Welcome back to, I guess we'll say the mid-morning session of our second day of the 2025 Global Healthcare conference here in Miami. I'm very fortunate to have Chris Peetz, CEO of Mirum Pharmaceuticals. How was the trip out, Chris? All good. Yeah, thanks for hosting. It's great to be here. Always happy to host people at my adopted home. Let's talk a little bit. We can dive right into the growth rate implicit in your guidance. Just talk about the base business level set, where we are in terms of LIVMARLI's growth and penetration, and then move down separately to sort of the growth, the base growth right now in the acquired assets. Sure. Yeah. First point out that I'll be making forward-looking statements, so refer to our SEC filings for more complete risk factor disclosure. Turning to the commercial side for Mirum, the commercial business is in really great shape, pointing towards $420 million-$435 million for the year. That's the 2025 guidance. Underneath that, see all brands growing and contributing to that growth rate. Starting with LIVMARLI, continues to be a strong growth driver and is really the bigger contributor to the growth when you look at moving into 2025, driven by Alagille continued penetration in the U.S., a lot of international launches for Alagille syndrome expected this year. Also the PFIC expansion that started last year continues. We're continuing to see nice new patient starts for PFIC contributing to LIVMARLI's growth. Bile acid products will continue to do what they've done. They've been steadily accumulating patients and growing over time. We just had the approval of CTEXLI for CTX. We see that as a way to help what we've been doing is to bend the curve a bit on that growth rate. The CTEXLI launch really is all about adding more patients through more active promotion, supporting diagnosis. We'll start to see some of that this year, but think of that as more of a gradual effect over time. Kind of putting it all together, I mean, LIVMARLI being the highlight of growth, one thing I'd point out is that that profile for LIVMARLI, we expect it to grow in a healthy manner throughout its life cycle. There's a lot of great tailwinds, not only on getting further into the current diagnosed patient population, but also you see a weight-based dynamic, weight-based dosing dynamic for LIVMARLI that continues to contribute, as well as further indication expansion, not only with PFIC, but also the EXPAND study being a third potential label expansion for LIVMARLI that we're working on. Let's start a little bit with the CTEXLI side. When you talk about bending the curve, operationally, what are the metrics that you're following so that you can bend that curve? What are the things you can do in operational terms to move that number? Yeah, a lot of it comes down to helping support diagnosis and awareness in some of the clinics where these patients present. We have deployed a number of different programs that really support genetic testing, getting those into the different specialists that would see these patients when they present. Some of that will be in pediatric ophthalmology, where bilateral cataracts can be a signal of CTX and a chance to potentially catch them earlier. In movement disorder clinics, having a panel of different genetic neurological conditions available. Those are different programs that we have recently launched to help support diagnosis. We also have a dedicated sales team now that is focused on medical genetics and neurology. In addition to the liver GI team, we do have a dedicated field team helping to support finding CTX patients. We do think that when a patient is diagnosed, they're very likely being prescribed. This is really all about patient identification and helping to catch those patients earlier and prevent some of the irreversible consequences of the disease. Let's move from CTEXLI over to LIVMARLI and talk a little about the depth of penetration into that market, U.S., EU, globally. Where are we in terms of the proportion of patients that are diagnosed out of the prevalent existing pool? For the U.S. and Western Europe, so these are the markets where we're commercializing directly, we think we're probably about 40% or so penetrated into the prevalent Alagille syndrome population. Kind of where we build from there is we do see the ability to penetrate further into that prevalent pool. We're deploying on making that happen. Also keep in mind that there are new diagnoses every year. It's a lot of catching the patients when they're diagnosed, typically in infancy, to be a treatment option for them when they kind of start some of their disease management decisions early on. Beyond that kind of U.S., Western Europe profile, we're still pretty early in a lot of these distributor markets. We're commercializing through partners that have the kind of on-the-ground expertise in smaller markets and leveraging a lot of their work as they find access to different rare disease funds to get reimbursement. You see more of those geographies potentially coming online this year. Call out Japan and Latin America are a couple areas that we're looking forward to having launches coming up this year. From a purely stock perspective, talk to me about how those distributor launches in some of those new economies, Latin America, Japan, et cetera, how will those flow through onto the income statements? Should we expect those to be chunkier? Should we expect them to show up sort of dribs and drabs over the course of the quarter? I know in some places, Brazil, for example, that tends to show up as a single chunk on an annual basis. How should we think about the income statement earnings impact in kind of the most granular way? Yeah, the dynamic that you're talking about, some