, if approved. As Eric referenced earlier, there is a clear recognition that FSCS is a leading cause of end-stage kidney disease and subsequent kidney failure. Unfortunately, the incidence and prevalence of FSCS is believed to be on the rise, and there are no approved medicines indicated for this disorder. As a result, Patients living with FSGS often require aggressive treatment options, such as immunosuppressive therapy, dialysis, and or transplantation. Even if these treatments are successful, they come with challenges for people to go about daily living. This significant unmet need provides us with a sense of urgency each day as we continue to advance our program. Following the announcement of the interim results from the ongoing pivotal duplex study, of spursantin and FSGS, our medical team has continued to receive broad support from the nephrology and advocacy communities. As we previously mentioned, sustained proteinuria reduction is recognized as a primary treatment goal amongst nephrologists managing FSGS. This is driven by the well-accepted link among the nephrology community that lowering proteinuria results in improved kidney outcomes in this population. We are at the forefront of development with the first pivotal study demonstrating a meaningful reduction in proteinuria compared to currently available treatments. If approved, we believe that sparsenkin can become an important new treatment option that physicians can use as the base of their treatment paradigm. As Eric outlined earlier, we are in the process of discussing our plans to pursue accelerated approval submissions for FHGS with regulators, and we continue to expect that will be in a position to provide an update on our regulatory pathway before the end of the first half of the year as planned. While we reached an important milestone with the duplex study, achieving its interim preliminary endpoint, we still need to complete the confirmatory phase of the study. Our blinded duplex team continues to engage sites and investigators to ensure patient retention and maintain high-quality trial conduct throughout the two-year EGFR endpoint of the study. I am very pleased with the progress of the study thus far, and we remain on track for top-line data from the confirmatory endpoint in the first half of 2023. Following the interim results from DUPLEX, enthusiasm amongst key opinion leaders continues for the upcoming readout of the Phase III PROTECT study of sparsantin in IgA nephropathy. Much like FSGS, IgE nephropathy is also a leading cause of end-stage Q disease. Notably, it is estimated to affect between 250 and 350,000 people in the U.S. and Europe combined. Similar to FHGS, inflammation, fibrosis, and proteinuria play key roles in IgE nephropathy. Sparsantin simultaneously and selectively blocks the endothelin and angiotensin receptors the area is believed to be responsible for the inflammation, fibrosis, and proteinuria in IgA nephropathy. Importantly, preclinical models of spore sentient have consistently shown the ability to prevent glomerular sclerosis and mesangial cell proliferation and reduce proteinuria in IgA nephropathy. And the importance of proteinuria as a treatment target and its correlation to EGFR continues to strengthen in IgA nephropathy as well. In IgAN, It is well established that the higher proteinuria one has at baseline, this generally translates to a fast progression of disease, and that reducing proteinuria is associated with improved outcomes. A recent publication from Dr. Inker at Tufts University, amongst others, further strengthened the link between early reductions in proteinuria and effects on EGFR slope and IgA nephropathy. The analysis evaluated 12 studies of multiple interventions and found the treatment effects on proteinuria accurately predicted treatment effects on EGFR slope. Specifically, the publication cited that an observed treatment effect of approximately 30% reduction in proteinuria would confer at least 90% probability for treatment benefit in slope of EGFR at two years. These findings are consistent with the design of our PROTECT studies. PROTECT is also similar in many ways to the duplex study, but there are some notable differences between the two. PROTECT enrolls patients with one gram per gram or more of proteinuria per day compared to duplex, which included those with 1.5 or more. While one gram per gram in IG nephropathy is progressive in nature, these values are reflective of the fact that FHGS tends to be a more heavily proteinuric disease. All patients are coming into the PROTECT study on max dose ACE ARB therapy, and there is no washout period prior to randomization. And finally, at the interim analysis and duplex, we measured FPRE, which is a combined endpoint that requires that patients meet both a threshold of greater than 40% reduction of proteinuria from baseline and to get below 1.5 gram per gram of proteinuria per day. PROTECT is designed with an interim assessment of relative percent reduction of proteinuria after 36 weeks of treatment. The study is powered to show a 30% relative reduction in proteinuria for sparsantan versus erbisartan. A treatment effect