Great. Thank you so much for joining us for this afternoon session. My name is Mohit Bansal. I am one of the biotech and pharma analysts here at Wells Fargo, and I am joined by Team BioMarin with us today. We have Greg Friberg with us, the head of R&D at BioMarin, and then Cristin Hubbard. She is the head of commercial at BioMarin. Thank you very much for joining us today.
Thanks for inviting us.
Awesome. Maybe let's just start with big picture. There has been a lot of development at BioMarin since you both joined. What makes you excited about all the accomplishments in last one year or so, and then tell us about the investment story at this point?
I'll start. Okay. We are really excited at BioMarin. As you've mentioned, we've had a lot of updates over the last year, and I'd say the last couple of years. I know you'll get into some of the R&D updates, but some of the things that we're really excited about is that when we look at our established business units, so we have two of them, one which we used to call enzyme therapies, but since the acquisition of Amicus, we're now calling it metabolic conditions. We have a lot of exciting activity therein. This was historically a durable franchise-
Right
If you think about it. We had five products that we consider in that, four of which were first in disease, and these are products that we've seen 9% CAGR over the last three years, going up to $2.1 billion at
full year last year. This was things that are not coming from new launches. We have NAGLAZYME, launched in 2005, hit $500 million last year. We have VIMIZIM, launched in 2014, $800 million last year. We have a really durable franchise there. We had the addition of Amicus. We closed this past April.
Right.
Really exciting growth story that I know that we will likely get into, but we were able to talk a little bit more about the opportunity in our Q2 call. This is where we are talking about the potential. These are two commercial fast-growing products that we have real potential to expand on, growing to possibly $1.4 billion for GALAFOLD and Fabry, and $1.2 billion at peak, in the mid 2030s, late 2030s for POMBILITI and OPFOLDA in Pompe. Really exciting growth areas for us, not to mention what we have going in skeletal conditions, which I will touch on quickly. We did just recently announce, just to start it off, a settlement with Ascendis
Right
which I think helps to clear some of the competitive overhang.
which I'm sure we'll get into. This is also an exciting area for growth for us in terms of VOXZOGO. We had 14% revenue growth at the quarter, 20% patient growth Q2 year-over-year, but also growing sequentially, and just a really exciting time where we're seeing great growth coming out of the younger population for VOXZOGO, but also importantly, we're seeing global expansion of this brand. Very exciting times. Then we've added some things to our pipeline that I know you'll get into, Greg.
Okay.
I'll hand it over to you.
Yeah, no. Hot off the press is, of course, this morning we were able to show the world the totality of our hypochondroplasia data.
Really excited about that, again, the opportunity for really a first-in-disease therapy for VOXZOGO as an extension. The results exceeded our expectations, and again, not only on the efficacy side, but the safety came out quite nice, and again, that currently has been submitted to the FDA for review. Similarly, we're looking across our portfolio and really trying to restock our pipeline.
That involves both internal as well as external innovation sources. We most recently closed a deal with Alesta Therapeutics for an HPP oral therapy.
Happy to get into if we
Sure
have additional questions. Then, of course, looking forward to our next generation CNP product in BMN 333, which we will turn over a card looking for superiority versus VOXZOGO in achondroplasia next year. I will just wrap it up by saying along with the Amicus acquisition, we also acquired the U.S. rights to a molecule called DMX-200 that we call BMN 820. This is for FSGS, focal segmental glomerulosclerosis. Again, that is an ongoing phase III study that will read out in the 2028 timeframe. Our pipeline is looking different than it did even a year ago when I was sitting here, and we are looking forward to continuing to build it, both with internal as well as external innovation sources.
You guys have been very busy between Amicus and all those deals you have done. Let us just start with the base business first. For years, this base business was growing at mid-single digit to low single digit. What is the secret sauce for this 9% growth in last three years or so? Is this extra effort on sales? Because this market is very sensitive to sales and marketing effort and finding patients effort as well. Talk a little bit about that.
