BIOMARIN PHARMACEUTICAL INC. STIFEL 2026 HEALTHCARE CONFERENCE - AMICUS THERAPEUTICS INC

all right great uh thanks very much uh happy to be uh moderating a chat here with the bomber in uh management team um i think brian cfo which i'm sure everybody knows is going to make some opening remarks and then i think we're going to use this as an opportunity to uh spend some time with greg and talk more about the pipeline that bomber is building out so please take it away brian thank you thanks paul appreciate it thanks for having us uh good afternoon everyone uh yeah So some opening remarks. We're just a week out of our Q3 report and lots of strong progress and results this year. We are executing on one of the core elements of our strategy, which is using our financial strength to fund future innovation. Very strong Q3 with revenue growth of 32 percent. We reached $1 billion of total revenue for the first time in the company history. A lot of that was driven by our Metabolics Conditions business unit with 44% growth. We're also growing earnings per share and profitability. One note there is that we have had two acquisitions in the third quarter, which are driving some level of in-process research and development expense. A lot of our growth is being driven by the recent acquisition of Amicus Therapeutics that brought two high-growth rare disease assets into our metabolic conditions portfolio. That is Gallifold for Fabry disease and Pompility and Opfolda for Pompe disease. These patients were growing patients at a double-digit rate. For Galliford, we shared in one specific market, we grew patients at 20% in the third quarter, year over year. And Pompability and Opsolda is earlier in its growth cycle, and revenues grew almost 60%. amicus is also more than just a revenue growth story uh we think the deal has the potential to be highly accretive to the bottom line we shared recently that uh we've identified roughly 50 percent of operating expense synergies on a non-gap basis when looking at the base amicus operating expenses we think those synergies of roughly 220 million dollars will be fully realized in the for a full year in 2028 the integration will be mostly completed by the middle of next year and we think that the amicus business can be run at a roughly 60 operating margin by the end of the decade which then gets to a healthy inflection on what was already the growing profitability profile of historical biomarin then i think the last thing i'll mention and this is really great to have Greg with us here today, is we are delivering on our objective of rebuilding our pipeline. We've added four new assets to our pipeline this year. The first is BMN 450, most recently announced. This is the first potential subcutaneous injection of a Fabry disease therapy, enzyme replacement therapy. Next is BMN-440. This is the first potential oral therapy for hypophosphatasia, which is a significant commercial opportunity. Next is BMN- 430, which is a preclinical program for an actually recently discovered disease area, disease in Renu syndrome. And then lastly is BMEN-820, which came to Biomarin through the Amicus acquisition. This is a partnered asset. We have U.S. rights. It's for FGFS, the rare kidney condition. So we're delivering on growth, innovation, and our value commitment objectives. And happy to go where you'd like, Paul. Thanks. Okay, thanks. Well, I'll just take the pipeline in a very slightly different order because I wanted to first talk about hypophosphatasia. You know, that's an indication in a market I've been interested in from covering Alexion. And, you know, maybe I was wondering what you could talk about the Alesta program, the thesis there, and sort of like the parts of the market that it could serve relative to Strenzik and the Astra follow on. Yeah, thanks for the question, Paul. We're really excited about it. We call it BMN 440. It's a small molecule. It targets ENPP1. And in that regard, if you think about hypophosphatasia, this is a condition where patients are missing an enzyme. They're missing alkaline phosphatase. And the result of that is they have an increase in their serum in their bodies in inorganic pyrophosphate. That increase leads to decreased bone mineralization and a variety of other problems through the patient's life. Now, the available enzyme replacement therapies, we mentioned a couple of them just now. are bone targeting agents that try to, again, metabolize that pyrophosphate to downstream products. What BMN 440 is, is a small molecule that's trying to inhibit its production. Think of it as a substrate reduction therapy, not dissimilar to Gaucher. And if you inhibit its production, does that ultimately shut it off and the excess that's around is cleared by the body? Is that the thought? So the thought is that you're actually decreasing the production of it all together. And so if you bring it down to a normal level, you can have the same benefits of improving bone mineralization. But unlike the enzyme replacements that are engineered to be bone seeking, a small molecule has the opportunity