BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript & Summary

Thank you for standing by. At this time, I would like to welcome everyone to the BridgeBio Pharma Achondroplasia Investor Webinar. [Operator Instructions] I would now like to turn the call over to Justin To. You may begin.

Good morning, and welcome to the BridgeBio webcast for the infigratinib program for achondroplasia. Before we begin today, I'd like to remind our audience that we will be making forward-looking statements today. For a discussion of these risks, please see BridgeBio's most recent financial statements. This is an exciting time for a program as we have recently achieved last participant's last visit for PROPEL 3, our Phase III clinical trial in achondroplasia, and we expect to announce top line results by the end of the first quarter. Today, we are excited to be joined by Dr. Janet Legare, Professor in Genetics in the Department of Pediatrics at the University of Wisconsin School of Medicine and Public Health. She is also an investigator in the PROPEL 3 trial, and she is the Director of the Midwest Regional Bone Dysplasia Clinic, one of the largest of its kind in the United States. She will be providing an overview of achondroplasia, its genetic pathophysiology and unmet medical need. We will then have Dr. Daniela Rogoff, who is the Chief Medical Officer of Skeletal Dysplasias at BridgeBio, go through the PROPEL clinical development program and design of PROPEL 3. Finally, I'll be then walking through the commercial opportunity for an oral treatment option in achondroplasia and what the preponderance of mechanistic nonclinical and clinical data suggests for our Phase III. We will then conclude today with Q&A. With that, I'd like to hand it off to Dr. Legare.

Thank you for that kind introduction. Again, my name is Dr. Janet Legare, and I run the Midwest Regional Bone Dysplasia Clinic. Our clinic is 45 years old, and it was started in 1981, and we see patients throughout the lifespan, which gives us a unique perspective in seeing how growth in childhood can affect the long-term outcomes and function of people with achondroplasia. Achondroplasia is the most common form of disproportionate short stature or dwarfism. In fact, more than 90% of patients we see with skeletal dysplasia have achondroplasia. It is a rare diagnosis of approximately 1 in 25,000, but that means that about 15,000 people are affected in North America. Achondroplasia is much more than just short stature. There are many health consequences of having decreased bone growth. And this is because how those bones grow affects the underlying structures. If a patient has achondroplasia, they have a 50% chance of having a child with achondroplasia. But by far, the majority of people with achondroplasia are born to average stature parents. What that means is that they are the first person in their family to have achondroplasia. Diagnosis of people with achondroplasia usually occurs in the first 1 to 2 days of life. It can occur prenatally and about 33% of the time, it does occur prenatally, but we only see it on ultrasound after approximately 26 weeks of gestational age. We can diagnose it prenatally via genetic testing in which we find an FGFR3 pathogenic variant. We can diagnose achondroplasia earlier in pregnancy if one of the parents has achondroplasia, and we are doing surveillance for the diagnosis. To understand achondroplasia, we need to understand types of bone growth. And then we're going to go down to the growth plate level and then ultimately, the cellular level. So we have 2 types of bone growth in our body. By far, the majority of bones grow through cartilage growth plates. These are called endochondral bones. We also have bones that don't grow through cartilage growth plates, and these are called intramembranous bones, and this is the top of the skull, the collar bones and the lower jaw. So what you will see in this picture is that all of those dark blue bones are bones that grow through cartilage. The orange areas are the growth plates. So that is the area where achondroplasia is really doing its work. So any intervention that we hope to have is going to also work at those same areas. You'll see that almost all bones in the body grow through cartilage growth plates. So let's go down to the growth plate level. Again, bones grow through cartilage growth plates. So on the left, you will see a typical growth plate in an average stature individual. And this resting zone is where you have cartilage cells kind of hanging out until they are stimulated to grow. Then they start dividing or proliferating. And you'll see that they are lining up in columns as they enter the hypertrophic zone. This is where those