Cory Kasimov, one of the senior biotech analysts here at Evercore ISI, and it's my pleasure to host our next discussion with BioMarin. Excited to have the company's Chief Commercial Officer, Cristin Hubbard, as well as the CFO, Brian Mueller, here with us today, so thank you guys both for coming and taking the time to sit down and talk, so going to start big picture. Obviously, there have been a lot of changes with BioMarin over the last year. Alexander took over as CEO. It's a new corporate strategy. You've done talking about cost reductions, added a number of new executives sort of across the board. Can you kind of describe or go through some of the key changes that have taken place and how you think this is setting the company up for success going forward?
Thanks so much, Cory. It's great to be here. We are very excited about BioMarin's path forward, and you touched on many of the key elements. I'll unpack those a bit more for you. But we believe that after the work this year, we've got the right strategy, team, and growth objectives to generate long-term value for patients and shareholders. You're right, Alexander just recently, within the last few days, I believe, reached his one-year anniversary with the company. It's been a busy year. We completed a full strategic review of the enterprise. This was top to bottom, end to end across the business, resulting in a revamped corporate strategy, organization and operating model changes, and compelling long-term financial targets. That includes a new team. So Cristin's here with us.
She was most recently the head of global product strategy at Roche and also spent a significant amount of time at Genentech. Hank Fuchs, our former head of research and development for 15 years, recently retired from the company. His successor, who's been on board a couple of months now, is Greg Friberg. He had a long 18-year career at Amgen, going across several roles. Most recently, he was the Head of Medical for the rare disease business unit at Amgen. And then the most recent team member to join the leadership team is James Sabry, former head of partnering at Roche. And he also had a long-time career at Roche and Genentech, a long-time biopharma career, both in partnering, founding companies, and CEO. So back to the reorganization. In terms of the high-level strategy, we are focused. The strategy is focused on innovation, growth, and value commitment.
From an operating model standpoint, we are organizing the company into business units. This is new for BioMarin. We have eight internally developed and approved products generating close to $3 billion in revenue. We previously were organized as a portfolio company, but there's enough opportunity to accelerate, prioritize, focus, optimize what are individual sort of therapeutic areas, if you think about it that way. Those are skeletal conditions, enzyme therapies, and then a small business unit for ROCTAVIAN, the gene therapy for severe hemophilia A. The revamped corporate strategy has been, we've been successful in executing on it already this year. We're generating record revenues, record profitability, and issued some compelling long-term financial guidance. We're expecting to reach $4 billion of total revenue in 2027, a non-GAAP operating margin of 40% in 2026, growing into the low to mid 40% from there.
That's a more than doubling of our non-GAAP operating margin in 2023, which was a little over 19%. And then long-term on revenue, beyond the $4 billion in 2027, we do expect that we can continue to grow revenue at a mid-teen, low to mid-teen, CAGR through 2034. That financial growth is also resulting in significant cash flow generation. Our long-term financial guidance includes $1.25 billion of operating cash flow in 2027. That level of cash flow accumulation, plus a recently healthier balance sheet after paying down a convertible debt maturity, opening up a $600 million revolving credit line, gives us ample firepower to be able to pursue a more focused BD, business development strategy, than BioMarin has done in the past. Again, James recently joining us.
So we believe that these are very compelling, rare to find in this sector for a company of our size, financial targets, and growth strategy elements. We're very excited, and we're off to a good start.
All right, great. So there's a lot to unpack in there, and we want to try to tackle most of it. One of the last things you mentioned on the BD front, with James being one of the new executives at the company, you have some early pipeline assets. I don't think investors are giving any credit for those now. There's obviously a lot of focus on looming competitive threats for VOXZOGO. With James on board, with the cash position you're in, how are you thinking about business development?
Yeah, thanks, Cory. It's a great question. So first of all, important to note that our long-term guidance, whether it be the $4 billion 2027 or the mid-teen, long-term CAGR growth, as well as the profitability guidance, is not dependent on business development. We can achieve those targets with our own internally developed, and by the way, already approved assets. VOXZOGO for hypochondroplasia is expected to launch in 2027, so it is a contributor, but a smaller contributor. So what that means is that any opportunities to augment either the development or commercial portfolio with external assets during this time can be additive and only augment what is already a significant growth story. And in terms of the strategy, we think BioMarin is well positioned to bring in external assets. We've always been focused on genetic disorders, and the science there is really continuing to emerge.
