Okay. Hi, good morning, everyone. Welcome to day two of our Cantor Healthcare Conference. My name's Olivia Brayer. I'm one of the senior biotech analysts here at Cantor, and really excited about this morning's fireside chat with the BioMarin team. We have Cristin Hubbard, who is Chief Commercial Officer, and Greg Friberg, who is Chief R&D Officer. Thank you both so much for being here and making the trip to New York.
Thank you for having us.
Thank you.
It's been a really busy year for BioMarin. A lot has changed. You've done some deals. You've added some new assets. Maybe just talk about the state of the company today, how it's evolved over time, and what the vision is for BioMarin going forward from here.
I will kick us off. For those of you following us, we are BioMarin. We are a leading rare disease biotechnology company. We operate specifically in genetically defined conditions. We have nine commercial products that are spread across our two business units, so skeletal conditions and metabolic conditions. Very recently, we announced the acquisition of Amicus, and with Amicus, that gave us two high-growth commercial products. One is Galafold in Fabry disease, which we just announced peak revenue estimates at $1.4 billion in the mid-2030s. The second being POMBILITI and OPFOLDA, which we call PomUp, in Pompe disease, which we have also announced expectations of $1.2 billion at peak in the mid to late 2030s. A really exciting acquisition, a huge strategic fit for us to really strengthen and diversify our portfolio.
At the quarter, we announced very strong results, 20% growth year-over-year. Really what we are excited about is the fact that we have got four products in our portfolio now that have the potential to be above $1 billion. Our first of which will be VOXZOGO, which in our 2026 full year guidance, we are saying that we will be at $1 billion - $1.05 billion is the range that we have given for the full year. Our focus as a company is really about driving top-line growth, about expanding our margins, and importantly, about generating cash flow. Because with that, we can then continue to invest in our pipeline. We have recently announced another acquisition for a pipeline asset, ALE-001, that Greg, I will give it over to you to talk a little bit about our portfolio.
Yeah. From the portfolio standpoint, a lot of news, again, fast-moving at BioMarin. We just revealed our data in hypochondroplasia, which again was published yesterday and presented in Europe at the ESPE meeting. Very excited. That result would provide us with another first in disease indication. This is for VOXZOGO in beyond achondroplasia and hypochondroplasia. Data really outperformed what we were expecting. We are thrilled about that opportunity. Similarly, we have been rebuilding our pipeline as well with a variety of different assets. Along with the Amicus acquisition came a molecule that we call BMN 820 or DMX-200. This is for focal segmental glomerulosclerosis. That is a study that will have a phase III card turning over in 2028. Similarly, we have two other pipeline assets now.
The recently acquired and closed last week, ALE-001 from Alesta Therapeutics for hypophosphatasia, as well as, of course, we have got our in-house created molecule, BMN 333, as a next generation asset for CNP. Again, looking for superiority over VOXZOGO. Both of those will have data to be revealed next year.
Yeah. A lot cooking. Well, maybe we will start with the Amicus deal. I think there has been a lot of investor interest in that Amicus deal. I know you all have given some recent updates in your second quarter earnings call just around some of those assets as growth drivers. Can you talk about how transformational that deal is for the company? Then Cristin, maybe to put it in context. When you think about your future cash flow opportunity, your future earnings power, what do those products actually do for you?
Yeah. As we have already talked a little bit about, driving top-line growth is an important component of our strategy, and these assets help us to do so. It is really exciting to think about what we can bend the curve on in terms of the treatment of Fabry disease as well as Pompe disease with both of these. But as you have mentioned, Olivia, there is the financial components here. And we really do see this as a huge accelerator. So what we talked about at the quarter were the fact that we are going to recognize about $220 million in synergies that will come in 2028. This gives us substantial EPS accretion in 2027.
And this is an area that, again, we are really looking to be able to use the cash flows that will come from this so that we can continue to allocate a lot of capital into growing our pipeline, investing in innovation, and so on. So we think that this has been a real accelerant on many fronts.
