Q4 2024 Biomarin Pharmaceutical Inc Earnings Call

Speaker Change: Ladies and gentlemen, thank you for standing by and welcome to the BioMarin Pharmaceuticals fourth quarter and full year's 2024 conference call.

Speaker Change: All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during that time, press star followed by the number one on your telephone keypad.

Speaker Change: As a reminder, today's call is being recorded. I will now hand today's call over to Traci McCarty.

Group Vice President, Investor Relations. Please go ahead.

Traci Mccarty: Thank you, Operator. To remind you, this non-confidential presentation contains forward-looking statements about the business prospects of Biomarin Pharmaceutical, Inc., including expectations regarding Biomarin's financial performance, commercial products, and potential future products in different areas of therapeutic research and development.

Traci Mccarty: Results may differ materially depending on the progress of Biomarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market, and developments by competitors. And those factors detailed in Biomarin's filings with the Securities and Exchange Commission.

such as 10-Q, 10-K, and 8-K reports.

Traci Mccarty: In addition, we will use non-GAAP financial measures as defined in Regulation G during the call today.

Traci Mccarty: These non-GAAP measures should not be considered in isolation from, as substitutes for, or superior to financial measures prepared in accordance with U.S. GAAP, and you can find the related reconciliations to U.S. GAAP in the earnings release and earnings presentation.

Traci Mccarty: Both of which are available in the Investor Relations section of our website. Please note that our commentary on today's call will focus on non-GAAP financial measures unless otherwise indicated.

Speaker Change: On the call from Biomarine Management today are Alexander Hardy, President and Chief Executive Officer, Brian Mueller, Chief Financial Officer, and Henry Fuchs.

Speaker Change: Chief Commercial Officer, and Greg Freyberg, Chief R&D Officer. I will now turn the call over to Byron's President and CEO, Alexander Hardy.

Speaker Change: Thank you, Traci, and good afternoon, everyone. Thank you for joining us today for our fourth quarter 2024 results update.

Speaker Change: We are pleased to see Biomarine's new strategic vision starting to be realized, amplifying our financial performance and creating value for shareholders, and most importantly, making a profound impact on the patients we serve.

Speaker Change: The specific initiatives introduced throughout 2024 include the prioritization of our most promising pipeline candidates,

The reorganization.

Speaker Change: Biomarine's operating model now centered around business units and the ongoing realization of the 500 million cost transformation program.

Speaker Change: Combined, these initiatives give us the framework to achieve our ambitious mid- and long-term growth outlook. We are already producing positive results.

Speaker Change: Starting with our financial performance, 2024 was a year of record growth and profitability.

Speaker Change: We are pleased to share that full year 2024 exceeded market expectations across our Guided Items.

Speaker Change: Year over year, top line grew 18%. Non-GAAP operating margin expanded over 900 basis points.

Non-GAAP diluted earnings per share increased 69 percent.

is financial strength.

Speaker Change: 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 Biomarine's increasingly profitable commercial portfolio.

Speaker Change: Leadership Across Skeletal Conditions is anchored to Global Expansion, BoxOgo for Achondroplasia.

Speaker Change: 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.

Speaker Change: strengthened 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 on this business unit.

Speaker Change: The strategic prioritization of our pipeline last year resulted in the advancement BMN-351 for Duchenne muscular dystrophy.

Speaker Change: and BMN333, a long-acting CNP, two candidates that may provide highly differentiated treatment options to the conditions they address.

Speaker Change: We look forward to early clinical data results later this year for both candidates.

Speaker Change: This year we plan to share results from our Phase 3 study with Pallan Zeke for adolescents.

Speaker Change: This potential age expansion represents an opportunity to provide 12 to 17 year olds significant

Speaker Change: a sustained fee response, as well as unrestricted diet should data be supportive.

Speaker Change: In summary, we're excited by the progress we're making at PharmAren.

Speaker Change: The strategic and operational decisions made last year yielding tangible results and allowing us to make an even greater impact for our patients, our employees, and our shareholders.

Speaker Change: 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.

Speaker Change: I would like to thank our employees around the world for their contributions in 2024.

Speaker Change: I look forward to the progress we will make together in 2025.

Speaker Change: 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.

Brian Mueller: 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 measures.

Brian Mueller: All 2024 results will be available in our upcoming Form 10-K, which we expect to file in the coming days.

Brian Mueller: We are very pleased with Biomarin's execution in 2024, especially during a year of significant transformation.

Brian Mueller: School 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.

