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

Good day. I will be your conference operator today. [Operator Instructions] Before we begin, I would like to remind everyone that today's call may contain forward-looking statements within the meaning of the federal securities laws, including, but not limited to, the statements about BridgeBio's future operating and financial performance, business plans and prospects and strategy. These statements are based on current expectations and assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from those expressed or implied in these forward-looking statements. For a discussion of these risks and uncertainties, please refer to the disclosure in today's earnings release and BridgeBio's periodic reports and SEC filings. All statements made here are based on information available to BridgeBio as of today, and the company undertakes no obligation to update any forward-looking statements made during this call, except as required by law. With that completed, BridgeBio, you may begin your conference.

Thank you, operator, and thanks to everyone for joining this call. Together with our incredible team, I'm grateful to be able to share with you, on behalf of the extraordinary physicians, participants, families and caregivers involved, the positive Phase III results of our PROPEL 3 clinical trial. The strongly positive and consistent data the community worked tirelessly to generate come together at this moment to portend a new and better day for the families we serve, and we are excited to continue our partnership with the achondroplasia community to ensure we meet their needs as we move our medicine into the commercial setting. As a reminder, the slide deck associated with this call is publicly available, and we will refer to specific slide numbers as we progress the discussion. Before I briefly set the corporate context in today's readout, I want to begin with the most important slide in this document, Slide 5. A thank you to the amazing and inspiring children and families, advocates, physicians, clinical research staff and collaborating research partners that made this study possible. As we have hopefully demonstrated in the past across conditions as disparate as MoCD Type A and ATTR cardiomyopathy, we recognize our responsibility to you now and therefore, plan to continue studying this medicine in additional settings and to provide it as broadly as possible for those who may want it. Turning to Slide 6. I'll take a brief moment to provide some corporate context for today's data. As many of you know, BridgeBio was founded 10 years ago to target well-described genetic diseases at their source. With this positive Phase III result, we extend our ability to serve communities with unmet need and build on our team's remarkable track record. Our 4 most recent Phase IIIs in ATTR cardiomyopathy, LGMD2I, ADH1 and achondroplasia have all been markedly successful and together lay the groundwork for a diversified and differentiated genetic disease company in the years to come. We do this work knowing that every minute matters for the communities we serve. As shown on Slide 7, we seek to minimize time and expense per program so that we are able to do and serve both large and small genetic marketplaces in economically responsible ways. We do this in part by employing small teams to run each of our programs forward, our belief being that at least in the R&D setting, smaller teams work harder, faster, sweat the details more and have more fun doing it. This style of work is particularly well suited for advancing programs in the Mendelian disease space, where we start with a strong understanding of patho mechanism and what is required of a medicine to matter. Selecting the right problems to work on, not just the right platform, is an underrated and hard-to-explain skill. A team's prowess in this regard can only be understood retrospectively. On Slide 8, we suggest that our strong scientific substrate and decision-making processes are yielding today, a high probability of technical success from our portfolio. Over time, we hope we can approach the engineering life success rates that Genzyme and Shire demonstrated when pioneering the ERT and PRT spaces. Finally, as suggested on Slide 9, there is no better time than now to be applying the principles of efficient operating and high-quality problem selection to the field of genetic disease. As our ability improves to resolve more clearly mechanism of disease, employing many of the advances referenced on this slide, so in turn does our opportunity to help greater numbers of individuals. That's where we're headed. But the floor today belongs to our efforts in achondroplasia and the remarkable results of PROPEL 3. With that, I'll turn it over to Justin, Daniela and team to tell you more.