of 30% will be expected to confer benefit on EGFR compared to erbisartan over two years, consistent with the comprehensive publications from tri-level analyses in IgA nephropathy to date. we are on track to report top-line data from the interim partner analysis in the third quarter this year. Enrollment in PROTECT remains strong. We recently closed screening in the study and anticipate randomizing the last patient in the near future. Elsewhere in the pipeline, we have successfully completed the integration of the Teg2Batinase program for HCU. As Eric outlined earlier, this is the newly assigned non-proprietary name for our TBT058 molecule that we acquired late last year. Our optimism to potentially develop and deliver the first potential disease-modifying therapy for HCU continues to grow as we spend more time with the program. We have been fortunate to engage directly with the HCU community and investigators, and we look forward to integrating their insights to optimize the program as we move forward. The Phase 1-2 dose escalation study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical effects of PEG-2-Batinase continues to advance. We have worked through some COVID-related challenges with the PEG-2-Batinase program, such as opening new sites, but we now have line of sight to enrollment of the final patient in the highest cohort that is currently planned. Assuming we remain on schedule, we will expect this to provide us with an initial look at how dosing and safety are progressing in the study later this year. This should provide us with the ability to determine if we have identified the optimal dose cohort or if the program could benefit from an additional cohort. In parallel, we continue to advance the ongoing natural history study. We expect this to be instrumental in gaining a deeper understanding of the progression of HCU and to establishing the regulatory pathway for the clinical program. We anticipate beginning our dialogue with regulators for HCU later this year. and look forward to providing additional insights as they become available. Overall, I continue to be very pleased with our clinical efforts and our progress in pursuing our mission of identifying, developing, and delivering life-changing therapies to people with rare disease. I'll now turn the call over to Peter for the commercial update. Peter?
spk12: Thank you, Noah. Our team has begun the year with great motivation to deliver our approved therapies and to prepare for the potential future Spar Center launches. The commercial organization has performed well through a challenging period and has provided a solid foundation for us to build upon throughout 2021. During the first quarter, we saw new patients initiate therapy for all three of our approved products. However, COVID-19-related dynamics resulted in a flat year-over-year net product sales performance. At the outset of the pandemic, in the first quarter of last year, we experienced increased demands from patients to have products on hand. This resulted in a revenue above expectations of approximately $1.5 to $2 million in the first quarter of last year. As expected, this did not recur in the start of this year. Another important dynamic is the cumulative effect that COVID-19 has had on patients visiting their physicians. Unsurprisingly, when COVID-19 cases accelerated in the fall and in the beginning of 2021, we did see fewer patient referrals for our approved products. This industry-wide trend has had an impact on our January and February demand and created a modestly slower than expected start to the year. That said, In March, we started to see stronger new patient referrals than the first two months of the year. And we have seen that momentum now continues through April. So we are encouraged by the underlying strength that is present. Also during the quarter, we experienced a higher gross to net factor driven primarily by the insurance resets in the beginning of the new year. This is expected in our business and consistent with previous years. And we anticipate this to return to our normal levels for the remainder of the year. Taking all of this into account, we believe we are in a sound position to identify and treat new patients through the balance of the year. As Eric mentioned before, we continue to expect mid-single-digit growth for our approved products in 2021. We are also continuing our work to prepare for launches in FSCS and IgA nephropathy, if sparsentin is ultimately approved. We continue to strengthen our understanding of the patient journey, and what it will take to provide broad access to therapy. We are continuing to do the foundational work to put the pieces in place to launch a product in a space that has seen limited innovation over the last few decades. We are confident that our established commercial infrastructure methodology, our rare disease expertise, and our ongoing insight generation and launch planning preparations will ultimately enable us to be successful in delivering sparse income to people living with FFDS and IgA nephropathy, if approved. I'd like to turn the call over to Laura now for the financial updates. Laura?
