Hello, welcome to the Travere Therapeutics Inc. top-line interim results from the phase III PROTECT study of sparsentan and IgA nephropathy. At this time, all participants are in a listen-only mode. Later, we will conduct a question and answer session, instructions will follow at that time. If anyone should require assistance during this conference, please press star then zero. 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, 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 and 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. William 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 16th, 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 three 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 pre-specified interim analysis. After 36 weeks of treatment, sparsentan-treated patients experienced, on average, a greater than three-fold 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 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. 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've 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 the study today. This is because the trial is ongoing in a blinded manner out through 110 weeks of treatment. We must remain vigilant in maintaining trial integrity to enable a high-quality completion. The PROTECT study is a global, randomized, multi-center, 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 end-stage kidney disease and dialysis. Patients in PROTECT were randomized one-to-one to receive sparsentan or irbesartan to the active control and a representative RAS blocker, 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 two-week period to the maximum dose, 400 mg of sparsentan or 300 mg of irbesartan 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 six 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 in 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 two 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 two 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 of 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 one 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 with 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 250,000-350,000 patients with IgAN in the U.S. and Europe, we believe that approximately 75,000-120,000 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. 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.
Thank you, Eric. Deborah, can you please go ahead and open up the lines for Q&A?
Ladies and gentlemen, if you would like to ask a question, please press star one on your telephone keypad. Your first question comes from the line of Joseph Schwartz with SVB Leerink.
uncertain, congratulations to the whole team. This is 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 were enrolled in DUPLEX. Are there any key ways that the enrollees are similar or different? Obviously, they have different diseases, in terms of 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, good morning. Thanks so much for the applause. I'll ask Noah to take the question about the baseline characteristics.
Hey, Joe. Great question. In terms of comparing the baseline characteristics across the two studies, I think what I'll first say is, as you noted, these are two different diseases, and we know that FSGS patients have higher proteinuria levels. You can imagine that that would be reflected and consistent with our expectations. In terms of the baseline use of therapies, specifically ACE and ARB therapy, within DUPLEX, there were a significant number of patients on ACE and ARBs, but they were not required. In PROTECT, we had 99, 100% of patients, almost 100% were all on baseline, were maximum tolerated or near maximum tolerated ACE/ARB therapy at baseline. Consistent with what we expected and with the 2 disease states.
Great. Okay. Thank you.
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. Thanks. I heard you say that you believe the preliminary eGFR data that's available now are indicative of a potential clinically meaningful treatment after two 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?
Yeah. I think, as you know, we really can't speak to the specifics of the data in the study. 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 two years in the eGFR models and PROTECT primary interim data available are consistent with that potential.
Okay, great. Thanks so much. Congrats again.
Thank you, Joe.
Your next question comes from the line of Greg Harrison with Bank of America.
Hi. Good morning. This is Mary Kate on for Greg. Congrats on the data, and thanks for taking our question. We were wondering what clinical benefit would you expect given this level of proteinuria reduction seen?
Noah, would you like to take that one? Thank you very much, Mary Kate.
Yeah. I think I'll point to the literature here. There's robust literature linking proteinuria reduction and overall outcomes to proved outcomes, specifically in the Inker meta-analysis. 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 benefits. I think that's as much as I can say.
Excellent. Thank you so much, and congrats again on the data.
Thank you.
Your next question comes from the line of Maury Raycroft with Jefferies.
Hi. Good morning, everyone. I'll add my congrats on the update today. Thanks for taking my questions. I was just wondering if you could talk a little bit more about how the data update today could inform your discussions with 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, in line, or different from what you saw in FSGS.
Good morning, Maury, and thank you so much for the question. I'll ask Bill to take your question about the regulatory engagements.
Good morning, Maury, and 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 glomerular nephropathies. That being said, they're independent programs, independent studies, so there shouldn't be an expectation that these data drive a different conversation. Certainly, robust results like this certainly bolster our confidence.
Thanks, Bill. 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.
Got it. That's helpful.
Maybe 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. We believe that it is indicative of what we could see in two 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. 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? For the irbesartan group, those patients are optimized on a RAS inhibitor with no washout. I guess, can you talk a little bit more about the effect that you're seeing in that group? If you can provide more color on if those patients are higher proteinuria patients.
Sure, Maury. Noah, would you like to take those?
Yeah. Maury, again, preliminary data and what I can say is that in terms of the baseline above and below reductions in proteinuria, looking at sort of the means right above and below, we're seeing a consistent effect of the drug regardless, and not surprising because it's really what we've seen all along throughout the history of this program. 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.
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 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. Okay. Thanks for taking my questions and congrats again.
Thanks, Maury.
Thanks, Maury.
Your next question comes from the line of Carter Gould with Barclays.
Great. Good morning, 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 bolsters or is going to drive an expansion of the development program? Then just to harp on the same topic everybody else has been, in terms of the eGFR signal, 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? Thank you.
