BioMarin Pharmaceutical - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 revenue was $747 million (+16% y/y), driven by VOXZOGO and steady enzyme therapies; non-GAAP diluted EPS rose to $0.92 and non-GAAP operating margin expanded to 31.1% as cost transformation benefits flowed through.
• 2025 guidance targets $3.1–$3.2B revenue, 32–33% non-GAAP operating margin, and $4.20–$4.40 non-GAAP EPS; VOXZOGO is expected to contribute $900–$950M, with growth weighted to H2 2025.
• VOXZOGO Q4 revenue reached $208M (26% U.S./74% OUS), while enzyme therapies rose 9% y/y; management emphasized early-treatment momentum in the U.S. 0–5 cohort and broader OUS penetration across 47 contributing countries.
• Consensus estimate comparisons were unavailable at the time of writing due to S&P Global access limits; use actuals below for trajectory and margin analysis (values from company documents).

What Went Well and What Went Wrong

What Went Well

• Margin and EPS leverage: Q4 non-GAAP operating margin hit 31.1% (+1,340 bps y/y), with non-GAAP diluted EPS at $0.92 (+88% y/y), reflecting revenue mix, discontinued programs, and cost initiatives.
• VOXZOGO expansion: Q4 VOXZOGO revenue was $208M (+42% y/y), with strong OUS mix (74%) and early-treatment focus in U.S. infants/young children; management noted published proportionality and guideline support for earlier therapy starts.
• Cash generation and efficiency: FY 2024 operating cash flow reached $573M (+260% y/y), supporting reinvestment and BD optionality under the $500M cost transformation program.

Quotes:

• “2024 was a year of record growth and profitability… non-GAAP diluted earnings per share increased 69%”.
• “Fourth quarter non-GAAP operating margin of 31.1% was boosted by cost transformation… and strong revenue growth”.
• “In the U.S., the majority of new patient starts… were for infants and young children under 5 years of age”.

What Went Wrong

• SG&A headwinds: Higher SG&A due to increased bad debt expense tempered some operating leverage in the quarter.
• Growth normalization pockets: Management flagged lower growth in 2025 for NAGLAZYME and ALDURAZYME given 2024 order timing bulges; overall FY25 growth profile is H2-weighted.
• Competitive and scale implications: VOXZOGO growth rates decelerate on a larger base; management modeled competition and expects “start-and-stay” stickiness but acknowledged growth moderating as scale increases.

Transcript

Operator (participant)

Ladies and gentlemen, thank you for standing by, and welcome to the BioMarin Pharmaceutical 4th Quarter and Full Year 2024 Conference Call. 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. 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 (VP of Investor Relations)

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

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, 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. On the call from BioMarin Management today are Alexander Hardy, President and Chief Executive Officer, Brian Mueller, Chief Financial Officer, Cristin Hubbard, Chief Commercial Officer, and Greg Friberg, Chief R&D Officer. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Alexander Hardy (President and CEO)

Thank you, Traci, and good afternoon, everyone. Thank you for joining us today for our4th Quarter 2024 results update. We are pleased to see BioMarin's new strategic vision starting to be realized, amplifying our financial performance, creating value for shareholders, and most importantly, making a profound impact on the patients we serve. The specific initiatives introduced throughout 2024 include the prioritization of our most promising pipeline candidates, the reorganization of BioMarin's operating model, now centered around business units, and the ongoing realization of the $500 million cost transformation program. Combined, these initiatives give us the framework to achieve our ambitious mid-term and long-term growth outlook while already producing positive results. Starting with our financial performance, 2024 was a year of record growth and profitability. We are pleased to share that full year 2024 exceeded market expectations across our guided items.

Year-over-year, top line grew 18%, non-GAAP operating margin expanded over 900 basis points, and non-GAAP diluted earnings per share increased 69%. This financial strength puts us on the path to 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 for Voxzogo 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. Strengthened from our enzyme therapies, growing at 9% in the 4th quarter year-over-year, and now approaching $2 billion annual revenues, gives us confidence in our long-term outlook, high single-digit GAAP on this business unit.