spk11: Thank you, Peter. For the first quarter of 2021, we reported net product sales of 47.4 million from our commercial portfolio, which was comparable to the same period in 2020. We reported a GAAP net loss of 53.9 million for the first quarter of 2021. After adjusting for non-cash expenses and income tax, we reported a non-GAAP net loss of 31.2 million for the first quarter of 2021. On a GAAP basis, R&D expenses were $47.9 million for the first quarter of 2021. The increase compared to 2020 is largely attributable to increased patient enrollment in the ongoing pivotal duplex and protect studies of sparsetin, as well as the integration and advancement of the PEG2-Batinase program in classical HCU. On an adjusted basis, R&D expenses were $44.7 million for the first quarter of 2021. Relevant non-cash expenses for the first quarter included $3.3 million of stock-based compensation and amortization. On a gap basis, selling general and administrative expenses for the first quarter were $36.8 million. The increase over the same period in 2020 is largely attributable to increased compensation expense to support the growth of our organization and initial investment in launch preparation activities. On an adjusted basis, SG&A expenses for the first quarter were $26.3 million. Significant non-cash adjustments for the quarter consisted of $10.5 million in stock-based compensation and depreciation and amortization. Looking ahead, we expect our operating expenses to increase modestly from Q1 levels. This may be uneven quarter to quarter. but is expected to occur throughout the balance of the year as we continue to support the ongoing pivotal duplex and protect studies of sparsetin, which will advance as planned to their respective confirmatory two-year endpoints. It also accounts for investing in the success of the PEG to BATINACE program in classical HCU and preparing our organization for potential commercial launches. Our financial foundation to support this activity remains strong. We ended the first quarter with $520.9 million in cash and cash equivalent. Notwithstanding additional business development, this total cash balance is expected to support our current operations beyond the next two years. I will now hand the call back over to Eric for his closing comments. Eric?
spk04: Thank you, Laura. Execution remains a core strength for our organization, and I would like to thank all of our team members and partners for their continued commitment to our mission. We have started off the year well. Our performance is in large part driven by the sense of urgency that is created by listening to patients' perspectives and the clear need for new treatment options. We will channel this as we continue our work with leaders in the rare nephrology community to break new ground in the pursuit of bringing the first innovation in decades to people living with FSGS and IG nephropathy. And it will continue to drive our efforts to further develop and deliver the potential first disease-modifying therapy for classical HCU. Let me now turn the call over to Chris for Q&A. Chris?
spk02: Great. Thanks, Eric. Brandon, can we please go ahead and open up the line for Q&A?
spk15: Yes, thank you, sir. We'll now begin the question-and-answer session. If you have a question, please press star 1 on your phone keypad. If you'd like to be removed from the queue, please press the pound sign or the hash key. If you're on a speakerphone, please pick up your handset first before dialing. Once again, if you have a question, please press star 1 on your phone keypad. And from SVB Lyric, we have Joseph Schwartz. Please go ahead.
spk16: Hi. Thanks so much for all the insightful commentary and for taking my questions. I guess my first one is just, you know, you referenced a lot of the continuing literature that supports the use of... your analysis that you'll be doing in PROTECT and IgA nephropathy and I know you worked really hard to hammer out a variation on that in FSGS years ago with the FDA so I'm just wondering just given you know it seems like there's a continuous string of surprises from the agency due to you know various reasons such as you know personnel shifts or maybe the same people looking at things differently now than years ago, and some unknown reasons, granted. I'm wondering if you could just characterize for us how much commonality is there between the personnel that you're dealing with now and how they might look at things versus when you established the analysis plan in FSGS. Thanks for hearing my long question.
spk04: Thanks Joe, very clear question and I'll have a few comments and then I'll ask Bill to provide further information. So I'd say that overall as we look at our programs, how they were designed years ago and where we are today in a very innovative trial design looking at proteinuria 36 weeks and EGFR in the longer term over two years, the literature to support that link has only grown. And as you mentioned, certainly so for IG nephropathy with some of the recent analyses. And I think that FDA certainly recognizes that. I don't want to speak for any regulators, but we believe they understand and are on top of the literature. Bill, do you want to provide further comments on how things have evolved with the agency from your perspective?
spk07: Certainly. And thanks for the question, Joe. I've been on these projects for almost four and a half years, and the group across the table from us at CardioRenal has been relatively quite consistent. There's been very little change in turnover. We've seen some members of the team be seconded to other areas of the agency for COVID-specific tasks and then return after a period of six to nine months, and the agency in that period shuffled the way they allocated statistical professionals, and that resulted in a change in some of the people on the team. But from the medical and leadership positions within the review division, we've been dealing with pretty much the same people the whole way through.