Thanks, Neil. Our belief in infigratinib, just like with any BridgeBio program, is rooted in the foundational belief that the status quo is not good enough for families and individuals living with genetic conditions. It's a belief that we can and that we should do better than current options by targeting the cause of biology, which for achondroplasia is directly inhibiting FGFR3 gain-of-function. PROPEL 3 is a culmination of a scientific journey that started back in 1994 when gain-of-function mutations in FGFR3 were first identified as the cause of achondroplasia. This discovery led to the [ SAML ] paper at JCI in 2016 by our scientific collaborators at INSERM, led by Dr. Laurence Legeai-Mallet, who used infigratinib to demonstrate for the first time, profound improvements in achondroplastic mice. 8 years later, we published our seminal results from our Phase II data in the New England Journal of Medicine, demonstrating proof of concept that directly targeting FGFR3 can lead to more types of efficacy and deeper efficacy in the clinic. And that brings us to today's top line readout for PROPEL 3, where the totality and consistency of evidence clearly demonstrates a best-in-class product profile that is able to do more and to do better than the status quo. Now moving to Slide 12. I'm pleased to announce that across every single key measure of efficacy, infigratinib sets a new bar while also being a safe daily oral. On the primary endpoint of change from baseline in annualized height velocity, where the bar has been stuck at plus 0.15 centimeters per year, infigratinib was able to demonstrate a mean difference against placebo of plus 0.21 centimeters per year and LS mean difference of plus 1.74 centimeters per year, with both Ps being less than 0.0001. This is the largest change ever observed in RCT for achondroplasia, which is all the more impressive given that we studied the broadest age range across any trial. On change in height Z-score, a secondary endpoint, where no treatment arm has been able to show more than an improvement of plus 0.3 standard deviations, we broke plus 0.4 for the first time on the treatment arm with an LS mean of plus 0.41 on the infigratinib arm and an LS mean difference against placebo plus 0.32 with a P of also less than 0.0001. Impact on upper to lower body proportionality has been the endpoint that has been most difficult for any 52-week placebo-controlled trial to show real impact on. We're excited to announce today that for the first time, a statistically significant result has been achieved against placebo. In a pre-specified exploratory analysis described in the [ set ], we demonstrated an LS mean difference of minus 0.05 against placebo with a p-value of less than 0.05 in children younger than 8 years of age. This was a subgroup that was nearly 50% of our trial population. In the overall population, we demonstrated a favorable trend with also a very strong treatment arm effect of minus 0.05. Finally, on safety, we're thrilled to repeat the results that we saw in Cohort 5 of PROPEL 2. We had a well-tolerated safety profile that was consistent with the lack of inhibition of FGFR1 or 2. There were no SAEs related to study drug or discontinuations related to study drug. There were only 3 cases of hyperphosphatemia. All 3 cases were mild, asymptomatic, transient and resolved without the need for either dose reduction or discontinuation. There were no AEs associated with inhibition of FGFR1 or 2, such as corneal or retinal. And importantly, we avoided the AEs associated with CNP analogs such as symptomatic hypotension, ISRs and hypertrichosis. Given the totality and consistency of this data, we believe that the future of treatment options for achondroplasia does not involve a needle, whether it be daily or weekly. I'll now hand it over to Dr. Daniela Rogoff, our Chief Medical Officer who has been with this program since day 1, to go over these results in detail. Keep in mind that these are just the top line data, and that more detailed results will be forthcoming in future conferences.

