BioMarin Pharmaceutical Inc.

Non-GAAP diluted earnings per share increased 69%. This financial strength puts us on the path for double-digit revenue growth in 2025 and enables our ongoing reinvestment in further innovation and growth. Our confidence is supported by Biomarin's increasingly profitable commercial portfolio. Leadership across skeletal conditions is anchored to global expansion VOXOGO for achondroplasia, which grew 56% year-over-year, with plans to expand into hypochondroplasia in 2027, as well as four additional skeletal conditions should data be supportive. Strengthen from our enzyme therapies, growing at 9% in the fourth quarter year-over-year, and now approaching 2 billion annual revenues, gives us confidence in our long-term outlook. high single-digit CAGR from this business unit. The strategic prioritization of our pipeline last year resulted in the advancement of BMN351 for Duchenne muscular dystrophy and BMN333, a non-acting CNP, two candidates that may provide highly differentiated treatment options for the conditions they address. We look forward to early clinical data results later this year for both candidates. This year, we plan to share results from our phase three study with Palantzeek for adolescents. This potential age expansion represents an opportunity to provide 12 to 17 year olds significant and sustained fee response, as well as unrestricted diet, should data be supportive. In summary, we're excited by the progress we're making at Biomarin. The strategic and operational decisions made last year yielding tangible results and allowing us to make an even greater impact on our patients, our employees, and our shareholders. Looking ahead in 2025, we expect to share clinical data from three of our advancing programs, drive double-digit global revenue growth, execute on our business development strategy, continue our journey towards delivering the mid- and long-term financial outlook provided at Invest Today last year. I would like to thank our employees around the world for their contributions in 2024. I look forward to the progress we will make together in 2025. Thank you for your attention. I will now turn the call over to Brian to provide an overview of our financial highlights for the quarter.

Thank you, Alexander. Please refer to today's press release for detailed fourth quarter and full year 2024 results, including reconciliations of GAAP to non-GAAP financial initiatives. All 2024 results will be available in our upcoming Form 10-K, which we expect to file in the coming days. We are very pleased with Biomarin's execution in 2024, especially during a year of significant transformation. Full-year total revenues grew 18% to $2.85 billion and set the stage for record results in 2025. Fourth quarter 2024 revenues increased 16% year-over-year to $747 million. Double-digit increases from Voxogo were a strong contributor to growth in the fourth quarter and full year. Also contributing to record results in 2024, the enzyme therapy business totaled over $1.9 billion for the full year, a 12% increase versus the full year 2023, with consistent growth across BioMarin's marketed brands. Moving to expenses, for the full year 2024, non-GAAP R&D expense was slightly higher compared to the full year 2023, primarily due to spending on development of VoxOGO and five new indications offset by a reduction in spend for deprioritized programs. In the fourth quarter of 2024, non-GAAP R&D expense was $159 million and lower compared to the same quarter in 2023 as the impact of discontinued programs was fully realized during the fourth quarter. We expect that R&D expense will increase in 2025 as we ramp up our BMN 351, BMN 333, and VoxOGO indication expansion studies. For both the full year and fourth quarter of 2024, non-GAAP SG&A expense increased year over year, primarily due to a bad debt reserve, higher VoxOgo commercialization expenses, and costs associated with our ERP implementation, partially offset by lower Roctavian spending. Moving to profitability, we are pleased with the positive impact of Biomarin's strong revenue performance, coupled with the ongoing progress of our cost transformation program outlined last year. As a result of this momentum, Non-GAAP operating margin reached 28.6% for the full year 2024, an increase of 9.2 percentage points versus the full year 2023. Fourth quarter non-GAAP operating margin of 31.1% was boosted by the benefit from the cost transformation initiatives, lower R&D spend related to discontinued programs, and profitability leverage from our strong revenue growth. In addition to significant revenue growth in 2024, Biomarin achieved its 2024 objective of accelerating profitability growth at meaningful and sustainable levels. Our full year non-GAAP diluted earnings per share increased 69% to $3.52, and our Q4 non-GAAP diluted earnings per share increased 88% to $0.92. Biomarin's increasing profitability is also generating significant levels of operating cash flow, with $573 million of operating cash flow for the full year 2024, a 260% increase over the full year 2023, and further puts Biomarin on track to achieve our target of greater than $1.25 billion of operating cash flow in 2027. By Marin's ability to generate meaningful positive cash flows is a key enabler of our top capital allocation priority of investing in long-term revenue growth, both through our internal research and development investments and external innovation through our business development strategy. Turning to our 2025 outlook and full year 2025 total revenues, we expect between 3.1 billion and $3.2 billion of total Biomarin revenue, which represents 10% growth compared to 2024. In 2025, strong growth is expected from Voxogo, Imizin, Palantzeek, and Brineuro. And we expect the majority of year-over-year revenue growth in the second half of the year, as growth in the business in the first half of the year translates to an increased revenue base in the second half of the year. In 2024, the enzyme therapies business benefited from unusually high alderazine contributions in the third quarter. Similarly, naglazine demonstrated very strong growth and benefited from new patient additions as well as order timing. Due to these unique dynamics, we expect lower year-over-year growth rates for naglazine and alderazine in 2025. Importantly, Biomarin's 2024 revenue performance and the expected growth in 2025 keep us on track for achieving our target of $4 billion of total revenues in 2027. FOGO is expected to be a strong contributor to full-year 2025 total revenue growth, and we estimate it will contribute between $900 million and $950 million to 2025 total revenue. While we are not changing our overall guidance structure of only guiding the total revenue These directional insights are meant to provide a framework to align your expectations with ours. Moving to non-GAAP operating margin for the full year 2025, we are guiding to between 32% and 33%, which represents 3.9 percentage points of expansion at the midpoint versus the 2024 non-GAAP operating margin of 28.6%. Our guidance is supported by continued strong revenue growth along with the impact of the ongoing cost transformation initiatives. While noting that 2025 also represents an important investment year for critical activities in our prioritized pipeline and sales and marketing to enable our long-term growth profile. Based on the continued implementation of these activities in 2025, this is an important stepping stone towards the achievement of our target 40% non-GAAP operating margin next year. Finally, For non-GAAP diluted earnings per share, we expect between $4.20, $4.40 per share for the full year 2025, which at the midpoint represents a two-times top-line growth rate over 2024, driving towards another expected year of leveraged profitability growth for BioMarin. Building on our strong execution in 2024, we expect continued high performance as we benefit from Biomarin's revamped corporate strategy and operating model in 2025 and beyond. I will now pass the call to Kristen to discuss the drivers of our commercial performance. Kristen?

