Travere Therapeutics, Inc. ($TVTX)

Good morning, and welcome to Travere Therapeutics Business Update Call. Today's call is being recorded. At this time, I would like to turn the conference over to Nivi Nehra, Vice President of Corporate Communications and Investor Relations. Please go ahead, Nivi.

Thank you, operator. Good morning, and thank you all for joining us to discuss Travere Therapeutics' exclusive licensing and collaboration agreement with Everest Medicines. Today's call will be led by Dr. Eric Dube, our President and Chief Executive Officer; Eric will be joined in the prepared remarks by Dr. Julia Inwit, our Chief Medical Officer; Chris Cline, our Chief Financial Officer, will join us for the Q&A. 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 disclaimer on the company's press release issued earlier today details the risks discussed in 2Q and 10-K by event are views only as of the date such statements are made to anteverspecifically 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. Good morning, and thank you all for joining us. Earlier this morning, we were very pleased to announce that Travere has entered into an exclusive licensing and collaboration agreement with Everest Medicines for seborbrutinib, also known as EVER001. A potential best-in-class reversible BTK inhibitor. Under the agreement, Trevere will receive development and commercialization rights to seborbrutinib in global markets outside of China and certain countries in East and Southeast Asia. This is an exciting and strategic transaction for Travere. We've been engaged on this program for some time, and now we are entering into this agreement from a position of strength with the ability to execute on the development programs quickly once the deal closes. Notably, the transaction brings a potential best-in-class product candidate into our rare kidney portfolio with proof of concept clinical evidence in primary membranous nephropathy or PMM, and a compelling mechanistic rationale across several immune-mediated rare kidney diseases, including immune-mediated FSGS, minimal change disease or MCD and potentially others. While seaborbrutinib is initially anchored in PN, a disease with no approved medicines today, its multi-indication potential is an important part of what makes this transaction strategically compelling and why we view it as a potential pipeline and a product. Importantly, seborgrutinib will bring a distinct immune-mediated mechanism to our portfolio alongside Pilbara's never protective role. In immune-mediated FSGS, Phil spar and seborbrutinib would give Travere 2 distinct medicines with complementary profiles and we see that as an important opportunity to further address unmet need in FSGS over time. Seborbrutinib will also provide further long-term growth potential and diversification alongside and beyond Philsphari and pegdibatinate, while remaining closely aligned with the areas work server has been greatest expertise and ability to execute. With this transaction, we are building on the momentum of our current portfolio, including recent strong performance in FSGS and IgA nephropathy. Travere has built its leadership by advancing medicines for rare diseases with significant unmet need and limited treatment options. With Silfari, the first medicine ever approved in FSGS and the first nonimmunosuppressive medicine approved in IgA nephropathy we have demonstrated our team's ability to successfully advance a rare kidney medicine for clinical development through commercialization. With pegatinase we are also advancing in development the first potential disease-modifying therapy for classical homocystinuria. Ceborbrutinib fits naturally with Trevira's expertise infrastructure and long-standing commitment to the rare disease community. It is a rare kidney disease product candidate and the development opportunity where we believe our clinical regulatory and commercial capabilities can add significant value. Everest is a biopharmaceutical company with a strong track record in the development and commercialization of innovative medicines and we look forward to collaborating with our team to advance this program globally. With that, I'll turn the call over to Julia to walk through the scientific rationale and clinical data in more detail. Jula?