spk16: Great. That's super helpful. Thanks for the color. And then you mentioned, actually Laura I think mentioned the starting to build out enhanced commercialization capabilities on top of what you already have. Can you just parameterize that for us both in the U.S. and then at what point do you think that it might make sense to build outside the U.S. if ever given you don't currently have much of a presence there but this could be a global brand?
spk04: Certainly. Thanks, Joe. Our plan certainly for Sparsentin is to commercialize in both the U.S. and Europe. And the approach that we take in Europe is still under review, whether we do that our own or whether we partner. But I'll ask Peter to talk a little bit about the activities that his team is undertaking to prepare for commercialization.
spk12: Yeah, thanks, Eric. So to start with the latter part of the question with regards to Europe. So we think the unmet need in Europe is equally high as in the U.S. But the dynamics in Europe are quite different. So what we are really focusing on right now is to get a good understanding of the addressable patient population in Europe as well as what is the burden of disease and what does it take, what is the requirement to gain broad access to patients. And we're making the disparate investments right now, and I think we are quite pleased with the progress. And as Eric said, we haven't made a public statement on if we would commercialize ourselves. With regards to the first part of your question, what are we doing from a commercialization perspective? Well, last year, and we gave a little bit of display of that during our R&D day, we invested mainly in insight generation, patient journey, and respiration population, the value framework. And this year, we are continuing that, looking also on field force size in second patient to ultimately say, like, well, what does the field force require? We also look at the distribution model and what is the best way to bring the product to patients, as well as educational initiatives, both to patients as well as physicians, because FSDS is an underserved institution. and I think educational efforts are needed to really gain understanding of the study that we conducted, but also FPRE is our endpoint.
spk16: Thanks again for all the insights.
spk15: Thanks, Jeff. From Bank of America, we have Greg Harrison. Please go ahead.
spk14: Hey, guys. Thanks for taking the question. Question is on the duplex study. Will there be an opportunity to see additional data from that study, particularly EGFR? And is this something that there could be periodic updates for or medical conference presentations planned before you were to get an accelerated approval?
spk04: So, Noel, why don't you take that one with regard to additional data and also any potential presentations?
spk05: Yeah, that's a great question. So, we, you know, in terms of the overall data for Duplex, as you know, you know, we really had to and continue to provide minimal data to protect the study integrity. You know, we've got the ongoing two-year confirmatory endpoint and, you know, We recognize the desire to see additional data, but we have no plans right now to publish further. We continue to evaluate potential opportunities that wouldn't introduce bias and be acceptable to regulators. We'll update you as we get there.
spk04: Thank you, Noah. The only thing that I would say, Greg, in addition, is that we have the approach that we're taking with Duplex to do exactly what Noah said, which is to maintain... the study conduct through to the end and to maintain the study blind which is of the utmost importance to us. I wanna share a little bit about how we're doing that and making sure that as we think about additional data, there is no plan for any additional unblinding at this point. And so there's a very small team that is working on those data to support the regulatory filings. But beyond that, there's nothing else that we have planned until we complete the studies.
spk14: Got it. That makes sense. And then one other one, I know this one's also maybe a little early, and if you can't give specifics, maybe we could just talk about the factors you'd consider. But I wanted to get your latest thinking as far as sparsentence pricing and just how you're thinking about balancing you know, pricing for the value provided to the patients versus, you know, providing broad access, especially I know you've talked about that it will likely be used eventually in combination with other treatments as other therapies are approved. So I just wanted to get your thoughts there.
spk04: Sure. So I think it is too early for us to talk specifically about pricing but what I can say is that our goal is to make sure that we have broad access to this innovation. So many patients have been waiting and we want to make sure that that does not become a barrier for these patients and that includes the potential to combine with other therapies and we know that that may be a concern for payers but I can say that Peter and his team are very much focused on making sure, as you mentioned earlier, on the value framework for access. Peter, anything else that you'd want to add?
spk12: I think you mentioned it all. I think it's good to take a step back and say, like, if you think about end-stage kidney disease, it comprises about 125,000 patients in the U.S., and the cost associated with that is about $50 billion. So these patients are among the most expensive patients for society. And if you look then at FSGS and IgA in property, they're on a fast path of progression, and they are disproportionately represented in that end-stage kidney disease patient population. I think there's a good base in that respect to come up with a solid value proposition, and that's the work that we're doing right now.
