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

Good day, and thank you for standing by. Welcome to the BridgeBio Phase II Data Results for Infigratinib in Achondroplasia Event. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Neil Kumar, Founder and CEO, BridgeBio.

Thanks, operator, and thanks, everyone, for taking the time to join us this morning. As a quick reminder, I'll be making forward-looking statements today, and please refer to our SEC documents for more information. We're collected to review our Phase II cohort 5 achondroplasia data, a data set that, as many of you will have read, accesses new heights in efficacy alongside a differentiated safety and convenience profile. With these data, we answer key questions that have previously [indiscernible] us, such as why have the responder rates reported across therapies to date been so low despite the consistency in specific FGFR3 point mutation in this condition? And why previously could we not access absolute annualized height velocities with therapy in the 7-centimeter per year or greater range? As we report this morning, higher response rates and magnitudes than previously reported can be achieved safely and with a convenient oral medicine. The promise of these data that we present today also correspond to a responsibility, a responsibility to study this therapy broadly and efficiently, both within achondroplasia and related skeletal dysplasia such as hypochondroplasia. I'll keep my introductory comments brief this morning, as I'm privileged to be joined by our own internal leadership team, helm by Dr. [ Danielle Rogoff ] and one of the leading experts in this field, Dr. Ravi Savarirayan, who has been a guiding light to many in the achondroplasia field and a true champion for patients across the genetic disease landscape. I'll refer to slide numbers as I'll walk through deck, so you can follow along. On Slide 3, the first of the content slides, I'll build on that last comment and thank all of the physicians, children, families and advocates associated with this trial. As ever, we depend on your efforts, past and present and are grateful to partner with you. Turning to Slide 4. This provides an executive summary of sorts. And I'll highlight 5 salient points that the team can expand on later in some detail. First, we're providing here the highest, at least to our knowledge, mean change from baseline in AHV with 3.03 centimeters per year, and as I referred to earlier, the highest known responder rate we've seen as well. The team will walk through the individual patient data later, so you can get a sense for the consistency of response. Second, we see here a mean absolute AHV of 6.77, and as will be referred to later a median of about 7.6 centimeters per year. This means the median patient is experiencing growth well outside the natural history of achondroplastic growth. We view these data as effectively top taking what's possible in AHV and are hopeful that they portend impact on key additional measures that are meaningful, such as proportionality and spinal stenosis, something we aim to study in Phase IV clinical trials. Third, across all characterizations of efficacy and inclusive of our key biomarker college intend, we see a dose response, consistent with our preclinical studies. Fourth, we're providing these data with 0 treatment-related adverse events, avoiding [ hyperphos ] and providing differentiation as compared to competitors that exhibit substantial injection site reaction rates and decreases in blood pressure. And finally, fifth, based on the totality of this evidence, we have commenced our Phase III achondroplasia trial. And again, thank the community for the enthusiasm and support we have already observed as we begin. We expect additionally to begin a study in hypochondroplasia later this year. Moving to Slide 5, a brief reminder of how this important program fits in with the broader late-stage mendelian efforts ongoing at BridgeBio. Importantly, by the end of this year, this will represent the second large program focused on the pediatric endocrine call point alongside -- and ADH1. It represents the first major readout of the year for us with the second and final being our Phase III readout in ATTR cardiomyopathy midyear. And finally, it's another good example of the capital and time efficiency we strive to for at the programmatic level. Okay. Turning now to the more detailed setup on Slide 6. I'll kick things off by reminding everyone of what the design principles were when we embarked on this program. We were aiming to accomplish 3 things: First was to maximize the efficacy by uniquely targeting the condition at its source, something we always do here at BridgeBio. In this case, a gain of function point mutation in FGFR3 and therefore, attempting to normalize signaling across both of the key effector pathways associated with chondrocyte differentiation and proliferation, namely the MAPK and JAK-STAT signaling pathways. Second, to achieve this efficacy safely and to avoid hypotension. And finally, with an understanding that we might be treating chronically for years to provide this efficacy in a convenient oral form that avoids injections. Slide 7 outlines the populations we have an immediate responsibility to assist with if we have the aforementioned design principles in hand. We're committed to the broad study of this agent, as I mentioned earlier, where ever experts and disease pathomechanisms suggest this drug could be helpful. Ravi has a deep knowledge of FGFR-driven skeletal dysplasias and beyond and the associated communities. So I'll hand it off to him at this point. Ravi?

