Earnings Call Transcript - BMRN Q4 2025

Operator, Operator

Thank you for waiting. My name is Kate, and I will be your conference operator today. I would like to welcome everyone to the BioMarin Pharmaceutical Fourth Quarter and Full Year 2025 Conference Call. I will now pass the call to Traci McCarty, Head of Investor Relations. Please proceed.

Traci McCarty, Head of Investor Relations

Thank you, operator. And starting on Slide 2. To remind you, this nonconfidential 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 now 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. Moving to Slide 3 and introducing BioMarin's management team joining today's call, Alexander Hardy, 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 CEO, Alexander Hardy.

Alexander Hardy, CEO

Thank you, Traci. And moving now to Slide 5. Thank you all for joining us today to discuss BioMarin's fourth quarter and full year 2025 results as well as our outlook for 2026, which will be an exciting year. We are particularly proud to have accomplished our strategic goals for 2025, while achieving outstanding growth. In 2025, total revenues grew by 13% to a record $3.22 billion for the year and operational excellence led to strong profitability and increasing cash flow. This result was fueled by a 9% increase in enzyme therapies revenue and a remarkable 26% rise in Voxzogo revenues. Importantly, enzyme therapies revenue has grown at a 9% CAGR over the last 5 years, demonstrating the durability and reach of this $2 billion-plus franchise across our 80-country footprint. With Voxzogo, now in its fifth year on the global market, we're very pleased with the consistent strong growth already achieved and have deep conviction in our ability to continue expanding should another product be approved. BioMarin's 2025 performance and 2026 outlook highlight both our deep global capabilities and the vital importance of our targeted therapies to the patients we serve. Building on the strong foundation in 2026, we will expand our therapeutic and commercial reach with the addition of assets from two significant acquisitions announced last year. The first, Inozyme, strengthened our enzyme therapies portfolio with the addition of BMN 401 for ENPP1 deficiency. This is a condition for which there is no approved targeted therapy. So we're really pleased about the possibility of launching what could be our sixth first-in-disease enzyme therapy should pivotal data be supportive. We look forward to sharing that update in the coming months and to filing submissions soon thereafter. Our second acquisition, Amicus, potentially adds both Galafold for the treatment of Fabry disease, and Pombiliti and Opfolda for Pompe disease to our commercial portfolio and is expected to close next quarter. This transaction presents a particularly compelling opportunity that further builds on Amicus' success by leveraging our scale and global capabilities to serve even greater numbers of patients. In addition to the expansion of BioMarin's portfolio from acquisitions, we're particularly excited to build upon at Voxzogo's leadership in achondroplasia with a potential addition for treatment of hypochondroplasia. Because CNP is the master regulator of bone growth and supported by the 1-year results from the investigator-sponsored study, we are excited to see and share the upcoming pivotal results with Voxzogo for the treatment of hypochondroplasia in the coming months. We look forward to the possibility of adding hypochondroplasia to our global skeletal conditions treatment offerings by early next year. On top of Voxzogo indication expansion, based on the very encouraging PK data recently shared, we're preparing to begin enrollment in our Phase II/III study of BMN 333. We believe this next-generation, long-acting CNP therapy has the potential to set a new standard of care and to demonstrate superiority compared to any candidates under development for achondroplasia. Those are just a few of the anticipated pipeline highlights expected this year so you can understand our enthusiasm for what's ahead in the coming months. Turning to innovation. During the period where we are deleveraging the financing associated with the announced acquisition of Amicus, we will remain actively engaged in business development activities targeting pipeline assets. This is an important component of a larger pipeline expansion plan, a plan that both accelerates our financial performance and further diversifies our portfolio to drive durable long-term growth. In closing, we are pleased that the transformational work implemented over the last 24 months has already delivered significant results and positions us for even more revenue growth, profitability and pipeline expansion. Prior to any contributions from the Amicus assets, this year, we anticipate BioMarin's enzyme therapies will deliver high single-digit growth and Voxzogo will continue along its trajectory towards blockbuster status. Following the completion of the transaction, we anticipate that integrating Galafold and Pombiliti and Opfolda will enable both medicines to reach more people around the world living with Fabry and Pompe, significantly enhancing our 2026 outlook and enabling accelerated revenue growth through the 2030s. With that, I will turn the call over to Brian to provide additional financial updates.