cells are getting bigger and differentiating and secreting compounds that are going to ultimately help the bone cells come in and form bone. Let's look at the achondroplasia growth plate. You'll see that there are less cartilage cells hanging out in that resting zone, and they're more disorganized in the proliferation zone and the hypertrophic zone. There are less cells and they're not lining up into columns. They're also not getting as big. And ultimately, this results in less bone being laid down. Now let's go one level deeper and go to the cellular level. So we have fibroblast growth factor receptor 3, which is a receptor that sits across the surface of cartilage cells or chondrocytes. And when fibroblast growth factor is bound to it, there is an activation of 3 important cellular pathways that ultimately decrease bone growth. These decrease the cartilage cell proliferation, another pathway decreases the differentiation and hypertrophy, and one more pathway increases cell death. So ultimately, activation of FGFR3 decreases bone growth through the activation of these intracellular pathways. So by blocking the activation of FGFR3, we can directly target the overactive FGFR3. And this is done through inhibiting the tyrosine kinases. So again, this is active inhibition of the FGFR3. And it doesn't just affect one pathway in the cell, it affects all 3 pathways, ultimately decreasing the effects of that FGFR3 gain of function variant. So how does this affect the clinical picture? So let's look at the clinical picture of somebody with achondroplasia a little bit more closely. What you'll see on the left is a typical girl with achondroplasia. She has a larger head, a flatter face, a little bit of frontal bossing, a narrower chest, short arms and short legs with some lower leg bowing and a fairly normal length trunk. She has short fingers with what we call a trident configuration and a flatter mid-face. We see these clinical features because of how the bones are affected, and we see the medical sequelae because of how the decreased bone growth affects underlying structures. So people with achondroplasia are born shorter than average stature individuals. And this is a typical growth chart from ages 4 years old up to age 20. And what you'll see on this blue line is the mean general population height per year of age. What you'll see on the lower curve is the typical growth curve for achondroplasia. Children are born shorter than their average stature peers, but they grow further and further away from the curve as they grow through childhood because they grow less per year than children who are average stature. So we want to use the correct growth chart. We want to use an achondroplasia growth chart. Z-scores are standard deviation from the mean. So we use the achondroplasia growth chart. And if that z-score is increasing, that tells us that a child is growing more than typical for a child with achondroplasia. It's not just short stature though. We need to look at proportionality. So in an average stature individual, your wing span equals your height by about age 11. Your upper segment ratio, which is the top of your head to your lower pelvis and your lower segment, the bottom of your feet to your lower pelvis are also equal to 1 at about age 11. What you can see from these pictures that, that is not the case in somebody with achondroplasia. Their sitting height is really almost normal, but their overall height is low. So this affects not only their height, but it affects their function. It affects how you can wash your hair, how you can wipe yourself after toileting, how you can reach things in a supermarket. So what we know is that this proportionality affects function significantly and contributes to the short stature. Ideally, if we can increase proportionality, that is going to improve function. So achondroplasia is associated with many medical issues. And again, this is because of the bone growth affecting the underlying structures as well as how differential bone growth affects other bones. So we are overall looking for improved health and decreased medical sequelae in all of these areas, but the easiest way to measure that is to measure height. And by measuring height and how much a patient grows in 1 year, which is called the annual growth velocity, that tells us if interventions are affecting the growth plate, which then subsequently affects the bone growth. Our overall goal is to improve health and decrease medical sequelae, but height is the metric. We also know that as height increases, mobility, function and quality of life are shown to be increasing. So it's important to remember that height is the metric, but improved health is the goal. Thank you.

