Good day. Thank you for standing by. Welcome to the BridgeBio phase II data results for infigratinib and achondroplasia event. At this time, all participants are in listen-only mode. Please be advised that today's conference is being recorded. I would 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 five achondroplasia data, a dataset 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 vexed 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? Why previously could we not access absolute annualized height velocities with therapy in the 7 cm 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, helmed by Dr. Daniela 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 walk through the deck so you can follow along. On slide three, 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 four, this provides an executive summary of sorts, and I'll highlight five 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 cm per year. 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 cm 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 collagen X, we see a dose response consistent with our preclinical studies. Fourth, we're providing these data with zero 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. 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 five, a brief reminder of how this important program fits in with the broader late-stage Mendelian effort 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 ADH 1. It represents the first major readout of the year for us, with the second and final being our phase III readout in ATTR cardiomyopathy mid-year. Finally, it's another good example of the capital and time efficiency we strive to for at the programmatic level. Turning now to the more detailed setup on slide six. 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 three 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. 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 seven 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, wherever experts and disease path mechanisms suggest this drug could be helpful.
Ravi has a deep knowledge of FGFR-driven skeletal dysplasias and beyond and the associated communities. 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. As Neil has said, achondroplasia is caused by an FGFR3-driven mechanism, and infigratinib attacks this condition at its very source. Indeed, we have numerous other conditions that I look after and many children with related FGFR3 conditions that have the same underlying mechanism. These include hypochondroplasia, but a variety of other FGFR3-driven disorders that affect the bone growth. This then leads to impaired function and other medical comorbidities. 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. This will access, as you can see, 15,000-25,000 children, but that's only in the U.S. and Europe.
Of course, worldwide, this would be many thousands more. Moving now to slide eight. 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 40 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 five years of life. The most severe of these is the risk of sudden death, which, if you have a child with achondroplasia, is 50 times 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. 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. It's important to remember that achondroplasia may mainly affect bones, 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. It's important to remember that achondroplasia is not a condition that only affects height.
Moving on to slide nine. Just to talk you through a little bit more about stenosis of the foramen magnum. This is probably the number one concern in terms of mortality and morbidity in children with achondroplasia. The foramen magnum is the large hole where the brain becomes a spinal cord. In all children with achondroplasia, this is narrowed, and this results in compression of the vital structures that pass through here that result in sleep-disordered breathing, problems with tone, and sudden death. Unfortunately, I've had the unfortunate experience of having two or three children in my career who have had sudden death who have been previously well and it's 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.
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-disordered 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 is a huge problem in people with achondroplasia. It can present as either obstructive apnea or central apnea, which we believe is related again to compression of the foramen magnum. 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 levels in people with achondroplasia. My colleague, who did his PhD on this, showed 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. 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. I will finish up by making some concluding remarks later, but I will now hand over to Daniela, who will talk you through the PROPEL clinical program. Thank you, Daniela.
Thank you. Thank you, Ravi, for the excellent presentation and for contextualizing the complexity of this condition and the need for treatment options. Good morning, everybody, and thank you for calling in. 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. I will provide more detail on the cohort five data that Neil summarized earlier. Lastly, I will share about our next steps. Let's start on slide number 12 with a high-level overview of our program, which currently consists of three studies. The run-in observational study, enrolling children with achondroplasia 2.5 to less than 17 years of age.
This study is designed to contribute to the characterization of the natural history of this condition and to collect the baseline, 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, PROPEL 2, is our phase II open label study of infigratinib in children with achondroplasia who are three to 11 years of age at study entry and who completed at least six months of observation 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 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 proposed cohort five data. On slide 13, we have the demographics of the children enrolled in cohort five. 12 children are actively participated in this cohort, seven girls and five boys.