Thank you, Justin. Let's start on Slide 14 with the overall Phase III study design. This was a double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral infigratinib in children 3 to less than 18 years of age with potential to grow. As you can see, PROPEL 3 covered the largest age range of any randomized controlled trial ever conducted in achondroplasia. Children had to have completed at least 6 months in our observational study, PROPEL, before being randomized in a 2:1 ratio to receive either infigratinib or placebo. Children received treatment for 52 weeks and then were offered the possibility to roll over to the long-term extension study, PROPEL OLE. The primary endpoint was the change from baseline in annualized height velocity compared to placebo, and the key secondary endpoints were the change from baseline in height Z-score in relation to reference data in achondroplasia and change from baseline in body proportions also compared to placebo. On Slide 15, we have the demographics and baseline characteristics of the participants. 74 children were randomized to the infigratinib arm and 39 to the placebo arm. As you can see, the age and sex distribution were very similar in both treatment arms. And likewise, the baseline annualized height velocity and height Z-score were also very similar, showing how comparable both treatment arms were. Now let's talk about the exciting efficacy results. We are starting on Slide 16 with the primary endpoint of change from baseline to week 52 in annualized height velocity compared to placebo. As Justin mentioned, the study's primary endpoint was met. On this table, we can see the mean AHV at baseline and at week 52 for both treatment arms. The mean difference in the change from baseline in the annualized height velocity between oral infigratinib and placebo was 2.1 centimeters per year, which was highly statistically significant with a p-value of less than 0.0001. The difference in the least square mean change from baseline in the annualized height velocity between oral infigratinib and placebo was 1.74 centimeters per year, which was as well highly statistically significant with a p-value of less than 0.0001. Both the differences in the mean change and the least square mean change are the largest difference seen in any randomized controlled trial in achondroplasia. On Slide 17, we have the results at the different age groups. We can see that the robust increase in annualized height velocity can be seen consistently across all age groups. To our knowledge, these increases are the highest reported in each subgroup. Slide 18 beautifully shows the absolute annualized height velocity. We can see that children that received oral infigratinib quickly increased the AHV to around 6 centimeters per year that is the mean for the average height pediatric population and continue to grow at that rate, whereas children in the placebo arm continued to grow at the average annualized height velocity of children with achondroplasia. The least square mean annualized height velocity on the treatment arm was 5.96 centimeters per year, the highest reported to date. Moving on to Slide 19. On this slide, we have the results on the key secondary endpoint of change from baseline in the height Z-score compared to placebo. These height Z-scores are calculated using reference data in achondroplasia. We can see that the increase in the growth rate with infigratinib translated in a continuous increase in the height Z-score, while the height Z-score persisted unchanged in the children that received placebo. The least square mean change from baseline compared to placebo was 0.32 standard deviation score, also the largest observed in 52 weeks in a randomized controlled trial. The increase in the treatment arm of 0.4 SDS, or standard deviation score, is also by far the largest seen to date. On Slide 20, we have the results of the other key secondary endpoint of change from baseline in upper to lower body segment ratio compared to placebo. When evaluating all the children, treatment with infigratinib resulted in a favorable trend to improvement in body proportions, showed by a decrease in the upper to lower body segment ratio compared to placebo with a least square mean difference of minus 0.02. However, and what we are most excited about are the results in the subgroup of children 3 to 8 years old. That is the baseline age window where changes in body proportions are more likely to be evident given the natural change in the upper to lower body segment ratios throughout childhood. In this age group, infigratinib demonstrated a statistically significant decrease in the upper to lower body segment ratio compared to placebo with a least square mean difference of negative 0.05 and a p-value less than 0.5. This age group made up nearly 50% of our trial. Oral infigratinib is the first drug to demonstrate a statistically significant difference in body proportions in a 1-year treatment trial. Now let's move to safety on Slide 21. Infigratinib was well tolerated with no safety concerns and no safety signal indicating inhibition of FGFR1 or 2. Most adverse events were Grade 1 or 2 in severity and typical for children of these ages. Treatment-emergent adverse events were well balanced between the treatment arm and the placebo arm. We did not have any Grade 3 or higher, any SAE or any adverse event leading to study discontinuation that were deemed related to infigratinib. Focusing on areas of interest, we had only 3 cases of hyperphosphatemia, all of which were mild, asymptomatic, transient and did not require dose reduction or discontinuation. We did not have any adverse event associated with inhibition of FGFR1 or 2, such as retinal or corneal adverse event. On Slide 22, we can see the phosphorus levels throughout the study. The darker blue line shows the mean and standard deviation of the phosphorus levels in the infigratinib arm, and the lighter gray line in the placebo arm. The colored area reflects the reference range. As you can see, the mean phosphorus levels were very comparable between both treatment arms at all time points and within normal ranges. There was no change in the mean phosphorus levels at week 52 compared to baseline in either of the treatment arms. Furthermore, the maximal change of phosphate levels observed for any child at any time point was within the typical intra-subject variability in the pediatric population. So in summary, these results show that oral infigratinib works and has a very favorable safety profile with no evidence of inhibition of FGFR1 or 2. The exciting results about body proportions suggest that infigratinib has the potential to improve clinically meaningful outcomes like functionality and activities of daily living. So what comes next? We are working on regulatory submissions to hopefully bring oral infigratinib to children with achondroplasia as soon as possible. We are planning to submit the New Drug Application to FDA and Marketing Authorization Application for EMA in the second half of 2026. And of course, we will be presenting the results from PROPEL 3 at medical and patient advocacy group conferences. Before I hand it over to Justin, I wanted to express our deepest gratitude to the study participants, their families, our principal investigators and their study team, advocates and collaborating research partners. None of these could have been possible without you. So now back to Justin.