Thank you, Brian. The team delivered strong growth in 2024, led by the continued global expansion of Voxogo, increasing palenzyme penetration, and demand for enzyme replacement products, and we expect 2025 to build on this momentum. Record VoxOga results and 56% year-over-year growth for the full year were driven by strong demand globally with a significant number of new patient starts in infants and young children. In the United States, the expanding prescriber base and strong demand from families with children in the zero to five-year-old age cohort drove increased growth in 2024. Consistent with prior quarters, the majority of new patient starts in the U.S. were for infants and young children under five years of age. In international markets, we also saw significant VoxOgo year-over-year growth throughout 2024. In deeply penetrated markets, such as Germany, we focused on early diagnosis and treatment of the incident population. In markets with significant expansion potential, we are leveraging Biomarin's robust global footprint and commercial infrastructure to drive awareness and adoption in the eligible patient population. To provide insight into these global dynamics, Today, we are providing the percentage of actual total Vox Sogo revenues split between the U.S. and the combined contributions from outside the U.S., or OUS. For full year 2024, of Vox Sogo total revenue of $735 million, 24% was from the U.S., and 76% was from all countries outside of the U.S. For fourth quarter 2024, of Vox Sogo total revenue of $208 million, 26% was from the U.S., and 74% was from OUS. Now moving to expansion strategies in 2025. In the United States, we look forward to realizing the growth opportunity ahead and building on the momentum of our growing prescriber base and continued demand from families with infants and younger children based on VoxOgo's proven safety and efficacy profile. Outside of the US and in our larger strategic markets, such as Germany and Japan, we will continue to focus on early diagnosis and treatment of the incident population to drive treatment with Voxogo from infancy to provide maximum therapeutic benefit. Now turning to growth strategies in other international markets, we intend to more deeply penetrate countries where Voxogo is already available and include patient starts in new countries that are added this year. By 2027, we are focused on increasing Voxogo access to more than 60 countries. To facilitate these growth plans, we are investing in commercialization efforts including but not limited to increased field personnel to enhance the referral and prescriber basis, additional platforms to broaden reach, and the introduction of new initiatives to raise awareness and adoption of VoxOgo treatment. Further supporting our expansion efforts, we are very pleased to see two publications highlighting the importance of early VoxOgo treatment. Recently published international guidelines recommend early diagnosis, followed by early VoxOgo treatment. These guidelines were independently created to facilitate maximum clinical benefit for children with achondroplasia and to provide families confidence when choosing Voxogo treatment for infants and young children with achondroplasia. Also, as published in the December issue of MED, Voxogo is the only treatment for achondroplasia to have demonstrated a statistically significant improvement in proportionality versus an untreated control arm after three years of follow-up. We are confident that this will be another year of strong execution and record growth for Voxogo, the only approved treatment for infants and children with achondroplasia. At the same time, we are using our experience in achondroplasia to prepare for the 2027 launch of Voxogo for the treatment of hypochondroplasia should phase three data be supportive. The commercial and medical team are creating programs to raise awareness and increase the diagnosis of hypochondroplasia so we will be ready to provide VoxOgo to those interested in treatment upon potential approval. Now, moving over to our enzyme therapies, global demand drove strong results across all of Biomarin's marketed products. Double-digit Palenzyk revenue growth in the quarter was the result of substantial patient uptake in the U.S. and ongoing expansion in Japan. In addition, we saw significant year-over-year growth in Maglozyme, Simazem, and Brunera during the quarter, enabled by our ongoing efforts to find new patients and maintain treatment continuity for those on therapy. We continue to make progress in finding and starting new patients with our enzyme replacement therapies. For instance, we have seen considerable success in certain regions where we have expanded our gene panel testing programs to help diagnose patients with MPS and CLN2. For example, in Brazil, these initiatives have resulted in an increase in new diagnoses, We expect to roll out these programs into multiple countries over the coming quarters. Now, moving to Palenzec, with its highly differentiated profile and that it works across all PKU phenotypes, growth has been driven by new patient starts and reinitiation of treatment from adults with PKU. We are also excited that adolescents with PKU may soon have access to the only substitute enzyme therapy that can deliver normal fee and an unrestricted diet. With phase three data coming mid-year, we look forward to potentially submitting our applications in the U.S. and Europe in the second half of this year. In conclusion, I am very pleased with the team's execution in 2024 during a year of transformation across the organization. The transition to defined business units is resulting in higher focus, accountability, and performance, and we are already seeing the benefits of this operating model. We have set the stage for greater performance in 2025 and are on course to achieve our target of $4 billion of total revenues in 2027. Thank you for your attention, and I'll now turn the call over to Greg to provide an R&D update. Greg?

