Okay, good morning, everybody. For those on the webcast, good morning, afternoon, or evening, depending on where you are. It's a great pleasure to be here. As you might remember, we did our last RDD a couple of years ago, and it was webcast because we were still in the tails of COVID, I guess. But now we can all get together in person. So, basically, we are... When we last met, we were in the middle of, you know, putting our strategy together for the long-term performance of the company. But now, I would say, BioMarin into- is turning into a financial growth story.
Whereby we have the luxury of being able to grow the profitability of the company, as we've had in the past few quarters, while continuing to invest in research and development to ensure a successful future of BioMarin beyond, you know, the end of the decade here, after, you know, Voxzogo and Roctavian, we start turning into more mature products. So it's a great pleasure to be here again. I think we've been successful in the past by staying true to our core four principles of research and development, selection of new molecular entities, and Hank, in a few minutes, will go over that. So again, if you look at BioMarin, we have a very strong history of successful innovation.
We have a very solid base business, which allowed us to build this company over the past 20 years, which is mainly ultra orphan, ultra orphan drugs in the enzyme replacement therapy field. And this business is still growing slowly but surely after, you know, 20 years. Aldurazyme is over 20 years old, Naglazyme is over 18 years, was launched over 18 years ago. These products are still growing, which is much better than the industry average. As you know, most biopharma products peak after nine years after launch.
Our products keep going after 18, 20 years, and it has to do with the fact that the manufacturing of this product is extremely expensive and complex, and it would be actually very difficult to come up with a biosimilar of this product, although not impossible, but I think we are protected for quite a while. And also, since we know all the patients around the world, we will see any potential competitors coming from very far away. So now we, you know, with the launch of Voxzogo and the launch of Roctavian, we're getting into a potentially new phase of expansion, and we are going to be able, after building this commercial infrastructure around the world for the past decade or so, I think we are gonna have some major financial leverage here launching these two products.
We kind of saw that already in Q1 and Q2 of this year, but that will continue, whereby, you know, $1 of additional revenue is gonna have a very positive impact on our bottom line. But, so again, we have the luxury again to be able to grow the top line, grow the bottom line, while continuing to invest in the R&D pipeline. We, as you will see today, have the strongest and deepest R&D pipeline that we ever had in the history of the company, thanks to the fact that we have resources to build up, to develop many products in parallel, which wasn't quite the case in the past, but we are in a...
So we, as Hank will say, we are, I think we have lined up, potentially filing nine INDs between now and the end of 2026. We've never been in a position like this in the past. I think also I want to highlight again, that we have a proven R&D strategy. Just want to emphasize, and I've said that before, or Hank said that before, but actually of all the eight approved products that we have, all these products, we, you know, developed them, selected them, developed them ourselves and all of them. So all the products that BioMarin put in phase 3 or in pivotal clinical trials ended up being approved. So I could say, "Well, how about Drisapersen ?" Yes, Drisapersen wasn't approved, but that's not a product we developed.
That was actually our mistake to acquire a product that we did not develop. But of all the products that we developed at BioMarin, for which we implemented the phase 3 trial, we got, you know, basically all of them approved. And not only that, we have created new markets. So if you look at all the products we've launched so far, except Roctavian, we have created a market. We created the MPS VI market, the MPS I, the MPS IV, the CLN2 market, the market. And now we have a lot of biotech companies copying what we've been doing, which is, I guess, you know, a good complement to the quality of BioMarin R&D's engine.
So, Roctavian now is getting into a space where there are alternative therapies, but we are, we are the first, and only at this time, gene therapy product for severe hemophilia. And with this, let me introduce, Hank Fuchs, our Head of Research and Development, who's going to, you know, talk about the core four and, all the plans we have, to prepare our, our pipeline into shareholder value creation. Thank you.
Thank you. Thank you. Good morning, everybody. It's great to see everybody in person, happy and healthy and well. I have a couple of housekeeping notes, first, to pass on. One is, Tracy just locked the door, so you're here for four hours. Oh, wait a minute. No, I was supposed to say that we're gonna go straight through, so if you have to get up and do what you gotta do, then do what you gotta do. We won't be offended. Those of you on the webcast can do whatever you want. The other thing that Tracy mentioned was there's no food after breakfast, so I think there are gonna be snacks at 10, not that we wanna advertise that, because the room will empty. No breaks, no food.
Oh, and, the other thing is that we're gonna have panel discussions, after which we'll have product-focused panel Q&A from the audience. And then, at the end of the whole thing, we'll have a Q&A for the executive management team. So those were my housekeeping notes. Did I miss anything? Nope. All good. Okay. So the agenda for today, just to go beyond housekeeping, just gonna, I'm gonna say a few words about the R&D engine, where we've been and where we're going. And then we're gonna have Tara Robinson from our clinical group talk about some updates on Roctavian. She'll give you a quick, fast overview of what's new.
And then we're gonna have this, a phenomenal panel discussion featuring, Johnny Mahlangu, who is, if not our highest enroller, our highest, you know, one of our highest enrollers. A tremendous amount of clinical and research experience in hemophilia. Guy Young, a professor at USC, who is really on the front lines right now of bringing Roctavian to patients. And then, great pleasure to welcome Amit Nathwani, the inventor of not just Roctavian, but also Hemgenix, and a real pioneer in the field. It's really a genuine privilege. Next, Elena Fishleva from our group is gonna give you some fast and furious updates on Voxzogo, and then we're gonna have a great Voxzogo panel discussion, which my colleague, Jonathan Day, is going to moderate, featuring Andrew Dauber, who...
Well, actually, let me start with Melita Irving, who is really a pioneer for us. This is Melita's second trip with us to R&D Day. She joined us when we were first talking about Voxzogo, so it's great to have almost a decade later, somebody with so much experience treating patients with Voxzogo. And Andrew has been really the guy with the flashlight, finding the way forward. And Andrew will participate in the panel discussion. And we welcome now, newly, Dr. Brad Miller from the University of Minnesota, who is a stature disorder expert, really been thinking hard about where there are limitations of current therapy and opportunities for future therapy. And then we'll again have a panel Q&A discussion.
And then, Dave Jacoby and Kevin Eggan, respectively, Head of Early Development and our Chief Scientific Officer, they're gonna tell us about stuff that's in the clinic, near to the clinic, and then the longer picture about things coming. And then, we're gonna end the R&D portion of the session, talking about the keys to the future. And I think that Kevin's gonna do a great job orienting you to why we are so committed to being a genetics-based company. And then, Brian is gonna wrap us up with a sort of a business perspective on doing the very difficult two things at once, both gaining further top line and bottom line growth, and at the same time, funding a robust pipeline of future, doing more than one thing at a time.
And then we'll have our Q&A. So the core principles of, of BioMarin, I just want to recapitulate, and hopefully, this is now very familiar to you all. The concept is to leverage genetic discoveries-leveraging genetic discoveries and tools, we develop a clear understanding of pathophysiology that underlies disease mechanisms. And with that, those insights about how diseases get caused from a genetic perspective, we can develop therapies that are targeted very specifically. It's almost like we're inserting a very specific key into the lock of a genetic abnormality. And we do it in a context in which the disease is so significant, and there are either clinical endpoints or biomarkers that can tell us relatively quickly in early development as to whether we're on the right track, towards developing a transformative medicine.
This pattern has been true for everything that we've done from the beginning, and will continue to be true to enable efficiency and effectiveness. Now, those of you that have been with us for a very long time recognize BioMarin's foundation. JJ's mentioned the enzyme business, and that created an incredibly solid foundation, this core four that I just spoke about, which really fundamentally enables very efficient development. And also gave us an opportunity to teach ourselves about complex biologic production. Let me welcome Greg Guyer, who's our Chief Technical Officer, to the group. And it, on some level, is the secret sauce of BioMarin, the ability to make these very complex biomolecules.
And that's why JJ was referencing the durable therapeutic opportunities that help things like Aldurazyme and Naglazyme represent because they're very hard to copy. And Greg's team has done a phenomenal job of making very difficult biomolecules, and that's produced this durable revenue stream. Where we are today, we've honed and scaled. We have these leverageable base indications, but now new gigantic expansion opportunities that we're gonna talk about in a little bit more detail. And then we see genetics now enabling a more than just perpetual influx of candidates, enabling us to be more than just enzyme replacement therapy. And we're making investments in antisense oligos and gene therapy platforms to increase our ability to target genetic mutations. And, you know, what's next?
What's the road ahead for us is continuing to amplify the value of the organization, amplify the contribution we can make to the lives of patients, by taking advantage of the leverage from the genomics revolution, to create an even larger clinical portfolio. As we enter a very challenging era in delivery of medicines, to develop the evidence packages to enable full access and adoption of our products for patients. Let me also introduce Marcia Kay off at the back of our room. Marcia is our Head of Medical Affairs, and a big champion of evidence to support access and adoption. It's a really key element that supports Jeff Ajer's team. Jeff is our Chief Commercial Officer in the front row.
And, you know, it's our dream to be able to make these medicines available to patients around the world. As JJ mentioned, in black are the coming INDs, and we haven't named what's in 2025, but you're gonna hear from Kevin today about some new opportunities that could represent INDs in 2024. It's great that the screen breaks up the timelines, so that it creates a little bit of vagueness about when we're gonna be doing things. I think a lot of the things you've heard a little bit about, and we're gonna dive, Dave, in particular, and then Kevin, we're gonna dive into a little bit deeper about the coming IND flow. In orange are proof of concept opportunities. I was mentioning sort of the core four.
Proof of concept for us is think about it as core 3. That is the first evidence generated in humans around addressable biomarkers that represent, reasonable, likely outcomes that predict transformative benefits, maybe even some early, registration opportunities, but certainly key inflection points for efficient and effective drug development. And if we don't have the biology of it just so right or the molecule just so right, then we can take that out of clinical development and invest elsewhere. And then, on the bottom are the new indication opportunities you're gonna hear a little bit more about today, to sort of represent not just the sort of the new things that are coming, but also new applications of Roctavian, Voxzogo and Palynziq.
And we're gonna go through, in some detail, plans for accessing additional patients for Roctavian, and then bringing Voxzogo, you know, farther forward and further forward in terms of enabling patients with severe statural impairments to experience a more full life. So, you know, sort of in wrap up, what I hope you take away from today, the five things would be: one, is Roctavian and Voxzogo's base indications fuel and feed near-term revenue growth, which in turn fuels further pipeline expansion, and leverages data to bring more of these medicines to patients around the world. Then you're gonna hear about next-wave candidates that are genetically enabled, targeted, readily accessible, and potentially transformative when they work.
Three, you're gonna hear about genomic insights and tools that sustain an influx of high-probability therapeutic candidates and further amplifying each opportunity by increasing expansion opportunities in their eligible populations. Kevin's got some great data about that, that you'll find interesting. As I mentioned, we're increasing the investment in robust data collection for generation of evidence that bridges between what health authority needs on the one hand, what payers need on the other hand, and what's gonna really drive access and adoption of these therapies, because they can transform people's lives, and we have the responsibility to bring the evidence forward that drives that. And then, lastly, the large volume of highly differentiated opportunities enables us to track towards, at this point, we're inflecting to 2 INDs per year, really represents a transformative moment for the company, doing more than one thing at a time.
Those are the five takeaways for the day. With that, it is a great pleasure to introduce Tara Robinson, who's been leading our Roctavian program. Tara?
Thank you, Hank. Good morning, everyone. I'm Tara Robinson. I'm a hematologist by training, and I'm very proud to lead the clinical development of the Roctavian program. Hank, how do you get the next slide?
The button on the other.
The-
No, no, it's that green button.
Wonderful. Thank you. So we're, of course, at a very exciting time for Roctavian. We are now approved in 2 major markets, and global commercialization is underway. You've probably heard that we've dosed our first commercial patient, and we have many more patients who are interested in stepping forward for therapy. In addition to the EU and the U.S., we have already filed marketing authorization applications in Taiwan, Brazil, and Mexico, and we will file in Australia by the end of the year. In addition, we have submitted a CTN to Japan just last month in August, and we're looking forward to getting a trial underway there soon. So in this brief update, I'm going to first start off with some new data from our phase 2 study.
We now have data out through the entire 7-year trial program for the 60-13 cohort, as shown on the left, and the 40-13 cohort has all completed 6 years, as shown on the right. This is a graph of chromogenic Factor VIII activity. As highlighted in the light blue towards the end of the graph, you can see that the Factor VIII activity for 60-13 is quite stable from last year's data, with the mean and median being 16.2 and 10.3 IUs per deciliter, respectively. Again, the same story on the right for the 40-13, that the most recent data cut looks very stable from the last. But more than what you can tell from this graph is the impact that it's had on patients' lives.
Even 7 years out, we continue to hear stories from their treating physicians about the impact of Roctavian and the ability for these patients to really lead a much more free life. And as of today, 11 out of 13 participants remain free from prophylaxis with good ABRs. So that's a little bit about our current trials, and I'd like to focus the rest of the talk on more forward-looking opportunities to expand the indication of Roctavian to new populations. We'll be talking a little bit about each of these activities we have here, and I'll go into more detail in subsequent slides. So the first is our efforts to dose patients with active or prior inhibitors. This is our Generate INH 205 trial.
So, it's important to start off with recollecting that approximately 25% of patients with hemophilia A will have a positive inhibitor test at some point in their life. So this is a really significant proportion of the population that has been locked out of gene therapy so far, and we aim to change that.... To show you some proof of principle, there's a graph on the left-hand side of the slide of some dog data. These are dogs with severe hemophilia A and active inhibitors, and they were given AAV-directed gene therapy at time zero. And you can see, following in the red line, that as we presumably start to see transgene expressed, although we cannot measure it at that time, we see an increase in the inhibitor as depicted by the red line, which eventually goes down and goes all the way to ground, indicating tolerance.
And then, as the inhibitor goes down, we can start to now measure the Factor VIII activity, as depicted in the blue line, and the antigen in the green line. And at the end of the graph, you can see that these animals were challenged with exogenous Factor VIII, and there was no reemergence of the inhibitor, really demonstrating the tolerance that can be achieved with AAV gene therapy. So where we are at in our clinical development program is we have two parts to our trial, Part A with active inhibitors and Part B with prior inhibitors. We have dosed two participants in each of these cohorts, and right now, what we have to share is just a high-level statement that we have not seen any safety signals, including no reemergence of inhibitors in Part B.
They are thus far acting just as we expect, no different from the pivotal trial population. We also see encouraging efficacy data, which is consistent with our expectations, and we look forward to sharing this at an upcoming congress. Next, we'll switch gears to Japan. As you can see on the left, the opportunity to treat a large proportion of patients exists in Japan. They have over 5,000 patients diagnosed with hemophilia, and about half of them have severe hemophilia. In discussion with the PMDA, we are going to be performing a bridging study to demonstrate the safety and efficacy in Japanese populations, and we do not expect to see any differences between them and the pivotal trial. We're at these efforts are, that we have met all requirements for initiating studies in Japan.
We have submitted the CTN to the PMDA in August 2023. And this is after a really successful engagement with the PMDA on study design to ensure that our clinical trial will meet all of the needs for review of the application. We have started feasibility, and we've had lots of interest from sites as well as patients. So the little timeline at the bottom, some important things to point out are that we anticipate dosing the first patient in the early part of next year, and altogether, this should lead to a filing in 2025. The next thing I'd like to review is our efforts to treat adolescent patients. And this is something that we're really excited about.
Of course, the adolescent population is quite a large opportunity, and I think there's also the opportunity to do a lot of good in these patients before they develop the chronic joint damage that can be disabling and lead to a lot of problems in adulthood. We also think that, in some ways, this population may be more straightforward than treating adults since they don't have as much of the chronic hepatitis that we see in adults who lived through the bad blood era, and they have very healthy livers. So we anticipate that this should be a pretty straightforward effort. We plan to take a stepwise approach to dosing younger patients, and the first cohort that we will start working with is 15-17 years old.
It's important to note that the liver size in these patients is generally of adult size, although they, you know, may not be completely done growing as a whole. On the right-hand side, I have some preclinical data to demonstrate the efficacy that we believe we can see in adult patients. The graph on the right is from preclinical data in the mouse model using a Factor VIII gene therapy. The mice were dosed at these various equivalent human ages, as indicated on the X-axis, and then taken down in adulthood. You can see that between 2 months and 15 years of human equivalent age, we see nice amounts of total Factor VIII RNA in the liver, demonstrating that we should see good efficacy in these groups, and particularly in the 15-17-year-olds.
Where we are at with these efforts is that we do have a pediatric investigational plan agreed upon with the EMA, and we are currently working on setting up an interaction with the FDA to align on a global program. We anticipate enrollment of these 15- to 17-year-olds after a six-month run-in, which will start in 2024. Switching gears now, we'll show you some new data from our efforts to treat patients with pre-existing AAV5 antibodies. This is in reference to the 203 trial. Patients with pre-existing AAV5 antibodies have been excluded from Roctavian registrational trials, and are also ineligible for per the indicated labels. But yet this is a very large and important segment of the population.
Across the globe, we have data to demonstrate that 30%-50% of patients with hemophilia A have these AAV5 antibodies. And so in our 203 trial, we have some data shown on the graph on the right. We dosed 3 participants with pre-existing AAV5 antibodies, and you can see their Factor VIII activity results in the blue lines. Please note that there are actually 2 participants represented along the X-axis, so it really only had good measurable efficacy in 1. And for reference, we're showing you the median Factor VIII activity from the 301 trial in the purple line. So overall, what we saw from 203 was that those patients did not show meaningful Factor VIII activity levels and really confirmed that anti-AAV5 antibodies are a barrier to treatment.
So we have been working in preclinical models on two different strategies to overcome this, and what we have here to show you are results from our preclinical models to demonstrate the viability of both of these strategies. In the middle, we have some data from an NHP model using Factor IX transgene as a surrogate marker. And these NHPs had pre-existing AAV5 immunity, and they were treated with the indicated number of plasmapheresis cycles as indicated in the first row of the table at the bottom. And you can see that after plasmapheresis, the animals with pre-existing antibodies did have measurable Factor IX DNA in the liver. And for comparison, you can see the blue animal, which had no pre-existing antibodies. So demonstrating that the more that we can get down the antibodies, we can start to see some successful transduction.
On the right-hand side, we have data from a rabbit model, and this again uses the Factor IX transgene. These rabbits with pre-existing AAV5 immunity were treated with an antibody-cleaving enzyme to cleave that pre-existing immunity. Again, when we get the antibodies down, we can start to see successful transduction as measured by Factor IX in the liver. The control animals in this graph on the right are represented by the, I guess, brownish triangles. So you can see that we can start to achieve that level of efficacy. So we believe that both of these strategies can represent potential ways to treat this large segment of the population, and we are currently working on developing plans to take this into the clinic.
Next, we have more new data to show you from the 303 trial. This was a single-arm study, which utilized prophylactic corticosteroids starting on day one and going through week 19 of the study. Participants could also receive additional reactive corticosteroids as needed if they had ALT elevations. At this time, we've had our first data cut, which includes at least one year of follow-up for all 22 participants, and the Factor VIII activity levels seen at that data cut were about one-third of those observed in the pivotal 301 study. In addition, prophylactic corticosteroids did not completely prevent or mitigate ALT elevations.
So we are very much looking forward to presenting these data in full at a conference early next year, and we have already begun preparation of a manuscript to get these data to the community. But the take home here is that these study results do not support a modification of the reactive corticosteroid approach in the approved labels in the EU and the US. And you will hear later on this morning from my colleague, Dr. Dave Jacoby, about how learnings from the Roctavian program are being applied to other gene therapy programs earlier in the pipeline. And the final thing that I have to share today is an update on our efforts to modulate transgene expression post Roctavian dosing.
So in January, we shared data at the J.P. Morgan conference on use of histone deacetylase inhibitors, and we have an update on that. While most patients have durable Factor VIII expression, we do see a small percentage lose expression over time, and some return to standard of care therapies. HDAC inhibitors may increase the expression of transgene by converting DNA from inactive to active forms. The new data that we have, as depicted at the bottom of the graph, is in vivo data from a mouse model. Last time, we had showed you in vitro data, and now we've moved on to mouse models.
We can see here, in a dose titration experiment, that approximately 10% of the clinical dose of the HDAC inhibitor, as used in lymphoma treatment as represented by the first blue box, can it lead to an increase of about, 30% of transgene expression after just a single dose. So to continue with these efforts, we continue to have ongoing preclinical studies to better understand the magnitude, variability, and duration of the factor VIII increase, and we are also planning for health authority interactions about how to design a clinical study to demonstrate proof of concept. So to summarize, there are a lot of ongoing activities, that we're doing to unlock the full potential of Roctavian.
We have phase 2 study data now that demonstrate a durable response in Factor VIII activity and hemostatic efficacy now out to 7 years, and we continue to hear from patients and physicians that there's a lot of interest in Roctavian in the community. In the near term, we have value that can be unlocked in Japan, in adolescents, as well as patients with prior inhibitors. And we continue to work on unlocking additional value in patients with AAV5 antibodies using various pretreatment strategies, as I've shown you, as well as active inhibitors. And we're continuing our important work on understanding how to modulate transgene expression with HDAC inhibitors. And with that, I thank you for your attention, and I will invite Dr. Hank Fuchs back to the stage to moderate our panel with Professor Johnny Mahlangu, Dr. Guy Young, and Professor Amit Nathwani.