Thank you, Dr. Legare, for the great presentation. In this part, I will be sharing about infigratinib and the clinical development program in achondroplasia. Let's start on Slide 18. Infigratinib is an oral, first-in-class FGFR1-3 tyrosine kinase inhibitor that is being developed as a treatment option in achondroplasia. Dr. Legare already discussed how infigratinib can work, so I will not go into too many details. Briefly, the FGFR3 is a negative regulator of the growth plate. In achondroplasia, the gain-of-function pathogenic variance in the FGFR3 leads to the receptor to be on an on status even in the absence of ligand. This leads to improper chondrocyte proliferation and hypertrophy, which caused the bone to grow slowly. We like to use the analogy of a car brake. The FGFR3 acts by pressing a brake on the bone growth. In achondroplasia, this brake is stuck, and it does not allow the bones to grow in a typical way. Infigratinib inhibits the kinase activity of the FGFR3 and with that decreases all the downstream signaling pathway, as a difference from CNP, which only targets one of the signaling pathways. This means that infigratinib targets the condition at its precise source. So going back to the analogy of the car brake, infigratinib releases that brake, allowing the chondrocytes to resume activities, restoring a more typical bone growth. One important point is that even when infigratinib is an FGFR1-3 tyrosine kinase inhibitor, at the doses we are using in achondroplasia, it is expected that only the receptor that is only overactivated gets modulated by infigratinib without getting to inhibit FGFR1 or 2. This is supported by the safety data from our Phase II study that I will be presented in a few slides. On Slide 19, we can see a picture of infigratinib. Infigratinib is being studied as a sprinkle capsule to be administered orally. Capsules, which are 1.1 centimeter in length can be swallowed whole or the content, meaning the granules sprinkled on soft food or taken directly. As you can see, the granules are very small of approximately 2 millimeters in diameter, which makes it very easy to take by children. The strength of each capsule depends on how many granules are inside and each child's dose is based on their weight. Moving on to Slide 20. On this slide, we have the summary of the development program of infigratinib in achondroplasia, which comprises of 5 studies evaluating the safety and efficacy in approximately 300 children ages 0 to 18. The first study is the observational study, PROPEL, that has the objective to collect baseline data on children that would participate in a clinical trial with infigratinib. In this study, data not only on growth are being collected, but medical complications, quality of life are also evaluated, among others. The second study was the Phase II PROPEL 2, which was defined as dose finding and as proof of concept to provide preliminary evidence of safety and efficacy. This study enrolled children 3 to 11 years of age. In the dose escalation portion, 5 ascending doses were evaluated. Cohort 5 dose level of 0.25 milligram per kilo per day was selected to be explored in the Phase III as it was the dose that resulted in the most effect while being safe. I will review the results of this study later in the presentation. Once we have the dose identified, the Phase III study started. Again, I will share a little bit more details later in the presentation as well. The next study is the PROPEL OLE that is our long-term open-label extension study where children received treatment with infigratinib until completing growth. All the children that participated in PROPEL 2 and PROPEL 3 and a group of treatment-naive children directly from PROPEL are offered the opportunity to participate in this study, which will provide information about the effect of infigratinib beyond 1 year and most importantly, the effect of infigratinib beyond growth. To complete our development program in achondroplasia, we have initiated an infant and toddler study, PROPEL I&T, where we will identify the dose and collect safety data and efficacy data in infants and young children 0 to 3 years of age. We are very excited that this study is already underway. As I mentioned before, our Phase II provided a preliminary