Thank you, Kristen. We're making great progress across our pipeline. Starting with BMN 333, recall that in non-human primates, we achieved sustained free CNP exposures several fold higher than those demonstrated for other long-acting CNP agents. Our goal for BMN 333 is therefore to leverage this potential for greater exposure to deliver superior efficacy while maintaining an acceptable safety profile. As of today, our PK study in healthy volunteers is well underway, and we look forward to sharing top-line data from the study in the second half of the year with detailed data to be presented at a scientific congress in the first half of 2026. For BMN351 and Duchenne's muscular dystrophy, our phase 1-2 study is advancing with enrollment and dosing in the 9 milligram per kilogram cohort. As previously shared, six boys were treated at the 6 milligram per kilogram level, and we are eagerly awaiting the 25-week proof-of-concept biopsy data for this cohort, which we expect to present to the scientific congress in the second half of this year. We believe these 25-week data will give us a clear line of sight as to whether our target of 10% dystrophin levels will be achievable at steady state in this six milligram per kilogram cohort. With Varxogo in additional skeletal conditions, we continue to advance our canopy clinical programs. Our pivotal phase three study in hypochondriplasia is rapidly recruiting, and we remain on track to complete enrollment to the treatment arms of the study in the first half of 2025. Pivotal data from that program will be available in 2026, and a potential approval could come in 2027, assuming that data are supportive. Our two Phase II canopy studies, one in idiopathic short stature and another encompassing Noonan syndrome, Turner syndrome, and shock deficiency, are screening and enrolling patients. Moving to Palomzeke. Our Phase III study in adolescents aged 12 to 17 is on track for data readout to support U.S. and European supplemental filings in the second half of the year. Recall, Palimzeek works across all PKU phenotypes, delivering potent phenylalanine reduction and can even afford some patients the potential for an unrestricted diet. We believe that this filing for adolescents could allow for patients and their families to manage the challenge of TKU and dietary restrictions from an early age, thereby supporting a smoother transition to independent adult living. Finally, with BMN349, an oral therapeutic for alpha-1 antitrypsin deficiency-associated liver disease, we are progressing well, having dosed the first cohort in the multiple ascending dose portion of the Healthy Volunteers Study. Following last year's strategic prioritization of the pipeline, the R&D organization is really hitting its stride, advancing our most high-impact candidates, and we look forward to keeping you updated on our progress in the coming quarters. Thank you for your continued support, and we now open the call to your questions. Operator?

At this time, if you would like to ask a question, press star followed by the number 1 on your telephone keypad. We ask that you limit yourself to one question. You may re-enter the queue for any follow-ups if time permits. As a reminder, today's call will end promptly at 5.30 p.m. Eastern time. Your first question is from the line of Philip Nadeau with TD Cowan.

Good afternoon. Thanks for taking our question. We want to zero in on the Vox Ogo guidance. We've already expected to be up 200 million year-over-year. That's healthy, but it is decelerating. Can you talk a bit more on where you expect that growth to come from and particularly which territories and whether they're currently reimbursed or new reimbursement will be coming this year. And maybe more generally on the pushes and pulls on the guidance, what could cause performance to be better and what could cause it to fall short. Thanks.

Hi, Phil. This is Brian. Thanks for the question. I'll start and then ask Kristen to provide some more color. So in terms of the overall guide, you accurately pointed out that, you know, at close to $200 million of absolute dollar growth, it's still strong growth. What we're observing here as Voxogo global revenue gets to scale at close to three quarters of a billion dollars that there's, you know, some law of large numbers at play here. Voxogo grew 56% in 2024, which was impressive. but not sustainable on this increasing revenue base. Just a reminder that the multi-year compound annual growth rate that we're targeting for skeletal conditions through the long-term guidance in 2027 is greater than 25%. And with a growth of 56% last year, 25%, as implied by the Voxogo range that we provided today, and continued growth in the what may be low 20% going forward. Again, the growth rate will decrease over time as the base increases. We are on track for both the $4 billion and the 25% plus CAGR.