Okay. Helpful context. Then you did just have a big update on VOXZOGO, especially from an IP legal perspective with the Ascendis settlement. Can you maybe just talk about how you are thinking about VOXZOGO as a future growth driver? Then maybe just give us a little bit of context around that settlement, what it does for you. Does it change your strategy at all around how you think about the way you are commercializing VOXZOGO, just given the economics that you do get from another asset now?
Yeah. VOXZOGO, I think we can talk about it a little bit in horizons in the different disease areas, right? We have achondroplasia, which I will get to, but also hypochondroplasia in the future. Then longer term, and maybe you will speak to this, Greg, looking out at BMN 333, which is our long-acting CNP that we look to develop the best-in-class CNP, which I know you will get to. But going back to kind of the near-term growth and achondroplasia in particular, as you have said, and as you have alluded to, Olivia, we did just reach a settlement with Ascendis Pharma. We think that this is very important both for BioMarin, but also importantly for the patients. This settlement allows us to get 20% royalty on net sales in the U.S. and 18% royalty on net sales in the EU, South Korea, and Brazil.
Really what this does is this enables us to capture value now. It is retroactive to any commercial sales. But also importantly, I think it enables us to clear a little bit of the overhang on VOXZOGO and really share in not only a percent for any patients that might switch off of VOXZOGO, but also importantly for any market growth that might start as a result of YUVIWEL now being on the market. We will now get to share in that and not just compete for it. So that at least helps us to clear that overhang. But importantly, thinking about VOXZOGO as a growth driver. We are confident in the growth going into next year with VOXZOGO, and that is in part based on how we are growing in achondroplasia.
That is largely where we are seeing the zero to two population, which is what we have a label in and anticipate having an exclusive label there, being the only company labeled there for the next couple of years. This is where we are seeing the most growth. Medical consensus guidelines tell us that it is very important to treat these patients at the time of diagnosis, which in achondroplasia happens very young in infancy. So to treat right then is most important, and that is where VOXZOGO is indicated and where we are growing most. We also have VOXZOGO marketed in 55 countries around the world, and that number is growing as well. Our international expansion is continuing. We are seeing continued revenue and patient demand growth in these countries.
I should say that 75% of our revenues are actually ex-U.S., so these are really important territories for us where we are continuing to grow. That expansion both in countries where we already are, but still newly launching countries, is continuing to help us grow. So as we build on that momentum, we also have potentially hypochondroplasia coming in next year, starting in the U.S., which we are very excited to grow in. Then, as I had mentioned, longer term going into 333. So I think along many horizons for the VOXZOGO and skeletal franchise.
Yeah, you did all just raise guidance for VOXZOGO to the higher end of your guidance range. What gave you the confidence to do that, and what are you actually seeing play out in the real-world market now that there is another asset for achondroplasia patients?
Yeah, we did, as you said, we've raised the guidance for the full year to $1 billion - $1.05 billion is the range. Really what this was based on is the strong growth that we saw in the first half. Looking out, that includes what we're seeing in terms of now there being a competitor that was launched in February in the U.S. market. What we shared at the quarter was that so far we've seen 90% retention on VOXZOGO treatment in achondroplasia. What we hear from patients and families alike is really that these are patients where they're seeing the efficacy, they're seeing the benefit of the treatment, and importantly, have made a daily routine for themselves that is working for that family.
All of the things that helped us to raise the guidance was the fact that we had the momentum going in the first half. We have an understanding of what that switch rate is looking like. We had announced that there were two big market access renegotiations that were on the horizon this year for VOXZOGO. One we have cleared with a good outcome, and the other is still in the works. With those things combined, that gave us the confidence and conviction behind our raise.
Yeah, you've brought up hypochondroplasia a few times. I know you just had data that came out this week. Can you maybe just, maybe Greg, at a high level, talk about the highlights from that data set? You've commented that maybe they were even better than your expectations.
Yeah.
So maybe what is it about that data set that is driving that sentiment at BioMarin?