of these tender type orders, we do expect to see that from some of the distributors and partners where you could see kind of more sizable orders that cover 6-12 months of supply for a given geography. The international side of the business, as we've actually seen historically, you can have kind of bigger quarters because of some of those orders from distributors that really are about their budget cycle when they have access to funds and when they're securing supply for their market. Talking a little bit about market evolution, you do have a competitor out in the field with a similar mechanism of action, although different data set, different label, different price. Talk to me a little bit about how the competitive dynamics in Alagille versus PFIC and to what extent is pricing a driver, to what extent is first mover advantage a driver? What are the key competitive metrics to follow in these markets right now? Yeah, so speaking primarily about the U.S., where both products have had both indications now for some time, it's a different situation in Europe. In the U.S., for Alagille syndrome, we think we're probably 90% share of IBATs for Alagille syndrome. A lot of that's driven by first mover. We were there getting some of those patients seeking treatment, getting them started on LIVMARLI. What helps us hold that position also is the pricing dynamic, where for Alagille syndrome, there is a pricing advantage for LIVMARLI that we've seen show up and get recognized in some of the policies where LIVMARLI is written as a first treatment for Alagille syndrome. That is kind of a helpful dynamic to really hold our position in Alagille syndrome. PFIC is from a current prevalent share. Definitely, it's clear that LIVMARLI has a smaller piece of that. What we're seeing for new patient starts, I think we're actually doing quite well. That pricing difference is not as straightforward because there's a range of doses that are prescribed there. We have been able to pick up IBAT treatment naive PFIC patients. That's one of the things that's been really great about the PFIC launch. We saw a lot of this show up the second half of last year from some of those kind of de novo IBAT naive PFIC patients coming to LIVMARLI first. As we think about some of the markets that are a little tougher to model, I think there's been a lot of crosswinds in the EU in particular. Obviously, you've got a lot of individual small markets. You've got repricing in Germany, et cetera, that happens across the life cycle of the drug. How should we think about modeling European growth, given it's a little more of a heterogeneous market? It's kind of the puts and takes, headwinds, tailwinds as people start to model growth in that market. From kind of thinking about the trends and how you model it, the Western Europe contribution to our international number that we point to, that is pretty steady and actually performs similar to the U.S., where you have a dispense is really closely tied to the actual revenue and the sale. The distributors that are on top of that, that creates some of the kind of quarter to quarter lumpiness when you get a larger order. Underneath that, for Europe, we think we're through some of those launch kind of price setting dynamics. For Western Europe, expect that to be a kind of steadier growth curve similar to what you have in the U.S.. We think about the sort of dynamic of weight-based dosing. You obviously have patients across a range of ages, so it's a little hard to just magically slap a number on there. A little irresponsible to do so. How should we think about the magnitude of that benefit? Is that something that we should expect to play out over the next few years, or is it something that the population will need to age into and more of a back half of the decade situation? We expect it will be just a continued kind of tailwind and driver to growth over the life cycle of LIVMARLI. When looking at one way to look at it, it's just the average dispense volume overall. That has kind of two components to it. You have the patients that have been on therapy for some time. Keep in mind, you're starting many new patients, most of them younger. A lot of the new starts are infants, newly presenting patients. The average dispense overall, because of that dynamic, rises kind of gradually over time because you're continuing to start younger patients that are at a lower dose, as well as those that are prevalent on drug, continuing to increase in weight over time. That's kind of just to bring it back to that. The average dispense has increased gradually over time, but it's not the same as following a single cohort of patients, which any given patient would have a bigger increase individually. That makes sense. Let's hop over to the adult side of the ledger. We had a fairly rich data year last year on PBC, PSC, getting a little more clarity on that opportunity. Give us a sense of how you think about competitive dynamics in PBC. I know this is a question I've asked you about 35 times. We know a little more about what that market's going to look like now than we did previously. Then we'll hop to PSC next. Yeah, you're really challenging me to start with PBC. PSC, that's the real, from a competitive standpoint, the real exciting indication, given the unique role that we're in. I'm trying to save his word for last. I'll humor you on it. I'll start with PBC. Within PBC, it's important to break down kind of the standard of care and where the lines of treatment currently are. PBC patients are almost universally treated with UDCA as a first line therapy. That can help control liver labs, in particular, the alkaline phosphatase level is what's monitored for potentially progressive disease with UDCA treatment that might