Hello everyone. My name is Farzin Haque, one of the biotech analysts at Jefferies in the Moor River Crops team. I'm happy to introduce Eric Dube, CEO of Travere Therapeutics. This is a fireside chat format. Thank you for joining us today, Eric.
Farzin and Jefferies, thanks so much for hosting us.
For those who are new to the story, can you provide a one-minute overview of your programs and strategic focus?
Yes. Travere Therapeutics is focused on rare disease, and our focus currently is providing hope to three rare disease communities by really transforming and upgrading the standards of care. We are in the midst of a launch of FILSPARI in IgA nephropathy with the aim to become the new foundational therapy within that disease. We also have a file with FDA for FSGS, another rare kidney disease, with a PDUFA date of January 13th of next year. We also have a program that is in phase 3 for classical homocystinuria, or HCU. We're currently working through manufacturing scale-up and will be initiating our enrollment in that phase three next year.
Great intro. Let's start with the FSGS, and that's what the investor focus is at. Your supplemental NDA was accepted, and you have a big update scheduled with an adcom planned. Since the NDA acceptance and the adcom request, have you gotten any additional insights from the FDA on why the adcom was requested and what the adcom is intended to discuss?
We have not heard specifically the rationale that FDA has for hosting an advisory committee. In the acceptance of our SNDA for FSGS, they indicated that they are currently planning for an advisory committee. We can only surmise that as FDA typically will call advisory committees where there are questions around the endpoint, questions around the clinical trial when an endpoint is not met, or around the safety and benefit risk of a therapy. Now, we are in a rather unique position where there was an independent public-private initiative called Parasol that worked to evaluate what the best endpoints in FSGS was, given the heterogeneity in this disease. What that group reported out last fall was that eGFR was not feasible for FSGS given the heterogeneity of this disease. It would be very difficult to power and to have a phase three program within two years.
What they did find is that levels of proteinuria independently predict a patient's risk over time of reaching kidney failure. Even though our phase three, which is the only phase three ever to be completed with an FSGS, was designed with eGFR as the primary endpoint for approval, we now know that that would be infeasible. We do have a very robust data set with proteinuria demonstrating a positive treatment benefit versus an active control, irbesartan, in that trial. We imagine that the advisory committee will be focused on the evidence to support proteinuria, but importantly, looking at the evidence specifically with FILSPARI, because this Parasol group was looking at registry data. We did not submit our phase three data to Parasol because we wanted to retain the independence of that analysis and the independent validity within our phase three program.
We look forward to, and we will be very well prepared for that advisory committee.
Great. Just curious, have there been any personal changes in FDA's cardiorenal division handling your application?
We're not aware of any changes within personnel of cardiorenal specifically. We certainly see the same headlines around FDA staffing changes that many of you see. Importantly, the lead reviewer and the Division Director, Aliza Thompson, is with the FDA. In fact, she recently became the Division Director, whereas previously she was the Deputy Director. We can't foresee what will happen in the future, but we are very pleased with the continuity of our reviewer staff over the years.
Got it. The Parasol, as you mentioned, it's just a clear framework for using the proteinuria as an endpoint to support full approval in FSGS. Based on the recent interactions or other actions you have seen from FDA make recently support, what is the direction they're really heading into?
I think, you know, as I mentioned in the first part, Parasol really was designed to better understand what are the endpoints for clinical trials and for regulatory purposes in FSGS that ultimately predict a patient's risk of kidney failure. It's really difficult within a rare disease to be able to power for hard outcomes like kidney failure. What we've seen from Parasol and FDA was part of Parasol is that proteinuria can in fact predict longer-term risk of kidney failure. In fact, for patients that are able to get below certain thresholds of proteinuria, which are consistent also with our phase three pre-specified criteria for proteinuria control, patients are able to reduce their risk of kidney failure over eight years by 85%-94%. It really is a profound independent predictor.