Thank you for the overview of the data, Daniela. On Slide 26, we would be remiss if we didn't acknowledge that the results of PROPEL 3 are just the beginning of our commitment to families and individuals living with achondroplasia. We hear the feedback that it's not just about changes in height, but more importantly, longer-term improvements on health and function. Today's results on proportionality are a promising start, but there is still a lot of work to be done. We will continue to study the longer-term impact of infigratinib on important measures such as body proportionality, spine parameters, physical functioning and other factors that may meaningfully impact quality of life. We look forward to sharing these results as they are available over time with the community. On Slide 27, I'd like to highlight that today's results are just the beginning of what's possible for a safe oral FGFR3 inhibitor. Within FGFR3-driven gain-of-function conditions, we have an active ongoing trial for infants and toddlers with achondroplasia, which we believe will be registration-enabling for that age group. In hypochondroplasia, the strength and consistency of the results today give us the confidence to significantly accelerate that program, which is also driven by FGFR3 gain-of-function mutations. We are now enrolling the observational run-in for our Phase III trial. Finally, within the category of FGFR3-driven conditions, we know much of the attention to date on therapeutic options for achondroplasia have been focused on individuals with growth potential. Given the mechanistic role of FGFR3 in spinal tissue, we believe that an oral FGFR3 inhibitor may uniquely be able to impact aspects of spinal health in an adult achondroplasia population, and we are planning for further exploration in this area. We also believe that outside of FGFR3 gain-of-function conditions, inhibition of FGFR3 may be able to increase growth in some other growth conditions. There is a growing body of evidence that there is FGFR3 overactivity in conditions like Turner syndrome and SHOX deficiency, and we have initiated planning for clinical studies in these conditions. Given the safety results seen today, it's clear that we will have the ability to explore higher doses in these conditions, if needed. I'd now like to hand it over to Matt Outten, our Chief Commercial Officer, to go over our commercial plans for infigratinib in achondroplasia.

Thank you, Justin. 6 for 6 has a nice ring to it, and I'm excited to share our commercial plans for infigratinib, the sixth rare disease medicine BridgeBio will potentially bring to the market. This matters because it means we have real experience planning and launching medicines, and we've built and proven a repeatable commercial engine in rare disease. This is a team that knows each other well and knows how to perform together. Many of us have worked side-by-side for years, and our playbook has delivered across multiple therapeutic areas. So what does that mean for infigratinib in achondroplasia? It means that we know how to reach the right health care professionals quickly and efficiently. We've listened carefully to the community, and we won't let them down with the subpar and lackluster support programs that are far too common in rare disease. Consistent with our program in ATTR-CM, we will offer the most generous and comprehensive programs in the space. And we know how to recruit and deploy top-tier commercial talent to build the strategy and execute the tactics required to win in a competitive market. In that spirit, I'm pleased to announce that Aaron McIlwain has joined BridgeBio from Ionis Pharmaceuticals as the Senior Vice President of Sales and Marketing to help us bring infigratinib to the market. Aaron has a strong track record across multiple product launches, and we are thrilled to have him join us in this next phase of commercial preparation. He will be joining many of the same individuals who drove the successful launch of Attruby and who will also be central to the launch of infigratinib. If we move to the next slide, you can see just how large the opportunity is in achondroplasia, both in the U.S. and globally. Of note, treatment is concentrated, allowing a reasonably sized sales team to effectively cover the entire U.S. market. We also plan to launch infigratinib in the rest of the world ourselves with the exception of Japan, where we have a partnership established. So why are we so confident in this launch? It starts with the data. The data discussed today represents the highest efficacy rates shown to date in a clinical trial across average height velocity, Z-score and stat sig improvements in proportionality. In addition, infigratinib was well tolerated, with no SAEs related to the medication. That combination, compelling efficacy and safety is going to translate to exceptional launch performance and set a new standard of care in achondroplasia. We will be updating our market research with this new and exceptional data, and we'll come back to you with updated market results soon. And let's not forget that on top of the efficacy and safety data, infigratinib will also be the first and only oral therapeutic option, providing freedom from injections, hypotension and injection site reactions, making infi the first and only disease-modifying oral medication and the new standard of care for achondroplasia. We're highly confident in our ability to launch successfully in achondroplasia not only because of the compelling data announced today, but because of the team, the platform and a proven track record that puts us in a strong position to deliver 6 for 6. Thank you, and I will now turn the call back over to Justin.

