Okay, great. Hey, good morning, everyone. My name is Olivia Breyer. I'm one of the Senior Biotech Analysts here at Cantor Fitzgerald. Thank you so much for being up early with us this morning to kick off our conference. We're really excited to start the day with someone special from BioMarin Pharmaceutical Inc., Chief R&D Officer. We have Greg Friberg. Greg, thanks so much for making the trip out here to the East Coast.
Thank you for the invite. It's great to be here.
A lot going on at BioMarin Pharmaceutical Inc. these days. Maybe just to kind of set the stage, give us a sense of, you know, top priorities heading into 2026. You know, there's a lot of R&D going on these days. Maybe just set the priority list, right, in terms of what matters most to the company. As you think about, you know, shots on goal, where do you feel like you guys have the best chance of success with your current R&D engine, so to speak?
Thank you for the opportunity to share what I think is some pretty exciting progress in our pipeline. When I think of, you know, again, our priorities, certainly our BMN 333 program, our long-acting C-type natriuretic peptide for achondroplasia, is one that I want to make sure that we talk about. That being said, we're actually turning over some cards when it comes to the pipeline over the course of the next year as well. Really excited to see the hypochondroplasia data for Voxzogo in the first half of next year. Similarly, we're filing both in the U.S. and Europe our data in adolescents for Palynziq, a big opportunity to expand a label there, and again, give patients something that we think is of real value to them.
Last but not least, in terms of near-term news, we'll be turning over a card with regard to BMN 401, which was acquired from Inozyme Pharma. This is a first-in-class, first-in-disease therapy for ENPP1 deficiency. The first study, the so-called ENERGY 3 study, we'll be turning over its card also in the first half of next year. When you think about the internal pipeline activities, I would be remiss also not to point out that we have a lot of enthusiasm in the business development space going on right now. We're in a fortunate position where we have cash, and we're looking for opportunities not just for early assets, but also for late-stage assets to be able to replenish the pipeline there.
We feel that the financial environment that we're currently in puts us in a good position given that we have those resources, and we're certainly preparing for those opportunities as well.
Yeah, maybe just to start with BD, because you mentioned it, how do you guys think about the business development strategy? I mean, you did do a deal this year. Is it one deal a year? Is it really not that frequent? Is it not really about the quantity, but it's about the quality of the assets? I assume rare disease has obviously been the company's wheelhouse. Are there certain indications or certain areas of rare disease that maybe you guys are more interested in exploring when it comes to BD?
It's more of the latter strategy, looking for quality opportunities. Yes, we want to pick our shots, but we also want to be opportunistic in the current environment. I would add that there is no quota in terms of number of deals that would be done. The Inozyme deal was one we're incredibly proud of. The work that Inozyme has done is great to get that molecule to where it was. We think, of course, as BioMarin, that we can add significant value bringing that forward. That being said, it was on the small side. We do have the opportunity and the firepower to look for larger opportunities as well, and they fall into a variety of bins. One would be the areas that we think we have strength already, certainly in the skeletal conditions, as well as enzyme replacement therapies, which is a big bucket.
Those are two areas that we're always on the lookout, making sure there are opportunities. There are adjacent opportunities as well in other indications in neuromuscular and pediatric neurologic indications, benign hematology, where we're continuing to look. That being said, the strategy is really one to look for genetically defined conditions. What that means to us, of course, is germline genetics, opportunities to use our strength, not just in terms of our financial strength, but in terms of our technical strengths. We have a footprint and boots on the ground in 70 countries around the world, reaching patients with so-called rare diseases, but again, genetically defined conditions.
We think that our ability to locate, find, and then ultimately treat those patients is something that gives us an engine that if we plug in additional molecules, we can really capture the value of those and do so at a speed that perhaps other organizations would struggle. We've been doing this for decades, and we want to bring these sorts of therapies to the world.
Yeah, and you led earlier with BMN 333, so maybe we'll start there. Maybe just talk about, and this is the long-acting CNP candidate that BioMarin's developing. You know, what makes this asset different or unique or special? Maybe just remind us where that program sits today. I know you had some early, or you had some initial healthy volunteer data. You know, maybe talk about some of the highlights from that data set, or at least what you've disclosed so far. What's next for that program?