Thanks, Sarah. And let me welcome, my colleagues to the stage. A little bit of a dance here to enable that. So the structure, again, Professor Mahlangu, has a huge amount of clinical experience treating patients with Roctavian gene therapy, but also, Johnny, you've been, a key author in, some of the development programs for, other therapies, transformative therapies in hemophilia, and know quite a bit about it. Dr. Guy Young is, at USC Children's, in L.A., and is really on the forefront in a big metropolitan area. Now having live discussions with patients in the United States about the potential. And then, as I mentioned earlier, Amit is... has been the, the guiding light for the program from the beginning, as the, the key inventor.
Let me start with you, Johnny, and maybe you can share a little bit of the experience that you've had in treating patients with Roctavian. What are the sorts of things you hear from the patients?
Well, thanks, Hank, and, thanks, everyone, for inviting us to this very important update. It has been a game changer in our patient population in many ways. And perhaps I could classify the kind of impacts that one is talking about into two. We're talking about the personal benefits of the patients out of the program, but more importantly, we're also talking about the potential benefits to the systems. I work in a system where, you know, resources may well not be optimal in the care of the patients. Now, from the patient perspective, I think, there are a number of notable changes that one has seen.
Perhaps the most important one and the one that patients keep on repeating every time we interface with them is the fact that they've reached a stage where they are beginning to have a hemophilia-free mindset. You know, having lived with a genetic condition all their lives, one would expect that, in fact, it would be difficult to get into a different mode of thinking. Most patients, in fact, have sort of forgotten about their hemophilia, and to me, that is probably the most revealing. The other aspects, of course, is the patients don't need to, you know, start to worry about their condition as they carry out their daily activities. Some of the motivations include, amongst others, patient actually wanted to get off prophylaxis.
As you know, with the current therapeutic modalities, the therapeutic requirement is that they inject themselves two to three times a week, and it has been an absolute pleasure for them to actually having to come off the prophylaxis. A number of our patients, in fact, had some surgeries scheduled that we canceled because, you know, with obviously the elevation of their factor level, it is quite clear that the indications for surgery had changed. And the second component is, you know, the benefit to the systems. Many systems take a little bit of strain when looking after chronic conditions, including hemophilia.
There's no doubt that, in fact, the fact that these patients do not come that often into the system, it allows the system to be able to care better for other patients with similar conditions. I'm going to stop there and perhaps allow my colleagues-
Yep.
To comment further.
Yeah. Well, let me switch over then to Guy. So Guy, you're at the forefront, and tell us about some of the conversations that you're having with patients.
Yeah. So, I've already had quite a few conversations with our adult patients, and I would say that, you know, there really is a lot of excitement from those patients. I mean, they're very interested in this type of treatment. And in fact, you know, once I explained it to them in some detail, some of them knew more about it than others based on patient meetings they went to. But I think to highlight what Johnny said is the sense of being able to live their life without being worried about hemophilia.
And I kind of use the term, you know, the baggage of hemophilia that they have to carry, which sometimes literally is baggage, full of boxes of factor and infusion kits or even Hemlibra that, you know, if you're going somewhere, you have to take a cooler 'cause Hemlibra is required to be refrigerated. So, so there's the sort of literal baggage that they carry with them, if you will, around their lives. But there's also, of course, the figurative baggage of: I have hemophilia, you know, can I play basketball today? When did I dose my factor? Is it safe for me to go? They're constantly making these types of calculations. And so for some of these patients, you know, not to have to worry about that at all, is something that they're really that they would really like.
And there is no treatment for hemophilia A other than Roctavian that offers that potential opportunity. So I think that's a big part of this. And, you know, a single dose that can offer factor levels where you don't have to do prophylaxis, where you're not bleeding is. You know, I mean, honestly, it is a transformative treatment that can completely change somebody's life, and obviously, therefore, patients are really excited about it. So, I mean, I have patients who—I mean, they're literally emailing me, asking me, you know, when can they get it? When can they get it? And, you know, we're working through the logistics of being able to infuse them and, you know, and hopefully, that'll happen, you know, soon in the coming months.
As you know, there's a fair bit of logistics, which I won't get into at this moment, but it's not a matter of, you know, if I'm gonna dose these patients, it's just really when am I gonna dose the patients.
Guy, you did a very nice job last week, speaking with one of our colleagues about sort of the business pieces of this. So we're gonna keep our focus today on sort of the medicine aspects of hemophilia. What would you say are some of the early keys that you're focused on in terms of from a medical perspective for your patients?
Yeah, I mean, obviously, we want to make sure that, you know, the dosing goes smoothly. Obviously, there can be infusion reactions. You know, we do wanna take this a little bit slowly at the beginning just because there's also a lot of the medical aspects of the follow-up, getting the lab testing. Basically making sure we do this right. And since it's a new platform for treatment, we have to put certain systems in place. In fact, we're hiring a nurse coordinator. I already have one nurse coordinator. We're hiring another one just to manage the medical follow-up of all of these patients 'cause we know there's gonna be quite a few of them both for hemophilia A and hemophilia B.
and so that's what we're focused on is setting up a system so that we can manage this properly, make the right decisions once patients get infused and make the whole process smooth so that, you know, what's seen in the clinical trial results, that we could do at least as well as that.
So, Amit, this is not your first rodeo in terms of treating patients with gene therapy. Maybe you can share some of the experiences that you've had along the way.
No, it's been a humbling experience to be part of this wonderful story. When you see patients who've had gene therapy have their lives completely transformed, being liberated, being able to do things that they previously couldn't, is really a phenomenal experience as a physician watching these patients. I've been doing this now for over 13 years, and, you know, the tingling effect of seeing patients benefit from gene therapy still doesn't vanish. It's just amazing. So it's a wonderful therapy, but we're at the beginning, and there is a lot of work to do in this area, to, as Tara said, unlock the full potential of gene therapy for patients.
You've been our guiding light for a long time, so I'm gonna come back and ask you a little bit more about sort of where it goes in the future. But, and now I wanna grind into some other, you know, tough questions here. So let me start with Johnny, you, and talk about, so the burden of, of the initial period, how has that gone? How has that been managed? What insights have been generated? Tell us a little bit about what a patient goes through at the front end and how that's been.
Yeah, I mean, when we dosed our first patient, in fact, obviously, we had no prior experience. And, of course, having a partnership with BioMarin makes a big difference because every time we cried loud for more resources, we're given. And, I think we're getting to the level, and Guy, you know, mentioned that to the level at which we now have standard operating procedures and the required ingredients for a successful infusion. I think when we started, my team actually came in to work at about 3:30 A.M., and that's how excited everyone was. And, the day, of course, was a bit on the long side.
We're doing this as an outpatient infusion, so there was no need to admit the patient. But we're getting better at doing that all the time with, of course, the resources that are made available by BioMarin.
And, Guy, that's another tough issue to run into is durability. We've heard a lot about... Boy, have I heard a lot about durability over the years. And, so what's it like on the front lines when you talk to people about the durability?
Yeah, I mean, certainly on the one hand, it's a little bit of a concern, but in the sense that, you know, I think this was set up by the original expectations, maybe going back, you know, 8 or 10 years. And I think, you know... Well, and also, you know, the Hemophilia Foundation, which is now called the National Bleeding Disorders Foundation, they had this campaign about funding for the cure. They were funding some research at a small level. You know, we're gonna cure hemophilia. We're gonna cure hemophilia. So I mean, the expectations, I think, were set a bit too high.
When you see data like Tara presented, where, you know, there is a fall off, certainly in the first, second year, stabilizing a little bit beyond that, yeah, I think, you know, clearly there was some disappointment. However, on the other hand, as Tara presented, patients seven years out, only two of whom have had to resume prophylaxis, and in the larger picture of the phase III trial, there's very few patients who've resumed prophylaxis out of over, well over 100. I mean, I think that, you know, the durability question is now changed into, you know: what is the benefit for me over this time?
And when I've told some of these patients, I said: "Look, I'll be honest with you, this may only last 2 or 3 years for you if you have a response, or maybe 5, or if you're lucky, maybe 7, or maybe possibly longer." So I've couched that. I've tried to set the expectations in a, in a proper level for them just based on the data.... And, you know, the response was a little bit surprising to me, honestly. Most of the patients said, "So you're telling me that for 5 or 7 years, I might not need to infuse any factor, and I can just, like, not bleed and just live a comfortable life?" But I said, "Well, yeah, that's what the data is telling us." "So then what happens after that?
What happens if my levels go all the way back down?" I'll say, "Well, you'll kinda be where you are now." And so they looked at me, and they said, "So then I don't really have anything to lose." And then so I couch them a little bit in some of the risks, and, you know, we do have to discuss, you know, short-term risks or long-term risks, but, I mean, we've seen that the product's really safe. And so in a sense, some of their mindset is: I'll take five or seven years if you'll give me that without factor, and then I'll worry about what happens five to seven years from now then. And if the worst-case scenario is I'm just back where I am now, well, you know, I'll enjoy those five to seven years.
So I think the durability question has been changed into, you know, from, Oh, this is so disappointing, to more of a cup half full view, which is, wow, it'd be great if I don't have to infuse factor for 5 or 7 years, and if it lasts longer for me, great. And if not, and my worst-case scenario, I'm so—so I'm just back to where I'm sitting in front of you today, well, I'm willing to take that opportunity, you know, to have that, to have that. So I, I, I think that's... We just have to set expectations in the right way based on the data.
You know, hopefully we can, for those who really drop off low, hopefully we'll have some good science that is being looked at with the HDAC inhibitors to potentially rescue some or many of those patients as well.
So, that's a great segue to Amit. Let's talk a little bit about, you know, mechanisms of expression loss. I mean, where, where's your head in terms of how you're thinking about this phenomenon?
Yeah, I had warned you, Hank, that factor VIII was always gonna be challenging.
Mm.
And it's challenging for two reasons. First, what we're trying to do with hemophilia A gene therapy is package a genome that is oversized into AAV, and that introduces complexities that we didn't see with our hemophilia B gene therapy program. And the other thing we're trying to do is express the protein out of hepatocytes, which is not the natural site for synthesis of Factor VIII. And these two parameters will clearly influence what happens to expression over time. But I think we are only now beginning to learn about the life cycle of AAV in the liver. And what we're learning from that is that actually, the genome is sustained and maintained in the liver for much longer than we had anticipated.
When we started this program, the hepatologist would tell us that within five years, you should see a 50% decline in expression, and that actually isn't happening for the majority of gene therapies targeting the liver. So we're learning that perhaps the hepatocytes don't divide as often, but we're also learning that AAV seems to find a way of persisting within the hepatocytes that allows us to come in and intervene with other interventions, such as HDAC inhibitors, that offer the opportunity to maintain expression for longer. So I think this is just the beginning. We're learning a lot, but I'm pretty confident that we'll be able to find a sustainable solution to expression of Factor VIII long term.
Let's go back to Johnny and the patients. Johnny, any dialogue that you hear among the patients? I mean, how do they share information with each other? What sort of information? You mentioned your staff was very excited. Where are the... Where's the patients' heads in terms of their experiences?
Absolutely. We have a program in our center that we approach the patient education quite seriously. Twice a year, we do meet with the patient community and update them on what we do, and I think they deserve to know what we do. And then the second component is we try and capitalize on patient-patient education. If patients do come and they're interested in gene therapy, by the way, just like Guy, I've got a long list of reminders from patients, even now, that, you know, "Please call me whenever there is a gene therapy because I'm interested." What we do is we bring in those who have had gene therapy to interact with those who are interested and sort of create an environment where they can sit together and chat.
in that way, when we meet with the patients, at least they've got a patient perspective, and that is very, very important. You know, they come with very sort of, you know, complex questions sometimes, which questions they might have actually got from the other patients. That is the way we basically bring the community to hear and know about the gene therapy. I just want to expand on perhaps on what Guy referred to. I mean, you do get this decline in the Factor VIII activity. What we found is that even in the context of patients with very low Factor VIII activity, the bleeding is actually not a reflection of their prior, you know, bleeding.
They bleed less, and sometimes they don't bleed at all. So there's a lot to learn, as Amit alluded to, about gene therapy and, in fact, you know, other things that we may not know much about at this stage.
On a very practical level, Guy, you know, so who manifests interest? So I get this question a lot, too. Like, is there any one specific patient type that is interested in gene therapy? Tell us a little bit about your thoughts there.
... I mean, yes and no. I mean, it's been across the board. I think I have patients who are, you know, very well educated. I have patients who are, you know, less educated. You know, I have accountants and construction workers and bus drivers, and actually, physicians with hemophilia. You know, there doesn't seem to be a specific theme. I mean, they all seem to understand, you know, what the potential is. Then, of course, all of these individuals have a life outside of their hemophilia and have a life outside of their professional life. You know, whether that's sports or traveling or whatever.
I think, you know, again, this liberating sense that you heard from Johnny talking about his patients is something that they really would like. And so, you know, just a few examples. So I have some young adults who are, you know, they're in university or graduate school, they're moving around a lot, and, you know, they describe how difficult it is, you know, every time they're moving to, you know, make sure that if they're using Factor or Hemlibra, oh, I need to make sure I have a refrigerator where I'm going, and then if I have roommates, they're gonna see that I've got these boxes of stuff, and they're gonna wonder what I'm doing, injecting myself, and they might think I'm a drug addict, and things like that.
Well, well, yeah, I mean, illicit drug addict, but yeah. So, those who are young adults, transient, moving around, it's really difficult. And then you also hear from the, you know, somewhat older adults who's starting a family, who says, "You know, I really hope I'll be able to play sports with my kids, and, you know, my joints are already a little bit iffy, and, you know, I'm doing the best I can with my current treatments.
And, you know, maybe by having a constant Factor VIII level that's much higher, maybe not entirely constant, but keeping a Factor VIII level at a high level for years, you know, could help me with, you know, turning some of my joints around so I can, you know, be a good husband, be a good father, you know, be able to enjoy, you know, being a dad, rather than, you know, watching my kids play, to actually play with them. So, yeah, I mean, you hear these kind of things from really every facet of life, and I think I'll close by just saying that one of the things I really enjoy about hemophilia is that I call it the ultimate democratic disease because it doesn't care what your ethnicity is, doesn't care how rich or poor you are. It doesn't care...
You know, it is an equally. It's a disease that affects, you know, all nations, all races, all ethnicities, all socioeconomic classes the same. And everybody from all those aspects has something to gain from not having to deal with or worry about hemophilia. So there's a win for everybody with something where, you know, with the data that we've seen from Roctavian that's been presented.
That's a good foundation, and let me now pivot on it. You did warn me correctly that this would be a difficult road ahead. It's amazing that we've gotten as far as we have. Now, Tara is presenting some data on some particularly challenging aspects of gene therapy. Give us your thoughts on how to, for example, overcome immunity.
That's an important question because I think the next challenge for us, having established gene therapy, progressed it to market, is to now open it up to a wider population. And it is true that in the early studies we did, we were ultra-conservative in setting the thresholds for antibody negative versus antibody positive, and those can definitely be widened. There are opportunities through enzyme treatment and plasmapheresis to open up gene therapy to many more patients, as a consequence of reducing the antibody titer. So it is critical that we continue developing these programs so that more patients can benefit. And very optimistic that these measures are likely to be successful, certainly supported by good science in the laboratory that suggests that we should be able to overcome these hurdles.
At the patient level, will patients sit through these procedures to enable gene therapy? Is that just gonna tilt the burden so overtly, negatively?
Well, I mean, I think to answer that question, you really have to understand the current burden of disease on patients with hemophilia. And as people who are not hemophilia sufferers, it's difficult to appreciate what these individuals go through. And so if you say to them, you know, 4 days or 5 days of plasmapheresis, but then you will have long-term expression for several years, this is, this is a challenge that they're up for, and they would definitely participate. And certainly, the sense that we have at our center is that if that is what they need to do, they will do it for long-term expression, which is important for these patients.
So, this has been great, Hank-led Q&A, and I'm wondering if it would be a good time, and I'm also mindful of staying on track time-wise, if we wanted to open up for questions. So start sharpening your, your pencils. I'm sure I heard Mohit hand shot up first. So go ahead, Mohit.
I think we are.
Well, but we're on the webcast, so we wanna have... Is that, Traci, is that how we're doing it? We're gonna have to come around.
I mean, these are working.
Oh, they are the-
Yeah. I mean, we have these. I don't know why they put these on us.
Well, 'cause Johnny wasn't working.
Oh, Johnny, yours isn't working? Oh.
Yeah.
Okay.
Okay. I'll let you do that. Okay, Mohit.
Thank you for doing this. I was not expecting to be the first question. Thank you. So, my question is regarding the prophylaxis use of steroid-... Are you surprised by those data that using steroid prophylactically does not help either the factor level or the immunogenicity there?
I think you're in the best position-
Yeah.
To answer that.
He's got a mic.
Oh, yeah. Use your mic.
Oh, yeah. Actually, I do have a mic. It works.
Here, John. Yes, you get to keep it.
To be honest, I am not terribly surprised. As you know, individuals who started the use of corticosteroids to preserve expression post-gene therapy, over time, we've learned a lot. What we have realized is that immunosuppression, starting early to avoid transaminitis, doesn't really work because what you'd really need is a situation where the immune cells have an opportunity to sense the impending increase in liver enzymes, to then expand the regulatory T cells, which is what you need ultimately for long-term tolerance to the transgene and the transgenic protein. So that aspect of immunology is something that we had overlooked when we started using prophylactic corticosteroids.
So I'm not totally surprised that prophylaxis actually results in lower levels of expression and does not prevent transaminitis because you're not giving the immune system a chance to develop the tolerance that it needs to, through exposure, to the transgene or the transgenic protein.
Yes, and actually, I mean, a follow-up question for Guy in terms of how people are perceiving the need for corticosteroid use. So now we're a little bit more solid in terms of, as we said, the label is the label, and we're pretty happy with that. Any, any thoughts on the burden of steroid therapy as we sit here today?
Yeah, no, I've talked, I've talked to the patients about a variety of the different burdens of the steroid therapy, which is obviously a medication that could have side effects for some period of time. There's also, you know, the burden of the frequent laboratory testing as well. I think I would just summarize it since we're in an investor meeting, is to say that, you know, patients have to invest something early on in order to see a long-term result. It's not just in gene therapy. There's other examples of that throughout medicine, in general, hematology in particular. So I mean, we need to just... Again, it's setting expectations. It's to let them know, like: "Look, you, you're going to need to do some work at the beginning.
You may need to end up on a medication that might be unpleasant with some side effects for some short period of time for the betterment of your long-term outcome." And so it's just, again, setting those expectations. I say: "Well, how long will I need to be on steroids?" "Well, typically 3 months or 4 months, some patients a bit longer. You may have some side effects. You likely will have at least some side effects. And but, you know, the steroids is not forever, and the lab testing is not forever. And so, yes, you, you're gonna have some burden up front, but that's to have a better long-term outcome." And that's an investment the patient has to put in for their long-term benefit.
Joe Schwartz.
Thank you.
Oh, there you go. Thank you.
Thank you, Hank, and thank you for the dramatic pause. So both Doctors Mahlangu and Young mentioned the importance of resources and systems. And we sense a great interest at the sites in ensuring that they'll be reimbursed with such an expensive therapy. So I'm just wondering, first, how much of a financial incentive or disincentive is there at your centers to use Roctavian? And is there anything that the company can do to assist sites in streamlining the process to treat patients with Roctavian?
Well, I mean, in terms of incentive or disincentive, I can tell you that I've basically switched my view 180 degrees, which is, you know, in the years leading up to the launch of the gene therapies, I was extremely concerned about the sustainability of hemophilia treatment centers as a result of a one-time treatment that you don't have to give over and over again. 'Cause for those of you, you're probably aware that we sustain our centers on the basis of our 340B programs, selling factor and other products to patients, and then we, in turn, use those profits to... That was dramatic, too. To support our centers.
But, now that we've evaluated the. You know, now that we see, you know, the costs, and just from the business side, you know, yeah, what it'll cost us to purchase the product and then what we can get from the payers, there's actually a huge financial incentive, you know, to treat the patients. And so, you know, I always have. You know, I wear two hats. You know, when I'm gonna be in my clinic next week, I'll have the doctor hat, and I'm just a doctor. But then when I'm in my meetings with my, you know, administrators and financial people, then we talk about the business side.
All I can say is, after we've done all of our analyses, now that we see the cost of Roctavian and Hemgenix, how we can procure it, the contracts that we'll have in place to procure it, financially, it's actually a huge incentive to get patients on it.
Okay, Selvin, you just raised your hand. The mic over to Selvin.
... Thank you. Just in the context of the totality of patients you treat, can you help us understand why a patient may not want to be on this therapy and feels comfortable on what they're currently being treated with?
No, thanks. A very, very important question. And, I always, you know, comment to my colleagues that we live in an extremely exciting era where there's this landscape of a large number of therapeutic agents that are being developed. Of course, gene therapy is one of them. You know, for some patients who may either not meet eligibility criteria or may choose not to have gene therapy, we are not at a loss. We do have novel therapies that are available to them and that will be able to, in fact, improve their lifestyle and improve everything, in fact, that they want with alternative therapies.
At least in my setting, we're never at a loss when patients come in and say, "No, uh, thank you, but thank you, I'm not interested in gene therapy," because there are a very large number of other alternative therapies that they may well be able to take.
