Travere Therapeutics, Inc. (TVTX) Earnings Call Transcript & Summary

Thank you, everyone. My name is Gena Wang. I'm mid-cap biotech analyst at the Barclays. I first hope everyone stay healthy, and I would like to thank all the participants, investors, companies, especially our event team and corporate access team, who made this virtual health care conference possible. With that, I would like to introduce our next speakers from Retrophin. We have Eric Dube, Chief Executive Officer; we also have a Chris Cline, SVP of Investor Relations. Eric, I will hand over to you.

Okay. Thank you, Gena, and thank you, Barclays, for the opportunity to present some updates on our company. Let me go to Slide 2. Today, I will be speaking to a number of forward-looking statements, and you can see our disclosures here, online and in our SEC filings. If you move to Slide 3, I'd like to give a brief overview of our company. At Retrophin, we are completely dedicated to developing and delivering medicines for rare disease. We're exclusively focused on rare disease, and we've made it our mission to deliver innovative therapies for the incredibly high unmet need that we see within the rare disease space. Our employee base brings a significant amount of expertise within rare disease. And we have proven capabilities to commercialize assets and a track record of being able to deliver year-on-year organic growth through the identification of new patients. We have a strong financial foundation, and we ended last year with $398 million in cash on our balance sheet, and we continue to invest in the advancement of our late-stage pipeline. We have a disciplined business development approach, where we will be continuing to focus in the area of rare and ultra-rare diseases and leveraging both our capabilities in late-stage development and commercialization as well as therapeutically in areas such as nephrology and rare hepatology. The real focus of our organization is in the delivery of our pipeline. And if you move to Slide 4, you can see a snapshot of our pipeline. I'll talk about it in 2 aspects. The first is in rare nephrology. We have sparsentan, which is in 2 Phase III programs for FSGS or focal segmental glomerulosclerosis and the second, the PROTECT Study in IgA nephropathy. We also have 2 earlier collaborative research agreements with the NIH and with 2 patient advocacy groups, the NGLY1 deficiency and Alagille Syndrome foundations. And these really help to leverage our expertise in rare hepatology. Let's move to the next slide, 5, which gives an overview of the addressable population, both for our current commercialized portfolio as well as with the potential in our pipeline. We have 4 products that are currently commercially available. And within those, such as in CTX bile acid synthesis disorders and cystinuria, we have the opportunity for continued organic growth, again, through the identification and treatment of new patients. In each of these conditions, we see that the majority of patients still remain undiagnosed or untreated. And so our focus with our commercial portfolio is to continue to help clinicians find and effectively treat these patients. If we move to the larger 2 concentric circles, these are the opportunities that we have to treat patients with rare glomerular diseases with sparsentan. This opportunity would be transformational, not just for the company, but for the treatment of these diseases where there are no approved medical treatments. Let's move to Slide 6, which gives a brief overview of the Phase II data from our DUET study with sparsentan in FSGS. These data represents the primary endpoint of change from baseline in urine protein-creatinine levels over 8 weeks, comparing sparsentan of 3 doses to irbesartan and ARB that is commonly used off-label for patients with FSGS. And you can see that there is a profound and statistically significant difference between sparsentan and irbesartan after 8 weeks. On the right-hand of the slide, you can see the safety profile for sparsentan versus irbesartan in that acute treatment phase. You can see that for many of these, there is no difference. There was, however, an increase in the proportion of patients that had a dose change or interruption based on sparsentan. Most of these were due to what you would assume with anti-hypertensive treatment such as dizziness and hypertension, and in the Phase III design, the dose regimen was adjusted to mitigate this from occurring. Moving on to Slide 7. You can see a longer-term view of proteinuria. And this measure was a secondary measure in Phase II, but is the interim proteinuria analysis in our Phase III DUPLEX Study. And I'd like to just briefly cover what FPRE is. FPRE is the FSGS partial remission endpoint, and we work in collaboration with a number of consortiums such as the NEPTUNE Consortium at the University of Michigan to help in understanding what measure of proteinuria reduction is prognostic of longer-term renal function progression, such as eGFR and progression to end-stage renal disease. And what we saw is that patients that are able to achieve complete or partial remission have a substantially reduced risk of progression in their renal function or renal decline. Here, you can see that after 8 weeks in the double-blind period, there was nearly a threefold increase in the proportion of sparsentan-treated patients that achieved FPRE compared to those on irbesartan. After 8 weeks, all patients in both arms were switched to open-label sparsentan. And so while there is a difference in color here, blue and orange, those continuous lines in the open-label extension represents sparsentan treatment. And you can see that there is a continued improvement in the proportion of patients that were able to achieve the FPRE endpoint. Nearly 50% of patients through the 84-week OLE. And I'll point out [ 8-week ] period, which is what will be the basis for the interim analysis in our Phase III DUPLEX Study. This will be the basis for our Subpart H submission to FDA and Conditional Marketing Authorization in Europe. Moving on to Slide 8. I'll give you a brief overview of the milestones you can expect over the next couple of years. Earlier this week, we announced a critical milestone for the company, where we were able to enroll the 190th patient in our pivotal Phase III DUPLEX Study. This then allows us to have the headline FPRE proteinuria endpoint in the first quarter of next year. By the end of this year, we expect to achieve complete enrollment of our DUPLEX Study to 300 patients. Moving on to 2021, we expect to have enrollment of our PROTECT Study in the first half of 2021, and we expect to submit our NDA for FSGS next year. In 2022, we would expect top line results from our IgA nephropathy PROTECT Study and then quickly submit both in U.S. and in Europe. And then we, in 2023, expect to have full eGFR results for both of those studies. I'll pause here, and Gena, I will turn it over to you for questions. Thanks so much for your attention.