Thank you, and we will now take questions.

[Operator Instructions] Our first question comes from the line of Biren Amin with Piper Sandler.

Maybe just to start off, as you think about how this data translates to a commercial opportunity, how are you thinking about peak year sales opportunity for infigratinib and overall market share based on the strength of the data that you presented today? And can you maybe share more on the commercial opportunity across both U.S. as well as ex-U.S. geographies?

Thanks for the question, Biren. Now this data set really represents the best case scenario for commercial TPP, superior AHV, superior changes in height Z-score, [ clean safety win ] and the surprise upside of show an impact proportionality, especially when it's commercially important in the [ 38 ] group. Now with clinicians that we've spoken with so far, they've used phrases like game changer or transformative. Now Matt, you can probably comment more on the market sizing?

Sure. Thanks, Justin. So I guess I would just call out the skeletal dysplasia market is already about $5 billion, including achondroplasia. And remember, the market research that we were using before -- it did and continues to show that injection burden is a significant concern, and families are eagerly awaiting an oral option. And in the research we've done before, we were using our old TPP. Even with that, we saw over half of the market being captured with infigratinib. And as I mentioned earlier, we're refreshing that data now and changing up our target profile with the new data announced today. And that has a significant improvement in terms of what we were testing before, especially in proportionality, and we'll report back to you all on what we see post that market research.

Our next question comes from the line of Cory Kasimov with Evercore ISI.

Look, these are super exciting results. And maybe the most surprising part, at least to me, are the data around body proportionality in the 3- to 8-year olds. So I want to ask how you believe or what you're hearing from like how regulators view proportionality, whether it's kind of supportive only versus potentially label relevant? And then separately, but related, from a treatment point of view, what's the ultimate clinical implication here of this proportionality benefit?

Yes. Thanks so much for the question. So let me hand it over first to Daniela to talk about the clinical implications, and then we can talk about the label.

Yes. Thank you. And thank you for the question. And the reason why we are very, very excited about body proportions is because the potential -- the great potential for improvement in a very clinically meaningful outcome. Particularly, improvement in this outcome in body proportion is -- will reflect or has or suggest the potential benefit of infigratinib in functionality and activities of daily living. So the implication is great. It is big on the community and on the children because this is something that really were the key points for them to expect a meaningful outcome in a clinical trial.

Yes. And Cory, given the totality and the consistency of the data on every single key metric of interest, given the size of the subgroup here on the proportionality endpoint making up more than half the trial, I think we're optimistic of our odds that language around that in the label, but still a little bit too early to comment.

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

This is Nick on for Tyler. Congrats on these results in the third positive Phase III in nearly as many months. So from us, safety has obviously been a common topic among investors, but the 4% Grade 1 hyperphos is impressive. What happened with these 3 children? And were these the only patients that had phosphate values above the normal range? Also for a quick follow-up, the value proposition in treatment-naive patients is pretty straightforward. But how about the prevalent switch patients? Is there anything to do or to explain to physicians to support this switch?

Yes. Thanks for the question. So I'll hand it over to Daniela first to talk about the hyperphos cases.