That was what we believe led to the recommendation of the Parasol group that proteinuria can be used as a validated surrogate endpoint for approval. We have been very encouraged that the FDA provided consistent feedback to another sponsor with a phase three in FSGS that proteinuria can be used for full approval. Certainly, we look forward to the ongoing review of our program.
Got it. For the adcom coming up, has FDA given you any guidance yet, and can you book in potential discussion topics?
FDA has not provided us guidance specifically. We expect that we'll learn more throughout the review of our SNDA. Typically, we'll learn more about an adcom, whether it's scheduled, when it's scheduled, et cetera, later in the review. What I can say right now is twofold. One is the review of our SNDA is going along according to our expectations, and it's very consistent in terms of the types of questions that we received when we had a file under review for the same medicine for IgA nephropathy.
We can also surmise from our type C meeting where we discussed the submission of this SNDA, where FDA said they recognize now that, you know, with the use of proteinuria and the recommendations from Parasol, that we can submit an SNDA for this indication, and that their review will likely focus on understanding our phase three results in the context of Parasol. Since that meeting, we have presented data, most recently at the NKF meeting in April, from our phase three program showing that patients who are able to achieve partial and complete remission have differential levels of kidney failure. If you're able to achieve those levels of proteinuria control, you have much lower levels of kidney failure within a two-year period of our clinical trial.
We also have demonstrated and published within the New England Journal of Medicine the fact that patients consistently across all of these thresholds of proteinuria control, patients on sparsentan are able to achieve far greater rates than active control max dose irbesartan. A very consistent result within our trial and results consistent with Parasol. We do look forward to those discussions, and we expect that that could be an area of focus for the advisory committee.
Got it. EMA has been less involved in the Parasol project. How does that shape your view on the EU regulatory path with CSL Vifor partner?
Sure. The EMA has been involved in Parasol. They were part, not to the same degree as FDA. The approach to changing or defining endpoints is different between FDA and EMA. With that said, we have confidence that EMA is considering what this looks like, given the significant unmet need within FSGS. Certainly, our partners at CSL Vifor are actively engaged in helping to find a pathway with EMA.
Just clarifying, the seven-year market exclusivity for orphan drug, should that trigger upon approval, and this would provide exclusivity into 2033?
That's right. We expect, given that we have orphan drug designation for FSGS, that we would get a term of exclusivity that runs in parallel, and that would be seven years from approval. Assuming approval in January of next year, excuse me, that would get us into 2033. We also expect to receive a six-month pediatric exclusivity that would extend beyond that.
Okay. What are your base case assumptions for what the FSGS market opportunity would look like? What do you expect the FILSPARI label to look like for FSGS in that context?
If we think about the opportunity, I think it's important to keep in mind what these patients face. The average patient with FSGS will face kidney failure within five to ten years. These patients oftentimes have degrees of proteinuria that are higher than any of the other rare kidney diseases, higher than chronic kidney disease, and is so severe that oftentimes they have symptoms of edema, facial edema, et cetera. This is really a significant burden for the patients, for their family, and for the health system. There's nothing that is approved for these patients. What's worse is, given the heterogeneity of this patient population, most of these patients do not respond to the most commonly used therapies, immunosuppressants like steroids and tacrolimus. There is a desperate need for something that treats the underlying condition within the kidney.
What we see with FILSPARI is a consistent benefit in reducing proteinuria of around 50%, and the only medicine that we've seen in a clinical trial to get these patients into complete remission. When we look at what the opportunity is, it's really to address and become the new foundational therapy by directly addressing the overactivation of angiotensin and endothelin. When we look at patients with primary and genetic FSGS, there are over 30,000 of these patients within the U.S. that are under the care of a nephrologist that are diagnosed and that are not already in dialysis or in kidney failure. This represents a significant opportunity for us to really change the lives and the outlook for these patients. We believe that, based on the feedback we've received from nephrologists and from market research that we've done, there will be a very rapid uptake.