Yeah, maybe I'll add to that. Thanks so much for the question, Phil. So to give you a sense of the geographies where much of the growth is coming from, I would say, you know, I'll call it certainly the U.S. as our largest single market opportunity, and I'll dig into a little bit of what we're doing there and to drive continued growth. We've also seen continued strong growth in our highly penetrated markets, Germany being a clear standout that we saw in 2024 and anticipate well into 2025 and beyond. And in our international markets, we're seeing growth around the globe, one of the bigger drivers being Brazil, which again will continue into 2025. So currently we're in 47 geographies where we have commercialization efforts ongoing and expect to expand into over 60 by 2027. But to give you a little bit of a sense of the U.S., so as we had mentioned, that's currently about 25% of the revenue contribution, and we anticipate that contribution to grow as we are putting a lot of energy and effort into it, given that it is such a large market opportunity for us. So just as a reminder, in the U.S., there was a bit of a delay in terms of the timing of when infants had access to drugs. So it was initially indicated for five years and older, and only in the end of 2023 did we get the expansion into the younger zero to five population. So where we're really seeing a lot of growth coming out is in new patient starts in that zero to five age cohort, which is really exciting because that's well in line with the international consensus guidelines that have recently come out where really the goal for all treaters should be to diagnose early and then immediately upon diagnosis treat with Loxogo. So we're excited to see that growth in that younger population. In addition to that, we're definitely working on expanding our prescriber base. So we're seeing that the biggest expansion in terms of growth of prescribers is in the pediatric endocrinologist, which is exactly the target area for us. And so what we're doing to continue those types of efforts is we're investing more in commercialization, namely in our field personnel. So out there driving both, you know, reach as well as depth and breadth and depth. We're also investing in platforms where we can ensure that we're getting the information out there to broader populations, namely in the pediatrician community, where we want to ensure that we can drive referral patterns back to treaters. And then we're leveraging, you know, our continued footprint outside the U.S. to build on this growth trajectory. So I'd say we're really focused, not only in the US, but of course in some of our international markets. And we see a lot of wind behind our sails, in particular with both the international guidelines I've already mentioned, and importantly, our new BU model, where we're really being able to drive that level of focus and accountability and do the right pushes and pulls as we see them.

Your next question is from the line of Jessica Fay with JP Morgan.

Hey guys, good afternoon. Thanks for taking my question. I was wondering if you could spend a little more time talking about your priorities for business development. For example, should we think of Biomarin as more focused on bringing in pipeline assets versus commercial assets to leverage your global footprint? And what's your appetite for clinical risk? And maybe just a quick follow up. Anything you would call out quarter over quarter or year over year for the first quarter

uh in the enzyme business like any international ordering patterns to think about there thank you brian do you want to start with the last question and then i'll handle business development yeah of course thanks for the question jess i wouldn't point to specific known ordering patterns granted we're just you know midway through the quarter here and you know uh As you know, our diversified global business, especially across the different enzyme therapy brands, you know, is subject to some of that large single payer bullish order pattern dynamic from time to time. So nothing specifically to point to there. But since you mentioned the quarters, I will point out, as I mentioned in the prepared remarks, you know, we do expect our growth in 2020 2025 to be weighted to the second half of the year. So, whether it be the enzyme therapies or Voxogo, you know, we're just ramping up on the ambitious plan that Kristen just talked about for 2025 here in the first part of the year. So, we expect our growth to be weighted to Q3 and Q4. Thanks.

Thanks, Brian. Hey, Jess. Thanks very much for the question. With regard to business development, yeah, we're very excited about the role that business development can play to add to what is already a pretty compelling work outlook over the coming years. Last year, as you know, was about setting the strategy for the company and clarifying where we wanted to play in terms of the business development space, making sure we've got the right business development team in place, the capabilities in place. And then obviously, these strong financial results are producing more strategic flexibility for us. And we're very excited about what we're seeing from the business development standpoint. The J.P. Morgan meeting, we had 155 meetings at J.P. Morgan. It's a reflection of recognition of the strengths of Biomarin from a research, development, manufacturing, commercialization, and specifically on the commercialization, what we hear from potential partners is our ability to commercialize across the globe. And we're now in the process of looking at these various assets. You asked, you know, what stage these assets are at. We're looking at a range of stages. We're looking at preclinical assets and also clinical assets. Again, we expect to be able to strengthen our outlook for growth into the longer term.

Your next question is from the line of Salvin Richard with Goldman Sachs.

Hi, thanks for taking your question and congrats on the progress. This is Tommy on for solving wondering if we can get your thoughts on the durability and safety as a growth hormone and CMP combo. Is this something that you may be interested in with 333 and just to follow up on 333 for the data. Could you just frame what you're looking for and help us understand any metrics to guide the translation here to AGV and later studies. Thank you.

Yeah, this is Greg Freiberg. Thank you, Sabine. Let me take the second question first. So, I believe your question was about the PK study with 333 and what we're expecting to see. Again, that is a healthy volunteer study. So, what we're hoping to see is purely PK in that regard. We'll be looking at the native species of BMN 333 as well as free CNP, and we're hoping to see several-fold increases in terms of reaching sustained levels, similar to the cinnamogus monkey model that we were referring to. We believe that several-fold increases, whether it's in AUC or time above sustained threshold, that that'll give us a chance, again, to try to recapitulate what we've seen in the animal models, which is a significantly greater growth dynamic in their long bones. With regard to the first question, can you just repeat the question for me? My apologies. I missed the nuance of the first question.

Growth hormone.