Yeah. So what we have really been focused on with regard to our metabolic conditions business is a platform, a commercialization platform, I would say, that we have built over the last couple of decades at BioMarin. What we focus most on is what we call the three pillars that we focus on. It is find patients where they are, start patients on therapy, and then work to make sure that they stay
Right
on therapy and adhere to therapy. A lot of what I would say the secret sauce has been is really in that find category. These are conditions for which there was no previous prior treatment, so it was not like you had people that knew to necessarily seek treatment. What we have done is we have put a lot of energy and resources into making sure that we are finding patients. This comes in the form of genetic screening. It comes in the form of family cascade screening, so once you identify a member in the family, how can we ensure that other members of that family get tested? We are now introducing new areas of using technology, AI technology, investing more in different forms of data
both structured and unstructured. In addition to just making sure that we are investing in digital campaigns to find patients, educate on these conditions, and then hopefully get them to a point where they can be treated. Lastly, I would say in terms of the starting, we have a country footprint that is 80 countries wide. These are not necessarily easy countries to find reimbursement and really navigate the reimbursement landscape they are in. So that is what we have also been focused on, is really understanding in each of these respective markets, how can we ensure that we have the right commercial medical, but importantly, market access capabilities so that we can get patients on therapy and keep them there.
Got it. Very helpful. That is a nice segue into, that is exactly what you talked about when you acquired Amicus, that you know. So you could use that infrastructure.
That is right.
for both GALAFOLD and Pompe. Amicus has done a tremendous job in selling that product by themselves as well. Help us understand which geographies they were not in and where you can actually add value to that franchise here.
Yeah. To your point, Mohit, I think Amicus did an incredible job at kicking us off in both Fabry as well as Pompe. What I would say is that we have gone by country by country
and understanding in our 80-country footprint where we think we could provide the most value. In some cases, for both Fabry and Pompe, this is going to be to accelerate in some of the countries they already were in.
When we acquired Amicus, GALAFOLD was already in 40 countries. Pomop was in 15 countries. We looked at this country by country and found that we very much think that we could successfully expand into 10 more countries for GALAFOLD and another 20+
countries for Pomop, just given where it is in its life cycle. Like I said, we wanted to make sure we understood the landscape there, what is the competitive dynamic in each of these countries, and how can we build on this? We have also found that even in countries where they were already marketed, we believe that there were areas that we could add additional resource to that could help us to accelerate in those specific countries. Again, we have done a country-by-country buildup, and that was what then informed those peak year revenue numbers that we provided.
Got it. Completely understand. That is the reason why you raised the guidance and-
That is right.
peak year revenue, everything. On that, the question is there is this recent shortage for Sanofi's drug related to manufacturing issues. Are you seeing any early signs of any switches to Pomop?
Yeah. What I can say at this point, and we will update as soon as we have more information and are able, we are definitely hearing about the shortages primarily in the EU. We have heard that from the community, physicians alike. What we are doing is we are working very closely with the community as well as the regulatory bodies to see where we might be able to provide product.
Got it.
Until we have more information.
Understood. I want to talk about VOXZOGO, and then we will get into BMN 333 with that segue a little bit. VOXZOGO has grown really well, and now you have settled with Ascendis as well. Can you talk a little bit about the thought process behind the settlement, first of all, and then the competitive overhang is still there. What dynamics switch versus non-switchers you have seen so far in the U.S., and do you think there is a bolus there that could stabilize over time? How should we think about that?
Yeah. With regard to the first part of the question,
Settlement
which was the Ascendis settlement, we just announced this very recently. This is something where we will get retroactive royalties
applied to any commercial sales, net sales for Ascendis, and that is 20% in the U.S. and 18% in the E.U., Brazil, and South Korea. We are really excited to do this because we think that it does help to clear the overhang, quite frankly. It also enabled us to actually capture value immediately because we were in the midst of our ITC litigation in the U.S. That does not actually provide rewards. They cannot rule on rewards.
Right.
We would have had to go through U.S. district courts and then litigations in multiple jurisdictions, in other countries. We felt like this was a very good
thing to just clear that overhang. Most importantly, it helps the community. We know that it is good for patients to have options, and if and where Ascendis is able to drive any additional growth in territories that we were not able to, we could also share in that value capture. Excited about that. But with regard to our commercial strategy and how it affects what we are doing on the day-to-day, it does not affect anything we are doing commercially.
Right.
