BioMarin Pharmaceutical Inc. (BMRN) Earnings Call Transcript & Summary

Please go ahead, JJ.

Okay. So welcome, everyone, and thank you for joining us on today's call. We are, as you can imagine, very pleased to share the news of FDA's approval of VOXZOGO for children, ages 5 and older. I want to thank the FDA, the families who participated in our cable programs, our investigators and advocates and especially my colleagues in clinical development and regulatory affairs at BioMarin who have all contributed to this important day for children with achondroplasia. VOXZOGO's approval in Europe in August and in the United States today marks a significant milestone for BioMarin. The teams have shown tremendous persistence and diligence with a single-mind focus on getting VOXZOGO approved for the benefits of families seeking a treatment option for achondroplasia. Perseverance is part of our company's culture, and it is achievers like today's that today's approval of VOXZOGO that keeps us motivated to continue our meaningful work even when times are challenging. I think I am so proud of what has been accomplished on behalf of children with achondroplasia. For our shareholders, we have today's approval demonstrates that we believe to be true, which is we believe that -- our Board strategy is sound, our R&D and regulatory organizations are unmatched and our prospects for the future unbundled. It is the unparalleled scientific discovery development, regulatory, commercial and manufacturing expertise that has given BioMarin a track record like no other company in our industry. We now have 7 approved products available in over 75 countries. And all of them are best or first-in-class treatments for serious genetics disorders. In addition, we are very pleased to have received, with this approval, the priority review voucher, or PRV, from the FDA. So thank you all for your support of BioMarin, and we will now continue with today's presentation. Next slide, please. To remind you, we may be making forward-looking statements today about the future prospects of VOXZOGO, and we recommend that you review our quarterly disclosures and future SEC filings for more information. Next slide, please. So next on the agenda will be Hank Fuchs, our President of Worldwide R&D, who will review the label approved today, and he will be followed by Jeff Ajer, our Chief Commercial Officer; who will review the launch plans in the United States, then we will open the call to your questions. So we now turn the call over to Hank. Hank?

Thank you, JJ. And I, too, would like to extend our gratitude to families, investigators and health authorities who have contributed to this important approval for children with achondroplasia. And as JJ did, I want to acknowledge and thank our employees for their special blend of perseverance and commitment to the mission of translating genetic discoveries into transformative medicines. That's really come alive today. We're very pleased with the outcome of both the indication as described and our label to increase linear growth in patients with achondroplasia 5 years and older with open growth plates as well as the post-marketing requirements, which will leverage our ongoing extension studies. And I'll touch on these in a moment. Today's accelerated approval is based on our Phase III study conducted in 121 subjects with genetically confirmed achondroplasia who are randomized to receive either VOXZOGO, 60 individuals or placebo 61 individuals. The dosage of VOXZOGO was 15 micrograms per kilogram administered subcutaneously once daily. The primary efficacy endpoint of this trial was the change from baseline in annualized growth velocity at 52 compared with placebo. Treatment with VOXZOGO for 52 weeks resulted in a treatment difference in the change from baseline in annualized growth velocity of 1.5 centimeters -- 1.57 centimeters per year after 52 weeks of treatment. After the 52-week double-blind placebo-controlled Phase III study 58 subjects initially randomized to VOXZOGO, entered into an open-label extension. Among the subjects who had 2 years of follow-up since randomization, the improvement in annualized growth velocity was maintained as is acknowledged in the clinical trial section of the U.S. label. Linear growth accurately reflects the benefits that have been demonstrated at the date of VOXZOGO and namely that it leads to an increase in annualized growth velocity in standing night as prespecified in the primary end point in our development program. Receiving today's approval demonstrates how far we've come since the FDA Advisory Committee meeting in 2018 about achondroplasia and is a testament to our ability to create clinical endpoints that demonstrate the effectiveness of our innovative products. The safety profile demonstrated with VOXZOGO as highlighted here in the important safety information in the product's label. Injection site reactions are the most common side effect. 2 out of 60 or 3% of VOXZOGO-treated subjects each had in total, 1 symptomatic episode of decreased blood pressure with dizziness and vomiting and dizziness alone, respectively compared to 0 out of 61 subjects on placebo. Both of these patients continue treatment without recurring event. We are delighted to have received approval of VOXZOGO, the only approved treatment for children with achondroplasia and when that targets the root cause of this condition. It's products like VOXZOGO that exemplify BioMarin's focus on translating genetic discoveries into transformative medicines. In our next slide, since the 2018 outcome on achondroplasia, we've partnered closely with the FDA to align about durability of final adult height, the latter, an important measure of the accumulated clinical benefit in this patient population. We believe that these post-marketing requirements are readily addressable through our ongoing extension studies. We have a good understanding of the requirements for conversion to full approval. We are well positioned to leverage our extensive ongoing clinical development program, including our 6-year Phase II study, in which a good number of children have already reached final adult height. Our Phase III study with 110 children, who are nearing their third year of study treatment and observation as well as the largest natural history study conducted in the United States, a study called CLARITY, in conjunction with Dr. Julie Hoover-Fong from Johns Hopkins, which includes over 1,300 children in a multicenter retrospective cohort study of achondroplasia. The post-marketing requirement will allow us to leverage both our Phase II and Phase III programs. as well as the large natural history study published earlier this year in Genetics Medicine. We believe we'll be able to satisfy the data requirements of this post-marketing requirement in the next few years, consistent with regulatory precedents as used in past approvals. Accelerated approval of final adult height as part of a post-marketing requirement is a good thing, and we'll answer many questions that have been raised by the achondroplasia community as well as the many benefits on health and quality of life beyond height that may only be ascertained with longer-term observations. Accelerated approvals consistent with input from the 2018 FDA advisory committee meeting on achondroplasia. Importantly, this initial approval is just the start of how we envision expanding access to VOXZOGO. Should data from our 206 study in 0 to 5-year olds be supportive early next year, we would hope to expand the age range for access to VOXZOGO through supplemental marketing applications in the U.S. and Europe. At R&D Day in November -- on November 30, we look forward to providing insights into the 206 study that help secure the approval for aged 2 years and up from the European Medicines Agency. Our long-term plans to the achondroplasia community include making VOXZOGO accessible to any child who can benefit from treatment. And therefore, I will now turn the call over to my colleague, Jeff Ajer, our Chief Commercial Officer; to discuss U.S. launch plans. Jeff?

