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

Hello, and welcome to the Travere Therapeutics, Inc. top line interim results from the Phase III PROTECT study of sparsentan in IgA nephropathy. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Chris Cline. Please go ahead.

Thank you, Deb. Good morning, and thank you all for joining us on short notice today to talk about the top line interim results from our ongoing Phase III PROTECT study of sparsentan in IgA nephropathy. A copy of the press release announcing the results are available on the Investors section of our website. Today's call will be led by our Chief Executive Officer, Dr. Eric Dube. Eric will be joined for the prepared remarks by Dr. Noah Rosenberg, our Chief Medical Officer; and Dr. Bill Rote, Senior Vice President of Research and Development, will join us for the Q&A session. Before we begin, I would like to remind everyone that statements made during this call regarding matters that are not historical facts are forward-looking statements within the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not guarantees of performance. They involve known and unknown risks, uncertainties and assumptions that may cause actual results, performance and achievements to differ materially from those expressed or implied by the statement. Please see the forward-looking statement disclaimer on the company's press release issued earlier this morning 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, August 16, 2021, and Travere specifically disclaims any obligation to update such statements to reflect future information, events or circumstances. With that, let me now turn the call over to Eric. Eric?

Thank you, Chris, and good morning, everyone. Thank you for joining us to talk about the top line interim results from the ongoing PROTECT study released earlier today. Over 3 years ago, our organization had the courage to embark on the PROTECT program to evaluate sparsentan for the treatment of IgA nephropathy or IgAN. Since then, our goal has been to deliver and develop sparsentan as a new therapy that can meaningfully reduce proteinuria and improve kidney function for people living with IgAN. Our organization has been driven by the significant unmet need that exists in this rare kidney condition. It is estimated that there are between 250,000 and 350,000 people living with IgAN in the U.S. and Europe combined. And there are no currently approved medicines indicated for this rare disorder. Patients currently rely on treatment options that are limited in efficacy and/or have long-term safety and tolerability challenges. As a result, IgAN is recognized as the most common cause of primary glomerulonephritis and a leading cause of end-stage kidney disease. Today, I am incredibly pleased to report that our pivotal Phase III PROTECT study has achieved its primary proteinuria endpoint with robust statistical significance in its prespecified interim analysis. After 36 weeks of treatment, sparsentan-treated patients experienced on average a greater than threefold reduction in proteinuria from baseline compared to those patients receiving the active control irbesartan. Historically, this level of proteinuria reduction would require the use of multiple agents and steroids. This is the first time in a single non-immunosuppressive agent has demonstrated this magnitude of effect on proteinuria reduction in a large well-controlled study. These results have exceeded our expectations. Based upon the interim analysis, we plan to submit an NDA under the Subpart H accelerated approval pathway in the U.S. during the first half of 2022. We also plan to submit for conditional marketing authorization in Europe. We look forward to engaging with regulators in the coming months as we prepare our submissions. Before turning the call over to Noah to walk through the data, I'd like to thank all of our employees, patients and their caregivers, patient advocacy organizations and investigators and site staff for their ongoing commitment to this study. Their participation and dedication are critical to reaching this milestone and to ultimately completing this important ongoing study in 2023. Let me now turn the call over to Noah to walk through the results in a bit more detail. Noah?