Yeah, I would just add to that to say that, you know, patients with hemophilia are, you know, we, we-- I like to say, persons with hemophilia. I mean, they're, they're human beings like all of us, and there, there are, you know, early adopters, there are those who are gonna just take a more wait-and-see approach. I, I, I kinda joke around with the analogies of, you know, some years ago, the people used to sleep outside the Apple store, waiting for the next version of the iPhone. You know, those are the ones who are gonna want gene therapy, like, tomorrow, right? And then there's those who, you know, clung to the BlackBerry until the bitter end. So I mean, it's true, right? I mean, we, we all saw that.
It's just, you know, there's this aspect, and I'm no expert in behavioral economics or anything, but I mean, we know that that applies to, you know, patients who are consumers of medicinal products. So I think, you know, we will see some patients like, "Well, Dr. Young, tell me after you've treated, like, five or six patients, and that they're doing well, and then I think I'll be ready after that, but I don't want to be the first one." And then there's others like: "I wanna be your first patient. I wanna be the one who's, you know, out there and telling the community how great..." So it, I think a lot of it actually boils down to that, more so than anything about their current treatment.
I mean, the current treatments are generally quite good. I mean, they're burdensome, but we know that they generally work fairly well. I won't get into the nuances of why gene therapy is definitely gonna be better in the long run. But, so I think that. I mean, we're just gonna see that. We're gonna see the early adopters. They're gonna want the treatment soon. We'll see the, some more in the middle of the road, take a wait-and-see approach, and then there'll be others later.
Okay, let's go to Phil.
We should say, "Hey, that fast.
Thanks. Hi, Phil Nadeau from Cowen. Dr. Young, two follow-up questions for you. First, on your comments about early adopters versus later adopters, could you quantify that for us? What proportion of your severe hemophilia A patients do you think will go on Roctavian over the next three years? And then second follow-up question, you mentioned that you have discussions about the durability of the therapy with the patients and that they'll basically be back to where they are today in five years if the factor levels decrease. But in some ways, that's not entirely true because they will probably have given up the ability to get another AAV-based gene therapy in the future. Does that come up in the conversations? And if so, how do the patients deal with that?
Yeah, I mean, let me handle the second one, the second point first. I mean, obviously, point very well taken, right? They're not really... I mean, they can't get another gene therapy. When I said they'll be back to where they are, it's whatever they're treating themselves with hemophilia now, that's what they'll probably ultimately go back to. But yes, they will have, I'll say the word forfeited is the right word, but they won't have the opportunity unless, you know, some of these other technologies of... Although I think that the post-infusion immune response or antibodies is probably gonna be extremely high, even probably different than the preexisting antibodies, although I'll let Amit comment on that if he wants to. So yes, I mean, that's a fair point.
You know, we let the patients know that with the technologies we have now for gene therapy, you know, this is your only shot. Now, I tell them there are other things that are, you know, being developed, being thought about, preclinical. They may work, they may not work, so there may be other things, other vectors, non-viral vectors, things, non-viral, yeah, non-viral vectors, things like that in the future that potentially they could get. But yes, that this is their one shot for the foreseeable future. We make sure that they're clear on that. In terms of the early adopters and quantifying that, I'm always a little bit cautious about that because, you know, what my patient population, it could be a bit different across the country.
But if you ask me, like, in the next three years, to estimate how many of my severe hema patients... and I'll say, the severe hema patients that are eligible, obviously, if somebody's AAV positive, I'm assuming you're thinking, like, those that made it through that, "Hey, you can get this." Is that...? You know, I can't imagine it would be less than 50%. And it could be a lot higher, you know, depending on how our results go and how our systems go. It could be higher than that. That would be, you know, my best guess.
Johnny, you have another?
Yeah. I just want to add to Guy's comment about early and late adopters. We did a small exercise in our clinic, and we wanted to count the number of patients who are carrying smartphones. And I would like let you guess, in fact, how many? It was over 90%. And my take on this is, it's not just about smartphones; it's about anything else that patients value and think in fact it's important in their lives. And gene therapy is no exception. So, and Guy is absolutely right. You know, obviously, one cannot generalize throughout the world, but my feeling is that there is a significant outlook there, that patients want technology and they want technology now, as opposed to a bit later.
Well, let me quickly add that I had a patient who was resistant to trying a new treatment. You know, I'm not—we're not talking gene therapy. And he was still on some old plasma-derived factor VIII, and he was clinging to that, you know, for whatever reason. And then he... So we're talking about new treatments. "No, Dr. Young, I've been on this for a long time. It works fine." And then, so I kind of pivoted, and I saw that he had, like, the new iPhone, newer than mine. I said: "Oh, that's... How is that phone working out for you?" Which he's like: "Oh, yeah, it's the iPhone, sir. It's awesome, the camera. Let me show you some pictures I took of my kids and everything." And I said, "So you like this new phone, right?
It's better than the previous one, right?" And he said, "Yeah, this, this thing is awesome." I said, "Well, trust me, the new factor product is better than what you're on now." And believe it or not, that worked. And this is a true story. You know, before he left, I was writing him a new prescription.
Question over here. Thank you. Oh, okay. Yep.
Gena Wang from Barclays. So maybe I have a little bit scientific questions, more about the existing neutralizing antibody, AAV, and maybe more for Dr. Nathwani. So why Hemgenix, you know, will be okay without, you know, can be treated without existing neutralizing antibody, while the Roctavian will have an issue? And also, related question, I think, Hank, also, you know, Tara also presented data, the plasmapheresis as well as the antibody cleavage. So how specific that is to the AAV? And then, you know, if after plasmapheresis and the AAV antibody cleavage, you know, what additional burden do you need to give back patient? All the other antibodies, they need to give it to the patient. Would that be a burden when we're thinking about broader the patient population?
Okay, these are all very good questions. So let me start by answering a question, not that you asked, but somebody else, around one shot gene therapy. There's data that's coming out from my group at ASH this year, which will tell you that antibody titers do decline over time. And so for a proportion of patients, there will be opportunities to have, other gene therapy options, over time. So why is, Hemgenix, different? A very important question. I think it, it is, different in the sense that they have set a higher threshold, a higher bar for antibody positivity, and that's because they have a gain-of-function mutation included within the transgene.
So even if you have low levels of gene transfer, because of the gain-of-function mutation, you will have amplification of expression, and so you will still maintain the patient within the therapeutic range. It is not true to say that with Hemgenix, that high antibody titers will not affect gene transfer. You know, we're going against immunology dogma. We know that antibodies have a neutralizing effect on viruses, and so it is very true that even with Hemgenix, antibodies will neutralize the vector if they're at a high titer. So it's a question of where you set the threshold. That's very important. And with regards what other burden do we have to add to the patient's lifestyle if we do enzyme treatment or plasmapheresis?
The answer is none, because we are essentially looking for a short window of opportunity where the antibody titers go down to a sufficiently low level for us to introduce the vector. We know that a 30-minute window would be sufficient to mediate efficient gene transfer of the liver, and that is achievable without leaving the patient with long-term immune deficiency. So no other replacement would be required with either of those measures. So I think I have answered all your questions.
Yeah, I think we have time for one more. Okay, I'll let you pick. Since you have the microphone.
I'm closest, so I think I win. Whitney from Canaccord. On the topic of durability and kind of the typical patient, I guess, as you're having these conversations, are there patients who are having this, "Oh, it might be two years, five years, seven years," etc., conversation, and they say, "You know, I still am interested, but I wanna wait until I'm, you know, my kid is born," or, you know, whatever the life event might be, that they kind of wanna preserve that treatment holiday, so to speak, for a particular time in their life. And is that coming up a lot in conversations or not really?
I mean... Essentially, I hadn't thought about that, and the short answer is, it has not come up.
The same with me. I haven't seen that kind of conversation. And perhaps one could also add to that, that the profile of patients who are interested in gene therapy are exactly the kind of patients you're describing. You know, they want to start family, they want to be more active, etc. And I haven't seen that postponement on the basis that we just want to see how it evolves over time.
... I mean, you know, the contraception issue is real, right? We know that from the prescribing information. I mean, if there's a guy who's really like, "Well, I'm gonna start a family, like, in the next few months," well, then, yeah, they'll have to postpone, obviously. Well, you'd have to postpone the gene therapy or they'll have to postpone the family, but, yeah.
We have time for one more question.
Thanks. Akasha Jeffries. Just regarding Hemlibra, I think a lot of people who work on Wall Street, they remember, you know, KOL calls as Hemlibra was launching, and I think there was a lot more skepticism about what the uptake would be of that product, right? It ended up being a pretty major blockbuster, but I think there was a lot of variability in terms of what doctors were thinking about for uptake. Are you seeing a similar dynamic with Roctavian? That, you know, as we've now gotten seven years of data, we have, you know, the quality of life information, that you feel like a lot of the skeptics, like you, Dr. Young, who were skeptical about maybe some of these gene therapies, the sentiment is starting to shift as this product actually gets to market.
And then I think maybe number two, why should we comp this launch versus Hemgenix? You know, is there any... You know, why would this hemophilia A launch for a gene therapy be better than, let's say, the hemophilia B gene therapies, which have shown better durability, at least in some of the clinical trials? Thanks.
Well, I mean, so what happened with Hemlibra in the U.S. is that when it launched, the centers who had participated in the trials and then select other people who, you know, were going to... You know, the real KOLs, going to all the meetings and getting a sense of it. We all... You know, I was in those trials, and we all, you know, we saw. I mean, I could see, you know, that this was gonna be, you know, huge. I mean, that this was gonna be transformative. And so those of us who were in the trials and saw that, we immediately started putting our patients on Hemlibra, whereas others who didn't participate, don't go to as many meetings, they were kind of like: "Well, what is this exactly?
Wait, let me try to figure this out." It took a little time, and then slowly, as that word started to spread through the community, between the patients, between the physicians, then, yeah, then you saw it really explode. And I think we're gonna see the same thing, honestly, with gene therapy. We've got centers who participated in multiple clinical trials. You know, I've—this is, you know, I've been in five, I think, gene therapy clinical trials, and, you know, I can see the benefits of, you know, those drugs that do make it to market. You know, you really do see the benefits. And I think that—it's incumbent upon, you know, us as KOLs and, you know, obviously, the company to some extent, to make sure that we educate.
The rest of the people who weren't involved in this, they're not going to every meeting. They're not as up-to-date on this, and they see this as something scary, to just to help them overcome that and to, and to see the value. And then to determine, you know, for them, for their own patients, to at least get them to a point where they can offer it to their patients comfortably. And if their patients want it, fine. If their patients don't want it, fine, as well. I do think... I just think we're gonna see the same thing with both Hemgenix and Roctavian. I don't, I don't really see... Yes, of course, there's differences. I'm not gonna say there aren't differences, but, the durability, things like that, the amount of steroids or whatever.
But I think, you know, at its core, they're achieving the same thing. And I think, yes, they'll probably be a bit of a slow start, but once things get going, I think, I think you're gonna see what we saw with Hemlibra.
Johnny?
Yeah, I agree with Guy completely. And my take on this, without giving away my age - is that we have seen it-
I'll give it away.
We have seen that excitement when you move from plasma-derived to recombinant, from recombinant to recombinant with improved pharmacokinetics. And in fact, we're seeing that excitement from moving from recombinant to non-replacement therapy. And my take on it is, it's not going to be different with gene therapy. It's just a slightly different excitement, but it will be exactly the same.
We are out of time. Thank you very much, everybody, for your questions. And I especially want to say thank you to our panelists, for starting with their scientific skepticism, for asking the tough questions, for making sure that the patients who go through the clinical trials contribute valuable, reliable, accurate information, for thinking deeply about the science of what we're doing, and for paving the way forward. So thank you very much, and thank you all in the audience for the questions. And with that, I'll turn the page. Now, I see BioMarin's gonna be doing more than one thing at the same time, and we're gonna switch gears now and talk about Voxzogo. And with that, it is my great pleasure to introduce Dr. Elena Fishleva, who's been leading the Voxzogo program, from a clinical perspective for several years now.
Take it away, Elena.
I'm trying to figure out which button to... Ah, thank you.
This one.
Oh, this one. Thank you, Tara. Good morning. It's my pleasure today to update you on VOXZOGO, milestones, achievements, and our plans to expand into short stature conditions. Oh, let me just see. Oh, that's back. Nope.
Every button does that. The big green. Big green. Now!
Oh, yes. Thank you.
Keep going.
Oh, that's better. Thank you. Sorry about that. So, in achondroplasia, our approved indication, we are expecting FDA PDUFA for under 5-year-olds and the CHMP opinion under 2-year-olds. We are already approved in Japan from birth, in Brazil and Australia from 2 years of age, and we are actively pursuing regulatory approvals globally. We will be initiating clinical programs in hypochondroplasia, idiopathic short stature, and genetic and other short stature conditions with monogenic cause. So, opportunities to expand Voxzogo potential are vast, and we're exploring a variety of short stature conditions with this regard. So in this year, we're expanding our label in achondroplasia in infants and younger children. We're also initiating natural history study in hypochondroplasia and progressing into pivotal development next year.
We will be initiating clinical programs in idiopathic short stature and select short stature conditions with monogenic cause, this also next year. Now I'm going to walk you through these opportunities step by step. This year, we released updated data in achondroplasia on durability from our ongoing long-term extension study in older children. The durability data confirmed that after 7 years of treatment, we achieved an incremental height gain of 9-13 centimeters. We also released the data in younger children, which is what you can see on the right-hand side, and this data showed that Voxzogo is associated with the restoration of substantial proportion of height deficit in this very young population.
Next week, we are coming to European Society of Pediatric Endocrinology with more data, more durability data in the youngest population, which supports the benefit of early treatment initiation. Now, beyond achondroplasia, the most logical step to progress with potential for vosoritide to deliver benefit would be in hypochondroplasia, and we're initiating pivotal study next year. Then we are expanding, as I already mentioned, into idiopathic short stature conditions and into the monogenic short stature conditions, and these two clinical programs will be initiated next year. Importantly, growth hormone is approved in these indications, either in the U.S. or globally. As I said, hypochondroplasia is our next most logical opportunity. With pathogenesis and epidemiology being similar to achondroplasia, hypochondroplasia presents with mild phenotype in terms of short stature, disproportionality, and clinical manifestations.
But we will target population with severe disease and with highest unmet need, with high deficit beyond three standard deviations below means. This is consistent with the population that's now being studied in the investigator-sponsored study. We have capitalized on the established efficacy, durability, and safety data in achondroplasia, and we have obtained some very encouraging preliminary data in hypochondroplasia from this investigator-sponsored study, and with that, we approached the FDA. We agreed on the single registrational, enabling 52-week, randomized, double-blind, placebo-controlled study with a primary outcome of annualized growth velocity, which we will be initiating next year. Now, why do we believe that in conditions like idiopathic short stature and select genetic short stature conditions, vosoritide can provide transformational benefit?
Well, I said that growth hormone is approved in these indications, but these are not growth hormone deficient conditions, and efficacy of growth hormone is very variable and not durable at all. We know that CNP is a pivotal physiologic stimulator of endochondral bone growth on the level of growth plate. So it's logical to assume that in these conditions, where there is no presence of growth hormone deficiency, no endocrine or metabolic factors, CNP or vosoritide can be a really targeted mechanism to promote growth. So we will be studying vosoritide in the population with the idiopathic short stature. Approximately 0.6% of all children who will have height deficit of more than 2.5 standard deviations, and two-thirds of them will have no specific diagnosis, which means they will have idiopathic short stature.
This is the population we'll be targeting, but we will also use genomic insights to further inform how we define the population for vosoritide. As I mentioned, growth hormone is approved in this indication, and has shown varying efficacy and modest effect on final adult height, and we believe that Voxzogo could transform management of this condition. We are talking to health authorities to confirm the design and initiation of the clinical program and plan to start natural history study next year, with anticipating dosing later this next year as well. Now, in a similarly very logical transition will be into select monogenic conditions of short stature, where CNP pathways are implicated on the level of growth plate, and these are Noonan’s, Turner syndrome, and SHOX deficiency.
Again, growth hormone is approved in these indications, but efficacy is not consistent and not durable. We have some preliminary positive data from with VOXZOGO from investigator-sponsored study in Noonan syndrome, and we are excited to see that it shows a lot of benefit. We are currently discussing with regulators the design and the how the clinical program would run, and we're planning to initiate interventional study next year. So in summary, I walked you through the imminent and the forthcoming expansion opportunities for vosoritide across the variety of indications, starting with label expansion in achondroplasia, agreed registrational program in hypochondroplasia. We're starting in natural history study this year, and first patient dosed in the interventional study next year, as well as expansion into idiopathic short stature and select short stature conditions next year. And now I would like to ask my colleague, Dr.
Jonathan Day, and on this presentation. Please welcome Dr. Andrew Dauber, Melita Irving, and Dr. Miller.
Wonderful. Thank you very much, Elena. Good morning, everybody. My name is Jonathan Day. I lead our late-stage clinical development group at BioMarin, and it's my great pleasure today to welcome our esteemed panel to the floor. So why don't we start just by doing a little microphone check, maybe with a very brief introduction. Why don't we start with Brad?
So I'm a pediatric endocrinologist. I'm at the University of Minnesota and have spent my time there, focusing on growth disorders in children, primarily with a focus on growth hormone therapy, but I'm also now expanding into achondroplasia therapy, and I've recently started a skeletal dysplasia clinic there with that intention.
Melita.
Testing, testing. I'll still go ahead, though, shall I?
Okay.
So I'm Dr. Melita Irving. I'm a consultant in clinical genetics at Guy's and St. Thomas' Hospital in London, and I've been an investigator on the vosoritide program since the outset, so over 10 years now.
I'm Andrew Dauber. I'm the Chief of Endocrinology at Children's National Hospital in Washington, D.C. My area of interest and expertise in research is on genetic causes of short stature and growth disorders. Relevant to this, as Elena was discussing, I'm the PI and investigator-initiated trial, looking at vosoritide, Voxzogo, in selected genetic causes of short stature.
Wonderful. So why don't we start off, maybe with a question for Melita? You've been on this journey with us for a, for a long, long time-
Mm-hmm.
and, you know, worked through the phase 2 as well as the phase 3, as well as now, the life cycle programs with us. And you may recall that, you know, I think we initially went into this program with some caution, maybe based on, perspectives in the little people community. And I wonder if you've got any reflections on just how the last year or 2 has gone since we had the initial approvals in 5 years and up in the United States, and obviously 2 years and up in Europe. And just with the kind of the first launch and, you know, the first few years' experience.
I think you're referring to the fact that we were mindful that there may have been some members of the community who did not want to have access to any treatment, didn't see a need for any treatment. I think that's quite a small group of people who strongly express their opinions. But there are a huge number of people who think differently from that small group, and that has really been borne out in the response to the availability of vosoritide or Voxzogo since it has been approved in a number of countries.
And I think there are some similarities with the hemophilia populations as well in that it's a very small world these days, and patients and families talk with each other on social media, and everybody knows what's going on, not just in their own countries, but globally. And so I think when Voxzogo was approved, there was a ripple effect across the whole community that people could see the benefit it was bringing, not just in height, but in terms of the medical complications that are so important in achondroplasia as a medical condition, that they wanted access to this drug as well for their children to benefit their children. So we saw a...
We're still seeing an incredible demand for Voxzogo in families with a child with achondroplasia that we just had no precedent over. That comes as well from especially in countries where there is strong patient advocacy. So we've seen this in Germany, France, Italy, Spain, Brazil, and in the U.S. as well, where there are strong patient advocacy groups really championing for access to Voxzogo for their people.
And this ripple effect that you referred to, I'm sure, Andrew, Brad, you've also probably been exposed to the consequences of that. I don't know, Andrew, maybe first of all, if you have got any comments to add.
Yeah, I mean, I think where I'm seeing the ripple mostly is moving into hypochondroplasia now. So, you know, I know we'll talk more about this in a minute, but I'm leading a study that includes patients with hypochondroplasia and patients around the world, the same thing. You know, they hear from each other. They know that, you know, I'm doing the study, and they know that their, you know, peers in their countries with achondroplasia are now able to access Voxzogo, and they're just that, you know, trying to beat down the doors. "When, how can I get Voxzogo for my child with hypochondroplasia?" I get emails from all over the world on a daily basis, as I know Melita does, you know, asking questions of: "When will this be available?
How can I get my child into your study?" I just been keeping a waiting list, you know, as it's going.
Mm-hmm.
You know, personally, pediatric endocrinologists haven't been involved in the care of individuals with achondroplasia too much extent in the last 20 years. There was some initial hope for growth hormone therapy that didn't show real benefit. But as a pediatric endocrinologist, we don't have very many geneticists in our area that are skeletal dysplasia experts, and so we have said we're willing to partner and develop that for our patients so that the available therapy can be accessed without having to go to a distant center. So we've taken that and I've worked to encourage more pediatric endocrinologists to become aware and participate.
Okay.
You see that permeating right now, Brad, like, you know, in the pediatric endocrine list serves, there are starting to be, like, these questions: "Oh, I have a patient on Voxzogo now, what do I do in this situation?" Or-
Yeah.
It's bubbling into the-
Mm.
pediatric endocrine community.
