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

Good morning. My name is Lisa, and I will be your conference operator today. At this time, I would like to welcome everyone to the Travere Therapeutics top line interim results from Phase III DUPLEX Study of the Sparsentan in FSGS conference call. [Operator Instructions] I would like to turn the call over to Mr. Chris Cline. Please go ahead, sir.

Great. Thank you, Lisa, and 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 DUPLEX Study Sparsentan in FSGS. 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 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'd 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 of our Forms 10-Q, 10-K filed with the SEC. In addition, any forward-looking statements represent our view only as of the date such statements are made, February 2, 2021. And Travere Therapeutics specifically disclaims any obligation to update Such statements 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 today to talk about the promising top line interim results from the ongoing DUPLEX Study released earlier today. First and foremost, I would like to thank the patients and their caregivers patient advocacy organizations and investigators and site staff for their ongoing commitment to our study, particularly in light of the ongoing COVID-19 pandemic. Collectively, they have enabled DUPLEX to become the largest interventional study in FSGS to date, and their continued participation has been instrumental in getting us to this important milestone today. There's been a lack of innovation in rare kidney disorders for decades, and new treatment options are desperately needed to slow the progression to end-stage kidney disease, transplant and dialysis. For the more than 40,000 patients with FSGS in each of the U.S. and in Europe, there are no approved medicines indicated for their condition. Physicians treating people living with FSGS rely on therapeutic strategies that are limited to ACE inhibitors, ARBs, calcineurin inhibitors and steroids. And they are often not enough, either due to limited efficacy or long-term safety issues. People with FSGS live every day coping with the fear of seeing their proteinuria increase, signaling progression towards dialysis. It is estimated that 30% to 60% of people living with FSGS progress to end-stage kidney disease within 5 to 10 years and 50% of patients with severe FSGS progressed to kidney failure within 1,000 days of diagnosis. This is why we have made our sparsentan investigational programs the highest development priority at Travere over the last several years. Today, I am pleased to report that our Phase III DUPLEX Study of sparsentan achieved a statistically significant response on the clinically meaningful interim proteinuria endpoint compared to irbesartan after 36 weeks of treatment. Based on the data from the interim analysis, we intend to pursue submissions for accelerated approval of sparsentan for FSGS. We will continue our engagements with regulators in the first half of 2021 with the objective of sharing additional details from the ongoing study and establishing next steps for filing with the available data set. In tandem, we plan to continue our NDA and CMA preparations as well as commercial and medical readiness activities to prepare to bring this important treatment to people living with FSGS, if approved. Before I turn the call over to Noah, I'd like to remind everyone that DUPLEX is an ongoing study. And as we previously guided, we can provide only limited detail from this interim readout in order to maintain the trial integrity for the full study out to 108 weeks of treatment. Now I'll turn it over to Noah. Noah?

