BioMarin Pharmaceutical Inc. (BMRN) Q2 2025 Earnings Report, Transcript and Summary

Good afternoon. My name is Audra, and I will be your conference operator today. At this time, I would like to welcome everyone to the BioMarin Pharmaceuticals Second Quarter 2025 Conference Call. Today's conference is being recorded. [Operator Instructions] At this time, I would like to turn the conference over to Traci McCarty, Investor Relations at BioMarin. Please go ahead.

Thank you, operator. 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 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. Introducing the BioMarin management team today on the call, we have Alexander Hardy, President and Chief Executive Officer; Brian Mueller, Executive Vice President, Chief Financial Officer; Cristin Hubbard, Executive Vice President and Chief Commercial Officer; and Greg Friberg, Executive Vice President, Chief R&D Officer. I will now turn the call over to BioMarin's President and CEO, Alexander Hardy.

Thank you, Traci, and thank you all for joining us today for BioMarin's second quarter update. Now moving to Slide 6. We were very pleased with our Q2 performance across all aspects of the business, including strong growth, exciting progress across the pipeline and delivery of our business development strategy. Starting with our strong growth in the second quarter, leveraging our business unit structure to drive focus and accountability, BioMarin achieved double-digit year-over-year revenue growth and significant profitability expansion. Turning to pipeline progress. I'm excited to share that BMN 333, BioMarin's long-acting therapy for children with achondroplasia achieved our target profile. Our goal is for BMN 333 to demonstrate superiority to VOXZOGO and set a new standard for the treatment of achondroplasia. We plan to advance the program to the next stage of development and expect to begin a registrational Phase II/III study in the first half of next year. Greg will provide additional details in a few moments. Moving to our business development strategy. We successfully completed the acquisition of Inozyme on July 1, broadening our enzyme therapies portfolio. We executed the transaction with precision and focus, moving from agreement to close in less than 2 months. A lead program BMN 401, formerly known as INZ-701, is a treatment for ENPP1 deficiency, a condition with high unmet need and no approved treatment options, and we look forward to the pivotal data readout from this program in the first half of 2026. Greg will provide an update on some anticipated milestones with BMN 401. Moving to Slide 7, our outlook for the remainder of 2025. Building on the strong momentum so far, we will continue to execute on our 2025 priorities with urgency to deliver value to our stakeholders. Looking ahead and building on the momentum, we expect continued strong growth throughout the remainder of 2025, leading us to increase our full year guidance for total revenues, non- GAAP operating margin and earnings per share. We are progressing our pipeline as announced today with BMN 333 advancing BMN 401 pivotal data expected to read out next year and a number of other updates anticipated over the coming quarters. And building on the Inozyme acquisition, we plan to continue to augment our portfolio with strategic business development transactions to diversify our growth strategy. In conclusion, with the first half of the year now complete, I'm pleased with our progress and remain enthusiastic about our potential to deliver for patients, employees and our shareholders through the remainder of 2025 and beyond. Thank you for your attention. I will now turn the call over to Brian to provide our financial highlights for the quarter. Brian?