Thank you, Eric. We are very excited about civovibrutinib because it brings together several attributes we look for in a development candidate, a compelling mechanistic rationale proof-of-concept evidence in a rare kidney disease with high unmet need and biologic rationale to support the potential for the treatment of several immune-mediated kidney diseases. Patients impacted by primary membranous nephropathy carry a high disease burden, which often includes fatigue, massive swelling with weight gain. -- and brain fog, which not only impacts their quality of life, but also their ability to attend school or work. Patients with primary membenous nephropathy need therapies that can rapidly reduce both disease activity and proteinuria to minimize ongoing kidney damage and the symptoms and complications of persistent nephrotic syndrome. While current off-label immunosuppressive approaches can be effective in some patients, they are often associated with delayed onset of action, prolonged B-cell depletion and increased risk of hypogammaglobulinemia and infections. There remains a significant unmet need for treatments that provide earlier disease control with less impairment of immune function to reduce the burden of chronic immunosuppression. We believe civoribrutinib has a differentiated potential best-in-class profile. Let me start with the mechanism. It is in oral covalent reversible inhibitor of Bruton's tyrosine kinase, or BTK. Its covalent reversible mechanistic profile is relatively unique within the BTK inhibitor class and is an important part of its differentiated profile. In simple terms, this means civoribrutinib is designed to bind strongly to BTK, while also allowing that binding interaction to detach and be reversible. Reversability is important because it may allow for targeted immune modulation as needed. BTK is a key mediator of B-cell receptor signaling and plays an important role in B-cell activation, maturation, proliferation and differentiation into antibody producing cells. That biology is highly relevant in immune-mediated kidney diseases where B-cell activation and auto antibody production can contribute directly to kidney injury. In primary membranous nephropathy, for example, the disease is often driven by auto antibodies, most commonly antiphospholise A2 receptor or anti-PLA2R antibodies, that target the podocyte. This leads to immune complex formation and deposition in the basement membrane and podocyte injury. This disruption in the kidney filtration barrier results in significant proteinuria and over time, leads to progressive kidney damage. Anti-PLA2R antibody levels are clinically meaningful because they reflect active autoantibody-driven disease and can help guide treatment decisions. Importantly, reductions in anti-PLA2R antibodies are often an early sign that the underlying immune process is being controlled. With reductions in proteinuria that follow as the filtration barrier begins to recover. By targeting BTK, civoribrutinib is designed to modulate B cell signaling upstream of autoantibody production. Importantly, this is distinct from B-cell targeted approaches, such as anti-CD20 antibodies, which deplete B cells, and April BAS inhibitors, which target pathways involved in B-cell and plasma cell survival. BTK inhibition is intended to regulate the immune signaling pathways that drive pathogenic B cell activity without depletion of B cells. Sevoribrutinib may also have beneficial targeted immunomodulatory effects compared to B-cell targeted approaches, including effects on myeloid lineage immune cells. That is important because multiple immune-mediated kidney diseases involve both auto antibody biology and inflammatory immune signaling that can contribute to glomerular injury, proteinuria and progressive kidney damage. The covalent reversible nature of stivoribrutinib is also central to why we are excited about this asset and its differentiated profile. It was designed to combine high potency and selectivity with reversible BTK inhibition, supporting a targeted and potentially flexible approach to immune modulation in chronic autoimmune kidney diseases with the goal of limiting side effects traditionally associated with immunosuppression. The fact that cevoribrutinib is a pill is also important. Many immune modulating therapies used today or in development are IV or subcutaneous biologics. An oral medicine could offer meaningful convenience for patients and physicians, particularly in chronic diseases where treatment burden, adherence flexibility and the ability to adjust therapy are important considerations. Taken together, the profile of cevoribrutinib is compelling. It is broadly administered, targeted, designed to provide reversible immune modulation and has the potential to address B-cell in autoantibody-driven disease processes that are relevant across multiple immune-mediated kidney diseases. Now let me turn briefly to the clinical evidence. Sevobrutinib is being evaluated in an ongoing Phase Ib/IIa study in patients with anti-PLA2 or antibody-positive PMN. This is an open-label, single-arm study with highly encouraging results to date that provide important clinical support for the mechanism. Across the study, sevavibrutinib demonstrated rapid and sustained reductions in anti-PLA2R antibodies and proteinuria with stable eGFR. Cohort 1 evaluated 100 milligrams once daily for 4 weeks, followed by 100 milligrams twice daily, while cohort 2 evaluated 200 milligrams twice daily. At week 12, anti-PLA2R antibody levels declined by approximately 62% in cohort 1 and 87% in Cohort 2. supporting the rapid immunologic activity observed in this study. There were also meaningful reductions in proteinuria with declines of approximately 77% and 80% in cohorts 1 and 2 at week 36, respectively. These responses, together with improvements in serum albumin, and stable kidney function provide important clinical support for the mechanism. We view the rapid reduction in anti-PLA2R antibodies as particularly meaningful because it is a direct marker of immunologic disease activity in primary membranous nephropathy and believe it also differentiates sevavibrutinib from other assets in development for PMN. From a safety perspective, sevaribrutinib was generally well tolerated in the data reported to date. Beyond PMM, we are particularly interested in immune-mediated FSGS and minimal change disease. Everest recently initiated an exploratory Phase II basket study that includes FSGS, MCD and IgA nephropathy. -- which we believe is consistent with the broader mechanistic rationale for civorebrutinib across immune-mediated kidney diseases. This is another area where civorebrutinib may fit well with Trevire's rare kidney disease portfolio. In FSGS, Silfari has an established role as a nephroprotective therapy. And cevoribrutinib as a distinct immune-mediated mechanism that may broaden Travers ability to help patients. including those outside Pilar's current indications. There is clear portfolio fit with continued innovation in FSGS potentially addressing different aspects of the disease biology. Our priority following the close of this transaction will be to work closely with Everest Medicines, FDA and global regulators to align the next stages of global clinical development, including the path forward and PM and our plans to evaluate civorebrutinib in FSGS, minimal change disease and potentially other indications. We are excited by the science encouraged by the clinical proof of concept in PMN and confident that Travere is the right company to advance this product candidate given our experience in rare kidney disease development and commercialization. With that, I'll turn the call back to Eric. Eric?

