Welcome to the afternoon session of the Bank of America Healthcare Conference. I'm Greg Harrison, one of the biotech analysts here at B of A, and this afternoon we have Travere Therapeutics with us. Representing Travere is Eric Dube, President and Chief Executive Officer, and Peter Heerma, Chief Commercial Officer. Eric's going to start off with a few prepared remarks, and then we'll jump into Q&A.
Great. Well, thank you, Greg, and Bank of America for hosting us. This is an incredibly exciting year for Travere. We have been working on both continuing our commercial presence as well as preparing for what has been early signs of success with approval of FILSPARI in IgA nephropathy, as well as the completion of several phase 3 programs within our pipeline, two of which are with sparsentan, both in FSGS and IgA nephropathy, as well as the potential initiation of a phase 3 with our PEG tibatinase asset later this year in classical homocystinuria. This is a company that's based in San Diego. We're focused on rare disease, and we're a diversified company across commercial and late stage development. Recently, we provided 2 updates.
One is an update on the overall business, including early launch metrics, which I'm sure we'll get into, and Peter Heerma will be able to provide further clarification on. We also provided an update on the completion of the blinded period of our phase 3 DUPLEX study, where unfortunately we did not meet our eGFR endpoint. We did see consistent benefit in the use of sparsentan in an incredibly challenging disease, FSGS. We are continuing to explore options for continuing that program. We also are on track to be able to complete the double blind period of the 2-year PROTECT study in IgA nephropathy later this year.
We remain very confident that the benefit we saw at the interim will be able to, and should predict, a significant benefit on, the two-year EGFR endpoint. Overall, a very busy year. We continue to execute very well on all fronts and, look forward to diving into several of those, in the discussion.
Great. Yeah, that's a great overview. Let's maybe start on the FILSPARI launch. You gave the update with your earnings for the first quarter and 146 new patients added. How should we think about that, the pace of new patients, you know, being added and how to kind of gauge what that could be going forward?
Yeah, maybe I'll just start by saying that we're incredibly pleased with the first part of the launch. What we reported was reflective of the first six weeks of the launch since we were approved in the middle of the quarter. We couldn't be happier with the early start and we'll ask Peter to talk about what really that 146 represents.
Yeah. Thanks, Greg. To Eric's point, very happy with the initial overview of the launch. We announced last week the progress we are making. Initially, we really focused on the 3 fundamentals in generating demand by educating the nephrology community on endothelin on top of, ARB, endothelin receptor antagonist, as well as, angiotensin receptor blockers.
That's an element that is new to nephrologists. That's a core element. We know historically that nephrology is relatively conservative in adopting new therapies and really want to understand the mechanistic approach. That's one of our core angles. In addition to generating demand, we're also focused on making sure there is a path for coverage, focused on making sure that there is payer access.
Initially, when you don't have the inclusion in the formularies, that's mainly through the prior authorization process. We see good success rates there, but what I'm more excited about is even the P&T committee started to discussing FILSPARI, and we see now the first product-specific inclusion in formularies as well. I think that's a second dynamic, fundamental that we are focused on. The third one is really focused on the fulfillment process, making sure that it's not only about demand generation, but also making sure that the patients get product as quickly as possible and having that exquisite first experience both for the patients as well as for the physicians.
Great. Maybe let's follow up on that a little bit. Could you walk us through the process the patient goes through from the time they see the doctor until they actually begin taking FILSPARI?
Yeah. It's what we are seeing right now. Often the question is like, do you see a bolus for patients? That's not the case because, like, it's still basically in most of the nephrology offices, basically a handful of patients that we see as addressable for FILSPARI. They're not being seen on a weekly base, but often at a quarterly base. Physicians go through the certification, the REMS certification process to make sure that once the patient come in, there is no paperwork to be done.
Once the patient comes in, there's the patient start form that is filtered by the nephrologist, as well as by the patient that goes through the laboratory work, and then ultimately goes to the specialty pharmacist that tests that the patients did the lab work and then gets the product, fulfilled.
Okay, great. What feedback are you getting to this point on the REMS process and how physicians are managing it and even just, you know, the general attitude towards, you know, going through the REMS?