So maybe I will just start with a question on sparsentan Phase III trials. Can you talk about the baseline characteristics of the Phase III patients? And how is that compared to the Phase II DUET Study?

Yes. In our Phase III program, our aim is to replicate what we saw in Phase II, the DUET Study that I briefly covered. We're very pleased thus far with the conduct of the study, including the high-quality enrollment of these patients. The data are blinded thus far, but what we have seen suggest that, overall, the baseline characteristics in DUPLEX are largely similar to what we've seen in DUET. And that is very much in line with our expectations. We'll continue to have that as endpoint as we complete enrollment throughout this year, but we believe this puts us in a very strong position to have a successful Phase III data readout next year.

Okay. And in terms of inclusion criteria, the urine protein -- creatinine-protein ratio in Phase II was over 1, but in Phase III that ratio increased to 1.5%. What is the rationale of the change? And what would be the implication to the patient population?

Yes. This was one of the few changes that we made moving from Phase II to Phase III. Now importantly, in the DUET Study, we saw a consistency of effect with sparsentan across all levels of baseline proteinuria. And so this was not based on what we -- whether we believe sparsentan would be effective. It really is based on, as I talked about, the proteinuria endpoint that we're using for Phase III, the FPRE. The FPRE is based on 2 measures of proteinuria. The first is that patients need to see at least a 40% reduction in their baseline proteinuria levels to qualify as a partial remitter, but these patients also have to achieve a UPC level less than 1.5. And it's really that basis that we changed the entry criteria in Phase III. We wanted to make sure that all patients from baseline were able to achieve FPRE. And as you can imagine, if we enroll patients from baseline less than 1.5, it really would compromise our ability to show that patients moved from non -- partial remission into remission.

Okay. And then another question is regarding FSGS disease. It is relatively heterogeneous disease. Any strategy have you implemented to reduce this heterogeneity in the DUPLEX trial?