spk14: Great. Super helpful. Thanks for taking the questions. Thanks, Frank.
spk15: From Barclays, we have Carter Gould. Please go ahead.
spk06: Yeah. Hi. This is Justin on for Carter. Thanks for taking our questions and congrats on all the progress. Just a couple from us on PRITEC. Can you remind us of the data and the decision-making process that informed the selection of the 400 milligram dose? Sort of what gives you confidence that that's the dose level that will be sufficient to drive a benefit, and then just to confirm, given how quickly you're enrolled, should we still expect the interim read to be around 280 patients, or could it possibly exceed that number?
spk04: Justin, thanks for the question. And I'll answer the second one, and that is the planned analysis is when the 280th patient hits the 36-week visit. And because we've got complete enrollment, it'll be plus or minus 280 depending on what enrollment was at that time. And as I mentioned, we're on track to be able to provide that analysis in the third quarter of this year. And I'll turn it over to Bill to talk about dosing and protect.
spk07: Thanks for the question, Justin. We believe that the data from DUETT show us, and also now from Duplex, that 800 milligrams is the right dose for the FSGS population. As you recall, both 400 and 800 milligrams were used in the DUET study, and they had largely overlapping results. When we looked at the PKPD curves, we also saw a high degree of overlap. Essentially, the 400 and the 800 are both at the top of a sigmoidal dose response curve. So while you have a larger numeric difference between the two, the effective difference isn't a doubling between 400 and 800. Specifically to IgA nephropathy and FSGS, they're different diseases and they present differently. Starting with FSGS, it's a highly proteinuric disease and has a high degree of nephrotic proteinuria. With that comes a loss of albumin and other plasma proteins, and sparsentin is highly protein-bound in circulation. So when you lose protein, you're also losing sparsentin. The 800-milligram dose in FSGS patients is designed to compensate for that potential loss. Contrast that to IgA nephropathy patients where proteinuria is lower, the rate of nephrotic proteinuria is much less, And so we don't see the need to have a higher dose there to compensate for that event. That, along with our modeling and where those two doses fall on the sigmoidal dose response curve, gave us confidence that 400 is the right dose for the IgA nephropathy patients.
spk06: Awesome. Thank you so much for the cover there.
spk15: Sure. Sure. From Jeffrey's, we have Marie Raycroft. Please go ahead.
spk00: Hi, everyone. Congrats on the progress and thanks for taking my questions. I know you mentioned you're not providing a regulatory update, but I'm wondering if you can clarify if you had an initial pre-NDA meeting and you're now in a back and forth dialogue, or is the ongoing engagement related to preparation ahead of a formal meeting scheduled for 2Q? And then as follow up, can you comment on potential scenarios for outcomes from the regulatory engagement?
spk04: Maury, thanks so much for your questions. Our typical practice is that we don't provide specific dates for our regulatory interactions, but as we've guided to previously, we are in the process of engaging with both EMA and FDA, and we're on track to be able to provide an update on those interactions by the end of this quarter. And with regard to your second question around scenarios, I would say it's probably we're not in a position to be able to speculate where that might be. We'll be able to provide updates on those interactions and, you know, any implications on our business later this quarter.
spk00: Fair enough. Understood. Okay, and then maybe one other question just on IGAN and PROTECT. You mentioned it's close to fully enrolled. Can you comment on baseline proteinuria range or anything else on baseline characteristics and whether it's in line with expectations? And if you can remind me if you expect greater proteinuria improvement in patients with higher proteinuria at baseline, or how do you think about that in IGAN?
spk04: Sure. Noah, would you like to take that one?
spk05: Sure. Great question, Corey. So as far as the approach that we take, keeping in mind that the PROTECT study is currently blinded. So any analyses we're doing, you know, really both groups together are blinded analyses of the data for, you know, quality going through, making sure that the data's, you know, high quality. It is reflecting that it's consistent with our expectations for baseline factors. So I think that's as much as I can say about the baseline characteristics. And, Maury, there was another portion of your question?
spk00: Yeah, just your expectations for patients with higher proteinuria at baseline. Do you expect them to have a greater magnitude of benefit or improvement?
spk08: Yeah, yeah.