The mean age at study entry was 7.24 years, with most of the children between five and eight years of age. Although majority of the children are white, there is a representation of other racial backgrounds showing diversity, which is very important to have in clinical trials. From the 12 children in this cohort, 10 had their month six visit completed, and those are the ones included in the main analysis presented here. The additional two childrens who have not had the month six visit yet, however, they seem to have a very good response to infigratinib based on their month three data that I will show in future slides. Moving to slide 14. As Neil highlighted earlier, cohort five showed an incredibly exciting data set that reflects the great potential of infigratinib to provide meaningful benefits for children with achondroplasia.
When evaluating all cohorts, infigratinib shows a clear dose response in the change from baseline in the annualized high velocity, with the cohort five dose levels resulting in a mean increase from baseline of 3.03 cm per year, which is the largest ever reported for this condition. 80% of the children responded to the cohort five dose level with a mean change from baseline among responders only of 3.81 cm per year. Cohort five also demonstrated a strong effect, with 60% of the children having an annualized high velocity over 7 cm per year at month six, which is above the 99th percentile for the growth curves in achondroplasia. Infigratinib also demonstrated a very robust dose response in absolute annualized high velocity.
We believe that change from baseline in the annualized high velocity is a better measure to account for inter-subject variability. Collagen X marker, a biomarker of skeletal growth, further supports the robust dose-dependent 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 slides. On slide number 15, we have the change from baseline in annualized high velocity from the 10 children who had the month six visit. You can see the clear dose response and the significant increase from baseline in the annualized high velocity of 3.03 cm 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 high velocity in cohort five that changes from an average baseline of 3.73 cm per year to a mean of 6.70 cm per year at month six, with a median of 7.6. The additional two children in cohort five who are not included in this analysis because they have not had the month six visit yet, also show a very strong response to infigratinib at month three. I will show this later in the presentation. Let's move to slide 16.
Ladies and gentlemen, please stand by. Your conference will resume momentarily.
Hey, operator, can you hear us?
Yes, I can hear you.
Okay, perfect. We'll just keep moving through the slides and hope that Daniela rejoins here. I'll hand it over to Justin To, who leads our business development and operations, to finish up the slides. We'll get into questions.
Great. On slide 16, following up from Daniela, here we show the response rate in cohort five. Again, back in cohort four, 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 five 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 from 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. On here is the individual level data across all of cohort five.
On the left-hand side, we have the 10 children who have completed their six-month visit. On the right-hand side, we have the two children who have not yet completed their six-month visit, but we have three-month age feed data for. Just as a reminder, you know, for the 10 children.
Can you hear me? Can you hear me now?
Yes. You're back on, Daniela.
Oh, I'm so sorry. I don't know, something went wrong with the connection, but tell me which slide was the last one I was here.
Yeah. We're on slide 17 now, Daniela. We're live.
We are fine? Okay, great. On slide 17, we have on this slide, we have the annualized high velocity of each of the children in cohort five. The gray bars represent the baseline annualized high velocity, and the blue bars, the annualized high velocity after six months of treatment with infigratinib. You can see the impressive change in the annualized high velocity after the six months of treatment in most of the children. You can also see how consistent the level of response is among the cohort. The two children that have not had the month six visit yet are included on the right side of the slide.
You can see, although three months is a relatively short period to adequately evaluate growth, you can already see the strong response that these children are also showing with treatment with infigratinib. Now on slide 18. As we said before, cohort five dose level resulted in a strong response. At month six, 60% of the children in cohort five had a velocity greater than 7 cm which is above the 99th percentile of the high velocity charts in children with achondroplasia. The median annualized high velocity for this cohort was 7.6 cm per year. 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 of active growth plates.
Upon endochondral ossification, 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. We wanted to see if the changes in growth that we observed in the study were also seen in the circulating levels of collagen marker. Indeed they did. A dose response in the change of collagen marker was observed with a significant increase in cohort five already seen at month three. We don't have the month six levels yet available, but we don't expect them to change from month three values. These results support with a blood biomarker the changes that we observe clinically. Let's go to slide 20. All this very promising and exciting efficacy responses is seen with a very clean safety profile.