Brian Mueller: Double-digit increases from VoxOgo were a strong contributor to growth in the fourth quarter and full year.

Brian Mueller: Also contributing to record results in 2024, the enzyme therapies 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.

Brian Mueller: 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.

Brian Mueller: 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.

Brian Mueller: We expect that R&D expense will increase in 2025 as we ramp up our BMN-351, BMN-333, and VoxOgo Indication Expansion Studies.

Brian Mueller: 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,

Brian Mueller: higher Voxelgo commercialization expenses and costs associated with our ERP implementation, partially offset by lower Roktavian spending.

Brian Mueller: Moving to profitability, we are pleased with the positive impact of Biomarin's strong revenue performance.

Brian Mueller: coupled with the ongoing progress of our cost transformation program outlined last year.

Brian Mueller: As a result of this momentum, non-GAAP operating margin reached 28.6 percent for the full year 2024, an increase of 9.2 percentage points versus the full year 2023.

Brian Mueller: Fourth quarter non-gap 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.

Brian Mueller: In addition to significant revenue growth in 2024, BioMarin achieved its 2024 objective of accelerating profitability growth at meaningful and sustainable levels.

Brian Mueller: 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.

Brian Mueller: Omarin's increasing profitability is also generating significant levels of operating cash flow.

Brian Mueller: with 573 million dollars of operating cash flow for the full year 2024. A 260 percent increase over the full year 2023.

Brian Mueller: Amarin'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.

Brian Mueller: both through our internal research and development investments and external innovation through our business development strategy.

Brian Mueller: 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.

Brian Mueller: In 2025, strong growth is expected from Voxogo, Limousin, Palanzec, and Brainura, and we expect a 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.

Brian Mueller: In 2024, the Enzyme Therapies business benefited from unusually high alderzyme contributions in the third quarter. Similarly, Eglizyme demonstrated very strong growth and benefited from new patient additions as well as order timing.

Brian Mueller: Due to these unique dynamics, we expect lower year-over-year growth rates for naglozyme and alderozyme in 2025.

Brian Mueller: Importantly, Bomarin'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.

Brian Mueller: Foxilgo is expected to be a strong contributor to full year 2025 total revenue growth.

Brian Mueller: And we estimate it will contribute between $900 million and $950 million to 2025 total revenue.

Brian Mueller: 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.

Brian Mueller: 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%.

Brian Mueller: Our guidance is supported by continued strong revenue growth along with the impact of the ongoing cost transformation initiatives.

Brian Mueller: 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.

Brian Mueller: Based on the continued implementation of these activities in 2025, this is an important stepping stone towards the achievement of our target 40% non-gap operating margin next year.

Finally, for non-GAAP diluted earnings per share.

We expect between $4.00 and $0.20.

$4.40 per share for the full year 2025.

which is the midpoint.

Brian Mueller: represents a two-times top-line growth rate over 2024, driving towards another expected year of leveraged profitability growth for Biomarin.

Brian Mueller: 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.

Brian Mueller: I will now pass the call to Cristin to discuss the drivers of our commercial performance.

Cristin?

Cristin: Thank you, Brian. The team delivered strong growth in 2024, led by the continued global expansion of VOXOGO, increasing palindzic penetration, and demand for enzyme replacement products. And we expect 2025 to build on this momentum.

Cristin: Record VoxZoga 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.

Cristin: 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.

Cristin: In international markets, we also saw significant VoxOgo year-over-year growth throughout 2024.

Cristin: and deeply penetrated markets such as Germany, we focused on early diagnosis and treatment of the incident population.

Cristin: 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.

Cristin: To provide insight into these global dynamics, today we are providing the percentage of actual total Voxelga revenues split between the U.S. and the combined contributions from outside the U.S. or O.U.S.

Cristin: For full year 2024, of Voxobo total revenue of $735 million, 24% was from the U.S. and 76% was from all countries outside of the U.S.

Cristin: For fourth quarter 2024 of VoxOgo total revenue of $208 million, 26% was from the U.S. and 74% was from OUS.

Cristin: 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 VoxOvo's proven safety and efficacy profile.

Cristin: Outside of the U.S. 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 benefits.

Cristin: 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.

Cristin: By 2027, we are focused on increasing Voxelo access to more than 60 countries.

Cristin: 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 Voxova treatment.

Cristin: Further supporting our expansion efforts, we are very pleased to see two publications highlighting the importance of early Voxogo treatment.

Cristin: Recently published international guidelines recommend early diagnosis followed by early Voxelgo treatment.