Thanks very much, Neil, and thank you, and good morning to everyone on the call. So as Neil has said, achondroplasia is caused by an FGFR3-driven mechanism and infigratinib attacks this condition at its very source. But indeed, we have numerous other conditions that I look after and many children with related FGFR3 conditions that have the same underlying mechanism and these include hypochondroplasia, but a variety of other FGFR3-driven disorders that affect the bone growth, and this then leads to impaired function and other medical comorbidities. So we believe that this medication will have a very broad platform well outside just achondroplasia and be amenable for other conditions that are caused by the same molecular mechanism. And so this will access, as you can see, 15,000 to 25,000 children, but that's only in the U.S. and Europe; of course, worldwide, there will be many thousands more. Moving now to Slide 8. It's very important to remember that achondroplasia is not a condition of just height. It comes with the risk of serious medical complications across the lifespan. As a clinician who has been looking after children and adults with achondroplasia for 30 years, it has always been my passion to not just preside over illness but to actually see how we can help these children to make their lives better so they continue to be healthy throughout their lifespan. Specifically in achondroplasia, there are incredibly life-threatening and important manifestations in the first 5 years of life. The most severe of these is the risk of sudden death, which, if you have a child with achondroplasia, is 50x more that than if you don't have a child with achondroplasia, that's 50-fold. We believe this is due to critical narrowing of the large hole called the foramen magnum, which I'll talk about more, with then compression of the spinal cord. And as the children grow on to young adults and into adulthood, they have severe spinal and orthopedic potential complications such as stenosis or narrowing of the spinal cord, limb deformities and kyphosis, all of which can decrease their function, increase their health problems and decrease their healthiness and ability to participate in their lives. And it's important to remember that achondroplasia mainly affect bone, but this has related effects on functioning and general health, including dental complications, ENT complications, sleep issues and all of this then leading on to challenges of activities of daily living, pain, impact on function and decreased quality of life. So it's important to remember that achondroplasia is not a condition that only affects height. Moving on to Slide 9, just to talk you through a little bit more about stenosis of the foramen magnum. This is probably the #1 concern in terms of mortality and morbidity in children with achondroplasia. The foramen magnum is the large hole where the brain becomes the spinal cord. In all children with achondroplasia, this is narrowed. And this [ will lead ] -- results in compression of the vital structures that pass through here that results in sleep disorder breathing, problems with tone and sudden death. And unfortunately, I've had the unfortunate experience of having 2 or 3 children in my career who have had a sudden death who have been previously well and has been one of the great motivators for me and my colleagues and indeed for companies like Bridge to make sure that we can find a treatment that can help with this. And at the moment, there is worldwide no consensus on an evaluation. There's no prevention, and we really do have an unmet need for a treatment here. Moving to the next slide. I touched on sleep disorder breathing, that is present in almost all children and almost all adults with achondroplasia and this leads to a lot of severe medical conditions, it leads to time off work, it can lead to traffic accidents due to adults being more tired when they're driving their car, and there's a huge problem in people with achondroplasia. And it can present as either obstructive apnea or central apnea, which we believe is related again to compression of the foramen magnum. So again, a really important unmet need in achondroplasia and people living with achondroplasia. Moving to Slide 11. This is the spinal complications I talked to you about. Children and adults living with achondroplasia from early teens can have an increased risk of debilitating spinal complications due to the narrowing of the spinal cord at all level in people with achondroplasia. My colleague who did his PhD on this show that up to 70% of adults have chronic back pain and spinal stenosis which decreases the ability for them to participate in work and decreases their employability as well as obviously decreasing their quality of life. And we still have no effective treatment or monitoring of this, and there is widespread practices. And so again, another clear unmet need in this condition. And I will finish up by making some concluding remarks later, but I will now hand over to Danielle, who will talk you through the PROPEL clinical program. Thank you, Danielle.