Thank you. With regard to the growth hormone combination, our goal is to develop a single-agent CMP drug that delivers not only best-in-class growth for patients, but also the kind of convenience and safety that we think the market demands. In addition to the challenges of two high-priced therapies, we think that, you know, trying to optimize the agents that we have available to us are our goal. Certainly, as data evolves, we can, you know, again, as we always do, reevaluate that strategy. But as of now, our goal is to have a single-agent therapy that's both convenient and efficacious for patients with achondroplasia.

Your next question is from the line of Corey Kisevmov. with Evercore ISI.

Hey, good afternoon, guys. Thanks for taking the question. Greg, maybe another one for you on the DMD program. I believe you've mentioned that steady state dystrophin levels in treated patients are attained at about the one-year mark. So when you mentioned this 10% goal, is that your expectation for the week 25 biopsies, or should they be somewhere below that? Thank you.

Yeah, thanks for the question. And it's an important point to make. We, of course, we've picked a chemical backbone, a non-morpholino backbone that has a slower in, slower efficacy, you know, delivery. What that affords us is the opportunity, again, to open a therapeutic window, which has been challenging in this space. We also engineered the molecule, again, to have some other factors that we think will cause significantly higher dystrophin expression once we reach steady state. The week 25 data will give us a line of sight. That's the word I would use for that. We have a very clear model of what success looks like. And that is something that, again, we think that once we have data from multiple time points at the 25-week moment, that we'll be able to have a pretty clear idea of what we're going to be seeing out of the year. Of course, we would ultimately want to demonstrate that with actual data, but the 25 week time point is going to give us a very solid read on our model of where we're headed and whether we're able to reach that. I'll just add that there's one other nuance here, which is we're talking about the six milligram per kilogram dose level, and we are going up in the dose as well. So we're in a nine milligram cohort right now. And again, there are opportunities potentially to go higher. This is a field where, of course, we want the lowest efficacious dose to be the one that we bring forward, and we're hopeful, again, that six milligrams is going to be able to give us a very clear indication of whether we're on that track for 10% or not.

Your next question is from the line of Christopher Raymond with Piper Sadler.

Thanks. Two questions, just on the ERT business. You guys have, I think, for some time now talked about being able to select sort of the demand higher on harmonizing diagnostic protocols, I think, across all geographies. I know this print was helped along by some government buy-ins, and I heard you, Brian, on your commentary on 25 being sort of back-end loaded in terms of growth. But any sort of color you can give us to the mix of contribution from this diagnostic harmonization? Is this something that's, you know, where are we, I guess, in terms of maybe which ending in terms of being able to affect that change? And then on 351 data timing, maybe splitting hairs a bit, but the press release says data second half, the slides say mid-25. Is this, are you indicating maybe you'll be top lining the data in mid-25 and then presenting the full data at a conference later, any sort of color there would be great. Thanks.

Yeah, this is Greg Freiberg. Thanks. Just to clarify, mid, of course, is the middle two quarters of the year. So, again, you can read into that what you will. They're both correct statements. We will be presenting it publicly in totality at a scientific congress in the early second half of the year.

Hi, Chris. This is Kristen Hubbard. To answer your question a little bit about the diagnostic component, broadly speaking, when we think about a lot of the efforts that are being put out in our new BU model, in particular across enzyme therapies, we are most certainly, in particular for MPS and CLN2, really looking at various activities that we can run across different countries in the world. around really understanding what diagnostic tools we can put into certain countries and really help with the diagnosis of both MPS and CLN2. So we've seen great progress already. We're using both gene panels. We're looking at cascade screening, which is basically looking at a family tree and seeing if there's MPS or CLN2 in the family tree and ensuring that we're getting the right patients identified so that we can then help start to get them onto therapy. And so we've done this very successfully, for instance, in Brazil and anticipate we will continue to push on these efforts in a select subgroup of countries where we know that this could be really meaningful. So that's certainly a part of the BU strategy. But I'd also like to talk a little bit about PKU because we're expecting a significant amount of growth coming out of PKU. As you saw with our U-over-Eager growth with Palantir alone, we put up 17% growth there and expect that to continue in double-digit growth into 2025. And at the end of the day, this was really driven by the efforts largely in the U.S. and Japan to help get new patients identified. And then importantly, and keep them on therapy. So really have adherence programs that keep them on the right dose. And then importantly, finding patients that have discontinued so that they can restart. And so we're seeing great progress with this. And really what we're hearing is that this is in large part because of the differentiated profile of Palancek, that it works across all PKU phenotypes. you have the potential for normal C levels and, importantly, the potential for an unrestricted diet. So I think we've seen great progress there, and we'll expect it to continue.

Your next question is from the line of Gina Wang with Barclays. Thank you for taking my questions.

I will ask one regarding the IT for your C&P franchise. I know you mentioned that you already started processing in Europe. Maybe if you can provide some update there and also your strategy in the U.S. And the second question is regarding the 349 AATD. You completed the SAD and also started MAD end of last year. Maybe share with us what you are looking for regarding the data update.

Thanks very much, Gina, for your questions. Alexander, I'll handle the IP questions and then hand it over to Greg. Um, so, uh, in, uh, in essence, I mean, we, we stay, uh, as we, uh, as we said in, uh, in January that, uh, we've initiated action against the send us in the unified court in Munich. Um, we have no further updates to, to provide on European IP action. Uh, it's underway. It's in process. Uh, and we expect at the moment. to receive a decision in the next 12 to 15 months. Should there be an update, we will, of course, provide that to you in due course. As regards the United States, if and when we see conduct that we believe infringes our intellectual property in the US or elsewhere, we will take appropriate action at that time to defend against infringement. So those are the updates, basically, as we go. We'll continue to keep us updated as this unfolds. But we're following through on our commitment to defend our intellectual property and our innovation. Over to you, Greg.