as well to reach compartments like the muscle and the joints, which particularly for certain phenotypes in the disease, that's where a majority of their problems come from. It's not necessarily rickets or soft bones that they're complaining of. It's more pain. It's more joint problems. It is sleep deprivation. Again, the hope is here that we can look at each of these sub-segments appropriately, deploy this molecule, and not just deliver an oral, more convenient therapy, but also one that might target these conditions in a way that treats the symptoms that are really bothering many of these patients. Got it. There is kind of a wide range of phenotypic severity within this, I guess, I don't want to say if it's like a family of diseases it's the same condition but you know there's like the infantile onset there's the adult like how do you think about positioning this yeah i think what we're learning and some great work done again here by alexia on az is that you need to think of these populations as um you know different opportunities different needs uh infants of course which we're not talking about for bmn 440 uh have uh mortality is as a major problem why not because just unseating strenzic is not realistic there? No, I think it's more that pyrophosphate isn't the issue in infants. There are other sort of vitamin deficiencies that alkaline phosphatase can also address where this approach wouldn't be appropriate. But for the children who are diagnosed, again, the phenotype pulls through as children. Those, again are the ones who have the soft bones, children that become adults or adults who are presenting for the first time later in life. Those are three different distinct populations that have different needs. In the youngest. It's about the soft bones. In the children who are then adults, we're thinking about things like the six-minute walk test. In The Adults, there may be factors involving pain and joint problems that we need to focus on. Our approach will be to develop the molecule in phase two, and each of these indications appropriately think about the endpoints, do endpoint development at the same time that we're doing dose ranging. The data that we have right now is phase one two data involves healthy volunteers also some patient data and we're presuming that next year we're going to be able to share some of that data not only is it pk but you can think of it as biochemical proof of concept so we'll be looking at blood markers and again ability to modulate pyrophosphate and as you think about these populations um going from children to older adults like is there is there varying probability of success across these populations? Is there like a spectrum on the degree to which there are other aspects of the disease in these populations that this could or couldn't address? Well, so the great news here is that pyrophosphate is as close to an approved, well, as close to a validated surrogate as it comes. Now, what I would say is that, again, Strunzik in 1850 has shown that many of the benefits that they've shown do track with pyrophophate reduction. Now we will be decreasing pyrophosphate through a substrate reduction mechanism. But again, as long as we can do that, there's good reason to believe that that's a marker for success. That being said, the established benefits are much clearer in the children when you're looking again at growth plate for things like the Ricketts severity score or looking at the six-minute walk test. Adults has been a bit of a challenge where six-minute walk test probably is too heterogeneous of an endpoint. And the work that we're going to do will hopefully not only benefit from a molecule that can reach different compartments than the bone, but also we're gonna build on the work that's been done, the great work so far, and make sure that we are measuring the right endpoints. Okay, okay. Makes sense. And so, did you say you have some PD data now that you haven't shown? So, during the process, we've been able to see both PK and the preliminary PD data. I haven't, uh, shown it publicly, but that was data that was an integral part of our thesis to acquire this molecule. Okay, okay. And just as we think about seeing the PD data next year, maybe just give people a little bit more context on not just the biomarker, but the thresholds for change that have historically translated into potential clinical benefit. Yeah, if you triangulate all the data, including genetic models as well as the preclinical models using this particular moiety, BMN440, We think that somewhere between a 30% and 50% reduction in pyrophosphate would get us into the levels that we're looking for. What does Strenzik show? Roughly the same. Roughly that. Okay. So that's reasonably well validated. Yes. Okay. Got it. And how penetrated is StrenZik? I know in the infantile population, it's just a no-brainer risk-benefit, but as you get older, what proportion of patients are on therapy? Yeah, it decreases as you go upwards. And in particular, adults, not only is there not an approved therapy, but what we have is a mix of, you know, willingness to try treatment. Some of that has to do with the profile of the drug. Some of it has to deal with being able to identify the patients. Good news here is that the alkaline phosphatase levels in the bloodstream should be a pretty obvious marker to at least begin some of that work. One of the metrics we have an understanding of is 9,000 diagnosed patients in the U.S., but approximately just 10% to 30% on treatment. 