Thank you, Ravi, for the excellent presentation and for contextualizing the complexity of this condition and the need for treatment options. And good morning, everybody, and thank you for calling in. So this brings us to our program of infigratinib in achondroplasia. In the next slides, I will give you an update on our program. First, I will summarize the current studies that are ongoing, then I will provide more detail on the Cohort 5 data that Neil summarized earlier, and lastly, I would share about our next steps. So let's start on Slide #12 with a high-level overview of our program, which currently consists of 3 studies. The running observational study enrolling children with achondroplasia 2.5 to less than 17 years of age, and this study is designed to contribute to the characterization of the natural history of this condition and to collect the baseline growth measurements in children who may participate in an interventional study with infigratinib. Additionally, baseline key endpoints, such as health-related quality of life, body pain, functional abilities, medical and surgical events are also collected in the study. The second study, PROPEL2, is a Phase II open-label study of infigratinib in children with achondroplasia, who are 3 to 11 years of age of study entry and who completed at least 6 months of observations in PROPEL. This study is designed to provide the preliminary evidence of efficacy and safety of low doses of infigratinib in children with achondroplasia and to select the dose of infigratinib to be explored in the pivotal trial. The third study is the Phase II open-label extension study in [indiscernible] complete an interventional study with infigratinib where we evaluate the safety, tolerability and efficacy of long-term daily doses of infigratinib. This study is key to evaluate the potential benefit of infigratinib in outcomes that will require longer [ time to present ] such as quality of life, functional abilities, pain and complications associated with achondroplasia. Today, we want to focus on the PROPEL [indiscernible] Cohort 5 data. On Slide 13, we have the demographics of the children enrolled in Cohort 5. Twelve children are actively participated in this cohort, 7 girls and 5 boys. The mean a study entry was 7.24 years with most of the children between 5 and 8 years of age. Although majority of the children are white that is a representation of other regional background showing diversity, which is very important to have in clinical trials. From the 12 children in this cohort, 10 had their month 6 visits completed, and those are the ones included in the main analysis presented here. The additional children who have not month 6 visit yet, however, they seem to have a very good response to infigratinib based on their month 3 data that I will show in future slides. Moving to Slide 14. As Neil highlighted earlier, Cohort 5 showed an incredibly exciting data set that reflects the great potential of infigratinib to provide meaningful benefit for children with achondroplasia. When evaluating our cohorts, infigratinib shows a clear dose response in the change from baseline in the annualized height velocity with the Cohort 5 dose levels resulting in a mean increase from baseline of 3.03 centimeters per year, which is the largest ever reported for this condition. 80% of the children responded to the Cohort 5 dose level with a mean change from baseline among responders only of 3.81 centimeters per year. Cohort 5 also demonstrated a strong effect with 60% of the children having an annualized height velocity over 7 centimeters per year at month 6, which is above the 99 percentile for the growth [ curve ] in achondroplasia. Infigratinib also demonstrated a very robust dose response in absolute annualized height velocity, although we believe that change from baseline in the annualized height velocity is a better measure to account for [ intersubject ] variability. Collagen X marker, a biomarker of skeletal growth, further supports the robust dose-dependent responses -- response to infigratinib. These are all very promising results with all of them showing a real clear response. I will be focusing on each of these results in next slide. On Slide #15, we have the change from baseline in annualized height velocity from the 10 children who had the month 6 visit. You can see the clear dose response and the significant increase from baseline in the annualized height velocity of 3.03 centimeters per year. This is highly statistically significant with a p-value of 0.002. On the table to the right, we also have the absolute annualized height velocity in Cohort 5 the changes from an average baseline of 3.73 centimeters per year to a mean of 6.77 centimeters per year at month 6 with a median of 7.6. The additional 2 children in Cohort 5 were not included in this analysis because they have not had the month 6 visit yet also show a very strong response to infigratinib at monthly, and I will show this later in the presentation. Let's move to Slide 16. [Technical Difficulty]

Hey, operator, can you hear us?

Yes, I can hear you.

Okay. Perfect. We'll just keep moving to the slides, and hope that Danielle rejoins here. I'll hand it over to Justin To, who leads our business development and operations to finish up their slides, and then we'll get into questions.

Great. So on Slide 16, following up from Danielle. Here, we show the response rate in Cohort 5. Again, back in Cohort 4 we demonstrated a 64% response rate with response rate defined as the percent of children who had a change from baseline of at least 25% from baseline. In Cohort 5 excitingly, we see an 80% response rate. And of the responders, we actually have a 3.81 change -- centimeters per year, change from baseline with a median change of baseline of 4.14. Again, showing that infigratinib has a broad effect that is fairly consistent among children with achondroplasia. Moving to Slide 17. This is something that really excites us. Here is the individual level data across all Cohort 5. On the left-hand side, we have the 10 children who have completed their 6-month visit and on the right-hand side, we have the 2 children who have not yet completed their 6-month visit, but we have 3-month AHV data cohort. Just as a reminder, for the 10 children that we...

Can you hear me? Can you hear me now?