So lots of change going on as the ripple continues. So we heard earlier from Elena with regards to the indication expansion with regards to the age groups in achondroplasia. I just wonder if maybe starting with Melita again, any comments on the implications of this expansion into younger children? Not only obviously, you know, a wider age range covered, but, you know, the clinical rationale to start earlier.
Yeah. So again, we heard from Elena that one of the benefits with respect to height of Voxzogo is the cumulative effect. So it's not a leap of faith to think the earlier that you give it, the greater height benefit that there will be. As clinicians, we don't just see achondroplasia as a stature condition, we see it as a medical condition. Because there are some severe complications of achondroplasia, including in infancy, a 50-fold increase in sudden infant death. So if we have a medication here that we can give at a young age to prevent some of those very concerning and early complications, that is the age group that we want to target.
And the cumulative effect not only brings an increase in stature and an improvement in general health and in stamina, and the things that the children can do, but it also improves bone growth in other areas as well, so particularly in the arms. So kids that couldn't do this before can now do this, which means they can reach the light switch, which means they can use their independent skills on a day-to-day basis. They don't have to rely on an adult to help them when they're in an age range, when none of their peers are being helped by an adult anymore. So starting it earlier will have this cumulative effect of overall health, but also in day-to-day living for the children themselves.
Your experiences, you know, over many years now working in the clinical trials, I know for a long time with yourself, but many of the PIs around the world have reported these other benefits or other maybe subjective perceptions and feedback from the families and the children of, you know, gains beyond height gain, which is important too, you know, one aspect. But there's more to this aspirationally for us in terms of what we're doing, but we are hearing encouraging stories.
Yeah, absolutely.
Yeah.
Similar to the Roctavian descriptions as well.
Yeah.
So, yes, we see. We measure height because we see a very—it's a scientific, reproducible metric to measure, and we see some very impressive outputs from measuring height. But it is not just all about height, it's about these additional effects, too, that take longer to demonstrate, and some of the things are not scientifically reproducible in a stringent way. But as a clinician and as a person who knows these families so well, because I see them very frequently, we all know each other very well. I can see that the. I can see these improvements.
So the children report that they have more stamina, they're stronger, they can take part in activities at school, sporting activities at school, and then they can do an after-school club as well. Which they couldn't do before because the pain and the discomfort that comes with achondroplasia meant that they couldn't do that. I was in Brazil recently, I'm hearing some of the early experience of the Brazilian doctors there treating children with Voxzogo, and they wanted to depict this by showing children in the same clothes and how they changed over a period of time. So this was only over about a six-month period. It's been, I think, quite a short time that it's been accessible in Brazil.
But there were a series of pictures of children from day one, at three months, and at six months wearing the same clothes, and you could very clearly see a change in that those clothes getting smaller on them. So, those things are really important tangibly to families.
Yeah.
Yeah, there are lots of examples like that.
Well, I heard a wonderful story of a little girl who was very pleased, not only because she was growing, but of course, she got a completely new wardrobe as a result. Brad?
I was just gonna comment the, in addition to the things that we can measure scientifically are some of the perceptions of what the medication will do over the long term. That's being realized in the, in the long term and, and trying to be quantified in the long-term studies. But it's some of that hope that's driving families to seek therapy more than the... They're pleased with the height, no question, and the durability of the height, but the, the potential for the benefits long term, are what's driving not only the, the children who are receiving therapy now, but the ones anxiously awaiting therapy to be approved at a younger age.
Okay, so why, why don't we turn now maybe to hypochondroplasia? Again, we heard from Elena a little earlier about our plans to move into clinical study designs, imminently. Maybe starting once again with Melita. From a genetic perspective, does this make sense?
Yeah, absolutely. And in fact, Hank, you alluded to the fact that I was here at the R&D day a number of years ago. I think it could have been around 10 years ago. And even in those days, there was somebody I think was listening in to the call and said, "I've got a child with hypochondroplasia. Do you think this will be available for my child sometime soon?" Well, roll the clock forward 10 years down the line. Yes, it is now looking like a reality. So thanks to the mystery PI, who's been doing the early work on hypochondroplasia with Voxzogo. But yes, BioMarin is now making this a reality. So hypochondroplasia is allelic with achondroplasia.
In other words, it is caused by a change in the same gene acting in the same pathway. So it's not a leap of faith to think that CNP, C-type natriuretic peptide, the sort of magical ingredient of Voxzogo, will be effective in treating that short stature condition as well.
Perfect. Okay. Well, why don't we turn to our mystery PI? Andrew, so, you know, you've really paved the way for us here, with regards to the study you've been doing with hypochondroplasia. Any updates, perspectives you can share?
Sure. So first of all, just in terms of, you know, when we started this study, when I started this study now a few years ago, it included and was targeted at six different genetic causes of short stature, all within the same, you know, signaling pathway for which there was, you know, logical reasons to suppose that VOXZOGO would be beneficial. And I didn't really know how we were gonna recruit or what was gonna happen, and, you know, COVID happened during that time as well. And we said we were gonna recruit 35 patients. And despite COVID, we fully enrolled. And actually, we enrolled...
Of the 35, 24 of the patients had hypochondroplasia, and it was going so well, actually, that we went back to the FDA, and we expanded the number of patients and are now, you know, trying to recruit more of the patients in the other cohorts. But we had to stop recruiting the hypochondroplasia because, as I said, I'm getting so many emails that there just wouldn't have been space to explore any of the other indications. And, you know, I'm happy to report that as of Friday, just a few days ago-
Mm.
-our last patient with hypochondroplasia, completed all 18 months of the study. So if you remember-
Mm.
There's a six-month observation period to get a baseline growth velocity, followed by 12 months of treatment, and all 24 subjects have completed all of that. We data locked yesterday, and my statistician is hopefully busily, if she's listening to this, cleaning the data and working on her analysis, which we hope to present at a meeting in the, you know, coming months. But just preliminarily, I can tell you that, you know, we've seen a very positive response, you know, on the order of magnitude similar to what was seen in achondroplasia, with obviously some variability between patients. But people have been really excited, really pleased. The last patient—I'll just give one quick anecdote.
The last patient on Friday is actually a family that relocated from Croatia to America to be part of the study, and the father was almost in tears. This one girl, she's growing twice as fast as she was during the observation period, and was just so unbelievably grateful and excited to see that his daughter's growth curve, it really is like, it's like she's still well below the curve, but she is, for the first time in her life, approaching the curve, and he was really overwhelmed. So it's really... It was really a special moment for our whole research team.
Well, many congratulations, and thank you. So I wonder, maybe turning to Brad, you know, do you perspectives on the demand, you know, from this community. You see a lot of people with many different short stature conditions in your clinic, but hypochondroplasia specifically, what are your perceptions just on the demand and the interest from this community?
Yeah. So, I think Andrew has spoken about the demand in terms of people reaching out and looking for a benefit, an actual targeted precision therapy for the condition. In my experience in growth clinics, we've seen a number of children with hypochondroplasia, and some of them have modest benefits from growth hormone therapy, so it's not been a persistent demand because there's not a lot of benefit from the treatment. So I think having a new treatment to treat a condition that really severely affects stature as well as other things, is exciting, something new that's targeting the growth plate, in the more severely affected kids.
Add a comment to that also.
Please.
Brad, I don't know if you're having this experience, but I feel like the way we're practicing as endocrinologists over the last few years has been changing, in that there's now much more widespread availability of genetic testing, which I've been, you know, preaching for a while. But also, I think that there were patients out there, and there still are lots of patients out there with hypochondroplasia, that previously we weren't finding.
Mm.
Now, both with the availability of testing and also the potential of a therapeutic option, people are more driven to do the testing, you know. And I anticipate, although I don't know that this has quite happened yet, but if you remember, when SHOX was made a growth hormone indication, all of a sudden, SHOX test popped out everywhere, and endocrinologists were like: Oh, I need to start ordering SHOX. I think that should this be successful, the same thing's gonna happen, right? It's gonna be like, hey, all these kids who are coming in, who maybe we didn't recognize before, we're gonna start recognizing and, you know, testing for.
It's part of why I got involved in the vosoritide development. As I saw new treatments coming, I'm like, we see a lot of children with growth plate disorders.
Mm.
When you think of idiopathic short stature, the majority of children do not have a growth hormone problem. And so, having a new therapy that's targeting the growth plate is so exciting, but also recognizing genetically, that most of the conditions that we've been trying to treat are variations of either monogenic short stature or polygenic short stature conditions affecting the growth plate rather than affecting the hormones.
Yeah.
... So thinking about the magnitude of the height deficit, in achondroplasia, we've been treating children, and young adults with height deficits of -4, -5 standard deviations. You'll have heard from Elena earlier, that our plan with hypochondroplasia is to treat in the trial 80% of those with height deficits of at least -3 standard deviations. So I just wonder if, from all of you, maybe starting with Andrew, any comments on just the severity of the height deficit, that we're targeting in hypochondroplasia. Thinking about conversations we'll have shortly as well with regards to other short stature conditions and the magnitude of height deficit. But maybe first, some thoughts from Andrew, but also some perspectives as to what levels of height deficit did you see in your trial, in your experience?
Sure. So I mean, like, in many conditions, there's a range of impact of the clinical severity. We had approximately, I would say, don't quote me on the exact number, but around 2/3-ish of the patients who came into the trial had heights below -3 standard deviations. And, I mean, if you think about severity, I know -3 standard deviation was, like, 1 in 1,000, right? If you tell a child that 1 in 1,000 is not severe, you know, they're the one. They'll look at you like you're crazy, and their family. Even, you know, -2.5 standard deviations, if you see a family, they're not... If you look at the growth chart, they're not close to the growth chart when they're -2.5 standard deviations.
And, parents and children are, I would say, passionately and extremely motivated to have available treatment options. It varies by family, varies by culture, but, you know, that has a significant impact on how they see themselves in the world and how they live their daily lives.
Growing up normally is a huge target-
Yeah.
a huge goal.
They get treated like they're two years younger than they are. They're excluded from certain activities. You know, it has an impact on how they feel, and, you know, there are many approaches to how to deal with that. But, you know, I think that there's clearly a need for options for those patients.
I think the severity of short stature is the key when we're thinking about who are the kids that are most affected.
Mm-hmm.
We're really trying to target the most severely affected kids with these therapies, so it's important.
Perfect. Any last words, Melita, before we-
Yeah, I think it doesn't cut it anymore to say to parents of a child with hypochondroplasia, "Well, it's not as bad as achondroplasia," because it's just, it doesn't cut it anymore. And yes, there is a range of height for any child with hypochondroplasia, as there is with achondroplasia, and in fact, some of the children with the shortest stature with hypochondroplasia are actually within the upper ranges of children with achondroplasia, so there is an unmet need.
Okay. So thinking now, you know, we've thought about. We've started off with skeletal dysplasias. We've started off with achondroplasia, hypochondroplasia, FGFR3. But of course, you heard from Elena earlier, you know, we're thinking beyond the skeletal dysplasias with other short stature conditions. And maybe starting with Andrew, you've obviously not only enrolled patients with hypochondroplasia in your trial, but you've paved the way with some other conditions as well and have some other experiences. Maybe you can share some early experiences around those other children with.
Yeah. So in our trial right now, besides hypochondroplasia, the three groups that we've been successfully recruiting are patients with mutations in the NPR2 gene, which is the gene that encodes the receptor for CNP that, you know, Voxzogo acts on. Heterozygous mutations in that gene, patients with mutations in the gene called aggrecan, which is a proteoglycan in the growth plate, and patients with mutations in the RASopathy pathway, primarily Noonan syndrome, are the ones in the trial. And we have between, like, 6-9 patients in each of those cohorts. So small numbers, but the preliminary results for those patients have been extremely encouraging.
You know, again, there's variability, but I'm seeing patients with growth velocities ranging from 8, even upwards of over 10 centimeters per year, which is a remarkable increase, you know, in growth. That's not their increase, their absolute growth velocity, but increases of more than 3 centimeters per year in many of those patients. And really just seeing a phenomenal response, which makes sense to me because this is a precision medicine for those disorders, right? We are trying to exactly, you know, fix isn't exactly the right word, but supplement or perhaps, you know, return back to a more typical level, the signaling through this pathway that's directly affected by those disorders. So it's really, really exciting.
Okay. Melita, we heard once again earlier from Elena with regards to CNP, maybe as a pan regulator of growth and thinking, you know, along these same lines with regards to other wider short stature conditions. Welcome some thoughts, perspectives on, on the impact of CNP beyond these skeletal dysplasias from a mechanistic genetics perspective.
Well, the phrase that pediatric endocrinologists like to use is idiopathic short stature. Idiopathic meaning we don't know what causes this short stature, whereas geneticists like me want to know more about what the underlying cause might be, such that we now know many of these idiopathic short stature conditions are genetic. So, just to contextualize Andrew's list of conditions that have been chosen for his extension study from hypochondroplasia. There are conditions that the rasopathy conditions are conditions, genetic conditions, which there is an abnormal signaling in the pathway that C-type natriuretic peptide, the magic ingredient of Voxzogo, interacts with, so that's why you chose those conditions. Aggrecan is one of these genes important in the idiopathic short stature list.
It's a protein that's expressed in the growth plate, and NPR2, another gene that is, the cause of some of these other idiopathic short stature conditions, is the receptor in which C-type natriuretic peptide interacts. So that's, that's the rationale behind those, those conditions. They are all growth plate-specific conditions. They're not growth hormone-specific conditions, they are growth plate-specific conditions. So a number of these idiopathic short stature conditions, which we can now call in many, in many instances, genetic short stature conditions, are related to growth plate activity. So that's why CNP, Voxzogo is, is a precision therapy for those conditions.
And I think you saw in the growth hormone development that there was initially growth hormone deficient children only. Then an expansion to non-growth hormone deficient disorders because growth hormone does target the growth plate to some extent, but with limited benefit. And there's continued to be at least a perception that there's a long-term problem with growth hormone or a long-term risk that growth hormone is gonna cause something, cancer, cardiovascular disease, et cetera, by having those therapies in children who aren't deficient. And so there's a positive benefit with growth hormone in these disorders, but it's not the target necessarily.
And so I think that's where, as we think about, targeting that same pathway in a more precise, method, I think you have a perceived safety as well as a perceived precision, as you expand to these different, conditions. And I think the other benefit is that, it's a common pathway within so many other of the idiopathic short stature conditions, that there's breadth there.
Maybe for both Brad and Andrew. So much along the lines as we've already discussed for hypochondroplasia, targeting significant height deficits. For idiopathic short stature, we're proposing to look at children with a height deficit of at least 2.5 standard deviations. So obviously, these are children that don't have achondroplasia necessarily, but again, just welcome perspectives on 2.5 standard deviations in an ISS population.
Yeah.
Is that clinically?
Yeah. No, I think that I wouldn't say that that's the majority of the patients that we see in clinic, but it's a substantial proportion of the patients that we see in clinic, have heights below -2.5 standard deviations. It is, you know, definitely a level of severity in which you see, you know, these impacts on the day-to-day life for the children. And definitely a level of severity that I think the majority of patients would want to intervene for. So yeah, that makes sense to me. You know, any cutoff is somewhat, you know, arbitrary, like exactly where you pick it, but I think that as a number, that makes sense to me of defining the severely affected population.
I think in the development of growth hormone, we saw that, in Europe, idiopathic short stature was not an indication that was taken up, and it was because of the severity question. As we look at children who actually have been treated with growth hormone in Europe, there are a number of children, even though it's not approved, who are treated for idiopathic short stature, and typically that's determined by a severity of short stature and then a response to treatment. So usually more than 2.5, and most often more than 3 standard deviations below. So it's more recognized that we're treating severity, in those circumstances, that's the rationale to approach it.
Okay. Maybe last question before we turn to growth hormone in ISS, but just the numbers of patients with ISS, you know, can you comment on that versus, you know, what we've been discussing earlier with achondroplasia and hypochondroplasia? What are we looking at in terms of what's making up the types of patients in your clinics?
Short stature is the number one referral to pediatric endocrinology, potentially aside from type one diabetes mellitus, and so it's what we do every day. The majority of children that we see do not have growth hormone deficiency, and so the numbers expand. When we talk about a threshold of -2.5, it's a smaller number than -3, but it's still a lot of children coming to see us.
Yeah. It's hard to give, for me to give you an exact number, but like, you know, we have many thousands of visits for short stature at our own center per year, right? And if you multiply that over every pediatric endocrine center in the country, in the U.S., you know, there are, I mean, there are, I'm sure, hundreds of thousands of short stature evaluations that happen-
Mm.
in the U.S. every year. So this is not a small population.
Okay. So before we open up to questions from the wider audience, why don't we just have a little dive into growth hormone, which is obviously, approved and used in this population, but has its challenges and limitations as well. So, you know, I'd welcome some comments just on the role of growth hormone in ISS. How many children are actually getting growth hormone, in these children? And of those that do get treated, what are the response rates like, and how many of them are staying on that, in the longer term?
...I'll first, so growth hormone deficient children tend to have a delayed bone age and have a significant catch-up growth, in response to growth hormone therapy. And that's not something that we tend to see in most children with idiopathic short stature. So we see a response, but it may not be as sustained. And so we definitely have responders, and we have non-responders. And so I think it's a challenge to say what's that percentage? But, we see a number of children who respond quite nicely to growth hormone therapy with idiopathic short stature, as if they had a growth hormone deficiency. And, access is another challenge just in terms of insurance coverage, for idiopathic short stature.
If you can demonstrate that a child is really responding to therapy, I think we have better access, but it is definitely a challenge.
Yeah. I mean, if you look at the best meta-analyses, you know, that look at effect on final height in idiopathic short stature, it's around 4 centimeters on average, right? You know, 1-2 inches. Which is not great. You know, if you start out at minus 2.5 standard deviations, minus 3 standard deviations, that's not. That's getting you some of the way, but it's not, you know, a complete, you know, resolution of short stature in many of these patients. But the response is highly variable, and honestly, people, there's no really great predictor still of like, who is gonna be a good responder versus a poor responder. Response is always best in the first year and then tapers off as the years go on.
Which often, I think, clinically makes it challenging for us always to decide, like, do we need to continue this? Do we not? Is it doing anything anymore? Which is, you know, a difficult question.
So is it fair to maybe conclude that, you know, there is space for a new treatment, should it be safe and durable, and in part, you know, a durable treatment effect on these children, then there really is an opportunity should these trials work out, potentially for Voxzogo here?
Yeah, I definitely think that there's an opportunity. There's clearly still an unmet need for many patients out there. Now, you, you're stating a whole bunch of caveats, right?
Yes.
That we have to prove, right?
We need to prove.
But I think, but I think that's the purpose of doing these studies, right? The purpose of doing these studies is to generate the evidence to see whether or not Voxzogo or other, you know, CNP molecules can have that effect. And CNP fundamentally has a different effect on the chondrocytes than growth hormone does. You know, and that's been shown in achondroplasia, right? It's logical to think that that is possible in other conditions as well, and we've just got to test that hypothesis and see.
Okay. So maybe last question from us. So, Andrew, you've also, you know, had some... We heard earlier, you know, about our plans for Noonan's, SHOX, Turners. You, of course, have some initial experience in Noonan's, and I know you have some new plans as well, so.
Yeah. So one of my colleagues, Dr. Roopa Kanakatti Shankar, who's the director of our Turner syndrome program at Children's National, just got approval to launch a study of Voxzogo in girls with Turner syndrome. So that was approved by the FDA recently, and our IRB, I think just last week or the week before, just gave final approval. So we are in the, you know, startup phase of getting everything ready to launch that trial. That's gonna be a really interesting study because that study is gonna enroll both patients who are naive to either growth hormone or Voxzogo, who want to initially start on it, and it's going to enroll patients who were treated with growth hormone but did not have an adequate response or are not continuing to have improvements in their height standard deviation score.
You know, the FDA was happy with our study design and, you know, let's move forward. So I'm really excited to see how that will work and, you know, look forward to sharing results once they have that. We haven't obviously enrolled anyone yet.
I think both Noonan and Turner's are good examples-
Mm-hmm.
-of having a lot of patients where there's some initial benefit and then later on, sort of a loss of height SD, compared to where the general population is.
With growth hormone.
Might continue therapy.
Yes, with growth hormone. Yeah.
I would say also in both of those populations, there are individuals who have concerns about, you know, long-term growth hormone use. I don't want to, you know, put too much. I think in general, growth hormone is a safe medicine. It's been around for many years. I use it all the time. But there are individual patients who have elected not to start on growth hormone because of their concerns, whether they're, you know, theoretical or evidence-based, and want another option. So that's-
Also groups of children who just don't respond well-
Correct.
to growth hormone.
Okay. So with that, why don't we open up to questions from the floor? I realize I've got my back to part of the room, so I will... You're the gentleman at the back here, your hand went up first.
Thanks. Akash, Jeffrey. So, I think it's a question for both you, Jonathan, and Dr. Dauber, because this is kind of an unusual situation where it's an investigator-initiated trial, but it does seem to be becoming registrational. The trials that are starting for idiopathic short stature, Noonan, et cetera, et cetera, are you able to use some of Dr. Dauber's data? I know you presented three patients' worth of data for Noonan’s, a few months ago. Is that going to be used in the clinical package, or is this a separate study that BioMarin is conducting in some of those new indications?