10% or 30%? Why is that range so wide, or is that based on age groups? I just think it's based on available information. Like epi and just kind of people guessing. I see. Okay, got it. It makes sense. There's a lot of untreated patients. The question, of course, is we need to put together a program that proves that, again, the adults can benefit. it. What we think is we have a good shot at it, given the small molecule moiety that can reach the muscle and joints. Okay. So when we get the data next year, like any additional color on like how many patients duration, things like that. Yeah. Not going to share too much more at this point, except to say there'll be both single and multiple dose. There'll be Both patients and healthy volunteers. And you can expect again, that the pyrophosphate levels are going to be an important part. And are you just unveiling data that you already have? Are you like in the process of generating additional data between now and then. The study's still ongoing. And again, from a typical phase one, two, as you can imagine, there are dose escalations involved. I got it. Okay, great. Anything else to add on that one? No, we're excited to have a molecule again as part of our pipeline that has, you know, not only promised to have good biology, but also can reach a fairly large population of unmet need. Yep, okay. Let's talk about the deal you recently did with Fabre. I'm a little bit like less familiar with his acid as like most people are. Maybe just give kind of the background on, one, what got you interested there? And, two, like how do you see it as complementary to Gallifold? Are there like different patients that could be served by this? Like how does it fit into the whole paradigm? Yeah, so the GC Pharma Hanmi deal, we call this one BMN 450, so we're moving in a routine fashion upwards. And what I would say is that this is an enzyme replacement therapy for Febre that has an aglicosylated FC attached to it. The point of adding that moiety onto the molecule is not only to increase half-life, but also to stabilize the molecule so it can be given as a subcutaneous delivery. As a quick reminder, all enzyme replacement therapies that are available for Febre right now are given intravenously. Again, that comes with its own treatment burden. So straight up, we think, again, the opportunity for a molecule to try to recapitulate some of that biology, but given as a subcutaneous delivery, is an opportunity, and we hear this from patients and treaters, something that they would value. For Biomarin, our footprint in this space with Galifold is currently limited to some degree because Galifhold, as an enzyme stabilizer, only addresses about 35% to 50% of the population. You need to have an amenable mutation, so to speak. And we know that that is the subset that is amenable. The beauty of BMN 450 is it would be mutation agnostic. It could reach all of the others. And again, we see this as an opportunity not just for more convenience, but we will be studying along the way whether, again, that affords some of the PKPD profiles that would allow us to look at other end organs, whether it's the heart or other areas, to see if it can bring other things to the table. Yeah. Okay. Interesting. So how do you think about the right, like, study and development path for that? Like, as you think About, like running trials that could register the drug, but also be useful from a commercial perspective, like are switching studies, things that you might think about, like what, how, and I guess there's been different paths, I think, to get drugs approved for Fabra. So how are you thinking about that piece too? Yeah. The great news here is there are well-established paths. I think there are a variety of subsets of patients, including those with preexisting anti-drug antibodies versus those that are naive that we'll have to incorporate into our thinking. there's also an opportunity to not only look for naive patients and you know straight up kidney biopsy endpoints but we could look at switching studies we can look again at other end organs and try to develop the molecule another very valuable factor here is that in early studies you don't have to sit around and wait a year and do kidney biopsies you can look at blood markers like lyso gb3 and again get a sense of whether or not you're normalizing the biology. So mea culpa, we've only had the drug for two weeks. So we haven't sorted through all of the development plans. We're supposed to know everything. Yeah, yeah. Well, so we're not the only people also involved here. We do need to interface with regulators. But what you can expect is we're