evidence of efficacy and safety. Results from this study were published in the New England Journal of Medicine. In the next couple of slides, I will go over the results of Cohort 5. On Slide 21, we have the summary of the safety in Cohort 5. Infigratinib was well tolerated with no safety concerns identified. There were no adverse events that led to treatment discontinuations. Most of the adverse events were mild in severity and assessed as not related to study drug. No hyperphosphatemia was observed and not corneal or retinal adverse events were reported. Moving on to efficacy now on Slide 22, we have represented the change from baseline in the annualized height velocity at month 6, 12 and month 18. We can see that treatment with infigratinib in Cohort 5 resulted in a robust increase in the annualized height velocity, which is sustained throughout the study. The change from baseline at month 12 and month 18 was 2.5 centimeters per year, which is highly statistically significant with a p-value of 0.0015 at month 18. At all time points, this response was greater than any other treatment approved or in development for this indication. Moving on to Slide 23. This slide is showing the height z-score and the change from baseline during the 18 months of treatment. As Dr. Legare explained, z-score is a way to standardize a measure, which in this case is height. A z-score of 0 indicates that the height is exactly at the mean of the population. A positive z-score indicates that the height is abide above the mean and a negative z-score indicates that the height is below the mean of the population. The mean plus/minus 2 standard deviation is where the majority of the population is. Height z-score is a widely used way to display and interpret growth measurements. Here, we can see the height z-score and the change from baseline in Cohort 5. An increase in the height z-score indicates that the average height is increasing in relation to the reference population, which in this case is children with achondroplasia. We can see that the height z-score is continuously increasing with a change of over half a standard deviation score at month 18. So when we put the change in annualized height velocity and the change in height z-score together, we can say that the cumulative increase in the growth rate observed during treatment translated into a statistically significant increase in the height in relation to the population of children with achondroplasia. Slide 24 shows the effect of infigratinib on body proportions represented by the upper to lower body segment ratio. At month 6, we had already seen a trend towards improvement in body proportion, which continued to show persistent decrease with longer duration of treatment, reaching statistical significance at month 18 with a p-value of 0.001. This improvement in the upper to lower body segment ratio after only 18 months demonstrates strong potential for a meaningful effect on body proportionality. In summary, results from the Phase II study were very promising and allowed us to start a Phase III pivotal study. On Slide 25, we have the study design of our pivotal Phase III study, PROPEL 3. This is a double-blind, placebo-controlled trial to evaluate the efficacy and safety of infigratinib in children 3 to 18 years of age with potential to grow. As you can see, PROPEL 3 covers the largest age range of any randomized controlled trial ever conducted in achondroplasia. Children had to have completed at least 6 months in PROPEL before enrolling in a 2:1 randomization ratio to receive either infigratinib or placebo. Children received treatment for 52 weeks and then are offered to the possibility to roll over to the long-term extension study PROPEL OLE. The primary endpoint is the change from baseline in annualized height velocity compared to placebo and the key secondary endpoints are the change from baseline in height z-score and in body proportions also compared to placebo. Other secondary endpoints are safety, change in quality of life, participant and caregiver evaluation of treatment benefit, which is done by qualitative interviews, among others. We are expecting top line results later in Q1, as Justin indicated in the introduction. So now I will pass it over to Justin. Thank you.