I think number two, we've seen data from infigratinib, which does look encouraging, numerically higher average growth velocity, but there is a big question about what level of growth is safe, and you don't have final adult height. So I think for maybe the panel, when you have a patient. Let's say that infigratinib is on the market with numerically higher average growth velocity... Would you switch patients who are currently treated with Voxzogo onto that treatment? Or really, because of the totality of the evidence, the durability of response you've seen with Voxzogo, you're gonna keep them on that treatment, irregardless of any new treatments that become available? Thanks.
Do you want to take the second part first?
Yeah, or do you-
You do the first part first. I'll do the second part.
There we go.
If we may, Chairman.
So as you said, this was. It's an investigator-sponsored trial. And, you know, when I launched it out, I really wanted. You know, I've been trying to get their attention, honestly, for a while, just to say: You know, I think this is gonna work for a whole host of different conditions. I wanna try this out as an academic investigator in a host of different conditions. And I had no idea, to be honest, what the uptake was gonna be and where this was gonna go. You know, and it's generated some really good data, which I think has been exciting, and we've shared, you know, publicly and will continue to share publicly. You know, BioMarin's been a great partner, and obviously, I'm sharing all of the data with them. You know, I. Maybe you can speak to the regulatory strategy.
I'm not gonna speak to that. I don't know that well enough. But, but it was not designed also as a study. It was designed as an academic study, not as a study, the way, probably, a company would have designed it. You know, so there are probably some differences there, but I don't know you can-
Well, why don't we do any sponsor questions in the executive session at the end, and then we can do that, but focus on the panelists here. Melita, did you have a comment to add?
Well, I, I can take the infigratinib question now. So infigratinib is a tyrosine kinase inhibitor. It is a. It has a different mode of action in the achondroplasia setting, specifically. The trials are in phase 2, so safety and tolerability. The highest dose cohort has shown a very interesting, a very positive response, but in a small number of children in a phase 2 setting. So we are yet to see its full potential in the context of a randomized, placebo-controlled trial. We're, we're all very interested to see what the outcome of that will be. But I think for the time being, Voxzogo is, in respect of our knowledge of it and the length of time that this drug has been in the clinical trial program, we are confident of its safety.
We're confident how it works. We're confident how it might benefit all of these different age groups, tackling the complications and the issues in these different age groups, that this is, what's the phrase you use? Best in class for, for, for what we have right now. So, yeah, there may be some things in the future. Will we swap from one indication to another? I don't know because we don't, we don't have that data yet. So for, for, for now, for the time being, and I think for, for a considerable time, we, as clinicians, are confident in the safety and the efficacy of VOXZOGO.
I think also just to add to that, from a patient perspective, often, if patients are on a therapy that's working for them for many years, they're not always looking to jump ship, you know, as we heard on the other panel as well. If it's working, they're seeing positive results, and we don't know... First of all, I totally echo what Melita said. I think it's, we're years and years away from even being able to have the data to compare anything like that. But you won't know how moving from one to the other, that's also gonna be an unknown. So I don't think that there's gonna be this rapid, like, oh, let's switch, you know.
I also think, just to follow up on that, I think that the potential for other conditions beyond achondroplasia is more so with vosoritide than it is with infigratinib in terms of the part of the system that it's targeting. So not to answer your specific question, but to go to the broader. So why don't we get a couple more questions? Lady in the front.
I got the-
Oh, he's got the mic.
I've got the mic.
All right, gentlemen, whoever's got the mic. Go ahead.
Geoff Meacham , BofA. Just another follow-up question, you know, on the competitive landscape. So a couple of questions. One is, maybe can you speak to, in the real world or the commercial setting, the persistent rates of Voxzogo if patients do discontinue, you know, what are the common reasons and how frequently is that? And then the second thing is: How attractive do you think it will be to patients to have, you know, a less frequent dosing or an oral administration? I'm just trying to think of, you know, differential ways if you had, you know, to improve on the profile, how would you do it, and then you guys obviously just answered the question on potential switching.
Yeah. So, what was the first question?
The first question was persistent, are people-
Oh, yes.
Persistent about it or
Yes. So thank you. So my experience from being an investigator for BioMarin is that I get to go to different countries and present the data and meet people who are using vosoritide in the real-world setting, so in particular, colleagues across Europe and Brazil, Australia, people I've already mentioned. And what I understand when they present real-world data when they give this to their patients is that the compliance is very high. There are very few dropouts. It's relatively early in using vosoritide in that setting. I think there will potentially be children who don't respond as well as other children, something that we've seen a little bit in the clinical trial setting as well.
So that could be a reason why children may not choose to continue on VOXZOGO over a number of years. But because we have to give it a number of years before we can see whether the cumulative effect has been desirable or not, I think it's gonna take a long time before we start to see people dropping out for that reason. As clinicians, we too are concerned that a daily injection might not be something that people wanted to do, but actually, we've not seen that at all. People are willing to give injections to their children. So it's the parents that give the injections. The children, they don't like it to begin with, but they get used to it. It works into their daily routine.
We see that in growth hormone therapy, in type 1 diabetes as well, children get injections. So it's not that alien, actually, for children to have injections. In answer to your question, if there was something that could make this stuff better, what would that be? A less frequent injection might be beneficial of Voxzogo, that we have this confidence in, in its safety and its efficacy. But I don't know if that's the plan, but for now, people are happy to inject daily.
So, following the mic, I'm afraid I'm being practical here. So, gentleman here, and then it's coming forward, the mic, 'cause there's some questions up front.
Yep. Thanks. Chris Raymond at Piper. This is a question for Jonathan. I guess, I don't think I've seen you guys address this, but just with the experience you've had in achondroplasia, is there an opportunity to start in younger patients out of the gate in hypochondroplasia, or is, are you gonna have to start with older patients and follow the same path you did with achondroplasia?
So I don't think we said too much yet on the slides around that, but we will be starting as young as practically possible, because, of course, that would be advantageous to us. So that's the intent, yes.
Thanks.
Maybe if the mic can go forward, I know there's a long-standing question at the front.
No, this lady here.
Well, this lady as well.
Oh, sorry.
That way.
Sorry, chairman.
We'll get there.
Thank you. Gina Wen from Barclays. I have two questions. The first question is: If, you know, you have approved Voxzogo, and then you also have, say, infigratinib for clinical trials, how would you decide which patient to go on each drug for clinical trial and versus approved drug? And the second question, I think, is for, Dr. Andrew Dauber. You mentioned that hypochondroplasia data will come in a few months. So I, I know you cannot say about the data, but from, say, your practice, what, what kind of, say, annualized growth velocity or Z-score improvement that you would consider very clinically meaningful?
Great, great questions. Okay, so for the first question, I can just tell you, as an investigator, I think that there are lots of patients who want to be in these trials, right? So I don't think that there's going to be a trouble, you know, filling the trials at all. And if there are multiple trials that happen concurrently, which who knows if that will be the case, I think the way I always approach this in any situation is just I tell the patients about the trials, I tell them about the risks and the benefits, I tell them about what's known, and then they decide because it's their decision about what they want to do. It's a research study. That would be my approach. I mean, others can comment on that.
I think when there's an available treatment, it's harder to recruit children for a clinical trial because they understand the safety and efficacy, and they appreciate the FDA stamp of approval. And so, we've seen that for long-acting growth hormone, for example. Once one's available, people don't want to be in the trial if they can get the one through their insurance. And so it's... It may impact trial, you know, choices. As an investigator, I would still offer the different options and tell patients about them.
Okay, so we're up on time, but last question. With a quick question and hopefully a very quick answer.
The clinical meaningfulness.
Oh, yeah. So just quickly, I mean, I think you have to put the clinical meaningfulness into the context of what the disorder is and into the severity that somebody's starting at. So, you know, if there are patients with growth hormone deficiency, they don't increase by more than, like, 0.3 SDs a year, that's really a poor response. However, you know, in patients where there is no other therapy and the, if the gains are going to be sustained over years, you know, I think of a Z, maybe a 0.2 or 0.15, a standard deviation increase, you know, but that's going to be multiplied over 5 years. That's a very meaningful outcome. We just, we don't know any of those numbers yet, right? Like, what's gonna happen over multiple years and what's gonna happen-
And plus the benefits beyond height.
Yes
that come with a medical condition like achondroplasia, that's not just short stature.
Yep.
So Traci's telling me one more question, and this gentleman here. She has the mic.
I have the mic.
Oh, sorry. Yeah. Sorry.
Thank you. Thanks for squeezing me in. Lisa Walter here on for Luca Issi at RBC Capital Markets. Just a quick one for the panel. What has been your experience with patients who don't view achondroplasia or short stature as a disease to be treated? How do you talk to them about new treatment options and, or are there some who remain unconvinced about treatment?
Yeah, there are people that do remain unconvinced that their condition is a condition. It's they see themselves as people with short stature and that's it. But I'm a clinician, and I see the devastating complications of achondroplasia, and I very much view it as a medical condition. And that's why we keep talking about we measure height because that's something reproducible, a metric that we can measure to show a benefit. Thank you, FDA. But that, to me, says the bones are responding, and every single bone is impacted in achondroplasia. Not to the same extent in hypochondroplasia, but certainly in achondroplasia, that brings with it additional and medical complications. I already mentioned the 50-fold increase in sudden infant death in the very early stages.
But these children have an enormous number of operations. I think the average is about eight. They cannot do the things on a day-to-day basis that their peers can do, and that's embarrassing, and they don't want to be taken to the toilet by a grown-up when they are, when their peers don't have to be. We already talked about the benefits of being able to do more than one activity, physical activity a day, because this brings with it an improvement in generalized stamina. So yes, there are people who don't want to access a treatment, and they don't have to. But it's a wonderful time now that there are these options.
This, this is not like it used to be when I first started out in skeletal dysplasia a number of years ago. This is a very different landscape. There are now options, and as we've seen in and across Europe and Brazil, it's flying off the shelves. People have. There's so much demand for this treatment for a condition that has significant medical complications.
So, I'm finally learning to follow the hands and the mic, so now this gentleman.
There's a lot of focus on the line of growth velocity in patients, and towards that end, how well does growth velocity actually capture the comorbidities of the disease? Do you think that over time, the focus moves from growth velocity to other endpoints?
May I?
Melita, please.
Yeah, I think in short answer to your question, yes, there will be a translatable element of growth velocity. We're already measuring. So we don't just measure height in the clinical trial setting or in the real-world setting. We measure all sorts of things. We measure body proportionality, we measure arm span. We match that with what the kids can and cannot do on a day-to-day basis, what they can reach, what they can't reach, what they can do for themselves, what they can't do for themselves. We monitor the medical burden of achondroplasia as a medical condition. It takes a longer time to demonstrate those additional benefits, but we're doing it.
I don't think we've talked about one of the last trials that we've recruited for in the vosoritide program. It is to protect the foramen magnum, the big hole at the base of the skull, which can become narrowed and squeeze off the spinal cord. That's in part what creates that increase in sudden infant death. What effects vosoritide may have on improving that. We're still collecting this data. We're still measuring all of these things in the clinical trial setting, in the real-world setting as well. I think we're all convinced that there will be additional messages that we can link back to annualized growth velocity, but showing these benefits beyond height. I think we'll have that data soon.
So with that, I'd like to conclude this session. Brad, Melita, Andrew, thank you so, so much, and thank you all for your questions. I think we could have done this all over again with the time we had, but I hope we've imparted exciting times for Voxo ahead, so thank you.
Thank you.
My duty, I should introduce Dr. Dave Jacoby to the floor.
All right, so I'm the head of Early Clinical Development, and I'm going to talk about a top-line overview of four programs that are in the clinic or near to the clinic going forward, starting with BMN 255. So 255 is a small molecule that inhibits the enzyme glycolate oxidase, which treats hyperoxaluria. And the development thesis here, which is sort of our mission statement in early clinical development, is that within a disease called non-alcoholic fatty liver disease, that there's a patient subset that has serious morbidities associated with hyperoxaluria that is treatable with glycolate oxidase inhibition. Let me spend a couple of minutes about how we get from one to the other.
It's not obvious that NAFLD is the patient population, but this is really informed by the genetic disease, primary hyperoxaluria type one, in which the mutation exists in an enzyme called AGT. You can see below kind of the liver pathway in which this enzyme exists, but basically, if you lose AGT, you lose a productive metabolic pathway to glycine. If you don't have it, you form oxalate. Oxalate is insoluble, it's not excreted, it deposits in the kidney, it causes nephrolithiasis and recurrent kidney stones. So the genetic disease is a very severe disease, which shows that hyperoxaluria is a primary driver of nephrolithiasis and recurrent stone formation.
It's always been known in non-alcoholic fatty liver disease, NAFLD, that there is associated, quote, "comorbidities of hyperoxaluria, recurrent stone formation, and chronic kidney disease." What's become evident recently is the reason that is true is because there's selective epigenetic inactivation of the same enzyme, AGT, in NAFLD, as occurs in the genetic form of the disease. So what we have here is a selective inactivation in fatty liver disease that is responsible for hyperoxaluria and recurrent stone formation. The other cool part of this is because it's a pathway, we can measure both the substrate and the product of the enzyme, and so the activity of inhibiting glycolate oxidase, you can measure with plasma glycolate. The driver of disease, which is urinary oxalate, is elevated in disease, and we can measure its reduction.
So when we're talking about the core four, these are genetically informed disorders. We have accessible markers of improvement and has a substantial burden of illness. So if we move to what the burden of illness is in this disorder, there's actually considerable healthcare resources involved in managing patients with recurrent stones and nephrolithiasis. It doesn't take a huge imagination to realize that this is debilitating pain, this is hospitalizations. There's actually a very large increase in the risk of infection. These types of patients with hyperoxaluria recur often, and they have this is an independent risk factor for chronic kidney disease. Current therapy is pain control. It's antibiotics for infection. It is trying to get the stone removed, both medically and or frequently surgically.
But there's no therapy that actually limits the formation of nephrolithiasis or, or, or new formation of kidney stones. And so the actual goal of treatment with BMN 255 is to make sure that new kidney stones don't occur. NAFLD is obviously a very large patient population, and we're in the process of trying to identify exactly which hyperoxaluric subsets are going to respond to therapy, but our initial estimates are this is a patient population of 800,000. So what's our evidence to date? We're in the clinic with 255, and we've just completed single ascending and multiple ascending dose studies in healthy human volunteers. And so the graph on the left basically shows day 14 of a multiple ascending dose of 14 days of dosing.
What you see is basically good dose response, plasma glycolate that's tenfold above baseline at the highest dose. We had no safety signal at this dose, and so we are going to bring the highest dose into a patient population. The next steps for us is to translate this observation in healthy volunteers into a patient population enriched for NAFLD, hyperoxaluria, and history of stones in order to show whether glycolate inhibition can reduce urine oxalate formation. We're also working... There's a little bit of a left arm, right arm. There are hyperoxaluria clinics, and there's NAFLD clinics, and we're trying to basically put the combined experience together to understand what is the clinical and biochemical identification of patients that are going to respond to therapy.
So if we can show a clinical benefit in patient populations and develop the algorithm to identify these patient populations within the NAFLD clinic, basically, our plans go straight to a pivotal phase 2/3 study. You see in our timeline below, we're basically we've gotten through healthy human volunteer dose-finding studies. We're going to initiate patient studies in 2023, and we'll have a determination of our proof of concept in 2024. Apologies for having to see me a couple of times. The next program I want to talk about is a different disease and a different modality. This is AAV-directed gene therapy. It's a replacement gene therapy for hereditary angioedema, so this is BMN 331. Our development thesis here is much like the analogous to Roctavian.
This is a single administration therapy that sustains normal expression of the gene that's lost in the disorder, and reduces the attack rate. So this is a disease that's well known. Its genetics is a loss of function. You have reduced expression of the protein C1 inhibitor, and the gene that's affected is SERPING1 . And this leads to uncontrolled stasis of angioedema attacks, which are unpredictable and occur in various locations in the body, the gut, the respiratory pathway, and oral facial. These are debilitating, they're painful, they're potentially life-threatening, so any attack really is a potentially serious event for a patient.
Not unlike hemophilia, C1 inhibitor levels are associated with the risk of attack, so we have clear markers, again, in terms of C1, too, the accessible measurement of clinical effect in terms of measuring both the levels of C1 inhibitor and the activity of C1 inhibitor, which correlate with clinical activity. The burden of illness I sort of described here, the angioedema is unpredictable. It occurs in areas that can be disfiguring, but also potentially life-threatening. There is good standard of care. Maybe I can just spend a little bit of time why we think gene therapy or replacement therapy actually has an advantage in this marketplace. The current standard of care is either replacement, prophylactic replacement therapy or inhibition of kallikrein activity, and there's a reduction in the attack rate.
But the proportion of patients that are disease-free still is relatively high. And we heard a little bit from Professor Mahlangu about this disease-free mindset and how it's it frees the patient from living their life. A significant amount of fear and anxiety exists with angioedema attacks in HAE. And so really the goal of replacement therapy with gene therapy here is to express C1 inhibitor at a level in which there is an increased proportion of patients that are attack-free. Let me kind of give you an update of where we are in the clinic. So we've got a protocol dosing paradigm where we dose sentinel patients, and if we get to a therapeutic level, we're allowed to expand.
I'm showing you basically two patients that were dosed at 6 × 10^13 viral genomes per kilogram of C1 inhibitor, BMN 331. And we're showing you the C1 inhibitor expression rates in these two patients... I've given two reference bars here. One is the lower limit of normal, and the second is that 10 mg per deciliter, which in replacement therapy is the sort of the level at which we have clinically meaningful reduction in the attack rate. So I'm setting the bars here for what I think is sort of like the minimum effective dose for sustained therapeutic benefit to a patient. And you can see with our 6 × 10^13 dose, we're sort of now approaching the level that we think might be therapeutically relevant. So next steps.
We saw in the 270 data that there is some modulation of transduction expression with corticosteroid therapy. And so we're actually gonna change the modulatory regimen for 331 in the next 2 patients that are dosed, hoping that we can take this expression level and augment it. And so the current therapy basically is an early start. We're gonna leverage the information we gained from 270 and actually have later start with corticosteroids and see if we can augment the gene expression into levels that we think will be even more therapeutically active. If we can do that, we can expand basically the dose of 10 and go to our proof of concept definition, which is 8 out of 10 responders.
The timeline again says we're just poised now to dose the two subsequent or further patients with the altered corticosteroid regimen, and by 2025, we hope to have enough patients to basically determine our proof of concept. The next program I'd like to talk about is, again, a different disease and a different modality. One of the things that, you know, is, we're not a platform or a technology-based company. So for each indication, we can think about the modality that basically addresses the pathologic driver of disease most completely. For Duchenne muscular dystrophy, we have an oligonucleotide, which is an exon 51 skipping, and it's driving the expression of a near full-length dystrophin as a replacement therapy for the loss of dystrophin in Duchenne.
So our development thesis here is that there's a novel splice site that we can target here, which is much more potent, which restores level of a near functional dystrophin protein at levels that will have profound clinical benefit for these boys. We have taken a slightly different approach than gene therapy. We've looked at population genetics, and the data there really does support the idea that small in-frame deletions around exon 51 result in a protein product that's associated with a much milder phenotype across the population. So we really do believe that you can... If you make a near full-length protein, it is more likely to have clinical benefit.
I think the other key component of this program is that there are other exon 51 skippers, but they're using the same site that basically was originally described with eteplirsen and drisapersen. They're just using basically targeting mechanisms to get more of that into the muscle. Our research group basically discovered a site which is a much more potent exon skipper. And so, we expect basically not to be able to get more in, but to have a greater biological effect with the molecules that we do get in. It's gone through kind of extensive research testing in vitro and human muscle cells, and we've developed a humanized Del52 mdx mouse, which is exon 51 skippable, and we've done extensive non-human primate studies. And the data here, I'll show in the next slide.
The transformational potential is, I think, fairly obvious. This is a terrible disease. It's a progressive disease that manifests early in life by ages 2 to 4. These kids basically lose their muscle function. It sort of results in being wheelchair-bound, usually in early adolescence, and they rarely survive past the fourth decade of life due to cardiopulmonary loss. Current therapy for this disease is pretty poor, so standard of care offers really no real disease-altering benefit. And the addressable patient population here is 7,600. So, the sort of better biology, we wanted to put together a little bit of a graphic that demonstrated how we think about this.
We leveraged kind of our human experience with the drisapersen clinical development, and we said, "Hey, if we can get 351 into muscle as efficiently as drisapersen, what would the animal studies predict we would have as dystrophin levels in Duchenne boys?" This graph on the left is meant to sort of convey that. The X-axis is the drisapersen concentrations at 12, 24, and at steady state in the clinical experience in humans. The Y-axis is the predicted dystrophin levels using the humanized mouse model as the extrapolation data. You can see at steady state, basically, we're looking at 20%-50% dystrophin expression of a near full-length molecule in striated muscle, and then we get double digits at 24 weeks of expression.
It's a little bit of a conservative estimate because basically, the non-clinical studies with 351 suggest it actually gets into muscle more quickly. So we have better exposure and better tissue penetration with 351 than we do drisapersen. So there's every reason to think this curve could be left shifted in clinical studies. So we're currently enabling a global clinical development plan. The protocols that we're using are gonna have biopsy-driven dystrophin levels, basically, as our readout of clinical effect, and that if we are able to get the dystrophin expression that we think we can, based on non-clinical studies, we obviously have early approval options in the U.S. and Japan. We are enabling a program.