Yeah, thanks, Gina. I love talking about BMN349, a molecule for, those who aren't familiar, for alpha-1 antitrypsin deficiency-related liver disease. So this is a small molecule. It will be titratable. It has the potential to bind to Z protein as it's created in patients who have alpha-1 antitrypsin deficiency. By doing so, it decreases that Z protein's ability to misfold and form polymers in the liver, which lead to fibrosis and ultimately in some patients, liver failure. The oral therapy is one that also, because it's titratable and because it has about a 100, 150-fold differential between how it binds to the Z protein versus the native M protein, it has the potential to be used in patients who are not just homozygous ZZ alpha-1 antitrypsin, but heterozygous as well. And the implication here is, of course, we're running a healthy volunteer study, multiple ascending doses. The usual PK, of course, along with safety profile will be looked at very closely from that. But there is a nuance in these protocols where a handful of patients, both of the MZ as well as the ZZ phenotypes, excuse me, genotypes, are going to potentially, you know, they are going to be able to be enrolled in And though, you know, again, these are limited duration studies, we may get some insights into the pharmacodynamics of circulating Z protein and circulating Z polymers as well. So fingers crossed, that study is open for enrollment, again, for the handful of patients as well as for healthy volunteers right now. And we're plowing forward, working with regulators around the globe also to clarify what the path forward is. both for ZZ as well as MZ genotypes would be for a molecule that can accomplish what I described.

Your next question is from the line of Paul Matias with Stifel.

Hey there. Thanks for taking our question. This is Julian on for Paul. I'm just curious if you'd be able to share a little bit more color on what you learned from the two biopsies that you did in the DMD study. And since they were at a relatively early time point. Just curious, you know, what were you looking for exactly in order to be confident in your assumptions and goals for this 10% dystrophin goal that you've laid out? Thank you.

Yeah, thank you, Julian. This is Greg Freiberg again, and I think you said it nicely. These were two biopsies done of the muscles of boys who had been treated at the six milligram per kilogram cohort for just 12 weeks, 12, 13 weeks. And so in that regard, if you have an S-shaped curve in terms of what we would expect in terms of over time and protein expression, we were not at the steep part of the curve yet. So there is a limited amount that one can say mathematically, but I will tell you that directionally, we wanted to ask a couple of really key questions. One was whether or not our assumptions with the modeling would translate into humans. Are we able to get the drug into the muscle? And we could quantify it as well. And the answer there was yes. The second question would be, you know, we are targeting a novel splice variant. Again, the goal here is to produce not micro dystrophin, but near full length dystrophin. And so from that standpoint, we were able to see that the gene product was being produced in the cells of these boys And finally, of course, the end, at least end of the biomarker story, would be to measure that near full-length dystrophin. And we were able to measure that consistent with our models. And so in that regard, we're hopeful, again, that this 25-week data is going to be very helpful at giving us a line of sight for whether or not that 10% target is going to be achievable. I would say that pertinent negatives were taken off the table that had never been tested in humans before. And though it's just two patients and though it's early, that gives us, you know, a good line of sight that when we hit 25 weeks, this is going to be useful information.

Next question is from the line of Akash Tiwari with Jefferies.

Hey, thanks so much. Maybe just on BD, I mean, if you think about infragatinib, there is, you know, this kind of potential of an oral therapy that has similar, if not better efficacy than Voxogo. And, you know, I think for a lot of investors, that's a big reason why they have difficulty modeling the terminal value on Voxogo. There are companies like Relay, which, you know, have assets that have the same mechanism as Infragratinib, and I think they're looking for strategic options. What's the appetite for Biomarin to kind of have their own Infragratinib-like approach in achondroplasia? Is your team very confident that CNP is the only way forward, or is there potential that, you know, you could be looking to in-license one of these assets? Thank you.

Thank you for the question, Akash. You know, our business development focus is really around genetically defined conditions. We're certainly interested in leadership positions that we're establishing in skeletal conditions. and that we already have in enzyme therapies. So that is somewhat of an overlay to our business development activities. But we're very comfortable right now with our leadership position, with the indications in development for VoxOgo, which is really exciting in so much that CNP can reach those indications like ISS and Nunes and Turners and Chocs. which is not a possibility, as you know, for FGFR. And in these sorts of disease states, efficacy is very important, but so is safety. And the profile of safety in CNP and treating from infancy is absolutely critical. And that's a hurdle, a high hurdle that any FGFR is going to have to establish and produce a significant amount of evidence to really, I think, reassure both physicians and caregivers. So it's a high bar. Right now, we're focused on CNP. We think that, at the moment, is the path to sustained leadership in skeletal conditions.

Your next question is from the line of Ellie Marley with UBS.