Thank you, Jula. We're excited to collaborate with Everest Medicines whose work has established an important clinical foundation for civorebrutinib. Together, we look forward to advancing the program towards its next stage of development with the shared goal of advancing innovation in areas of significant unmet need for patients living with rare kidney disease. To summarize, we believe this transaction is an excellent strategic fit for Trever for 3 key reasons. First, civorebrutinib is a differentiated oral BTK inhibitor with potential best-in-class attributes including rapid onset of action, convenient oral administration and a potentially favorable safety profile with proof-of-concept in PMA. Second, civorebrutinib will bring pipeline and a product potential across multiple immune-mediated kidney diseases to driver's rare kidney disease portfolio. Importantly, we believe continued innovation in immune-mediated kidney disease, including FSGS, will involve approaches that address multiple aspects of disease biology. And with civorebrutinib, we will have the potential to add a distinct but complementary profile alongside TilsparI and its nephroprotective role. And third, we are entering into this transaction from a position of strength, supported by strong performance at Pilspari in both FSGS and IgA nephropathy. With our established clinical development, regulatory and commercial expertise and infrastructure we believe civorebrutinib has the potential to become a meaningful long-term growth driver alongside and beyond Pilar and Pegabatnase. With that, I'll turn the call back over to Nii for Q&A. Nivi?

Thank you, Eric. Operator, we can now open up the line for Q&A.

We will now begin the question-and-answer session. [Operator Instructions] We will now take the first question from the line of Joe Schwartz with Leerink Partners.

And congrats on this deal. I was wondering if you could share civorebrutinib's actual kinome selectivity panel in terms of the full selectivity over tech, ITK, EGFR and ERB 2 and also, what is the resident time and occupancy half-life at BTK versus the OFF targets? And does platelet function recover between doses?

Joe, thanks so much for the question. Starting off with the specific questions for Jula, why don't you take that, and you can share what's available to date.

Yes. Thanks, Joe, for the question. So part of the rationale for cevo/ribrutinib is because it has such a high selectivity for BTK -- there is some data that Everest has put out with regards to selectivity over EGFR, ITK and tech -- and it has a better profile when you compare it to many of the other BTK inhibitors with regards to selectivity, -- and that's why we believe that we're going to have a better potential safety profile versus others. What we've seen to date, while I don't have -- I think you asked about the platelet activity in between doses -- what I can tell you is the safety data that we've seen to date, and there's been a little over 150 patients and healthy volunteers exposed. And we haven't seen the off-target decreases in platelet count and other adverse effects that have been seen with some of the earlier generation BTK inhibitors. .

Your next question comes from the line of Vamil Divan with Guggenheim Securities.

This is Arseniy on for [indiscernible]. Maybe just a follow-up on that question and ask more generally. When we compare it to CD20, Obviously, it's oral. But what is the main potential advantage? Will it be safety onset? And then in terms of safety, practically, -- can you interrupt the treatment if the patient has an infection or is going for surgery? Do you preserve vaccine response when you're taking this incubator versus -- just any color on the differentiation would be helpful. .