Thank you, Hank, and welcome, everyone. On behalf of the commercial organization of BioMarin, we also want to thank the families, patient, advocates, investigators, clinicians and colleagues who made today's approval of VOXZOGO possible. The U.S. approval is a big step forward in the global launch cascade that is underway since EMA approval in August. The early experience has been encouraging with strong prescription demand with a substantial number of commercial patients already started on commercial therapy in France and Germany. We have also seen high prescription demand and interest in name patient sales in a number of markets that fall outside the EMA approval and expect it will take some time to translate to commercial patients and we have the expertise and experience to do it. More filings under review, most notably Japan, the only region where growth hormone is approved for the treatment of achondroplasia until we launch their next year, assuming timelines track to our current expectations. As the first experience where BioMarin received approval in Europe before a U.S. approval, we look forward to meaningful growth in both regions in 2022. As many of you know -- next slide, thank you. As many of you know, VOXZOGO builds on our long history of experience commercializing global brands with an experienced team and a global footprint of over 75 markets. The team is now in place and well prepared to launch what will likely be BioMarin's largest brand to date. Next slide. With the prevalence estimated to be 1 in 25,000, we estimate 21,000 children with achondroplasia in BioMarin's commercial footprint, underscoring a large market opportunity. Of the estimated 3,000 children with achondroplasia in the U.S., we estimate nearly 2,000 fit the label indication of 5 years and older with open growth plates. Virtually all of these patients would have received the diagnosis of achondroplasia, eliminating a major barrier to treatment access. Next slide, please. In the absence of a pharmaceutical treatment specific to achondroplasia, we estimate the majority of eligible children in the U.S. are not currently in the care of an achondroplasia medical home suitable to start and supervised treatment with VOXZOGO. Commercially available claims data gives us visibility in the positions providing care for these children. The first priority for the team in the U.S. will be to leverage existing relationships with genetics and skeletal dysplasia clinics that do provide care for eligible patients and which can initiate treatment with VOXZOGO. Pediatric endocrinologists are the growth disorder specialists, and we believe will constitute an appropriate treatment home for VOXZOGO. Next priority is to establish a referral network for eligible patients to interested VOXZOGO prescribers. This is a new and addressable call point for BioMarin. Our experience to date with pediatric endocrinologists indicates that many are interested in achondroplasia and VOXZOGO. The U.S. team is extending our rare connections reimbursement case management services immediately to support VOXZOGO. And our experienced market access team is taking immediate action to prepare payers to review early prescriptions while working toward the issuance of coverage policies beyond the immediate term. Our confidence in this experienced and highly prepared U.S. team's ability to drive rapid access is high. Next slide, please. we are pricing VOXZOGO in the U.S. at a flat WAC price of $899 across 3 SKUs. Dosing guidance in the label will result in consumption of 1 vial of VOXZOGO per patient per day. Flat pricing ensures that the cost of VOXZOGO does not escalate as patients get older and heavier. Net of expected discounts and compliance rates, we estimate the annual net revenue per patient to be approximately $240,000. Next slide, please. As noted on our recent earnings call, we intend to provide information to help you evaluate the progress of the launch for the coming 6 quarters. More specifically, each quarter, we will provide net VOXZOGO product revenues. The number of active markets with sales and the identity of those markets. The total number of commercial patients at the end of the quarter and other color commentary on the launch that will be helpful for you to evaluate the status and progress of the launch. Next slide, please. In closing, we are so excited for the opportunity with VOXZOGO and the impact it can have for eligible children with achondroplasia. Pictured as Annika, a 14-year-old girl living with achondroplasia and who received VOXZOGO as a participant in our Phase II clinical trial. Thank you for your attention. I will turn the call over to Traci, so we can take your questions.