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, continue to engage with the nephrology community and understand where there are areas of greatest unmet need. The rationale for us going first into FSGS and IgAN is that consistently we hear that these are the two toughest-to-treat patient types within the rare renal space. We want to make sure that we do everything possible to get this product to them. Stay tuned on further discussion and development there. Apologies, it may be that I need my second cup of coffee. Can you just repeat the second question?
Sure. Obviously you're using 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 you're seeing from the FSGS results?
Thank you. They are two different trials, but one thing that I will point out, and that we've discussed leading into today's announcement, are two very important differences between the trials. The first is that patients in PROTECT are required to be on max-tolerated ACE or ARB for at least 12 weeks before being randomized. Also, the maturity of the data and the follow-up, just based on the enrollment trends, were quite distinct. In PROTECT, we saw very steady and linear enrollment trends that led to a 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. Those are the two differences between the trials that I would point out.
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.
Congrats again. Thank you.
Thank you.
Your next question comes from the line of Liisa Bayko with Evercore ISI.
Hi. Thanks for taking the question, I want to reiterate my congratulations on the data. Good stuff. Just as a follow-up to baseline, the question on baseline proteinuria, can you maybe talk to the proportion of patients that got to below 1 gram per gram? That's a pretty meaningful threshold leading to better outcomes. Wanted to know if you could comment on that at all.
Thank you, Liisa. Noah, I'll ask you to take that one.
Thanks, Liisa. That's a great question. While we can't comment on specifics, because again, it's preliminary data, we're just getting it out there now. What I would say is a substantial proportion of patients, as you can imagine, got below 1 which is the goal of the study. Clinically meaningful reductions in proteinuria.
Can you talk about dose? I know there was a dose titration up to 400 mg if tolerated. Can you maybe speak to what proportion of patients got to 400 mg versus 200 mg?
I would say there also, Liisa, pleased with the results in the titration, as you're correct. They titrated from 200 mg- 400 mg, and a substantial number of patients were able to achieve the 400 mg dose, which was consistent with our expectations.
Okay. Anything to comment on with respect to edema?
Yeah. We can't speak to specific AEs in the study given it's blinded, but we can say is there were no new safety signals related to this. We continue to see sparsentan perform consistent with its previous reserved profile. I can also say we haven't seen any cases of CHF a cross our program, including PROTECT.
Okay. You're planning to file for accelerated approval in the first half. Can you walk us through the key steps between now and then? Is there any more granularity on when in the first half? It seems like that's a pretty big range and we're pretty early in the second half still of this year. What are the key rate-limiting steps between now and then? When you file, will you have more mature data? I know you're going to take a look at 58 weeks. What would you report to the street when? Thank you.
Thanks, Liisa. Bill, I'll ask you to take those.
The filing will be based on the interim data cut. The cut was triggered by 280 patients reaching 36 weeks. At that point, we take a data cut and provide the data in total. All patients provide data into that analysis. That will be the data that goes in for review. It'll be this proteinuria result plus all the rest of the safety and efficacy data from the study at that interim point. We won't be providing more data than what we have now. The rate-limiting steps that guide the submission of that, there's some regulatory discussions. We'll be scheduling the pre-NDA meeting with the agency. In parallel to that, we're already working on the submission, and in anticipation of these results.
The long pole in the tent is going to be the clinical data and getting the clinical study report, the clinical summaries and summaries of safety, and all of that. It's a lot of centers, multinational, and that's generally what's driving it.
Yeah
We'll give you greater granularity.
Okay. Fair enough. Thanks for taking the questions.
Thanks, Liisa.
Your next question comes from the line of Tim Lugo with William Blair.
Hey, guys. This is Lachlan on for Tim. Thanks for taking the questions. I'll add another congrats on the strong results here. On the topic of that pre-NDA meeting, are there any different considerations that you have going into this one than you did the DUPLEX one? Aside from being a different data set and a different disease, are there any other major differences in the considerations you've got for that?
Bill?
Structurally, they're going to be very much the same. Because we've had one pre-NDA meeting, that helps us set up. A lot of the questions are the same around how the NDA is put together and assembled. Ultimately, we have two studies, both with positive results, both that we believe will lead to accelerated approval submissions. The difference here is it's a different study, different disease. Looking forward to getting these results in front of the agency in the form of a submission.
Thanks, Bill. I think the only other thing is that we're in a stronger position because we're smarter in having engaged on FSGS and DUPLEX. We continue to take all of those learnings as we move forward, as we have with this program, and apply those as we prepare for further engagements.
Great. Thanks.
Thanks, Lachlan.
Your next question comes from the line of Michelle Gilson with Canaccord Genuity.
Hi, thank you for taking my question, and I'll also add my congratulations here. Maybe if you can clarify what data were available for you to look at in terms of, you went over all of the data at week 36, but is there anything you can offer us in terms of maybe the average follow-up that these patients had or the number of patients that are out to one year and two years? If the enrollment curves were linear, I think it's like 90 or 100 patients that you had two years of data for, if you can maybe confirm that range. Just because I've been getting this question, can you confirm that the eGFR data that you're looking at is completely unblinded?