Yeah, I think there was a lot of attention initially when we made the announcement that the FDA required the liver monitoring. What we are seeing so far is that for physicians, it's not really an issue, especially within the context of the very robust efficacy profile of 50% reduction in proteinuria. Also, what physicians see as a benign safety profile when they look in context to irbesartan. If you really have the opportunity to talk about the product profile, both efficacy as well as safety, and then you talk about the REMS certification, it's not an issue for the physician. I mean, it's a few minutes. It's an attestation of the nephrologist that he or she has read the label and the prescriber guide.
There's no issue there. In the fulfillment process, I was just talking about it, there is one additional step for the patients to make sure that the lab work is done. I think that whole fulfillment process is much in line with what I have experience with and what you see in rare kidney disease in general, but I think in rare disease overall.
Yeah, agreed. I think the, you know, that issue's been a little bit overblown. One of the things I wanted to ask is, you know, as you build more of a safety database with more and more patients treated, you know, what are the expectations for the future of the REMS, whether it could be removed down the road?
Yeah, that certainly is our expectation. That expectation is based not just on precedent that, you know, within the endothelin class as well as others, that it has been removed with additional data. It's also what FDA shared with us in when they made the decision to include a REMS for liver monitoring, is that, you know, because this is an approval through accelerated approval, that our safety database and our benefit and efficacy database is still evolving. You know, they would evaluate with additional data whether the REMS is needed.
You know, we believe that with the additional data from the DUPLEX study that was just completed, where we see that for, you know, longer duration of 2 years and at double the dose of 800 versus 400 studied in IGAN, we see very similar rates of AST/ALT elevation that we did in IGAN and comparable to active control irbesartan, with no cases of Hy's law or drug-induced liver injury. We're very reassured by what we see in the DUPLEX study. That obviously will be part of the safety database that we would share with FDA, as well as the completion of the PROTECT trial out to 2 years later this year. There will be an evolving database. We do have an open-label extension for both of those trials.
Patients that are on irbesartan will be switched to sparsentan that would allow for even broader exposure. As part of the REMS, we would be able to capture any potential cases that exist in the real world against a denominator of all patients that are exposed to sparsentan in a commercial setting. We will have regular updates to FDA. You know, we can't speak to what the timeline would be for FDA to review and potentially, you know, evolve or remove the liver safety monitoring of the REMS, but that's certainly our plan is to be able to provide that the additional data and request removal if we continue to see what we do. Importantly, any medicine that has an endothelin blockade component will still require a REMS for embryo-fetal toxicity.
That is something that we, you know, have always planned for and expect will continue through the life of sparsentan.
Okay. That's helpful. What other feedback have you received? I know there, you know, aren't a lot of patients that have been on drug so far, but just any feedback you've received from patients or physicians and maybe any anecdotal kind of evidence of the activity of the drug.
Yeah. I happy to do so. I mean, we have the first patients that have received now third shipment, so we have some patients that have been on product for a little bit longer. I mean, it's almost three months ago since we had the approval. You see the first patients coming back in the physician's office right now, and the feedback we have been receiving is really rewarding. I would say very consistent to how it is being characterized in the label, that you have high consistency of effect across different patients, and that consistent 50% reduction in proteinuria, that's what we're hearing from physicians as well, which is really remarkable. I mean, I had one physician I spoke with a few weeks ago, and his literal words were like astonishing.
Astonishing results in a patient, 37-year-old patient that was on the path of rapid progression with a proteinuria level of five grams per gram. Actually he was managed to go back to 1.7 in six weeks' time. Very consistent proteinuria reducing effect and very encouraged and rewarding to see that and hear that feedback from physicians.
Great. That's great to hear. When we think about, you know, the rest of the early launch, what should investors keep in mind, you know, when they're trying to project how it's, how it's progressing, and what metrics do you think are most important to really measure the success of the early launch?
Yeah-
May, maybe I can speak to sort of how we characterize the first year and at a high level, and Peter can speak to, you know, what his team is doing and what we're, what we're measuring. I think, you know, it's really important for us to think about the first part of the launch as laying the foundation. We're not providing guidance on what the first year of the launch would look like, because we do recognize that there are gonna be some consistent dynamics that we need to work through, which Peter can share.
I think importantly, when we look at consensus or we look at the range of what other rare renal launches have done in the first year, we're very comfortable with what those look like to be able to deliver performance at or above those.