Yes. Thank you. Let me start by reiterating that infigratinib had a very favorable safety profile with no safety signals indicating inhibition of FGFR1 or 2. Regarding the 3 cases of hyperphosphatemia, we were very careful and used stringent criteria in our clinical trial. These 3 children had a very mild elevation of phosphorus. And even though their phosphorus values were above the reference range, they reflected an increase from their baseline of no more of 0.4 milligrams per deciliter that is absolutely within the expected variability in the phosphorus levels. Again, but it's important to reiterate that these elevations were transient and did not require dose reduction or treatment discontinuation. And to give a little bit more detail on these 3 cases, all these were boys around 13 years of age, that is an age where the reference range for phosphorus changes. The values in all 3 cases were mildly elevated for the strict reference range used in the study. And -- however, these values would not have even been considered as above of normal ranges had we used a less strict range, for example, the clinically accepted reference range of [ CALIBRATE ]. So this, in addition to the data showed earlier where the mean phosphorus was within normal ranges at all time points, it shows that there is no signal of infigratinib inhibiting FGFR1.

Yes. And to your question around the switch marketplace, I think there's still definitely a very significant opportunity there for us uniquely. Now going back to kind of the investor webinar we did a few weeks ago, when we did a lot of clinician research, the #1 reason why physicians today and families today aren't interested in therapy in the United States, in particular, is around the want to avoid daily or weekly injections. So we think we're uniquely set up for the treatment-naive population and for the switch population as well. There's already a lot of interest from families and clinicians on having kind of the needle-free option.

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

A number of the key ones have been asked, so I want to dive into a little bit of commercial strategy and market segmentation, if all right. Obviously, this has for VOXZOGO been an OUS growth story more recently. Can you give us a sense of to what extent you think proportionality and better AHV for you can potentially expand penetration into the TAM? Are there subpopulations of patients who are specifically less compelled by height itself as an endpoint that might be brought into the market? And to what extent is that playing out in the U.S. versus OUS markets in terms of patient segments, achondroplastic children with achondroplastic parents as opposed to normal stature parents, et cetera?

Yes. Thanks for the question, Mani. So we actually did some interesting work kind of looking at different oral analogs, seeing that when they first enter the marketplace, how they change the dynamics and the total addressable marketplace when it's been previously only been injectables. And on average, I think within the first 5 years, the total marketplace grew, I think, by an average of three- to fivefold. I think that's really kind of just like speaks to how important it is to have an oral alternative for these chronic conditions, I think, regardless of geography. And again, I think that's consistent with the research that we've done in the United States, where we've heard that the #1 reason why families aren't on a therapy today is around not wanting to deal with the burden of injection. And I think having the very strong signal on proportionality at week 52, especially in the 38-year-old subpopulation, which again, I think could be one of the most commercially important populations, is just kind of even more reason for people to consider looking at the FGFR inhibitor.

Question comes from the line of Salim Syed with Mizuho.

Congrats on the data. It looks really good. Neil, Justin, maybe just a couple from us. One, just on the 5.96 centimeters per year absolute AHV. Could you just clarify, what was like the upper end of what you saw in the individual patients? Like were there any cases of hyper growth? Or are we still all talking about patients being under any -- like still within normal, but at the very, very top end of that range? And then the second, just -- I think I missed a comment on the p-value of less than 0.05 for body proportion, is the base case that, that will get into the label with that p-value? Or will you need to combine it with PROPEL 2 or -- or what's exactly the status there and the body proportion into the label with that p-value?

Yes. No, I think thanks for the question. So why don't we first talk about the 5.96, right? I think that's actually -- thanks for picking up on that. That's actually one of the numbers we're most excited about. When we've looked at historical literature across multiple different [ payers ] and natural history studies, the average AHV for the population of average [indiscernible] is 6 centimeters per year, right? So I think the fact that we are essentially at that level just kind of goes to show, one, that really being able to inhibit FGFR3 at the source is able to kind of restore levels of growth back to kind of the wild-type level. And two, there's really not much kind of room for further improvement. We really didn't see any concerns around [ hyper growth ] or anything like that. And I think, again, it is a really nice data holistically. Now with regards to your question on proportionality. Again, just kind of given the consistency of the data that we've seen in all the different measures, right, across AHV, Z-score, the strong proportionality signal that we saw in this large sub population and the totality of the data, again, it's always too early to comment on kind of the regulatory discussions. But given the fact that we have breakthrough therapy designation with the FDA and a very collaborative relationship with the FDA to date, I think we're optimistic that I think this will be a really differentiated label.