Brian Mueller, CFO

Thank you, Alexander. Please refer to today's press release for detailed fourth quarter 2025 results, including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-K, which we expect to file in the coming days. Starting on Slide 7. Our fourth quarter results reflect strong global demand, with total revenues of $875 million, representing 17% year-over-year growth. This strong performance was broad-based across our portfolio with Voxzogo delivering 31% year-over-year growth and enzyme therapies achieving 13% year-over-year growth in the fourth quarter. Palynziq revenue increased 25% in Q4, marking its fourth consecutive quarter of 20% or higher year-over-year revenue growth. For the full year, Voxzogo revenue increased 26% over 2024, totaling $927 million and underscoring the strong global expansion since its launch over 4 years ago. For the full year 2025, approximately 73% or nearly $680 million of the $927 million of total Voxzogo revenue was generated outside of the United States, reflecting BioMarin's differentiated global reach and infrastructure, deep rare disease expertise and ability to execute at scale. Full year 2025 enzyme therapy revenue increased 9% year-over-year, led by 22% growth for Palynziq and 7% growth for Vimizim, underscoring the durability and strong demand for these established brands. As expected, Q4 revenue benefited from the timing of large orders in both Voxzogo and enzyme therapies. In Q4, we recognized revenue from an approximately $30 million contracted government order for Voxzogo, the magnitude of which we do not expect to repeat in Q1 2026. Additionally, in Q4, we saw stocking levels increase in the U.S. and select global markets for Voxzogo, Palynziq and Vimizim. Now moving to Slide 8. As an update on our plan to divest Roctavian, we recently made the strategic decision to withdraw it from the market. As a result, during the fourth quarter, we recorded approximately $240 million in special items on a GAAP basis. Approximately half of that amount relates to an inventory write-off that does not get adjusted out of non-GAAP income. BioMarin reported $3.15 of full year 2025 non-GAAP diluted earnings per share. And looking past the 2025 IPR&D and Roctavian charges included in non-GAAP income, our underlying business earnings per share grew by approximately 34%. This performance contributed to $828 million in full year 2025 operating cash flow, a 45% increase versus full year 2024, further demonstrating the strength of our operating model and providing meaningful capital to reinvest in innovation. We are pleased to see the operational transformation implemented over the last 24 months drive this level of profitability. Together with our revenue growth plans, BioMarin is positioned to sustainably grow profitability and cash flow while still investing in the business. As we prepare to close the Amicus acquisition, we were pleased to secure approximately $3.7 billion of debt financing consistent with the strategy that we shared upon announcement of the transaction. Confidence in the strength of BioMarin's business and financial outlook supported a positive credit ratings outcome and helps drive demand for all components of the capital raise, which enabled favorable pricing across the capital structure. Now moving to Slide 9. Looking ahead to full year 2026, we are providing initial guidance that reflects BioMarin's growth expectations, excluding any post-close contributions from the announced acquisition of Amicus. Please note that currently available BioMarin consensus estimates include a combination of revenue estimates, some that include Galafold and Pombiliti and Opfolda revenues and some that do not. We plan to provide updated guidance on the combined business following the close of the acquisition expected in the second quarter of 2026 and we request that you wait for those details prior to updating BioMarin's models with the post-close Amicus contributions. Turning to 2026 guidance items. We expect enzyme therapies revenue of between $2.225 billion to $2.275 billion, and Voxzogo revenue of $975 million to $1.025 billion. We expect continued high patient demand across both the enzyme therapies and Voxzogo in 2026, resulting in high single-digit growth rates of both business units at the midpoint. Outside of enzyme therapies and Voxzogo, we are expecting significantly lower royalty KUVAN and Roctavian revenue in 2026, which affects year-over-year comparisons of total revenue. We estimate those revenues to be between $100 million and $125 million in 2026, representing a 3% headwind to total revenue growth when compared to 2025. Taken together, we anticipate 2026 total revenues in the range of $3.325 billion to $3.425 billion. Again, this excludes any contributions from the Amicus products. And while we will wait for the acquisition to close to provide more details on 2026 revenues for the combined business, we are expecting a meaningful uplift to our 2026 total revenue growth rate once the transaction closes. We anticipate 2026 non-GAAP diluted earnings per share in the range of $4.95 to $5.15. Please note that our guidance reflects approximately $0.25 per share of preclose integration preparation costs and interest expense related to the Amicus transaction. On non-GAAP operating margin, our underlying organic operating margin expectation without the Amicus transaction is approximately 40% for 2026, consistent with our previously communicated target. In the announcement of the Amicus transaction, we shared that we expect the Amicus acquisition to be modestly dilutive in 2026, which we expect to be a slight headwind to operating margin that could drive it slightly below 40% for the year. Aside from the impact of the Amicus transaction, we recognize that over the last two years, BioMarin has been able to solidify its revenue growth potential and transform its cost structure to realize the potential of a strong operating margin profile well into the future. I will also comment briefly on quarterly dynamics in 2026. Coming off our strongest revenue quarter on record, we expect similar trends in 2026 as those observed in 2025. For example, we expect the first quarter of this year to be the lowest total revenue quarter of 2026, with both total revenues and Voxzogo revenue expected to be on par with Q1 2025. Q1 non-GAAP diluted earnings per share will have the additional impact of the vast majority of the pre-close Amicus cost just described, resulting in it being our lowest anticipated EPS quarter for 2026. For both Voxzogo and enzyme therapies, we anticipate large international order timing to contribute to higher revenue in the second half of 2026 compared to the first half and weighted to Q4, similar to the 2025 dynamic. Our underlying business has consistently produced profitability growth that has outpaced top line growth and today's guidance reflects our commitment to continue to grow the business, operational efficiency and prioritize reinvestment in innovation.