Yes. So first, let me talk about the heterogeneity of the disease, and then we'll talk about what that may mean in terms of variability in our trial. FSGS is a heterogeneous disease. We know that some patients will have primary FSGS where the etiology is unknown and others, it may be secondary, whereas for others, it is -- there is a genetic component. We are focusing our inclusion/exclusion criteria that is consistent between Phase II and Phase III, where we very much are focusing on those patients with primary and genetic forms. And we exclude patients for whom their FSGS is secondary to conditions such as diabetes. And while there is heterogeneity even within the population we're studying, importantly, I'll point out in Phase II that we saw the antiproteinuric effect of sparsentan that is consistent across subgroups of baseline characteristics such as age, gender, based on proteinuria and eGFR. And that is important for us to keep in mind that even with this heterogeneity, sparsentan, based on its mechanism of action, has had a consistent effect across different subgroups. Patients that we are studying need to have a biopsy-proven FSGS or documentation of a genetic mutation. And we believe that the approach that we have with inclusion/exclusion criteria really increases our probability of success in Phase III.

Okay. Any differences between community versus academic centers in terms of patient enrolled?

Yes, Gena, that's a great question. And you might imagine that patients that are seen in a community setting may be less severe or less complicated cases compared to patients that may be referred to academic centers. And while that largely is true within rare disease, I think what we see thus far and what we've heard from nephrologists is that, that's not necessarily what we're seeing in FSGS or in IgA nephropathy, and that's largely because these patients are oftentimes diagnosed very late in their disease. And so we believe that there's not as big a difference between academic and community settings thus far. We also know that the type of referral patterns within nephrology are not as well-established as perhaps other specialties given that there's not been a substantial investment in innovation and clinical trials within nephrology. And so we believe that as we continue to pioneer this space that, that may change, and one of our aims, once approved, is to help in identifying and diagnosing patients earlier in their disease, which may ultimately change how these patients are treated between those 2 different settings.

Okay, great. For the Phase III trials, what is the assumption of proteinuria percentage reduction for irbesartan at the 36 weeks?

So our assumptions around irbesartan are limited by the lack of research that's been done within this space. As I mentioned, irbesartan is off-label for FSGS. No pharmacotherapies are approved. And so we don't have the type of natural history or clinical trial history that you might want to see in such a trial. We have, however, looked at the data from our Phase II study that looked at patients through 8 weeks. And we also can glean from other conditions for which irbesartan and ARBs have been used. We don't believe that there's going to be a substantial increase in the proteinuria effect beyond 8 weeks. And we believe that if there is, that, that would be consistent between the 2 treatment arms because sparsentan has a dual mechanism of action, where there is a blockade of angiotensin, much like an ARB does as well as with endothelin blockade. And so we believe that we will be in a good position to demonstrate a significant treatment effect at 36 weeks and beyond.

Okay. So just I'll take one step back regarding the study design assumptions. So basically, based on the 8-week reduction rate, is it right, the -- in terms of statistic perspective?

Yes. So much of the design and the powering was based on what we saw at 8 weeks, but also what we've seen in this area as well in FSGS, such as the NEPTUNE Consortium and the FSGS clinical trial database that has studied large number of FSGS patients to look at their natural history, but also how FSGS proteinuria reductions correlate with changes in eGFR over time. So much of that was really the input into the design and powering of our Phase III.

Okay. And could you share with us the powering assumption? And also the interim analysis, what is the p-value there?

Yes. So what we would need to see is, with 190 patients, we are powered to detect the difference in the partial remission proportion between the treatment groups. It is powered at over 90% with a two-sided alpha of 0.05. We believe that this treatment difference in FPRE at week 36 will be consistent with the effects that we saw at week 8. Again, we don't believe that there will be a tremendous increase in the proportion of patients on irbesartan beyond 8 weeks that achieved partial remission or complete remission. Remind you that at 8 weeks, about 9% of irbesartan patients achieved partial remission, none of the patients in irbesartan achieved complete remission. After 8 weeks, 28% of sparsentan patients achieved partial remission and 4 patients achieved complete remission. And the experts that we've spoken with do not see any substantial increase in patients that have proteinuria reductions on ACE or ARB beyond that acute treatment phase.