The CNP ecosystem is one where the biology is rapidly evolving. Native C-type natriuretic peptide, it's 22 amino acids. It's got a half-life measured on the order of minutes. Voxzogo was created, Vosoritide, it's CMP39, engineered to have a half-life on the order of an hour. Given subcutaneous and daily, we've seen certainly that this is both a safe and effective drug in achondroplasia, helping a lot of patients right now, continuing to work to see whether or not Voxzogo can help patients with additional short stature conditions. That work is ongoing. We're also thinking of the CNP biology as giving us an opportunity to develop franchises. We've engineered a molecule in BMN 333 that offers an even longer half-life and a PK profile that will allow us to get more CNP on board.
There's a nuance here, which is that when you have a short half-life molecule, you're often limited in the amount that you can give patients by what's called the Cmax. There's a very well-known side effect with blood pressure drops. It's not life-threatening, but it's measurable with tachycardia, particularly in adults that one can see when you get up to high Cmaxes. A longer half-life will allow you to avoid those Cmaxes and yet increase, rather than a sawtooth pattern, increase in a broad stroke the AUCs that one can see. We've taken the CNP that we described, CMP39, and we've attached it to an albumin-binding peptide, similar to other molecules that are out there. That is BMN 333. Think of it as like a depot form of CNP where slowly CNP is released into the bloodstream.
We're running a Phase 1 study right now, and we've announced that in these healthy volunteers, a single-dose study, we've been able to see not just equal, but we've seen in multiple cohorts three times the AUC that other long-acting CNPs have been able to achieve. Why 3x? In the animal models that we've seen, 3x appears to provide a meaningful increase in linear growth as compared to 1x with a simulated long-acting CNP as well. The study's got six cohorts. We've completed all six. As we mentioned in the earnings call recently, when we reached cohort four and five, they had already reached our 3x threshold. Six we haven't announced yet, but we just completed it. From that standpoint, this molecule really exceeded our expectations with regard to the PK profile.
We believe that we have the right reagent in hand to test the question of whether higher exposures will deliver higher growth. That's a hypothesis that's supported by a couple different sets of data. One would be the animal models that I mentioned. Another would be human genetics, where if you have activations in these pathways, those patients get quite tall. Interestingly, it appears that the only side effect they have when there's very high C-type natriuretic peptide (CNP) levels are skeletal related. No off-target, no off-skeletal toxicities, which is reassuring. Finally, these levels of area under the curve (AUC) have not been tested in humans before, but there does appear, even with the other long-acting CNP agents, to be a linear relationship between dose and growth. Does that curve continue upwards?
We think it's a good bet, and we think we have the right reagent to test that in BMN 333.
Yeah, and maybe just contextualize that 3x AUC. I mean, I imagine 3x AUC isn't necessarily equal to 3x growth, right? It's not a linear relationship. What are you all expecting to see in terms of the impact on growth? I mean, maybe not necessarily a number that I'm asking for, right? As you think about the relationship between growth and AUC, and then maybe as a follow-up to that, I'm sure you'll get to it on your own, but why AUC, right? Why is that a more important metric at this point than Cmax?
Yeah, very fair questions. With regard to the amount of growth we're looking for, I can say that in the rodent models, the 3x AUC plus doubles the amount of attributable growth in the model that one sees as compared to a healthy dose of Voxzogo or a similar dose of the 1x long-acting. Will we see that in humans? To be determined. What I would say is that we've talked to physicians and patients, and we're designing studies that would have a meaningful increase over what's been seen with Voxzogo previously. With regard to the targets, I would add that the animal models tell us that increasing levels of AUC do appear to have a linear relationship with the amount of growth that can be delivered.
One of the reasons we can't do the same thing with Cmax, we can't run the same experiment, is you run into the Cmax-related toxicities. It's similar to the analogy my preclinical colleagues remind me of, running a race. If you got to run a mile, are you going to sprint the first 100 m and then, you know, jog it in the rest? Or are you going to have a nice brisk run for the entire period? Different measures, but clearly you can't sprint the whole way. If you could continue to increase the AUC, as the metaphor continues here, the goal is that we would be able to unlock more growth.