call for a second line therapy. Currently, that's the PPARs or OCA. Seladelpar, Elafibranor, that's where those were recently getting their approvals, is in patients with elevated alkaline phosphatase despite UDCA treatment. In the PBC segmentation, about two thirds or 60% of patients are in that first line setting on UDCA. They haven't yet progressed to be considered for a second line treatment. What's unique about the volixibat program, and GSK also has an IBAT that's taking a similar tack, is that we've enrolled patients across all settings. Similar to the just background prevalence of PBC patients, about two thirds of the patients in our study have been first line UDCA patients. About one third have been kind of the second line elevated alkaline phosphatase presentation. We expect our labeling to be across all lines of therapy for the traditional way to think about PBC treatment and addressing the itch and symptomatic burden across all of these settings, because UDCA does not actually have a great response for symptomatic improvement. Now we get to the more enjoyable part of the conversation. The less complex one, I guess, actually. Fairly straightforward. Let's talk about PSC and how you think about the opportunity set and sort of timing to launch, commercialization, and how we should think about market building there. The PSC indication for volixibat is really unique in that, given the mechanism and the dramatic response that you can drive on itch with an IBAT inhibitor, we can use that as an outcome in our program. The PSC program, which is tracking well after the interim analysis last year, is on track to complete enrollment the second half of this year, six month endpoint, so sets us up for the top line readout next year. I am really excited about getting to that data, because it actually is a tractable endpoint that you can drive an outcome for the patient and measure that within a six month period and use that as a basis for an NDA submission. Let's talk a little bit about how to think about the opportunity set in terms of pricing strategy, et cetera. Is it reasonable to assume that you're likely to price volixibat to value for PSC, given that's the more greenfield opportunity? Is that the reasonable assumption? Absolutely. In particular, because it comes first. The pricing strategy, we approach it based on the first approval. Fully expect that to be PSC. We kind of point to the PPAR launches as kind of the most recent approvals and prices set in the space. With the PSC indication, really unique in that we're tracking to be potentially the first and only product for this indication. I'm going to pivot into the earlier stage pipeline. Talk to us a little bit about the strategy and Fragile X and more broadly how that reflects your view on business development and the right type of asset to join the bag for you guys. Yeah, so I'll give a little background on how we thought about looking for that program. It was part of a deliberate search in genetic neurology on the back of bringing on the bile acid programs. We were looking ahead to the CTEXLI approval and launch, having a dedicated sales team on really the neurologists that are in these movement disorder clinics or tertiary centers that are treating some of these more complex neurological conditions, and thought, how can we leverage what we're building for CTEXLI? That's kind of how we, that's why we started looking in the space. As we were looking across a number of different genetic neurological conditions, it's actually a data set for a different PDE4D inhibitor that caught our eye. Really clear, convincing phase two data out of a program with Shionogi that was recently published that showed that with a PDE4D inhibitor, you can actually move cognitive functioning endpoints in Fragile X patients. Real huge advance for programs for Fragile X. This just has not been seen with other programs. A lot of the prior research has been done on behavioral endpoints and not really getting at the cognitive potential. When we saw that data set, we thought, you know, when you look at their data, it looks like they were limited in their dose window by some of the emesis. That's an on-target mechanism for PDE4 inhibitors in general. We found 3379, which actually has a quite wide therapeutic index for what we expect to be the target dose for Fragile X, mostly driven by just improved CNS penetration. It can get more drug to where it's supposed to be. We think we'll be able to avoid some of the dose limiting emesis that's mechanistic for PDE4D inhibitors. Before we dive into that, how do you think about your capacity to develop additional assets? Because you've now rolled through the acquisition of CTX assets. CTEXLI's approved, has moved entirely to commercial story. You've got Fragile X is brought on, still in the development stage, phase two, et cetera, regulatory conversations. There's still a little bit of work to do until the development before that becomes a commercial story, market building, et cetera. How do you think about capacity or appetite to continue to expand the bag? Or is that something that you think comes after the Fragile X story has moved a little bit further down the field? We're actively looking and interested in continuing to expand the Mirum in general. We've been able to pull together a team that can execute in rare disease, commercially, regulatory expertise, and clinically. Bringing more products to this team, I think we can add a lot of value. In terms of capacity, we think of it as we've now set up the company to be financially independent, cash flow generating with a strong commercial growth trajectory. We have capacity and we'll continue to be able to even grow that with margin expansion on the commercial