That is based not only on the unmet need, but also in the high recognition that these patients need to lower their proteinuria. This is different than IgA nephropathy, where nephrologists are trained historically that IgA nephropathy is a slowly progressing disease that represents a low risk of kidney failure within a patient's lifetime. It is clearly not the case, and it is certainly not the case with FSGS. We expect there to be rapid uptake. There also are no therapies on the near-term horizon for other treatment options. FILSPARI could be the only therapy that is available for these patients for a number of years. At double the target dose for adult patients, this represents a significant opportunity for us to transform not only the community, but also for us to transform Travere.
With regard to, I think you asked about the indication statement, our planning assumption is similar to what we have indicated for IgA nephropathy. It's for the treatment of IgA nephropathy. We would expect that to be similar. That would allow us to reach those 30,000 plus patients. We believe that that addressable population will increase over time as there's greater recognition and greater incentive to biopsy patients earlier, which is currently the standard way of diagnosing FSGS.
Of the 30,000 patients, all of them are biopsy-proven?
The majority of them are biopsy-proven. When we did our analysis of estimating the addressable number of patients, we looked at biopsy confirmed, which is the standard. There is an increased awareness and use of genetic testing, but that's still very early, and that still represents a small proportion and the smallest proportion of FSGS. While there may be an increase, we believe that biopsies will still be the standard by which these patients will be diagnosed.
Got it. Okay, switching gears a bit to the FILSPARI launch in IgA. The PSF growth was sustained going from Q4- Q1 for the last two quarters. How are you setting commercial expectations heading into the second half of this year with regards to PSFs as well as persistency?
Sure. We are very pleased with the uptake, particularly the increased demand since we received full approval in September. Over the last two quarters, we exceeded around 700 new patient start forms per quarter. Our Chief Commercial Officer, Peter, indicated that that should be the new baseline as we move forward. Certainly, there are a number of new treatment options that are or will become available, but we believe that the unique clinical profile and positioning of FILSPARI will allow us to compete very effectively as we continue to reach more patients. The important aspect of our FILSPARI business is that the compliance and persistence rate is and continues to be very high. That average number of 700 patient start forms that we've seen over the last two quarters is added on to a very solid base of patients that continue to retain their therapy.
We expect that the revenue growth will continue. Our goal is to continue to reach more patients and continue to increase the breadth and depth of prescribing by nephrologists because the overwhelming majority of patients with IgA nephropathy, 90% of them are on an ACE or an ARB and are not at the goal of proteinuria. These patients continue to progress and continue to be at risk. We really are offering something better with upgrading their ACE or ARB to FILSPARI.
Got it. A little bit more on the commercial dynamics. What do you expect with the Novartis atrasentan and Venrafia market entry? That is coming in without REMS, but has a more limited UPCL label.
Yeah, so we are very confident in the clinical profile of FILSPARI. Not only do we have full approval across the broad indication of IgA nephropathy, whereas atrasentan under accelerated approval is limited to those patients at greatest risk of 1.5 grams of protein and above, we also have two-year data. That two-year data reflects not only a sustained reduction in proteinuria, it reflects a differential rate of achieving complete remission of proteinuria, as well as an accumulation of benefit of eGFR the longer a patient is on therapy. The clinical profile really reflects what nephrologists are looking for in the treatment of a kidney-directed therapy, a foundational therapy like FILSPARI. We certainly are expecting that Novartis will continue to grow the endothelin class by reaching more patients. We expect they will have an uptake.
We're very pleased that we have another therapy that's talking about the importance of not just angiotensin blockade, but endothelin blockade. We believe that that's going to continue to drive with our efforts the growth of a far better foundational therapy than patients have historically been treated. With regard to the REMS, they did launch with no REMS. We've not seen the REMS be a barrier. We have had the greatest uptake of a rare kidney launch over the last five years, and that is with a REMS. We also have a PDUFA date coming up in August to modify the REMS from monthly testing to quarterly testing. We also will have our pregnancy testing REMS removed. We believe that that will become much easier for patients and will level the playing field in many ways.