Peter?
Yeah. No, I think that's actually what I would say. Like, we're really focused on the fundamentals, which is demand generation through education of the nephrology community. It's making sure that there is a path of payer authorization and inclusion in the formulary. We're making rapid progress as well. The third fundamental is really, like, the pull-through of patients and the whole fulfillment process in getting drug to patients. Those three we are really focused on right now. Once you have that well established, in particular also inclusion in formularies, then I think you will start to see a further uptake.
The metrics that we indicated that we will be periodically announcing reflecting on that as well, like, patient start forms, new patient start forms is reflecting on the demand generation. The coverage amount of lives is with regards to payer access. Then, the revenue is talking about the pull-through, how many patients we have, paid patients we have that are on product. Good development in that aspect. Then I think in addition, it's, it's a little bit beyond your question, but also we have now the first publication in The Lancet that is very well received by the nephrology community. We're included in UpToDate, exactly where we position FILSPARI as well, like right after ACE and ARBs.
We see very good developments that further allows us to continue to accelerate that demand generation as well.
Great. now looking at ex US, what are your expectations in Europe, for example, if approved in IGAN? Maybe just if you could talk us a little bit through your agreement with the partner over there.
Sure. We did decide to partner with CSL Vifor. We believe that they are a leader within the renal space and have the depth of experience both commercially and from a regulatory and HTA/payer perspective. We're really pleased with that partnership. You know, when we look at the addressable population, largely it's a similar size in IgA nephropathy to the addressable population in the U.S. We think that it is a very important opportunity for us to be able to provide a treatment option that fundamentally should become the new foundational therapy, replacing the roles that ACEs and ARBs have played off label for such a long time. You know, the dynamics within Europe are quite different.
Both Peter and I worked in Europe and know that it's not just about getting approval, but it's about getting access through the national and regional HTA bodies. This is a major part of what we've been working on to have a strong evidence base for those dossiers. You know, that's really where the CSL Vifor team will be able to provide, you know, their expertise in navigating those processes. You know, as part of the agreement, they have the commercial rights in that region. We did receive an upfront payment with this partnership of $55 million.
We have additional milestone payments that are tied to regulatory and commercial milestones, up to $135 million, with then a tiered royalty up to 40% on revenues from that region, that start above the royalty obligation that we have to Ligand. We believe that it's a great deal. It's a great team. We have every confidence that they'll be able to navigate success as we expect to have also in the US.
Mm-hmm. Great. Let's move on to the DUPLEX update. Maybe if you could just walk us through the data we saw there and the benefit you saw on proteinuria, and then, the extent to which that translated to eGFR.
Sure. Well, I think if we take a step back to say, what did we see at the interim analysis, which was a primary endpoint for proteinuria? We saw very consistent reduction in proteinuria with sparsentan that we saw in our phase 2 DUET study. What we saw was, you know, a 50% reduction in proteinuria at 36 weeks. The primary endpoint at that time was partial remission, so a very robust measurement of proteinuria control. Importantly, what we now see at the conclusion of the 2 years is that patients were not only able to get their proteinuria down quite substantially at 50% quickly after initiating sparsentan, but they were able to maintain that through the 2 years.
You know, that is a very profound result in the context of a very severe proteinuria and progressive disease. We were very encouraged by that, but more importantly, the investigators and a lot of key thought leaders in the FSGS space were very reassured by the rapid and consistent benefit and the predictable benefit on proteinuria. There are other measures of proteinuria that are even more rigorous and predictive of longer term out-endpoints. The first and/or primary one is complete remission. So we saw 18% of patients on sparsentan achieve complete remission of proteinuria versus 7% on active control irbesartan. When we look at irbesartan, I think the thing that surprised us in this trial was just how well this did.
I mean, in all other trials in this space, they are comparing them to placebo on top of standard of care. This is perhaps a much more rigorous trial design where patients were washed out of their medicines for two weeks and then randomized to sparsentan or active control irbesartan. What we saw is that at that 36-week time point, irbesartan achieved a 30% reduction in proteinuria, which was sustained through the two years. That was quite surprising because when we look at the natural history of these patients, because there are no other trials to rely on, looking at ACE or ARB in FSGS, we do see that these patients progress despite being treated with off-label ACE or ARB or other therapies.