Thank you, Alexander. Please refer to today's press release for detailed second quarter 2025 results, including reconciliations of GAAP to non-GAAP financial measures. All 2025 results will be available in our upcoming Form 10-Q, which we expect to file in the coming days. Now moving to Slide 9 and starting with revenue. We were very pleased with our strong performance in the second quarter of 2025. Total revenues grew 16% in the quarter and 15% in the first half of 2025 compared to the same period in 2024. These results were driven by the underlying strength in global demand and new patient starts across the portfolio. Looking ahead, BioMarin is positioned for continued growth in the second half of this year. Revenue highlights in the second quarter include VOXZOGO revenue increasing 20% year-over-year to $221 million, fueled primarily by the ongoing success of the product's global expansion. Midway through the year, as I previously noted, we expect second half VOXZOGO revenue to be higher than the first half. And further, we expect second half revenue to be weighted to Q4 and due to both the impact of our strategic Skeletal Conditions business unit initiatives and order timing outside of the U.S. Therefore, with better line of sight into the dynamics in the U.S. and outside of the U.S. For the remainder of the year, we are targeting full year VOXZOGO revenue of between $900 million and $935 million. Enzyme Therapies revenue rose 15% year-over-year to $555 million, reflective of both strong demand and order timing from regions across the globe. With PALYNZIQ, we continue to see strong year-over-year growth with Q2 marking 2 consecutive quarters of 20% growth. VIMIZIM was also a strong contributor to second quarter growth, increasing 21% year-over-year. ROCTAVIAN revenue was $9 million in the second quarter, led by contributions from the United States and Italy. All of these factors contributing to our strong Q2 revenues give us confidence to bring up the lower end of full year 2025 total revenue guidance to $3.125 billion, with the midpoint of our guidance range representing double-digit year-over-year growth. Now moving to Slide 10 and operating expenses in the second quarter of 2025. Non-GAAP R&D expense in the second quarter was lower compared to Q2 2024, benefiting from focused R&D investment in prioritized assets following last year's strategic portfolio review. Non-GAAP SG&A increased in Q2 year-over-year, mostly due to our investments in the company's enterprise resource, planning system implementation and business unit strategic initiatives. As mentioned in our first quarter update, we expect both non-GAAP R&D and SG&A expense to increase over the second half of 2025 due to our historical spend patterns, incremental operating expenses related to the Inozyme acquisition and continued advancement of our clinical programs and commercial initiatives. These investments include R&D expense for VOXZOGO in new indications and BMN 333, as well as expansion of commercial initiatives in our Skeletal Conditions and Enzyme Therapies business units. Non-GAAP operating margin expanded significantly in the second quarter as compared to Q2 2024, driven by strong performance across the P&L, including underlying revenue growth and current operating expense trends. We anticipate that higher operating expenses in the second half of 2025 to support our business unit initiatives will decrease second half operating margin as compared to the first half of the year. Further, as just outlined with revenue being back weighted to Q4, together with the expense timing, we expect profitability to be lower in Q3 as compared to Q4. All in all, continued strong revenue performance and underlying cost discipline enables us to raise full year 2025 non-GAAP operating margin guidance to between 33% and 34%. Now moving to Slide 11 to highlight BioMarin's increasing profitability and operating cash flow. The bottom line continues to outpace top line growth at an impressive rate. In the second quarter, non-GAAP diluted earnings per share of $1.44 increased at more than 3x the rate of revenue growth, reflecting the flow-through of strong operating margin performance to the bottom line. Looking through the remainder of 2025 and as with operating margin, we do expect increasing business unit investments to result in lower earnings per share in the second half of the year as compared to the first half, with a decrease concentrated to the third quarter due to timing. Supported by the strong first half performance, we are raising full year 2025 non-GAAP earnings per share guidance to between $4.40 and $4.55. In addition, BioMarin's increasing profitability continues to generate significant operating cash flow, reaching $185 million in Q2, a 55% increase versus the same period in 2024. Increasing operating cash flow is expected to continue going forward in support of our innovation expansion opportunities and future growth. Now moving to Slide 12. And to summarize, we are pleased with our financial performance across the business in the second quarter, and today's full year 2025 guidance update reflects our expectation of continued strong growth and value creation for shareholders. Separately, with the Inozyme acquisition completed on July 1, we expect to account for the transaction as an asset purchase and record the impact of the acquired in-process research and development or IPR&D expense in our financial results in the third quarter of 2025. Today's guidance updates do not yet reflect the IPR&D, and we will update full year guidance when we report Q3 as the transaction is reported. Thank you for your attention. And I will now turn the call over to Cristin for an update on commercial activities in the quarter. Cristin?

Thank you, Brian. Now moving to Slide 14. I'd like to acknowledge the contributions from across the global teams that led to the strong second quarter performance from BioMarin's portfolio of 8 innovative therapies. Starting with VOXZOGO, 20% year-over-year revenue growth in the second quarter across a combined 51 countries was supported by new patient starts as well as strong treatment adherence. We were pleased to see strong uptake in the 0- to 4-year-old cohort in the U.S., new initiatives in the U.S., including increasing the field force as well as investments in digital promotion to drive VOXZOGO expansion are working. As a result, we doubled the number of leads generated year-to-date year-over-year, which translated to an increase in net new U.S. patients. With these initiatives firmly in place, we expect U.S. patient uptake over the remainder of the year to be strong, while noting that the revenue results from these initiatives will be realized over the coming quarters. Now outside the U.S., VOXZOGO expansion came from deeper penetration into existing countries as well as good adherence from children on therapy with incremental contributions from newly added countries. In summary, we are pleased to expect VOXZOGO's full year 2025 revenue growth of 25% year-over-year at the midpoint. Now moving to Slide 15 and turning to hypochondroplasia, the next indication we are studying for VOXZOGO treatment. Hypochondroplasia is a rare skeletal condition characterized by impaired bone growth leading to disproportionate short stature along with a wide range of medical complications and functional challenges. The comorbidities are highly varied and can look like any combination of disproportionality, macrocephaly, ear, nose, throat and musculoskeletal-related issues. Because hypochondroplasia is a clinically and genetically heterogeneous condition, it may be diagnosed late or not at all. Unfortunately, there is significant unmet need as the condition has no approved treatment, except for growth hormone in Japan. People with hypochondroplasia can face significant health burden and reduced quality of life. To date, data from Dr. Andrew Dauber's investigator-sponsored study has provided encouraging proof-of-concept results with VOXZOGO and hypochondroplasia. Enrollment pace in BioMarin's pivotal study exceeded internal expectations, giving us a good indication of demand for the treatment of this condition. We are leveraging our established capabilities to raise awareness of the upcoming Phase III hypochondroplasia data set, which we plan to share in the first half of 2026 to support a potential launch in 2027. And at this stage, we are actively engaging with the medical community to advance education on disease awareness and management. Through strategic partnerships with health care professionals, including achondroplasia thought leaders, advocacy groups and academic institutions, we aim to improve early diagnosis and hypochondroplasia to shape future treatment decision-making with VOXZOGO. Now moving to Slide 16 and our Enzyme Therapies business unit. In the second quarter, combined products delivered 15% growth year-over-year. PALYNZIQ's strength in the quarter was driven by greater numbers of patients titrating to their daily maintenance dose and strong adherence. Incremental new patient starts were encouraging in the quarter, and we look forward to them achieving their maintenance dosing over the coming quarters to realize the full benefits of PALYNZIQ. And if approved, we look forward to the opportunity to make PALYNZIQ available to adolescents in the U.S. and Europe based on its demonstrated ability to lower fee into the normal range and allow for an unrestricted diet even in people with the most severe form of PKU. We believe these 2 attributes will be particularly transformational for those preparing to transition into adult. VIMIZIM was also a strong performer during the quarter, growing 21% in year-over-year revenues and benefiting from ongoing patient demand globally as well as the timing of large orders in certain regions. Across Enzyme Therapies, we expect strong trends to continue through the second half of 2025 despite potential quarter-to-quarter fluctuations due to order timing as we've observed historically. In summary, the team delivered another quarter of strong performance across the globe. Despite the significant macro challenges many companies in our sector are facing, the essential nature of our medicines, our strong patient support programs and BioMarin's global reach keep these important therapies available for the people who need them. I want to thank the team for their continued commitment and perseverance. I'll now turn the call over to Greg for an update on R&D progress in the quarter. Greg?