There's more genetic discovery of causation of disease than there ever has been in terms of the pace of discovery. Lots of innovation in early-stage companies, but the capital environment is still constrained in terms of IPOs and raising money, so we think it's a target-rich environment. Next, you look at where BioMarin has what we believe is a right to win. Our core research strategy, which has, again, generated these eight internally developed and approved commercial assets, we call them the core five research criteria. We'll apply that same filter to external assets, and we think we should be the partner of choice because we've got this world-class proven capability in early to mid-stage clinical and regulatory capabilities, plus a global commercial infrastructure, both global market access, where we have shown the ability to obtain access and maintain value over time, plus the geographic footprint.
We sell our existing products in approximately 80 markets. So if you're an early-stage biotech looking at launching a rare disease or genetic therapy, we think we should be the partner of choice. And then the last element is the financials. I touched on that a bit. But our ability, we are now profitable, cash flow positive, which means we're accumulating cash. We have access to non-dilutive debt, which can increase our firepower. We said that we'd be targeting deals less than $1.5 billion in terms of size. And we think whether it be late-stage clinical, commercial, commercial partnerships, all of those have an opportunity to be additive to that growth story. And in the meantime, I should also be clear, one thing that we have been active on and successful in the past and will continue to focus on is early-stage research, licensing, filling up that early-stage pipeline.
I know James hasn't been around for that long just yet, but what's the early feedback that you're hearing from him in terms of his excitement level for the assets that are out there and available today?
Yeah, thanks. James is off to a great start. Again, it's just been a few weeks, and you can imagine he's working on getting integrated in the company. But watching him at work in that regard has been outstanding. One thing that I have seen that's unique about James is really trying to understand BioMarin's scientific approach and how we approach both research, clinical development. But then also really, when it comes to the BD strategy, he really digs in on the science first. He is an MD, PhD, and then has all that business and partnering experience after that. So that's been impressive. Also with Greg Friberg, recently joining, watching the two of them partner together in these early days has been impressive.
I think bringing that back to the commercial lens with Cristin, it's part of where this team and this strategy has a lot of opportunity to add value to the company.
Okay. And you mentioned in your comments upfront about the goals you've set out there, the 2.7 revenue guidance, the operating margin guidance. With all that, what's the pitch you're making to investors to own this stock over the next year, over the next three years? And kind of what are the valuation metrics that you're most focused on as you make this pitch?
Yeah, thanks. So whether it be one year, three years, or even longer, when we scan the sector, when we benchmark valuation multiples, we've noticed a very high correlation between long-term revenue growth and the highest of multiples and other valuation metrics. That's even above profitability. So when you look at our guidance, whether it be the $4 billion in 2027 or that mid-teen CAGR, low to mid-teen CAGR through 2034, when we compare that to other biopharmas with between $2 and $10 billion in revenue, it's top quartile. So we think that's really attractive. We also observe that this is or would point out that this is coming from, again, approved products versus a product that's still waiting for a clinical readout or has to go through a regulatory pathway. These are approved products.
And then on the profitability side, reaching profitability at a company of our size was a really great milestone a couple of years ago. But now to be able to be a profitability growth story, I mentioned how operating margins are expected to double over the next three years. And we didn't give long-term earnings per share guidance, but you can see in our P&L that things like taxes and other income and expense and our share count, they're not very volatile. So if you do math around that revenue growth and operating margin, we're going to expect to grow earnings per share significantly over the next several years as well. So mostly de-risked. And by the way, that operating margin, we see as also top quartile, even against biopharmas with greater than $10 billion in revenue.
So we talked a long time about having aspirations for large pharma-like operating margins. This guidance delivers that. So whether it be the revenue growth, the profitability, the cash flow accumulation, the earnings per share growth, we think this is a very compelling investment thesis. And then I'd also add, particularly at this valuation level.
