Good day, and welcome to the Travere Therapeutics corporate update call. Today's call is being recorded. At this time, I would like to turn the conference call over to Nivi Nehra, Vice President of Corporate Communications and Investor Relations. Please go ahead, Nivi.
Thank you, Rachel. Good afternoon, and thank you all for joining us today. Earlier today, we announced a corporate update related to the enrollment of our phase III HARMONY study. A copy of the press release can be found on our corporate website. Today's call will be led by our President and Chief Executive Officer, Dr. Eric Dube. Eric will be joined by Dr. Bill Rote, Senior Vice President of Research and Development, and Chris Klein, our Chief Financial Officer. 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 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, September twenty-sixth, twenty twenty-four, 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, Nivi, and good afternoon, everyone. Earlier today, we announced the company's decision to voluntarily pause enrollment in the phase III HARMONY study, evaluating pegtibatinase for the treatment of classical HCU. This is a decision the company chose in order to address process improvements in our manufacturing scale-up to support full enrollment in the phase III HARMONY study and future commercial access. The development of biologics is complex, and the process of manufacturing scale-up is not always straightforward. As you might imagine, we're going to be limited on details today, given the need to finalize next steps. As you will hear from Bill, we have an excellent team and outside partners that I am confident will resolve this scale-up challenge, but understandably, it will take some time for us to complete the necessary process improvements and restart enrollment. Most importantly, our confidence in pegtibatinase is unchanged.
All of the positive safety and efficacy data from the phase I/II COMPOSE study and the clinical profile to date that underscore the potential for pegtibatinase to become the only disease-modifying therapy for HCU remain. We know that the HCU community is hoping for a better treatment regimen, and our team remains committed to moving as quickly as possible. I'll now ask Bill to share additional specifics and next steps. Bill?
Thank you, Eric, and good afternoon, everyone. As we have previously communicated, and as agreed with the FDA, we initiated enrollment in the Harmony study using smaller-scale batches of the study medication, with the plans to transition and expand enrollment upon successful manufacturing at the commercial scale. This practice is common in rare disease development, where time matters. While we have made progress overall in scale up, including meeting specifications along the way, we have concluded from our latest work that more process improvement needs to be done. Specifically, following a comprehensive analysis of material made under our current commercial scale process, earlier this week, an internal Travere committee, with input from external experts, evaluated the available scale-up data to determine suitability to supply clinical material for additional enrollment in the phase III Harmony study.
Based on this evaluation, we determined that the desired drug substance profile was not achieved with the current scale-up process. As a result, the decision was made to voluntarily pause enrollment in the phase III HARMONY study while we address process improvements in our manufacturing scale-up. To date, all patients in the pegtibatinase studies have been receiving study medication manufactured at a smaller scale, which is unaffected by the scale-up process and will be able to stay on medication for the duration of the trials that they are participating in.
You'll recall that we initiated the phase III HARMONY study in December of last year, following the positive safety and efficacy data from the phase I/II COMPOSE study, which demonstrated a rapid and sustained 67.1% mean relative reduction in total homocysteine from baseline at 12 weeks of treatment in patients treated at the 2.5 mg per kg dose. Due to small batch supply constraints, ensuring continuity of supply for patients, and needing to use commercial scale product for enrollment in the pivotal HARMONY study, we are unable to continue enrollment of new patients in our studies while we institute our process improvements. Timing for restarting enrollment will depend on how quickly we can complete our process improvements and validation, and we'll need to take into account the finite CDMO capacity.
Our best estimate is that the earliest we would be able to restart enrollment would be in 2026. As you might imagine, our focus right now is with our CDMO partners, who have deep experience with working through challenges in manufacturing scale-up to improve our process. Based upon what we know today, we are confident that we will be able to optimize our process and ultimately be in a position to deliver pegtibatinase as the first disease-modifying therapy for HCU. Let me now turn the call over to Chris to briefly discuss the financial implications of this update. Chris?
Thank you, Bill, and good afternoon, all. From a financial perspective, we expect that today's update will result in a decline in expected operating cash use next year, as some of the pegtibatinase-related expenses shift beyond 2025. As you would expect, we had planned for a meaningful increase in R&D-related expenses for pegtibatinase, with further enrollment in the HARMONY study, including additional sites opening and more patients enrolling globally, as well as investing in large-scale production to prepare for commercial supply and further enrollment in HARMONY. This additional investment in the pegtibatinase program was expected to have been partially offset by sparsentan R&D investments winding down as our two phase III programs progress towards completion.