going to move as quickly as we can. There will be a combination of multiple different studies, and we'll be looking at endpoints that go beyond the classic measured endpoints from the regulators. And when could we see some data? Yeah, we haven't committed to when we're publishing the data, but I will tell you that the study is ongoing. Again, it's a case where this phase 1 slash 2 is being done in patients. And so it's in its dose escalation phase. As I've mentioned publicly before, we've seen a very low double-digit number of patients. But, again, we've seen what we need both on the PK side as well as, you know, some of these early markers of biologic activity that we feel confident that this is a very good molecule to be testing in this space. And when we have that totality of data, we'll be laying out what you can expect shortly in terms of public disclosures of the data. Okay, great. All right, let's hit on BMN 333. So I think this is one that everyone's fairly familiar with, right? Everyone knows Vox Ogo and the space and the once-weekly thesis here. I want to maybe ask a more specific question, and I know you're not maybe going to get exactly into the numbers, but forgive me because I'm going to give a little bit of context. So in achondroplasia, I think we've seen a number of programs go from showing something like a two centimeter benefit in phase one, two studies to closer to one and a half in phase three. And so in the context of that, I'm wondering what you think you would need to see in a mid-stage trial to really have conviction that any sort of implied effect size delta will hold up for power for superiority in phase three. Yeah, so we're very fortunate here in that we have a wealth of data from Voxogo that not only tells us about the variability of response that is inherent in these individuals, also tells us About the factors that go into determining that variability, things like baseline AGV, you know, age, gender are really important. So we of course, have a PK PD model, or I should say a PD model that really tries to get at that. And as we dissect our data, we're going to use that, leverage it, and make sure we understand what we have with 333. I think you're also highlighting the fact that when you look at any uncontrolled data source, it's important to look at things like LS means and look at normalized data to the patient population. It's disingenuous to look at raw data and talk about it, you know, again, apples to apples. Now, looking again at that, we believe we've designed a study with 3-3-3 that is testing three doses of 3-4-3. It 30 patients. There's an internal control of 10 patients on Voxogo, and that will be supported by a wealth of historic data as well. We have a Bayesian model, again, that will look at dose response and will be targeted for an X percent probability of repeating in phase three. We haven't said what that posterior probability is yet, but you can assume, again. that it's something that's meaningful. If we see that, we move forward to phase three, and again, we think we have the right molecule with 333. The hypothesis is that dramatic improvements in AUC, we're talking not just, you know, one or twofold, but, you Know, in our phase two study, as high as eight or more fold of free CNP AUC as compared to a drug like UV well, that there is more biology to be explored on the dose response curve. It's not a debate about whether there is a dose response curve. I think there's a lot of debate about whether or not that curve has been well characterized and whether there's a shelf. We would argue that the preclinical models and even the clinically available data suggests that this is an unanswered question. And we know that 3-3-3 gives us both the PK as well as the early PD. Cyclic GMP from our healthy volunteer study showed that when you go up higher levels than what UVL can achieve, that we're seeing two to five-fold increases in cyclic Gmp. The ultimate question will be the card that we can turn over next year. And again, I think in the following quarters, we'll give a little bit more clarity on the timing of when we can expect that phase two data to read out. What we've said publicly is it will be in 2027. We're actively recruiting to the study around the globe right now. And again, looking forward to give updates shortly. Yeah. Okay. That's great. I know I may look young, but I did a deep dive on Voxogo in 2013 when it was like the animal data and the thesis, super interesting program. Yeah, it was maybe a little too early. But I remember two concerns back then were, one, if you drive growth velocity too much, you can exacerbate other parts of the disease, spinal stenosis. And two, there was a lot of concern about hypotension, which ended up not really being a big deal with the first gens. But, I'm wondering with the greater exposure here, if that could end up being a problem. Yeah, very fair questions. And I think we've had some posters that have shown this data. We have compelling evidence that the hypotention is driven by the C-max of the molecule. And by having a