Okay. So let's start diving into some of the products. And not surprising, we'll start with VOXZOGO . So I think this is where the biggest disconnect exists, right, between what you guys think is going to happen with this product and where investors are right now. And so the overhang of overhangs has now become TransCon CNP. Assuming this reaches the market relatively near term, how does VOXZOGO grow through that? People don't seem to have that expectation. So can you kind of speak to that and maybe what KOLs are telling you and how you think TransCon CNP would be incorporated into the market?
You bet. I'll take that. Thank you for the question. So just starting off, I want to be very, very clear that, of course, any of the guidance and the growth targets that we've put out there, including the fact that we anticipate greater than 25% growth baselining in 2023 out through 2027 with VOXZOGO , we have competition built into all of our models. And that includes the potential for the Ascendis asset. And I think one thing I want to say is that I think competition is important. I think it's good for patients. I think it's good to keep us sharp. And let's be honest, it raises a share of voice and awareness around the disease areas in which we're operating.
That all being said, the reason that we feel confident that we can grow throughout this kind of more competitive horizon. There's a few areas that I'll touch on. The first of which, I think one thing that competition can never catch up to is the fact that we have a best-in-disease evidence package. We have been studying this. We have nearly eight years of data in single patients. We have over 6,000 patient years of efficacy and safety data, and this is something that that amount of evidence and confidence in the product is something that no other competitor can catch up to. In addition to that, we also have a global label, right, in countries across the world, and I'll get into our global footprint, where we can treat from infancy.
Again, that might not be the case for some competitors ever and maybe not at the start for others. And I think this is really important because the consensus guidelines are from the medical experts across the entire community that it is very important that you treat achondroplasia patients as soon as possible so you can maximize the therapeutic benefit. And this is, of course, for growth, which is what you know the first, the top line data that you see, but importantly for the overall health of these patients. And that's what we're really focused on in terms of our evidence generation, is ensuring that the quality of life and the overall health data that is so important with this treatment is out there.
Then the third advantage I'd say that we have at BioMarin, which is really unique for a company of our size, is our global footprint. We operate in 80 countries with our overall portfolio. As of Q3, with Voxzogo alone, we were operating in 44 countries. We are going to, we plan to build on that with another 20 countries by 2027. And this is something that we've been able to do, looking back at our portfolio with over 20 years' experience of figuring out the commercial, the medical, and the access pathways in each of these respective companies, which is something that's really hard to replicate out the gates. And so these are all the areas that I'd say that really kind of provide us a bit of an advantage in terms of our leadership in skeletal conditions.
But then also importantly, what we're doing in terms of our strategies is ensuring that we are getting to all patients who are eligible for this treatment. And what that means is not only do we have some markets where we've got high penetration, and we've created what I'd say is almost an incumbent market where we've got the bulk of patients treated in some of these countries. And so now we're really targeting infants and right at birth, kind of getting treatment for those patients. But importantly, in other areas, what we're doing is we're really focusing, looking at all age groups, how can we get this medicine to as many patients as possible, get the news out there? Because I think that what is going to be important is that we're creating a bit of a switch market for competition.
What we're hearing to your question, Cory, about what are KOLs saying, what are we hearing from the community, including caregivers, is that when you have your child or your patient on a treatment and you see the benefit, you see the efficacy that it's happening, the bar or the barrier for switching to a therapy that maybe doesn't have the same amount of evidence or you don't have the same experience with it is actually quite a bit higher. So I don't think that there's going to be an immediate switch, in particular for those patients who are already on treatment. So we're really targeting ensuring that we can create as much of a switch market as possible. And then the last thing I'd say for VOXZOGO in particular is we're really building out the life cycle plan for this asset. We're not stopping at achondroplasia.
We are really looking to build our leadership position across skeletal conditions. So that includes hypochondroplasia as hopefully the next indication in which we'll launch in the 2027 timeframe. And then building on that in idiopathic short stature, Noonan syndrome, Turner syndrome, SHOX deficiency, all of these areas will really help us to build out that leadership position and will enable us to grow in the face of competition.