The strategic prioritization of our pipeline last year resulted in the advancement of BMN 351 for Duchenne muscular dystrophy and BMN 333 for long-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. Mid-year, we plan to share results from our phase three study with Palynziq for adolescents. This potential age expansion represents an opportunity to provide 12 to 17-year-olds significant and sustained Phe 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 are 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, and continue our journey towards delivering the mid- and long-term financial outlook provided at Investor Day last year. I would like to thank our employees around the world for their contributions in 2024. We 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.

Brian Mueller (CFO)

Thank you, Alexander. Please refer to today's press release for detailed 4th quarter and full year 2024 results, including reconciliations of GAAP to non-GAAP financial measures. 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. 4th quarter 2024 revenues increased 16% year-over-year to $747 million. Double-digit increases from Voxzogo were a strong contributor to growth in the 4th 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 Voxzogo and five new indications, offset by a reduction in spend for deprioritized programs. In the 4th 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 4th quarter. We expect that R&D expense will increase in 2025 as we ramp up our BMN 351, BMN 333, and Voxzogo indication expansion studies. For both the full year and 4th quarter of 2024, non-GAAP SG&A expense increased year-over-year, primarily due to a bad debt reserve, higher Voxzogo 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. 4th 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. BioMarin'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 Voxzogo, Vimizim, Palynziq, and Brineura, and we expect the majority of year-over-year revenue growth in the 2nd half of the year, as growth in the business in the 1st half of the year translates to an increased revenue base in the 2nd half of the year. In 2024, the enzyme therapies business benefited from unusually high Aldurazyme contributions in the 3rd quarter. Similarly, Naglazyme 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 Naglazyme and Aldurazyme 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.

Voxzogo 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 and $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 Cristin to discuss the drivers of our commercial performance. Cristin?

Cristin Hubbard (Chief Commercial Officer)

Thank you, Brian. The team delivered strong growth in 2024, led by the continued global expansion of Voxzogo, increasing Palynziq penetration, and demand for enzyme replacement products, and we expect 2025 to build on this momentum. Record Voxzogo 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 0 to 5-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 Voxzogo 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 Voxzogo revenues split between the U.S. and the combined contributions from outside the U.S., or O.U.S. For full year 2024, of Voxzogo total revenue of $735 million, 24% was from the U.S. and 76% was from all countries outside of the U.S. For 4th quarter 2024, of Voxzogo total revenue of $208 million, 26% was from the U.S. and 74% was from O.U.S.

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 Voxzogo's proven safety and efficacy profile. 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 infant population to drive treatment with Voxzogo from infancy to provide maximum therapeutic benefit. Now, turning to growth strategies in other international markets, we intend to more deeply penetrate countries where Voxzogo is already available and include patient starts in new countries that are added this year. By 2027, we are focused on increasing Voxzogo 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 bases, additional platforms to broaden reach, and the introduction of new initiatives to raise awareness and adoption of Voxzogo treatment. Further supporting our expansion efforts, we are very pleased to see two publications highlighting the importance of early Voxzogo treatment. Recently published international guidelines recommend early diagnosis followed by early Voxzogo treatment. 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. Also, as published in the December issue of Med, Voxzogo 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 Voxzogo, 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 Voxzogo for the treatment of hypochondroplasia should phase III 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 Voxzogo 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 Palynziq 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 Naglazyme, Vimizim, and Brineura 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, and we expect to roll out these programs into multiple countries over the coming quarters. Now, moving to Palynziq, with its highly differentiated profile in 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 Phe in 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 2nd 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?