Thank you, Cristin. Now moving to Slide 18. We're very pleased to share the first clinical update on BMN 333, BioMarin's long- acting CNP candidate for the treatment of achondroplasia. Today, we announced that we have observed encouraging PK results from our healthy volunteer study where BMN 333 demonstrated free CNP levels more than 3x greater than the AUC levels reported for another long-acting CNP as described in the British Journal of Clinical Pharmacology from June 2022. This profile represents a potential best-in-class molecule with the opportunity to drive even greater improvements in growth parameters versus available therapies and by extension, to further improve measures of health and wellness in children with achondroplasia. Our own preclinical data, along with publicly available dose response data for long-acting CNP agents, suggest that additional growth should be achievable with greater CNP exposures. We believe that safely achieving these PK results with BMN 333 means we have the right agent in hand to immediately test this hypothesis. Based on these results, we're planning to initiate the dose-finding arm of our Phase II/III registration-enabling program in the first half of 2026 with a targeted approval in 2030 should the data be supportive. The Phase I study continues as planned with ongoing monitoring of safety and pharmacokinetics at our sixth and final planned cohort. We anticipate sharing this full data set publicly at a conference in the first half of next year. We are very encouraged by these results thus far, and we'll continue to look for opportunities to accelerate the program. On Slide 19, moving to our next regulatory filing. We're on track to submit applications for an age extension for PALYNZIQ to include adolescents with the U.S. and EU applications planned for the second half of this year. Recall that our PALYNZIQ adolescent study, similar to our previous adult study, required participants to have sustained fee levels greater than 600 micromol per liter despite available dietary and pharmacologic treatment. This is a more severe population than those in which the BH4 analogs have been routinely used. Beyond simple fee lowering, the promise of PALYNZIQ is that it may offer adolescents the potential to consume more native protein during their formative years and to decrease or eliminate the need for medical food. We plan to share the complete data from our Adolescent Study at a scientific congress in the second half of this year, and we look forward to the possibility of expanding the PALYNZIQ label into adolescents with potential approvals in 2026. On Slide 20. Now turning to another Phase III asset. We're very pleased that the Inozyme acquisition was closed so rapidly, allowing us to carry forward BMN 401 for the treatment of ENPP1 Deficiency. ENPP1 Deficiency is a rare, serious and progressive genetic conditions that can affect blood vessels, soft tissues and bones in infants, in children and in adults. BMN 401 has the potential to be the first genetically targeted medicine for ENPP1 Deficiency. We look forward to sharing a first look at the pivotal data from the ENERGY III study in 1 to 12 year olds in the first half of 2026 and the progressing clinical development in other age groups once we finalize the integration and determine the most efficient path forward. In addition to this initial focus on ENPP1 Deficiency, we are already evaluating other potential indications with BMN 401, and we will share more details as they become available. Finally, on Slide 21. Here is a snapshot of a few highlights expected across our pipeline through the next 6 quarters. Following today's healthy volunteer PK update for BMN 333, we look forward to the start of our Phase II/III study in the first half of next year. Also in the first half of 2026, we'll be sharing pivotal VOXZOGO data in hypochondroplasia with submissions planned in the second half of 2026 to support a potential approval and launch in 2027. We plan to submit our PALYNZIQ adolescent data before the year's end in support of potential launches in the U.S. and Europe in 2026. BMN 401, as already mentioned, is expected to read out the ENERGY III study in the first half of 2026 in 1- to 12-year olds, followed by a potential regulatory submission in that age group in the second half of next year with the goal of launching in 2027. With BMN 351 for the treatment of Duchenne's muscular dystrophy, our study is progressing as planned. In addition to previously discussed 6 and 9-milligram per kilogram cohorts, which have fully enrolled. The study data monitoring committee recently approved escalation to a third preplanned cohort of 12 milligrams per kilogram, which should complete enrollment by the end of the year. We remain on track to share a more detailed clinical update by the end of this year. BMN 349 for alpha-1 antitrypsin deficiency is also progressing in the clinic, and we're planning a Phase II study start in the first half of 2026. In summary, we have a number of exciting readouts and regulatory filings on the horizon, and we look forward to sharing updates as they progress over the coming months. I want to thank you for your attention today. We will now open the call to your questions. Operator?