Cohort five continues to demonstrate the safety and tolerability of low doses of infigratinib, with no serious adverse events, no adverse events related to study drug, no adverse events that needed adult modification or discontinuation, no adverse event at the eye level and no confirmed hyperphosphatemia. Additionally, no accelerated progression of bone age was observed, same as no worsening of body proportions. Across all cohorts with a follow-up out to 961 days, infigratinib continues to be well-tolerated, with no treatment-related SAEs and no discontinuations due to adverse events across all cohorts. Let's move to slide 21. What is next for the program? Enrollment for phase III has started. We started enrollment of children in the run-in 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 meeting 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 initiating plans to develop infigratinib in other FGFR-driven skeletal dysplasias, 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-function variants of the FGFR3. 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 healthcare community as well. Ravi, I hand it over to you.
Thanks very much. Thanks very much, Daniela. I'm gonna 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. I think most importantly, we've seen a fantastic increase in growth and a very broad response rate in our cohort five patients that were presented today. As someone who's been working and leading virtually all of the therapies for this condition, this is by far the best result we've seen in a medication. This is extremely important and will very likely result in meaningful improvement of functional abilities.
In fact, in 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. We're already seeing these things, and these will be cataloged and further delineated better, as the studies move forward. 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. We have not seen any treatment-related adverse events of any kind, in cohort five 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 taking. 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 option 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 safe and effective, such as infigratinib for children with achondroplasia, will be a game changer.
I work in many countries in which, in fact, injections and the cold chain and keeping things sterile are really not an option. This is a great worldwide option for children and families with achondroplasia. These data are extremely promising, and it is hoped that these translations in annualized height velocity will translate into functional gains, which we've already seen, proportionality. 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.
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. That mouse had significant improvements in the diameter of the foramen magnum and the width of the spinal canal as well. There is every reason to be optimistic that we will have the same effects. Obviously, we'll need to work out the best timing of the initiation of this therapy in achondroplasia. Obviously, these impacts as well as these questions will be measured over time in the PROPEL studies that Daniela has spoken to you about.
Today for me, not working for BridgeBio but working with BridgeBio, is 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. 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 tee 'em up.
Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. One moment while we compile the Q&A roster. Our first question comes from Tyler Van Buren with Cowen. Your line is open.
Great. Thanks very much, guys, and congratulations on the stellar results. I'd like to ask, how are you going to design and enroll the phase III to ensure that these AHV results hold up? When should we expect the full data set and the 12-month data for cohort four? 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. How long could it take to fully enroll the trial and get top-line data?
Thanks, Tyler. Appreciate the question and the time this morning. In terms of the phase III design, we expect that it'll look very similar to BioMarin's in timing of enrollment. It's too really early to comment on that. 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. That's good news.
Then in terms of, you know, what the design would look like, I think it would be with a one-year primary endpoint to the point that you made. If you look at BioMarin's FDA submission, there's fairly consistent data as you go six months, nine months, 12 months out. The means are pretty stable. It's just obviously the standard deviation comes down a little bit. We full well expect that the drug's efficacy and safety will hang in there. The final part of your question pertained to, oh, cohort four data. Yeah, we'll release the totality of the data set at an upcoming conference.
We'll have to work with our key KOLs and advisors to figure out exactly what that is, ASBMR or something else, but sometime soon. Did I get everything?
Yep. Thank you very much.
All right. Cool. Next question.
Thank you. Our next question comes from Anupam Rama with JP Morgan. Your line is open.
Yo. Hey, guys. Thanks so much for taking the question, and 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? You've talked about this 80% responder rate. I think there were two patients, I think patient one and four, where you saw minimal changes. Was there anything in the baseline characteristics worth noting in those two patients? Thanks so much.