Thank you, Daniela, and thank you, Dr. Legare. Ahead of the PROPEL 3 readout, I wanted to summarize the holistic totality of evidence that makes infigratinib potentially the best-in-class treatment option for achondroplasia. As Daniela and Dr. Legare mentioned, it is the first treatment option in development for achondroplasia that is a true precision therapy, targeting not just MAPK, but STAT1 and all other important pathways downstream of FGFR3. In the definitive mouse model, we saw some of the most profound efficacy to date on long bones and most importantly, for the first time, efficacy in the foramen magnum and spine. In PROPEL 2 across multiple dimensions, we saw the largest degree of efficacy in any clinical trial. the largest change from baseline in annualized height velocity, the highest absolute AHV, the largest change in height z-score and most notably, a statistically significant improvement in upper to lower body proportionality. These results were all published in the New England Journal of Medicine. We are the first and only recipients of the breakthrough therapy designation from the FDA in this space, having met the regulatory requirement of showing evidence of substantial improvement over standard of care. And most importantly, if approved, we will be the first oral treatment option in this space, avoiding the significant challenges associated with the CNPs and repeated injections from hypotension and injection site reactions and the psychosocial burden for both caregivers and children. Given the totality of this evidence, we believe infigratinib, if approved, can be the market leader in this space. We will be sharing some of the market research that supports this hypothesis in the next few slides. Now before we get into what the market research tells us, it's important to highlight the forecasting capabilities we have built at BridgeBio. By incorporating comprehensive physician surveys, analogs and the multiplicity of proprietary databases and models, we are able to better predict physician behavior and preferences. This has been proven with our earlier market research on Attruby, which has predicted our strong commercial uptake to a remarkable degree of accuracy. We've applied this rigor and methodology to conduct extensive research on infigratinib, which I'll be going over in the next few slides. Now we conducted an extensive physician survey with nearly 100 HCPs who together see approximately 40% of children with achondroplasia in the United States. Above all, one message was loud and clear from this research that the value proposition for an oral FGFR3 inhibitor is incredibly compelling to physicians and families. Across almost every TPP we tested, we are projected to win over 50% market share in a 3-way market. Notably, this market share number was consistent regardless of the point estimate on AHV that we tested. This finding is consistent with analog research that we've done in spaces like rheumatoid arthritis and PAH, where stakeholders place a premium on the holistic benefit for families across convenience and quality of life. It's clear that as long as there is a safe oral option available, physicians will want to use it. On the next slide, to better understand these market dynamics, clinicians were asked to rank on 1 to 9 scale, the attributes most likely to drive switching from current therapies. The strongest driver by far was oral administration with 94% of respondents citing the ability to avoid injections as a compelling reason to switch. This was closely followed by targeting FGFR3 to address the causal biology. Both of these factors ranked well ahead of incremental gains in efficacy. Now moving on to the next slide. We wanted to place this all in the context of the overall market opportunity and the remaining white space. Globally, there are over 55,000 individuals living with achondroplasia with open growth plates, which implies a market opportunity of over $5 billion. Only about 10% of these individuals are on a treatment option today. We believe an oral therapeutic option is not only helpful but necessary to unlock the full market opportunity in achondroplasia. On the next slide, we try to better understand this treatment-naive population. By far and away, reasons relating to the burden or tolerability of injections are described as some of the most significant barriers to uptake today in the United States. 94% of physicians surveyed included in their top 3 reasons and 45% of clinicians had this as their #1 ranked reason for not prescribing today. This is backed up by what we've heard from caregivers and family members. There are many families who are on the fence about trying treatment and having to go through daily or even weekly injections makes this discussion a nonstarter. We hear constantly from families about the psychological stress of giving their children with repeated injections with concerns about how it impacts the relationship with their kids. We can and we should do better for families of children with achondroplasia. Now moving to the next slide and bringing this together. We see PROPEL 3 as the culmination of a scientific story that started in 1994, when gain-of-function mutations in FGFR3 were first identified as the cause of achondroplasia. This led to the seminal paper in JCI in 2016 by our collaborators at [ Inserm ] that demonstrated profound improvements in achondroplastic mice for the first time with infigratinib. Eight years later, we published our seminal results from PROPEL 2 in the New England Journal of Medicine, demonstrating proof of concept that directly targeting FGFR3 can lead to more and deeper efficacy in the clinic. And that brings us to the PROPEL 3 top line in Q1, where the totality of evidence we've discussed today leads us to believe that we can and should be doing more and be doing better for families of children with achondroplasia. Now with regards to the PROPEL 3 readout, what does doing more and what is doing better look like? First, on safety, it will be important to not have symptomatic hypotension or injection site reactions. And we would want to see a low-grade hyperphos (sic) [ hyperphosphatemia ] rate of less than 10%, which, by the way, is far below the rate seen on the labels of other growth-promoting agents that were commonly used like weekly growth hormone. On growth, there's 2 dimensions that matter. The first is that we want to be able to see a change from baseline in annualized height velocity of more than 1.5 centimeters per year against placebo. Second, and just as importantly, we want to be seeing an improvement of more than 0.3 standard deviations on height z-score on the treatment arm, which is the upper limit of what was seen by the CNPs. As mentioned by Dr. Legare, change in height z-score helps contextualize the child's height against the achondroplasia age and gender match population. On proportionality, we want to see a decrease of 0.05 or more from baseline on treatment arm, which would be the largest effect seen at 52 weeks in any trial. A home run scenario would be if we see statistical significance, which would be unprecedented in a 52-week trial. Either of these outcomes could potentially lead to a significantly differentiated label. We are doing all this in the backdrop of running the most ambitious pivotal trial in achondroplasia spanning ages 3 to 18. While we know that this may impact our primary endpoint, given that in other trials, the youngest and the oldest kids showed the least treatment effect, we think it is important to aim for the broadest possible label at launch. Finally, in terms of doing more for families, I would be remiss without mentioning our commitment and our interest in looking at measures beyond height in our longer-term open-label extension trial, particularly impact on skeletal changes, quality of life and continued impact on proportionality. To conclude, we are excited for infigratinib to not only just be a potential first-in-class oral, but the potential best-in-class treatment option for children and individuals living with achondroplasia, and we expect top line results for PROPEL 3 by the end of Q1. We are building the capabilities required to support a global launch and are actively interrogating opportunities to deliver on the full potential of the molecule, first starting with hypochondroplasia and potentially other FGFR3 implicated conditions like Turner syndrome and SHOX deficiency. With this, I'll turn it over to the moderator to begin the Q&A portion of today's call.