Hopefully, by the end of 2023, we can, we can get into the patient, but shortly thereafter, and we have our proof-of-concept determination in 2025. And the fourth program I'm gonna talk about is now another small molecule. This is a treatment for alpha-1 antitrypsin deficiency. This small molecule actually preferentially binds the mutant protein that is made in this disease. So if we, if we look at the development thesis, this, this molecule is binding the mutant protein. It rapidly mobilizes the deposition of mutant proteins that exist in the liver and thereby normalizes the liver function and improves outcomes. So let me just describe a little bit about the disease.
The vast majority of alpha-1 antitrypsin is caused by a single amino acid substitution, which basically destroys the normal conformation of the enzyme, and so it can't get out of the cell, it can't get across the endoplasmic reticulum. It basically precipitates in the cell. Over time, the cellular mechanisms of autophagy are overwhelmed, and basically, the mutant protein just polymerizes as globules in the liver. So the driver of disease here is a gain-of-function mutation. It's associated with progressive liver disease, fibrosis. Many patients progress to cirrhosis. It is a cause of liver transplant in the patient community. BMN 349 basically binds the mutant protein. It allows its facilitated transport through the ER into the plasma. So what we're doing is we're stopping the new formation of polymers in the liver.
We're exporting the mutant protein out into the plasma, and we're allowing the autophagy in the liver basically to mobilize the preexisting liver polymers in the disease. This is, again, a progressive liver disease. There's really no current standard of care for it. It is associated with fibrosis. Many patients progress into the stages of portal hypertension, cirrhosis. It elevates the risk of hepatocellular carcinoma, so it is a severe gain-of-function liver disease. Currently, there is no standard care for the disorder. So, the potential addressable patient population is 52,000 homozygote adults with ZZ. So the evidence to date, here, we're not in the clinic yet, but there's an animal model that's homozygous for the Z protein that basically exhibits the same forms of illness that the humans do.
Their Z protein doesn't get out of the cell, so it's not in the plasma. It collapses in the liver and forms basically polymers and globules. And so this is a treatment paradigm in the PI, the homozygous mouse model, in which we treat with three four nine for 30 days. And it's an active disease model, so if you see on the left, the blue mice, they accumulate, on average, about 50% more liver polymers over the 30-day treatment period, sorry. At 2 low doses, we don't affect the sort of formation of polymer in the liver. But you see at the medium dose, basically, we significantly stop the formation of new polymers.
At the high dose, which is something that will be humanly equivalent and something we can use in the clinic, you can actually see that we not only stop the formation of new polymers in just a 30-day treatment period, but we actually allow the liver to mobilize existing polymers. So you see that there's a decrease in the polymer burden over the treatment, the 30-day treatment period. So we think that this is really exciting data to take into the clinic. We've just completed our IND-enabling studies. We've had good conversations with health authorities both in the U.S. and in Europe, and we've agreed on doing sort of safety tolerability, and dose-finding studies in healthy volunteers, and then pivoting quickly to symptomatic adult ZZ patient homozygotes as our proof-of-concept studies.
As you'll hear from Kevin coming up, we're really interested in the ability of genomics to provide prognostic information for both identifying new patients and for enriching for patient populations that are gonna respond to therapy. And because we have, I think, a mutant-selective treatment, we're gonna try and use the genomics to basically enrich for patient populations that are gonna respond to therapy, but also expand to potential populations, both in the pediatric space, but also heterozygotes that have liver disease, which is potentially a large patient population. Cool. So the timeline here is that we are ready to submit our IND. We hope to be in the clinic in 2024, and by 2025, we're gonna have a proof-of-concept definition.
So again, going back to what Hank showed you earlier, we have really a robust timeline for not only putting things into the clinic for INDs, but also when we're gonna have determinations for these proof-of-concept definitions. With that, I would like to introduce my colleague, our Chief Scientific Officer, Dr. Kevin Eggan, who will talk to you about some of the things we want to put in the clinic in the future.
Thanks, Dave. Hi, everybody. I'm Kevin Eggan. It's nice to meet all of you, many of you for the first time. As Chief Scientific Officer, I'm accountable essentially for everything that happens in a laboratory in BioMarin, whether or not it's our discovery efforts, our IND-enabling studies, or biological efforts that support our clinical programs. To begin today, I wanna tell you about 3 programs which represent our early efforts to get a toehold in the space of genetic cardiovascular disease. If you look back over the last 10 years and ask yourselves: What's one of the biggest breakthroughs that came from the invention of exome sequencing? It was the realization that common cardiovascular maladies like hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, as it's increasingly known, are really collections of genetic diseases.
They are genetically heterogeneous conditions, which are largely caused by large effect variants in individuals that we thought simply had common diseases, where we knew there was some extent of heritability. We felt that that was a great opportunity to build into a new area based on our established expertise of developing targeted genetic conditions. Sorry, can't help myself but to wander.
We're giving you a mic.
Yes, it's gonna be great. I can, I can stay, stay here. The first of these that we're gonna be bringing into the clinic is BMN 293 for MYBPC3 hypertrophic cardiomyopathy. The cardiac myosin-binding protein C is a critical component of the sarcomere, which regulates the contractility of cardiac muscle. And when its levels are reduced in patients which have this form of HCM, it leads to pathological contraction that leads to hypertrophy within the muscle, both obstructive forms and non-obstructive forms. But these patients generally suffer from more frequent arrhythmias because of the distortion in their cardiac anatomy, pain, fatigue, dizziness. This can be one of the leading causes of sudden cardiac death. Mutations in MYBPC3 are the leading genetic cause of hypertrophic cardiomyopathy.
Really today, the main management is through beta blockers in order to try to reduce arrhythmias within these individuals, and increasingly on the scene are now, cardiac myosin inhibitors. But our goal was to really try to go right to the heart of the problem that is causing this disorder and restore MYBPC3 expression throughout the myocardium. Really, we believe that we should be able to readily assess that through a variety of widely used cardiac biomarkers, like a direct reduction in left ventricular mass, an area that we should be able to measure through cardiac imaging, and the use of certain biomarkers like NT-proBNP. Right now, we estimate that the potential addressable patient population for this condition is more than 150,000 people in BioMarin territories.
So what are the reasons to believe that this will be possible with gene therapy? Well, we've done a lot of work in a variety of model systems to optimize capsid selection for a cardiac tropic capsid, and to develop a transgene that delivers selective expression of the MYBPC3 protein within the myocardium. In the bottom left-hand corner, you can see expression in red of the cardiac myosin-binding protein in animals that would normally lack this protein because of a homozygous deletion in the murine gene. And you can see the red protein very clearly localizing to the correct location in the sarcomere. More importantly, these animals develop, when they completely lack MYBPC3, a severe cardiac phenotype, one of which the features is this increase in left ventricular mass.
So if you compare the blue data to the red data there, you can see this dramatic increase in left ventricular mass, which is improved significantly by the administration of BMN 293 in this model. We also see very widespread transduction of the large heart in non-human primate, which gives us increased excitement about the translation into humans as we go forward. We've moved this into IND-enabling studies. Those studies are almost complete now, and we're working towards IND filing. Next steps will be to work with Dave's team on dose range-finding studies in the clinic as we move out towards human proof of concept in 2026. Now, our efforts to develop this program have really allowed us to build momentum in cardiac gene therapy.
In building off our knowledge that we gained from this program, both in capsid selection and in transgene design, we've been able to move forward very rapidly into our next gene therapy program for another genetic form of cardiomyopathy, this time, BMN 365 for arrhythmogenic cardiomyopathy, which is caused by mutations in the PKP2 gene. PKP2 encodes the protein plakophilin-2, which is a critical component of the desmosome. The desmosome is sort of the staple that holds cardiomyocytes together in the myocardial syncytium.... That close coupling of cardiomyocytes is essential for normal electrical conductance and maintenance of the cardio muscle within the heart. In the absence of the desmosome or with, or with reduced desmosomal function, two things happen.
The first is the electrical conductance doesn't work as well in the heart, and the second is you start getting fibrous fatty invasion into the myocardium, which disrupts and weakens the heart muscle. So as a result of these two phenomena unfolding in patients with PKP2 mutations, the first thing is that as they grow up and become young adults that are more active, they become immediately at risk of sudden cardiac death during athletic exercise. This is usually addressed with anti-arrhythmic mutations, but increasingly, as this progresses, they have more and more cardiac ablation surgeries in order to try to address arrhythmic scars that begin to form within the heart. Eventually, many of those patients will also be put on ICDs in order to address these arrhythmogenic storms that become more and more common.
A subset of patients that's increasingly appreciated will also go on to heart failure because of their condition as well. So our view was that taking the learnings that we had with BMN-293, we could widely deliver plakophilin-2 to these individuals and restore the normal syncytial structure of the heart, and therefore, address the root cause of this progressive disease in these individuals. And again, there are around about 150,000 people we calculate in BioMarin territories that would be addressable with this therapy. So what's the evidence that this looks like it might be a going concern non-clinically? First is the first really, I think, sign of excitement was even in syncytium of cultured human cardiomyocytes, when they lack PKP2, they don't contract normally, and there are dramatic changes in the contractile behavior of those cells.
And even in that case, small numbers of fibroblasts that are in those cultures begin to invade the syncytium, and you can see this microscopically. Both of these phenotypes were corrected by transduction of those cell cultures with PKP2 AAV gene therapy. We, again, also saw a very efficient transduction, and tolerability in mice and non-human primates that gave us increased confidence that we could deliver PKP2 throughout the heart. But I think most excitingly is this recent data on the left that we've obtained in collaboration with Mario Delm ar's group here in New York.
That suggests that not only can we prevent arrhythmias and death from occurring if we treat early, but also that if we wait for animals with reduced PKP2 function to actually become ill, which is of course, what we would largely expect in the clinic, that after they've already developed arrhythmias, we can deliver AAV PKP2 in the form of BMN 365 to these animals, and we can rescue arrhythmias and prevent early onset lethality within this model, which I hope you can see in the bottom left-hand corner of this slide. So, with this exciting data in hand, we're now moving into toxicology and GMP manufacturing for this program. We're gonna work towards completing our IND-enabling studies. We hope in time to initiate our 2025 global clinical program, aiming for a POC for this asset in 2027.
Right now, of course, we're working closely with Davis Group to finalize the design for those studies to enable that. Now, while we're certainly building on our experience with gene therapy, there are many other opportunities within the genetic cardiovascular space to bring other modalities to bear, and we're certainly doing that here. One of the opportunities that we spied early on was to make a difference in genetic Long QT syndromes. So many of you will probably know that Long QT syndrome, especially familial Long QT syndrome, is caused by mutations in a variety of ion-gated channels, which function in cardiomyocytes to control the cardiac action potential. Mutations that decrease potassium outflow from cardiomyocytes or gain-of-function mutations which increase sodium influx into cardiomyocytes all have the net effect of elongating the cardiac action potential and the QT interval.
Now, why is this, why is this a bad thing for patients? It's a bad thing for patients because when they exercise or they're under increased cardiac load, more and more rapid heartbeats push the frequency of beating to a level where the beat starts earlier and can't be accommodated by this change in electrophysiological behavior. The net effect of that is beating irregularities, which can turn into arrhythmogenic storms called the Torsades de Pointes. This can cause sudden cardiac death in these patients and is a real source of concern for people who are living with Long QT syndrome. Currently, the main approach, which is used for treating this, is again, beta blockers, which essentially block the adrenergic inputs into the heart to keep the heart rate from increasing when people become excited or they exercise.
The problem is that it's easy to have breakthrough events, either because of increased exercise or just some people don't respond well at all to that mechanism of action. This has led to increased use of generalized sodium channel modulators like mexiletine, which have their own problems from blockading other sodium channels throughout the body, even though they can be useful, especially in individuals that have mutations in SCN5A. So our goal was to try to take a different approach to try to address this based on genetic discoveries in long QT biology, but also to take a biologics approach to address some of the concerns about selectivity of small molecule sodium channel modulators.
The first thing that got us really interested in this problem was the genetic observation that individuals, of course, who have loss-of-function mutations in KCNQ1, which encodes the Kv7.1 channel, have long QT syndrome. But there are also a small number of individuals who have gain-of-function mutations, which increase efflux through this channel, which have short QT syndrome. Okay? And so this really provided important evidence across a large number of individuals that beginning to increase that efflux could also have a meaningful effect on on QT. Now, the second challenge was how to do that. As many of you will know, it's devilishly challenging to develop small molecules which selectively modulate ion channels because of the great similarity there are between paralogous channels within the body.
So one molecule is likely to not only block one channel, like SCN5A, but also to affect other sodium channels in the body, right? And that's one of the big challenges with mexiletine. But we, we, recognized that an opportunity could exist to develop a biologic, which would bind to the extracellular surfaces of a potassium channel like Kv7.1 with greater selectivity than could be achieved with a small molecule. And work from Rod MacKinnon's lab in Rockefeller here in New York, and other investigators at the University of Bern, supports that point of view.
We became increasingly excited that we might have an opportunity in the more than 120,000 people in BioMarin territories that have long QT syndrome based on some early findings, both looking at the selectivity of agonism of potassium channels with early versions of these antibodies, but also our ability to correct changes in ectopic beating and the QT interval in cultured human cardiomyocytes, while having little activity to no activity on other channels. This enthusiasm has been growing as we've been optimizing these molecules, and we can now administer the lead molecule that we've selected for toxicology and GMP manufacturing subcutaneously to rabbits and see a shortening of the QT interval with a single dose for as long as 30 days.
You can see the dose responsiveness in this response in QT shortening, and I think really strikingly, even at doses that could be readily formulated for sub-acute administration. So we're looking forward to pre-IND interactions with health authorities around this program and in moving it forward. So now with that, I'd like to tack to a different topic, which is: What is the reason to believe in BioMarin for the longer term? And, and why is it a safe bet that the approach that we've been using for translating genetic discoveries into translational medicines has a long road ahead of it that is only going to get more interesting? And I think to begin to make my argument to you about this, I want to just fly over a couple of points I hope to make to you.
The first is that really, the catalog of human genetic information that we have at our disposal for understanding human biology and interventions in medicine, is only growing more and more rapidly every day, and that that's gonna have a number of important and predictable effects on our business going forward. The first of this is that we are going to be able to predictably treat many more patients with existing therapies that we market today and forthcoming therapies based on an increasing ability to diagnose patients with genetic tools. I believe we'll also be able to identify many patients earlier for treatment than we do now, and I'd like to be able to make a case for that. The other thing that's really interesting is that our discovery of genetic variants is proceeding much more rapidly than our ability to understand them.
For those of us who are focused on specific problems and have strong genetics and genomics teams, this is going to be able to allow us to make insights and to fuel discovery, and to build confidence in therapeutic approaches, that will drive us forward in interesting ways going forward. I'll give you two examples of how that's happened to us recently. Then lastly, for a company that has at its disposal, the fruits of investing in several different therapeutic modalities in collaboration with the manufacturing group in recent years, we'll have the ability to be rapid movers with the right therapeutic approach and modality as those opportunities become apparent to us, and I think that puts us in a very compelling position.
So first of all, I think all of you are well aware that, sequencing capacity is one of the few things that's growing more rapidly than, the increase in computer processing speed based on Moore's Law. And you can look at that in many different ways. Lots of people show the number of DNA bases that are sequenced every year to try to demonstrate that, but one of the things I find compelling is actually, what's the net output of that?... And here you can see our own analysis at BioMarin of the number of reported human single nucleotide polymorphisms. These are single sequence-based variants that have been reported to public databases from human sequencing. And you can see the exponential growth in this data in recent years.
These are actual measured human genetic variants that have been reported in people, that we know can be contributing meaningfully to human biology, both directly to disease, but also to provide insights to us about how different pathways and proteins are shaping human health and contributing to different phenotypic outputs. We are using that information to inform decisions that we're making all the time in R&D at BioMarin. Let me give you a couple of examples of how I think this is going to shape things going forward, based on recent history and how things are changing. Just look at a case like mutations in the MYBPC3 gene, which I was telling you about for BMN 293 in hypertrophic cardiomyopathy.
If you look back just a few years ago to 2015, there were only about 200 mutations that had been identified in that gene and known to be pathogenic. But now, if we look at the dramatic uptick in sequencing that's happened in recent years, and you begin to apply, newer approaches, as we have, for understanding the variants in this gene, like new variant calling methods using machine learning, you can see that this has improved dramatically and is increasing our confidence in the number of addressable patients that are out there for us to treat. But you can also see that there are still many individuals that have variants of unknown significance, and we project a very large number of those actually have variants that are affecting their HCM.
But only with time will more certainty come from further sequencing of individuals, which will better connect that genotype to their phenotype. But inevitably, that is going to come. There is no doubt about it. Another example of building confidence from this groundswell of genetic data, I think, comes from studies of height. We heard today from the panel about how we have increasing confidence in our understanding of the genetics of heights and, you know, of height and final adult stature. And that's really backed up by the data. If you look at the rate of discovery of genes that are implicated in final adult height and short stature, it's growing remarkably, okay? And it will continue to grow.
I think what's really interesting about that is that if you look at common tools that are used for trying to assess or estimate someone's final adult height in the clinic, looking at the child's height and looking at their final adult height is a good approach for doing that and has a good deal of predictive power. And you can see you can make a prediction that has a reasonable amount of accuracy from it. But if you now begin to layer on approaches which use genome-wide sequencing and approaches like polygenic risk scores, you can much more accurately predict someone's final adult height than you could before. And tools like this will undoubtedly, in the future, allow earlier diagnosis of future states with this type of genetic information.
Only time will tell whether or not we'll be able to use approaches like this to diagnose that idiopathic short stature earlier and be able to provide a treatment like VOXZOGO. But this is certainly the sort of thing that we'll be aiming to do. So then, finally, I'd like to end on this point, which is, so far, I've told you all the interesting things that are becoming possible and are becoming apparent from the discovery of genetic variants we do understand what they do. What's even more remarkable is how many genetic variants have been discovered that we don't understand yet. And there is going to be a lot of exciting discovery within our industry and at BioMarin from diving into understanding what those variants do.
I'd like to show you two examples of that that are shaping activities in the clinic right now at BioMarin and giving us a great deal of confidence. The first is around variants of unknown significance that shape height and shape the function of the receptor, NPR-B, that CNP functions through. We heard today from Dr. Dauber and the panel about how there's growing confidence that CNP and Voxzogo ought to be extremely useful in children who have mutations that broadly affect the MAP kinase signaling pathway. And there's mounting evidence from Dr. Dauber's studies that that's true. But what evidence is there, or what evidence do we have that something like BMN 111 should also be very useful in other forms of idiopathic short stature?
To gain insights into that and to build confidence around that, we again went to human genetics, and one of the things that we did was to look at variants of unknown significance that were in the receptor that CNP signals through. On the left-hand side, you can see variants that our genomics and genetics team identified within the UK Biobank, and you can see them arrayed across the length of the protein coding sequence and the gene for the receptor. What they did was then go into the lab and said: Do these variants actually do anything to the function of the receptor? And what they found was that some of those variants, in fact, more of those variants than not, as you would predict, do damage to the function of the receptor. But some, a minority, but an important informative minority...
Actually increase the amount of signaling through that receptor. And because those variants came from a large biobank, we could then ask, what is the final adult height of those people? And what did carrying that variant, that relatively common variant in the NPR2 gene, do to their final adult height? And you can see across a very sizable number of individuals, a very compelling relationship between the function of their NPR2 receptor and their final adult height in standard deviations. And so this gives us human genetic evidence to suggest that across a variety of genetic backgrounds, a variety of different variants that do the same thing that VOXZOGO does, can lead to a final adult height, which is greater. And really, that's a key observation which is fueling our drive into idiopathic short stature. Another example is BMN 255.
You know, really the one of the key compelling aspects for me about excitement about moving forward into broader nephrolithiasis in individuals with NPHLD comes from emerging evidence that comes again from studies of very large biobanks largely in Europe where we have the intersection of genetic information and phenotypic data. And we've been able to carry out our own internal genome-wide association studies which return much larger numbers of genes that are associated with nephrolithiasis than had ever been reported before. And the biology from those outputs is pointing to this pathway really as an important potential point of intervention across a number of individuals that's much greater than we had imagined for PH1 originally. And so time will tell how well this particular set of genetic observations is predictive in that case but I'm excited to see what Dave's team produces.
Now, many of you could say, "Okay, well, a lot of companies have great genetics teams." I think we have a particularly good one, and I think we have the evidence to support that, but I would acknowledge that point is true. So what are the other reasons to bet on us? Well, I think one of the biggest reasons is that our track record of success and the investments that we've made on the back of the last approvals in order to prepare for this moment.
We now have expertise in research, in clinical development, in medical affairs, in our commercial organization, in delivering therapeutics in a number of important therapeutic areas where genetic discoveries are delivering real opportunities, whether it's hematology, whether or not it's the skeletal dysplasias, whether or not it's following on from Brineura in genetic neurodevelopmental disorders, or where we're trying to get our new foothold in cardiovascular disease. Then I think even more importantly, in many ways, is the major investment that we've made in manufacturing and technical operations over the years, and our ability to bring forward rapidly complex therapies like protein biologics, oligonucleotides, and gene therapies, means that when these discoveries are made, we can rapidly move to a approach which has a big biological effect on that system.