[Operator Instructions] We'll take our first question from Paul Matteis at Stifel.

Congratulations on the quarter. I had a couple of questions on BMN 333. I just wanted to clarify that the competing program you're referring to is TransCon CNP relates to the comparison to AUC data. And then as it relates to the data itself, can you just confirm the safety profile that you're targeting and whether or not increased exposure is running into any increased risk of hypotension or other side effects?

So Paul, this is Greg Friberg. I can confirm that the agent you're referring to is in that reference that we commented there. With regard to the profile we're seeing with 333 from a safety standpoint, absolutely nothing unexpected, though we have to remember this is a healthy volunteer study. It's in adults, not in children. That being said, nothing unexpected. And again, we also look at the genetic data in this disease, where -- from the standpoint of patients who either have inborn mutations that cause them to have high CNP levels or activated receptors, nature has shown us that those patients, the only problems that they tend to have in their lifetime is that, number one, they're quite tall and there are skeletal complications of being over 7 feet tall. But reassuringly, those patients don't have challenges in other organ systems. So again, we're hopeful that, that read-through will again be recapitulated when we pharmacologically go to higher levels of CNP.

We'll go next to Cory Kasimov at Evercore.

Great to see the continued execution in the preliminary 333 data. On the achondroplasia front, I'd be interested in your thoughts on the evolving competitive landscape here with the recent data showing a long-acting CNP in combination with growth hormone and how you think that could impact the market down the road?

Thanks, Cory. This is Greg Friberg, again. I'll take a stab at that. When the early data for the growth hormone combinations card turned over, it was not surprising to see that there was added growth at a very early time point when growth hormone was added to CNP. Being able to achieve small or at least short-term increases has never been the problem with growth hormone. On the contrary, it's been whether or not those accelerations of growth can persist over time. Of course, achondroplasia is a condition which is not growth hormone deficient. And long-term follow-up of these patients particularly even the Japanese patients where it's approved in Japan have only shown a couple of centimeters an increase in final adult height. Similarly, the kind of evidence beyond growth that we're seeing with CNP affecting facial morphology, looking at tibial bowing, all of these evidence of improving the patient's well-being and health. Those haven't been as profoundly documented with growth hormone. So the question with the growth hormone combination, there are a few of them. One would be, is this something that's achievable over time. Secondarily, do we see mechanisms that accelerate bone age, do we see those? You won't see those in the first 6 months. So we'll want to -- as I think as field, we'll want to see additional data before the story is written as to whether that combination will add anything significant for patients with achondroplasia.

Next, we'll move to Salveen Richter at Goldman Sachs.

This is Tommie on for Salveen. Just on the VOXZOGO guidance, which was slightly adjusted. Could you lay out the contributions of the various factors as you think about ex U.S. order timing, demand and your U.S. expansion initiatives?

Yes. Thank you so much for the question, Tommie. So as we had mentioned, we are expecting higher revenues in the second half relative to the first half of the quarter. And really, when we think about it throughout the quarter, this is primarily due to some of the shifting of large OUS orders that we see that we expected later in the quarter that will shift out a little bit, some into the beginning of 2026 as well, which will, therefore, kind of bring down the number a little bit. Not to mention, we are coming closer with only 5 months to go in the year, and we just have a much better sense of kind of what we're trending toward and what we can forecast throughout the year. So what we did, as you see, is we brought down the top end of the range from $950 million to $935 million, but I want to emphasize that, that still represents 25% year-over-year growth.

We'll go next to Jessica Fye at JPMorgan.

This is Adam on for Jess. I just wanted to ask, can you walk us through when we should expect the next updates from the ITC proceedings?