Thank you, Jeff. [Operator Instructions] Our first question today comes from Joe Schwartz. Joe, you're on the line. I think you're muted. Please go ahead if you have a question. Thank you. Okay, I think, Joe is on mute. So we're going to go to our next question. Phil, you're on the line to ask a question.

Congratulations to the team on important approval. Two questions from us. First, on the post-approval requirements, what exactly needs to be demonstrated by those to convert the approval to a full approval? Do you have to show some cohort of patients who reach growth plate closure actually have a higher adult height than would be expected? Or is the data short of the adult age acceptable? And then second question is commercial. Do you have any estimate of the number of patients who are currently being seen by a VOXZOGO prescriber today? What is kind of the immediately accessible population to BioMarin?

Hank first question and Jeff second.

The exact specification of final adult height will be specified in the final protocol that will be evolved shortly. I think at this stage, we have a broad brush structure agreement with the agency on who to study and what to compare it to, and we're still ironing out the final details of the exact measurements to be made.

Phil, thanks for the question. So we don't have an exact number of the patients under the care of genetics or skeletal dysplasia clinics that would be interested to prescribe VOXZOGO but probably a minority of the 2000. As you can tell from our slide, those patients are spread out all over this vast country of ours, as you would expect based on kind of population densities. And while there are connections back to skeletal and genetics clinics, some of those connections may be tenuous. So we're counting on initial demand coming from those clinics. And we'll be able to provide more color as we get into the launch.

The next question is going to come from Cory Kasimov from JPMorgan.

Thanks, Traci. And good morning, guys, and congratulations as well for me. Obviously, great to see. I'll also ask to First for Jeff, I'm curious how you're thinking about the pending initial rollout in the U.S. in terms of the amount of heavy lifting that's really required it obviously sounds like European launch is off to a great start. That also includes the 2- to 5-year-old age group, which we weren't expecting to see in the U.S. just yet. So curious how similar or different you believe the U.S. might be from a ramp standpoint. And Then for Hank, can you just remind us how hypotension was dealt with when encountered in clinical trials and how much of a problem or burden it presented, if at all?

So thanks, Cory. I'll start and address your commercial question. So a little bit of color from the EU launch so far and also from the prescription demand that we're seeing from countries outside of the EMA approval. The initial prescription demand is coming in batches, not 1s or 2s or. So we're seeing interest in batches of 4 or 5, 6 patients in a lot of cases, which is really encouraging and a different experience for us relative to our enzyme replacement therapy products, for example. Now the model of care in our first markets, France and Germany, is more organized and more concentrated than the model of care in the United States. So a lot of achondroplasia kids are in an achondroplasia center that you could call a medical or a treatment home for VOXZOGO. We think that we've got a more dispersed situation in the United States. Also to note, in France, the ATU approval, which is our reimbursement approval for the first year or so is for children ages 5 and up. And the French prescribers are taking advantage of that, and they're actually targeting children in the older age window and saying, look, we've got an opportunity and an open window to treat these kids. Let's get the started on therapy, and we'll worry about the younger kids later after we open up that reimbursement window for 2 to 5. That's also a really encouraging signal about the interest and the desire for treating older children. So in the United States, as I said, we've probably got early demand coming from genetics and dysplasia clinics where we've got really good relationships already. But beyond the immediate term demand, we're going to have to make referral connections, drive those patients from the random pediatrician in Des Moines or an ear, nose and throat doctor that are seeing achon kids but aren't an appropriate treatment home and drive them to pediatric endocrinologists. And ped endos are natural here. They are the growth disorder specialists. They're interested. They can prescribe and treat with VOXZOGO and treat achondroplasia. So we're really excited about that opportunity. But that is our heavy lift on this one.