Thanks, Arseniy. Jula?

Yes. Part of the reason we're excited about cevoribrutinib is because it's highly selective, and it modulates B-cell signaling, unlike CD20 targeted therapies that broadly deplete B-cells. So we do believe that with functional B-cell modulation rather than B-cell suppression that can help you potentially reserve some immunoglobulin, so you don't see widespread immunoglobulin, IgG, IgM, IgA depletion rather than targeting intracellular signaling to reduce the formation of those pathogenic autoantibodies. So that's what gives us the confidence that this could potentially be safer. Over the long term versus B cell depletion. And then the other aspect that gets us excited is, oftentimes, when you're targeting early B cell line lineage such as CD20. It takes longer to reduce that antibody formation because you're waiting for the B cell survival and you're not targeting the plasma cells that are producing the antibodies. And so the onset of action with this mechanism that we've seen in the Phase I/II data with the reduction in PLA 2 are occurring very early and then followed by proteinuria reduction. -- also gives us the confidence that this is a solid approach to continue to development.

Your next question comes from the line of Anupam Rama with JPMorgan.

And congrats on the deal here. Can you speak to the -- maybe building off the last question, maybe speak to the off-treatment data that you're seeing here and what that could mean from a formulation and/or dosing frequency considerations in the future?

Thanks, Anupam. Jula?

Yes. We do see continued durability of off treatment, but it is still very early to be able to discuss that and we haven't made final decisions around dosing or duration -- once the deal closes, we'll be able to give more details around our strategy and planning for that. Because I think what you're getting at is this a long-term treatment? Is this induction treatment. The fact that there is some durability off target is promising, but those decisions around duration of treatment haven't been determined yet. .

Your next question is from the line of Prakhar Agrawal with Cantor Fitzgerald.

Congrats on the deal. So maybe on the PN indication first. I think other BTKs like zanobrutinib has some data in PM as well. So how would you characterize some of the early data that has been generated by risk in PMN versus some of the other BTKs. And then just as a follow-up, what could the development patter look like in PMN.

Thanks, Prakhar. Jula? .

Yes. So the only other BTK inhibitor that has early data provides proof of concept that the mechanism likely works However, that's -- and I think you mentioned it's an ibrutinib. However, that is a slightly different mechanism. That is an irreversible covalent BTK inhibitor. And therefore, we do believe that the fact that we are covalent reversible has a potential for a better safety profile overall with regards to why we believe in cebiribrutinib as a potential best-in-class for patients with primary members nephropathy.

Your next question is from the line of Gavin Clark-Gartner with Evercore ISI.

I guess just a follow-up on Prakhar's question a little bit more specifically. Last we saw Everest was planning to start the registrational PMM study this year. Is that still your plan? And on this topic, it seems like 72-week complete renal response is a pretty established registrational endpoint. -- even based on recent conversations. Is that what you're planning to pursue? Or are you discussing a different path with regulators?

Gavin, thanks so much for the question. With regard to timing, we'll be able to talk a bit more about after the deal closed. But certainly, part of our intent is to make sure that we can move very quickly moving forward. Jula, do you want to comment on regulatory interactions and endpoints?

Yes. So we again, when the deal closes, we'll have greater ability to share more with regards to the endpoints, but you're not far off with regards to -- it's known that you can utilize complete remission and select time frames for it, but we'll provide more after the deal closes as far as our strategy and plans for our Phase III design. .

Your next question comes from the line of Laura Chico with Wedbush Securities.

I guess I had 1 more bigger picture strategic question. So obviously, there's a lot of reasons to stay in rare nephrology, -- but I'm curious what other disease areas or therapeutic verticals were considered when you were seeking out other assets? And would you consider still seeking additional assets in rare nephrology.

Thanks for the question. We certainly have been looking broadly within the rare nephrology space, but not limited there. I think if we think about the work that we're doing in pegbatinase. There are a number of other areas that we've been interested in. For us, this 1 was the right asset, not only for the reasons clinically and strategically that we've talked about but also the timing of development being able to take that over and move through the next phase of development. As we look forward, business development will continue to be a very important part of Trever and the long-term focus on growth. So we'll continue to evaluate other potential assets, and we'll look within and beyond rare nephrology. But we're -- with what we have now, particularly the pipeline and appeal potential, we're very excited about bringing this into our portfolio.