With the pause in enrollment, the time to complete process improvements, and a continuing decline in R&D investments for sparsentan, we now estimate that our recurring research and development expenses in 2025 may be reduced by more than $30 million compared to 2024. This will result in further decline in near-term expected operating cash use, and we continue to expect that our cash balance, totaling approximately $325 million at the end of the second quarter, can support operations into 2028. Let me now turn the call over to Eric for his closing remarks. Eric?
Thank you, Chris. We believe the potential for pegtibatinase to become the first disease-modifying therapy for classical HCU remains unchanged. Our commitment, first and foremost, is to the HCU community and the patients in our study. As Bill mentioned, the patients currently receiving study medication using the smaller scale batches can continue to stay on study medication for the duration of the trials they are participating in. Looking forward, we are confident that we will be able to work closely with our manufacturing partners to institute the necessary process improvements to supply pegtibatinase for commercial use and restart enrollment in the pivotal HARMONY study. We are undeterred in our goal to deliver pegtibatinase to people living with HCU and will provide an update once we've completed our process improvements.
Independently, we continue to be very pleased with the progress of the FILSPARI launch, including the full approval of IgAN earlier this month, and we will look forward to furthering our efforts to potentially enable a pathway for sparsentan in FSGS. Now, let me turn the call over to Nivi for Q&A. Nivi?
Thank you, Eric. Operator, we can now open up the line for Q&A.
Thank you. If you are dialed in via the telephone and would like to ask a question, please signal by pressing star one on your telephone keypad. If you are using a speakerphone, please make sure your mute function is turned off to allow your signal to reach our equipment. As a reminder, we ask that you limit yourself to one question. If you have another question, please rejoin the queue. We will now take the first question from the line of Anupam Rama from JP Morgan. Anupam Rama, your line is open.
Hey, guys.
[crosstalk] Hey, guys.
Thanks so much for taking the question. How do you guys plan on staying engaged with the sort of HCU patient and physician community while you're working on this manufacturing scale-up? I'm just trying to understand what enrollment dynamics could look like, you know, upon initiation, and how do you maximize that, this curve in this time period where you're working on manufacturing? Thanks so much.
Yes, Anupam, thanks for the question. So what I can say is that earlier today, we engaged with leaders within the HCU community to make sure that they understood the situation. Like us, they remain very committed to this study and this program and are optimistic about the ultimate potential for pegtibatinase to be available more broadly.
And what I can say is that the engagement in the clinical trials has been very aligned with our expectations. We've been very pleased with how the study's been conducted. And, you know, as we have raised awareness around our HARMONY study and pegtibatinase more broadly, I've been really pleased with the number of patients that have raised their hand to want to be part of this study. So as we work through this and we are able to re-enroll, we will actually have a number of patients that are ready to make sure that they can enroll. So we would expect to go very quickly once we reinitiate. And, you know, we'll look to move as quickly as possible to get to that point.
Thanks so much for taking our question.
Your next question comes from the line of Carter Gould with Barclays. Carter Gould, your line is open.
Hello, this is Maya on for Carter, and I just wanted to ask if you expect the profile of pegtibatinase to change at all with the process improvement? If you could comment on that, that would be helpful. Thank you.
Yeah, Maya, thank you very much for the question. I, I think the shorter answer is no. Bill, you can talk a little bit more about what this means and what it doesn't mean, but fundamentally, the strong efficacy profile that Bill alluded to in his opening comments remains the same. Bill, do you want to comment further?
Yeah. I think that, you know, at a higher level, the objective for any scale-up is to make the same material at the large scale that you made at the small scale, and that's assessed analytically. Once we've made the process improvements, those evaluations will be, and that's part of the gating element of what it takes to get back into the clinic. So I don't expect to see any change, nor should we see any change in the profile clinically, either on the safety side or the efficacy side, with the larger scale material.
Okay, thank you.
Your next question comes from the line of Joseph Schwartz with Leerink Partners. Joseph Schwartz, your line is open.
Hi, thanks very much. I was just wondering if you could give us any insight into the aspects of the product which you aren't satisfied with, and whether you have an idea about what might need to be changed, and how long the list of potential options to make process improvements that you suspect could solve the issue or issues might be? That would be helpful, and how long will each process change and testing for each process change take place relative to that, you know, the new guidance that you have for starting again sometime in 2026 ? Just trying to understand, if we can, more fundamentally, what's actually going on here.