Yes, you're back on, Danielle.

I'm so sorry. I don't know something went wrong with the connection back [indiscernible] tell me which slide was the last one I was [indiscernible].

Yes, we're on Slide 17 now, Danielle. We're live.

We are fine. Okay. Great. Perfect. So on Slide 17, so we have -- on this slide, we have the annualized height velocity of each of the children in Cohort 5. The gray bars represent the baseline annualized height velocity, and the blue bar, the annualized height velocity after 6 months of treatment with infigratinib. You can see the impressive change in the annualized height velocity after the 6 months of treatment in most of the children. And you can also see how consistent the level of response is among the cohort. The 2 children that have not had the month-6 visit yet are included on the right side of the slide. And you can see, although [ 3 months ] is relatively short period to adequately evaluate growth, you can already see the strong response that these children are also showing with treatment with infigratinib. So now on Slide 18. As we said before, Cohort 5 dose levels resulted in a strong response. At month 6, 60% of the children in Cohort 5 had, had a velocity greater than 7 centimeter [indiscernible] percentile of the height velocity child -- in children with achondroplasia. The median annualized height velocity for this cohort was 7.6 centimeters per year. And as you can see this strong response was seen in both girls and boys. Slide 19 shows the percentage change in Collagen X marker. As a background, Collagen X is synthesized and deposited [indiscernible] of active growth plates. And upon [ diversification ], Collagen X is degraded and part of it is released into circulation. Circulating Collagen X is a marker of bone growth, and it has been shown that it correlates well with growth velocity. So we wanted to see if the changes in growth that we observed in the study were also seen in the stipulating levels of Collagen marker. And indeed, they did. A dose response in the change of Collagen marker was observed with a significant increase in Cohort 5 already seen at month 3. We don't have month 6 levels yet available, but we don't expect them to change from monthly values. These results support with a blood biomarker the changes that we observed clinically. Let's go to Slide 20. And all this very promising and exciting efficacy response is seen with a very clean safety profile. Cohort 5 continues to demonstrate the safety and tolerability of low doses of infigratinib with no serious adverse events, no adverse events related to study drug besides that needed a dose modification or discontinuation, no adverse event at the high level and no confirmed hyperphosphatemia. Additionally, no accelerated progression of both age was observed, same as no worsening of body propulsion. Across all cohorts, with a follow-up out to 961 day, infigratinib continues to be well tolerated with no treatment-related SAEs and no discontinuations due to adverse events across all cohorts. So let's move to Slide 21. So what is next for the program? Enrollment for Phase III has started. We started enrollment of children in the running for the Phase III pivotal trial with 59 slots already requested. BridgeBio expects to complete regulatory interactions with the FDA end of Phase II meeting and an EMA scientific advice meetings expected mid-2023 to align on the Phase III study design and regulatory path. Additionally, and building on the promising results in achondroplasia, BridgeBio has initiated plans to develop infigratinib in other FGFR-driven skeletal dysplasia, beginning with hypochondroplasia, which has a similar prevalence to achondroplasia and a similar mechanism as well with majority of the cases also due to gain of fusion variance of the FGFR3. So this completes the presentation, and I want to hand it back to Ravi to get his perspective of what this could mean for the individual living with achondroplasia and for the health care community as well. Ravi, I hand it over to you.