The goal is to maximize the effect that CNP can deliver and to have a really best-in-class CNP to not only unlock that profile, but even in a future state where there might be rational sequences or combinations, that this would be the drug of choice that would want to be partnered in those for these patients.
Yeah, and you guys have spoken publicly about wanting to move into a Phase 2-3, and even running it as a superiority study versus Voxzogo. What can you tell us at this point? I mean, have you decided on the trial design? Are you still engaging with regulators about the trial design? Where are you at and what can you tell us at this stage about that Phase 2-3?
This still remains a dynamic process. We're engaging with regulators. Now, when we engage with the regulators, we have what's called a study concept design. It's not a full protocol. It's not locked in, but it has all the elements that we're speaking about here. What we've envisioned and what we've agreed upon for the path forward is a combined Phase 2-3 study. This would give us an opportunity to move immediately into patients. There's no multi-dose study in healthy volunteers that's needed. We would immediately move into achondroplasia patients, and we would offer them a Phase 2 study that would have potentially four arms: a high, a medium, and a low dose of BMN 333 and a control arm of Voxzogo. No placebo there, of note. That would allow us, in short order, to determine, again, what we think the go-forward dose should be.
Of course, we want it to be as effective as possible. Effective meaning not just linear growth. That is what we can measure. It's what we can measure at six and 12-month time frames. What we ultimately want to deliver is better health and wellness for these patients. We'll be measuring other factors along the way. We're leveraging the data that we have from our ongoing Voxzogo program to, again, preclude the need for a placebo arm. We can model that arm, and that's been acceptable thus far to regulators. Of course, from a statistical standpoint, we're using as much borrowed information from Voxzogo to try to limit that arm as well. Once we've had that dose, we'll immediately move into a Phase 3, which would be a head-to-head study in achondroplasia of a chosen dose of BMN 333 versus Voxzogo. Again, no placebo here.
We think that, again, in this world, not only would that be attractive to patients, they wouldn't necessarily have to sign up for a placebo-controlled arm, but we also think this is what the marketplace wants. Not just an E2 drug, not just a convenience lever, but they're going to want something, again, that offers them more value. Not just in linear growth, again, but also in the health and wellness. We're continuing to show that with Voxzogo, again, the first-generation molecule, this isn't just about growth. This isn't just about final adult height. We're seeing tibial bowing improve in these patients. We're going to be presenting next week some data with regard to spinal alignment, spinal canal width. We're seeing facial morphometry improvements, which, of course, are a surrogate for things like eustachian tube abnormalities, ENT abnormalities.
We want these patients to live their best lives with the most wellness that they can. We think it's part of our job not only to develop new agents, but take the agents we have and show as much data as we can and be transparent on what that value is.
What gives you confidence that you think you'll show superiority over Voxzogo?
There are three data sets. I mentioned the animal data set. Of course, we mentioned before the genetic data that suggests, again, people with activating mutations of NPRB or of high levels of C-type natriuretic peptide have quite a bit of growth that can be uncorked. Quite frankly, if you just look at the clinical data that's out there with long-acting C-type natriuretic peptide agents, there is not a suggestion so far that there's a data point where the efficacy seems to flatten out. Continuing that curve upwards on the area under the curve, we think this is a very good bet.
We suspect it will be a very safe opportunity, and our goal is to prove that and ultimately to measure that in patients with achondroplasia. The next step is to be in patients in the first half of next year, and we're moving with urgency to be able to deliver that.
Okay, great. We're looking forward to that study kicking off and the data that's coming up from the healthy volunteer study. A lot going on outside of achondroplasia too. Obviously, hypochondroplasia phase 3, Voxzogo data coming next year, but even beyond that, there are a number of other short stature indications. I know you've talked about wanting to move into Phase 3 with Voxzogo, but also the potential now for BMN 333. Maybe just walk us through the thought process in terms of the development path forward for some of those additional indications. I hate to ask the question about timelines, but when will we get the next update? How do you think about now that you do have these two molecules that you could potentially move forward with development?