Okay, great. Can you remind us, roughly speaking, how much of VOXZOGO 's sales are currently U.S.? And when you have these projections out there for a 25%+ growth into the future with this, how do you expect that to evolve? You talk about bringing 20 more countries online, the opportunities that are out there, rest of world, where I agree you have a huge advantage over the competition. Can you kind of speak to the evolution of those trends?
Yeah, and I know we don't give the regional breakdown in terms of the contribution, but I can say this. The U.S. is by far our single largest market, single market opportunity. And so we are laser-focused on really building our penetration in that market. And there's various strategies that we're employing, a lot of which actually is ensuring that there is a broad awareness of the fact that there is a treatment out there for achondroplasia, because some of these patients, you can imagine, are being currently treated in general pediatrician offices. So what's really, really important, and this is something that we're working on, is ensuring that there are referral patterns back to a specialty that's more comfortable with treating with these types of therapies, namely pediatric endocrinologists. And we're really working on making sure that that referral pattern exists.
And as a result of that, we saw in Q3, for instance, that that was the largest growing group of treaters in the U.S. So U.S. is by and large still our greatest single market opportunity. In the other countries where we have high penetration, so using Japan and Germany as examples, this is what I was mentioning that we're really focused on because we already have high penetration, we're really focused on that kind of early treatment at infancy type of strategy. And then lastly, in some of those other markets, we really are just looking at building penetration from the ground up. We're using a lot of the skills and capabilities that we have from our MPS and CLN2 experience and building into new markets.
Okay. And you talked as well about sort of the life cycle with VOXZOGO , and you follow on product, you're once weekly. I'm curious strategically how you're thinking about this, especially as the market becomes more competitive in the future, ways to speed up the process with some of the other indications. Are there accelerated pathways you could use given the track record that's been established with VOXZOGO , things like 505(b)(2), for example, stuff like that? And are there ways to accelerate, I guess, the once a week and bring it into some of these indications right off the bat?
Yeah, so I'll start with that. So I think that (b)(2) is actually using outside data for your pathway, whereas all of the studies that we're doing would be BioMarin's data. So we are certainly looking at the various regulatory pathways that we can leverage, including data that we have in-house from our previous studies, namely with VOXZOGO . Those are all things that are being explored and nothing that we've commented on as of yet because those strategies are still under development. But I will say that the team is very actively looking at all the ways in which we could appropriately accelerate development, again, where that's appropriate.
We also, though, of course, have to balance that with the fact that we want to make sure that we have the evidence package that is going to ensure that we can get access to these therapies in all the countries in which we're operating. So you can imagine that's the balance that we're looking at. Specifically with BMN 333, we've just cleared our IND, and we anticipate having our first-in-human dose actually very early into next year. So we're really excited by that and hope to have internal data anyway to look at the PK profile of this asset so that at that point in time, we can publish it when appropriate, but also then look at what is the appropriate clinical development plan moving forward as accelerated as possible. Those are still to be determined.
Okay. With 333, what's the objective, right? Is this like just compete with TransCon as a once a week? Is this a better VOXZOGO ? I mean, based on the preclinical data that you're generating, do you think this has the chance to be more efficacious?
I'll start with that. What I can say is that certainly our target profile is to have a superior benefit risk profile than that of VOXZOGO , for instance. This is not just a convenience play about having a once-weekly asset, but importantly, really leveraging the fact that we can have prolonged exposure potentially of the CNP, and that for that will enable us to have a more efficacious drug in the end, but again, these are all things that have to be determined, and that's what we'll be looking for in the studies.
Do you know from a regulatory point of view yet what you'll need to do in the clinic with this? Or maybe it's not a regulatory requirement, but what you would want to do? Would you run a head-to-head with VOXZOGO ?
Those are precisely the plans that are under development now that we haven't yet shared publicly.
Okay. All right. Fair enough. Let's switch over, and we can come back and talk more about that if we have time. But to cover the enzyme therapies, I mean, this is another underappreciated part of the company. There's high single-digit growth for this. Again, not something that people are giving you credit for. It feels like looking where consensus is. So very underappreciated. How confident are you in these numbers? How ambitious of a goal is the high single-digit percent growth?