Hank, will you answer the question on hypertension in a couple of patients?

Yes. So there were 2 patients. One each who had vomiting and dizziness and other had doneness covering hypotension. And that's out of -- I think it's important to reflect on, that's out of probably 100,000 injections in the treatment group compared to 0 out of the thousands of injections administered to the placebo group. And I think the important thing there is that those 2 children were able to continue to receive therapy and didn't experience recurrent events. And as a consequence, the agency put a warning out there, which I think is a really good idea to ensure that patients are adequately hydrated and to remind prescribers that children with heart conditions should not be treated with achondroplasia because we haven't studied those children adequately in clinical trials. And that, of course, is relatively rare by itself. And so I don't view that as a particularly burdensome set of responsibility. And I think these children recovered reasonably straightforwardly and without any further intervention. And that's why I think the warnings reflect just a little upfront caution in the consideration of who and how to treat.

Our next question comes from Gena Wang from Barclays. Gena, hopefully you can hear us.

Yes, I can hear you. Can you hear me?

Yes.

Perfect. Also, I wanted to add my congrats. That's a long waited and really exciting for this. So I have a few questions. First, regarding the pricing -- sorry, the prices -- the flat price. Just wondering, logistically, how do you control the different vials will be under the same price and won't be used to have like models out of the higher dose vials. And the EU price, do you also have the reimbursement discussion, where do you see the pricing cycling now you give a U.S. price of $240,000. And for the post-marketing study, just wondering how many patients will be in that study? And would they be on commercial drug or BioMarin will pay for the drug? And quickly you mentioned the immediate demand for -- from the geneticist. Just wondering what percentage of a 2,000 patients you think that source will cover?

Jeff, you want to cover this?

Okay. Let me start off with the flat pricing. So Gena, the driver behind the flat pricing across the 3 SKUs is we didn't want to create a situation where older, larger children that were growing and responding to VOXZOGO would have an escalating cost of care associated with them and create a gradient against continued payer support for those patients. So we've got the 3 SKUs. The dosing bands that are approved in the label will result in 1 vial per day being consumed by an achondroplasia patient. We don't think there's a risk of having a larger vial being used for multiple days, if that was the question, these are single-use vials and our research with both prescribers and payers indicate that they wouldn't tolerate the risk of trying to create a larger vial into a multi-day dose. So it's 1 vial per day per patient. It's really just that simple I didn't pick up exactly what your second question was about where pricing was settling in. And in terms of the percent early, I think I noted a couple of times, we don't have an exact number. It's not been possible to dial that in, we'll get a better read now that we have a product approval and we can get in and have more specific conversations with genetics and skeletal dysplasia clinics in those prescribers. But think about that early demand coming from a minority share of the 2,000 patients that we estimate are eligible based on the label.

Gena, did you have any follow-up questions there or remind Jeff of the 1 maybe that we didn't get to.

Yes, sure. Sure. Yes, that's at EU pricing. Just wondering where do you see the price was settling in after the initial phase?

Okay. So the U.S. price at WAC is right in a corridor with our established list pricing in France and Germany so far. In the U.S., we're estimating that based on government discounts, other allowances and compliance, our net revenue per patient will be a substantial discount off of that WAC list pricing. And as we go through the reimbursement approval process in Europe, which will take about a year from that August approval to get to our first kind of negotiated reimbursement prices. We anticipate a substantial discounting off of those list prices, about $300,000 per patient per year in France and Germany that we indicated. So we were anticipating kind of a similar discounted price maybe not too dissimilar to what we're guiding to in the United States, all in the desire to try to keep a coherent pricing corridor going in our global markets. And there was a question about, maybe, Hank, you want to take this one about the post-marketing commitments and whether that's clinical drug or commercial drug.

Yes. So the details of the post-marketing study are to be unfolded. I think that what the approval letter acknowledges is in broad brushstrokes agreement on the nature of the post-approval study, which would be to follow children who were treated in the clinical trials for a longer period to final adult height whose specific definition was also to be delineated in greater detail on the final protocol. But broad conceptual agreement with the FDA on longer-term follow-up extension of these children, which is reassuring because to the FDA because they know that those data will be available. It's not like, oh, there's a study and the can, can be kicked on when that study started these children are already under treatment and an agreement that the comparator here will be the natural history databases that we've already used in our original application. And I think one of the most important points about all this is that we have really rich patient-level data, both on several hundred people in a natural history study and also hundreds of people in our ongoing clinical trials. So this is going to be definitive evidence of an effect on final adult height when it matures. And as to the details of the commercial access of those patients I think we need to defer that question as well. In general, once the product is approved, patients do transition to commercial drug, and that shouldn't be able to -- shouldn't preclude our ability to study them in this type of post-approval study. But again, details to follow-up.