spk05: Yeah, and I'll just add also, and again, we would expect a slightly lower proteinuria level, right? If a lower entry criteria, just the first question, right? Okay. And as far as the percent reduction, we did see a slightly – we saw a protein reduction in duet and duplex above and below the inner product range, but it was slightly diminished in the higher group compared to the lower group. So, you know, we might expect that, but remember that in IGAN, we're having a less proteinuric population than we are in FHGS, so probably, you know, wouldn't have as much of an impact that we had to predict. Again, we'll have the data back in August, and we'll know that for sure.
spk00: Got it. Okay, thanks for taking my question.
spk15: From Evercore ISI, we have Lisa Baco. Please go ahead. Hi.
spk10: I just wanted to clarify. Is it your expectation that you're going to file an accelerated approval? Just to clarify, because it's just the way you phrased it. I wanted to make sure that it's your expectation that you are going to file for accelerated approval. Accelerated approval based on the data you have, correct?
spk04: Hi, Lisa. Yeah, so accelerated approval is our base case, and we're currently planning and writing the NDA for that. But obviously, that's going to be subject to the ongoing interactions with regulators, and that's something that we'll be able to provide updates later this quarter. And I think that's also why we want to make sure that we're engaging very closely with FDA so that we understand, you know, their expectations for the package and reviewing the data with them prior to submitting so that we have an aligned approach on accelerated approval.
spk10: Okay. And then can you maybe just review, like, you know, kind of For separately, for FSGS and for IgA nephropathy, what kind of, what gives you confidence that you can file an accelerated approval, not withstanding the data, but using proteinuria, this idea of using proteinuria? Can you maybe review kind of what's in the public domain or what's been kind of communicated with FDA that, you know, leads you to believe that that's your base case?
spk04: Yes, certainly, and I'll ask Bill to take that one.
spk07: Certainly. If we start with the public domain, there's a growing body of literature that links reductions in proteinuria to preservation of renal function in the long term, and specifically the work coming out of Dr. Anker's lab and others. Troost is another out of Michigan, and Troyanov. all are showing a consistent story that reductions in proteinuria confer a slowing of the decline of renal function. In all of us, we have a lower GFR year by year as we age. In these patients with glomerular diseases, that rate is faster. If you're able to reduce the proteinuria in these patients that's expected to and has been shown to confer a reduction in EGFR over time. I think the other element to answer your question, we've been in discussion with the agency as well as the EMA in Europe around trial design with the surrogacy of proteinuria at an interim endpoint being used to predict the reductions in EGFR at the two-year confirmatory end. So the combination of both what's in the public domain and the dialogue we've had with regulators gives us confidence that this is a path that they are aligned with that could be used for accelerated approval.
spk04: And I think the other aspect, Lisa, is that there is consistency in how other sponsors who obviously engage with FDA have designed their programs and the use of progeria. So I think that consistency, while we can't speak to other programs, I think is reassuring in the approach that we've received and the guidance that we've received.
spk10: Okay. Thank you.
spk15: Thanks, Lisa. From William Blair, we have Tim Lugo. Please go ahead.
spk01: Hi, guys. This is John on for Tim. Thanks for taking our questions. I was just wondering if you guys could provide some commentary on how payer discussions are going for sparsentin and FFGF, and maybe a bit more specifically if you could provide some color on how the payers are responding to and thinking about the interim protein urea data. Thanks.
spk04: John, thanks for your questions. And Peter, would you like to take this one?
spk12: Yeah, thanks for that question. I think it kind of like builds on the conversation that Bill was just outlining, how the relationship between proteinuria reduction translates into reduction of progression of disease and ultimately delay of end-stage kidney disease. And I think some of the work that we have done is informative to have those conversations with payers. You may remember the R&D day where Dr. Barrett was presenting how 30% reduction in proteinuria actually translates an IgA nephropathy on a patient-level base to about over 10 years delay of end-stage kidney disease. And we are in the work right now to do similar work for FSGS, and I think that's the kind of data that payers are very interested in, to gain an understanding of the translation of proteinuria reduction into ultimately hard endpoints in delay of progression of disease.
spk01: All right, thanks so much for that caller.
spk15: From Candidate For Ingenuity, we have Michelle Gilson. Please go ahead.