Yes. Thanks very much for the question. With regard to the ITC update, we're expecting that has been publicly communicated that we're going to see the initial determination on the beginning of June, actually June 8, 2026, then a completion date, the target date for the completion of the investigation of ITC of October 8, 2026. So those are the time frames that have been publicly communicated. There is a possibility of a summary determination for that time, but these are very much what has been communicated by the ITC at this point.

We'll go next to Akash Tewari at Jefferies.

Can you just give us a little more detail about the design of that 333 superiority trial? Because when I look at the VOXZOGO Phase III, you had about 55 patients per arm. You were 90% powered to get a 1.75 average growth velocity delta. I feel like if you have the same powering per arm and you're going for superiority, you're probably looking at like a 0.8 to 1 centimeter improvement between 333 and VOXZOGO for that trial to hit on superiority. Is that the right way to think about efficacy? And like what gives you the confidence you can do that? And then maybe number two, can you talk about the potential to pursue maybe beyond weekly dosing with the profile that you showed in healthy volunteers?

Thanks, Akash. Just dissecting your questions one by one. From the standpoint of the Phase III study, we're not going to go into details on powering today. But we do have confidence that this is biologically a very reasonable hypothesis to test. Of course, we have the preclinical data and the mice where, again, in terms of attributable growth, we were able to almost double the amount of skeletal growth that we saw in those models using the kind of doses with 333 that we've now been able to show at least in the single-dose study or safe in humans. Similarly, we mentioned the human genetic data on the safety side. We also know that those individuals born with activating mutations in the pathway, they grow quite substantially, almost a 7 feet tall or farther. But finally, if we look at the available data that's published for another long-acting CNP agent, marching upwards to the highest dose, there is proportionately an increasing amount of growth at each step along the way. By being able to then in our minds, continue that curve upwards with increased exposure, we feel we confidently have the right molecule to test that hypothesis with 333. I'll just add that we have -- we mentioned we're in our sixth cohort right now. We've completed 5 and 2 of them have met our criteria. So again, we feel like we have on the PK side, quite a bit of headroom and feeling very good about the results that we've seen. With regard to the amount of attributable growth that we're going to look for in the Comparative Effectiveness Study, what I would add is that we certainly have talked to patients. We've talked to physicians, we've talked to their caregivers. And again, we've come up with an amount that we think again would be meaningfully differentiated in the marketplace. And I would be remiss if I didn't add that this -- while this is a story where we talk about growth, and talk about the number of centimeters, we also want to pull through to, of course, the markers of health and wellness. Spinal stenosis, of course, is something that we're following very closely. The additional skeletal facial morphometry studies, all of those, we would be measuring and we would hope to see meaningful improvements in the quality of life of these patients, these individuals who have this condition. So with that regard, we'll be sharing more information over time on the study design. I'll just simply add that from -- as you can extrapolate from some of the AUC comments I made, we would have the opportunity if desire to consider less frequent intervals than weekly. The question becomes which parameter do you want to prioritize? And for us, increasing efficacy, increasing the ability to drive health and wellness in the patients is what we're prioritizing at this point.

We'll take our next question from Joseph Schwartz with Leerink Partners.

[Andrew Park] dialing in for Joe. I know you're working on BMN 333 with the goal to launch in 2030, but in the meantime, how predictive is your low discontinuation rates for VOXZOGO in an environment where there is no competition. How do you think about the discontinuation rates when there are other options, including once weekly or once daily oral prior to the availability of BMN 333?

Yes. Thank you so much for the question. This is Cristin Hubbard from Commercial. And just speak to the adherence rates that we know today. We continue to see that the vast majority of children that are on therapy really do adhere to their daily dosing, and this is true across the globe. And we are really expecting that many of the new initiatives that we've started will continue to ensure this high compliance going forward. Now I will say that this is something that we've invested in, in terms of patient support programming. We think it is incredibly important that patients do adhere to their therapy. And so we've definitely put some support programming in place that will aim at driving adherence and really ensuring that we have an improved experience, in particular, in some of those more high-risk populations where we're truly seeing strong results in terms of adherence. And I do think that this is something that is one of BioMarin's core strength at large across our portfolio. It's truly about finding patients through diagnostic efforts, it's about starting patients on treatment. And then importantly, it is really important that we keep patients on therapy because we know this is the most important thing for long-term outcomes. That's what we're investing in and continue to do so.

We'll go next to Sean Laaman at Morgan Stanley.

Just thinking a little forward to your $4 billion revenue aspirations in '27, I think it is. Just wondering how important other indications for VOXZOGO are after that? And what sort of contribution do you think they might make? And even going beyond hypochondroplasia indications such as Noonan and Turner, when might we expect those?