Yeah, Joe, thanks for the question. I'll hand it over to Bill. What I can say at a high level is this is a narrow list of elements that we want to improve, and we are very confident that we've got the expertise and understanding to be able to do so. I'll ask Bill to provide a bit more detail on why we remain, you know, confident and clear on that.
Yeah. Yeah. Thanks, Joe, for the question. With the scale-up process, we're consistently in looking at all the analytical parameters that we can measure, to evaluate the process and the material that's output. So you're looking at in-process specifications, process controls, and an initial and additional analyses that are beyond the specification. You really want to be able to evaluate the consistency and the robustness of the process. I won't go into specific details today, but we understand, looking at the information across multiple manufacturing runs, where the challenges lie. We also have, thoughts on how we're going to improve that and working with our internal team, expert consultants, as well as the individuals and the teams at the CDMOs, who have had experience with precisely these types of issues.
We're confident that we'll be able to sort this out and get back with material that matches our needs and our expectations, and additionally, matches to the small scale process material and get back into the clinic.
It's very helpful. Thank you for the call.
Mm-hmm.
Your next question comes from the line of Liisa Bayko with Evercore ISI. Your line is open, Liisa Bayko.
Hi. Thanks for taking the question. Hopefully, you can hear me properly. It's a little fuzzy on my end.
We can hear you clearly. Thanks, Liisa.
Okay. Okay, great. Must be my phone. I was curious about how many patients you've enrolled so far in HARMONY, and will those patients be able to roll over into the ENSEMBLE portion of the Phase III study?
Bill, do you wanna take that?
Sure. We don't disclose specific enrollment data for our clinical studies until we reach key milestones, but enrollment, I can tell you, has been aligned with our expectations to date, and we've been pleased with the conduct of the study as well. With respect to the rollover, the short answer is yes. The patients that are currently in HARMONY, in that study, will have the option to roll over into ENSEMBLE when they complete the blinded portion of HARMONY. Additionally, we're in the process of completing the transitions of patients from the COMPOSE open label study also into ENSEMBLE as well. And so all the patients that are currently in our studies will be given the option to stay on study medication for the duration of the trials, and we'll be able to continue collecting those data.
Yeah. And importantly, those data will be important for the BLA. So I think it's important, first and foremost, that the patients have continuity of medicine, and that they can have the ability to complete the trials, and fundamentally, to be able to utilize those data to ensure a very strong regulatory package.
Okay, and then, how many CDMOs are you using?
Bill?
So we, we don't disclose the specifics on our CDMOs, but suffice to say, they're some of the best in the industry, and we are managing with more than one to help enhance our ability to manufacture and to improve just overall capacity.
Okay. Thank you.
Mm-hmm.
Thank you. Your next question comes from the line of Tyler Van Buren with TD Cowen. Tyler Van Buren, your line is open.
Thanks for taking our question. This is Nick on for Tyler. Just a quick one from me, but given the delayed enrollment, how does this change expectations on when the data will be released? And would you anticipate releasing data on the patients that are already enrolled at this point, or will that wait for full enrollment? Thanks.
Nick, thanks for the question, so our focus right now turns to resolving the scale-up manufacturing challenge, and you know, our best estimate now is that re-enrollment would start in 2026 , and certainly, if that time changes, we will provide an update at the right time. I would say it's prudent for me not to provide estimates of when the data will be available until we reinitiate enrollment. What I can say, based on the level of interest that we've had to date, and also we will continue to raise awareness in parallel, we fully expect to have patients being able to enroll and enroll very quickly, as I mentioned previously. So, you know, the timeframe to be able to get top-line data may actually be accelerated based on those efforts, so we'll provide updates at the right time.
In terms of providing any additional data along the way, I can't commit to that right now. We wanna make sure that because the study is still blinded, that we, you know, preserve that as we move forward, and if anything changes along the way, we certainly will let you know.
Very helpful. Thank you very much.
Your next question comes from the line of Maury Raycroft with Jefferies. Maury Raycroft, your line is open.
Thank you. Thanks for taking my questions. Just wanted to clarify, will the patients currently enrolled in the study be included in the study's efficacy analyses, or will you have to enroll beyond the estimated seventy patients needed? And then, is the work that needs to be done to improve the process, is that being driven by Travere, by the CDMOs, or by third-party consultants?
Okay. Bill, would you like to take those?