Importantly, the dynamic we expect to see with atrasentan is a continued expansion of the endothelin class, and we certainly will continue to grow our business along with them.
What about the degree of Tarpeyo and Fabhalta use you're seeing in real-world prescribing pattern?
I think with Tarpeyo and with Fabhalta, those represent a very different part of the treatment algorithm. The global guidelines, the KDIGO guidelines for IgA nephropathy, very clearly spell out that patients with proteinuria should have combination therapy. They should have therapy that directly addresses the damage in the kidney. That is where FILSPARI, where SGLT2s fit in. With our head-to-head data showing superiority over RAS inhibitors, we believe, and we are very confident in our ability to become the new foundational therapy along with SGLT2 combination. In fact, this month, at the ERA meeting, we are presenting data on combination of FILSPARI plus SGLT2s demonstrating an additive benefit and a clear safety profile that should continue to support that being the new foundational therapy moving forward.
The KDIGO guidelines on the second part of the treatment algorithm talk about needing to address the overactivation of the immune system within IgA nephropathy. That's where Tarpeyo and steroids and Fabhalta fit in. What we've seen to date is that those therapies are largely focused on more severe patients. We've seen them be used in combination with FILSPARI, and we don't see them as competitors. We see them as complementary, and that's certainly how physicians see them, but certainly reserved more to higher proteinuria level patients.
Got it. Since you have the full approval label, how many of the payer policies have updated since then? Do you expect the payer policies to look similar or different between FILSPARI and atrasentan?
Yeah, we've been very pleased with our payer access. Since full approval in September, it's only gotten better, particularly with regard to either removing or lowering the proteinuria thresholds for a physician to prescribe. We see a very broad access that is continuing to improve. It's very early for us to look at the atrasentan approvals. What I would say is that we would expect over time that they're going to look similar. Many of them will likely limit the access given the accelerated approval and the limited indication.
Okay. On the REMS, you mentioned briefly, you submitted the additional data to the FDA. What is your latest thought on whether they could potentially remove it completely given that atrasentan did not get REMS?
Yeah, so our plan all along since approval in February 2023 was ultimately to remove the REMS. We've discussed that with FDA, and our approach has been a two-step approach, which we believe allows for the fastest, most efficient access for patients. The first would be, as we've submitted the SNDA, to modify the REMS from monthly testing in the first year to quarterly. We do believe that there is an opportunity to fully remove. That may happen this time, or it may happen later. We've said that we'll take every opportunity, but that was not the original request of this SNDA, but certainly we'll take that opportunity to have that discussion. We are confident that we will have this shift to quarterly given the increased exposure that we've had since the submission and that we still have no cases of drug-induced liver injury, no cases of DILI.
Based on the increased exposure, we've been able to rule out one case of DILI in 1,000, which is an important threshold. We will continue to provide FDA with those safety updates. If ultimately it's not removed now, our plan was to go back with a second step with broader exposure and ultimately get this removed.
Makes sense. There's obviously a lot of data coming up in the near term in the IgA treatment paradigm. How do you see the competitive field developing as well as FILSPARI will play a role in the near and longer term?
Yeah, I think within the broader rare kidney disease, which has suffered historically from very little innovation, it is an incredibly exciting time with an IgA nephropathy. We can foresee within five years that the majority of patients will never have to face kidney failure because of the increased innovation and the treatment options that are there. If we think about what the KDIGO guidelines recommend and our understanding of this disease, a patient should be on therapy that is nephroprotective and directly targets the kidney. The best option that we've seen based on the clinical data is a combination of FILSPARI and SGLT2s. With regard to addressing the immune system, the data that we've seen recently from the April Bliss or B-cell targeted therapies are really exciting and very aligned with our expectations that we've had over time.