Yeah, thanks, Cory. I'll start with that one. I would absolutely agree that the value and the potential of the enzyme therapies is underappreciated. I believe that what is well understood in the investor community is that the enzyme therapies, and for those of you that may not be familiar, these are enzyme replacement therapies for severe monogenic disorders where we have a recombinant human enzyme that we're replacing in a weekly IV infusion to create the missing part of the metabolism, if you will, and it's got great benefit to patients. I think folks recognize that that is a durable franchise. While it's a $2 billion roughly revenue franchise, it's very diversified. There's five enzyme therapies we sell in these 80 markets, very high barriers to entry in manufacturing because these are incredibly complex biologics to manufacture.
However, what is underappreciated is that this business is actually still growing robustly. It grew 8% over the last three years, 11% over the last five years. And this existing growth, because these are lifetime therapies, so patients are doing well, so you start to get both an incidence population effect, but we are still actually identifying new patients. Where the potential comes to maintain that growth, to your question, is a few factors. The first thing I'd point to is back to my opening remarks, the establishing of these business units. One of the business units is the enzyme therapies. So we are organizing our efforts globally for the folks that are working on the enzyme therapies. They'll be focused on that exclusively. And that's not just a management tactic and we'll get top to bottom P&L management. There's great benefits there to the business.
But where there's value is really starting to share and leverage the ideas and what's been successful in certain markets or certain products as a global business discretely. Again, when we were managing BioMarin as a portfolio company, you can imagine that a particular head of a region or head of a country, when we were trying to work through the ROCTAVIAN launch challenges as an example, that was a massive area of focus. That's what that person was focused on during those times, probably a little less so the enzyme business. So 100% focus for the folks dedicated to the enzyme therapy business unit will allow us to leverage these success factors over time that may not have been shared effectively globally and cross-functionally. Those include maintaining compliance. So a key factor in these weekly infusions is maintaining the compliance rates with those infusions over time.
Second would be new patient identification tactics. Again, there's certain methods. This is a genetic disease. There's familial genetic considerations. There's been certain tactics that have been effective in one market or region that may be very applicable to another region, and they just haven't shared that information yet, and there's the third which I'm struggling with. Those are the two big ones.
Okay. One of the products in there that is potentially facing competitive headwinds is PALYNZIQ. How do you think about that product in the context of your guidance, and what are your expectations for competition there?
Yeah, I can take that one. So PALYNZIQ is certainly a very exciting medicine that I'll get into here in just a moment. But it is a major component of our growth trajectory for the enzyme therapies, which, as has already been stated, that high single-digit growth over the next decade. Now, importantly for PALYNZIQ , of course, there is in PKU in general, we're definitely seeing more competition on the horizon, which, as I've already said, is a good thing for patients. It's more options. But what I think I would go back to in terms of thinking about the growth and why we have built it out the way that we have is because there are unique attributes to PALYNZIQ in PKU that we aren't necessarily seeing on the competitive horizon. And in particular, I mean, the science is there.
This is a substitute enzyme therapy, directly substituting the defective enzyme. That all being said, what you see with that is you see a real normalization of Phe levels as well as ability to liberalize these patients on their diets, right? And that's a really big part of this is being able to liberalize them from medical nutrition therapy. I think is really important in a lot of what we hear from both treaters and patients alike. This isn't necessarily confirmed in some of the other areas. And this is true for PALYNZIQ across all PKU phenotypes, so irrespective of severity. And so I think that this is a really important component. And so while, yes, there is competition on the horizon, I still think that there's a very important place in the world for PALYNZIQ .
Okay. And.
I mentioned there was a third growth tactic on the enzyme therapies. It's just skipping my mind. It's selective geographic expansion. So when we talk about this 80-country market footprint for the company, that's not all of our therapies in all 80 of those markets. It's been a deliberate growth strategy over time. But we think there's opportunities to launch even some of the existing therapies in targeted markets that'll help contribute to that high single-digit growth in our expectations.
Okay. And then expectations across the rest of the enzyme therapy portfolio, not including PALYNZIQ . I mean, some of these products have been off patent for quite a long time, still growing. Do you have expectations for generics ever coming for any of these?