Yeah, and it's important not to put the cart ahead of the horse here. Of course, achondroplasia and hypochondroplasia are fairly related conditions. Even the regulators allowed us with hypochondroplasia to move right into Phase 3 without dose ranging. For additional short stature indications, whether they're proportional with idiopathic short stature or disproportional with, for example, Noonan syndrome, Turner syndrome, and Sachs syndrome, we are doing and looking forward to seeing data from dose ranging studies with Voxzogo. We have publicly stated that that data will allow us to make a decision to start phase 3s in those indications in 2027. Now that happens to line up quite nicely with our dose ranging that we will see coming out of our BMN 333 as well, where in achondroplasia we'll have an idea again of dosing schedule, effect size, and so forth. I mentioned schedule.
It's planned for weekly at this point for 333. It could be an opportunity to elongate that, but that's not our goal right now. That data will line up in the 2027 timeframe, and we'll be able to look at not only the efficacy and safety, but also the totality of data from the three programs. We're also considering other indications. The nice thing about C-type natriuretic peptide is it's not dependent on an FGFR3 mutation in order for it to have its activity. It is a master regulator of growth. By administering it to patients with a variety of conditions, we do believe there would be an opportunity to address their underlying condition. That being said, the dosing schedule and the effect size may be very different in indications that are not as so-called dysplastic as hypochondroplasia and achondroplasia.
As a result, doing the dose ranging is going to be a very important part, not just from a regulatory standpoint, but also from a safety and appropriateness standpoint in order to choose those doses. We're going to have a lot of data in that 2027 timeframe, and I think, again, we're going to be in a good position to be able to make an evidence-based decision.
Yeah, and of those additional indications, right? I mean, you have Turner syndrome, Noonan syndrome, idiopathic short stature, etc. Are there certain, you know, is there a higher probability of C-type natriuretic peptide mechanistically yielding successful results in one over the other, or is that not necessarily the right way to think about it?
It's hard to say. I think when you think about the success in different indications, I mentioned the growth plate biology, and there are certain indications where the orderliness of the progression at the growth plate is disturbed. Achondroplasia and hypochondroplasia are one of the extremes there. There are shades of gray in the middle for some of the other monogenetic disorders. There are also collagen deficits in some of the disorders as well. It brings up, I think, the larger order question that, you know, will the biology be the same in all these indications? The best data we have right now is from Dr. Daber's investigator-sponsored study. He's looked at a variety of indications and, again, shown that, yes, there is growth that can be unveiled in a variety of Noonan syndrome, Turner syndrome, Sachs, hypochondroplasia, ACAN deficiency.
The question will be, what's the right dose, and is the profile one that the benefit-burden we can stand behind? That's what's being explored right now in our randomized studies, in our Phase 2 studies. The hope is that we would have an opportunity to expand the use of Voxzogo, potentially next-generation agents, but we've got to do the experiment at this point. I do think it's a good bet. In particular, the patients that are most burdened by comorbidities other than just height, that's where we really would want to make sure that we can unlock opportunities to offer them something, again, of value for wellness and health.
Great. Why don't we talk a little bit about your Inozyme deal that you all, I think, just closed maybe a month or two ago? That's BMN 401. Maybe just give us a rundown of why you all decided on that company, on that program, what gives you conviction in it, and what have you seen so far in that clinical profile that you're excited about?
The deal was announced in May, and July 1, we closed it. A nice proof point that we're acting with urgency. The Inozyme molecule, formerly called INZ-701, now BMN 401, is a molecule. It's an FC fusion. It's an ENPP1 enzyme replacement for patients with ENPP1 deficiency. This is a devastating illness in infants. It's a genetic disorder where, sadly, 40%- 50% of the infants die before their first birthday. Those that live, unfortunately, are burdened with a variety of comorbidities. The biology is such that when you're missing this enzyme, you have low levels of what's called pyrophosphate and AMP. The end result is you get rickets, osteomalacia. It's getting solved. Paradoxically, calcium, rather than being deposited in the bone, is deposited in your arterial beds. You can have things like mesenteric ischemia, strokes. It's quite devastating.