half-life on the order of 99 hours, I believe it was, instead of one hour with Voxogo, you can deliver it 3-3-3 in a way that avoids the C-maxes by multiple fold that we see not only in humans, but also our animal model, in this case a non-human primate, has given us confidence. So the hypotension doesn't appear to be something that we're worried about. And by the way, we didn't see it in the phase one as well. with regard to your second question, which is, is there a level of growth that is too much in our clinical too fast, too fast in our clinical studies for achondroplasia and hypochondriplasia for that matter, we haven't seen that to date. And again, uh, being true, we can always ask the question about benefit risk profile, something that we're going to follow very closely again, in the achondriplegia and hyprochondroplegia market, uh haven't seen it in our studies to date, I think you've also said that, you know, a superiority study, is somewhat ironically or counterintuitively to people actually smaller than a non-inferiority study. Again, obviously, depending on your assumptions, if it turns out that a noninferority path is safer here, or you miss that Bayesian probability cutoff, will you still advance this? Yes. So two answers to that question. And when I refer to the study being larger, that's really about a two-sided non- inferiority. There are step-throughs that you could think about where you pass to do two-sided yeah yeah for a formal in my world what a non-inferiority study is yes you do but there are ways to actually have a step through so you could have a second bite at the apple that is not the hypothesis that we're testing with 333 we think again that the animal models the clinical data that's out there and again the molecule that we've produced is designed to test this hypothesis that dramatically higher AUCs of CNP are going to explore that right side of a dose response curve. And that's what we're focused on at this point. Now, again, do we have, you know, contingency plans where we could think about options? We always think about how we could, you Know, have other, you Now, other approaches, but that is not what we want out of this molecule. And it's not what We think society is valuing. Yep. Okay, fair enough. All right, let's hit on the FSGS program quickly. And then I'll go back to hitting Brian on a couple quick questions. But, you know, as it relates to that program, so there's already some protein area data that's out there. Maybe speak to the data generated so far. And, you know, I mean, protein area is a well-accepted endpoint. We've seen a number of drugs approved in protein area at the FSGS. You know, what is ultimately the thesis on how this would be positioned? Yeah, we're in a very fortunate position where regulators and cooperative groups have worked to move the field. No longer do we need to wait for two years, three years, five years to see EGFR decline or some other harder endpoint. Two-year proteinuria reduction is an approvable endpoint for full approval with the FDA right now in this condition, and so some great work done there. That is the endpoint that we're looking at with the molecule we're talking about, 880, and 820, excuse me, and, so, from that standpoint, the study, the molecule is a CCR2 inhibitor, so it's working on macrophage-driven inflammation. It's an oral therapy. It is designed to be used on top of angiotensin receptor blockade. And the goal here is to see whether or not, again, you can build upon some of the great work that's been done on the vascular side with an orthogonal mechanism of action and improve that proteinuria reduction. There was a small phase two study, again, small in number, though it was mighty in terms of some double crossover there, that showed proteinuria reduction. And again, the phase three study that's fully enrolled had a futility analysis that's been passed through, again, looking to see whether that proteinuria production was something that met that threshold or not. So we're now in a period where the study's fully involved, and it will be in 2028 when the card will be turned over and ultimately show whether that proteinuria reaction is achievable. The promise here, again is that you have an alternative mechanism of action to the purely vascular targeting agents. You would potentially not have a black box warning. And of course, the opportunity to target patients that don't have any restrictions on levels of proteinuria. So we're talking about nephrotic syndrome or not. Again, the study is running. It remains blinded. And we're looking forward to seeing those results. Okay, great. Timing of that data? 2028. 