Okay, very helpful. And what is the correlation between proteinuria reduction and the eGFR improvement? Is there a threshold that you need to see or you need to achieve for proteinuria reduction in order to see eGFR improvement?

Yes. So let's actually take a step back and think mechanistically about the importance of proteinuria as a marker of disease severity and progression. Proteinuria is a measure, obviously, of proteinuria -- protein in the urine, but it's a marker of injury in the glomerulus, an injury of the filtering structure within the kidney. And as proteinuria increases, it signals that the level or degree of injury is worsening. And that leads to a progression of renal function decline, which is what is measured by eGFR. The approach that we've taken in looking at the relationship between proteinuria and eGFR is very much based on the scientific literature and what the nephrology community has been studying. It's well believed within the nephrology community that proteinuria is linked to eGFR. And that's been strengthened by a number of publications and recent analyses presented at ASN in November of last year that really demonstrated that measuring proteinuria is -- does lead to or is prognostic of changes in eGFR or the progression towards end-stage renal disease. Now you asked about whether there is a specific threshold. Really, that's where we helped to define partial remission here. It was well understood that complete remission significantly reduces the risk of progressing towards end-stage renal disease and in reducing eGFR. But we also know now from a number of analyses that achieving partial remission is significantly reducing the risk of patients that have worsening eGFR or progression to end-stage renal disease. And so it's really that FPRE endpoint that we're focusing on as a robust measure of risk towards eGFR reduction.

Okay. So you mentioned that the alpha will be 0 -- sorry, 0.05. Do you have interim analysis that proteinuria reduction or the measurement of proteinuria and then the final endpoint? How the alpha is splitting between interim and the final? Is it 0.025 for the interim?

So we've not disclosed what the splitting of the alpha would be between the interim and the final. I can say that we are confident in our ability to achieve the successful interim analysis. What we've also designed as part of this study, before the study was implemented, was the ability for us to look at the data and reassess the sample size that's required to demonstrate a positive eGFR analysis as well. And while we've not achieved that, we don't believe that, that's necessary at this point, it does allow us to mitigate any risk from a powering standpoint on eGFR.

Excuse me, this is the operator. The presentation is about to end.

We have 1 more minute, actually. Okay. So also, the -- are you planning for the interim analysis? Are you planning to share eGFR data also at the 36 weeks?

So what we plan to present in the interim will be depending on a couple of things. The first is we want to make sure that we are collaborating with the FDA given that this would be an ongoing study. We want to make sure that we can clearly articulate what we see in the FPRE endpoint, but the rest of it will be based on the clarity of the results and what we and FDA would be comfortable with presenting. We would not want to jeopardize the integrity of the study in an ongoing -- since it would be ongoing.

Okay. And then the -- if interim endpoint was missed, what could be the next step for DUPLEX?

Yes. So if we -- first, we believe that the conduct of study and the powering of the study would be sufficient. But if we do find ourselves in that situation, we, of course, would be looking at the data in totality at that time to make sure that we're making the right decisions and that we would be prepared for any scenario that occurs. And at the end of the day, we'll make sure that we do what is best for patients.

Okay, great. So let's keep our fingers crossed, and hopefully, this will be a positive trial. But I do want to quickly ask one last question. THIOLA EC, just wondering if you could provide the update on the IP. When should we expect to see the IP issuance?

Yes. So currently, we do not have IP for THIOLA EC. We have filed a patent with the U.S. Patent office, and that is currently under review. So unfortunately, there isn't anything more that I can say definitively at this time. We will continue to grow our cystinuria business by identifying new patients, and that's our primary goal with THIOLA EC.

Okay, great. Thank you very much.

Thank you, Gena.

Thank you, Chris, and Chris -- Eric.

Thank you, Gena.

Thank you, and bye-bye.

Thank you, everyone, for dialing. This concludes our call.