Greg Friberg (Chief R&D Officer)

Thank you, Cristin. 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 2nd half of the year, with detailed data to be presented at a scientific congress in the 1st half of 2026. For BMN 351 and Duchenne muscular dystrophy, our phase one-two study is advancing with enrollment and dosing in the 9mg/kg cohort.

As previously shared, six boys were treated at the 6mg/kg level, and we are eagerly awaiting the 25-week proof of concept biopsy data for this cohort, which we expect to present at a scientific congress in the 2nd 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 6mg/kg cohort. With Voxzogo, in additional skeletal conditions, we continue to advance our Canopy clinical programs. Our pivotal phase III study in hypochondroplasia is rapidly recruiting, and we remain on track to complete enrollment to the treatment arms of the study in the 1st half of 2025. Pivotal data from that program will be available in 2026, and a potential approval could come in 2027, assuming the data are supportive.

Our two phase II Canopy studies, one in idiopathic short stature and another encompassing Noonan syndrome, Turner syndrome, and SHOX deficiency, are screening and enrolling patients. Moving to Palynziq, our phase III study in adolescents, age 12 to 17, is on track for data readout to support U.S. and European supplemental filings in the 2nd half of the year. Recall, Palynziq 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 PKU and dietary restrictions from an early age, thereby supporting a smoother transition to independent adult living. 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 volunteer 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?

Operator (participant)

At this time, if you would like to ask a question, press star followed by the number one 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 Cowen.

Philip Nadeau (Managing Director and Senior Biotechnology Research Analyst)

Good afternoon. Thanks for taking our question. We want to zero in on the Voxzogo guidance. 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 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.

Brian Mueller (CFO)

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 close to $200 million of absolute dollar growth, it's still strong growth. What we're observing here as Voxzogo global revenue gets to scale at close to $750 million, that there's some law of large numbers at play here. Voxzogo 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%.

With the growth of 56% last year, 25%, as implied by the Voxzogo 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.

Cristin Hubbard (Chief Commercial Officer)

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, 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 0-5 years old population.

Where we're really seeing a lot of growth coming out is in new patient starts in that 0-5 years 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 Voxzogo. We're excited to see that growth in that younger population. In addition to that, we're definitely working on expanding our prescriber base. We're seeing that the biggest expansion in terms of growth of prescribers is in the pediatric endocrinologists, which is exactly the target area for us. What we're doing to continue those types of efforts is we're investing more in commercialization, namely in our field personnel. Out there driving both reach as well as depth, so 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 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 U.S., 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.

Operator (participant)

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

Jessica Fye (Managing Director and Equity Research Analyst)

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 1st quarter in the enzyme business, like any international ordering patterns to think about there? Thank you.

Alexander Hardy (President and CEO)

Brian, do you want to start with the last question, and then I'll handle business development?

Brian Mueller (CFO)

Yeah, of course. Thanks for the question, Jess. I wouldn't point to specific known ordering patterns. Granted, we're just midway through the quarter here, and as you know, our diversified global business, especially across the different enzyme therapy brands, is subject to some of that large single payer bolus 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, we do expect our growth in 2025 to be weighted to the 2nd half of the year. So whether it be the enzyme therapies or Voxzogo, 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.

Alexander Hardy (President and CEO)

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 growth outlook over the coming years. Last year, as you know, it 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 a business development standpoint. The J.P. Morgan meeting, we had 155 meetings at J.P. Morgan.

It's a reflection of the recognition of the strengths of BioMarin from a research, development, manufacturing, and 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 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.

Operator (participant)

Your next question is from the line of Salveen Richter with Goldman Sachs.

Salveen Richter (Managing Director and Global Investment Research Analyst)

Hi, thanks for taking our question and congrats on the progress. This is Tommy Owen for Salveen. Wondering if we can get your thoughts on the durability and safety of a growth hormone and CNP 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.

Greg Friberg (Chief R&D Officer)

Yeah, this is Greg Friberg. Thank you, Salveen. 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 cynomolgus 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. With regard to the first question, can you just repeat the question for me? My apologies.