Cristin Hubbard, Chief Commercial Officer

Thank you, Brian. I'll open by highlighting the outstanding work of our teams around the world. Their focus and deep expertise have been instrumental in driving another year of impressive commercial performance. Now moving to Slide 11 and starting with enzyme therapies. In 2025, enzyme therapies delivered year-over-year revenue growth across every product in the portfolio, leading to 9% growth, driven by new patient starts across all products and consistently strong therapy adherence rates. With 22% year-over-year revenue growth, Palynziq, again, outperformed expectations. As the only approved enzyme replacement therapy for PKU, Palynziq stands alone in its ability to enable people with PKU to reach physiologic phe levels while reducing dietary restrictions regardless of severity. The performance further highlights our leadership in the PKU market having established invaluable partnerships with our stakeholders during almost 20 years treating people living with PKU. In 2026, Palynziq is expected to remain the primary growth driver in today's enzyme therapies portfolio, supported by the anticipated adolescent label expansion with the U.S. PDUFA target action date of February 28 and an anticipated European approval later this year. Excitement is building among the treating physicians and families around the value proposition that Palynziq represents to the adolescent PKU community. This label expansion will enable young people with PKU to start treatment while living at home, supported by caregivers and under the guidance of their health care providers. Adolescence is a pivotal time where dietary therapy typically starts to become unsustainable for those living with PKU, which can result in rising blood phe levels. The opportunity for adolescents to use Palynziq may provide dramatic fee lowering, the ability to eat more like their peers for social inclusion and ultimately, a better setup for them to enjoy an independent, successful life. Now turning to Slide 12. Voxzogo continued to be a standout growth driver, delivering 26% year-over-year growth in 2025. It's particularly gratifying to know that well over 5,000 children with achondroplasia worldwide were being treated with Voxzogo at the end of 2025. Now going forward, with Voxzogo in its fifth year of commercialization, our growth strategy is focused on a multipronged approach. First and foremost, we are driving new starts globally across all ages with a particular emphasis on children under 2 years of age, an age group where we do not expect another approved product for the next several years. Next, in highly penetrated countries, which have become incident markets, our priority is to continue to find and start treatment-eligible infants going forward. In addition, we see meaningful opportunity to more deeply penetrate larger countries where we already have established commercial presence and large growth potential remains. And finally, we are expanding uptake in fast-growing newly launched markets where significant pools of eligible patients exist and streamlined care pathways are enabling access. To provide more context on the results that these strategies are producing, I'll share a couple of recent examples illustrating BioMarin's deep global capabilities, commercial scale and more than 20-year track record serving patients around the world. In a recently launched country in the Asia Pacific region, Voxzogo reached approximately 40% penetration within 7 months of launch. This success stemmed from early non-promotional prelaunch activities and strong relationship building with clinicians. We ensure that there was a focus on patient identification beforehand and strong support for each patient's experience throughout the journey. In another example, in a midsized European country, Voxzogo achieved approximately 70% penetration within 12 months of launch. This was driven by early non-promotional engagement with clinicians and patient advocacy groups to build strong relationships with local stakeholders and drive momentum and awareness of Voxzogo. We tailor our approach to meet the needs of the patients and the respective country's ecosystem. We will build on these successes to drive deeper penetration in existing markets and to prepare for new country launches in 2026. These strategies are crucial to our growth outlook with Voxzogo since roughly 75% of total revenues are generated from countries outside of the United States. In the United States, we are driving increased penetration across all age groups, supported by investments in data, digital and field force. We're seeing particularly strong momentum in the under 2-year age group, reflecting international guidelines for achondroplasia, recommending early diagnosis and treatment with Voxzogo as soon as possible and long-term data supporting its safety and efficacy from infancy. Approximately half of the new starts in the fourth quarter were children under age 2. Since we believe Voxzogo will be the only approved therapy in this age segment for the next several years, driving new patient starts in children under 2 is a key pillar of our growth strategy. With the potential full approval of Voxzogo on the horizon, we believe families and caregivers will have even greater confidence in Voxzogo's established safety and efficacy profile when considering treatment for their infants and children with achondroplasia. In conclusion, I'm incredibly proud of what our teams have accomplished and energized by the opportunities ahead. I will now hand it over to Greg for an R&D update.