And so that's an engine that I'm really excited about trying to turn the crank on for the next several years, and where, because the investments we've made, there are real opportunities to grow the top line while using the investments that we've brought forward to manage bottom-line concerns, too. So just a few examples of that kind of momentum that we're trying to build and that I hope is clear to you is, you know, first of all, we're trying to build confidence around very defined genetic conditions that exemplify a biological effect that in many cases, we think could be useful for many more individuals, and that's really the VOXZOGO story. But I think it's...
I hope in the future, going to be the 255 story as well, and something that will repeat itself in many other conditions, I hope, like genetic long QT syndrome, too, where there are also many acquired forms of long QT syndrome, where modulating the same potassium channel may have very beneficial effects. Or it's our historical investment in gene therapy, where the successes that we've had with Roctavian really informed what now looks like an interesting going concern for BMN 331 in HAE, and building on that expertise now an opportunity in genetic cardiovascular conditions. Or for myself, based on you know, my own background in nervous system and nervous system disorders for many years, Brineura is an absolutely transformative therapy for a small number of children with CLN2 Batten disease.
Our experience there in identifying, children collaboratively with, with physicians using exome sequencing, has really shown us what an exciting opportunity there is more broadly in neurodevelopmental disorders. With those teams in place, I think it'll be quite exciting to bring other therapeutics into the pipeline in that area in coming years. So if we look at our total activities in research and early clinical development, as J.J. led at the top of the hour, they are more expansive as they have ever been before. But by staying in these lanes and trying to build on the momentum that we've already generated in this way, we're increasing our output and the opportunity that we're creating the company, while managing the total investment that we're making within that space. And I think that's an exciting opportunity to look forward to, in the future.
Now, I'd just like to close with one last point, and that is that we are only at the beginning of this, and we're much closer to the beginning of our understanding of how genetic shapes human biology and human health than we are to the end. Even though we've identified more than 1 billion variants in human genetic sequence, we're closer to the beginning of that journey than we are to the end of that journey. And that's because most of our sequencing has been done at a relatively low depth, and has been almost exclusively carried out in Western European populations. And we know from studies like the Thousand Genomes Project that if we just sequenced everybody that we'd already sequenced more deeply, we would double the number of genetic variants that we know about, okay?
And so that's not even notwithstanding new approaches like wider use of whole genome sequencing or RNA sequencing, which are gonna deliver a much greater understanding of genetic variation. Likewise, we're more and more pushing out our sequencing efforts into individuals who are of different ancestries and have a different human history, and therefore, have a totally different genetic architecture, which is shaping their biology and their health. And we know that that's gonna deliver many, many more pathway insights into disease in the years ahead, and we're gonna be well equipped to realize those opportunities. And now I'd like to hand it over to to Brian, who's gonna explain to you how we're gonna afford to do that.
Thanks, Kevin, and thanks, everyone, for the time today. Hopefully, you have a deeper understanding of this exciting pipeline that we've built at BioMarin. As Kevin mentioned, I'm Brian Mueller, Chief Financial Officer for the company. For those of you asking yourself: Why is the CFO speaking at R&D Day? My goal is to link the exciting science in all of these pipeline opportunities that you learned about today with the business impacts and the potential for value creation and creating a sustainable, profitable, financial growth story. I love that Kevin's last section, you know, was titled Sustainable Pipeline. So now, if we could draw that connection to a sustainable business, sustainable financial growth, that's my goal. BioMarin has a solid history of scientific innovation and commercial success.
We are one of very few biotech companies in history to reach $2 billion in revenue from 8 internally developed and commercialized assets. And our financial growth strategy is to leverage this profitable and growing enzyme replacement therapy portfolio, plus the large revenue growth opportunities now with VOXZOGO and ROCTAVIAN approved globally. We strive to both grow revenue and profits, while at the same time, as you heard earlier today, continue to invest in the business and this innovation, and that starts with increasing R&D investments. As you heard today, we've got a pipeline here worthy of healthy investment. We've got both opportunities for these late-stage assets. These are the indication expansion opportunities for VOXZOGO and ROCTAVIAN, which are largely de-risked.
And then what you just heard in the last section, there are more assets in early-stage development than any other time in the company history. In terms of level of investment, if we look at the midpoints of our 2023 financial guidance, our 2023 business plan provides for roughly $750 million of research and development expense. Our plan for 2024 is to maintain that level of R&D investment on a percentage of revenue basis. This means because we are expecting significant revenue growth next year, if we maintain that level of investment constant on a percentage of revenue basis, that will translate to a significant amount of R&D spend. It's important to note that we are realizing significant operational leverage from our day-to-day R&D capabilities.
So what this represents is a specific, deliberate investment because of all the opportunities we saw today. Next, increasing investment isn't enough. It's critical that we strategically prioritize these R&D investments in the right places. We are focused on assets that have both the highest potential for technical success and significant returns on investment. For example, there are several assets that did not meet our strict investment criteria and didn't make the cut as high priorities. We believe that if we stay loyal to the core four scientific attributes that Hank referred to earlier, plus disciplined portfolio governance, that we can achieve this objective. And then finally, our plans for leveraged growth.
Again, growing revenues, operating expense constraint, operational leverage, operational excellence, we believe can add up together to not just drive meaningful margin expansion, growth in profits and cash flows, but also, over time, generate significant levels of cash flow. And that will create capital allocation optionality, including continued organic or internal investments, external partnerships, and increasing shareholder return. BioMarin has a great track record of not just the scientific innovation that you've heard about today and seen over the years, but converting that to actual commercial success, which relates directly to shareholder value. We created this chart here, which shows the Voxzogo and Vimizim commercial launches for their first sequential eight calendar quarters of launch.
I'll share that we benchmarked this data for first 8 quarters of launch against several other, orphan launches, some very successful launches, and, VOXZOGO and Vimizim lead the pack. Please recall that for most of our product launches, we created markets that previously didn't exist. Also noteworthy is the number of markets that we're selling in. For our mature portfolio, we sell in almost 80 countries. VOXZOGO is still approaching its second year of global launch, and we're selling in almost 40 countries. So we can take these new product launches and plug into this global infrastructure that we built over the years for rapid uptake. Finally, as we look forward to the next phase for BioMarin, we are excited about the future. This is my final slide, and it visualizes some of the comments that you've heard today.
Through 2021, we spent those years making meaningful investments in our infrastructure, capabilities, and innovation. In 2022, we made the important transition to sustainable GAAP profitability. We continue that journey into profitability growth here in 2023. As we look forward to the middle of the decade, with now Voxzogo and Roctavian approved globally, with the existing marketed portfolio, we believe that we can achieve between $4 billion-$5 billion in revenue by the middle of the decade. Over time, grow operating margins at a level that is consistent with our larger biopharma peers. In fact, when we look around at the current peer group and benchmark our operating margin growth rates, we believe we're in the top quartile of operating margin expansion opportunity over the next several years.
And again, not just committing to large biopharma peer margins and making those consistent, significant investments in the pipeline for sustainability, but cash generation, which is gonna provide a lot of optionality to where we make the right investments, not just this year or next year, but well into the future. So in closing, we're truly at an exciting moment for BioMarin, and our transformative growth expectations are not only within line of sight with this marketed portfolio but are credible when you look at all these pipeline opportunities through that lens of our industry-leading development track record. So thank you all for your attention today. I will pause and invite my BioMarin colleagues back up to the stage as we begin the management Q&A session. And thank you all.
We look forward to keeping you updated on our progress.
Thanks. Tracy, who were we imagining we would bring up on stage? All of BioMarin, the whole company? All of BioMarin, the whole company. Come on up. All of BioMarin. Sharpen your pencils, get your hands ready to raise and shoot into the air, and ask questions. We're gonna be taking questions. I'm gonna be the moderator. I think, unless you want to moderate, you're more than welcome. Thank you very much. Okay, we got a passing microphone. Okay. Tracy, I'm gonna let you do the calling out from you and Casey.
Thanks. Good morning, George Farmer from Scotiabank. I was wondering if you could comment on BMN 351. Anything on, on, on how that's being delivered? Is there any improvement, any improvements there? And you have something about your own delivery technology that might be different from others. And also, just on a more broader strategic level, I mean, very deep pipeline, but do you see any need for M&A in the future?
Dave, you want to start? And then we'll flip over to JJ.
Sure. I think Kevin's probably well equipped to answer the question. It's a naked oligo. It's using phosphorothioate, so the sort of the chemistry that we know about, but the actual composition is optimized. So the oligo has better kind of like exposure and penetration kinetics than the traditional old school phosphorothioates. But it's not a facilitated transfer. So, you know, one of the things we see with transferrin receptors or peptide is that it gets more in, but there's toxicities associated with the actual delivery. So we're kind of sticking with the chemistry that we know, and we've optimized that.
Sort of related, from the drisapersen days, we delivered drisapersen subcutaneously. The people that started the drisapersen program had the idea that, well, if this other drug is gonna be administered intravenously, we can gain competitive advantage by delivering it sub-Q. One of the things that got learned in that program was that sub-Q phosphorothioates can be toxic to the skin. So in the clinic, we're gonna be delivering 351 intravenously. And one of the other aspects of these programs that's really interesting is that the dystrophin protein that gets created has an extremely long half-life.
So whereas the early clinical program will speed to steady state, 351 concentrations in muscles, over time, our expectation would be that dosing frequency can relax to improve tolerability while maintaining high dystrophin levels, and I think that's gonna be another key ingredient to the competitive advantage of 351. The fact that we can drive a lot into the muscle and then, relax the dosing frequency. JJ, do you want to say anything about-
...Do we have a second microphone so we don't? Yeah, so I would say two, a couple of things have happened in the past year or so. One on the environment, which is the fact that biotech assets valuations have come down substantially, which potentially could create some opportunities for us because, you know, 18 months or so ago, valuations were pretty insane for many companies. So obviously, we looked at all—I'm not talking about M&A in general, but just biotech assets, whether they're molecules or companies. So I would say it's getting a bit easier now. And two, so that's the environment. But then for BioMarin itself, we now are cash flow positive, profitable, consequent, and we have already $1.3 billion or so of cash balances.
So our cash balances are gonna start increasing pretty substantially over the next few quarters. And consequently, you know, it will allow us to have some, you know, firing power to potentially acquire late-stage assets. And we, I would say there is nothing imminent. We know we have. You saw the BioMarin pipeline, which is pretty exciting here, so we're gonna have a lot of, you know, projects to fund. But at the same time, if we do find something at the right price that complements, what we're doing, whether it's in terms of commercial abilities or scientific and clinical abilities, then we might, you know, we may make a move. But, but we have plenty to do already with our internal pipeline.
Also the fact that a lot of the molecules you heard about today, some of them came from BioMarin internal research, but many of them actually came from some in-licensing deals we did in the past 2, 3 years of early-stage compounds that are becoming BioMarin compounds and moving into the clinic or about to.
I think I'm next. Hi, Leland Gerschel with Oppenheimer. At the same time, this is sort of a question on M&A, but in maybe a different direction. At the same time that you continue to invest in your pipeline, you also have made significant investments in the facility for gene therapy. You know, it seems like this is a you know, highly valuable asset on its own. And I want to ask, you know, we don't know too much about it, a bit of a black box, but seems like it's something which would be a rare asset for perhaps a strategic to take hold of for, you know, further expansion of other gene therapy programs. So I want to ask Dr.
Eggan, having come into BioMarin a couple of years ago and from your academic background in that area, sort of how do you see that at BioMarin as being a highly desirable asset that others would be interested in? And, and what's the replicability by others if they want to set up their own similar type of facility? Is that something which is feasible or really much more proprietary?
Okay, so we'll start with Kevin, and then Greg Guyer, head of technical operations, will also provide some answers.
Yeah, two-part harmony across this beautiful collaboration. You know, I think one of the things that I didn't have as much appreciation for until I joined was how useful it was not only to just have one manufacturing approach at your disposal, like the insect cell platform that's been used for Roctavian, but to have two at your disposal, including the new proprietary approach for mammalian cell packaging. Which really, you know, based on our experience, looks well ahead of what other people have been able to achieve for scalability and for the titers that we're achieving in production. I'll let Greg say more about that, but that's allowed us to make real data-driven decisions about what works best, you know?
Although, you know, there are lots of reasons why folks choose insect cell production, for us, the driving reason was that it worked better with those constructs in many assays. Likewise, the reason we've gone with the HEK293 platform for these cardiovascular programs is because it works better, and like, not a little bit better, but, like, a lot better. And that's been a big driver of decision-making. So from my perspective, I don't know anybody else who really has that at their disposal and has a team that's willing to make that choice in favor of what works better, rather than, "This is what we got, so this is what we need to do." And I'll let Greg say more about that, but, you know, that's, that's incredible.
Yeah, I think it's a tremendous strategic asset for us. Our ability to go from very small scale to medium scale to large scale with the amount of gene therapy programs that are coming through. What we've been able to do is to take the learnings of Roctavian, the learnings with 331, and start to apply them to these new 293, 365 programs you saw today. What we've done is we've created a platform, both of process and analytics that support it, that has given us really scale and speed. We've been able to bring these products faster based upon that experience, and every program, we learn more and more, and we put it into the pilot plant, which is where the programs start and they move. That actually has the same scale as our commercial facility, which is probably 40 yards away.
Also, we can transfer, actually engineers as well, that can go with the product. So it's created a tremendous capability for us to be able to scale, but also the tech transfer is almost seamless because it's the exact same equipment that can move both places. So that was a really great strategic investment, and then we added the pilot plant just a couple of years ago. But it really is. We were learning, and we do have some proprietary ways in which we are transfecting agents and different things that are really getting us the kind of productivity that we need as these programs come through. So you're correct, it is a tremendous strategic asset, and what I wanna do is I wanna fill it up.
... I want to get these gene therapies to market and then start to use it, because one of the things that's very interesting in gene therapies, different from like a Voxzogo, is it's a one-time administration. So you don't have the kind of chronic flow that comes through a manufacturing facility. So our ability to look at multiple gene therapies and then start to use the facility for them in a way that's driven by the demand that comes from commercial, gives us, I think, a unique ability to do that, because when you're contracting out to a third party, then you're kind of at their behest of how much you can make when, and you have to make those decisions well in advance, 13, you know, 18 months ahead. We don't have that.
We can make those decisions, you know, four months ahead and then transfer over. So I think that flexibility is also something that will be differentiating for us.
Jeff Beacham of BofA Securities. A little bit of detail on the last question. When you think about AAV as a platform technology, at BioMarin, obviously, you guys have a lot of experience with that. Would you view that as sort of the default or the cornerstone technology, you know, for the pipeline, given, you know, some of the back and forth you had with FDA on Roctavian, you know, on safety tolerability? Or do you think that, you know, it's worth it to explore other viral-delivered, you know, systems or even cell therapies? Thank you.
We're certainly watching that space carefully, but mostly watching. You know, because I think if you look at other non-viral approaches beyond AAV, they have a lot of proof points to achieve before they're really going concerns. And, you know, we're certainly positioning ourselves, and we're certainly, I would say, sampling those technologies from time to time to stay up with them. But at this point, nothing has really achieved anything that feels remotely close to what AAV can do. And so it remains, I think from our point of view, with regard to gene transfer technologies, a very attractive approach.
I think when you combine that with the types of continued innovation that Greg's team has done in downstream processing, which allows us to continue to make a more and more well-defined, more and more potent product, which I think is contributing to some of the success that we're having clinically, it feels more and more of a protected and privileged space that other people are gonna be challenged to equal. But my job is to not be happy with that and to always be looking for something that will be better. And if we see it, then I'll be the first to put my hand up. But I'm not willing to put my hand up yet.
But part of the opportunity also is that we don't have to just do gene therapy. We don't... So but many of the things that you saw from Kevin pertaining to the early-stage pipeline, the best key for that particular lock may be something else other than gene therapy. And I think one of the things that enabled—I don't know if you were gonna say it or if I was gonna say it. One other... You know, Kevin could have gone anywhere, right? I mean, this is a guy that was in fairly high demand all over the world when he made his decision that he was gonna transfer out of academic life and into industrial life. And I think one of the things that he reported that was the hook for BioMarin was to be modality independent.
That is to say, to use the tool that does the best job, and nothing graduates out of BioMarin's portfolio into humans unless you've got substantial evidence that it's reasonably likely you're gonna see an accessible benefit in humans with the condition of interest.
Yeah, I wanna make that very clear. I was answering that question very much in the context of gene transfer, you know, approaches that we are seeing for, you know, getting DNA in a durable way into patients to have a biological effect. But as Hank said, you know, that's not our only platform at BioMarin, right? I mean, BioMarin was built on a biologics platform, and that's not something that we are forsaking, as you can see. You know, whether or not it's peptides, antibodies, complex biologics, when we see the opportunity to bring those to bear in a program, we continue to have the research and manufacturing muscle to be able to bring those forward through tech dev.
Likewise, you know, we think that in certain circumstances, oligonucleotides are becoming more and more established approach, where some of the bugs around safety are being worked out, and particularly in the nervous system, where we're seeing some exciting readouts in early clinical studies. So we, you know, we are certainly gonna move in that area as well as we go forward and continue to, let's say, not have, at this time, you know, a huge discovery research effort around small molecules because of the expense that has to be put into that. But we feel that there are many, many opportunities to bring in early-stage small molecules and take advantage of the medicinal chemistry expertise that we have to finish those molecules off and get them into the clinic.
We will continue to do that, as you've seen, for things like 349 and even 255.
You know, related, I wanna unpack a bit of a comment I made earlier about BioMarin's secret sauce. So, Greg's predecessor is a quality-oriented guy. Greg himself was in quality for 10 years at the FDA.
... And, you know, you've you got all this skills for so long, you, you appreciate that so many refusals by the FDA, complete response letters and like that, have to do with manufacturing quality types of considerations. Now, you flash forward to where we are, and so I, I'm in, in the regulatory group is in my area, so I get to watch everything that Greg's team is doing. And, it was really kind of humbling that Greg's team got to the finish line so well, so far, so fast, in these very complicated discussions with Center for Biologics. You talk about platform and knowledge creation, we're in a whole different level, I think, and we have a number of former FDA employees who, like, you know, I think Kevin's in great demand.
A number of the people who are leaving the FDA from some of these very technical groups, who wanna go to industry and be part of creating that new future, are coming to BioMarin because of BioMarin's reputation as a high-quality organization, which begins at the beginning of everything that we do and is embodied in the career attributes of the leaders of our organization. So it's an amazing actually, it's an amazing, amazing capability. Back to your question about strategic value of something. This is an amazing capability to stay out of trouble from a CMC perspective.
Debjit from Guggenheim. A couple of questions. First, on the alpha-1 antitrypsin program, how do you fight stoichiometry given that we make about 2 grams of protein per day? So how do you tune PK of a small molecule drug? And number two, any updates on the fill and finish issue, which could affect Voxzogo next year?
So the answer to the first question is, we actually have the secreted mutant protein to be able to follow in terms of being able to do PK/PD relationships. And so we can actually show levels of Z protein in the plasma that, you know, approach the heterozygote levels or even normal expression. So we do have a PD marker to follow for drug titration.
Once you've cleared the polymer, and you're only dealing with newly formed Z protein, the amount that you need may not be the same steady state as at the beginning of the program.
I'll just add on the Voxzogo side. Since our second quarter earnings call, where we talked about some of the supply constraints that we had, we've worked very hard with our partner, and pleased that we've been able to secure some more supply. Still want more, and we're working on that as well. But I think so far for 2024, we've secured well over $700 million in what would be revenue from a number of new patient starts. But our aspirations are to get more, so we're still working on trying to free up even more capacity, but we have made progress even since the end of the second quarter earnings call.
Remember Dr. Irving's comments earlier about being surprised. You know, I think the big challenge was that one of the big challenges was that there were so many families who were at home, relatively more quiet about how they considered achondroplasia, and it turned out that that volume was just gigantic and a little hard to appreciate at the starting line, but we're catching up.
Yeah. Again, I mean, want to emphasize this was a very short-term issue, and as just Hank just said, I mean, the demand is way superior to anything we were expecting. And I think it's based on, you heard from different experts, the social media, you know, news that the drug is having a substantial effect on the patient's quality of life beyond AGV, is spreading very quickly around the world and also beyond, potentially, just achondroplasia. So, so we wanna gear up to potentially supply, you know, very large amounts of Voxzogo. The good news is that we do, we manufacture the active substance. The drug substance is within BioMarin's control, and Greg has told me we could, you know, easily sell. There is almost no limit to our capacity there. $3 billion, $4 billion, $5 billion, no problem.
So but this is, VOXZOGO is turning into a very large product. I think we'll, we'll be between $900 million and $1 billion in 2025, and then we're gonna go beyond that. Then, where that goes depends on, you know, all these new indications we're exploring and how quickly we can generate data, but, but again, this is a short-term issue. It's not a drug substance issue. There's no manufacturing problem. It's just a pure capacity issue at a vendor that we're using as—and as Greg said, that's, that's why you want to control your manufacturing because otherwise, you're dependent upon the scheduling of your vendor. So that's what we've been facing here. That's not a big issue.