Yeah. So we are certainly grateful for the patient community and their commitment to this study. The contribution that they are making is meaningful from those patients, and it will be part of the BLA. Ultimately, we'll need to negotiate with the agency on just how we use those data, but certainly, their data counts, and it's not my expectation that that would expand the size of the study. Your second question was around, you know, who made the decision? This was not an easy decision for us to make.
This was an internal Travere decision, ultimately, and it was in the best interest of the program to take this pause and to optimize the process so that it's done once right now, and that we can then move forward and be successful with a large-scale process that will cover all of phase III, our approval, as well as launch for the program. So getting this right now is critically important.
Okay. Thanks for taking my questions.
We will take our next question from the line of Jason Zemansky with Bank of America Securities. Jason Zemansky, your line is now open.
Hey, this is Cameron Bozdog for Jason Zemansky. Thanks so much for taking our question. I'm curious if you expect any structural changes will be needed to be made to the trial in the wake of the pause?
Thanks for the question. Our expectation is that the trial design and the protocols remain intact. This is really about a specific, you know, part of the, manufacturing process scale that is required.
Thank you.
Thank you. We will take our next question from the line of Laura Chico with Wedbush Securities. Laura Chico, your line is now open.
Hey, thanks very much for taking the question, guys. I have one just... and this is kind of more related to cost, but in terms of site activation, I think I only saw one site listed in the ClinicalTrials posting, but obviously, you're recruiting from others. What happens to additional sites that have been activated but don't yet have participants? Is the plan to shut those down? I'm just trying to understand kind of the cost runway here and what happens to those sites in the interim while the pause is on. Thank you.
Yeah. Bill, do you want to take the site activation? And, Chris, you can take any, you know, specifics on cost.
Yeah. We've been judicious in how we've opened up sites as we've started enrollment in this study with a metered approach. That's part of why you don't see a lot of sites open. The sites that are open will remain open. They'll manage the patients they have, and those that don't have sites, those that don't have patients, we'll have to address the specifics of that, and I quite frankly, don't know the detail on that one. The cost impact should be minimal.
And, and-
Go ahead, Chris.
Laura, just on the expense side of things, I think the guidance that we provided in terms of the investment shifting would include anything related to clinical sites, and really there, we're not going to be expanding at the same pace or same timeframe as what we had originally anticipated, both on the number of sites and then also on the number of patients that would be coming into the study, and so that's incorporated into it, as well as, you know, investments in CMC that will be shifting. As you would imagine, we would be expecting to run more large-scale batches in this time period, but those are gonna be pushed out further, and so that's really what's incorporated with those numbers.
Yeah. I think the other thing, Laura, that I would add is a benefit, if I can frame it that way, of having the ability to engage the patient community and know where the patients are who want to engage in this trial. Because as you probably know, with a lot of rare disease trials, you have to open up many more sites than perhaps even enroll. And we will have the insight about where the patients are and make sure that we are activating further sites in an area that would optimize the chances of patients being enrolled at that site.
Thanks very much, guys.
Thank you. We'll take our next question from the line of Vamil Divan with Guggenheim Securities. Vamil Divan, your line is now open.
Yeah, great, thanks for taking the question. So I think most of mine have been addressed. But a couple if I could, just on in terms of you've been sort of scaling up the product. Have all the patients that have received drug received drug from the same batch? Or has there been some change along the way where patients have been receiving sort of newer product, and then you sort of realized this issue about scale up? So maybe you can just sort of clarify that. And then the second question may be broader than today's discussion. You mentioned just like the competitive side of things and the commercial potential here and your confidence on the product. Ultimately, maybe you can just comment a little bit on what you see as the commercial landscape here and the competitive dynamics.
It seems like you have a pretty open, you know, space here, but just if there's just a delay of 18 months or a couple of years, is it to the potential risk losing some of the opportunity to a competitor?
Yeah, I'll take that first question, Vamil, or the second question first, and then I'll have Bill comment on the batches. So, with regard to the evolving treatment landscape, you know, while there may be some things that are being assessed earlier, we don't see anything on the near term horizon that would be a competitor or a different treatment option. Our expectation and our assessment remains that pegtibatinase will be the first and for the foreseeable future, only therapy for, you know, that is disease modifying for HCU. You know, that certainly may evolve, but this, you know, this delay, we don't believe changes that significantly.