I think there are two factors. We actually just published the data. It is in NEJM Evidence, if any of you are interested in looking into it. Two factors in particular that popped off the page. One was that as a marker for pharmacodynamic activity, we look at AGV. We look at annualized growth velocity, and we saw more of a delta, more of an attributable AGV than we had seen in other conditions like achondroplasia. We saw 2.33 cm of AGV. Interestingly, that was a result that was consistent across a variety of subsets, whether it was by mutation type. Again, in comparison to achondroplasia, lots of different FGFR3 mutations in hypochondroplasia. Seeing consistent results across different AGVs, different genders, different mutations was great data. But the second factor I want to highlight is this wasn't just about linear growth.
In that testing cascade, we had preserved Alpha, we had type one error control, and we were able to show that in that year of randomization, again, you only get a year in these studies where you truly have double-blind placebo control. Then everybody goes on therapy after a year. In that year, we were able to show a highly statistically significant improvement in arm span as well. Why is that important? Well, as you can imagine, it is a big contributor of quality of life. Think about being able to brush your hair. Think about being able to reach off of a shelf or even drive when you are an adult. These sort of factors actually are driven by arm span more than simple linear height alone.
Having those with a robust data package and of course, a safety profile that was consistent with, if not maybe a little better than what we saw in achondroplasia. These are results that we know our physicians are excited about. At the conference yesterday, I think there was a lot of excitement about, and we are looking forward again to getting this to patients. Hypochondroplasia is slightly different than achondroplasia also in terms of its diagnosis. The patients are not born with the same deficit in their height, so they are not as readily diagnosed in utero, for example. A lot of the work that we are doing is trying to advance the field, get diagnosis at a younger age, spread the word that again, this isn't just a mild form of achondroplasia. This is a stature deficit that has health and wellness consequences as well.
We have submitted our file to the FDA. We will look forward to updating when we have additional information. It is our second file with the FDA. We have the full approval for achondroplasia being reviewed with the PDUFA date in February as well. Hypochondroplasia does represent a pretty big opportunity for us.
I guess all I would say too, just looking at the potential commercial opportunity there, you could imagine the teams are certainly gearing up and getting ready for a potential launch coming soon. Really focused in and around what Greg has talked about as it relates to diagnosis, but also important in disease awareness so that that urgency to treat is there. What we have shared is that while the genetic prevalence is estimated to be that of achondroplasia, there is a gap in diagnosis as we have discussed. We have said that we think the global total addressable patient population is around 14,000. As I said, we are getting ready for what we hope to be a very successful launch.
As you think about the opportunity set that you do have with hypochondroplasia, a 14,000 addressable market, how big do you think this could actually be in terms of a commercial opportunity set for you and from a diagnosis rate and penetration rate? What kind go into some of your assumptions when you think about the ultimate growth curve that you do have with hypochondroplasia?
We have not shared estimates yet on what the total opportunity will be, and that will come as we near getting ready to go to market. What I will say is that what really helps us out in this regard is that the treaters, a lot of the surrounding community, is very similar to that of achondroplasia. We now have extensive experience in this regard, both from a kind of physician relationship component, but also importantly from a market access component in the different countries in which we operate across our 55 countries.
That really helps us to accelerate, which we are not building from scratch like we had to in achondroplasia, having been the first therapy in that space. That is the helper. The part that paces us, I guess, is really around the diagnosis rate and that urgency to treat. That is why we've had our medical teams very compliantly working on really trying to drive that in advance of the launch so that we can accelerate that as much as possible.
I'll just add that we know that there's a pent-up desire to have a therapy here. We hear it from the patients, and there's a new advocacy group as well. They're self-assembling. We also saw in our pivotal study where we just reviewed the data, we recruited multiple quarters faster than we had originally anticipated. We're seeing a similar finding in the infant study as well, where there are patients out there, and there's a desire to have treatment.
It's interesting because we've seen this time and time again, that when there's a treatment is when you really start to see the energy and kind of the dialogue happening, the kind of the self-organizing, if you will because now there's an option on the horizon. I think that that will also inflect for us.