I do have to make sure to be back to the pricing question evolution in Europe, again, as Jeff said. So the U.S. would be around $240,000, $250,000 net of compliance and discounts and the Europe, not to be similar, probably between $220,000 and $250,000 in a year or so from now once negotiation is completed with Germany and France.

Thank you, Gena. So the next question I'm going to read is from Joe Schwartz of Leerink. We have noticed you've used the words product and launch somewhat interchangeably when describing your expectations that VOXZOGO will be your biggest product as well as your biggest launch. I'm just wondering if you can clarify whether this is intentional such that you expect VOXZOGO to ramp faster than Vimizim from the get-go. How do you expect the initial ramp to compare to Vimizim, which has been your biggest ramp to date? Jeff, do you want to start with that? And Brian maybe have some additional comments.

Sure. Thank you, Joe, for the question. I don't think we've been deliberate in mixing the use of product, brand and lunch. What we think -- what I believe is that VOXZOGO has the biggest long-term revenue potential relative to the products that have been approved before it, including Vimizim, which is our largest marketed product to date. The dynamics of treating achondroplasia in a global cascade starting in 2021 are so different than the dynamics of enzyme replacement therapy launch in 2014. I don't -- I would not recommend that you try to use Vimizim as a proxy for VOXZOGO uptake. We will be providing guidance on the fourth quarter earnings call about our revenue expectations for VOXZOGO in 2022 so stay tuned for that. And as I've said now on a couple of occasions, we'll be trying to provide you quarterly metrics and other color that will help you guide expectations for launch.

Yes. Thanks, Jeff. Thanks, Traci. Maybe just to add, it is important to pay attention to some of the nuanced differences between this VOXZOGO now global launch and prior launches such as Vimizim and Naglazyme. One, of course, is the larger patient population, but another is the more robust diagnosis for the achondroplasia patient community. Just a reminder, many of you know this, but when we were launching Naglazyme and Vimizim, as Jeff noted earlier, it was one patient at a time our sales and marketing efforts. We're focused on educating physicians in the medical community on mucopolysaccharidosis generally. And with achondroplasia, we now believe that diagnosis happens at birth or in utero, and that's a good head start in terms of disease awareness in the community. But one big similarity to our prior launch is this is the first time a pharmaceutical is available for achondroplasia. So we are establishing the market, and that's the same as Vimizim and Naglazyme and our prior launches. So that will be the challenge that Jeff was referring to earlier with the referral networks in the treatment homes.

Next question, I'm going to read is from Paul Matteis from Stifel. Can you speak more about the commercial build-out in the U.S. and EU? How much of your existing infrastructure can you leverage? What proportion of patients are at centers of excellence right now? Maybe that's you, Jeff.

Okay. We actually have a global commercial footprint covering more than 75 markets. And much of that infrastructure is leverageable today. So our operations teams, our market access teams, they're in place, have been in place, have been working on launch brands, multiple launch brands. All of that is leverageable. Many of the physicians that will be treating VOXZOGO are known to us through our work with Vimizim and Naglazyme. Those would be geneticists and skeletal dysplasia specialists and pediatric orthopedics. We're able to directly leverage those teams and our relationships. And in the early markets, France, Germany and the United States, we have had specific VOXZOGO sales teams in place and doing market conditioning and establishing initial relationships to facilitate this launch. So we don't have to go out and put teams into place. They're already there. They're ready to go.

Our next question is going to be from Aspen Mori from Bank of America. Aspen. Can you hear us?

Traci, can you hear me?

Yes, thank you.

I'm on for Jeff. Just wanted to get a sense of how many patients are on VOXZOGO in clinical studies and what the time line for conversion to commercial drug could look like? And then additionally, on the post-marketing study, I guess how critical do you think adding that post-marketing study data to the label, whenever it is down the line is from a commercial perspective in terms of making sure BioMarin can have VOXZOGO reach the largest addressable market possible.