Thank you, Eric, and good morning. I'd like to also start by thanking the many patients, families, caregivers, investigators and site staff who continue to make this study possible. I'd also like to thank our teams who have been working tirelessly to get to this point. Before moving to the study results, I would like to remind everyone that consistent with our previous guidance, we will be limited in what we can share from this study today. This is because the trial is ongoing in a blinded manner out to 110 weeks of treatment, and we must remain vigilant in maintaining trial integrity to enable a high-quality completion. The PROTECT study is a global, randomized, multicenter double-blind parallel arm active controlled Phase III clinical trial, assessing the efficacy and safety of sparsentan in 404 patients with IgAN ages 18 and up. The main goal of this interim assessment is to evaluate the primary proteinuria endpoint after 36 weeks of treatment. Proteinuria is widely considered to be predictive of a poor prognosis and is a biomarker of disease severity in IgAN. In order to be eligible for the study, patients had to be on a stable dose of maximally tolerated ACE or ARB therapy for at least 12 weeks prior to screening and have proteinuria greater than or equal to 1 gram per gram per day. Patients with proteinuria greater than 1 gram are at high risk of rapid disease progression to kidney failure and dialysis. Patients in PROTECT were randomized 1:1 to receive sparsentan or irbesartan to active control and a representative RAS walker, which is considered one of the current standards of care in the absence of a medicine indicated for IgAN. Following randomization, patients were dose titrated over a 2-week period to the maximum dose of 400 milligrams of sparsentan or 300 milligrams of erbistartin as tolerated. The PROTECT study protocol provides for an unblinded interim analysis to evaluate the interim primary efficacy endpoint, the change in proteinuria defined as urine protein-to-creatinine ratio at week 6 from baseline, following the first 280 patients reaching 36 weeks of treatment. I am very pleased to report that after 36 weeks of treatment, patients receiving sparsentan achieved a mean reduction in proteinuria from baseline of 49.8% compared to a mean reduction of proteinuria from baseline of 15.1% for irbesartan-treated patients. This result with sparsentan demonstrating a greater than threefold proteinuria reduction compared to an active comparator is clinically meaningful and statistically significant with a p-value of less than 0.0001. As many of you will recall, we designed the PROTECT study to be 90% powered to detect a 30% difference in the geometric mean ratio of proteinuria reduction between sparsentan and irbesartan. Based upon the established and robust literature linking proteinuria reduction to kidney survival in IgAN as well as our modeling to design the study, a 30% difference in the geometric mean ratio of proteinuria reduction would translate to an expected clinically meaningful outcome on eGFR at 2 years. Today's results demonstrate a 41% difference in the geometric mean ratio of proteinuria reduction between sparsentan and irbesartan. While we will not be able to provide specific eGFR values, we do believe that preliminary eGFR data available at the time of the interim analysis are consistent with our powering and are indicative of a potential clinically meaningful treatment effect after 2 years of treatment. In following the PROTECT study protocol, patients will continue in a double-blinded manner to fully assess the treatment effect on eGFR slope over 110 weeks. From a safety perspective, we continue to be encouraged by a consistent profile. The preliminary data suggests that both treatments were generally well tolerated to date in the study and sparsentan appeared consistent with the previously observed safety profile with no new safety signals emerging. Overall, we continue to be pleased with the conduct in the study and the commitment of investigators and site staff. The interim results from this landmark study further build upon the robust clinical evidence supporting sparsentan's potential to meaningfully reduce proteinuria for people living with rare kidney disorders. We continue to hear from the nephrology community that there is a clear need for a therapeutic option to meaningfully reduce proteinuria over and above widely used ACE and ARB treatments and without the long-term safety challenges associated with immune suppression. We believe these results bring us 1 step closer to achieving our goal of delivering sparsentan as that treatment option. Looking ahead, our team will remain focused on continuing the trial through the blinded portion of PROTECT to completion in the second half of 2023. In parallel, we are already beginning to prepare our regulatory package the expectation of submitting for accelerated approval in the U.S. in the first half of next year. I'll now turn the call back over to Eric for his closing comments. Eric?

Thank you, Noah. These results from the PROTECT study represent an incredible step forward for people living with IgAN and for our organization. Looking forward, we will remain focused on completing this important study and preparing for regulatory submissions in parallel. Of the 250,000 to 350,000 patients with IgAN in the U.S. and Europe, we believe that approximately 75,000 to 120,000 patients would be good candidates for treatment at launch if sparsentan is approved. And we believe this number has the potential to increase with greater awareness and diagnosis over time. This means that we have considerable work ahead and our organization is in great shape to prepare. Finally, later this quarter, we continue to expect a regulatory update on the potential to also pursue an accelerated approval submission of sparsentan in the U.S. for FSGS next year. Let me now turn the call back over to Chris for Q&A. Chris?

Deb, can you please go ahead and open up the lines for Q&A.

[Operator Instructions] Your first question comes from the line of Joseph Schwartz with SVB Leerink.

Congratulations to the whole team. This is a cause for applause. I was wondering if you can give us any information on the baseline characteristics of the patients in PROTECT? And how they compare to those who are enrolled in DUPLEX? Are there any key ways that the enrollees these are similar or different? Obviously, they have different diseases, but in terms of like prior therapy degree of proteinuria, any information on the dose effect that you can share on the proteinuria only? I understand you need to be careful with the GFR, of course.

Joe, thanks so much for the applause. And I'll ask Noah to take the question about the baseline characteristics.

Joe, great question. So in terms of comparing the baseline characteristics in SGLT2 studies, I think what I'll first say is as you noted, these are 2 different diseases. And we know that FSGS patients have higher proteinuria levels, so won't -- you can imagine that, that would be reflected and consistent with our expectations. In terms of the baseline use of therapy, specifically ACE and ARB therapy, within DUPLEX, there were a significant number of patients on ACE and ARBs, but they were not required. And in PROTECT, we had 99%, 100% of patients, almost 100% who were all on baseline, were maximum tolerated or near maximum tolerated ACE/ARB therapy at baseline. So consistent with what we expected and with the 2 disease states.

I think the only other thing, Joe, that I would add is that there are other trials in IgAN, and I think that there's a consistency in what we've seen in the baseline characteristics for this trial.

Okay. That's helpful. And then I heard you say that you believe the preliminary eGFR data that's available now are indicative of a potential clinically meaningful treatment after 2 years of treatment. Can you give us any color commentary at all on whether that picture differs at all from what you've seen in DUPLEX to this point?

Noah?

Yes. I mean I think -- as you know, we really can't speak to specifics of the data in the study. But I think what we can say is it's a more mature data set as we have anticipated and that a proteinuria reduction of this magnitude, we believe, would translate to a clinically meaningful benefit after 2 years in the eGFR models and PROTECT preliminary interim data available are consistent with that potential.

Okay. Great. Congrats again.

Thank you, Joe.