Thanks, Anupam. Appreciate the comments and the questions. Maybe I'll take the first, and then I'll pass it over to Justin and Daniela for the second on the specific baseline characteristics of the non-responders. 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. Certainly from the standpoint of the achondroplasia population, makes very little sense for us to interrogate a higher dose. In fact, we don't wanna put people into hypergrowth. That's been something that we've been concerned with. We would move forward with this dose just as quickly as possible.
As ever, you're trying to balance basically the efficacy, safety and, you know, your ability to serve the patient population as quickly as possible. 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 that fine 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, we haven't seen much of that. Yeah, our expectation is we could dose higher if we needed to, perhaps in the context of a non-FGFR-driven condition that's that could be a, you know, a growth-associated genetic dysfunction.
I think within the context of hypocon and achon, we feel pretty good about this dose. On the non-responders, Justin, Daniela?
Yeah, just one thing to add there about the dosing. We're still an order of magnitude lower than the doses we use in oncology setting. With regards to the responders versus non-responders, to your point, you know, we had 80% response rate. You know, the two children who did not respond, you know, children one and child four, you know, there's nothing apparent from the baseline characteristics that would indicate why, you know, there was not a response. Although I would like to call out that for child four, they had the highest baseline of the study at 6.4. The fact that we, 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.
Yeah, I mean.
Thanks so much.
It's an interesting question I know we've talked about before, like, why is there non-response? Could be modifiers, could be. We don't have the fine PK, as I mentioned, yet, so it could be that there was just a different metabolism of the drug in that context. Yeah, we'll just have to see as we get more data.
Thanks, guys, so much for taking the question, and congrats again.
Thank you.
Thank you. Our next question comes from Mani Foroohar with SVB Securities. Your line is open.
Hey, guys. Thank you so much for taking my question while I'm on the road. First of all, congratulations on what looks to be a best-in-class efficacy profile. As you look forward to presumptive commercial continuity with VOXZOGO, can you talk about when and if it will be appropriate to do a small additional study in switch patients to establish what a profile would be for patients coming off VOXZOGO onto infigratinib for the remainder of the time their books are open?
Yeah, great question, Mani. appreciate it. Yeah, we've thought about that in the context of our post-phase III lineup. I think we would wanna wait till post-phase III to interrogate that. I mean, people have also asked us about combination studies. The issue here is obviously the CNPs are targeting one of the two effector pathways that we target just downstream. 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. Obviously all those things need to be interrogated in the clinic and proven.
At least from the context of the pathomechanism of the disease, both switches as well as, switches should be highly probable, and I would say the combination would be less obviously useful.
Great. Thanks. Congrats again.
Thank you, Mani.
Thank you. Our next question comes from Salim Syed with Mizuho. Your line is open.
Hey, guys. Massive congratulations from me as well. Can I just give you guys a shout-out for telling us when you're actually gonna 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. 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? Then also just on preliminary thoughts here, just given the data today, is there any potential thoughts to premium pricing here versus VOX?
Thank you.
Thanks, Salim. Appreciate it, and I appreciate the shout-out on the on the press release and the and the heads-up. I think on in terms of the slots requested, we don't know. Those are coming from the site, so I'm not exactly sure unless Daniela or Justin know if the children are already on 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. We want, we wanna make sure the children are gonna be able to answer the questions we want. They have not had received any growth-promoting agent.
Just on your second question... Thanks, Daniela. Just on your second question, Salim, it's too early for us to really understand how pricing is gonna play out here, obviously. One of the things that we've always been focused on is, as you know, from ATTR cardiomyopathy is global access. I think actually in the context of a small molecule, there may be abilities for us to access the broadest of patient population. We'll just have an eye on that and, you know, geographic-based pricing, we'll just have to think about as we get the final piece of data and think about things. But yeah.
Super helpful. Thanks so much, guys.
Thank you.
Thank you. Our next question comes from Paul Choi with Goldman Sachs. Your line is open.