We were surprised to see that patients were able to sustain that. Effectively, what we saw is that the effect size on proteinuria, while we saw a very strong result for sparsentan, it was less than what we had hoped for and power the trial. In FSGS, we believe that proteinuria at 36 weeks does predict or should predict what happens 2 years on eGFR, which is more the longer-term measure of kidney function. At that 2-year period, what we saw was a clinically meaningful difference, a benefit of sparsentan of 0.9, which would be clinically meaningful and likely to translate into about a 3-year delay to end-stage kidney disease. However, it was not significant. We believe that that's likely for 2 reasons. One is that irbesartan performed better.
In fact, you know, the rate of eGFR decline actually was lower than what you see in the natural history of these patients. Also, the variability was far greater. We do know that FSGS is a quite a heterogeneous population with a relapsing and remitting progress. All of that really led to what we believe is a nonsignificant effect on eGFR, which was the primary endpoint at two years. When we look at all of the other measures of efficacy, whether it's proteinuria, eGFR, or hard endpoints like progression to renal death or kidney failure, they all favor and trend in favor of sparsentan. Importantly, we also looked at the safety database, and we were very pleased to see that there was a consistency between the two treatment arms.
You know, it gives us quite a bit to then say, what is the totality of evidence that we need to then go to regulators who have stated that, you know, if we don't achieve a significant endpoint or difference on the eGFR endpoint, that they could evaluate the totality of the data in recognition of just how difficult this disease is to study.
Mm-hmm.
A long answer, but I think.
Sure.
you know, hopefully a good overview of what we've seen. There's a lot more work that we need to do. I mean, when we think about the heterogeneity of FSGS, subgroup analyses are gonna be particularly important here. We wanna make sure that we can help in understanding who might be benefiting. A bit more work for us to do, but we wanna quickly go to FDA and understand how they think about it and whether there is a regulatory pathway. We should be in a position, hopefully to do that by the end of this summer.
Okay, great. Just one quick follow-up on that, and that's, you know, when you think about the unmet need there in FSGS and the strong trends in favor of sparsentan that you saw, you know, what are the potential paths forward in terms of, you know, evaluating the totality of the data versus would you be willing to, you know, generate additional clinical data?
Sure. Well, I would say, you know, first, this is the only phase 3 trial ever to be done and completed in FSGS. It's an incredibly difficult study to and a type of trial to enroll and to study. And we've seen, unfortunately, a number of other companies abandon their programs in FSGS, I think, because of the difficulties in this. We do see this as an incredibly important database to be able to understand of the disease. You know, the early feedback that we're getting from experts in the field is that we do need to move forward in understanding the totality of evidence-
Mm-hmm.
because you are seeing a very consistent benefit with sparsentan on proteinuria. The question is: Is eGFR the right measure of confirmatory evidence long term? We don't know that. We need to continue to explore that, but that really is now the question that's beginning to emerge. That's very different than what we see in IgA nephropathy, where there is a consistent predictive value of proteinuria to longer-term eGFR and renal outcomes. I think we've got to continue to ask our questions about the disease as well as the benefit risk of sparsentan. Again, we wanna move very quickly. We wanna provide the certainty of what this means for this patient community. Again, we'll hope to do that, you know, by the end of summer, early fall.
In the meantime, we'll look to complete the IGAN study and obviously continue the strong execution of the FILSPARI launch.
Great. Yeah, that brings us to the next point, which is you'll have the update from the PROTECT trial in 4Q-
Mm-hmm.
where you'll be looking at eGFR in IGAN patients. Could you help us set some expectations there, for what that data could or should look like, and what would be successful?
Sure. I think, you know, the trial is designed to be able to first show a superiority in the reduction of proteinuria at 36 weeks. What we saw was a 50% reduction, strikingly consistent to what we saw in FSGS phase 2, phase 3. The treatment effect versus active control irbesartan was even greater. I mentioned in DUPLEX that at 36 weeks, irbesartan reduced proteinuria by 30%. In the IGAN PROTECT study, it reduced it by only 15%. The effect size on proteinuria is far greater in IGAN.