Hey guys, thanks so much for taking the question. So for Voxoco, do you expect the mix of U.S. and ex-U.S. revenues to remain stable, or do you see the contribution from ex-U.S. increasing over 25 and 26? And then in the U.S., I guess, what's the proportion of eligible patients with a contraplasia who are not currently treated? And I guess for those patients, why do you think this is? Is it that the patients aren't, you know, currently under care by the right prescribers? or do you expect less penetration in the older patients? I guess, what do you see sort of longer term as the potential for uptake and penetration into this population? Thanks.

So, thank you so much for the question. I think that, you know, first to the first question in terms of the contribution of the U.S., being at roughly 25% today, we definitely see that increasing. As you know, our overall portfolio, the contribution from ex-U.S. is about two-thirds. It's split two-thirds and one-third in the U.S., and so we certainly anticipate the U.S. contribution increasing over time as we continue our growth trajectory in the United States specifically. Now, in terms of your question around patients not treated, I mean, I do want to come back to the fact that where we are seeing the bulk majority of new patient starts, is in the zero to five population today. That, of course, was not the case when we were first launched. We launched in the five-plus-year-old cohort, and so, of course, that was where the bulk of our patients were. So the rough split today, if you just look at how many patients are on treatment in the rough split, it skews more toward the zero to five, but that's a timing component. So really new patient stars were really targeting the youngest patients. And in terms of patients not treated, the why, I mean, I think that there's, probably a myriad of reasons that we could conclude. Some of it would be awareness. Some of it would be knowing where the prescriber, the treater, would actually be. They might be being treated in pediatric offices today. And that is precisely why we are really, really focused on ensuring that there is broad awareness of the treatment options, seeing that Voxogo was the first and the only treatment option for aches and dyplasia. So we want awareness and then comfort with the treaters and prescribers We want them to be very comfortable using it, and that's precisely what we're working on, and that is why we're increasing our commercialization efforts in the United States to ensure that. I know, Greg, you might have something to add.

If I could just add as well, I mean, it is, of course, a complex decision that patients and their families go through with their physicians, whether to treat or not treat. What we are focused on in the R&D organization is continuing to provide data continuing to build on the data set that we have out there. Again, this is not just a story about one-year average growth velocity. We want to publish our two-, three-, four-year data. We have over 6,000 patient years of safety data at this point. And again, these are infants. So again, that means something to those treaters. And finally, this isn't just a story about AGV or even final adult height by itself. The story, of course, is all about the wellness and health of these patients. And, you know, we've recently published our proportionality data, you know, at three years. That's statistically significant compared to control. You know, quality of life measures, we've published these, craniofacial, foramen magnum. Again, you put all of this together. And then, of course, seeing the community evolve and seeing the guidelines, the independent guidelines that were published, you know, identify these patients, start them as early as possible. We're hoping that that starts to tip the balance with the comfort level when the physicians are in the office with these infants and their parents making these decisions.

Your next question is from the line of Cortez Polares with BMO Capital Markets.

Hi, everyone. Thanks for taking our question and congrats on the strong numbers. Great to see that three-fourths of OXOGO sales coming from ex-U.S. Maybe one question follow-up on Akashi's question on DD. In the alpha-1 in the patient's space, there are that can address both the liver and the lung manifestation of the disease, and these approaches already have clinical validation, early clinical validation. Given your interest in that space, would you consider different modalities to complement your pipeline modalities, or You prefer to go only with one modality in that disease. Thank you.

I believe we were talking about the alpha-1 antitrypsin patients. And I'm sorry, it broke out a little bit. And the disparity between liver and lung, does that?

I was asking about RNA editing approaches in alpha-1 antitrypsin deficiency patients. and whether you would have interest in such approaches to complement your approach in your pipeline.

With regard to BMN349, you're correct. It's focused on the liver, and again, the challenges of trying to solve both the lung and the liver problems we've seen across the industry, we've focused on a mechanism, again, that is liver-focused. Now, presumably, because of the difference between selectivity for M and Z protein, this would be a therapy that could be given in conjunction with enzyme replacement as well, which would address some of the lung challenges. As of this point, that's our approach from the R&D standpoint. And Alexander, anything that you want to add from a strategic?

I think you said it well.

It's early days, and we're very hopeful, again, that we're going to have a differentiated mechanism of action that might work quite nicely in combination with other therapies like enzyme replacement, potentially others.

Your next question is from the line. I'm Mohit Bensal with Wells Fargo.

Hi. This is Sadia Rahman on for Mohit. Thanks for taking our question. Another question on DMD. So are there any biomarkers like splicing levels that would be presented this year that could help us understand how compared to other agents? And can you talk about how those biomarkers were tracking in that early data? And also your decision to go up to nine mgs per keg to initiate that cohort. wondering if that was based on the analysis that you did on the 13-week data at six megs. Yeah, thank you.

Yeah, thanks for the question. Let me take the second question first. The nine milligram cohort was a planned step, and there could be potentially another step as well. The trigger to open that was simply one from the data monitoring committee, the independent DMC, and again, nice to know that they, again, approved that, and that speaks to, again, the safety and the benefit that they were seeing. Your other question was with regard to other biomarkers. We only looked at the muscle biopsy in those patients at 13 weeks, and I've shared with you what we've looked at in those. Of course, how you measure full-length dystrophin is can be different. And we've seen that, again, whether you're looking at normalized values, which assay. Suffice to say, we're actually looking at multiple different assays for dystrophin levels, and we will be as transparent as possible when we present our data. we'll want to make sure, again, that that totality of the data is represented in addition to the clinical and PK data that's available. So nothing else to share now, but we're absolutely looking at a variety of not only biomarkers, but we are measuring functional levers in these patients as well. And our, of course, ultimate hope is that we're not just treating to increase dystrophin, but to make these boys' lives better and have them be more functional. So more to come, but nothing else to share at this point.