I missed the nuance of the first question.

Salveen Richter (Managing Director and Global Investment Research Analyst)

Growth hormone.

Greg Friberg (Chief R&D Officer)

Thank you. With regard to the growth hormone combination, our goal is to develop a single-agent CNP 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 too high-priced therapies, we think that trying to optimize the agents that we have available to us are our goal. Certainly, as data evolves, we can, 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.

Operator (participant)

Your next question is from the line of Cory Kasimov with Evercore ISI.

Cory Kasimov (Senior Managing Director and Biotech Analyst)

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.

Greg Friberg (Chief R&D Officer)

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 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 6mg/kg dose level, and we are going up in the dose as well. So we're in a 9mg 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 6mg is going to be able to give us a very clear indication of whether we're on that track for 10% or not.

Operator (participant)

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

Christopher Raymond (Managing Director and Senior Biotech Analyst)

Thanks. Two questions. Just on the ERT business, you guys have, I think, for some time now talked about being able to sort of elicit higher demand 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 2025 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, where are we, I guess, in terms of maybe which regions 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 2nd half, the slide say mid-2025.

Are you indicating maybe you'll be toplining the data in mid-2025 and then presenting the full data at a conference later? Any sort of color there would be great. Thanks.

Greg Friberg (Chief R&D Officer)

Yeah, this is Greg Friberg. 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 2nd half of the year.

Cristin Hubbard (Chief Commercial Officer)

Hi, Chris. This is Cristin Hubbard. To answer your question a little bit about the kind of 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. 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 year-over-year growth with Palynziq 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, 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 Palynziq, that it works across all PKU phenotypes. You have the potential for normal Phe 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.

Operator (participant)

Your next question is from the line of Gena Wang with Barclays.

Gena Wang (Manging Director and Biotech Equity Research Analyst)

Thank you for taking my questions. I'll ask one regarding the uptake for your PKU 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 then the second question is regarding the 349 AATD. You completed a SAD and also started MAD end of last year. Maybe share with us what you are looking for regarding the data update.

Alexander Hardy (President and CEO)

Thanks very much, Gena, for your questions, Alexander. I'll handle the IP questions and then hand it over to Greg. So in essence, I mean, we stated, as we said in January, that we've initiated action against the Sandoz in the Unified Court in Munich. 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. 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 U.S. or elsewhere, we will take appropriate action in time to defend against infringement. So those are the updates. Basically, steady as we go, and we'll continue to keep you updated as this unfolds.

But we're following through on our commitment to defend our intellectual property and our innovation. Over to you, Greg.

Greg Friberg (Chief R&D Officer)

Yeah, thanks, Gena. 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- to 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 be able to be enrolled. And though, 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, both for ZZ as well as MZ genotypes, would be for a molecule that can accomplish what I described.

Operator (participant)

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

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

Greg Friberg (Chief R&D Officer)

Yeah, thank you, Julian. This is Greg Friberg again. And I think you said it nicely. These were two biopsies done of the muscles of boys who had been treated at the 6mg/kg 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, 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.

Though it's just two patients and though it's early, that gives us a good line of sight that when we hit 25 weeks, this is going to be useful information.

Operator (participant)

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

Akash Tewari (Global Head of Biopharmaceutical Research)

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

Alexander Hardy (President and CEO)

Thank you for the question, Akash. 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 Voxzogo, which is really exciting in so much that CNP can reach those indications like ISS and Noonan’s and Turner’s, SHOX 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.

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.

Operator (participant)

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

Ellie Merle (Executive Director and Biotech Equity Research Analyst)

Okay. Thanks so much for taking the question. So for Voxzogo, 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 2025 and 2026? And then in the U.S., 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 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.