[Operator Instructions] And your first question comes from the line of Salim Syed with Mizuho.

Just one for maybe the physicians on the line around hyperphos (sic) [ hyperphosphatemia ]. Can you just maybe clarify -- I know you kind of -- I know, Justin, you referenced this less than 10% number here. But for the physicians on the line, just maybe could you put it into context for us, just how do you think about hyperphosphatemia as a safety consideration in the space for FGFR inhibitors for this disease? And just related to that, Justin, can you just remind us if the BridgeBio team has access to blinded safety data for this PROPEL 3 study?

Thanks so much for the question, Salim, and thanks for everyone for joining the call today. So I'll take this first, and I'll kind of bring it over to Dr. Legare to give her clinical perspective. So again, as we mentioned earlier, we've done a lot of research with clinicians and low-grade hyperphosphatemia isn't really something that concerns them, especially if it's less than 10%. Now it's quite common with other growth-promoting agents. And again, to contextualize this, the hyperphos (sic) [ hyperphosphatemia ] rate on the various daily and weekly growth hormones are like 20% to 40%, and they don't require any special monitoring. And now I'd like to pass it over to Dr. Legare to give her clinical perspective.

Thank you for the question. This is a really good question. And I thought about it a lot when I joined the trial, to be quite honest. And I also spoke with my nephrology colleagues to make sure that this wasn't getting brushed over. Let's talk about hyperphosphatemia first. Levels are higher in younger children, and they stay high as they grow. And over 2 decades, they eventually decrease to levels that are seen in adulthood. So I am specifically not worried about any level that's 7 or under. But with decades, and again, decades, like 30, 40 years, hyperphosphatemia levels in like 8.5 to 9 range, you might see a little bit of vessel calcification. But chronic low-grade hyperphosphatemia is extremely well tolerated. So I am specifically not concerned, and we really can't use a blanket statement on hyperphosphatemia because it, again, varies throughout childhood. Another thing to put out there is that if you are a late bloomer, for example, you go through puberty at a later age, your fast -- first level is going to be higher. And so this really needs to be looked at in the context of the whole child. So again, I'm not worried about it. Chronic low-grade hyperphosphatemia is extremely well tolerated. And as Justin mentioned, these are -- this is seen in human growth hormone as well. And that's, again, any time you're stimulating growth, you might see some increase in phosphorus levels.

Okay. And just, Justin, can you just answer the other part of the question here? Do you guys have access to blinded safety data here? I mean are you flying in blind? Just give us some context.

Yes. I mean recently, we just achieved last participant's last visit. So the study is still kind of undergoing the data cleaning before database lock. So again, I don't really see that.

Your next question comes from the line of Biren Amin with Piper Sandler.

Maybe to start off with a question for Dr. Legare. In your practice, roughly, what proportion of patients remain untreated today? And what are the most common reasons why they're not choosing to go on treatment? And how do you think families and patients would view the possibility of an oral therapy?

Biren, thanks for the question. I'll hand it over to Dr. Legare for this one. I think she's going to be the best one to talk about it.

Thank you for the question. I think it's a really good one. Approximately 40% of the patients I see with achondroplasia who would technically qualify for a treatment modality are not on treatment. And the reasons vary. One is the shots. There's no question that the primary reason is the injections. The second reason is that people are in puberty. And they are like, do I really want to do a shot every day for 2 more years to maybe get another inch. So I think it's really important that we start treatments early. I think it's important that we show disproportion. They don't want to just be taller. They want to have improved function. But primarily, it's that they don't want the shots. There's no question. And I think as we're showing more data and specifically, if we can show proportionality, if we can show improved height, then that's going to be a game changer. I think there's a lot of room for people to be on treatment. And again, my hope is that as we're improving height and we're improving annualized growth velocity, that's going to tell us that these bones are growing and ultimately transition to decreased medical sequelae. And I'll be honest, I have quite a few people on injections, and they are all asking when is the oral going to be available. It is very rare. I might have 1 or 2 people or 1 or 2 families who have not asked me that question. They are all just buying their time until the oral is available. And so I feel like more than half of my patients on injections are going to be switching if or when this is approved by the FDA, if the results are promising, which I anticipate. Does that help?

Yes.

Your next question comes from the line of Tyler Van Buren with TD Cowen.

Another one for Dr. Legare. From a Phase III and real-world decision-making perspective, what minimum magnitude of improvement in annualized height velocity would you view as clinically meaningful for families considering a daily oral therapy that would lead to broad uptake or at least half, if not a majority of patients going on an oral compared to the injectables?

Thanks so much for the question again. I'll take this first, and then I'll hand it over to Dr. Legare to chime in. It's interesting, again, from our research and discussions with physicians and more importantly, caregivers. Many already view this as like a best-in-class therapeutic option given the totality of evidence from the mechanism and us having like a route of administration that fits into life with children, right? Would you rather have over 4,000 injections, over 600 injections or 0, right? And so on efficacy, given what we see on the Phase II, we also expect to outperform on efficacy across multiple dimensions. And I'll hand it over to Dr. Legare to talk about what's kind of the bar she would expect or want to see for families to think about switching.

So this is another great question. The -- for patients to want to switch, we only need to see the same efficacy as with the daily injection. So we need to see an extra 1.57 centimeters per year that they are on the treatment. So really, a home run would be seeing more than that. But I think that at least 50% of my patients that are on treatment would be changing if it was at least as -- if it was even just as efficacious as the current injections. Now again, I believe having seen some of the Phase II data that came out and just looking at the class that this is inhibiting all 3 cellular pathways instead of just that MAPK pathway. I believe that this is going to be more effective. But again, it only has to be the same for it to be meaningful and for it to have a significant market share, I believe.

Your next question comes from the line of Andrew Tsai with Jefferies.

There are obviously these -- a few programs out there for ACH. Ascendis just reported some combination data this week. So I wanted to gauge your guys' thoughts on those findings specifically. And then broadly speaking, maybe talk about the potential for infigratinib to be a combination treatment. Is this a truly winner take-all for infigratinib? Or can it be actually combined with the CNP analog since its mechanism is pretty unique?