Gregory Friberg, Chief R&D Officer

Thank you, Cristin. We have a very busy year ahead for R&D with multiple meaningful milestones. Moving to Slide 14. As Cristin mentioned, we are preparing to submit the full approval package for Voxzogo and achondroplasia. This submission will allow us to present a comprehensive story around final adult height as well as a broader health and wellness outcome data set. We have collected over 10,000 patient years of safety data, including data for some children who have been on Voxzogo treatment for more than 10 years, underscoring the value of Voxzogo across all age groups, including meaningful impacts on quality of life and anatomic outcomes. In addition to linear growth, Voxzogo's broad evidence package demonstrates the treatment's impact on key complications associated with achondroplasia, including foramen magnum stenosis and symptomatic spinal stenosis as well as improvements in body proportionality, arm span and leg deformities like genu varum and tibial bowing. These extensive data also show clear functional benefits with improvements in measures of mobility, gait and quality of life. Together, these findings support our plans to submit the full approval package to the FDA and to continue sharing additional data through peer-reviewed publications and scientific forums later this year. Now moving to Slide 15. BMN 333 is our long-acting CNP therapy for achondroplasia. We previously shared our plan to initiate a combined Phase II/III study in the first half of this year. Today, we're pleased to share more details on the Phase III study design and powering assumptions. The Phase III portion of the study will enroll 60 patients into each arm and will have 90% power to detect a 50% increase in annualized growth velocity versus Voxzogo. This translates into a growth increase of 2.25 centimeters per year over placebo, an effect size that would represent a clear best-in-disease effect. This represents a floor, not a ceiling. We also anticipate that this would translate into greater benefits in other measures of health and wellness for achondroplasia, including proportionality, and health-related quality of life. Our goal is to establish BMN 333 as the new standard of care for achondroplasia and potentially for other skeletal conditions. Now turning to Slide 16. We have several additional exciting highlights expected across the pipeline in 2026. To note a few, we anticipate Phase III data readouts for Voxzogo in hypochondroplasia and for BMN 401 in ENPP1 deficiency, both serving as key steps towards potential approvals as the first genetically targeted therapies for each of their indications. We are approaching the U.S. sBLA action date for Palynziq for the treatment of adolescents with PKU. Given the unique clinical benefits of Palynziq, we believe families with teenagers seeking treatment will be particularly interested in a therapy that can deliver potent fee reduction as well as the potential to enjoy an unrestricted diet. Our PDUFA action date is February 28, and we look forward to sharing that outcome when it becomes available. Finally, BMN 351 for Duchenne muscular dystrophy demonstrated 5% mean absolute dystrophin expression at week 25 and in the 9-milligram per kilogram cohort, a level that translates to a predicted 10% absolute level at steady state. We are currently enrolling in a 12-milligram per kilogram cohort and plan to share those results in the second half of the year. Full results for the 6- and the 9-milligram per kilogram cohort will be presented in an oral presentation at the Muscular Dystrophy Association meeting in March. In summary, 2026 will be an important year of many data readouts, clinical advancements and regulatory activities across our R&D portfolio. We'd like to thank all of the patients, families and caregivers whose dedication and support enabled the advancement of these programs. Thank you for your attention today. We will now open the call to your questions.

Operator, Operator

Your first question comes from Mohit Bansal with Wells Fargo.

Mohit Bansal, Analyst

Congratulations on all the progress. I have a question about the current dynamics in the achondroplasia market now that we have data for the oral medication. How do you see this market evolving with the availability of both weekly injections and the potential for oral options in the future? Additionally, if you achieve a growth velocity of 2.25 centimeters or more with BMN 333 compared to the placebo, do you believe that injections could become the primary therapy before the oral solutions?

Gregory Friberg, Chief R&D Officer

Thank you, Mohit. This is Greg Friberg. I think I'll take the first half of your question, and then I'll hand it off to Cristin. With regard to the recently released data for the FGFR3 inhibitor, our take there, of course, was that this was generally comparable to other CNP class effects at 1 year. Of course, this is 1-year data. We'll need to see both durability as well as safety data over time. And the read-through, of course, in terms of how we believe Voxzogo can deliver value here is that Voxzogo not just having one year of data has a tremendous amount of supporting evidence behind it. We talk about the 10,000 patient years of safety. We also, of course, have a deep a wealth of information with regard to evidence beyond height, whether it's foramen magnum, physical function, tibial bowing, quality of life, all of this data, again, creates real confidence that, that data is something that patients can rely on. With regard to 333 and the effect size, we've stated again what the powering assumptions would be, and we do believe that the 2.25 centimeters of growth not only are differentiating on a clinical level, but we have some preliminary market research that suggests as well that that would be important. It's important not to get too caught up in the growth being the outcome that we care most about because the growth is a surrogate for the health and wellness of these patients. Again, going back to Voxzogo, we do believe that increase in growth would, in all likelihood, again, lead to a best-in-disease profile that patients, payers and physicians with value. So with regard to the market dynamics, I'm going to hand it off to Cristin.

Cristin Hubbard, Chief Commercial Officer

Yes. Thank you, Greg, and thank you, Mohit. Having more options is certainly important for patients, and we'll see how that continues to develop. Greg has done a great job explaining the recent data releases. It's crucial to understand where Voxzogo fits into this situation. First and foremost, it's vital to recognize that early treatment is the most significant factor for patients, as supported by both data and international guidelines. We have evidence to show that early treatment leads to longer-term benefits, and we have collected 10,000 patient years across all pediatric age groups. This is a key aspect. Another factor to consider is the switching behavior of patients who are doing well and may consider moving to another therapy. Our market research and field interactions indicate that there is considerable hesitation among patients who are satisfied with Voxzogo; most of what we hear suggests that there will be little motivation to switch quickly, particularly since long-term safety and efficacy data for alternative products are still pending. Healthcare professionals and key opinion leaders will share the available data, but ultimately, it will be the patients and their caregivers who drive the decision to switch. This highlights the importance of long-term safety and efficacy data, which will be significant as we observe this dynamic unfold.