Thanks for the question, Aspen. There are about 130 commercial trial patients across the program, and those patients are spread out in clinical trial sites all over the world. So not a material impact, I would say, of converting U.S. patients to commercial therapy. And as Hank noted earlier, the details of how to follow that post-marketing commitment need to be ironed out. So we'll be watching that, but I would call that more of a detail than a major force for commercial. And let's see, in terms of the post-marketing studies, there is -- the post-marketing studies are of a piece with some of the other efforts that are going on with VOXZOGO to continue studying this drug and to facilitate label expansion over time, which should unlock new patient populations for us. A great example of that is the 2- to 5-year-old population in the 0 to 2-year-old population which are being studied. So we got that 2 to 5 population in the EMA approval, and we think that's really valuable. We think that we will likely be able to get that over time in the United States. And similarly, with that 0 to 2-year-old population. And as Hank indicated, the initial approval based on linear growth reflects what we've been able to capture so far. But the post-marketing studies over time will allow us to elucidate other important outcomes from the treatment of VOXZOGO. And I might just ask Hank, if he wants to add anything to that.

Yes. Thanks, Jeff. I think another aspect of the conversion to full approval for the products label will be that there will then be a product to improve the outcomes of achondroplasia individuals on a full -- on a real -- on a full clinical endpoint, which means that accelerated approvals through the linear effect on annualized growth velocity will no longer be possible from a regulatory perspective. And in so far, as we have 110 patients who are now 2 and 3 years on therapy, respectively, for placebo and trial patients. We have the largest data set, and we will be obviously the first across the finish line of documenting an effect on final adult height. So I think the expectation is that in the future, hundreds of patients will be required to cross the finish line at final adult height before any followers can enter into this market and offer their where as an additional option for patients. So we feel really good about the post-marketing requirement because it establishes a fairly high bar for subsequent approvals. And as the pioneer in this field as the leader in the field as the group doing all of the work we deserve the benefits of all that.

Next question is from Kennen MacKay from RBC. Kennen can you hear us?

Can you hear me?

Yes.

Great. So huge congrats on the approval to JJ and the whole team. Hank, I know this was a marathon effort with the FDA, bringing the first treatment for achondroplasia. So huge congratulations there. My question is maybe for Jeff or maybe, Brian, based on your physician and patient surveys, wondering if you're anticipating this U.S. launch curve function is going to represent a launch into all of those prevalent patients, age 5 to 20-ish when growth plates close or whether it might look more like an incident launch of the patients on the younger end of that range with growth coming from compounding of newly incident patients every year given those patients might benefit the most from a decade plus of treatment with the drug throughout the entirety of their growth curve.

Maybe I'll start with that and see if Brian has anything he wants to add. So our research has indicated that the long-term value proposition is the strongest for patients that start earlier on therapy and then maintain treatment over time for a long period of time. That's kind of a theoretical value proposition because we don't have the data that we will have on the long-term benefits of treatment with VOXZOGO. I mentioned earlier to a different question that our experience in France has been both encouraging and instructive in France, where the ATU approval is for patients 5 years enough. The prescribers in France have taken that as a queue to focus on starting older patients first, and working down the age queue on the logic that they have an open window to start treatment for those older patients. And they want to derive the benefits that they can during that open window. That kind of flies in the face of the high-level value proposition that I described earlier for treatment benefit greatest for early patient starts but maintain therapy over time. So if that France experience is an indicator, we may be able to see a logic and a value proposition for starting older patients as well as starting younger patients that would be my desire.

Yes. Well said, Jeff, that much more to add there except initially here, frankly, we view it as both a prevalent population launch and an incident population launch. This is a large market opportunity, again, with no approved therapies for achondroplasia until VOXZOGO. So we saw patients from a variety of ages in our clinical trials, and we saw the clinical benefits there. So both accessing this larger prevalent population. But on an incident basis for now more than 5-year olds, you're right, every year, there's new achondroplasia patients turning 5, and hopefully, we'll get to the children under 5 over time as well.

Maybe just a follow-up housekeeping question. In patients with achondroplasia, can you maybe help us understand when the epiphyseal plates do you completely close it in wild-type individuals that can stay open up to age 24-ish or so in men, but would love to understand if there are any differences in patients with achondroplasia.

Well untreated achondroplasia probably have growth plates close a little earlier than treated achondroplasia patients, and that's yet to be determined. The growth velocity flattens out as you get into the 14, 15, 16-year age range for girls and boys, respectively. And I don't know that there's like a fantastic amount of literature documenting the relationship between epiphysial closure and age in achon children specifically. And that's why I think, we have to get in a little bit more detail for Phil's earlier question about what actually will constitute a final adult height. And of course, some of those details especially from a statistical perspective, will be proprietary to buy rent because there'll be the special ingredients, which enable the conversion to full approval. And we'll then, as I've mentioned earlier, constitute the full approval standards for any potential followers. So I think we're going to be a little bit cagey about how all of that will come together when it comes together.