The other important aspect of that 36-week proteinuria is that there's a meta-analysis of about 13 clinical trials in IgA nephropathy, really, you know, to look at what is the predictive value of a reduction in or a treatment effect on proteinuria to a 2-year eGFR endpoint. A much more robust literature upon which to rely compared to FSGS. When we look at that, we actually powered and designed the trial to show a low single-digit difference in eGFR slope at the end of 2 years. That would, we believe, based on the 41% treatment effect at 36 weeks that we observed, is greater than what we powered the study on, which was a 30% treatment effect.
We believe that we're in very good position to be able to then demonstrate, that two-year eGFR. There are some important differences between our FSGS trial and our PROTECT trial that we believe there's very limited read-through in what we saw at DUPLEX, which was a nonsignificant difference...
Mm-hmm
on eGFR. We believe that those do not apply based on trial design and population differences. We remain very confident in being able to demonstrate that. If we show a low single-digit significant difference, one, it allows us to go to FDA for full approval. It also would then be, you know, a very important, you know, database on safety and efficacy to be able to hopefully expand the indication and be able to, you know, reach more patients with a therapy that is superior to, you know, how patients are currently treated with off-label ACE and ARBs.
Great. Now, if the data are positive for PROTECT, you know, how does that help accelerate the launch in IgAN?
Peter?
Certainly we'll build further confidence in the marketplace and we'll further expand our prescriber base as well. I think it's really almost like a rolling launch. I was talking about earlier the publication that we recently had, you know, UpToDate, where you have the inclusion of FILSPARI, the full data set of PROTECT will help there. You have the KDIGO guidelines that are likely to be updated by the end of the year. I think all those data points further confirms the confidence of the profile and also further expands the prescriber base. It certainly will help.
I have to say what I'm seeing so far is that based on the robust and strong magnitude of proteinuria-lowering effect of FILSPARI, I haven't heard physicians that say like, "Well, I'm waiting for that data." That may also have to do with the targeting and segmentation that we did. We are very focused on the patient, the physician population that are more eager to adopt innovation, but it will certainly help in the broadening the prescriber base.
I think maybe, Greg, if I can add one more thing to what Peter's outlined, is, you know, we will have a robust data set that allows us to really leverage this 2-year lead time that we have in our launch compared to anything else that might be coming to the IgA nephropathy market. It's really important that we continue to stay ahead of what may be other medicines and other classes that come to this community, and we think that it's gonna be very important for us to take advantage of this 2 years to establish FILSPARI as the new foundational therapy, given the robust and consistent profile that we've seen to date.
Yeah. That's helpful. Well, a couple minutes left. Wanted to make sure and touch on the pegtibatinase program. We're expecting an update there later this year. What's clinically meaningful there when we're trying to interpret this data? What are the next steps in development for the program?
Sure. Well, we're really excited about our pegtibatinase program. This is a PEGylated enzyme replacement therapy for classical homocystinuria. This is a genetic metabolic disorder where patients really are not able to consume protein other than medical protein. So very challenging and can lead to thrombotic events in, you know, or adolescence and early adulthood, up to 50% by the time patients are in their 20s. A high unmet need. We believe that pegtibatinase could potentially be the first and the only disease-modifying therapy in HCU. Really for success coming out of our phase 2 program and our Cohort 6 at the highest dose we're studying really would be incremental efficacy and a consistent tolerability and safety profile compared to what we showed at Cohort 5.
In Cohort 5, we were able to demonstrate that within two weeks, patients were able to get all patients on pegtibatinase were able to get below the threshold of 100 micromolar of total homocysteine. That's important because that's the threshold recognized in the literature that would help in substantially reducing the risk of some of these symptoms and complications. What we would be looking for in our Cohort 6 is even further reduction in homocysteine levels so that we are able to then test the ability for what patients want most, is to actually liberalize their diet, to be able to, even just one day a week, eat a normal diet with their family, with their friends.
While we do absolutely need to stay focused on reducing some of the clinical outcomes in homocystinuria, we do really wanna make sure that we're delivering on the number 1 need that we hear from patients consistently. That incremental efficacy it would allow us the ability to explore that potential.
Great. Well, with that, our time's about up. I'd like to thank you, Eric and Peter for joining us today, and thank you everyone out there for listening.
Great.
Thanks, Greg.