We expect that they're going to replace the role traditionally that steroids have played and will be used likely chronically for these patients, but only in combination with a foundational targeted kidney-targeted therapy. In fact, all of those trials looking at immune-targeted and B-cell therapies are on top of kidney-directed therapies. We do not see them as competitive. They are very aligned with the KDIGO guidelines saying that patients with proteinuria should be treated with a combination.
Yeah, I agree on the combo aspect, but the payer policies maybe will push back on the prohibitive cost of combining the two drugs.
I think we still need to see how those therapies are priced, and we need to see what the longer-term benefit and risk is. That's how payers will typically make these decisions. What we can speak to is our access and our pricing and our benefits. When we engage with payers, we're very confident going in and saying that we have head-to-head data showing superiority over the other treatment option of a kidney-directed therapy, which is ACE inhibitor and ARB. We also have two studies demonstrating additive benefits when you combine with an SGLT2. I can't speak for companies that have immune-targeted therapies, but we do know that those that are available can and are being used on top of FILSPARI, and that's something that they'll need to discuss with the payers.
I think this is another aspect of having the lead time that we have, being able to demonstrate the benefits and talking about the long-term two-year data on eGFR, particularly superior to active control, whereas it's going to be some time for any of those companies to have eGFR data long-term to be able to discuss with payers.
Makes sense. Are there any other FILSPARI clinical or potential ex-U.S. regulatory updates that we should be aware of, either for FSGS or IgA in the next 6-12 months?
Yeah, so we've been very pleased with the progress within Europe. Our partner CSL Vifor and Travere have been able to convert approval in Europe and the U.K. to full approval in IgA nephropathy. CSL Vifor has launched in a number of countries, and we've been very pleased with the uptake thus far. We expect that that will continue, and patients in Europe will be able to receive FILSPARI in more countries over time. We also expect data from a pivotal trial from our partner Renalis that is developing FILSPARI within Japan and parts of Asia-Pacific in the second half of this year. We are on track in being able to help provide FILSPARI to patients globally in the years to come.
How big is the market opportunity in Japan?
In Japan, the estimates are continuing to be refined. It is not a rare disease in Japan. It is much more common in many parts of Asia. We can certainly provide updates on that as we move forward and as our team and Renalis refines their estimates for launch.
We have four minutes left. For the HCU program, do you have any updates on the expected timeline to restart the enrollment?
We are on track with our pegtibatinase program to initiate enrollment next year. We have made very good progress, and we are exactly where we would hope to be this year.
Looking ahead, can you talk more on the pipeline expansion and BD opportunities this year?
Yeah, so we certainly would like to expand our pipeline, and our focus will continue to be in rare disease with a particular focus in rare renal disease. We believe that we have quite a bit of expertise and experience in clinical development and in working with regulators and in commercial launch. We're going to continue to be very disciplined. As you can imagine, with a PDUFA date in January and an advisory committee and a continued launch, our primary focus is there, but in parallel, we'll continue to survey the landscape.
What is your cash position and runway assumptions? Kyle, key updates that we should be looking forward to.
Our cash position at the end of Q1 was $322 million, and we expect this quarter to receive a $17.5 million milestone payment for the full approval in Europe from CSL Vifor, as well as future milestone payments later this year for market access and commercial milestones. That, along with our growing revenues from our launch, we expect to be in a very good position. We've guided that our cash runway is into 2028 and beyond. With regard to catalysts for the rest of the year, certainly the continued uptake of the FILSPARI launch and IgA Nephropathy will be important from a quarterly standpoint.
The REMS modification, PDUFA on April 28, as well as the advisory committee, which is yet to be scheduled, but certainly will be very important as we prepare for the potential approval and launch in FSGS, and then ultimately being able to reach the HCU community by reinitiating the phase three enrollment sometime next year.
Thank you, Eric.
Okay. Thank you very much.