Christopher Raymond, Analyst

I understand your point about the switcher dynamic and the idea that patients doing well may have less incentive to switch. However, we were surprised to learn that a competitor expects around half of their patients in early achondroplasia trials to have experience with Voxzogo. Their commentary suggests that there are indeed a significant number of parents and patients interested in switching to another option. Could you share what you're observing more generally? Are there any demographics or other factors, aside from performance, that might influence the decision or desire to switch? Additionally, regarding drug 351, I find the dystrophin data quite compelling, as it appears to be quite differentiated, if not superior to existing options. Could you elaborate on your plans to communicate this? I know the complete data will be presented at the MDA conference next month, but I would appreciate your insights on how you plan to communicate the milestones for that drug.

Gregory Friberg, Chief R&D Officer

Thanks so much, Chris, and this is Greg Friberg, again. Let me take your second question first. I would agree with you. The data is quite encouraging from BMN 351. The 5% absolute dystrophin measure, again, which if you look at our PKPD model predicts roughly 10% at steady state, that is an unprecedented number for the exon 51 skip amenable patients. Now what we also know from the program is that data monitoring committee has allowed us, again, to go to a higher dose level and complete the study. So we see quite a bit of value to continuing the experiment for a variety of reasons. Number one, of course, the 12-milligram per kilogram level, we'll see whether we can see something superior to that number, knowing that within all these patients, there's some degree of variability. Number two, we'll obviously get to see more chronic safety data as well. And this is something, again, that in this field, of course, where benefit-burden is key is something that we absolutely want to continue to follow. And finally, we'll get our first look at some functional data as well as we treat these patients for longer and look at, for example, the Stride Velocity 95C data. We expect that this next tranche of data will have it before the end of the year. And in the meantime, we will be presenting our complete 6- and 9-milligram per kilogram data at the Duchenne Muscular Dystrophy Association meeting in March, just a couple of weeks away. So we're sitting tight. And again, encouraged by what we've seen. We want to see more data there for this weekly IV administered antisense oligonucleotide. With regard to Voxzogo, your question is a nuanced one. It's one of whether or not, again, patients, physicians, their caretakers, whether they can have the confidence in the data package for the medicine that they're given in many cases, to very, very young infants. And of course, with Voxzogo, we have a wealth of data. We're looking forward to present that in our full evidence package that we'll be presenting for full approval to the FDA in the coming months. And I think I've gone through some of the package there, that goes through, again, some of those data points. With that, though, from the commercial perspective, I want to give Cristin a chance to share her perspective.

Cristin Hubbard, Chief Commercial Officer

Yes. Thanks for the question, Chris. And I'd be happy to kind of both dig in on the switching dynamic but also important on the market dynamic in the different geographies in which we operate. So again, going back to that notion of why switch, what we hear disproportionately is that above all else, efficacy and safety are the highest priority. Convenience is the third. So the fact that we have both kind of long-term safety and efficacy data but also importantly, durability. We are showing data now that shows that Voxzogo continues to work year-over-year data that we published going 7 years out, which really matters to these caregivers, these patients and importantly, the physicians. So I think that this is going to be in the near term, in particular, when there is more data in favor of Voxzogo, I think that, that's going to be part of the switch decisions. Now importantly, when I think about the markets, we've got very different categories or phenotypes, if you will, on markets. We've got some which are larger markets, which we have highly penetrated. And these have become ends incident markets. So really where we intend to grow Voxzogo there is going to be really in newborns, where our label enables us to. Then moving over to some of the bigger growth opportunities, I think we have where Voxzogo can really play a meaningful role. That's going to be both in countries that we're already in that still have meaningful opportunity ahead of us. Now let me be clear, these are more complex markets. They take a little bit more time. But we think that the value proposition of Voxzogo is there, and we'll continue to grow there in but also, as you heard me say in the prepared remarks, we have some exciting markets where they are fast-growing, there's access pathways, and we're growing quickly in those. And so between all of this, when you look at kind of 75% of our revenues being weighted outside the U.S., I think there's an important value story and important story for Voxzogo and all.

Philip Nadeau, Analyst

Another question on Voxzogo, but on hypochondroplasia. Can you help us frame the upcoming results? What magnitude of growth velocity increase do you think would be meaningful in hypochondroplasia patients? And can you talk about the dynamics of that market? Would you expect uptake as quick as in achondroplasia? Or are there other factors which could make it less rapid?

Gregory Friberg, Chief R&D Officer

Thanks, Phil. This is Greg again. I'm going to take it for a stab, and again, I hand it to Cristin at that point. With regard to the study, again, we're very excited that we'll be turning the card over in the first half of this year. The study is designed to measure an effect size roughly equivalent to what Voxzogo delivers for achondroplasia. That being said, that's a fairly conservative assumption. We know that Dr. Dauber's data, for example, is showing slightly larger, more like a 1.8 centimeter growth of AGV in the hypochondroplasia patients. And it's our goal and intent also to follow through, as I mentioned previously, not just measuring AGV, but also looking at measures of health and wellness for these patients. So we believe we've designed the right study. Now it's a question of reaching the endpoint and turning it over, and we're very excited to see the data. Cristin?