Your next question comes from the line of Mohit Bansal with Wells Fargo.

This is Sadia Rahman on for Mohit. So it looks like a very robust data in China. I'm just curious how you expect that data to translate to a Western population -- and specifically, can you comment on any differences in background treatment usage in China versus the U.S. .

Thanks, Sadia. Jula, I'll turn that 1 over to you. .

Thanks for the question. We do believe that the efficacy data based on what we understand of the underlying disease biology, within primary membrane will translate into comparable efficacy as well as safety. Obviously, we still have to do the development plan to demonstrate that. but no reason for us to believe that we won't see similar treatment effects and safety within a different population, including U.S. And again, we will plan to do this globally. So more to come on that. .

Your next question comes from the line of Alex Thompson with Stifel.

I was wondering if you could comment on whether we should expect to see more follow-up data from the Phase Ib Phase II study. It looks like the cutoff here was about a year ago. So curious if we should expect more data in the near term. .

Thanks, Alex.

Yes. Actually, Everest is planning on presenting data later this week at ERA. Some more to come soon. .

Your next question comes from the line of Maury Raycroft with Jefferies.

This is Cristin on for Maury. So a quick question on the safety profile. Like how are you thinking about potential for liver tox signals that have hindered other BTK inhibitors in the systemic autoimmune trial and potential class read-throughs. .

And thanks for the question, Jula, would you like to comment on that?

Yes, so BTK inhibitors are not interchangeable. They can differ quite a bit in binding profile, reversibility, selectivity, potency, dosing, as well as the underlying patients that you study the medicine in. I would say that ivabibrutinib is differentiated from other BTK inhibitors because it's covalent reversible with high potency and selectivity and as well as reversible target engagement -- so the data that we've seen today, as I mentioned earlier, in healthy volunteers and PMN patients has shown that seboribrutinib has been generally well tolerated -- and with regards to AEs, we haven't seen the AEs that have been associated with some of the earlier irreversible BTK inhibitors such as things like neutropenia or cardiac effects as well as the liver safety concerns. We do know that there's a potential class risk around liver and that, as I mentioned earlier, depends on how you dose in other aspects. But we have not seen safety signals to date to raise concern. Obviously, we will do careful evaluations of safety throughout our development plan as well.

Your next question comes from the line of Jason Zemansky with of America.

Appreciate you taking our questions. And congrats on the deal. I appreciate talk necessarily about time lines yet. But maybe can you outline what are the steps needed to get civorebrutinib into a pivotal study? What needs to happen in order to get that underway just given an idea of what needs to happen next.

Jason, thanks so much for the question. So this is something that we'll comment more on once the deal closes. -- once it is in our hands. But certainly, our intent is to move quickly once we have the asset. .

Your next question is from the line of Yigal Nochomovitz Citi.

This is Caroline on too. Congrats on the deal. Can you tell us more about your strategy positioning this asset alongside SOAR and overlapping indications? -- would you pursue it as a monotherapy or combination or only in patient subsets that fall outside of Safari's current label?

Thanks so much, Caroline, for the question. We are certainly excited about the potential to have another potential medicine for particularly FSGS. And there's a very clear role for both fiSpARI and civorebrutinib. As you might know, FSGS is a heterogeneous disease and some patients really would benefit from medicines that address more than 1 aspect of their disease. For example, filspari being nephro protective whereas something like siborbrutinib would be addressing the immune-mediated disease biology. And what we're particularly excited about is that this would give Trever 2 distinct medicines with complementary profiles that we see the potential to be able to address that over time. With regard to the development and the strategy there, that's something that we are not going to be commenting on today, but certainly look to the future to be able to provide more detail. .

Ladies and gentlemen, this concludes the question-and-answer session of today's conference call. I will now hand the call back over to Nivi.

Thank you, everyone, for joining today's call. Have a great rest of your day.

And this concludes today's call. Thank you all for attending. You may now disconnect.