Yeah. You bring up a few interesting points. You obviously have achondroplasia as a great analog, but you also have the achondroplasia market has been built out from a reimbursement perspective, from a go-to-market strategy perspective. So as you think about hopefully being the first to market, that can be a great positive. But it also means that you can sometimes have to build out the market and find the patients yourself. So how do you think about or maybe how should we be thinking about that adoption curve? Is it something similar to what we saw with achondroplasia? Could there be maybe a faster go-to-market, or maybe not go-to-market strategy, but actually getting this to patients in a number of different countries? What are some of those pushes and pulls?
Yeah. We will share more about this as we get closer to launch. I think really thinking about it that what will accelerate is what I just talked about. The fact that we have built this infrastructure, we know where to go, we know the physicians, we know what the access landscape can look like. What will slow us down is this diagnosis rate and the urgency to treat. I think that between those two things, they start to balance each other out, quite frankly. The hope is that we can continue to get out ahead of that education, that awareness, et cetera. We are putting a lot toward that, and that that can help to accelerate.
Two quick breadcrumbs just for you to follow the trail. We are doing all the work to try to make sure that, again, the community has the tools they need. Some international consensus guidelines were just published about a month ago for hypochondroplasia. Some great work by an independent group of physicians on what the diagnosis takes. Cranial circumference, tibial length in ultrasounds and so forth.
A second factor that we have been working on is reclassification of certain FGFR3 mutations from what we typically call the dreaded VUS, a variant of uncertain significance, into pathologic criteria. Again, we feel a duty and an obligation, but also an opportunity that we can help the field move along. We have been able to take the data that we have and allow for some of that reclassification. These are the kind of activities, again, that started years ago, and we are going to continue those as we go into launch phase.
Cristin, you mentioned earlier that you do expect VOXZOGO to grow in 2027, especially with the opportunity set that you have with hypochondroplasia coming online. Can you talk about the geographic split that you see across that market? I do not know if there are numbers that you are able to put. You have that 14,000 addressable patient population, but how do you think about the ex-U.S. opportunity, the European opportunity, the U.S. opportunity as you think about that rollout and that TAM?
We haven't prospectively shared geographic splits for hypochondroplasia, except to say that for achondroplasia, we're 75% ex-U.S., 25% in the U.S. But trust that we will follow in every country that we possibly can and do our best in every country. It remains to be seen what that split will be.
Okay, fair enough. You do have a next generation CNP that's in development.
We do.
I know that's in a phase II, III. Can you just talk about what the ultimate goal is with BMN 333?
BMN 333 was designed to, again, build upon our learnings from VOXZOGO. VOXZOGO has got a very short half-life, under an hour. It is administered daily, again, think of a PK profile that is more like a sawtooth, where you have daily quick administrations, but quick declinations from a PK standpoint. We engineered this using albumin-binding lipid technology and a hydrolyzable linker to have more of a continuous exposure of CNP.
The hypothesis here, both from preclinical models as well as genetics and some human available PK/PD data that is out there, to be able to continue to push that growth response curve beyond what has been achieved by drugs that are available today. What was dose limiting for VOXZOGO with that very high Cmax that came down quickly, was that there are blood pressure abnormalities that when you go up too high in a Cmax, can drive dose limiting effects.
By having a more continuous exposure, you can avoid those Cmaxes and have more of an AUC approach, where the area under the curve drives the growth. What we saw in our phase I study was that BMN 333 was able to have up to 13-fold the AUC for the free CNP, that is the drug that is released from the total construct, as compared to the other marketed long-acting CNP product out there. Along with that, we also saw that there were increases in a plasma biomarker called cyclic GMP. This is systemic, it is not at the growth plate, but seeing two to five-fold increases over what would be expected from the dose of the other agent gave us confidence, again, that there is more biology to be had there.
When you put all of that together, we feel that we have designed the right study to test this question, whether more CNP exposure will lead to more growth. We are running a phase II dose ranging study right now that will ask that question. It is measuring that versus VOXZOGO, and the goal here is to have a superior product. We have a phase III designed, presuming that that study reads out the way that we are anticipating.