Cristin Hubbard, Chief Commercial Officer

Yes. So I think once we see the data, the scientific rationale will have been proven. But I do think that the enrollment rate of the trial in and of itself shows the excitement level that could be here for hypochondroplasia, assuming that all plays out well. And I think that this is yet another example, though, of our leadership in skeletal conditions where we're out there defining an area where nothing exists now. And so when I think about what the biggest opportunity is, and we've said it before, it's really in and around diagnosis. This is an underdiagnosed condition, and it doesn't quite have the infrastructure that is needed to ensure that that can happen rapidly for these patients. So we're out there now doing a prelaunch non-promotional work. We're educating on signs and symptoms requiring further evaluation and genetic testing for hypochondroplasia. We're really talking a lot about the burden of the condition to really enhance that sense of urgency to treat. And we're working actually on establishing and disseminating guidelines for when to refer and test for these patients so that we can shorten that journey to diagnosis. So all in all, we really are working at ensuring that diagnosis which I think will be the biggest problem statement for hypochondroplasia that we can get out there and tackle that early. To remind you, the total TAP side that we understand it to be today is we expect that the prevalence is in and around that of achondroplasia. But because of these diagnosis rates being so much lower, we said that the TAP is around 14,000 patients. I hope that helps you to understand. We're really excited about this and think there's a lot of work there and help to grow space.

Siyue Wang, Analyst

This is Siyue Wang on for Akash. One on Voxzogo again, just following on the infigratinib data, where does this fall in your scenario analysis for your 2027 revenue outlook? And additionally, can you talk about the importance of the full approval for Voxzogo with the final adult height and how you expect that to impact patient preference?

Brian Mueller, CFO

This is Brian. I'll take the first part of the question on '27 and any impact from infigratinib data. We don't have new updates on '27 at this time. I will say in response to your question, that the assumptions we made in the more competition impacted scenarios when we did update our views on that range, this is in line, we assumed two competitors and comparable data to Voxzogo.

Gregory Friberg, Chief R&D Officer

And this is Greg Friberg. Just commenting on the full approval. This is a real chance for us to work with regulators to present our totality of the data set. We know that we have confidence in the 7, 8, 9, 10 years of safety and efficacy data that we have in achondroplasia. We will have the opportunity to also put in front of them those measures of health and wellness. I mentioned the foramen magnum data, the physical function, tibial bowing to see again whether or not it meets criteria for label inclusion. It's an important moment, having full approval, build on that confidence, there are some other technical, I think, benefits that come along with full approval. But most importantly, again, we see this as our opportunity to put forward what we see as a leading evidence package for achondroplasia.

Tommie Reerink, Analyst

This is Tommie on for Salveen. We just wanted to drill a little bit more into the factors assumed in your Voxzogo guidance, especially as it relates to new starts and potential switching in the context of upcoming competition. And also for 333, kind of your confidence in establishing as the preferred option for new patients from switching given that the long-acting competitor will have a bit of a head start here.

Brian Mueller, CFO

Tommie, it's Brian. I'll start with the first part of your question. Thank you. In terms of the Voxzogo guidance for '26, first of all, just to note, we're really pleased to have grown the product 26% in '25. Its fourth year on the market. And with respect to the range, the $975 million to $1.025 billion really just reflects a handful of scenarios. On the lower end of that range, you can assume a stronger competitive impact from the first competitor potentially coming to market in '27. I'll also share that we're being guarded on a couple of routine market access renegotiations in '26. These are normal course of business. Again, the product is fifth year on the market. Those will resolve this year, but we're being measured on those. And then at the high end of the range, it would just assume a lesser impact from those couple of swing factors in the guidance. Cristin, anything else to say on patient additions, and where they're coming from.

Cristin Hubbard, Chief Commercial Officer

No. I mean, we're continuing to generate patient demand. And really, our priorities remain the same. Now our execution at a country level may look different depending on what choices are available inside country. But at the end of the day, our priorities remain the same. And these profiles that we've seen so far are very much in line with what we anticipated. And importantly, where we tend to continue growing patient demand is what I've said: it's in that 0 to 2 population and ensuring that we're really protecting switching.

Gregory Friberg, Chief R&D Officer

Yes, this is Greg. With regard to the 333 question, the ultimate issue here is whether or not convenience is the lever that we're focused on or whether or not patients, physicians, regulators can have confidence in the data package we put forward. We believe that we've designed the appropriate study to show that 333 can have a superior growth profile over all the available agents. And in that regard, really have an opportunity to differentiate itself as the most active agent in the field, not just for AGV, but also the pull-through of health and wellness as well. The study is certainly powered to detect the size difference that we mentioned there. But the question, I think, behind your question was whether those prior assumptions were aggressive or conservative. And I would argue that they're somewhat conservative. Our animal model data as well as our PK/PD model or dose response model suggests that any one of the doses that we're putting into Phase II could potentially deliver the profile we're looking for.