Thanks very much. Thanks very much, Danielle. So I'm going to finish up with my perspective as a physician treating children and adults with achondroplasia and what do these results mean for people with achondroplasia and for doctors treating them. Well, I think most importantly, we've seen a fantastic increase in growth and a very broad response rate in our Cohort 5 patients that were presented today and someone who's been working and leading virtually all of the therapies for this condition, this is by far the best results we've seen in a medication. So this is extremely important and will very likely result in meaningful improvement of function abilities. In fact, the children that I look after in Melbourne, Australia, we're already seeing them being able to do more, to be less tired and to access their environment better in a world designed for people of average stature. So we're already seeing these things, and these will be cataloged and further delineated better as the studies move forward. So this significant increase in growth is an excellent outcome. Most importantly, any medication, we first have to make sure the medication is safe, and that is the primary purpose of these Phase II trials, and we have not seen any treatment-related adverse events of any kind in Cohort 5 or indeed any other cohort, which is very encouraging when we are talking to the patients and their families about any medication that they have to be taken. And of course, I think one of the game-changing things that infigratinib offers is an oral treatment option for families. The first oral treatment, potential oral treatment options for families with this condition because certainly, injections are certainly not very child or family friendly and having an oral medicine that may well be a safe and effective, such as infigratinib for children with achondroplasia, will be a game changer. And I work in many countries in which in fact, injections in the cold chain and keeping things sterile are really not an option. So this is a great worldwide option for children and families with achondroplasia. And so these data are extremely promising, and it is hoped that these translations in annualized height velocity will translate into functional gains, which I've already seen proportionality, but also all of the things I spoke to you about earlier in the presentation, the severe medical complications, not just height the impact on the foramen magnum, the level of sudden infant death and mortality, the need for operations in young teenagers and adults because of the narrowing of their spine. And really, I think we can be quite hopeful that we will see these impacts over time because what we have seen on the growth and the long bone growth in children with infigratinib very much mirrors what we saw in the mouse model of the achondroplasia mouse that was treated with infigratinib and that mouse had significant improvements in the diameter of the foramen magnum and the width of the spinal canal as well. So there is every reason to be optimistic that we will have the same effects. Obviously, we will need to work out the best timing of the initiation of this therapy in achondroplasia. And obviously, these impacts as well as these questions will be measured over time in the PROPEL studies that Danielle have spoken to you about. So today, for me, not working for BridgeBio, but working with BridgeBio, an extremely exciting day, and I'm looking forward to telling my patients and families about these possible impacts and potential benefits for their children. So I will thank you for listening and then hand you back to Neil Kumar. Thank you very much.

Thanks so much, Ravi, and thanks, everyone, for listening in. At this time, we're prepared to take questions. Operator, I'll turn it over to you to team up.

[Operator Instructions] Our first question comes from Tyler Van Buren with Cowen.

Congratulations on the stellar results. So I'd like to ask, how are you going to design and enroll the Phase III to ensure that these AHV results hold up? And when should we expect the full data set and the 12-month data for Cohort 4? And then in addition to that, I understand that you started the Phase III run in to assess baseline measurements. And presumably, you'll have to get FDA feedback in the next few months before you start dosing later in the year. But how long could it take to fully enroll the trial and get top line data?

Yes. Thanks, Tyler. I appreciate the question and the time this morning. In terms of the Phase III design, we expect that it will look very similar to BioMarin's and timing of enrollment, to really early to comment on that. But there's been quite a bit of enthusiasm from the community to date, some 59 slots have been requested in the context of our ongoing enrollment. So that's good news. And then in terms of what the design will look like, I think it would be the 1-year primary endpoint to the point that you made. And if you look at BioMarin's FDA submission, there's fairly consistent data as you go 6 months, 9 months, 12 months out, the means are pretty stable. It's just obviously the standard deviation comes down a little bit. So we [indiscernible] expect that the drug's efficacy and safety will hang in there. And the final part of your question pertained to Cohort 4 data, we'll release the totality of the data set at an upcoming conference. We'll have to work with our key KOLs and advisers to figure out exactly what that is, ASBMR or something else, but sometime soon. Did I get everything?

Yes.

All right.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on the data. With the safety results being pretty clean here, was there any thought to dosing a little bit higher in PROPEL or is that next sort of dose threshold where you worry a little bit about some of those oncology AEs? And then you've talked about this 80% responder rate. I think there were 2 patients, I think patient 1 and [ 4 ] where you saw minimal changes? Was there anything in the baseline characteristics worth noting in those 2 patients?

Thanks, Anupam. Appreciate the comments and the questions. Maybe I'll take the first and then pass it over to Justin and Danielle for the for the second on the specific baseline characteristics of the nonresponders. In terms of dosing up, I mean, I think as I said at the outset, we sort of view these data as what can be accomplished in terms of AHV. So certainly, from the standpoint of the achondroplasia population makes very little sense for us to interrogate a higher dose. In fact, we don't want to put people into hyper growth that's been something that we've been concerned with. So we would move forward with this dose just as quickly as possible as ever you're trying to balance basically the efficacy, safety and your ability to serve the patient population as quickly as possible. So our every expectation is that we'll be moving forward and not interrogating higher doses. We're still well below. I mean I don't have the fund PK yet, but we're still well below the AUCs where you see any sort of even consistent hyperphos in the oncologic setting. Obviously, things can vary between the pediatric and adult setting, but we haven't seen much of that. And so yes, our expectation is we could dose higher, if we needed to, perhaps in the context of a non-FGFR-driven condition that could be growth associated genetic dysfunction. But I think within the context of [ hypochond and achond ] we feel pretty good about this dose. On the nonresponders, Justin, Danielle?