We will select the winner dose and put that against VOXZOGO, looking for an effect size that is about a 50% improvement in attributable AGV with a 90% power. I have a lot of confidence in the molecule. It is the right molecule to test this hypothesis. This is, again, a molecule we have been working on for quite a while. It was made in-house, and we are looking forward to seeing that data in 2027.
Yeah, and Greg, can you just talk about the decision to run this as a superiority study-
Yeah.
Versus VOXZOGO, and you mentioned the 50% treatment effect size. How did you come up with 50%?
Yeah. A couple of factors go in here. Of course, we're very proud of the work we've done with VOXZOGO, and it's being reviewed for full approval right now at the FDA with the PDUFA date on Rare Disease Day, February 28, next year. So in a world where there's not only multiple marketed products, but one that's fully approved, we want to move the bar. We want to develop a molecule that we think, again, moves the field. It's not just an aesthetic convenience, but one that actually offers something more of value. Now, we measure that with AGV.
That being said, all the markers of health and wellness that we know have tracked historically with AGV are things that we're going to continue not only to measure with BMN 333, but also create the evidence package to remind the world that more growth will translate into faster and better outcomes with health and wellness. So that's more work to do. With regard to the AGV increase, we picked a number that from a practicality standpoint, was something that we felt was achievable.
That was a combination of not only the PK/PD that's available in the public space for other long-acting agents, but also our preclinical work. Ultimately, we landed at this 50%. We think that that's a meaningful improvement. That is not the minimum detectable difference. You can do the math and back calculate that, but this 2.25 cm is our target. It's what the study's powered to detect, and it's a combination of the preclinical and the clinical data that's available there.
Okay, great. That is assuming about a 1.5 cm change for the VOXZOGO arm.
For VOXZOGO, yeah. All of the agents that are out there, if you actually normalize for age and baseline AGV, they all have about that range. We are looking for a 50% improvement in that attributable growth.
Okay. Makes sense. What can you tell us at this point about how that study is progressing just in terms of enrollment, and when can we hope to start getting updates from that phase II portion?
This is one of our highest priorities this year. Speed to enroll is, again, one of the rate limiting steps to being able to get the data on the back end. We are in seven countries around the globe right now. These are studies that are enrolling CNP naive patients, treatment naive patients with achondroplasia. The mix of countries, of course, requires us to go to countries where either reimbursement or penetrance of the molecules that are commercially available are not as profound. We are actively enrolling. We need to enroll 40 patients, 40 , in our phase II portion of the study, and we are on the steep part of the enrollment curve right now.
What we would anticipate is that in future earnings calls, we would be giving you updates on that recruitment timing, and we will then be able to zero in a bit more on the quarters by which we would have data that would ultimately read out from the phase II.
Okay, great. Then maybe I will ask you both longer term, how do you think about VOXZOGO and then ultimately BMN 333 coexisting and maybe even being complementary?
Yeah. From the data standpoint, if we have the opportunity with proof and evidence that we have a superior product, we would want that product to be the one that we would get to as many patients as possible.
Yeah. I share that sentiment.
Okay, great. Maybe we will talk a little bit more about your Amicus products, PomUp and Galafold. You did just decide to raise long-term peak sales guidance for both versus what you all had previously communicated. Cristin, maybe just talk about the decision to do that. Why now? What gave you confidence in those peak sales numbers?
Yeah. It is a great question, and what we did since the time that we signed the deal was really look market by market to understand where we think the real opportunities are. What we shared is the peak numbers, $1.4 billion for Galafold, $1.2 billion for PomUp, but the CAGR going out into that, so 10% CAGR for Galafold, over 20%, around 20% CAGR for PomUp. What gave the confidence is really in the drivers of how we intend to do that. First and foremost, we will have geographic expansion of both of these products into our country footprint, so additional 10 for Galafold, and an additional greater than 20 for PomUp. Also importantly, what underlies that growth is really how we intend to get after it. For Galafold and Fabry disease, we really believe that the driver here is in diagnosis.