Thanks. Robyn Karnauskas from Truist. I just thought maybe you could elaborate a little bit on, for the patients with antibodies or former antibodies, like these new technologies, whether it's the HDAC or whether it's the, apheresis, what are the reasonable timelines for those products coming to market? Like, how do we think about that? And I noticed you didn't mention any of the new capsids for repeat dosing that make it around, current antibodies. Are those dead? And then lastly, for cardio gene therapy, there's other companies playing in the space. What are the-- It seems like it's great because you have less turnover for cells, but are there any risks, like, could we run into, like, longer duration? What’s the, what’s the the FDA gonna complain about this time?
Tara, why don't you take the Roctavian questions, and then I can handle capsids and cardiovascular gene therapy.
That sounds good. Thanks, Kevin. So for our activities to dose patients with pre-existing immunity, as I said, we've just finished up a lot of the preclinical experiments that demonstrate that this should be a viable solution in the clinic, and we'll be seeking advice from health authorities. In the interest of getting this, you know, to market as quickly as possible, we'd be very interested in novel trial designs that allow us to expedite this process. But I think it's a little too early at this point to, you know, to give you an exact date, but other than we also share the interest in being able to dose this patient population, as soon as there is good evidence that it is safe and effective to do so.
...One thing to just add about timeline expectations, you know, we talked about whether it's apheresis or cutters of IgGs or HDAC inhibitors, and people think, "Okay, Roctavian is approved. Those other things are approved. You know, this should be like an NSAID and omeprazole, and tomorrow, doctors can start writing prescriptions." Well, in this space, it's a little bit more complicated, especially given the novelty of the kinds of things that we're talking about. And I think Dr. Nathwani mentioned how important it was to be careful and deliberate at the beginning of each of these journeys.
And so we're a little bit more vague on the timelines for some of the advanced things that we're undertaking, and a little bit more focused on some of the more near-term opportunities, so, for example, with Roctavian in Japan, adolescents, et cetera. So that means that there will be a relatively long life cycle of opportunity expansion for Roctavian. Kevin?
Yeah. On capsids, I'll just say this seems like a much more proximal opportunity given the approval state of AAV5 factor VIII. And, you know, changing capsids would change the underlying product and would mean going back to the beginning in many different ways. And if we can get there sooner, we wanna do that, and so this is much more proximal. So, you know, it's not that we've eliminated capsid research at BioMarin, we're just, you know, we're. I would say, chastened by how far away we know that is and are mindful of the more immediate revenue opportunity that's in the now from what we see with AAV5.
And we were talking about, like, redosing capsids kind of earlier in the program, and there was a lot of early attention to the change in Factor VIII expression. But now, as we're getting longer-term data, you know, 11 out of 13 patients now through 7 years, 6 and 7 years, who are remaining off prophylaxis, it you know, it suggests that maybe durability is gonna be, it you know, still on the radar, but it's not an imminent threat to the business that would warrant the the invention of a new drug to deal with it. So we remain interested in alternative capsids to escape zero reactivity, but there isn't quite that same urgency as maybe at first.
Yeah. Then with respect to cardiovascular gene therapy, yeah, of course, health authorities remain focused on high-dose risks, and one doesn't have to look any further than the AdCom that took place, now maybe two years ago, looking at concerns around high-dose toxicity, either from—you know, sort of perceived theoretical risks around vector integration or whether or not it's concerns about DRG toxicity. And so, of course, watching all of that very closely in all of our non-clinical experiments to ensure that we have the smoothest path forward into IND for these first cardiovascular gene therapies. And we intend to put a robust non-clinical package forward in front of the FDA that gets out in front of those sorts of concerns that they've been talking about in order to get going. And we've also...
You know, the good news is, probably BioMarin knows more about, you know, immunogenicity of products because of the types of products that we've developed over the years than just about anybody. And so when you think about some of the immunogenicity-related risks that have surfaced with high-dose AAV, you know, that's led to a lot of conversation between my team and Dave's team about what approaches that we should take, either prophylactically or responsively, to deal with those risks, if and only if we need to go to the doses where that would be needed. And I think, you know, from my perspective, because of the collaborative work with Greg's team, we're seeing really compelling results at doses which don't necessarily go into those sorts of ranges.
I won't say more about it than that, but, you know, I think that's also contributing to my own personal enthusiasm around these programs. I hope that's helpful.
I wouldn't cap the ability of the FDA to surprise us under-
Yeah.
In any circumstance going forward. But what I would say about that is that the more volume of interaction you have with them, the more patient data that you're presenting to them, the more products you're presenting to them, the more Whack-A-Mole you're playing, the fewer opportunities there are for surprises, the more ahead of the curve you are in terms of anticipating what their questions are gonna be. And I think that the platform has given us the opportunity to have a lot of those dialogues.
Thank you. Joe Schwartz at Leerink Partners. Sort of a follow-on question to the last. I was wondering if you could talk about the vectors and level of dosing that you think you might need to use for the gene therapy programs in cardiomyopathy. And it seems like factor VIII and PKU and HAE were difficult targets, and you prevailed with in, in heme, and you're still trying to work out the challenges in HAE. So I'm wondering how you view and assess the technical challenges for gene therapy in the cardiomyopathies.
Well, I don't know that we're gonna get yet into the specifics on the starting dose levels and some of that is just, you know, still ongoing discussions between us and health authorities as INDs get activated. I think what remains the case is nobody really wants to start at too low a dose. And so, where possible, I think there's gonna be eagerness on the regulatory side to get to, you know, as quickly as possible, effective doses. Now, the safety issues that you're touching on, and Kevin just touched on, are gonna be important considerations. Although I will say there's a lot of knowledge emerging in the field as an overall matter in terms of what determines the safety of some of the higher doses that people have been using.
I hope that, with some of that experience, we can fold into the clinical programs from the get-go so that some of the observed side effects from different capsids can be managed proactively, much better because there's a lot of learning that's out there. For example, Dr. Kaul, I was introducing at the beginning. She came from Novartis, where she was responsible for Zolgensma in the medical portfolio on a global basis, learned a lot about how to make sure that products were safely administered. So I think that's gonna be a key platform for us going forward.
... You know, we've had discussions with the FDA on the pre-IND, so we have sort of, you know, tacit agreements on what the protocol design would look like, what our safety signal detection needs to look like in order to go forward. So we have a really kind of a rapidly dose-expanding protocol to assign dose and then move on into the pivotal studies.
But, you know, also digest for a second the data that we showed you. If you start prophylactic steroid therapy, and maybe we don't fully understand the molecular basis of why that effect was, but you have a third of the expression when you start on day one versus when you are reacting, and that's a pretty key insight in terms of how to manage safety and achieve optimal gene expression. I mean, it's possible that if we got threefold increase in expression in the BMN 331 program as compared to what we've observed so far, right? Right now, we're at the bottom of the therapeutic range. We'd be feeling pretty good about that in a grand scheme of things.
But with this additional data on steroids, we now have the opportunity to raise expression by moving the steroid window out in time, and the benefit of that could very well be enabling lower doses. So I think we're tuning now in terms of how to optimize gene expression and safety.
Great. Jess Fye, J.P. Morgan. Two-part question on Voxzogo. Can you put some context around how you think about the revenue opportunity for the additional Voxzogo indications you talked about, either individually or collectively, maybe benchmarking off of what you expect for achondroplasia? And then second, can you clarify how you're thinking about the development strategy in some of the other conditions you're pursuing with Voxzogo, where growth hormone is approved? Would you think about running trials in combination there, or would you try to study patients who are not treated with growth hormone or not responding well to it?
I don't know, Jeff, if you want to say anything qualitatively about that?
Yeah, I think I can briefly address the revenue potential. So where we started off with achondroplasia for Voxzogo, which was a really great choice because, you know, the high unmet need, we were able to really establish the high unmet need, which pairs when you're developing a new indication, as was talked about today. That really pairs with the safety and efficacy of the treatment to create a new indication. So really great starting with achondroplasia. If you thought about hypochondroplasia, for example, you'd say, well, overall patient population, similar to achondroplasia, there is a concern for all of the follow-on indications that we want to try to retain the relative value that we've established for Voxzogo for achondroplasia. So we'll be thinking about that and taking action accordingly as we go forward.
As you heard Elena say, for example, we'd likely be targeting the most severely affected portion of that hypochondroplasia population. Then that question, qualitatively, that question continues as you look at potentially larger populations that could benefit from Voxzogo.
Let me just tag on, you know, because you know, we talk about mutation frequency, disease prevalence, as we understand it today, based on the mutations that we've characterized today. So don't forget Kevin's chart about where is that gonna be in two years or in three years or in four years. So, it's Jeff likes to say it's very difficult to characterize, you know, commercial opportunities at times of launch. Well, think about also the size of the patient population expanding on our own, you know, on their own feet. And you heard people like Dr. Miller and Dr. Dauber talk about, you know, we see all these patients who were formerly called idiopathic short stature. Well, how many of those people that have formerly called idiopathic short stature actually have a genetic condition affecting the FGFR3 pathway?
That number is almost certainly likely to be very different in the future than what we understand today. So that makes it challenging. Elena, do you want to comment on clinical trials designs that are-
So maybe before I'm back to the market size, actually, at your conference in January, the J.P. Morgan conference, we presented a slide, if I remember, that showed that if you only look at GSS and ISS patients that are more than three, I think, standard deviations, even five standard deviations from normal, for all those potential indications, that's about 600,000 patients. Obviously, it's unlikely we're going to be able to treat all of them, but even if we can go after 10% of them, that's 60,000 patients. That dramatically increases the potential of Voxzogo, which is more like, you know, 12, 12, 15 thousand patients today.
That, by the way, that 600,000, is referable to the inclusion criteria of Dr. Dauber's study.
Yes.
And so as we think about including more monogenic indications, and he's already talking about expanding his early studies into much more prevalent conditions. So, Elena, thoughts?
Yeah. In terms of design of the clinical development program, obviously, it depends on the regulatory feedback that we'll receive. But yes, particularly in idiopathic short stature, as you know, growth hormone is not necessarily approved globally, so we will have to consider all possible options, including placebo and growth hormone as our competitors—comparators.
So there's, you know, a bunch of different ways to win there, and we're still in discussions both with the academic community as well as the health authorities about, you know, for example, choice of comparator. And there's a lot of different ways to approach that. That could be placebo-controlled, that could be head-to-head against growth hormone. Reflect for a second on the chart that was in Elena's presentation and was referenced by Dr. Miller. Qualitatively, growth hormone after about 2 years doesn't do much, and Dr. Dauber mentioned that final adult height gain for some of these studies is only about 3 or 4 centimeters. So not very effective, not very durably effective. Head-to-head against growth hormone shouldn't be off the table. And then you heard about loss of responsiveness to growth hormone.
That shouldn't be off the table. So I think there's a lot of different ways forward, and I think that plethora of choices is, on its own, great opportunity, but it's also a little bit of a big challenge to chew through, like how do you start the next wave of improving central outcomes in patients?
Hello, everyone. Kostas Biliouris from BMO Capital Markets. One question on 331 from us. Can you discuss how are you thinking about the competition in HAE, given that there are investigational treatments at advanced stages with great data where they almost eliminate the attacks? And secondly, can you provide some more color on the attack rate of these 2 patients who reach the low level of normal? Thank you.
Sure. So, my response to the first part of that question is similar to the response to, you know, kind of the growth statistics in the phase 2 program in achondroplasia. It's very early days for some of these programs, which are kallikrein inhibitors, be it the ASO knockdown or the CRISPR therapy. So I think broader patient populations, more clinical experience, more sort of time to understand what the true treatment benefit is, is something that we're definitely tuned to. The second part of your question, you know, the attack... We're too early to really basically, I think, give you a meaningful kind of set of data on what the attack rates are before and after. But, and it's only two patients really to go on.
So I think I'm gonna defer. But, we do think that, based on the 270 experience, that a stable constitutive expression of the replaced gene has the ability to have more clinical benefit than trough levels, and so that, that level of 10 mgs per deciliter is a true therapeutic goal for gene therapy. We'd like to be able to prove that in the clinic, and so I think over time, we shall.
With one exception, the goal of therapy—I mean, there's a lot of these, you know, interesting, and it's kind of an established market, but they're all chronic therapy markets. So the one exception is editing. And, you know, that has the same potential feature in regard to a one-and-done kind of a benefit. But the flip side of that is it's early days for CRISPR, and I think we do need to appreciate that. If you measure the cycle time from sort of first in human to first FDA approval of AAV gene addition, you know, that is sobering in terms of the kinds of timelines that one could expect for knockdown therapies for CRISPR for gene editing.
There's a lot of technical complexity that has yet to come to the fore.
Hi, Julian Harrison with Stifel. For Dr. Jacoby on BMN 351, do you anticipate that your novel approach and splice site will impact the lag time from exon skipping to dystrophin expression? So when do you all anticipate to take a first look at dystrophin expression when you're looking to establish proof of concept? And then for Dr. Eggan, which cardiovascular program do you find the mechanistic rationale and the preclinical evidence so far to be the most compelling, and why? Thank you.
It's an excellent question. I think, you know, one of the difficulties with taking too early a look in the disease state is the muscles are very differentially affected, proximal versus lateral, and also in terms of the disease progression. So I'm a little wary at looking at biopsy results too early and extrapolating that data. But you did see from that graph, and, and I think we can do even better than this, that the data at 24 weeks is really highly suggestive of a great clinical benefit. So I think we're looking at those biopsy results at 24 weeks as being something that could we can really, you know, feel comfortable with.
Okay.
Yeah, and then with respect to the cardiovascular programs, you know, look, they're, they're all based on really fundamental human genetics, so it's hard to choose between, you know, the fruits of that effort. And, I think they're all very, very compelling. If I was to choose, if I was forced to choose one of them, I would say that, perhaps PKP2 is particularly attractive since the data suggests that, perhaps, you know, just restoring PKP2 in a modest number of cardiomyocytes might have big effects on, stapling the tissue back together. And that, you know, we were kind of worried, well, what, what, what might happen if you just put the protein back in a small number of cardiomyocytes? Would that make things worse for arrhythmias?
At least in non-clinical settings, it really seems like the on-ramp to improvement is pretty early in the number of cells rescued. So maybe that's something that I would point to as you know something to watch. But I'm really excited about each of these based on the mechanistic data and the human genetics that we have.
Salveen Richter , Goldman Sachs. With regard to your Duchenne exon 51 asset, you talked about full-length dystrophin here. Just help us understand when you think about the PMO or PPMO platforms, compare and contrast how we should think about the, you know, the profile that could emerge here versus what we've seen. Hank, you talked about gene editing. Is, is this something that you're looking to bring in-house at, at any point as a, as a modality? And, and then finally, you also mentioned $4 billion-$5 billion in revenue by middle of the decade. Could you speak to, to long-term margins here or longer-term margins? Thank you.
Do you guys want me to grab the first two, or Dave, do you wanna do PMOs?
I'll take a stab at the first, and if you disagree, you can jump in and—
I'm likely to.
Smack my wrist from across the table. So, you know, in terms of the facilitated transfer and the new chemistry, you're getting more in, but you're doing it at a weak site, and so you're working on a fairly shallow dose response curve. So getting more in doesn't necessarily get you more dystrophin. And even going to the new chemistry actually reduces the affinity of the oligo for the target. So they actually have to expand the number of residues that they use in order to overcome that loss of affinity. So for us, we're not so worried about getting it in, but working with a site that has much more potency because we know when we get it in, we're gonna be on a very steep dose response curve. We're gonna have more protein made because the splicing gap is gonna be so much more efficient.
So I think, Hank will say also that, you know, if we can demonstrate that, then adding facilitated transfer to that is just gonna be a bonus. But we think the real key for therapeutic benefit, what's gonna be transformational to the boys, is actually having the higher rates of skipping that occurs with greater biological potency.
Yeah. I mean, I would just add to that to say that, you know, I think we bring a really compelling thesis to the table for families with Duchenne. You know, I think you look at the PMO, you look at efforts from groups like Avidity, and they're trying to either change the chemistry or the targeting to improve the therapeutic index. Well, another approach is to improve the biology overall and to actually better understand what's regulating that event and actually targeting the thing, which is more important, so that with a smaller number of molecules, you have a much bigger biological effect. And that's really what we found in this instance, and that is exactly having the types of properties that that Dave said.
I think, you know, that's an interesting story for those families, because on one hand, they can think about these other changes in chemistry, but they can also contemplate, you know, really what taking a slightly different biological approach would do, and that seems to really resonate with, with clinicians.
And potency is not just a trivial matter here. Some of these other approaches have their own dose-limiting toxicities before they get to the steeper part of the dose response curve. The nice thing about the platform here for us, from an oligo perspective, is we have a pretty good sense of the state of the safety profile of systemic exposure to phosphorothioates.
I'll touch on the margin question. Thanks, Selvene. So yeah, two things to say here. One, you know, at that goal of the $4 billion-$5 billion, and when we talk about, you know, approaching larger biopharma-like margins, you know, there's a wide range of those if you look, you know, call it 30%-40%. So we're talking about crossing into that territory, you know, 30%+. But importantly, this is why I like the question, we're not done at that point. Part of why we're talking about this sustainable business and sustainable pipeline is that in the productivity of our R&D spend, is that we hope to launch some of these assets in the later part of the decade and getting into the next decade.
The $4 billion-$5 billion is hopefully just the next launching pad or stepping stone for BioMarin into that next phase of growth. Back to your margin question, I think that would likewise get us into that next tier of, again, we strive for, you know, top 50 percentile, top quartile. Thanks.
I think we have time for one more question here in the front and the middle.
Hey, guys. Olivia Brayer from Cantor Fitzgerald. One of the panels earlier alluded to less frequent dosing for Voxzogo. And so the question is: Is that a priority for you all at this point to study in the clinic, just considering how the competitive landscape is changing and that there is a bigger conversation around mode of administration? And then just bigger question, obviously, you guys have a lot going on in your internal R&D pipeline right now. So I guess the question is: How do you think about prioritization of assets, or beyond assets, even therapeutic areas of interest?
Well, with respect to long-acting CNP, let me just say that, you know, you've heard today about the many different, I think, exciting applications to CNP and growth, but we've spent very little time talking about the many other, potential applications for CNP and other therapeutic contexts. And so, you know, we've been thinking about that, like, what are the biologies that would be best addressed by a longer non-pulsatile exposure to, to CNP, and have been letting that biology drive us towards that. I think we have increasing, resolve around that and are pushing us towards the IND for that long-acting form of CNP, next year. And we'll be ready to, I hope, say more about that next year as we move towards that. And then, the...
You know, I think there was another part of that question as well, but is that-
In terms of prioritizing, it's really the beauty of the Core four. If we're working on diseases in which we can translate the genetic understandings into mechanistic information that will allow early insights into effect size. And so, and we're really the transformational, the fourth part of the Core four is really the key for us. We're not trying to nibble around the edges. We're really trying to hit home runs. And so the cool thing about this and the proof of concept definitions we put up are, they're really our internal insights about what it would need to be in order for us to feel like we're transformational in the disease areas that we're going into.
Brian also mentioned, increasingly robust governance structure that can look at, you know, time and probability and development costs against sort of what the return is. And, and I think that, that has a lot to do with, sort of he mentioned deselecting certain things, but also, not to minimize the amount of money that gets spent prior to proof of concept, but the real critical decision is, at the gate between a proof of concept result and moving into pivotal clinical trials to represent transformative benefit. That's where the real spending happens. So if we can, see a negative signal early, that's beneficial to the rest of the portfolio.
If we see a positive signal early, it says, go, go, go, because, you know, again, the structure is we understand the biology, and we understand the therapy potential of the asset. So that's, I think, gonna continue to be an abiding set of principles for decision making.
Maybe more comments on VOXZOGO, the way we see it, which is long-acting. So, first of all, you heard from the panel that the observance to compliance by the patient is extremely high right now. Two, we haven't talked much about it today, but we have a pen injector in late-stage development, which is gonna make VOXZOGO even easier to administer. We're gonna launch that, you know, probably in the 25 timeframe. And then three, I mean long-acting CNP is great, but I would say so far, the data presented on the long-acting once a week product from our competition, it doesn't seem to be quite as good as the once a day that we have already on the market in terms of efficacy.
And then for the other compounds as a whole, I think there's still a lot of way to go and make sure that their response is sustainable, and then that there is no toxicity or safety issue, since we are dealing with, you know, very young patients here. You know, we treat a 10-year-old patient in Japan, so I think it's gonna take a while before some of our competitors can generate safety data to make the doctors and the families comfortable with that.
All right, I think we have time for one more. Is that right? Yep.
Thank you for taking my last questions. I know this morning we had a lot of discussion from, you know, the panel discussion regarding Roctavian, and a lot of the interest or patient demand and also commitment from hospital. Our own due diligence also shows similar feedback. However, it seems like the uptake might be a little bit slow, and there is a lot of steps to, you know, get to the step to treat the patients. So my last question is: are you still very confident to maintain this year's guidance of the $50 million-$150 million for Roctavian?
Well, we always escape the day without that question.
Yeah, there is no changing guidance. We will... When we report Q3, then we'll update the guidance, but at this time, there is no reason to change the guidance.
Very good. So I think we're gonna draw to a close and invite you all to join us on a non-lunch. But seriously, grab a water bottle on your way out, and thanks so much for those of you who participated virtually and for those of you who took the trouble to come to meet with us here in New York City. This has been a great opportunity to interact. So have a great rest of your day.
Are you sure? Thank you, guys.