Sean, this is Brian Mueller. Thanks for the question. I'll take that one. So first, some remarks on the $4 billion revenue target in 2027. Given the many developments since we unveiled our new corporate strategy and 2027 guidance of $4 billion last year, we are taking full account of the latest information and plan to provide an update on our 2027 revenue guidance and our long-term targets by the end of this year. So stay tuned on that, we will revert shortly. I would answer the other part of your question that in the previous guidance, hypochondroplasia was the only indication expansion for VOXZOGO that was launching in that 2027 window. So there's a modest contribution from hypochondroplasia in that original number.

We'll take our next question from Gena Wang at Barclays.

I also will ask about the 333 program. So Greg, you said that now you already dosed the sixth cohorts. What are the thoughts when you go into the patient population? Is the aim is to maintain area on the curve over 3x, any upper limit you will be looking for regarding the safety. And then the -- if you can remind us the VOXZOGO low dose, high dose. What was the area under curve comparison. We do understand the Cmax could be very different. But when you look at the area under curve, what was the difference between the low-dose and the high-dose of VOXZOGO?

Thanks, Gena. And let me take those in order. With regard to the data we have in hand for 3333, we feel that it's going to give us a totality of evidence that will allow us to pick relatively speaking, a low, a medium and a high dose at least several of those will be, again, at this 3x or above is what we're anticipating, though picking those final doses will require us to finish the study and do the formal pharmacokinetic analysis. As we mentioned, this sixth cohort, while recruited hasn't completed in terms of its data collection. So that is ongoing. With regard to the original VOXZOGO studies, the AUCs because the half-life was 30 minutes to 60 minutes as you note, the calculations of AUC in terms of precision, we don't have a whole lot of confidence that comparing the 15 to the 30, for example, is going to give us all that meaningful data. But those numbers were much lower than the AUCs that we're seeing with the long-acting, which has a half-life on the order of days instead of a half life on the hour of minutes in the 30 to 60 minutes. Beyond that, I can't give you any more details in terms of the numerics, but if you have any specific questions afterwards, be happy to follow up with you offline.

We'll move next to Ellie Merle at UBS.

This is Jasmine on for Ellie. Just another one on 333, trying to understand why the 3x greater AUC proceeding means, from your preclinical work, can you give any more color on what this level of CNP exposure translates to in terms of growth? And then secondly, given the data that you've now seen how this impact your thinking on prioritizing 333 versus VOXZOGO for other growth disorders going forward?

Thanks for the question. With regard to the 3x growth, at least from a numeric standpoint, the preclinical model is probably the best because, again, there's a case where actually we were able to recapitulate this sort of increase in exposure. So the control animals had -- were treated with a very healthy dose of VOXZOGO. And again, all of the growth that, that could deliver, followed by increasing titrating doses of 333. And what we saw was at roughly what we're projecting are 3x margin compared to, again, what's been published for other long-acting programs that we were able to unlock additional growth. And so the 3x, again, is what we believe is a meaningful difference in exposure compared to what we've seen before. And in the animal models, again, we know that there's additional growth there. The question is going to be just how much is there. What we know for sure is that we have, what we believe to be the right agent in hand to test that hypothesis. We believe that we're going to be able to test multiple doses at that threshold or higher in the dose-ranging Phase II and that before, certainly, the initiation of the comparative effectiveness study, we're going to have a good handle on how much growth is there to be at. That being said, it is an unanswered question. The preclinical, the genetic and the data from other long-acting CNPs can only get us so far. And so having the right agent to test is the next step, and we're thrilled to be moving forward. We're excited about 333 beyond just achondroplasia. We're putting together our hypochondroplasia plan as we speak. All of the additional indications do require us to do a dose-ranging study. So doing that as quickly as possible is the key to unlock that. And again, having that arrow in our quiver is also going to allow us to think about additional indications where we might want a best-in-class long-acting CNP agent. And again, that's what we're hopeful that we have in BMN 333.

We'll take our next question from Olivia Brayer at Cantor.

Can you give us an update on where you are with the citizen position? Have you had any back and forth dialogue with the agency? And maybe just any comments on how confident you are that there will be action taken by the FDA here? And then just wanted to follow up on some of the comments made around the long-term guidance metrics. Is there something in particular that you're waiting to hear about before having better visibility into what those numbers could look like?

Thanks very much for the questions. I'll take the first one. This is Alexander. So with regard to the systems petition, we have submitted that to the FDA. The FDA considers that during the review process for the competing molecule with regard to determining the validity of our orphan drug extension. So we do not expect to hear anything from the FDA until PDUFA. As you know, that is November 30. So that's all the information we have to share right now on the situation with regard to this system competition. Now I'll hand it over to Brian to handle the second part of your question.

Yes. Thanks, Olivia. Following up on the $4 billion in 2027, there is not a specific event that we're waiting to pass before we give that updated view. It really is just working through our collective refreshed view across everything that's changed over the last year. There's puts and takes. We're considering recent trends in market research across our portfolio. We completed the Inozyme acquisition this quarter. And of course, the VOXZOGO IP litigation is still ongoing. So we're working through that. And once we do, we'll share the perspective.