Our next question will come from Michelle Gilson from Canaccord. Michelle, can you hear us?

Yes, can you hear me?

Yes.

I'll add my congratulations here on the approval. And -- can you guys give us a sense of time lines on when the data around final adult height might accrue or when you expect that conversion to full approval? And I know you've guided to mid-22 data from the younger patient cohorts in that Phase II study. Can we expect those data to support label expansion or even full approval if you do have -- if you do show any data on, I guess, other outcomes than height?

Well, as I indicated, the details of the specifics are still in progress. And I think you can imagine that our motivation to get converted to full approval as soon as humanly possible is going to exist. And so stay tuned as to when to expect us to guide to that. if we are successful in our 0- to 5-year-old study, and as I said in my prepared remarks, when you come to R&D Day, you'll see some evidence of why Europeans think that this is likely to happen and why we think it's likely to happen. Then a supplementary application would be filed in the United States for indications in children 0 to 5. Now the indication statement there will be potentially very specific and will inform the application status as regards overall approval. And as we sit here today, I think there are several different concepts of what could flip us into a full approval mode. And as I said before, we're in the catbird seat in regard to driving that conversation forward because we already have so many patients accrued and with 3 years of follow-up and so many patients in the 0 to 5-year-old study that are ongoing that I think we'll be able to both leverage the information that comes out of that for the benefit of patients and their families and decision-making, but also benefit the company in terms of protecting the proprietary position of VOXZOGO in the marketplace. So stay tuned.

And if I could add a follow-up here for Jeff. Is there any difference in the strategy for laying those referral networks and how that patient journey might evolve from diagnosis, diagnosis. When -- if you do get that I guess, label expansion for younger patients versus 5-year-old patients in terms of, I guess, who the physicians currently seeing those patients would be?

That's a great question, Michelle. So as we start here today in the United States, which, as I noted earlier, is a little bit different in Europe where they have a more organized and concentrated care model. What we're talking about is kind of getting access to prevalent patients who know that they have a diagnosis of achondroplasia, but for whom many don't have a medical home. So the idea is to establish ped endos as that treatment and future medical home and drive a referral to those patients. Imagine that we're 3 years from today, and we have an expanded label for 2- to 5-year-old patients or even 0 to 2-year-old patients in the United States. You're right, the paradigm shifts now when a child is born with achondroplasia and the parents are receiving a diagnosis. The guidance will no longer be go home and take care of your child. There will be some complications, but we really can't do anything about the achondroplasia. Now the guidance will be -- that there is a pharmacotherapy for achondroplasia it's VOXZOGO and having established medical homes with ped endos and genetics and skeletal dysplasia clinics. The paradigm for starting these patients will be totally different 3 years from now than it is today. So thank you for that question and observation.

Our next question comes from Joel Beatty from Baird. Joel, can you hear us?

Yes, can you hear me?

Yes.

Congratulations on the approval. And I guess in first question is with a high percentage of the patients already diagnosed. Does that create more of an opportunity than maybe for other drugs to reach out directly to those patients with information on the drug as opposed to going through providers? And then second question is could you share if you have any plans for the PRV.

Why don't you start, Jeff, I'll answer the PRV questions.

Thank you, Joel. In most markets in the world, direct promotion to patients is not allowed. And so that's not a practice for us essentially outside of the United States. In the United States, there is some direct-to-patient promotion that is allowed. Of course, we're very careful to do that in ethical and compliant fashion. But you're right, the fact of patients and their parents having a diagnosis allows us -- gives us an opportunity in the United States to be reaching out directly and we'll do that through a variety of means, mainly digital to help drive awareness of VOXZOGO as a treatment option, and we'll be looking to leverage that to get patients access to VOXZOGO.

So regarding the PRV question, because of the nature of the product we developed, generally, they get priority review, Consequently, I would say, for us the need of keeping a PRV for future development is limited. So we haven't made a final decision yet, but it's likely we will, likely will sell it sometime next year but we haven't decided.

Our next question comes from Kripa Devarakonda. Kripa, can you hear us?

Can you guys hear me?

Yes.

Great. Congratulations to the whole team. This is great news. So I just had a question. Did you guys have any idea that accelerated approval was a possibility? And in that context, when you had your discussions with payers, did you get a sense of whether it was going to be just approval as normal? Reimbursement is normal? Or do you expect any sort of restrictions because of the accelerated approval. And then given that you've -- Jeff, that you've been talking about the preparation to launch this drug. You've talked about commercial preparedness. Can you talk about why there's going to be a gap of about a month or so before the drug is available for patients?