This is something that we constantly monitor, and quite frankly, we have not seen anything out there on the horizon that would cause us to change our trajectory or how we're looking at it. You've mentioned some of our products have already gone off of patent expiry, and we haven't seen competition on the horizon, and there's just high barriers to entry in these markets. It's the dispersion across the geographies. It's the difficulty in manufacturing. There are a lot of barriers to entry, which is why we don't see any formidable competition on the horizon.
Okay. I wanted to throw one question in on the third unit product segment, ROCTAVIAN . It's amazing. It never gets talked about at all anymore. You updated your strategy for it over the summer. Where do things stand with it? Do you see any sense of increasing traction here with this, or is it kind of much the same where you were over the summer?
You want to start?
Yeah, sure.
Importantly to your comment, Cory, about ROCTAVIAN being talked about less, it was important that internally and externally we went through, and this was a key element of the strategic review this year to really reset expectations for ROCTAVIAN . ROCTAVIAN got approved and launched with a very attractive clinical package. We've got more than four years now of roughly 85% of patients still not taking chronic prophylactic factor injections, decreases in bleeding rates, and some of the anecdotal patient stories are really amazing. The key challenge in the launch has been reimbursement. As we work through those reimbursement challenges, it was important to reset the expectations. What we've done there first was right-size the investments in ROCTAVIAN and the cost envelope.
When we launched ROCTAVIAN , when expectations were higher and faster, you can imagine talking about our global footprint today, that it was a robust geographic launch in a multitude of key markets. There's also on the R&D side, there are a number of label expansion, lifecycle management opportunities for ROCTAVIAN , reaching other segments of severe hemophilia A, like the prior inhibitor population as an example, adolescents as an example. When expectations were higher on ROCTAVIAN , those were all prioritized, funded within the ROCTAVIAN cost envelope. So last year, we were spending over the last couple of years almost $200 million a year on ROCTAVIAN , R&D, and SG&A, when, because of these reimbursement challenges, the revenues were not yet showing up. And so the P&L was upside down. So we did an evaluation.
We determined that it does make sense to give the asset more time in this launch. And we are making progress on some of those reimbursement challenges. But in order to make that work for the business, we significantly reduced the level of investment. So our goal for next year is to have operating costs for ROCTAVIAN , both R&D and SG&A, of approximately $60 million. So that's a pretty significant reduction from that close to $200 million. And as we hopefully make progress on the launch and commercial uptake over the next year, we expect the product to be profitable by the end of the year. And one way we're doing that is focusing on three key markets. These are three markets where we have high commercial potential and federal reimbursement. And that's the U.S., Germany, and Italy.
The two markets within those three where we're still having some reimbursement challenge is Germany. The product is approved and registered at the federal level in terms of pricing and reimbursement. We've had some challenges securing actual reimbursement at the sub-insurer level in Germany, and in the U.S., we have very good payer coverage. Payers understand the high cost of severe hemophilia A on their systems. Products like even traditional factor, long-acting factors, HEMLIBRA, these can cost $800,000-$1 million a year for life. So a single infusion of ROCTAVIAN , albeit a high-priced therapy, if it offers freedom from those other therapies, becomes cost-effective pretty quickly. The pharmacoeconomics on ROCTAVIAN are very good. Payers understand that. We've got great coverage. Where we're still struggling and where the market is struggling is the site economics and contracting, so within the system, beyond the payer coverage, there's an HTC.
This is often a 340B clinic, and so there's a significant rebate involved. There could be a parent within that system. Hemophilia treatment centers are often within university healthcare systems, so you have to deal with the parent system. And then there could be other parties in between. So that level of contracting, because the standard of care has evolved and patients are more controlled than they were when we started the ROCTAVIAN program, it's less of a priority to work through those challenges. But that's the focused effort. I'd also point again to this business unit approach where we are going to have a small-focused ROCTAVIAN team that's waking up every day just working on these issues. So we're still working through it. Look forward to updating everyone on our progress from quarter to quarter. But we think we've got the right plan for the next year.