spk13: Hi, this is Michael Conventi on for Michelle. Congrats on the quarter. So for the duplex filing, and I got some questions about Sparsantan, so it seems like you are engaging with regulators. I guess more specifically, do you anticipate the filing for FSGS would come before FSGS? or after the interim PROTECT data in IGAN, and then sort of a little more broadly, do you see any read-through to the FDA recently accepting other applications for rare glomerular disease to the agency's view of what the complete data package would be for these diseases?
spk04: Michael, thanks so much for your question. And with regard to your first on the timing of filing and whether that would occur before or after the PROTECT interim, We wouldn't be in a position today to comment on the sequencing of that, but we are on track to provide both the data from PROTECT in the third quarter, and then we'll provide an update on our regulatory interactions later this quarter. So that may be something that we can provide greater detail on very soon. With regard to read through of recent regulatory filings, I would say, you know, a couple of things. One is that, you know, certainly there is recognition of significant unmet need, you know, very much in what I shared in my prepared marks with regard to rare kidney disorders. And we believe based on our interactions that regulators clearly understand this need. And, you know, we're encouraged by other progress in other programs just given that it's, you know, several steps closer for patients to potentially have an approved therapy. But each program is different and so we can't really make comparisons between those and I certainly wouldn't want to draw conclusions anyway to our programs. Our focus is to continue the trials and to continue our NDA preparation and as I mentioned, we're in the process of engaging with regulators so we'll be able to provide an update soon.
spk13: Excellent, thank you. Just switching gears, just one more, actually switching to TBT058, or now newly named pegdibatinib. So it looks like there's a potential delay due to COVID. You mentioned an impact on opening new sites. Is there any other way that COVID is affecting the trial? Perhaps issues with already open sites or anything else you haven't discussed? Thank you so much.
spk04: Great, thanks for the question. Bill, would you like to provide your thoughts on that?
spk07: Certainly. The trial has not been free of impact from COVID, as you note. I think to your question of specific sites, it depends on the site and it depends on the timing. There are certain times during the past 12 months where some of these centers, some of which are children's hospitals, have not been open for anybody except for specific patients. and in that exclusion list would be somebody in a clinical trial potentially that might be on placebo, as an example. This is something that's dynamic, as our lives have all been throughout the last year with COVID. We are seeing these restrictions ease as the rates of COVID have come down around the nation, but it's very individualized, center by center and month to month. We've responded to these by looking at the protocol and changing some of the visit schedules. For example, using nurses that go to the home to collect samples as opposed to patients having to come into the hospital for a visit in order to maintain the progress, the forward momentum in the study, and also not to miss key samples or key data points.
spk13: Excellent. Thank you. That's all for me.
spk15: Thanks, Michael. From Wedbush Securities, we have Laura Chico. Please go ahead.
spk09: Thanks very much for taking the question. Apologies if this was already asked, but I know you mentioned the INCRA publication. I just wanted to circle back with one on PROTECT. So one of the limitations mentioned in the INCRA paper was the heterogeneity of the trial data that they examined. And so I was just wondering if you could talk to how you've tried to address that with the PROTECT study and also maybe your assumptions around statistical powering. Thanks.
spk04: Thank you, Laura. Bill, I'll ask you to take this one. Sure.
spk07: I think the challenge with the INCRA paper is not unusual in the rare disease community in that there aren't a lot of clinical trials to draw from. If you're doing a meta-analysis in a cardiovascular space, you're going to pull 75 studies and whittle it down through an exclusion criteria to the 50 that really matter. In the case of the INCA publication, they basically took all the treatment studies, interventional studies in IgA nephropathy and grouped them together. Taking out those that might be different for this reason or that would leave them with too small a sample set. So the end result was the input was a fairly heterogeneous group. I think the consistent message coming, well, and the result of that is they cite it as one of the potential weaknesses of the analysis, but also it results in a greater uncertainty in the measure when you start to look at the correlation and draw regression lines. If you look at the signal overall and the consistency of the message, it's clear with the analyses that have been done by others as well as the work that we have done internally with registry data and other data in that reductions in proteinuria are linked to preservation of renal function. So I don't think that the heterogeneity cited in the Inker paper is something of a concern. I think it was an apt description of their input data, but I think the output message in it was really quite clear.