Cristin: These guidelines were independently created to facilitate maximum clinical benefit for children with achondroplasia and to provide families confidence when choosing Voxzogo treatment for infants and young children with achondroplasia.

Cristin: Also, as published in the December issue of Med, Oxogo 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.

Cristin: We are confident that this will be another year of strong execution and record growth for Voxobo, the only approved treatment for infants and children with achondroplasia.

Cristin: At the same time, we are using our experience in achondroplasia to prepare for the 2027 launch of Voxobo for the treatment of hypochondroplasia should Phase III data be supported.

Cristin: 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

Cristin: Now, moving over to our enzyme therapies, global demand drove strong results across all of BioMarin's marketed products.

Cristin: Double-digit Palanzec revenue growth in the quarter was the result of substantial patient uptake in the U.S. and ongoing expansion in Japan.

Cristin: In addition, we saw significant year-over-year growth in Maglazym, Zimazim, and Brunnera during the quarter, enabled by our ongoing efforts to find new patients and maintain treatment continuity for those on therapy.

Cristin: 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.

Cristin: 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.

Cristin: Now, moving to Palantzik, with its highly differentiated profile in that it works across all PKU phenotypes, growth has been driven by new patient starts and re-initiation of treatment from adults with PKU.

Cristin: 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 III 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.

Cristin: In conclusion, I am very pleased with the team's execution in 2024 during a year of transformation across the organization.

Cristin: 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.

Cristin: 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.

Thank you, Cristin. We're making great progress across our pipeline.

Greg Freyberg: 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.

Greg Freyberg: Our goal for BMN 333 is therefore to leverage this potential for greater exposure, to deliver superior efficacy while maintaining an acceptable safety profile.

Greg Freyberg: 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.

Greg Freyberg: For BMN 351 and Duchenne's muscular dystrophy, our Phase 1-2 study is advancing with enrollment and dosing in the 9 mg per kg cohort.

Greg Freyberg: As previously shared, six boys were treated at the six 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.

Greg Freyberg: 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 6 milligram per kilogram cohort.

Greg Freyberg: With VARCSOGO in additional skeletal conditions, we continue to advance our canopy clinical programs. Our pivotal phase 3 study in hypochondroplasia is rapidly recruiting and we remain on track to complete enrollment to the treatment arms of the study in the first half of 2025.

Greg Freyberg: Pivotal data from that program will be available in 2026, and a potential approval could come in 2027, assuming the data are supportive.

are two phase two canopy studies.

Greg Freyberg: one in idiopathic short stature, and another encompassing Noonan syndrome, Turner syndrome, and Shocks deficiency are screening and enrolling patients.

Greg Freyberg: Moving to Palantzek, our phase 3 study in adolescents age 12 to 17 is on track for data readout to support US and European supplemental filings in the second half of the year.

Greg Freyberg: Recall, Palin-Zeke works across all PKU phenotypes, delivering potent phenylalanine reduction and can even afford some patients the potential for an unrestricted diet.

Greg Freyberg: We believe that this filing for adolescents could allow for patients and their families to manage the challenge of PKU and dietary restrictions from an early age, thereby supporting a smoother transition to independent adult living.

Greg Freyberg: Finally, with BMN 349, 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.

Greg Freyberg: 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.

Greg Freyberg: Thank you for your continued support, and we now open the call to your questions. Operator?

Speaker Change: At this time, if you would like to ask a question, press star followed by the number one on your telephone keypad.

Greg Freyberg: 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.

Speaker Change: Your first question is from the line of Philip Nadeau with T.D. Cowan.

Philip Nadeau: Good afternoon. Thanks for taking our question. We want to zero in on the VoxOgo guidance.

Speaker Change: We've never expected to be up 200 million year over year. That's healthy, but it is decelerating. Can you talk a bit more on...

Philip Nadeau: where you expect that growth to come from, in particular, 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.

Philip Nadeau: Hi, Phil. This is Brian. Thanks for the question. I'll start and then ask Cristin to provide some more color. So, in terms of the overall guide, you accurately pointed out that, you know, close to $200 million of absolute

dollar growth.

It's still strong growth.

Philip Nadeau: What we're observing here as VoxOgo Global Revenue gets to scale at close to three quarters of a billion dollars that there's

Philip Nadeau: you know, some law of large numbers at play here. VoxOgo grew 56 percent.

Philip Nadeau: in 2024, which was impressive, but not sustainable on this increasing revenue base.

Philip Nadeau: 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 percent.

and with.