Eliana Merle, Analyst

Just what's your latest expected timing for the data readouts from the Phase II CANOPY basket study for Voxzogo? And second, just to ask a bit more on the Voxzogo guidance. Could you comment specifically on what the guidance reflects or how you're thinking about U.S. growth versus ex-U.S. growth over the course of the year? And then if you could just elaborate on that last comment that you're being guarded on a few routine market access conversations and sort of the implications for that for Voxzogo?

Gregory Friberg, Chief R&D Officer

And this is Greg. Maybe I'll knock down the CANOPY question first, if that's okay. We're anticipating that we're on track for data in the 2027 time frame, as we've stated previously. No updates in that regard. And that refers to IFS, and the Noonan, Turner, SHOX program. Our CANOPY study, of course, also includes hypochondroplasia, which we're excited to turn the card over in the first half of this year.

Brian Mueller, CFO

Thanks, Ellie, this is Brian. I'll start with your question regarding guidance. We are not providing further details on individual growth in the U.S. and outside the U.S. As we've discussed before, we aim to grow in all markets. Even with competition, we are pleased that Voxzogo is performing well, and we confidently project a high single-digit growth rate in '26, with the potential for the product to achieve blockbuster status. I want to remind you that we expect to maintain 100% of Voxzogo's market share in the U.S. despite competition. Cristin has also mentioned opportunities outside the U.S. We will continue to update you quarterly on growth dynamics, but we will not provide more detailed breakdowns at this time.

Alexander Hardy, CEO

Hi, Ellie, this is Alexander. I'm just going to come back to your question about the reimbursement processes that Brian mentioned to just give a little bit more color on those. They're in a number of markets, when you get into 5 years on the market and the product is very well established and has broad usage. You tend to go under formal reimbursement processes. And this represents actually an opportunity for us to broaden the access in those countries. Up to that point, they may well have been under a named patient single patient access type approach. So you go into a negotiation and you offset potentially a reduction in price but with the opportunity to significantly expand the population. Obviously, in the first year that it happens and there's two of these countries where it's going to be happening in 2026, you obviously have a price reset on your entire population. But then in front of you, you have the potential to reach many more patients. So it's a very exciting actual opportunity for Voxzogo in those markets and overall.

Adithya Jayaraman, Analyst

This is Adi on for Cory. I had a question about BMN 333. Based on the preclinical data and initial findings, should we expect the safety profile to be similar to Voxzogo, or are there any significant differences emerging that could set the profiles apart?

Gregory Friberg, Chief R&D Officer

Thank you for the question, Adi. Our preclinical models and in this case, the cynomolgus monkey models, in particular, have not demonstrated any additional safety concerns for 333 over Voxzogo as a free drug. The reality actually is that the profile for free CNP allows us to go up to much higher exposures when given in the form of 333 as compared to the daily administration of Voxzogo. And again, that's opened this therapeutic window that has allowed us to go to 3x, 5x, 7x and higher AUC exposures. And again, we're quite hopeful that recapitulate what we've seen in efficacy animal models that we're going to have a best-in-disease profile.

Paul Matteis, Analyst

I'm not sure how limited you are, and how you can speak about Amicus and things going forward, but I thought I'd give it a brief try. Just as it relates to the integration of the business, Alexander, you, I guess, reorganized BioMarin's commercial infrastructure with different business units, and this was kind of, I think, more in reaction to Valrox a number of years ago. But how do you think about Amicus fitting into that going forward? And how much do you think you can leverage a lot of the reps you have, the units you have existing relationships versus kind of building out a whole new way of selling some of these products?

Alexander Hardy, CEO

Thanks very much for the question, Paul. Yes, I mean these two products, our intention is post closure, these are going to drop right into our enzyme therapy business unit. I mean they just fit perfectly. The entire go-to-market model is exactly the same as our current portfolio. So the opportunities and the opportunities for us to drive synergies on the top line as well as synergies in terms of the way that we operate are tremendous. We're looking forward to sharing more post close. We're on track right now for a second quarter close. And then we'll share more about our specific plans and our expectations for what these really exciting products that Amicus has done such a good job bringing to market what the pro forma looks like when you add those into BioMarin. So more to come, Paul.

Brian Mueller, CFO

Yes. Thanks a lot, Paul. I appreciate the opportunity to clarify that. The comment was based on entirely just the mixed bag of some analysts having post-close Amicus revenues included in their BioMarin models and some not. Thanks for the opportunity to clarify that had nothing to do with the direction of what we see and those that are including it.

Joe Schwartz, Analyst

One of the growth strategies you mentioned when announcing the Amicus acquisition involved initiatives to identify undiagnosed patients with Fabry and Pompe diseases. I believe Amicus conducted some pilot programs for this in a few centers. I was curious if BioMarin had a chance to review the results of these pilot programs and if they align with your plans for rollout. Could you provide some insight into your initiatives in this area?