We will still continue to grow
and to compete just the way that we have always been. Really where we see the biggest drivers for VOXZOGO are in what I talked about with the zero to two population. This is about getting patients as early as possible, treating them when we know that this provides the most benefit to their overall health. We will have exclusively, we believe we will have the label in those zero to two population exclusively for the next couple of years. An area that we certainly intend to drive growth. In addition to the broad swath of countries that we are continuing to commercialize in, we have built a network in 55 countries where we are commercially available. This is not necessarily easy to catch up to. This has taken time.
Right.
And we anticipate that it would take any competitor time to do that as well. With specific regard to your question about Ascendis and how we're doing with the competition, we were able to report in the quarter that we have retained 90% of our patients to date on therapy. We believe in large part these are families that have seen the benefits of VOXZOGO and have gotten used to the daily routine that they have, and we anticipate continuing to do what we can to keep these patients on therapy. It remains to be seen whether or not this is a bolus, if this is a steady state in terms of the competition, and we'll look to provide color in future calls.
Got it. Makes sense. But then, so the guidance you have given, you assume some amount of competition for the year.
Yeah. So, what you're referring to is the guidance that we updated on the quarter call. So we raised the midpoint for global VOXZOGO sales to be at $1 billion, at the midpoint. And really, this did take into consideration the switching rate that we were seeing. It takes into consideration the growth that we're seeing globally-
not only in the U.S., but also in addition to that, globally. And importantly, we had talked a little bit about, there were two major market access renegotiations that are underway. One has come through favorable to us, and the other is still underway. So all of this was taken into consideration as we looked at the updated guidance. And I do want to say, we did not update the guidance, nor do we think that there'll be a big impact in this year due to the settlement itself.
Got it. Completely makes sense. You did touch upon the international markets. They are the bigger portion of the business here. What are the puts and takes in those markets? Are they similar to U.S. market? Are they different versus U.S. market? There is a time element there. You have to negotiate country by country.
Yeah.
It takes time to get there. So how defendable do you think your position is in international markets versus U.S. market?
Yeah. Our global business outside of the U.S. is 75%, currently 75% of our revenue contribution on VOXZOGO. We believe that this is a defendable state, if you will. Like I had mentioned earlier, it certainly takes time to understand local market dynamics, how to expand in those dynamics, and really how to build those relationships. What we have seen is it really does depend on country. In some cases, you find more centralized single-payer countries, which you can really get out the gates quickly on. You can treat the broad population quickly, and we have seen that in some countries. In others, it is a little more of a build. So it does depend country by country, but what I would say is that I think that many of those countries are going to take longer for any competition to really entrench into.
Got it. Completely makes sense. From defense to offense, actually now. BMN 333-
that is the offense. Talk a little bit about. The dose selection was very interesting. In the PK study, you had the 5 mcg per kg dose actually produced significantly higher increase in free CNP level. I think almost 14x the
Yeah, 13.6.
0.6 or, yeah, something like that, right of the other longer-acting CNP. How do we think about the greater free CNP translating into AGV improvement here, and then the reason for selecting the 350 mg dose versus the 500 mg dose?
Yeah.
It is pretty typical in single-dose studies to test one dose higher.
Right
than you're going to go in your multi-dose study, and that has to do with the fact that it's a 100-hour half-life molecule.
Right.
There's some accumulation.
That's really the only reason that, again, there was a higher dose in
Okay
the single-dose study. The three doses that we picked, 150, 250, and 350 mcg per kg, all represent levels that met our criteria of what we were looking for. We were looking for a sustained 3X AUC exposure to free CNP, and that gives roughly three, five, and seven X. Interestingly as well, and this was in our poster from the phase I study, all of those also provide increases in plasma cyclic GMP levels.
Okay.
Again, that's systemic, but again, a nice biomarker that we're getting closer to the physiologic activity and showing that there is more biology to be had there. Beyond that, what we've looked at, of course, is the exposure response as well as the dose response data from the available therapy, from the Yuviwel data. Again, we're convinced that there is additional growth to be had there. There are a variety of ways to measure the sigmoid curves that are there, but again, there is a good belief that not only do we have a lot more free CNP that we're going to be able to deliver, but that we believe that there is no plateau that's been clearly established if you look at the mathematics behind those curves.