Yes. No, thanks so much for the question. I'll take this first, and again, we would welcome Dr. Legare's thoughts on this as well, given her experience. So again, we weren't really surprised by the combination therapy data that was released yesterday. So again, numerically, it looks really impressive. But if you look closely, the data -- all data, whether it's change of baseline AHV or absolute AHV that was released yesterday is remarkably consistent with what's been shown in the literature for nearly 30 years now of the fact that human growth hormone monotherapy in achondroplasia and other growth conditions where there isn't growth hormone deficiency like Turner and other conditions. So what you see in those conditions with growth hormone alone and in achondroplasia is you see like absolute AHV in the 8s and 9s for about 18 to 24 months before it falls off significantly, which is why it's never been approved by the FDA, nor is it why -- nor why it's not used by clinicians in the United States today. So it's very unclear if anything, what CNP is doing on top of that, which is probably why they didn't really show a CNP -- sorry, a human growth hormone-alone control arm. The analogy I like to use is if you're going like a fast car going 100 miles per hour and you throw a ball out of the window, the ball is technically going 100 miles per hour as well, right, but car that's doing all the work. Dr. Legare, I would welcome your thoughts on kind of combo with human growth hormone as well.

So I'm going to answer 2 parts of that question because I think there were 2 questions. One was, what do I think of the human growth hormone and TransCon CNP combination data. But then if I'm correct, your second question was, would we ever use a tyrosine kinase inhibitor like infigratinib combined with the CNP analog. Is that correct?

Yes.

Okay. So let me answer the first question, which is the human growth hormone and TransCon CNP. This came out of the COACH trial through Ascendis. And this is using the weekly human growth hormone combined with the weekly CNP, which is navepegritide. I think this was -- it's obviously very impressive data. What we know, like Justin was saying, is from all of the previous studies, you get a really good response with growth hormone really in anybody for the first 6 to 9 months you are on there, but then -- on it, but then it peters out. And so I don't think that using human growth hormone and CNP together is ever going to be a long-term option. I do think that it may be one of those options where if a child isn't responding really well, maybe you use a boost of that for 6 months. But it is never going to be a long-term option where they are on this for their life. So that's kind of for that first question. We know from a hormone standpoint that achondroplasia arises because of a difference in the growth plate. It does not arise because there is less growth hormone. So you can stimulate this pathway all you want, but then ultimately, it will equilibrate and it will become less effective to the human growth hormone, whereas these specific medicines, they work at the cellular level and the cell and the growth plate are not going to become tolerant of them, if that makes sense, whereas they will become tolerant to the growth hormone. An answer to the second question, which is, do I ever see a role for combination therapy of using the FGFR3 inhibitors compared with the CNP analogs. Gosh, in an ideal world, I would love to see that maybe in the infant population so we can decrease foramen magnum stenosis, which one works better or if we use both together, can we really prevent these infants needing cervical medullary decompression. So I could see a time when maybe there's a combination, but the question is really going to be in the American market, will an insurance company pay for both? And I would love to see it, especially in those first few years of life when we could really make a big impact. But as a physician, I am going to choose whichever medicine is going to block the most of -- the most pathway in an infant because I want the biggest efficacy. And I want to work -- I really want to get the most bang for my buck. And at this point, I think you're looking at the FGFR3 inhibitors a little bit more than the CNP analogs for blocking more of those cellular pathways. Does that help?

Helps a lot.

Your next question comes from the line of Mani Foroohar with Leerink Partners.

Thanks for taking the question and for taking the opportunity to give us a little bit of table setting ahead in the data here and some perspective. I've got a couple of follow-up questions on colleagues that have asked previously, but we'll start with the age range of the Phase III study. Can you give us a sense of what kind of the advantages and the strategy is behind studying a broader age range? And how we should think about efficacy in terms of AHV for each age group, the younger patients below 11, the very youngest, the oldest above 11, et cetera.

Yes. Thanks much for the question, Mani, and happy to take that. So again, just as a reminder, this is the broadest age range that's been studied in a Phase III trial, again, looking at 3 years to 18 years old. And the reason is we want to look for the broadest possible label. Obviously, there's a trade-off here where there is less of a treatment effect that's been seen in the previous trials in the space in a 3- to 5-year-old population and those above 11 years old. I think it was like [ 0.77 ] per year in the BioMarin Phase III when you look at the 11 population. And when you look at the various populations like less than 5, it's like about plus 0.1. Again, given what we saw in our Phase II data, we thought it was really important to be ambitious here, right, because it's really important to -- based on all our market research, what everything is indicating that as long as there's an approved option in a given age range, physicians are really interested in using it. So that really kind of drove our strategy of why we wanted to go so broad with the Phase III to kind of get the broadest possible indication here so we can kind of get access to as many as possible. Now I think with regards to kind of the different ages that we would expect in these populations, it's going to be tough to tell, right? Because obviously, there's only been a few trials run in this space. So again, I think overall, it's going to be, for us, a win here, honestly, is what Dr. Legare mentioned that at least looking around parity would be really important here.