The language in the PR suggests that the eGFR data could be indicative of a potentially clinically meaningful treatment effect after two years for eGFR. Is that synonymous with statistically significant, I guess, or is clinically meaningful also would be considered statistically significant in terms of what you guys are powered to, I guess, detect in terms of the difference in eGFR at year two?
Michelle, thank you very much for the questions. Noah, I'll ask you to start on those.
Yeah. Michelle, I just want to make sure I track and get all the there's a number of questions in there, and as usual, very good questions. In terms of the follow-up, I'll say there's proportionally a very substantial number of patients at one year and a number of patients out to two years. It's a pretty substantial follow-up and consistent with what we've said before, greater due to the linear nature and the smooth nature of how the recruitment went from the very beginning, as opposed to DUPLEX, which took a little bit of time to get going. I think I can say that's how much I can say about that. I have your third question, but just fill me in on the second one.
I have clinically meaningful versus stat sig, and I think there was. Well, let me start with that one, and then maybe we'll go back. Yes, the results, if you look at the Inker analysis, the meta-analysis, you can see there that patients with even a 15%, 20% reduction have clinically meaningful outcome or link to clinically meaningful outcome. Again, I think what we have here, again, it's preliminary data, right? It's our interim analysis. It's not our final endpoint, but I think we can say that it's indicative that we would have a potentially clinically meaningful outcome. Those are the two questions, first and third. I think you had a second question, if you could just clarify that.
Maybe if you can just remind us the powering for PROTECT in terms of what eGFR is, or what difference in the eGFR slope that PROTECT is powered for at two years.
Yeah. I mean, we're powered for UPCR, that UPCR is a 90% power to show a 30% geometric mean reduction. That ties into the models, right, that we've seen with the Inker data. I think that's clearly associated with longer-term benefits. Just want to make sure that that's clear, and I think that's probably as much as I can say at this point.
Okay. Just one more small one if I can, just because I've been getting this. Can you just confirm that all the data that you've been able to see from this week 36 analysis is unblinded?
Yes. A very small, limited group in order to maintain integrity of the data has looked at this. Remember that we're moving now from looking at the data to actually, to Bill's point, filing a package. We've kept it very small, very limited. Yes, we have seen that data set.
Thank you, Noah. Michelle, if we take a step back, one of the important things that Noah mentioned in his prepared remarks is that the benefit that we saw in this interim around UPCR, that 41% geometric mean ratio between the arms, is higher than what we assumed and powered based on the literature looking at a 30% geometric mean ratio. Again, this is where we believe it exceeded our expectations and gives us confidence that the results are indicative of that longer-term benefit on eGFR.
Okay. Thank you guys so much for taking my questions and congratulations again on these data. They look great.
Thank you, Michelle.
Your next question comes from the line of Laura Chico with Wedbush Securities.
Good morning. Thank you very much for taking the question, and congrats on the readout. My apologies if I missed this from earlier, but just two questions for you. Following DUPLEX, you observed some continuing improvements in proteinuria reductions over time. Could you just help me understand how are you thinking about this dynamic in the PROTECT and IgAN setting? Then I have a quick follow-up.
Noah?
Yeah. I mean, we saw, as you recall, from DUET, from eight weeks to 36 weeks, improvement in proteinuria reductions. I think it's important to point to the mechanism of the drug. The drug has an acute hemodynamic effect. It's nephroprotective, and you see an initial drop. Over time, there are additional anti-apoptotic, anti-inflammatory effects that are associated with that improvement in proteinuria. That's something we're looking for. We're out to 36 weeks. We've reported the data here. As you noted, it's quite robust, the data here. We'll continue to follow these patients out and I think the longer-term data set we'll keep an eye on, but hopefully bears out similar to DUET where we continue to see that progression.
Okay.
I think the one thing, Laura, that I would add is that the data that we've seen at this interim is consistent with what we've seen in how sparsentan performs with proteinuria. You see a rapid and sustained improvement in proteinuria that continues to improve over time. Certainly, this is one look at that 36-week cutoff. We'll continue to evaluate that over time, but we see consistency in the effect in IgAN.
That's very helpful.
To add on there, we have seen long-term improvement, to your point, over time in DUET. We've seen those long-term improvements.
Okay. Just one quick follow-up. We noticed the phase II sparsentan basket study in pediatric glomerular conditions, and I just wanted to double-check. Would today's results serve as a gating factor to moving forward with that study? Just what is the rationale in advancing in a pediatric-focused study? Thanks.
Thank you, Laura. Noah, would you like to take that?
Yeah. The pediatric basket study is actually a requirement. It's a European requirement. We were asked to look at a pediatric population, a broad set of glomerular diseases. We will move forward with that study. We've announced that study is moving forward, and we're extremely excited to bring those patients there and give them the opportunity to have access to sparsentan.
Thanks very much.
Thank you, Laura.
We have no further questions in queue at this time. I would now like to turn the conference back over to Mr. Chris Cline.
Thank you, Deb. Thank you all again for joining us on short notice today to talk about the exciting interim results from PROTECT. This concludes our call. We look forward to speaking with you in the coming months as we provide further updates on our sparsentan program. Have a great rest of the day.