Got it. Completely makes sense. How much room there is for this mechanism to improve the AGV here? Because there is a natural barrier, right? These kids grow at what, 6+ cm per year? Normal, healthy kid, versus these kids are more like four, three and a half to four.
Yeah. Our investigators always kindly remind me that during growth spurts, teenagers can be 10, 12, even 14 cm a year. So physiologically, there's growth to be had. With the achondroplasia, and to a lesser extent, but still true with hypochondroplasia, part of the challenge also is fighting that growth deficit that they're either born with or because of the lack of the growth spurt is there. The question of whether there is a plateau and when it will be reached is an unanswered question.
What we think we have with BMN 333 is the right molecule to answer that question. Again, from an AUC standpoint, the cyclic GMP, and again, the behavior of the molecule, we think that the weekly administration of BMN 333 is going to be able to answer that question. So in phase II, we are measuring three different dose levels.
Right.
We have a control arm of VOXZOGO as well. Of course, we've got the world's largest supply of data for VOXZOGO also that we can use.
Right
When it comes to looking at the Bayesian model. Our goal there is to have that result, which we would have next year, and be able to again inform what a phase III study for superiority versus VOXZOGO would look like.
Is this a six-month trial or one-year trial? Is this a six-month trial?
Predicted AGV coming from at least six months of data.
Right
for all patients on the study. We are going to use the totality of data.
Right
once we have completed, but it will be at least six months on every individual patient, and we will be projecting towards what the AGV, so the one-year data would be.
Got it. Completely makes sense. Can you help us set expectations around that? Like what exactly you want to see.
Yeah
to claim this could look like a superior drug because there will be investment going in for that. Just maybe on the side note.
Well, the most direct answer I can give you is to talk about the design for the phase III study.
With 60 in each arm, there is a 90% power to detect a 50% improvement. That would be just doing the math out from about 1.5 delta of AGV-
Yeah
up to about 2.25 cm.
Right.
Now, that is not the minimum detectable difference, but that again is the powering of the study.
Right.
And certainly, we believe that that would be a meaningful increase.
Right.
We talk a lot about AGV, but we have learned a tremendous amount from VOXZOGO on all the measures of health and wellness that actually track along with AGV.
Part of our goal with BMN 333 is going to be to leverage that data, not only to measure in the study during the randomized portions, but also put together the evidence package that more linear growth will translate into more measures of health and wellness as well. More to come there, but again, that is the ultimate goal here. Not just children that are taller, but children that are healthier and straighter.
Got it. Just scenarios here. In case it is less robust than what you are thinking-
Yeah
in phase II, what are the aspects of phase III design that could still be altered to improve the probability of success?
Well, I think if we look at the six-month minimum cumulative data and the results are not as clear to us, we could always run the study out to 12 months
Right
and look at the data as well. We are not planning for that.
Right.
Again, we are planning for a weekly administration for a superiority endpoint. Of course, if that hypothesis did not play true, we could evaluate other opportunities, but that is not what we are planned for.
Got it. There is also data for growth hormones plus
Yeah
plus CNP. If you talk to 10 doctors, you get 10 different responses on that, by the way.
Yeah.
Some believe in something that
Yeah
it does help, some things it does not help.
Yeah.
Now, let's just say if the benefit lasts for two years, which is a big if at this point, would you think differently about BMN 333? Would you change anything about the clinical trial design here?
Yeah. A couple of thoughts off the top of my head. Growth hormone is not approved for achondroplasia-
Right
in almost every jurisdiction around the world for a reason.
Right.
That is that it can uncork a year or two of growth, but that has not historically resulted in an improvement in final adult height.
Right.
That has the specter of whether or not, again, the growth plates are closing earlier.
Right.
Uncorking more growth at the expense of the amount of time that the growth plates remain open. That is an unanswered question. I think that with regard to the data that's out there, combining with CNP, the jury's still out. It's too premature. Again, we're seeing salami slices of every six months, whether it's increasing or decreasing, we can argue that.
Right.
What we believe BMN 333 offers is it would offer the world one drug
that would offer the superior growth. We think that that will be valued. Even if growth hormone is there, combining with the best CNP product is what we believe the world is going to value most. We think there's a place for BMN 333, and again, sticking with the plan at this point, it's premature to think about adding growth hormone into that paradigm.