Great questions, Kripa. Thank you. So specifically for the United States, the accelerated approval from a commercial perspective is a regulatory, I wouldn't call it detailed, a regulatory feature that we will need to work through. But -- but the value proposition for the treatment of achondroplasia with VOXZOGO is clear, and it's very well supported with the clinical data that we have to date and with the label that we have now approved. And we are -- we have a value dossier that's already created for payers. In the United States, we are allowed to have payer conversations before product approval that facilitate kind of a rapid turnaround with payers, and we've taken advantage of that. And I would say that we've gotten a pretty warm reception about the unmet need for achondroplasia and the possibilities of treatment with VOXZOGO with payers. So I don't consider that to be a major issue. With respect to the timing, now that there's an approved label, the next step in being able to treat patients on the one hand, is to drive prescription activity. And on the other hand, is to get a final approved product with the approved label released and into commercial warehouses where we can ship. That latter step takes a little bit of time, 4 to 6 weeks. And we've done this before. This is not our first time doing this. So our supply organization is all over this one, but it does take 4 to 6 weeks. And then the process of driving prescription demand and then getting those prescriptions over to payers through an exceptional medical exception review process takes a little time. So that's what it is there.

Great. And a follow-up question for you. The label has a restriction for patients who have renal impairment. I apologize if I missed any conversation about this. But how much of a concern is this -- in this patient population? Like is it a significant number of patients who might have the issue? And what sort of monitoring do you expect to have to do for these patients?

I think that's a reflection also of who we studied, not necessarily a very specific concern about the medication. So I don't think that, that's been a major impediment to the inclusion of patients in our trials or to the management of the patients that have been on the trials.

Our next question comes from Andreas Argyrides from Wedbush. Andreas, can you hear us?

Yes, I can hear you. Can you guys hear me?

Yes.

All right. Congrats as well. Just continuing from the last question asked on the payer dynamics. And I think it was kind of mentioned, but maybe you can expand a little bit more. To what extent do you see the early part of the launch going through the exception process. and how that kind of -- how we should manage expectations on how you ran payer coverage.

Thank you, Andreas, for the question. So as is typical for a new product approval, even for the payers that we've had early conversations with until the product is approved, there's an approved label. We can complete the value dossier for a review by clinical teams at payers. There will be an automatic new-to-market block placed on VOXZOGO. And that will remain in place until there is a published coverage policy. And what you know and I know from watching many, many launches in the United States is some payers will come out with coverage policies in the first few weeks, other payers may take several months or even longer to issue a coverage policy. And we have a highly diversified set of payers, commercial payers, in particular, in the United States. Fortunately, BioMarin has done this many times in the United States, and we have a team in place to manage through that process. What we also know is that early prescriptions can get an individual patient review at those payers on a medical exception basis means that an individual patient's prescription will get reviewed even if there isn't a coverage policy that's been issued by a payer. And of course, BioMarin has been working through those channels for years and with all of our products. So we'll be pushing the early prescriptions through the medical exception process. That will evolve over time. I don't think that will have a huge effect on the uptake of VOXZOGO. But it will take a little time to navigate from having a prescription to having a payer approval and being able to start commercial therapy. And that is exactly analogous to what we've experienced for Palynziq, Brineura before that, and Vimizim before that.

Our last question comes from Debjit Chattopadhyay. Debjit, are you on the line?

I'm here. Can you hear me?

Yes.

Congrats on the team. Just a quick follow-up question here. Given the in utero diagnosis, how are you planning to tackle patients between the ages of 0-5? The reason I asked that question is in our recent pediatric endocrinology survey, the docs indicated very high willingness to treat as early as possible, independent of label.

Well, we have an ongoing study in children 0 to 5 years of age. Obviously, we don't -- can't support off-label prescription use, but our game plan is that when that study reads out, the information will be made available at medical scientific meetings and that we would then turn and interact with the Food and Drug Administration with a proposal to expand our label. And that's near at hand because that study is fully enrolled, and we expect the readout of that study in the early half of the year. And we're very excited about the prospects for that. As I mentioned, when you come to R&D Day, you'll see what gives us the underlying confidence to believe that study is going to read out positively.

We thank you all for joining us today. Thank you for your time and attention. JJ, Hank, Jeff, Brian, really appreciate everything. If you have further questions, please reach out to BioMarin IR, we are here. Thank you.

Bye.

Thanks everbody.

Thank you, bye.

Thank you all.