Next, we'll move to Konstantinos Biliouris at BMO Capital Markets.

Congrats on the progress. Maybe some more color on some comments you made earlier on the 3x difference between AUC. Can you please clarify how exactly you performed the comparison? Was it 3x -- at least 3x across all doses you compared or only in the highest dose or only in some doses? And the follow-up is on Cmax. Does Cmax matter at all here maybe for safety or efficacy? And how does your Cmax compare with TransCon CNP.

Thanks for the question. With regard to the ongoing study, just to repeat something I said up, but I might have gone through too quickly. We've completed and analyzed 5 escalation cohorts. It's a healthy volunteer single-dose study. And 2 of those cohorts already have met our AUC criteria of being greater than 3x. That is greater than 3x the AUC, of which is published and we put the reference in our slides for the other long-acting CNP agent that's been discussed. From that standpoint, again, we have a sixth cohort that's running right now. All of these have been avoiding the kind of Cmax ranges where with VOXZOGO, we knew that we started to see a very predictable effect on the vasculature, which was the drop in blood pressure and some tachycardia in patients. That is Cmax that is well understood from the preclinical models and from our own experience, and we're still almost tenfold away from that with regard to what we're seeing. Nothing is for free, and of course, as your AUC goes up, so does your Cmax. And so from that standpoint, the Cmax, we predict will be greater than the other long-acting CNP out there. The question is, is that problematic? And so far, it has not been problematic. We're moving forward. And again, this is why we will, in patients do a dose ranging of a high, medium and low, that's a relative term, but a high, medium and low dose of BMN 333 moving forward in order to test not only what kind of growth and effects on health and wellness that we can see, but also to make sure that, that is safe in those patients.

We'll take our next question from Jason Gerberry at Bank of America.

One just follow-up on the HCH opportunity and the commentary about getting to the patient earlier. I guess we observed with ACH or achondroplasia that getting the below 5 indication was really key commercially in a number of geographies. And with ACH, at least in the prior Phase II work, I think the average age was about 6 years of age, your enrollment criteria is 3 years. So I wonder given it's a milder disease, the motivation to treat and sort of the risk, I guess, from a patient perspective, they're going to come on later in life and may not get the sort of lifetime benefit that they see in HCH. So just wondering if you can maybe expound upon some of those efforts and how you see that evolving.

So I'll start, thank you very much for the question, Jason. And so I'll start a little bit about the opportunity because you're absolutely right that these patients do tend to get diagnosed later. It doesn't mean that there isn't a large unmet need in these patients. And I've mentioned a little bit on the prepared remarks, and that is that you have comorbidity that we see disproportionality being the big one microcephaly, ENT issues and musculoskeletal skeletal issues, excuse me. And what we know is that as we see in achondroplasia, the earlier that you can treat patients, the better. And so we are very focused on leveraging much of our relationships, our infrastructure to ensure that we are educating on the unmet need that is here in hypochondroplasia, and importantly, that we can encourage diagnosis as soon as possible, given that this is both clinically and genetically heterogeneous condition, it's important that we educate on the importance of diagnosis, and that's precisely what we are focused on now as we await the Phase III data.

Yes. And I would just add that the studies for ages 3 to 18. So again, given the current state of diagnosis, we believe, again, it will serve a good number of patients. There is an Infant Study that's ongoing as well that will need to continue to enroll, and that will be delivering its data at a later time point. But the bigger question that you bring up is, again, making sure that we do our part to not only measure, but also report to the world, the health care burden that these patients and their families are experiencing. And we began that process. We published some abstracts continuing to do work, again, health care utilization, resources required by countries in order to care for these folks. But that will be an important part of the process here to continue to, again, create not only a data set in the label, but also an urgency to treat based on what these patients are experiencing in the real world.

We'll go next to Alex Hammond at Wolfe Research.

Just a few on VOXZOGO. So BioMarin has mentioned investing more in clinical coordinators to reduce the time needed to see a specialist. What's the average time from prescription that we're seeing currently? And where do you aspire to be? And then on increasing prescriber referrals from pediatricians to endocrinologists, how is that strategy progressing?