And your next question comes from the line of Greg Harrison with Bank of America

This is [ Mary Kate ] on for Greg. Congrats on the data. We were wondering what clinical benefit would you expect given this level of proteinuria reduction seen?

Noah, would you like to take that one? And thank you very much, [ Mary Kate ].

Yes. I mean I think I'll point to the literature here. There's robust literature linking proteinuria reduction and overall outcomes are proved out to specifically in the anchor meta-analysis. So I think we would expect a significant potential -- this is indicative of a significant potential clinical benefit for patients and really exceeded our expectations. And our modeling was based on significant clinical benefit. So I think that's as much as I can say.

Excellent. Congrats again on the data.

Thank you.

And your next question comes from the line of Maury Raycroft with Jefferies.

I'll add my congrats on the update today. So I was just wondering if you can talk a little bit more about how the data update today could inform your discussions with the FDA on FSGS? And if you can provide any more color or clarity into what you're seeing on eGFR and if that is similar and in line or different from what you saw in FSGS.

Thank you so much for the question. I'll ask Bill to take your question about the regulatory engagement.

Thanks for the question. Well, ultimately, we believe that these data further strengthen and support the profile of sparsentan and its use across the group of rare kidney disorders, specifically glomera nephropathies. That being said, they're independent programs, independent studies. So there shouldn't be an expectation that these data drive a different conversation, but certainly robust results like this certainly bolster our confidence.

Thanks, Bill. And the only thing that I would add, Maury, is that we remain optimistic in aligning with the agency around our path with FSGS. And as we mentioned today, the results exceeded our expectations with IgAN and are planning an accelerated approval submission. And the eGFR question, I think we can just maybe add that it's preliminary eGFR data, but it supports our confidence in submitting for accelerated approval. And so we believe that it is indicative of what we could see in 2 years' time. And importantly, for where we are today, we remain very confident in submitting for accelerated approval next year.

Got it. That's helpful. And maybe one other question. Just on proteinuria for sparsentan. I guess are you seeing greater responses in patients with higher or lower proteinuria at baseline? And for the irbesartan group, those patients are optimized on RAS inhibitor to a washout. I guess can you talk a little bit more about the effect that you're seeing in that group? And if you can provide more color on if those patients are higher proteinuria patients?

Sure, Maury. Noah, would you like to take this?

Yes. So Maury, again, preliminary data, and what I can say is that in terms of the baseline above and below reductions in protenuria, looking at sort of the means right above and below, we're seeing a consistent effect of the drug regardless. And not surprisingly because this is really what we've seen all along throughout the history of this program. So I think that's the key there. Sorry, Maury, can you just repeat the second question there?

Well, for the irbesartan arm, so you are still seeing some responses there. And just wondering if there's any relevant trend that you're seeing in that arm based on the baseline proteinuria?

Yes. I mean I would just say that the groups are balanced between groups, Maury. So I don't think there was anything really driving it. Remember, as you said, these patients came in and fully optimized ACE/ARB treatment. And I think the reductions that we saw with the irbesartan were modest and consistent with our expectations.

Got it. Congrats, again.

Thanks, Maury.

Thanks, Maury.

And your next question comes from the line of Carter Gould with Barclays.

I'll -- let me offer my congrats to Eric, Noah and the team as well. Given the magnitude of effects you're seeing here, can you comment around how this either like bolsters or is going to drive an expansion of the development program? And then just to harp on the same topic everybody else has been, in terms of the eGFR signal, I mean you're using distinct language here from what you used in FSGS. Is that safe to assume the data you're seeing here is distinct from the trends you saw in FSGS?

Carter, thank you so much for the congratulations and for the questions. With regard to development, what I can say is that we're very pleased with the data that we've seen this year and particularly from the results that we announced this week. I think we want to make sure as we have done so far, we continue to engage with the nephrology community and understand where there are areas of greatest unmet need. And the rationale for us going first into FSGS and IgAN is that consistently we hear that these are the 2 toughest-to-treat patient types within the rare renal space. And so we want to make sure that we do everything possible to get this product to them. So stay tuned on further discussion and development there. And then apologies it may be that I need my second cup of coffee. Can you just repeat the second question?

Sure. It was -- obviously, you're using a distinct language here to comment on eGFR relative to how you guys addressed that topic on the FSGS readout. Is that safe to assume that this is a distinct signal that you're seeing from the FSGS results?

Thank you. So they are 2 different trials. But one thing that I will point out and that we've discussed leading into today's announcement are 2 very important differences between the trials. The first is that patients in PROTECT required to be on MAX tolerated ACR or ARB for at least 12 weeks before being randomized. And also the maturity of the data and the follow-up just based on the enrollment trends were quite distinct. And in PROTECT, we saw very steady and linear enrollment trends that led to much greater kind of longer-term follow-up when you look at this interim compared to the enrollment dynamics with DUPLEX, which were later and a large bolus later on, which, as we discussed, could increase the likelihood of seeing the expected acute hemodynamic effect. So those are the 2 differences between the trial that I would point out. But again, let me just take a step back and say the data that we've seen gives us confidence that we will be able to submit for accelerated approval in the first half of next year.