2028, okay. It's two full years of required follow-up. Yeah, okay, great. All right, back to Brian. How should we think about what the hypochondriplasia launch could look like in year one versus ACON? Yeah, thanks, Paul. So just a brief recap, hypochondriplasia is the second potential indication for VoxOgo, with achondroplasia being the first indication approved back in late 2021. I'd frame it up as there's both a tailwind and a headwind for the hypo-con launch when comparing it to achon. um i'll start with the headwind which is more complicated uh diagnosis which uh has a lower diagnosis rate overall um and can take more time do you guys have a good estimate on like the diagnosed prevalence of that versus acon do we have a rate we have uh you know we're following a variety of markers including time to diagnosis we again have genetic testing numbers if i said to you that our market research suggested it was like one-third as common diagnosed does that pass the smell test well so genetically it should be roughly similar equal but i mean in terms of diagnosed the number we've put out is as compared to 24 000 achondroplasia patients around the world in our markets we think there's 14 000 addressable patients now that assumes that they're being diagnosed and that's that's the work it's really getting them to diagnosis faster getting them into the right physician, having the testing, and then identifying them and pulling them through to the treatment option. There is a cut, of course, for severity of disease as well. Our study roughly was minus two standard deviations or less. Again, interestingly, when you looked at the subsets, patients who were between minus two and minus three, as well as minus three or more negative, seemed to do similarly. It was great data, and we think, again, we have a great opportunity with the PDUFA date coming up on May 30th, uh, with the data that we've put in. Yeah. So what, while there's other factors in that cut from 24,000, which again, for achondroplasia and hypochondroprasia, the, the incidence is, is, or prevalence is relatively similar. Part of that cut is the diagnosis among other things. So that's one way to think about, uh. how we reduce the addressable population. So, that's been some of the work thus far. Um. And I mentioned headwind and tailwind. the tailwind would be all of our years of experience of being in the achondroplasia market and building that over the last few years. Again, diagnosis was already robust from a diagnosis rate standpoint for achondraplasia, but the treatment centers, our objective in the ACON launch was to build a pediatric endocrinologist as this treatment home. Since then, there's been this great evolution in single physicians that would see a handful of patients uh of building out skeletal dysplasia centers and now they're seeing hypochondriplasia patients so uh between that uh you know again diagnosis efforts uh once we're approved digital marketing efforts uh we think that's a real tailwind where acon being first in disease we were really starting from scratch yep okay so for so for next year it's a may padufa so like Do you, when you guys guide, will you include contribution for that, for Hypo? We're working through, you know, finalizing the 27 operating plan, you know, as we speak, and that includes talking about, you know, how we guide, you know, on one hand with a May 30th PDUFA date and not having full clarity on label and any other timing elements, you You know, that gives me some pause on guiding to it at the beginning of the year. But on the other side, you know, it's a mid-year launch, and, you know, the ramp with any rare disease launch over the first few quarters, it's largely a second half launch, as it were. So, you know, will we be able to ballpark it and include it? Possibly. So stay tuned on this front. Okay, thanks, Brian. And then maybe just the last question for you is just, you guys have obviously done a nice job of rebuilding the pipeline here. What else should we expect for BioMoran on the M&A side over the next year? And how do you think about the types of deals or deal capacity? Yeah, so again, starting with Amicus, which was really just a great strategic fit of these already commercial assets, you know, still on a strong growth curve, highly synergistic with the company. So that was a unique transaction. We then prioritized rebuilding the pipeline. And we've talked a lot about today bringing in some of these, you Know, early stage assets. that'll continue to be the focus uh is clinical stage assets ideally within our uh therapeutic areas our business units but if not there's other areas that are tangential that that we're comfortable with um we see bomber and do like a bigger deal or do you kind of shy away from something like that by bigger i mean you know billion plus yeah at the moment you know we're focused on deleveraging from the amicus transaction which as we realize the synergies and as we grow our earnings profile and cash flow profile will do that. We've been able to fund these deals thus far this year from our balance sheet with cash on hand and have not changed our deleveraging target of less than two and a half times by the middle of next year. So as we delever, yes, we will be able to restore firepower and afford more over time. But at the moment, not committing to specific size of deal. Fair enough. Okay. Well, thank you guys so much for the chat. We appreciate it. Thanks for all the R&D questions. Appreciate it. Thanks, everyone.