Your next question is from the line of Olivia Breyer with Kantar Fitzgerald.

Hi, good afternoon. Thank you for the question. How are you guys thinking about the level of growth that we might see from the enzyme business over these next couple of years? I know you've talked about a high single-digit CAGR over the next 10 or so years, but what about for 25, 26, 27? And then any comments around what the margin expansion could look like for that enzyme franchise? just especially considering, you know, patients getting older and some of these medicines are weight-based. Thank you.

Yeah, thanks, Olivia, for the question. This is Brian. I'll handle that one. So you commented on that high single-digit CAGR over the long term. That's also the goal for the midterm as well and part of what supports the $4 billion in 2027. you know, there's going to be different dynamics based on the brand, any particular brand from year to year. I mentioned, for example, this year, Naglazyme had some of that additional buying in 2024, which, you know, flattens out the growth rate a bit in 2025. Likewise for Aldurazime, which Omrin revenue is not based on or tied directly to end patient demand, but you know, supply to Santa Fe. Likewise, we expect that to be more flat in 25 over 24. But over these next couple of years, high single digit across that franchise is the goal. And within that, just a reminder, Kristen touched on it earlier, the key driver is Palantzeek. You know, we think we've got more market penetration to go there, healthy double digit growth in Palantzeek and then continued sustained growth in the enzyme business. And you're exactly right. You know, you said margin, but then kind of talked about kind of some of the individual patient dynamics. I'll touch on both. We don't disclose, you know, business unit operating margin and profitability at the business unit level, but, you know, I'll share that both of the primary business units are, you know, substantially profitable with, you know, healthy operating margins well above our consolidated global operating margin, which includes corporate costs and some unallocated R&D for the pipeline. So both franchises are generating substantial margin. And part of the sustainability and durability of that enzyme business is the patient dynamics. These patients are doing well. It's a weekly infusion for life, the enzyme therapies. And you mentioned the weight-based dosing. So that by all means is part of the durability of that franchise.

Your next question is from the mind of Alex Hammond with Wolf Research.

Thanks for squeezing me in. Just quickly on Voxogo, can you provide any color on the expected degree of switch market dynamics following potential competitor launches? And just to follow up on that as well, can you kind of dimensionalize how those dynamics may differ across geographies as well as patient age groups?

Yeah, so thank you very much for the question. So just to be very clear on our Vox Sogo numbers, I mean, competition has always been modeled into any of the assumptions we've put out there. And so I just want to make that clear. Not to mention, I think, you know, competitive landscape is not a bad thing. I think, honestly, like raising the awareness around this disease and the fact there's treatments around it is always a good thing. But to speak specifically about where we think we will, you know, continue our leadership position in particular in achondroplasia, I think that there's multiple dynamics here. You know, you can talk about certainly the notion of the potential for switching from Voxogo to another compound should it become available. And we do believe that there's going to be some stickiness to being on Voxogo so that it's almost kind of like a start and stay paradigm that we're really looking to achieve. We know that, you know, what we hear in the real world and through market research is that when patients and caregivers and their HCPs are seeing a positive experience, the barrier to switch becomes much higher because it's a trusted compound. You know what's working in that patient. And so switching, that adds an element of risk that some will not choose to take. Not to mention, this is, you know, Voxogo is a very trusted, it's a very trusted compound at this point in time. We have over 6,000 patient years of safety and efficacy data that is growing. And we're building on that body of evidence that goes well beyond height, but really talking about the overall health of these patients. Not to mention, just thinking of the experience, we have a high compliance rate. So we see on average about 95% compliance rates across the globe that is both in the U.S. as well as outside the U.S., which is really important that we continue to build on that and that we leverage that. Now thinking, I've talked a lot about what's happening in the U.S., but to remind you, 68% of the total addressable patient population lives outside of the U.S. And so these markets where we have an entrenched global footprint and a lot of experience in understanding the local dynamics in those markets, this is an area where we really think that Biomarin has a strategic advantage in so much as we have this global footprint where we know a lot of those patients are going to be. So we really do see a lot of stickiness to our business over time, both in the United States as well as ex-U.S., and we really look forward to building on this leadership position.

Thank you. This does conclude today's Q&A portion of today's call. This also comes to the conclusion of today's presentation. We thank you for joining. I will now hand today's call over to the CEO for any closing remarks.

Thank you, operator, and thank you all for joining us today. Thank you for your interest in Biomarin. As you've heard, the strategic and operational decisions that were made last year and yielding tangible results and enabling ongoing investment in innovation and growth make even greater impact on all of our stakeholders. We expect continued high performance as we benefit from Biomarin's revamped corporate strategy and operating model in 2025 and beyond, and look forward to keeping you all apprised of our progress. Thank you so much, and have a great day.

This concludes today's call. Thank you for joining. You may now disconnect your lines.