Hi. Good morning, Neil and team. Let me add my congratulations as well. These are stunning data. Two questions from us. First, given what you've seen with cohort five here, can you maybe think about, you know, what the potential efficacy implications are for the kids who are ages two to five or, you know, perhaps even recently born? 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, you know, observed patients, any benefit on either a limb or trunk proportionality that you can comment on?
Yeah, great questions. Thanks, Paul. Actually, I'll kick it over to Daniela to address both of those, the two to five cohort as well as the proportionality.
Yes. Thank you. Thanks for the question. Regarding the two to five, it is in our plans to go to younger than three. It is in the plans, and we are going to be working on those. Regarding the body proportionality, it is a little preliminary to say with a few children and six months data. When evaluating the cohort five, we didn't see any worsening of the proportionality, and there could potentially be a trend of the lower segment growing a little bit more over the upper body, so to a trend towards improving the body proportionality. It's very early to say, and we need a longer time and more children.
Okay. Great. Thanks for taking our questions.
Thanks, Paul.
Thank you. Our next question comes from Eliana Merle with UBS. Your line is open.
Hey, guys. Thanks so much for taking the question and 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. Just in hypochondroplasia, can you discuss a bit more about your timelines for dosing? Last question, just for Ravi, you mentioned in some of your remarks some of the functional benefits you're seeing in patients in PROPEL. Maybe can you just anecdotally maybe put that in the context of some of the functional benefits you've seen with vosoritide? Thanks.
I'll kick it to Ravi first to get that third, and then I'll come back to those first two. Thanks, Ellie.
Yeah. 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, increased independence in terms of accessing public transport, decreased fatigability, straighter legs and more efficient gait. All of that's 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.
Children who potentially have two parties to go to on a weekend would only go to one 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 go for a bike ride with their children their friends after school, they're not able to do that. We're seeing significant differences in that. We have a lot of patient testimonials regarding that, and we'll be collecting real-world 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.
This is the most objective and meaningful endpoint in terms of a trial. In terms of real-world evidence, my families and my children, and their parents are telling me about all these extra benefits. I would suspect that with this increased height benefit, we're gonna get increased functional functionality. We'll be looking at all of that in fine detail. It certainly is great when my families tell me that they've not had any side effects and that they feel better. Thank you for the question.
Ellie, your first question was on super responders. I'll kick that over to Daniela and Justin.
Daniela, you wanna take this one?
Yes. We have not had any adverse event reported associated with any excessive growth. We haven't had any abnormal findings on images. We are not concerned about individual excessive growth. That's the investigator is the best person to evaluate the potential impact of how a growth rate is affecting each individual child. As a cohort overall, we know that the median height velocity, it is within the growth rate that we are expecting. We are not concerned about excessive growth.
Maybe on Hypocon, 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. We'll just be quick as possible there.
Great. Thanks, and congrats again.
Thank you.
Thank you. Our next question comes from Eun Yang with Jefferies. Your line is open.
Thank you. You are planning to meet with the FDA or the European Regulatory Agency mid this year. Assuming that you start enrolling toward end of this year, how do you see the enrollment would it go? Based on this data, whether you could potentially accelerate enrollment. Second question is on the eligible patients on your slide, 7,000-10,000 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 actually comment a little bit more on that? Follow-up question on hypochondroplasia. That's less severe than achondroplasia, how do you see the regulatory requirement might be differ from achondroplasia? Thank you.
Yeah. Maybe, I'll ask Justin to comment on the second question, and then I can go to the first. Yeah.
With regard to the question around hypochondroplasia and the regulatory path there, you know, we still anticipate having regulatory discussions with the various agencies to look at the path. We think, you know, the primary endpoint there will be very similar to that of achondroplasia, looking at annual height velocity and change from baseline. Daniela, back to you for others.
What was your first question, Eun?
7,000-10,000 eligible children in the U.S. and Europe. What age group? Yeah.