Got it. Completely makes sense. Rounding out this topic, how are you thinking about the oral that is coming to the market in this space? How do you think about that as a competitor?
You want to start?
From a science standpoint, again, I think the one-year data, again, which was published, speaks for itself. That is a very different scenario, though, than looking at 10 years of safety data.
Yeah.
Again, we put in our full approval package, not only for what we call final adult height, but again, all of those measures of health and wellness over time. It is a bit premature to compare one to the other. I do think that with the small molecule tyrosine kinase inhibitors, we are always interested in seeing the long-term safety profile as well. This was a drug that, again, had a life before it was given at these doses.
Yeah.
It's got a label, it's got an animal tox package, it's got warnings and precautions. Those are things that, again, I would want to see additional follow-up data before we would try to compare them head to head. That being said, again, it's good for patients. The fact that there is multiple therapies out there, this is something that we're prepared for. Again, what we have with CNP is an undeniable safety and efficacy profile that patients can depend on.
The only thing I'd add to that, just looking at the marketplace, I think to your point, one of the things that we see as most valuable to these families is the safety profile, especially because you're treating young kids. So that'll obviously be something that everybody's looking to. I also think that if we even look at the entry so far of another competitor, I think it does show that this is not necessarily an easy marketplace, if you will, thinking about the U.S., just to come into overnight. Certainly these are patients that are not seen very often. They're dispersed among specialties, and you still have some reticence to treat in some cases. So I think that this also will be an evolving landscape.
That it will be interesting if more entrants come into it.
Got it.
See what happens over time.
If I could just add one other comment, which is we're talking about achondroplasia.
I think when we think about hypochondroplasia, we're very proud of the data
Right.
published online this morning in NEJM Evidence.
Right.
This may be a different biology that we're dealing with. The mutation in FGFR3 that causes achondroplasia is, for the most part, it's a single mutation.
Right.
There's a large basket of mutations that are involved in hypochondroplasia. Pre-clinical data, it's published, have suggested that the IC50s for those mutations might be variable for a small molecule inhibitor. Our published data for hypochondroplasia showed that across the different mutations, we have the same effective range. The CNP story in hypochondroplasia might be slightly different than it is in achondroplasia.
Got it. Very helpful. Sorry, I did not get a chance to look at the NEJM paper this morning.
No worries.
And there's a-
I'm really excited about it.
I was stuck here.
Thanks for letting me get a plug in.
Thank you very much. Appreciate it. A bunch of other pipeline questions as well here. BMN 351, the DMD asset.
Yep.
I think we'll see data for the higher dose, 12 mg per kg dose later this year. Talk a little bit about what do you need to see to move forward.
Yeah
How should we think about the
The name of the game in Duchenne muscular dystrophy now is the benefit-risk profile.
Right.
At the end of the year, we are going to have additional data from a higher dose level. That is the 12 mg per kg. Most importantly, when you think about benefit risk, yes, it is benefit with regard to dystrophin levels, but the field is also interested in, I think, the pull through to the more functional measurements. That is normalization of CK. That is looking at mobility measures, whether that is with Stride Velocity 95th Centile, whether it is with the North Star Ambulatory Assessment, all of those go into the totality of the package, and we will have additional follow-up on those endpoints, both from the nine as well as we will have the 12 mg per kg. Of course, on the safety side, we are going to see, again, that chronic safety profile and weigh that.
Ultimately, it will be the benefit risk profile that will allow us to make a decision about whether or not, again, moving forward with BMN 351 makes sense.
Got it. Very helpful. The last couple of questions on the pipeline side. HPP asset, right?
Yeah.
Obviously there is STRENSIQ out there.
The question here is that this is an oral, so how do you think about the differentiation? Is it because it's an oral, it can go early in the disease spectrum or do you think it could replace the injection here?
Yeah. Our goal is not to develop a molecule that's a more convenient version of what's already available.
Right.
The oral therapy actually targets upstream.
This is a disease where pyrophosphate increases, and that's a direct inhibitor of bone mineralization.
Right.