Cristin Hubbard (Chief Commercial Officer)

So thank you so much for the question. I think that first 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, our overall portfolio, the contribution from ex-U.S. is about 2/3. It's split 2/3 and 1/3 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 0 to 5 years old population today. That, of course, was not the case when we were first launched. We launched in the 5-plus-year-old cohort.

Of course, that was where the bulk of our patients were. The rough split today, if you just look at how many patients are on treatment and the rough split, it skews more toward the 0 to 5 years old, but that's a timing component. Really, new patient starts, we're really targeting the youngest patients. 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 or the treater would actually be. They might be being treated in pediatric offices today. That is precisely why we are really, really focused on ensuring that there is broad awareness of the treatment option, seeing that Voxzogo was the first and the only treatment option for achondroplasia.

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.

Greg Friberg (Chief R&D Officer)

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 dataset that we have out there. Again, this is not just a story about one-year annualized 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 we've recently published our proportionality data at three years.

That's statistically significant compared to control 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, 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.

Operator (participant)

Your next question is from the line of Kostas Biliouris with BMO Capital Markets.

Kostas Biliouris (Director and Biotech Equity Analyst)

Hi, everyone. Thanks for taking our question and congrats on the strong numbers. Great to see that three-fourths of Voxzogo sales coming from ex-US. Maybe one question follow-up on Akash's question on BD. In the Alpha-1, I think in the editing space, there are approaches that can address both the liver and the lung manifestation of the disease. And these approaches already have 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.

Greg Friberg (Chief R&D Officer)

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

Kostas Biliouris (Director and Biotech Equity Analyst)

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

Greg Friberg (Chief R&D Officer)

With regard to BMN 349, 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?

Alexander Hardy (President and CEO)

I think you said it well.

Greg Friberg (Chief R&D Officer)

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.

Operator (participant)

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

Sadia Rahman (Equity Research Associate)

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 this compares 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 9mg/kg to initiate that cohort, wondering if that was based on the analysis that you did on the 13-week data at 6mg/kg. Yeah, thank you.

Greg Friberg (Chief R&D Officer)

Yeah, thanks for the question. Let me take the second question first. The 9mg 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 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.

Operator (participant)

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

Olivia Brayer (Director and Senior Biotech Analyst)

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 talked about a high single-digit CAGR over the next 10 or so years, but what about for 2025, 2026, 2027? 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 (CFO)

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. 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 a bit in 2025. Likewise, for Aldurazyme, which BioMarin revenue is not based on or tied directly to end patient demand, but supply to Sanofi. Likewise, we expect that to be more flat in 2025 over 2024. But over these next couple of years, high single-digit across that franchise is the goal. And within that, just a reminder, Cristin touched on it earlier, the key driver is Palynziq.

We think we've got more market penetration to go there, healthy double-digit growth in Palynziq, and then continued sustained growth in the enzyme business. And you're exactly right. 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 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 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.

Operator (participant)

Your next question is from a line of Alex Hammond with Wolfe Research.

Alex Hammond (Director and Head of Therapeutics)

Thanks for squeezing me in. Just quickly on Voxzogo, 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?

Cristin Hubbard (Chief Commercial Officer)

Yeah, so thank you very much for the question. So just to be very clear on our Voxzogo 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 a competitive landscape is not a bad thing. I think, honestly, raising the awareness around this disease and the effective treatments around it is always a good thing. But to speak specifically about where we think we will continue our leadership position, in particular in achondroplasia, I think that there's multiple dynamics here. You could talk about certainly the notion of the potential for switching from Voxzogo to another compound should it become available.

We do believe that there's going to be some stickiness to being on Voxzogo so that it's almost kind of like a start-and-stay paradigm that we're really looking to achieve. We know that 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 it'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 Voxzogo. 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. 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.

Operator (participant)

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.

Alexander Hardy (President and CEO)

Thank you, operator. And thank you all for joining us today. And 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 and enabling ongoing reinvestment in innovation and growth to make even greater impact for 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.

Operator (participant)

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