Philip Nadeau: The growth of 56% last year, 25% as implied by the Vox Ogo range that we provided today, and continued growth in the what may be, you know, low 20% going forward. Again, the growth rate will decrease over time as the base increases.

Philip Nadeau: We are on track for both the $4 billion and the 25% plus CAGR.

Speaker Change: 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 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.

Speaker Change: 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.

Speaker Change: 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.

Speaker Change: where we have commercialization efforts ongoing and expect to expand into over 60 by 2027.

Speaker Change: 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.

Speaker Change: So, just as a reminder, in the U.S. there was a bit of a delay in terms of the timing of when infants

Speaker Change: 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 0-5 population.

Speaker Change: So where we're really seeing a lot of growth coming out is a new patient starts in that 0-5 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 Voxogo.

Speaker Change: 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.

Speaker Change: 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, so breadth and depth.

Speaker Change: 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.

Speaker Change: And then we're leveraging, you know, our continued footprint outside the U.S.

Speaker Change: to build on this growth trajectory. So I'd say we're really focused not only in the U.S., but of course in some of our international markets.

Speaker Change: 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

Jessica Fay: Your next question is from the line of Jessica Fay with J.P. Morgan.

Jessica Fay: 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.

Jessica Fay: 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.

Speaker Change: Anything you would call out quarter over quarter or year over year for the first quarter in the enzyme business, like any international ordering patterns to think about there? Thank you.

Speaker Change: 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.

Speaker Change: I wouldn't point to specific known ordering patterns, granted we're just, you know, midway through the quarter here and, you know,

Speaker Change: 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 bolus order pattern dynamic from time to time. So nothing is specifically to point to there, but since you mentioned the corridors, I will point out, as I mentioned in the prepared remarks.

You know, we do expect our growth in 2020.

Speaker Change: 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 Cristin 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.

Speaker Change: Thanks Brian. Hey Jess, thanks very much for the question with regard to business development.

Speaker Change: 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.

Speaker Change: making sure we've got the right business development team in place, the capabilities in place, and then obviously, you know, these strong financial results are producing more strategic flexibility for us.

Speaker Change: and we're very excited about you know what we're seeing from the business development standpoint. The JP Morgan meeting we had 155 meetings at JP Morgan.

Speaker Change: It's a reflection of the recognition of the strengths of bimarin from a research, development, manufacturing, and commercialization, and specifically on the commercialization, what we hear from potential investors.

partners is our ability to commercialize across the globe.

Speaker Change: And we're now in the process of looking at these various assets. You asked what stage these assets are at. We're looking at a range of stages. We're looking at preclinical assets and also clinical assets.

Speaker Change: Again, we expect to be able to strengthen our outlook for growth into the longer term.

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

Speaker Change: 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.

Speaker Change: in terms of reaching sustained levels, similar to the Sinomagus monkey model that we were referring to. We believe that several fold increases, whether it's an AUC or a 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.

Speaker Change: With regard to the first question, can you just repeat the question for me? My apologies. I missed the nuance of the first question.

Glucose Hormone.

But yeah.

not only, you know, best-in-class...

Speaker Change: 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,

Speaker Change: 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, re-evaluate 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.

Speaker Change: Your next question is from the line of Corey Kasemov with Evercore ISI.

Corey Kasemov: 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,

Speaker Change: 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.

Speaker Change: We, of course, we've picked a chemical backbone, a non-morpholino backbone, that has a slower

Speaker Change: 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.

Speaker Change: 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 at a year. Of course, we would ultimately want to demonstrate that with actual data, but the 25-week time

Speaker Change: 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.

Speaker Change: 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.

Speaker Change: 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 percent or not.

Speaker Change: Your next question is from the line of Christopher Raymond with Piper Sandler.

Speaker Change: Thanks. Two questions just on the ERT business. You guys have, I think, for some time now talked about being able to inflect, you know, sort of the demand higher on harmonizing diagnostic protocols, I think, across all geographies.

Speaker Change: I know this print was 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 you know contribution from this

Speaker Change: Diagnostic Harmonization, is this something that's, you know, where are we I guess in terms of maybe which inning in terms of being able to affect that that change?

Speaker 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

Speaker Change: 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.

Speaker Change: Yeah, this is Greg Freiberg. Thanks. Just to clarify, it 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.

Speaker Change: This is Cristin Hubbard, and to answer your question a little bit about the kind of the diagnostic components.

Speaker Change: 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,

Speaker Change: 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.