side, as long as we don't disrupt that financial independence that we have currently. That's the way we think of it, is there's capacity that we could bring on clinical stage programs that will continue to expand as we grow the commercial top line. Maybe more of a CFO question, but talk to us a little bit about we talked about becoming cash flow positive this year. You obviously have some non-cash amortization that lives in your gross margin post the CTX acquisition, which optically influences how things look like on our earnings, but isn't a cash expense. That dollar is already out the door. Talk to us how you should think about the amount of operating leverage in the business as structured now, recognizing there's going to be a little bit of extra spend as you build out genetic neurology. And it grows, one hopes. Yeah, so the way we kind of analyze the financial performance and the commercial margin in the business is that when you look at the basically cash commercial margin coming off of the current programs, it's about 50%. It was last year. Expect that to expand, that margin to expand into this year. That commercial business contribution and margin expansion is something that we see growing and will continue to drive on the financial performance side. What's below that is what we're reinvesting in the clinical side and is where you have potential for new product acquisition from that kind of 50%+ contribution margin. We think about one of the other conversations that I've had in terms of the ability of the company to not just accelerate growth and bend the growth curve upwards, is to what extent the company is able to expand into different areas. Obviously, genetic neurology is novel, although you sort of daisy chained your way into it through a transaction that was quite tangential to existing salesforce. How do you think about what the sort of circle of competence for the company is? Will that continue to grow? At some point, do you say, or is there a focus on it's not the same rare disease, liver neurology, we have room for one or more, but at some point you get too diversified? We talk about rare disease as the therapeutic area for Mirum. What we've seen in our experience and expanding into for the CTEXLI commercial team and the ability to bring on a program like 3379, what matters in these rare disease settings is kind of how expansive your field team needs to be. We're able to leverage what we have on the internal operations side, the payer team, all of the support functions. Those are highly leveraged as you add on another call point in these tertiary centers. It's quite efficient. We don't see ourselves limited to liver GI and just genetic neurology. There are other settings where the added field team would be 10-15, quite small increment if we did bring on another specialty area. The rest of the team that we've built is highly leverageable, some really great leaders in rare disease and people that are excited to take on more programs. I guess changing the angle of consideration from therapeutic area to modality, you've been fairly disciplined, or maybe it's just been a function of the opportunity set, and remaining in what is a fairly high margin, simple from a manufacturing perspective modalities, no cells, no viruses, largely small molecule, relatively straightforward from a manufacturing perspective, but certainly not necessarily from a commercial perspective. Has there been any change in how you think about the universe of modalities that are appropriate? And sort of would you consider moving up the complexity curve, or is that something that's less interesting to you? We're open to it to an extent. The lens that we put on it is, is there an established third-party ecosystem to be able to manufacture? That's why we do exclude gene therapy, cell therapy, things that require a lot more capital-intensive investment to be able to manufacture. Antibodies, for example, there's a very well-established third-party CDMO infrastructure that would make us comfortable if that's the right medicine and we're excited about the therapy itself. That's kind of the criteria we put on it, just that we don't have to go out and invest in building out our own infrastructure on the manufacturing side. That makes sense to me. I think the final debate that I have with some investors is around exclusivity duration, because I think there's a little bit of complexity, because people look at the acquired CTX assets. CTEXLI obviously has orphan drug exclusivity extended now post the approval. And they say, as you continue to accelerate these assets, presuming you do bend the growth curve, at some point, do they become large enough to attract genericization interest? How practically possible is it for a generic to enter these markets in the out years? Speaking about the bile acid program specifically, relative to other medicines where you do see generic entry, they're still quite small, frankly, compared to some of these others. The patient numbers are in general not that attractive for a new entrant because you do have to support the patient finding and prior authorization, some of these things that are really part of the investment in building a rare disease platform. It does not mean it's not possible, but any new entrant we expect would be also a premium-priced product because that's what you need to have to support the infrastructure for the small patient number in these indications. That makes sense. I think we're coming down to the end of time. Thank you, as usual. It's been a great conversation. Looking forward to seeing more from you throughout the year. Yeah, thanks again for hosting. We're excited about the year for Mirum and more to come. Awesome. Pleasure as always. Thanks, Mani.