By inhibiting the upstream enzyme, the goal here is to have almost a substrate reduction therapy, similar to say, Gaucher disease, where
Right
enzyme replacement and upstream have been successful. Our goal is to have this upstream decrease, again, that will afford the ability to provide an oral therapy, but more importantly, as a small molecule, it also allows us to administer a drug that could potentially reach compartments that a bone-targeting biologic would not be able to address as robustly. That being areas like the muscle, where when you think about patients with HPP, particularly the older patients, the older phenotypes, it tends to be muscle pain, fatigue, more of these malaise-type symptoms that become of interest. Great work has been done, again, by the alkaline phosphatase replacement therapies. We would hope to build upon that both for children as well as adolescents and adults. Anything else that you want to
Just to add that, and it is a commercially validated market,
if you will, given how STRENSIQ has done since launch, and I think that this is an area that we know we believe there is about 9,000 patients alone that are estimated in the U.S., and only 10%-30% of them are currently on treatment. We think that there is a real opportunity to bring something different to market that could be commercially successful as well.
The phase I data that is currently still enrolling, both in healthy volunteers as well as patients, we will plan to share that next year.
Got it.
That will be a moment where, again, we can reveal some of the data that we have seen already.
Got it. Very helpful. Speaking of data reveal, obviously, phase III for FSGS is fully enrolled now.
Yep.
I think readout is in 2028, but can you talk a little bit about your thoughts around this particular asset? It doesn't get talked about a lot.
Yeah.
You got it via Amicus. I mean, FSGS, we cover Travere, they are selling quite nicely in that market.
Yeah.
How do you see your asset there? Does it need to be differentiated? It's a different mechanism, can you talk a little bit about your thought process there?
What we're calling BMN 820-
formerly known as DMX-200.
Yeah.
Again, being developed by a company called Dimerix.
Yep.
We are partnered with them and have the U.S. rights for the molecule. This is being studied as a CCR2 inhibitor.
Yeah.
Again, it works slightly differently than prior generations of CCR2 inhibitors. This blocks the dimerization with the angiotensin pathway, and so in that regard, gives an opportunity to target the disease at a very different place than the pure vascular targeting agents.
Right.
Unlike say, sparsentan, this is a study that's a slightly different design. It takes patients on angiotensin receptor blocking therapies, and it layers on
Right
either BMN 820 or placebo.
Right.
Some great work that's been done in the field, both by investigators as well as some of the other products, really to move the FDA's position.
Right.
Now 2-year reduction in proteinuria is a legitimate, validated endpoint for full approval.
Right.
That's what this study is built to measure. It's a study that's fully enrolled, as you mentioned. It's of course made its way through a futility analysis at this point. We believe that the study's appropriately powered. The promise of the molecule is that this different pathway targeting macrophage-driven inflammation will offer not only a different mechanism of action, but a potentially differentiated one. We're looking for meaningful reductions in proteinuria. Of course, we'll measure eGFR as well.
Right.
Again, the promise is that there wouldn't be the liabilities of, for example, a black box warning or again, limitations based on nephrotic syndrome.
Right.
Again, the hope would be that this would have a broader targeted group of patients, and we're looking forward to, again, seeing that data in 2028.
Got it. Very helpful. One last question for both of you. Fast-forward one year, Wells Fargo 2027 Healthcare Conference. I hope you both are here. I hope I'm here.
Yeah.
What would make you look back at the year and say, "It was a great year for us"?
You want to start?
I'll start. We are in the midst of a restocking of our pipeline.
We're going to continue that process.
Okay.
So that will mean additional organic as well as inorganic growth opportunities, whether it is clinical stage or preclinical. Again, we have the ALE1 molecule we have talked about. Did a smaller deal with a company called n-Lorem recently. We want to keep going both from a BD standpoint as well as our organic development, and I am hoping that a year from now we will have more to talk about on the pipeline side.
I think on my end, really focused on execution and making sure that we do not miss a beat. When I think about the skeletal condition side, I want to be talking about an incredibly successful launch in hypochondroplasia.
Right.
That will be just an amazing thing to do, and then talk about what the global expansion plans for that are. For metabolic conditions, I want to see continued strong growth and the continued real growth trajectory for the Amicus product, showing that we can not only integrate a company, but also grow it at the same time. We will have a lot of exciting things to talk about, I think.
On that high note, thank you very much for joining us today, and all the best. Thank you so much.
Thanks for having us, Mohit.