Okay. Back to the pipeline. And we talked about the long-acting CNP program. I think the other asset that's starting to get a little bit of attention ahead of next year is the DMD program, so BMN 351. You obviously have some pretty compelling preclinical data. What's the bar you need in this initial human proof of concept study to kind of validate what you've shown preclinically?
Yeah, thanks for asking about BMN 351. Cory, this is an asset we're really excited about and an asset where we are expecting proof of concept data middle of next year. So BMN 351 is a next-generation exon skipper for Duchenne muscular dystrophy. Interestingly, the underlying science actually was in the lab back when we made the Prosensa and drisapersen acquisition in 2015. And so while that compound didn't work out, we were already working on what is a true next-generation skipper. And because the way the first- and second-generation skippers work is instead of the initial compound, drisapersen skipped on the first place on the exon, which essentially resulted in a modest amount of microdystrophin. The second-generation skips at different places on the exon and is intended to enable a near full-length dystrophin.
And so what that means is because a lot of the other products, whether they be the conditionally approved or fully approved products, in addition to the opportunity to improve efficacy, are still delivering this highly truncated dystrophin. And so what a near full-length and greater level of dystrophin can mean in expression. So instead of low to mid-single digits of dystrophin expression, our bar is 10%. And we believe that's meaningful because in the phenotype of patients, muscular dystrophy patients, you can think of these as sort of the Becker muscular dystrophy patients. Patients that have in the phenotype a natural level of dystrophin at 10% have a much different phenotypic outcome. They're ambulatory for decades where you do not see that in Duchenne's. In our animal models, we've seen, again, this near full-length dystrophin expressed at 30% to 40% to even 50%, so even higher than our target.
But our target's 10% because we believe that's the therapeutic zone to really get meaningful clinical benefit. And we believe there's a significant unmet need in this area.
Okay. Terrific. So we have a few minutes left. I was hoping we'd have some time to circle back to VOXZOGO . And we do. When you talk, you put out that long-term opportunity, right? You put the patient populations out there, talk about this being a $5 billion opportunity in the future. Another competitive agent that we've all known about that's coming is still a year away from phase III data would be infigratinib. What are your expectations of the potential impact infigratinib can have in this market, both for achondroplasia as well as beyond achondroplasia where they're going to look at hypochondroplasia and we'll see if they can go beyond that or not? How does that play into your expectations and into the guidance you provided in September?
Yeah, I can share that we certainly have that in our modeling as well, knowing that that could be a potential agent in the timeframe that you've just mentioned. In terms of achondroplasia, what that could offer potentially would be an oral dosing, which what still remains to be seen is what is the safety profile, and I think that that's true as well as you've already mentioned for hypochondroplasia. The jury is still out on what the dosing is going to have to be based on some of the preclinical models for infigratinib, and so I think the question's going to be at what dose can they find an efficacious, is there an efficacious dose? And then importantly, what does that mean in terms of on-target potential safety events, namely phosphate levels, et cetera? And this is just something that remains to be seen.
But nonetheless, we've looked at this as being a potential agent in the bag of treaters. And I think it could be an important one if it comes to pass and if it has the right benefit-risk profile.
Okay. And.
Sorry, but on the other indications, so we understand that the FGFR inhibitors do affect or can affect the pathway for achondroplasia and hypochondroplasia. But the other indications that BioMarin is pursuing, which by the way are the significantly largest portion of the VOXZOGO and BMN 333 indication expansion opportunities, this is idiopathic short stature, Noonan syndrome, SHOX, and Turner syndrome. We understand that those are not impacted by the FGFR pathway. And so we don't think that those compounds would be eligible.
Okay. Like you said, I mean, you put out the $5 billion number. You knew about infigratinib doing that. The TransCon news came later, but you've since reiterated. The confidence in the long-term opportunity for VOXZOGO is still very much there.
And I'd come back also. I think Cristin mentioned this in her remarks on the competition. In that $5 billion, we've still assumed just a modest penetration of what is a 420,000 total addressable patient population. So share of voice, this is such a large market where even if competition emerges over the long term where we have a lead, there's room for more than one player.
Okay. Terrific. With that, we are out of time. Thank you guys very much for being here.
Thank you so much, Cory.