Speaker Change: 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 NPS 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.

Speaker Change: 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 Palanzec 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.

Speaker Change: 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 palin-seq that it works across all PKU phenotypes.

Speaker Change: You have the potential for normal fee 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.

Speaker Change: Your next question is from the line of Gina Wang with Barclays.

Gina Wang: Thank you for taking my questions. I will ask one regarding the IP.

Gina Wang: for your C&P franchise. I know you mentioned that you already started processing in Europe.

Gina Wang: maybe if you can provide some update there, and also your strategy in the U.S. And the second question is regarding the 349 in AATD. You complete a SAD and also started MAD end of last year. Maybe share with us what you are looking for regarding the data update.

Speaker Change: Thanks very much, Gina, for your questions. Alexander, I'll handle the IP questions and then hand it over to Greg.

Speaker Change: In essence, I mean, we stay, as we as we said, in.

Speaker Change: in January that we've initiated action against the senders in the Unified Court in Munich.

Speaker Change: We have no further updates to provide on European IP action. It's underway, it's in process, and we expect at the moment to receive a decision in the next 12 to 15 months.

Speaker Change: Should there be an update we will of course you know provide that to you in due course.

As regards the United States...

if and when we see conduct.

Speaker Change: that we believe infringes our intellectual property in the U.S. or elsewhere, we will take appropriate action at that time to defend against infringement. So those are the updates basically steady as we go. We'll continue to keep us updated as this unfolds.

Speaker Change: But we're following through on our commitment to defend our intellectual property and our innovation.

Greg Freyberg: Over to you, Greg. Yeah, thanks, Gina. I love talking about BMN-349, a molecule for, those who aren't familiar, for alpha-1 antitrypsin-deficiency-related liver disease.

and because it has about a 100, 150-fold...

Greg Freyberg: a 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...

Greg Freyberg: All of these people are patients both of the MZ as well as the ZZ genotypes.

Greg Freyberg: are going to potentially, you know, they are going to be able to be enrolled. 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

Greg Freyberg: both for ZZ as well as MZ genotypes would be for a molecule that can accomplish what I described.

Paul Matias: Your next question is from the line of Paul Matias, Westifel.

Thank you.

Paul Matias: Hey there. Thanks for taking our question. This is Julian on for Paul.

Paul Matias: 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

Paul Matias: 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.

Paul Matias: 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.

Paul Matias: 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.

Paul Matias: 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, we are targeting a novel splice variant. Again, the goal here is to produce not micro dystrophin, but near full length dystrophin.

Paul Matias: And so, from that standpoint, we were able to see that the gene product was being produced in the cells of these boys.

Paul Matias: 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, you know, 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.

Paul Matias: for whether or not that 10% target is going to be achievable.

Paul Matias: 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.

The next question is from Lionel Vakash Tewari with Jeffries.

Speaker Change: Hey, thanks so much. Maybe just on BD, I mean, if you think about InfraGatnib...

Speaker Change: 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.

Speaker Change: There are companies like Relay, which, you know, have assets that have the same mechanism as InfraGrandNib, and I think they're looking for strategic options.

Speaker Change: What's the appetite for Biomarin to kind of have their own infragratinib-like approach in achondroplasia? Is your team very confident that C&P 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.

Speaker Change: 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 a somewhat of a

an overlay to our business development.

Speaker Change: activities. But we're very comfortable right now with our leadership position, with the indications in development for Vox Ergo, which is which is really exciting in so much that CNP can reach those indications like ISS and Noonan's and Turner's shocks.

Speaker Change: which is not a possibility, as you know, for FGFR. And, you know, in these sorts of disease states, efficacy is very important, but so is safety.

and the same profile of safety in CNP

Speaker Change: and treating from infancy is absolutely critical. And that's a hurdle, a high hurdle, that any FGFR is gonna have to establish and produce a significant amount of evidence to really, I think, reassure both physicians and caregivers.

Speaker Change: So it's a high bar right now. We're focused on CNP We think that the moment is the path to sustained leadership in in skeletal conditions

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

Ellie Murley: 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?

Speaker Change: And then in the US, I guess, what's the proportion of eligible patients with achondroplasia 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?

Speaker Change: I guess, what do you see sort of longer term as the potential for uptake and penetration into this population?

Speaker Change: So, thank you so much for the question. I think that, you know, to the first question in terms of the contribution of the U.S. being at roughly 25% today, we definitely see that increasing over time. As you know, 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.

Speaker Change: 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.