In fact, one of the opportunities that we will make sure that we do is to continue to invest in raising awareness of this condition, to ensure that patients that may benefit from a medicine like pegtibatinase are under the care of a physician, reengaged in care, or are diagnosed to be able to ensure that they can access the care that they need. And Bill, why don't you comment on the batches that patients have received thus far?
Sure, sure. So we have been manufacturing multiple batches at the small scale to support the phase I/II COMPOSE study, and we negotiated with the agency that we would begin the phase III HARMONY study utilizing the small scale material, but then transition to the larger scale material once that was ready. So everything that's been done in the clinic to date has been from multiple and reproducible batches made at the smaller scale. And we are currently manufacturing and working on the scale-up at the much larger scale, and it's really around evaluating whether or not we can do that consistently and fine-tuning that process so that we have the confidence in a robust process that it duplicates what we did at the small scale and will be consistent over time.
Just to reiterate as part of that, we have not dosed any patient with medicine from a larger scale. That is unaffected and does not introduce any, you know, risk into the program. You know, we have the ability to improve a process and ensure that any future batches that are used from a larger scale are those that would be comfortable as we, you know, look to commercialize.
Okay, thank you.
We will take our next question from the line of Alex Thompson with Stifel. Alex Thompson, your line is now open.
Great. Thanks for taking my question. Just a two-parter on the CDMO side of things. Are these same small batches, the same batches that you were using in the COMPOSE study as well as in early phase III patients? And then has your CDMO mix changed, as you've scaled up? Thanks.
So the batches have changed as we've gone from COMPOSE into the phase III HARMONY study, but it's the same manufacturing process all along. It's just multiple batches that have been made to supply the clinic. The CDMO mix has not changed as part of this process. They're the same CDMOs that we've been working with, and they're currently assisting us on the overall scale-up process.
Thank you. Once again, if you would like to ask a question, please signal by pressing star one. We will take our next question from the line of Ed Arce with H.C. Wainwright. Ed Arce, your line is now open.
Hi, good afternoon, everyone. This is Thomas Yip asking a couple questions for Ed. Thank you for taking my question. So, you touched on this a little bit earlier regarding clinical trial sites. Can you further expand on what's the process of restarting enrollment? What would the study feature the same investigators and any regulatory filings will be needed? And also, how should we look at the expense, should we look at the reduction in expected R&D next year to be shifted to when the trial will resume? Is that the right way to look at it? Thank you so much.
Okay. Bill, why don't you take the question around enrollment? Chris, you can take the question around cost.
Yeah. Yes, we will be utilizing the same investigators. With rare disease, you often have a small cluster of very passionate investigators who are researchers as well as clinicians, and are very closely associated with these patient communities, and a HCU is no different. We have spent time getting to know the key players in the field and those that are most passionate about the program, and our commitment to them and theirs to us is really unchanged. We just need to pause while we get through this delay. Your second question was around what regulatory filings would be required.
With any change in scale, there's a process of alignment and review that happens with the agency around what are the parameters that we need to look at to show the similarity between material made at two different scales, or could be the same scale at two different sites, very similar process. That's pre-negotiated, and that would happen in any circumstance. Here, we're just gonna delay that interaction with the agency to the point where we have optimized that, and that's all part of the plan.
Yeah, Bill, let me just add to that last part before, Chris, you talk about the expense implications. You know, this. We've had very good engagement with FDA along the way. I think, Bill, you're referencing as we look forward, but as we've made good progress on the manufacturing of pegtibatinase along the way, we certainly have engaged FDA, and they were aligned with the plans as we started out. I think as we look forward to future scaling, you know, Bill's team will engage them at the appropriate times. Chris?
Sure, and Thomas, on the question for the expenses, we're still gonna make the investment, so this is more of a question of when, not if, and the way that I would think about it is it'll be shifting out of 2025 and into later years. You know, there, it's really gonna be in a period in which we have even greater revenues coming through from FILSPARI and IgAN and potentially FSGS in the future. So you know, we'll be sure to give greater clarity on that as we get through our budgeting cycle for next year and into next year. But I would look at it as a shift rather than a you know, avoidance of cost necessarily.
Understood. Thank you so much for taking our questions.
Thank you. Once again, if you would like to ask a question, please signal by pressing star one on your telephone keypad. Ladies and gentlemen, this concludes the question and answer session of today's conference call. I'll hand the call back over to Nivi.
Great, thank you all for joining us for this afternoon's corporate update call. Have a great rest of your day.