Yes. Just one thing to add there about the dose. We're still in order of magnitude lower than the doses we used in oncology setting. With regards to the responders versus nonresponders, to your point, we had 80% response rate. The 2 children who did not respond, one including child 4, there's nothing apparent from the baseline characteristics that would indicate why there was not a response. Although I would like to call that for Child 4, they had the highest baseline of the study at 6.4. And so the fact that the AHV was maintained at that very high level is very encouraging as well. It would probably have been hard to show response there, just given how high their baseline was to start with.

Yes. I mean it's an interesting question. I know we've talked about before, but like why is their nonresponse? Could be modifiers, could be -- we don't have the PK as I mentioned yet, so it could be that there was just a different metabolism of the drug in that context. But yes, we'll just have to wait to see as we get more data.

Our next question comes from Mani Foroohar with SVB Securities.

First of all, congratulations on what looks to be a best-in-class efficacy profile. As you look forward to presumptive commercial composition [ company ] like Voxzogo and you talk about when an answer will be appropriate to a small additional study in switch patients to establish what a profile would be for patients coming off of Voxzogo onto infigratinib for the remainder of the time their growth plates are open?

Yes. Great question, Mani. I appreciate it. We've thought about that in the context of our post-Phase III lineup, I think we would want to wait till post-Phase III to interrogate that. I mean people have also asked us about combination studies. The issue here is, obviously, the CMPs are targeting one of the 2 effective pathways that we target, just downstream. And so it's not immediately obvious to me why a combination therapies would work. It's not immediately obvious to me why a switch wouldn't work. But obviously, all those things need to be interrogated in the clinic and proven. But at least from the context of the path and mechanism of the disease, both switches as well as -- well, switches should be highly probable. And I would say the combination would be less obviously useful.

Our next question comes from Salim Syed with Mizuho.

Massive congratulations from me as well. And also, can I just give you guys a shout out for telling us wondering actually have the data. I think that's a super great practice that more companies should employ so that we can actually be at our desk when data hits. So thank you for telling us that as well ahead of the data. A couple of questions from me. Neil, I know you had mentioned that you might look at a switch study in a post-Phase III, but just curious of the 59 participant slots already requested. How many of those are actually from patients on Vox and then also just on preliminary thoughts here, just given the data today. Is there any potential thoughts to premium pricing here versus Vox?

Thanks, Salim. Appreciate it, and I appreciate the shout out on the press release and the heads up. I think in terms of the slots requested, we don't know. Those are coming from the sites. So I'm not exactly sure unless Danielle or Justin know if the children are already on Vox.

Yes.

I doubt it, honestly, but I don't know.

Yes, Neil, I can answer to that. No, the slots that are being requested are not children that have been receiving any growth-promoting agent. These children that are enrolling in PROPEL are the ones that are hoping to then participate in the Phase III. So we want to make sure that children are going to be able to answer the questions to one. So they are not -- they have not had received any growth-promoting agent.

Yes. Just on your second question -- thanks, Danielle. Just on your second question, Salim, it's too early for us to really understand how pricing is going to play out here, obviously. But one of the things that we've always been focused on, as you know, from ATTR cardiomyopathy is global access. And I think actually, in the context of a small molecule, there may be abilities for us to access to the broadest patient population. So we'll just have an eye on that and geographic-based pricing, we'll just have to think about as we get the final piece of data and think about things.

Our next question comes from Paul Choi with Goldman Sachs.

Let me add my congratulations as well. These are stunning data. Two questions from us. First, given what you've seen with Cohort 5 here, can you maybe think about what the potential efficacy implications are for the kids who are ages 2 to 5 or perhaps even recently born? And second, I know on Slide 20, I think it is, you commented on no worsening of body proportioning, is there any evidence even if preliminary in any observed patients, any benefit on either a limb or trunk proportionality that you can comment on?

Yes, great questions. Thanks, Paul. Actually, I'll take it over to Danielle to address both of those, the 2 to 5 cohort as well as the proportionality.

Yes. Thank you, and thanks for the question. So regarding the 2 to 5, it is in our plans to go to younger than 3. So it is in the plan and we are going to be working on those. And regarding the body proportionality, it is a little preliminary to say with a few children and 6 months data, but when evaluating the Cohort 5, we didn't see any worsening of the proportionality and there could potentially be the trend of the lower segment growing a little bit more over the upper body, so a trend towards improving the body proportionality, but it's very early to say, and we need a longer time and more children.