Speaker Change: your 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 and the rough split, it skews more toward the zero to five, but that's a timing component.

Speaker Change: So really new patient stars. We're really targeting the youngest patients.

Speaker Change: And in terms of patients not treated, the why, I mean, I think that there's...

Speaker Change: 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

Speaker Change: of the treatment option, seeing that Boxogo was the first and the only treatment option for aches and dysplasia. 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.

Speaker Change: 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

Speaker Change: we've also had Washington Post, which of course is a really good source for legal complaints. That quote there is really critical. We did really well. We remember this? We know people were just being fairly repetitive throughout the evening. We were just trying to find number of people we knew that were on the line. We are wonder people are needing help. We just received an email at about 10 previously from the Department of Justice at a post office, and they said, hey, we are looking at finding number of people with cancer. We also received, or they received a card from the hospital to find something quicker. So I don't know what the use of health is always in a trusted lab. I've probably seen a couple of things

Speaker Change: 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.

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

Cortez Pilares: Hi everyone, thanks for taking our question and congrats on the strong numbers. Great to see that three-fourths of Oxfogo sales coming from ex-US. Maybe one question follow-up on Akash's question on BD. In the Alpha-1 analysis in this page,

Cortez Pilares: approaches that can address both the liver and the lung manifestation of the disease and these approaches already have clinical validation, early clinical validation.

Speaker Change: 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.

Speaker Change: 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

Speaker Change: I was I was asking about RNA editing approaches in Alpha-1 and whether you would have interest in such approaches to complement your your approach in your pipeline

Speaker Change: Well, 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, you know, 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.

Speaker Change: As of this point, that's our approach from the R&D standpoint.

Speaker Change: 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.

Speaker Change: Your next question is from the line of Mohit Bansal with Wells Fargo.

Thank you.

Speaker Change: Hi, this is Sadia Rahman on for MOHEAD. 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.

Speaker Change: And can you talk about how those biomarkers were tracking in that early data?

Speaker Change: and also your decision to go up to 9 megs per keg.

Speaker Change: 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.

Speaker Change: Yeah, thanks for the question. Let me take the second question first. The 9 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.

Speaker Change: 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.

Speaker Change: 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 can be different, and we've seen that, you know, 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 review when we

Speaker Change: 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 you know at a variety of not only biomarkers but we are measuring functional 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.

Speaker Change: So, more to come, but nothing else to share at this point.

Speaker Change: Your next question is from the line of Olivia Brayer with Cantor Fitzgerald.

Olivia Brayer: 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?

Olivia Brayer: 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 patients getting older and some of these medicines are weight-based? Thank you.

Brian Mueller: Thanks, Livia, for the question. This is Brian. I'll handle that one.

Brian Mueller: 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...

Brian Mueller: 2027. 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 flattens out the growth rate of it in 2025. Likewise for Aldurazyme.

which...

Brian Mueller: is not based on or tied directly to end patient demand, but 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.

Brian Mueller: And within that, just a reminder, Cristin touched on it earlier, that the key driver is Palanzec. You know, we think we've got more market penetration to go there, healthy double-digit growth in Palanzec, and then continued sustained growth in the enzyme business.

Brian Mueller: And you're exactly right, you know, you said margin, but then kind of talked about kind of some of the individual patient dynamics.

Brian Mueller: I'll touch on both. We don't disclose business unit operating margin and profitability at the business unit level, but I'll share that both of the primary business units are substantially profitable with healthy...

Brian Mueller: operating margins well above our consolidated global operating margin which includes corporate costs and some unallocated R&D for the pipeline.

So, you know, both franchises are generating substantial margin.

Brian Mueller: And part of the sustainability and durability of that enzyme business is the patient dynamics.

Brian Mueller: You know, 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.

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

Alex Hammond: Thanks for squeezing the 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?

Alex Hammond: Yeah, so thank you very much for the question. So just to be very clear on on our VoxOgo numbers, I mean competition has always been modeled.

Alex Hammond: 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

Alex Hammond: 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.

Alex Hammond: 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.

Alex Hammond: 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.

Alex Hammond: 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.

Alex Hammond: which is really important that we continue to build on that and that we leverage that.

Alex Hammond: Now, thinking, you know, 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

Alex Hammond: 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

Alex Hammond: 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.

Alex Hammond: 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.

Speaker Change: Thank you, Alparetta, 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 are yielding tangible results.

Speaker Change: and enabling ongoing investment in innovation and growth to make even greater impact for all of our stakeholders.

Speaker Change: 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.

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