Thank you, Eric, and good morning to you all. I'd like to start by repeating Eric's gratitude for all those participating in our DUPLEX Study. As you'll recall, the ultimate goal of our sparsentan programs is to deliver the first novel non-immunosuppressive medicine indicated for people living with FSGS and IgA nephropathy. The ongoing DUPLEX Study in FSGS is a landmark trial and one of the first of its kind. We believe that it has the potential to not only support eventual approvals for sparsentan but to also significantly advance the understanding of FSGS for the nephrology community. It has been formed and designed with the key learnings from the prior successful DUET Study of sparsentan in FSGS and data from more than 600 subjects in aggregate from the program's clinical history. The DUPLEX Study is a global, randomized, multicenter, double-blind parallel arm active controlled Phase III clinical trial, assessing the efficacy and safety of sparsentan in 371 patients ages 8 to 75 years with primary FSGS. After a 2-week washout period, patients are randomized 1:1 to receive either sparsentan or irbesartan, the active control, and a representative RAS blocker, which is considered standard of care in the absence of an approved medicine for FSGS. Patients are then dose-titrated over a 2-week period to the maximum dose of 800 milligrams of sparsentan or 300 milligrams of irbesartan as tolerated. Overall, we continue to be pleased with the conduct in the study and the commitment of the investigators and site staff. Because the trial is ongoing, we must remain vigilant in the conduct of the trial to ensure a high-quality completion. This means that we will focus on maintaining strong patient retention and minimize any chance of biasing or inadvertent unblinding of the trial. As such, today, we will not be able to provide data beyond the planned interim program assessment. The DUPLEX Study protocol provides for an unwind analysis of at least 190 patients to be performed after 36 weeks of treatment to evaluate the interim efficacy endpoint, which is the proportion of patients achieving and FPRE or FSGS partial remission of proteinuria endpoint, defined as a UP/C or urine protein-to-creatinine ratio of less than or equal to 1.5 gram per gram and a 40% reduction in UP/C from baseline at week 36. Complete or partial remission of proteinuria is widely regarded as beneficial in the slowing of progression of FSGS and is recognized as a treatment goal amongst nephrologists. Achieving FPRE has been shown to be a clinically meaningful and robust correlate of kidney survival in patients with primary FSGS. This has been demonstrated across 5 independent cohorts from clinical trials in the field. As Eric mentioned, the DUPLEX Study met its interim FPRE endpoint. After 36 weeks of treatment, 42% of patients receiving sparsentan achieved FPRE compared to 26% of irbesartan-treated patients, and the results were statistically significant with a p-value of 0.0094. To date, sparsentan has performed in line with our expectations for FPRE response and consistent with the findings from the Phase II DUET Study. The confirmatory primary endpoint of the DUPLEX Study to support full regulatory approval is the rate of change in eGFR over 108 weeks of treatment. As of the time of the interim analysis, available long-term eGFR data for the confirmatory endpoint were limited given the long-term nature of this endpoint. Consistent with the DUPLEX Study protocol, patients will continue in a blinded manner to assess the treatment effect on eGFR slope over 108 weeks. From a safety perspective, we are very pleased with the interim results, which indicate sparsentan has been generally well tolerated and that the safety profiles in the study to date have been generally comparable between treatment groups. Of note, the Independent Data Monitoring Committee recently submitted -- completed their fifth scheduled meeting to assess safety in both Duplex and our PROTECT Study in IgA nephropathy. And I am pleased to report that the DMC recommended both studies proceed as planned based upon their safety review. We will not be able to provide further data on efficacy or safety because this is an ongoing trial. And we must do all we can to protect the blind and full completion of the trial to ultimately support full approval. I would like to commend our internal biostatistics and medical teams for achieving an expeditious and high-quality readout. These interim results build upon the foundational evidence generated by the Phase II DIRECT Study. We believe These data provide further support for the potential of sparsentan, an innovative product candidate combining selective endothelin A receptor, an angiotensin receptor blockade to treat the high unmet need in rare kidney disorders, if approved. I would like to again thank the patients, their caregivers, investigators and site staff whose continued commitment is critical to reaching this milestone and to ultimately completing this important study for those living with FSGS. As Eric mentioned earlier, we look forward to meeting with regulators in the coming months to share the available data set and establish next steps for potential accelerated approval. I'll now turn the call back over to Eric for his closing comments. Eric?

Thanks, Noah. There is a clear unmet need in FSGS, and we are very encouraged by the data release from the DUPLEX Study today. We believe this interim analysis brings us another step closer to realizing our goal of delivering a new treatment standard for people living with FSGS. Moving ahead, we look forward to engaging with the FDA and EMA with the available data set from DUPLEX as well as the robust and supportive data from our previous Phase II DUET Study to establish next steps in our intent to pursue accelerated approval. Additionally, we will remain focused on maintaining excellent study conduct and integrity in DUPLEX to enable a high-quality readout of the confirmatory eGFR endpoint. Finally, we are looking forward to the upcoming readout of the PROTECT Study of sparsentan in IgA nephropathy. PROTECT remained on track to deliver top line interim results from its 36-week proteinuria endpoint in the third quarter of this year, and if successful, could serve as the basis for accelerated approval submissions of sparsentan in IgA nephropathy as well. Let me now turn the call back over to Chris for Q&A. Chris?

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

[Operator Instructions] Your first question comes from the line of Maury Raycroft with Jefferies.

Much congrats on the update today. So on your 3Q '20 call, you implied that it might be important to see a positive trend in eGFR at week 36. So I'm not necessarily asking for data on this because it seems like you're not providing much more data, but just asking if there was a positive trend in eGFR at week 36 that you can comment on.

Yes. Thank you, Maury, for the question. And you're right. As we mentioned, we're going to be very limited in the information that we share. And certainly, we will be looking at data that are going to be critical for our submissions to regulators and evaluation of the early read of eGFR will certainly be part of that along with other measures of efficacy and safety. Noah, is there anything else That you'd like to add to Maury's question?