We want to do the best that we can to use our commercialization capabilities that we have built over decades, really in driving diagnosis and then creating that urgency to treat once these patients are diagnosed. We think that there is a lot of opportunity there, not only from family cascade screening and genetic testing that we do today, but also a lot of really important AI advances in a platform that we are working on to help to find these patients. Patient data tokenization is helping with that, really buying different types of datasets where we can look at some of this data and get insights to find where these patients are at. That is going to be the biggest driver for Galafold. On the PomUp side, this is really about having these patients have the confidence in switching to POMBILITI and OPFOLDA as a treatment for them.
Now, what we've found is that really helping patients to understand what it looks like when they are not improving on their current therapy, or they might even be clinically waning, and not waiting for the doctor to do a technical assessment for that, but helping the doctor understand, "Hey, I don't get up my stairs the same. I'm not having my daily activities happen the same." We want to encourage that conversation so that they understand that that is the time to think about switching to a new therapy. In addition to building real-world evidence that helps provide that confidence that when you do switch to PomUp, that that is in fact a benefit to those patients. I don't know if you want to speak to that, Greg.
No, I would just add that, again, this is a case where data often comes from real-world evidence when we're showing again what the opportunities for this next-gen product is, when there's just a high prevalence of treatment with the first generation. I would just add that there are some registries that are currently enrolling around the world where, in other healthcare systems with the tender process, there's often an entire population that will switch. We have a couple examples of those. We're following them very closely, and they do provide opportunities to show whether it's Lumizyme, NEXVIAZYME, moving to PomUp or vice versa, what the results of those would be from a clinical standpoint. We want to generate the right evidence so that the patients feel pulled to their next opportunity, not just the disappointment that one therapy might be not meeting their needs.
The confidence comes from zeroing in on those strategies and then looking market by market at how we can do that.
Yeah, there's been a lot of interest just in the level of accretion that you all could see from a deal like this and from these two assets. How much of that accretion actually comes from the revenue opportunity set and the upside and the growth from a top-line perspective versus some of the cost synergies that you were mentioning earlier?
Yeah, I think it's both.
Yeah. So it is indeed both. Substantial non-GAAP EPS accretion in 2027, and the realization of $220 million in synergies in 2028, which will largely come from G&A is the biggest driver of that. But when you ask about what's driving that, I'd say the bigger driver is the revenue growth of the two, but all of these things combined really help us with accretion.
Okay, great. And maybe the last question I'll ask is for you, Greg. You guys have spent a lot of time rebuilding and broadening your pipeline.
Yeah.
Are you happy with the pipeline that you have today? Are there still any gaps that you see or that you'd like to fill?
Yeah, and you don't sit in my chair if you're entirely pleased with the scenario. We want to continue our journey here. We have spent the last few years shifting our pipeline focus. We have a future that we know exactly what we want to be and where we want to go. We have our two business units. We have some areas additionally that are adjacent to those that we're thinking about. Internally, we've pivoted away from gene therapies, well understood, looking at more classic off-the-shelf pharmaceuticals. We have a couple of, I think, important molecules that we've added, even in the last couple of months. The DMX-200 that we call BMN 820 for focal segmental glomerulosclerosis. We have the U.S. rights to that acquired through Amicus Therapeutics. We've also added in the skeletal space, we have added ALE-001 for Alesta, small molecule for hypophosphatasia.
Again, with the opportunity to not only be a substrate reduction therapy, but one that biodistributes to the muscle and potentially the joints where some of the more bone targeting agents might not have their best efficacy. These are the kind of molecules that both externally we want to create and internally from an organic standpoint. We have a focus again on reimagining the molecules that we bring forward, and I think what you're going to see in future years is that our pipeline evolution is going to be roughly a 50/50 mix of those, organic versus inorganic.
We're in a fortunate position from a balance sheet standpoint where we have the ability to go out and bring in those molecules that we think in our hands we could not only use our development machinery, our patient finding machinery, but ultimately our commercialization machinery to bring forward. To answer your question directly, we've made a lot of good progress, and we are going to keep going. We have the luxury of keeping going, and I think we have the knowhow how to get these molecules and move them through the system.
Great. Well, Cristin, Greg, thank you very much. Great discussion. Thanks for being here.
Thank you.
Thanks for having us, Olivia. Thank you.