Great. When you talk about being ambitious here, should we think about a need to reformulate for newborns to less than 2-year olds? Is that same formulation, but it's a different study? And how should we think about the time line?

Yes. No, great question here. So we are running a separate study for infants and toddlers with achondroplasia basically from birth to 3 years of age. And so -- that's actively ongoing right now. And what's interesting is basically for almost all kids, but the very youngest, they can actually take kind of the same formulation, which is like mini tablets -- the mini-tablet formulation that we have. It's really only for those that are the youngest, but basically those who are less than 6 months, we're looking at a slightly different formulation, but there's past precedents of different oral formulations that are suitable for kids younger than 6 months of age. Does that help answer your question?

That's helpful. And one sort of second question, which I've gotten a couple of inbounds about. You guys have talked quite transparently about your market research. There's been a lot of very transparent investor communication. One of the conversations I've had with [indiscernible] the market recent you guys are testing are hyperphosphatemia at the less than 10% ratio sort of being a sweet spot. Should we take that to be your expectation on this study in terms of proportion of patients showing hyperphosphatemia? Is that the wrong expectation? Like how -- what should we be looking for and expecting?

Yes. No, I think, again, the less than 10% number is something that we've extensively tested and have thought about. And again, just kind of really given the totality of what we've seen in the Phase II would be something that I think would be kind of an appropriate bogey for us to be thinking about here. Again, I think that's also -- as Dr. Legare mentioned early in the presentation, it's really far below the rates that have been seen on other growth promoting agents as well. So I think less than 10% would be a huge win.

Your next question comes from the line of Danielle Brill with Truist.

I guess one for Dr. Legare. Are there any advantages in your view of infigratinib's profile versus other emerging FGFR3 selective assets in the pipeline? And then based on the data that had been generated so far, what is your view of infigratinib's profile versus these other emerging approaches? And maybe quickly, just a quick reminder from Justin. Can you remind us what the latest thinking on plans for ex-U.S commercialization are?

Yes. I'll take both questions. So on the ex-U.S. commercialization piece, I think we are very interested in looking to commercialize outside the United States, given that this condition is really seen at a few concentrated centers of excellence in other countries. And so we're actively looking to build our footprint in those geographies and think between the profile of the drug, the data that we hope to see and our relationships with these kind of key sites that we can really be set up for success here with a kind of thoughtful build. Now with regards to the other FGFR3 inhibitors in development, I think there is kind of fundamental issue with their key hypothesis, right, which is they think they can do better by sparing FGFR1 and 2 and therefore, which could lead to a higher therapeutic index. And I think there's 2 kind of fundamental flaws with that. The first is around the actual benefit of sparing FGFR1 and FGFR2. From the data to date with infigratinib and from what we expect to see in FL3, I think it's clear that we're far from the doses where we're really inhibiting FGFR1 and FGFR2 compared to FGFR3. And I think we have a significantly broader therapeutic index than what's being portrayed. And so if there's, for some reason, ever a need for more efficacy for a subset of individuals, I wouldn't see any challenges with exploring a higher dose of infigratinib in that subset. And so that, in my opinion, really obviates the need for other FGFR3 inhibitors, which would be significantly behind. I think the second issue with that is what this trade-off with FGFR3 selectivity actually entails. So what happens is when you're trading off selectivity for FGFR1 and FGFR2, they actually trade off for more selectivity on off-target effects like FGFR3, which we know is closely linked to spermatogenesis and angiogenesis. And so as a result, some of the other programs that have this liability have been required by the FDA to kind of essentially discontinue males once they get close to puberty. And we also know from genetics that there are conditions caused by loss of function in FGFR3 like Milroy disease and other conditions as well. So hopefully, that answers your question.

Due to time constraints, that concludes our question-and-answer session for today. I will now turn the call back over to Justin To for closing remarks.

Yes. Again, I really appreciate everyone being able to join the call today, and we'll talk to you all on the other side of the top line. So thanks so much.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.