Yeah, that's associated with the inclusion criteria of five and above. I think that, yeah, the market might change a little bit as we go to younger ages. You know, these stat epies are always, they have reasonable error bars around them. You know, 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. We'll be looking and seeking to do that. How many more children that means, I, you know, I don't know actually.
Okay. Then another question was on the enrollment.
Oh, yeah.
How long?
I think about 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 bet 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. Really the rate limiting step, as you know, will be up to enthusiasm amongst physicians in the community.
Yeah. Just to add something there, just to reiterate, you know, we've had about 59 if not more participants slots already requested from the various sites. There really a lot of enthusiasm there before, you know, even the data was available. We anticipate, yeah, even more enthusiasm with this data out there.
Thank you.
Certainly from the physician perspective, we're very excited by these results, and we'll be moving the program forward, and my colleagues share my optimism. We'll also be doing our best to answer these questions.
Thank you. Our next question comes from Greg Harrison with Bank of America. Your line is open.
Hey, congrats on the data, and thanks for taking the question. With this level of growth velocity you're seeing, do you think it'll be possible for children to essentially catch up on growth over time and achieve closer to a normal height? Are there any safety or proportionality considerations if they're growing faster than normal?
Let me ask Ravi and Daniela to comment on that. Maybe, Ravi, I'll turn it over to you, and then Daniela, you can fill in.
Sure. Sure. Thanks for the question. I guess it really depends on, I think that one of the key things is when we initiate treatment. Obviously the earlier we initiate treatment, if you look at those growth curves, that Daniela showed, they were from a prospective dataset collected, through the BioMarin program. We know that, children with achondroplasia, their growth is less than average stature children in the first two years of life, but are much more, there's not a 2 cm difference like children five and over. There's 20 to 30 cm difference. Obviously, if we can bridge that gap at an earlier age, we're gonna get better final outcome heights.
It's a lot more complicated than that because every child will have a different response based on their own the genetic makeup and what their growth velocities are, which can vary a little bit. 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. In as is in the 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.
Daniela ?
Thank you, Ravi. I don't think I have much to add to that.
Yeah, I think that's pretty solid.
Yes.
Was there another question in there? I can't remember.
Just if there's any safety or other considerations if they are growing faster than the normal rate.
I think from what we've seen thus far, it just, we're in that zone where, again, we're hopeful that based on pre-clinical studies, not only are we at reasonable AHV levels, that we also might have some impact on some of these other manifestations that Ravi alluded to. Not worried, yet about anything else.
Great. Thanks for taking the question.
Yep. Thank you.
Thank you. Our next question comes from Tom Shrader with BTIG. Your line is open.
Good morning. 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 for an early read? 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? Thank you. Congratulations.
Thanks, Tom. Appreciate the question. I'll kick it over to Daniela actually to address that. Just on the FDA side, we're aware of no case examples that suggest either combo or switch data would be required, especially so early in the new treatments launch. I'll ask that Daniela to comment of the proportionality question.
Yes. We are evaluating body proportions in our studies. We the main ones that we are focusing are on the upper to lower body ratios as well arm span to standing height as well as head circumference to standing height. All those are good indicative of how the growth is occurring, we are actively evaluating those in all our studies. We not only in the phase II, that is a shorter period, but also in the open label extension, where we monitor these children for long time and where we most likely are able to observe changes in these aspects. I hope it answers your question.
Beautiful. Thank you.
Just to add to that, Ravi here. I think if you wanna look for one parameter that gives us the best indication of proportionality would be the upper to lower segment ratio. We have really good data for natural history data that with the children with achondroplasia. I think generically speaking, for all of these products that target the growth plate, we know the biggest growth is at the knee joint. We would expect longer legs and improved body proportionality. It makes a lot of plausible biologic sense knowing about the action of these medications that target FGFR3 and knowing about normal growth and proportionality in children with achondroplasia.
Thank you.
Thank you. 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, appreciate everyone taking the time this morning. We look forward to following up if there are additional questions. 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.