Yes, I think eGFR is a long-term endpoint that really is measurable at 108 weeks. So any book right now will not be fully mature. And I think to your point, if you were to speak about it, we would potentially introduce bias at the trial. So we need to keep those patients in the study long term. This is aligned with the regulatory view and in the best interest in the study conduct. So I think he covered it well.

Got it. And also wondering if you can talk more about the correlation between FPRE and predicting EGFR and FSGS. And so if FDA extrapolates and predict based on your FPRE results, can we assume the extrapolation will indicate eGFR falls into the approvable scenario? Or what else could influence that prediction?

Sure. Well, maybe I'll have Noah talk a bit about some of the existing data and those cohorts that he mentioned to support the development of FPRE. But I would say that from a regulatory perspective, we're going to need to continue to meet with them and make sure that we understand what their needs are for data understanding that they will be looking at FPRE looking at longer-term eGFR and certainly assuming that they will evaluate the totality of the data. As Noah mentioned, the eGFR data at this point is not a mature endpoint. It's an 108-week endpoint that is meant to serve the basis for the confirmatory approval. Noah, do you want to share a little bit more about how we're thinking or maybe, Bill, on the way that regulators might be looking at eGFR?

I can go ahead and get started. Bill, if you want to follow in. So just in FPRE as you alluded to, is really a very relevant endpoint given its clinical meaningfulness to kidney survival. So it's been linked in databases in a number of studies to improvement in outcomes and stabilization improvement in eGFR. So it's something that across renal diseases has been shown, but also within FSCS. Bill, maybe I'll turn it to you for the regulatory perspective.

Certainly, I think that -- thanks, Noah. We believe that the FDA is very engaged in the glomeruli nephropathy space, looking at the linkage between proteinuria and effects on eGFR, preservation of eGFR based on a reduction in proteinuria. This is evidenced based on their interaction with joint workshops with EMA and the National Kidney Foundation and publications that they participated in. So I think that the field as a whole is on the same page here and is enthusiastic about this as a way to provide attractable development path for innovative therapies in nephrology.

Your next question comes from the line of Michelle Gilson with Canaccord Genuity.

You indicated that you're intending to pursue an accelerated approval submission. Is it safe to assume that results are generally in line with what you've previously discussed with the FDA? Or are your plans to reengage regulators to discuss anything specific in the data set that you're -- that you've observed?

Michelle, and thanks for your question. So we are confident in the interim proteinuria results and that they can support accelerated approval. And as we have been, we'll continue to engage with regulators to make sure that we understand what data analysis they would want to see from this trial given that it's ongoing, and that the evidence we have now is based on a surrogate marker for the longer-term endpoint. And so we will look to understand and meet their expectations in our file. And certainly, those would be planned meetings that we have in the first half of this year.

Okay. And if I could, just one more. It looks like the placebo arm outperformed some investor expectations. I am just curious if what you saw in these results on the proteinuria changes or evolves the way that you think about the study in IgA nephropathy at all?

Yes. So Michelle, that's right. The one thing that I will say is that it was an active control. So irbesartan placebo. I'll ask Noah to give his perspective on how it performed.

Yes. Thanks, Michelle. As we've shared previously, we knew there was limited data for irbesartan in FSGS, and this is the first long-term study that includes irbesartan FSGS. So we're learning about this and sparsentan over time. Having said that, we accounted for this level of response to FPRE. Notably, despite the increase in FPRE in the irbesartan arm, we saw a clear difference between arms. And sparsentan showed a statistically significant response. FPRE is a clinically meaningful endpoint, and we are encouraged by the 42% response for patients treated with sparsentan after 36 weeks.

Your next question comes from the line of Joseph Schwartz with SVB Leerink.

Congratulations on the positive data. I was wondering if you've had the opportunity to look at the proportion of patients that were able to get to other remission thresholds like complete remission. And tied in with that, if you've been able to analyze the impact of -- or the benefit of higher doses towards achieving that for FPRE.

Joe, thank you for your questions. And I'm going to reinforce that we're just not going to be able to comment on any of the additional analysis that have or will be conducted in this interim analysis. We really want to ensure that we're not introducing any bias to the trial. So I recognize that we're asking for your patience in this. But certainly, we will be looking at a number of different measures of efficacy in this study. But importantly, much of that will be once the study is fully completed. Noah, anything further that you would like to add?