Cristin Hubbard, Chief Commercial Officer

Thanks for the question, Joe. It's Cristin. You're correct that we have been running pilots with various models. I want to emphasize that we're currently focused on understanding the process from signing to closing, evaluating what works for us compared to what is happening over there. For now, we are operating as two independent businesses. They are continuing their work on the ongoing pilot programs. We are particularly excited about the opportunities for both Galafold and Pom, Op, as Alexander mentioned, and how they fit within our business unit for enzyme therapies. Importantly, there's a significant opportunity to increase diagnosis rates for both Galafold and Pom, Op. For Pom, Op specifically, we are focused on driving the conversion. These are key areas we will continue to address, and we are in the process of gaining a deeper understanding of the situation.

Olivia Brayer, Analyst

I have a few follow-ups on Voxzogo. First is just maybe can you talk about level of confidence in actually hitting the numbers that you laid out this year? Just in light of a weaker first quarter due to those ordering patterns that you highlighted, Brian. Anything more you can tell us on those ordering patterns and why they might be so heavily weighted to the fourth quarter this year? I'm just trying to understand how having a new entrant on the market could impact some of those patterns and just the cadence of quarterly Voxzogo revenue this year? And then a quick follow-up on hypochondroplasia. When do you think we could realistically see that launch and uptake in those patients? Especially as you think about navigating some of the competitive headwinds in the achondroplasia market next year.

Brian Mueller, CFO

Thanks, Olivia, this is Brian. I'll start by providing some insights into the quarter. I appreciate your question. Firstly, we've historically dealt with these types of bulk orders and the resulting fluctuations in quarterly revenue. Typically, we see a decrease from Q4 to Q1, and this year was no different. During Q4, we did observe significant purchasing globally, which isn’t solely about inventory levels; it sometimes involves individual national payers working through their budgets. Several factors influence this, and the situation in Q4 was more pronounced this year than in the past. Additionally, regarding competition, there are two points I'd like to highlight. First, when we align our revenue with global patient additions for Voxzogo, it’s striking how consistently these additions correspond to each other quarter after quarter over recent years. However, revenue can fluctuate due to the timing of orders. For instance, while Q4 had a bulk effect, in some markets it acted as a catch-up because revenue was trailing behind patient additions. Second, I expect this trend will continue into this year. To help you estimate Voxzogo's revenue contributions, we anticipate the quarters will be comparable to last year. I've mentioned that Q1 aligns with the previous year's Q1, but we expect much of the revenue to be back-loaded to Q4, and any assumptions regarding competition are fully accounted for.

Cristin Hubbard, Chief Commercial Officer

And with regard to your second question, so as you've heard us say, we'll be presenting or sharing the top line data in the first half of this year for hypochondroplasia, and then our submissions will happen in the second half of this year. So what that means is, hopefully, approvals coming in 2027 and we would expect to see immediate revenue impact at that point in time. And we'll share as we see the data, we'll share more on our go-to-market plans as we move further along in the process.

Jason Gerberry, Analyst

Regarding the Phase III powering at 2.25 centimeters per year, is that seen as a threshold effect during your Phase IIs? If it turns out that this target might be too ambitious, would you adjust your statistical analysis plan? I believe you mentioned not to focus too much on the 2.25 figure. If your trajectory looks more like 2 or 2.15, would it still be worthwhile to proceed with Phase III for BMN 333? I wanted to clarify whether this is considered a go-no-go threshold in your dose-ranging study.

Gregory Friberg, Chief R&D Officer

Yes. Thanks for the question, Jason. And that 2.25 really comes from the sample size that we've laid out, that's 60 versus 60. There's some standard deviation, some alpha numbers behind that as well. But we wanted to share with you again what our ambition was, what we thought not only statistically significant but clinically meaningful. We will have a chance to look at our Phase II data. It's not a straightforward black-or-white situation. We're doing actually a Bayesian approach where we'll be looking at the totality of the data. And setting a certain threshold for confidence to move forward. Rather than get into the details there, I will just answer your question directly and say we would have the opportunity to potentially modify the protocol thereafter. But those numbers and announcing them again, I think they stated appropriately our ambition of what we think a meaningful and clinically relevant improvement over what is already a well-established, safe and effective therapy in Voxzogo would look like.

Alexander Hardy, CEO

Thank you, operator, and thank you all for joining us today. We're particularly proud to have accomplished our strategic goals for 2025 while achieving outstanding growth. In 2026, we will build on this momentum and expand our therapeutic and commercial reach with the addition of high-growth assets from two significant acquisitions announced last year. We also look forward to sharing a number of key regulatory milestones, data readouts and label expansions throughout the year, setting us up to deliver even more growth, profitability and pipeline expansion. We're energized by what lies ahead this year and intend to deliver again on an ambitious set of priorities, demonstrating our dedication to innovation and sustained growth in ways that we believe will benefit patients, employees and shareholders. Thank you for your continued support, and we will speak to you soon.

Operator, Operator

Ladies and gentlemen, that concludes today's call. You can now disconnect. Thank you, and have a great day.