Our next question comes from Eliana Merle with UBS.

Congrats on the data. Just in terms of the like patient-by-patient data, were there any predictors of higher response, just looking at patient 12 looks to be somewhat of a super responder? And then just in [ hypochondroplasia ] can you discuss a bit more about your timelines for dosing? And then last question, just for Ravi. You mentioned in some of your remarks some of the functional benefits you're seeing in patients and PROPEL, maybe can you just anecdotally maybe put that in the context of some of the functional benefits you've seen with the [indiscernible].

I'll kick it to Ravi first to get that third, and then I'll come back to those first 2. Thanks, Ellie.

Yes. Thanks very much. I mean, with vosoritide, we're seeing a lot of real world evidence that children with increased height are able to access their environment better increased independence at school, increased independence in terms of toileting, increasing independence in terms of accessing public transport, decrease fatigability, straighter legs and more efficient gate and all of that basically improving their quality of life and improving their school and home experience. We're also seeing less fatigue in those children that have more height because they become more efficient. So children who potentially have 2 parties to go to on a weekend would only go to 1 party because they're exhausted after the first party or they come home from school, where they've been okay, but rather than go and throw the ball in the backyard or to go for a bike ride with their children, their friends after school, they're not able to do that. And we're seeing significant differences in that. And we have a lot of patient testimonials regarding that, and we'll be collecting real worth evidence in terms of this because it really is important. We use annualized growth velocity as a marker and I've been to FDA, trying to work out whether we can have better endpoints and more meaningful endpoints, but this is the most objective and meaningful endpoint in terms of a trial. But in terms of real world evidence, my families and my children and their parents are telling me about all these extra benefits. And I would suspect that with this increased height benefit, we're going to get increased functional -- functionality, but we'll be looking at all of that in fine detail, but it certainly is great when my families tell me that they've not had any side effects, and they feel better. Thank you for the question.

Ellie, your first question was on super responders, I'll kick that over to Danielle and Justin.

Yes, Danielle, do you want to take this one?

Yes. So we have not had any adverse event reported associated with any excessive growth. We haven't had any abnormal finding some images. So we don't -- we are not concerned about individual excessive growth. That's the investigator is the best person to evaluate potential impact of how our growth rate is affecting each individual child. We -- as a cohort, overall, we know that the median height velocity, it is within the growth rate that we are expecting. So we are not concerned about excessive growth.

Yes. Maybe on hypochon, just briefly, I don't know if we expect to dose later this year, early next year. I do know that we'll be accelerating those efforts just as quickly as possible because I think it is our responsibility now. Given the preclinical data that's been published, Ellie, as I know you know, I think that's an exciting opportunity to serve. So we'll just be as quick as possible there.

Our next question comes from Eun Yang with Jefferies.

So you are planning to meet with the FDA or the European and European regulatory agency mid this year and assuming that you start enrolling toward the end of this year, how do you see the enrollment would it go? And based on this data, whether you could potentially accelerate enrollment? And second question is on the eligible patients on your slide, 7,000 to 10,000 patients in the U.S. and Europe eligible children, is that based on the age group that you are targeting in clinical trials? Can you comment a little bit more on that? And then a follow-up question on hypochondroplasia. That's a lesser severe than achondroplasia. So how do you see the regulatory path might be deferred from achondroplasia?

Yes. Maybe I'll ask Justin to comment on the second question, and then I can go to the first. Yes.

With regards to the question around hypochondroplasia and the regulatory path here, we still anticipate having regulatory discussions with the various agencies that will take [indiscernible]. We think the primary endpoint there will be very much to that of achondroplasia looking at annual height velocity change from baseline. So let me go back you for others.

What was your first question, Eun?

7,000 to 10,000 eligible children in the U.S. and Europe, what age...

Yes, that's associated with the inclusion criteria of 5 and above, but I think that -- yes, so the market might change a little bit as we go to younger ages. These stat up these are always -- they have reasonable area bars around them. I do think, just given the -- what's understood about the condition going earlier will be advantageous and will provide us the opportunity to actually have a more meaningful impact on some of the broader manifestations of the condition that Ravi mentioned. So we'll be looking and seeking to do that. How many more children that means, I don't know, actually.

Okay. And then another question was on the enrollment and then how long...