spk04: And Bill, to the question around powering?
spk07: Oh, in powering, we're powered at 90% to show a 30% relative reduction in proteinuria on the interim analysis endpoint, and that is... gives us what we believe to be a very clinically relevant reduction in proteinuria and, more importantly, predicts a clinically relevant reduction in EGFR loss or preservation of EGFR slope. So that's how the study is powered. And I guess the other piece that I would mention when we talk about On your first question around heterogeneity, with our study, we have inclusion-exclusion criteria that really are designed to control that heterogeneity on the entrance to the study so that we get a pretty even group of patients with similar baseline characteristics.
spk04: That's great. Noah, is there anything else that you wanted to add on that one?
spk05: Yeah, I think I agree with everything that Bill said. I think when you're in the setting of a clinical trial, randomized phase three study, we have the opportunity here to take patients with specific inclusion and exclusion criteria. So having a UPC greater than one enriches this population. Doing things like having an herbicide standardized control is critical to ensure that we have a stringent interpretation of the results. You know, in many studies, you know, the backgrounds and standards of care are different, and they're variable. So I think by providing that standard of care, standard of a certain dose for every patient, and by enriching, again, with UPC and getting a population that's a little more uniform, I feel like we're in pretty good shape. You know, if you compare across the duplex, you know, we felt when we were going into FHS, it was a much more diverse population, a heterogeneous population. And we were able to show the similar numbers in effect. And so I think the size of the study is also important to point out. Having 380 patients gives us that ability. A lot of those studies that Bill cited are really smaller studies. And so I think those are some of the reasons why we feel confident we're able to address it. And also the statistical analyses are very robust as well. So I think those are some of the keys. Thanks, Tom.
spk15: from BMO Capital Markets. We have Do Kim. Please go ahead.
spk03: Hi, everyone. Thanks for taking my question. I was hoping that you could go over your expectations for what the FDA is looking for during these interactions. Back when you or the company had the end of phase two meeting and the FDA ended up requesting a phase three study, They confirmed that proteinuria reduction is a potentially approvable endpoint, but they wanted a longer treatment duration. What drove that? Are there other aspects of the interim data that they are specifically interested in, like safety or EGFR trends? Joe, let me...
spk04: And I'll ask Bill to provide any further comment. You know, the expectation that we have for a regulatory submission on FSGS is a clinically meaningful, statistically significant reduction in proteinuria, which, you know, we provided in February. As we mentioned, you know, the confirmatory endpoint will be on EGFR, and certainly, you we believe that they're gonna be looking at safety and the totality of evidence. And I think because in many ways we're charting a new path in the use of proteinuria in this trial design, this is why very much we're engaging with them and sharing with them the data so that we can align on what they need to see for accelerated approval. I think at this point that's as much as I would be able to say in terms of expectations, but I'll ask Bill to provide anything further from his perspective.
spk07: Eric, I agree with everything that you say. I think the only color that I would add to that is in this situation with accelerated approval being based off of a surrogate endpoint, in addition to the totality of the data, the agency is going to need to see or want to see enough evidence that provides a clear picture of the prediction of reduction in proteinuria to preservation of EGFR that would be significant at the two-year endpoint. You know, that's part of why we're currently engaged with the agency, making sure that the submission that we put forward meets their needs.
spk03: Great. That's helpful. And a question for Laura. Could you provide some additional color on the quarter-over-quarter step-up in R&D expenses? Is it broadly from all the clinical studies or is it primarily from the addition of the HCU program?
spk11: Ido, yeah. Really, it's a combination of all of that. So, yes, you're correct as far as the egg to baton H program. This is the first full quarter that we've had that program here at Travere. And then in addition, it's the continuing... study progression for Duplex and Protect, and just recall that those studies continue on to their EGFR endpoints in 2023. So there's continued monitoring assessment, so that requires continued investment. So it is across those programs that you mentioned.
spk03: Perfect. Thanks for taking my questions. Thank you, Dawn.
spk15: And we have no further questions at this time.
spk02: Great. Thank you, Brandon. And thank you all for joining us today. This concludes our call for the first quarter. We look forward to providing you updates on our progress in the near future. Thank you, and have a great rest of the week.
spk15: Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for joining. You may now disconnect.
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