No, I think that our key here really is we're charged with the 36-week at [ pure ] endpoint, and that's what we've reported out. Obviously, we'll continue to look at additional analysis potentially for the submission. But at this time, that's what we're comfortable with. We don't want to do anything, as we said earlier, to impute or bias the results and want to make sure to maintain the entirety of the study out to the full 108 weeks.

Right. That's very understandable. I appreciate that. And then just based on your prior discussions with the FDA, how much of a trend towards showing a positive eGFR benefit do you think that they want to see in order to grant the go ahead to file for accelerated approval? How strong does the trend need to be? Is it sufficient? Do you think if as long as it doesn't go against the drug in a more neutral scenario? Do you think that they would like to see any degree of positive impact on GFR given the limited amount of data that's going to be available?

Thanks, Joe. So I would -- let me put it perhaps this way, that we will continue to understand how they want to see these data as they are limited and an interim based on a longer-term measurement. And so I would say there's not a specific threshold at an interim look at this endpoint. But again, this is part of why we want to make sure we continue to have dialogue with FDA and EMA to understand what data they would like to see in the submissions.

Our next question comes from the line of Tim Lugo with William Blair.

Congratulations on the impressive results, especially around managing this trial through COVID. It's very impressive. One question, though. Can you discuss maybe the slope of effect at earlier time points, such as week 8, 16, 24. And if those earlier time points were in line with what we saw with DUET in the OLE.

Thanks, Tim. So maybe I'll ask Noah to talk a bit about that. But let me just reinforce that we're not going to be able to share any further data from this trial other than the week 36 analysis on FPRE. Again, we want to make sure that no patient can look at their individual data and unintentionally blind themselves. Noah, anything further you'd want to add and perhaps inferences from DUET rather than DUPLEX?

Yes. That's where I was going, Eric. I think that -- let me start -- we're encouraged by what we've seen in the first [ 6-week ] analysis. And we can't speak to specific trends in DUPLEX. But I think, Tim, to redirect you back to do that, I think we've got a pretty good idea of how this drug behaves as well characterized. We've gone out to 6 years. We published the recent 42.5 month median analysis. So I think I would just earn your attention there. That's not unexpected for us in DUPLEX, but I can't speak directly to the data. And as I said earlier, the top priority is really to maintain product and flies.

Understood. Can you maybe speak a little bit of just generalizations around the side effect profile in the PR interim safety look to be comparable, but can you talk maybe about some of the serious side effects that came up? And were those relatively balanced between arms?

Yes, I can take that one. So again, for the reasons we sited, it's not -- won't be speaking to specific AGs, but looked across a number of different avenues, including some of those that you mentioned. And we are encouraged by these interim results from the study to date, indicating that spar has a probable safety profile at this current time. It's an ongoing study to the comparator's irbesartan. I'll also add that we just completed a fifth data monitoring committee meeting. And they, of course, have access to unblinded data, and they gave us the green light to proceed as planned. And we're, of course, monitoring adverse events, serious adverse EOIs carefully as we continue on with the study.

Your next question comes from the line of Liisa Bayko with Evercore ISI.

Congratulations on the data. A couple of additional questions for me. First of all, can you speak to the balance and use of background meds like steroids and immunosuppressives? Are you comfortable with how they look at baseline?

Noah, why don't you take that one?

Yes. We're not guiding, as we said, to any specifics on baseline. But we can say that in general, we've published the 36 week with the knowledge that The groups were balanced in general at baseline between groups with regard to demographics and background treatments. Of course, we'll do a much deeper dive for the NDA, but we're encouraged by the results, and I think we're seeing that balance between groups.

Okay. In the DUET Study, there seemed like there was a greater treatment differential over irbesartan in the more mild patients. What are you seeing here with respect to kind of the above 3 grams versus below 3 grams in terms of kind of treatment benefit? Is it pretty much the same despite severity? Or are there some nuances there?

Yes, what I can say is we're not going to be guiding to specifics and specific subgroups, but we did mention on the previous call that the baseline characteristics in DUPLEX or similar to DUET with regard to UP/C. And so I'll just say that we're very pleased with the 42% achievement of response for FPRE with the baseline as opposed to DUET, I'd imagine there will be a significant number of patients above and below that threshold. So that contributes to that overall effect.

Okay. Did you actually -- just to ask a little bit more about FPRE, and I know you can't comment, but did you look at it yourselves at this interim. Just trying to get a sense of if there was output spend on this interim on term -- in terms of eGFR.

So as we discussed previously, the higher -- the statistics were hierarchical, maybe I'll ask Bill to talk a bit about that.