Yes. Thank you very much for the question. And I can say that what we are focused on is certainly reducing the time it takes from diagnosis to get patients on treatment, which can take on the order of months to do. I do want to give a little bit of color in terms of where we're seeing the growth right now, which I think is really important. And where we saw strong uptake that continued into the second quarter. And what we saw is that this was especially in our youngest patients. So our biggest cohort that grew quarter-over- quarter was 0 to 2 year olds. And this is really important because this is expected to be the only approved treatment in this age group. But we also saw strong growth in the 2 to 4 year olds. And I think that this is really important because we're out there really trying to emphasize the importance, and this is true when we saw the consensus guidelines as well in terms of early treatment so that we can ensure the maximum benefit of the therapy. Now in terms of how we are driving, as you've mentioned, referrals from pediatricians into treaters, whether those be pediatric endocrinologists primarily, but also geneticists, that has been a successful strategy so far. We are seeing many of those new initiatives that are really taking place and taking off, and that was in part where we saw the growth being driven in the second quarter. So we expect that to continue over the quarters to come. And what we saw is when we look at the treater base in terms of where we're seeing growth in treaters, it's actually happening across all treater types. So we're seeing growth in geneticist, in endocrinologists and in pediatrician. So we're very happy with the results so far and anticipate continued investment in these areas.

Our next question comes from Ellen Horste at TD Cowen.

Congrats on the existing quarter. Just regarding BMN 401, I'm wondering what success looks like for the ENERGY III trial, including potential functional endpoints that might be required for approval outside the U.S.? And then if you can remind us how many patients have been identified so far and what's involved with identifying the 2,00 and 2,500 prevalence you estimate in your territory?

This is Greg Friberg. Just taking that first question first, with the 401 card that's turning over for those who aren't as familiar, this is the ENERGY III study. So this is in the children and as opposed to infants or adolescents and adults. We'll be turning the card over in the first half of next year. And the success has 2 categories here. Those have been mortalized as co-primary endpoints in Europe, as you noted, and those are not only normalizing the pyrophosphate levels, which is a sign again of biochemical normalization, but also functional endpoints. And in this case, it's the radiologic index that's noted. That, again, is looking at the quality of bone in these children that still have their growth plates open. We have clear agreements with the Europeans as to what those functionality endpoints mean, and we're continuing to work with the FDA and other regulators to work through, again, the details of those. But it is a combination of both pyrophosphate as well as functional endpoints, as you point out. And we'll be measuring pain and some others in the protocol as well. But that's what's been agreed upon with the European regulators. To answer the second question, I think I'll -- with regard to number of patients, I'm going to hand it off to Cristin.

Greg. So as you referred to, you're absolutely right in that in terms of the overall target patient population -- addressable patient population, we do estimate that the range will be on the order of 2,000 to 2,500 patients. Now I want to be very clear that the literature on this is very disparate and there's very high ranges. This is our current estimate in terms of what we believe the prevalence to be as well as our ability to ensure that we get diagnosis of these patients. Now Inozyme had already identified over 600 patients, and we are carrying on much of the work that they were doing as we've taken this on and they have had great work and great success in building KOL networks that have been highly successful in finding these patients, but we believe that we can expand on that, again, going back to it being a core strength of ours and that is investing in diagnostic efforts to ensure that we're diagnosing and finding these patients. It's also really useful that this will slot right into our Enzyme Therapy business unit where it's highly complementary to the relationships and the established networks that we have today. So the specialties that we now treat ENPP1 Deficiency are certainly include but are not limited to the treaters that we already call on and that would be geneticists and endocrinologists. So we're very much leveraging our infrastructure and networks there in to ensure that we can properly find these patients and then hopefully should the data turn out to be positive, get these patients on therapy as soon as possible.

We'll go next to Allison Bratzel at Piper Sandler.

Another one on BMN 333. Just a clarification, I'm sorry if I missed it, but can you help us better understand what exactly is gating to initiation of the dose-ranging portion of the registration trial? And I think you've received FDA alignment for the Phase II/III plans. But could you just talk to your confidence in achieving regulatory alignment ex U.S. and timing there?

Thanks for the question. And I'm very excited to share that we have regulatory alignment with multiple players around the globe at this point. And so the gating factor is, of course, completion of the current Phase I study, it's very typical for healthy volunteer studies actually to study doses sometimes that are higher than what you'd study, again, giving you some PK buffer in Phase II. And in that regard, having that complete data set is a requirement before we move forward. I'll also add, though, that we are moving very quickly. We're in the midst of protocol, not only writing, but we're very far along in that process. And really, the next steps will be to initiate the study in the first half of next year. So if there is a gating factor, it's completion of the sixth cohort of the pay of the PK profile, but that is more of a formality in order to be able to, again, convince regulators and patients that again, we have the data set in hand to justify moving forward in all of the doses that we've proposed. So more to come, but in that regard, we're thrilled to be able to be moving to this next step for the dose ranging of 333.

And that concludes the Q&A portion of today's call. I will now turn it back to BioMarin's President and CEO, Alexander Hardy.

Thank you, operator, and thank you all again for joining us today. We're proud of the strong execution in the first half of this year and energized by the opportunities ahead. Continued momentum across our commercial pipeline, business development efforts, we believe BioMarin is well positioned to deliver significant value creation, patients, employees and our shareholders through the remainder of 2025 and beyond. We look forward to updating you on our progress in quarters to come. Thank you very much.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.