In the older patients, the 1 year- 12-year-olds, there's a little bit less of the arterial endpoints, though they still have challenges there. The bones become a little bit more of a focus: pain, hearing loss, of course, bowing of the legs, classic rickets that you'd think about. In adults, the phenotype is a little less severe, but it's still, with pain and bone softness, can become a challenge. The study that's ongoing right now, the ENERGY3 study, is in this middle group, this 1 year- 12-year-old group. The study is designed not only to look at, can you normalize the biochemistry? This is the pyrophosphate levels, inorganic phosphate levels, and so forth. It's also asking the question of whether there's a functional impact on the bones, looking at radiographic scoring indexes. When your growth plates are open, that's a very effective way to ask, are you reversing rickets?
The study will turn over its card in the first quarter of next year. We're excited to see the results. We see that as really the tip of the spear. The largest indication would be in adults, about 75% of the opportunity. From that standpoint, we're designing a pivotal adult study right now, working with regulators, and hope to get that study up and running, the ENERGY 4 study, next year. What makes me most excited about the Inozyme molecule is that it works to do what it's designed to do. Weekly subcutaneous injections normalize the biochemistry very rapidly in almost all the patients at a variety of dose levels. We see pyrophosphate normalize. We can see inorganic phosphate start to normalize as well. In the adults, we even saw the FGF-23 levels, which is sort of a marker of phosphate wasting yet from the kidney, normalize.
This is an opportunity from a biochemistry standpoint to really normalize what's going on in the patients. The question will be, can we get that dosing schedule right to pull through to the functional endpoints? That's what the study is looking at right now. We are incredibly humbled and pleased to see what the Inozyme team has been able to deliver up to this point. We think that this is an indication and a biology that really fits so nicely into the BioMarin Pharmaceutical Inc. portfolio. Smack dab on top of our enzyme replacement therapy unit. In fact, many of these physicians, I don't call them call points because I'm an R&D guy, but many of the physicians I meet with are, you know, for Voxzogo.
In fact, I was at a meeting when the deal was announced, and it just so happened that our Voxzogo investigators were the same investigators on these studies. Pediatric endo and medical geneticists are a lot of the same physicians that we work with. It fits very nicely into our portfolio. From a deal perspective, it was a somewhat small disease, but we think it will have a big opportunity to help a lot of patients. In our hands, again, with that 70-country footprint, we think that we can get this molecule to the world in the fashion that others would struggle to do.
Yeah, for that Phase 3, is it powered to meet a pre-specified delta on some of the endpoints?
It is on both. Now, it's a fairly small study. You know, again, these are super rare diseases. Twenty-seven patients. It is powered to look at a Δ for pyrophosphate, and it has a powering level as well for the radiographic index.
Okay, great. Once we get those data in first quarter, maybe just an overview of the granularity or what we should expect. Obviously, both primary endpoints, right? Anything beyond that that you all are planning to publicly disclose?
Sure. I think our philosophy is that we recognize we're a publicly traded company, and we want to make sure that for our stakeholders, we discharge any confidential information. Did the study meet its primary endpoints? Did we see any unexpected safety? What I would expect is beyond that, that most of the details will be saved for an academic presentation thereafter, so that the totality of the data can be seen by the audience that we intended to be seen from a technical standpoint. That being said, again, we're committed when these cards turn over to make sure that we share that with our stakeholders in the financial community.
Okay, great. Next steps for additional age groups. I know you've talked about the adults. Have you thought about going into infants as well there?
Yeah, thanks for the question. Adult study designing, hope to launch that, initiate it next year. Infants, the...
That'll be a Phase 3 that you...
That would be a dedicated Phase 3 study. Studies in infants that are already ongoing are single arm studies. There's both phase 1 data as well as an expanded access program. As we mentioned, this is really a devastating condition where the lives of these infants are certainly at risk. As part of any filing strategy, we would include that data in the packages sharing with regulators. Inozyme had previously stated they believed that this would be part of the first approvals. These will always be review issues, and we're engaging with regulators to make sure that they see the totality of data, not just safety, but efficacy data, including from infants as well.
Okay, great. Unfortunately, we're out of time, but Greg, thank you so much. Really appreciate it. Great discussion.
Thank you.