Yes. [ It's about ] a year in a year like a year to enroll a year to finish up on BioMarin. I suspect just given the enthusiasm right now, I mean, again, too early to tell, to be honest, but like I thought we could accelerate that enrollment. Certainly, we'll be working and using all of the capabilities that we have to move as quickly as possible. But really, the rate-limiting step, as you know, will be up to enthusiasm amongst physicians in the community.

Yes. And just to add something there. Just to reiterate, we've had about 59, if not more, participants really requested in the various sites. There's really a lot of enthusiasm there before even the data was available. So we anticipate, yes, even more enthusiasm of the data out there.

And certainly, from the physician perspective, we are very excited by these results, and we'll be moving the program forward, and my colleagues share my optimism. So we'll also be doing our best to answer these questions.

Our next question comes from Greg Harrison with Bank of America.

Congrats on the data. With this level of growth velocity you're seeing, do you think it will be possible for children to essentially catch up on growth over time and achieve closer to a normal height? And are there any safety or proportionality considerations if they're growing faster than normal?

Let me ask Ravi and Danielle to comment on that. Maybe, Ravi, I'll turn it over to you and then Danielle, you could fill in?

Sure, thanks for the question. I guess it really depends on -- I think that one of the key things is when we initiate treatment. And obviously, the earlier we initiate treatment, if you look at those growth curves that Danielle showed, they were from prospective data set collected through the BioMarin program. And we know that children with achondroplasia, their growth is less than average stature children in the first 2 years of life, but are much more -- there's not a 2-centimeter difference like children, 5 and over, there's 20 to 30 centimeter difference. So obviously, if we can bridge that gap at an earlier age, we're going to get better final outcome heights. But it's a lot more complicated than that because every child will have a different response based on their own genetic makeup and what their growth velocities are, which can vary a little bit. But to be general, we'd expect greater growth from an earlier time and we'd have to wait and see about the actual data on how much we can show. But in -- as is in the public domain, children who have been on other treatments are sort of bridging that gap between their own growth charts for achondroplasia and a new growth chart, which trends towards the average stature growth chart. Danielle?

Thank you, Ravi. I don't think I have much to add to that.

Yes, [indiscernible].

Yes.

Was there another question in there? I can't remember.

Yes. Just if there's any safety or other considerations if they are growing faster than the normal rate?

No. I think from what we've seen thus far, it just -- we're in that zone where, again, we're hopeful that based on preclinical studies, not only are we at reasonable AHV levels that we also might have some impact on some of those other manifestations that Ravi be alluded to. So no, I'm not worried yet about anything else.

Our next question comes from Tom Shrader with BTIG.

Let me add my congratulations. Most good questions have been asked. But in terms of looking for disproportionate growth, are there any key ratios we should be looking for an early read? And then you guys are fully in this space. Can you give us a sense of what is the FDA history about asking for switch data or combination data in situations like this, is there any history we can look into?

Thanks, Tom. Appreciate the question. I'll kick it over to Danielle actually to address that. Just on the FDA side, we're aware of no case examples that suggests either combo or switch data will be required, especially so early in the new treatments launch. But I'll ask Danielle to comment of the proportionality question.

Yes. So we are evaluating body proportions in our studies, and we -- the main ones that we are focusing are on the upper to lower body ratios as well and spine to standing height as well as head circumference to standing height, all those are good indicative of how the growth is occurring, and we are actively evaluating those in all our studies. So we -- not only in the Phase II, that is a shorter period, but also on the open label extension where we monitor these children for a long time and where we most likely are able to observe changes in these aspects. I hope it answered your question.

And just to add to that, Ravi here. I think if you want to look for 1 parameter that gives us the best indication of proportionality would be the upper to lower segment ratio. And we have really good data for natural history data that -- with the children with achondroplasia. And I think generically speaking, for all of these products that target the growth plate, we know the biggest growth is at the knee joint. So we would longer legs and improved body proportionality. So it makes a lot of plausible biologic sense knowing about the action of these medications that target FGFR3 and knowing about normal growth in proportionality in children with achondroplasia.

There are no further questions at this time. I'd like to turn the call back over to Neil Kumar for any closing remarks.

Well, I appreciate everyone taking the time this morning. We look forward to following up with their additional questions, and I'd like to thank all of the team here and especially Ravi, for taking the time this morning on our end. Thanks so much.

Thank you. Ladies and gentlemen, this concludes the program. You may now disconnect. Everyone, have a great day.