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

Congrats on a great outcome here. So I've been getting some questions on the 2 different change from baseline scores in AHV, the 2.10 centimeters per year and the 1.74. I guess, what does the LS mean actually adjust for? And which of these is the most appropriate for comparison versus CNP and your Phase II signal?

Thanks for the question. Now first, I want to comment that infigratinib's efficacy was remarkably consistent between the Phase II and the Phase III data. 2.1 centimeters per year is the unadjusted mean between treatment and placebo, which is also the way it was measured in the Phase II. The 1.74 number is a statistically adjusted number. We actually wanted to include both numbers because it can be opaque at times, what statistical models different companies use to adjust the observed meaning. And so we thought it was actually probably the best way to allow for apples-to-apples comparison. No matter which number you will choose to focus on, though, we have the highest AHV seen in this area to date. And really, I think this effect size, the magnitude of this effect size is further supported by the consistency and the totality of the magnitude effect that we've seen in all the other endpoints, whether it be absolute HV, change in Z-score and especially proportionality. And again, this is especially noteworthy given that we studied the broadest age range enrolled across any trial in the States to date.

The next question comes from the line of Paul Choi with Goldman Sachs.

Congratulations on what is very impressive data. There's been some questions and debate in the investment community with regard to the role of FGFR inhibition on the CNS, both centrally and peripherally. Can you comment on if you saw any observations or any measurable effects there? And second, just given the data and the fact that there isn't an oral option available currently on the market, do you think you can get a priority review with your infigratinib filing?

Yes. Thanks for the question, Paul. I'm going to turn it over to Daniela first talk on the CNS side of things.

Thank you. The results of the study clearly demonstrated that infigratinib was well tolerated, with no safety signals indicating inhibition of FGFR1 or 2. We just discussed, for example, the phosphorus, where we showed that phosphorus values were comparable to the placebo arm, and the 3 cases of hyperphosphatemia would not have even been considered hyperphosphatemia should we have used less strict reference range. So regarding the claims of CNS safety issue, these are unfounded claims based on neonatal knockout mouse model experiments, which are certainly not relevant for the treatment with infigratinib of children with achondroplasia, the doses used here. This is supported by clinical data not only from the PROPEL 3, as we just showed, but data up to 5 years in nearly 200 kids in our study. Furthermore, in human PBMCs, at this exposure level, there were no inhibition of FGFR2. So again, infratinib showed a very favorable safety profile and with no signal of FGFR1 or 2 inhibition like hyperphosphatemia or corneal or retinal disorder. So the claims of CNS safety issues are not really scientifically or clinically substantiated.

Yes. And just to add a final point on that. It's actually remarkable, some of the outright lies one of our competitors in the space are saying. All they can do is make stuff up about other players in the space because they're not happy with the results. I think we stand firmly and proudly behind our safety profile. We're going to let our science [ stake ], and we're not going to stoop to their level. Now Paul, going back to your question about prior review. So given the fact that we have Breakthrough Therapy Designation in space, I think there was a recent study shown that there's like a 90% correlation between breakthrough therapy status and priority review. So kind of given the totality of the data that we're seeing today, I think we have a good shot at priority review.

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

Congrats on all the success so far. Hopefully, more to come. I distinctly remember you guys mentioning to look at Z-scores when you hosted the webinar last month. Really, your height Z-score seems to outperform your peers. So what do you guys think this finding precisely means for the community? And then secondly, these scores do increase over time when we look at the kinetics in your slides, which then raises a question to me, how much more improvement we can get on even more dosing past 52 weeks. So can we expect you to share another cut from the open-label follow-up data maybe this year? Or does that come later?

Yes. Thanks for the question. So let me hand it over to Daniela first on the Z-score.

Yes. So to address the significance of Z-score, it normalizes the height for the agents across the reference population that in this case is the achondroplasia reference population. This is the highest improvement in Z-score with an LS mean value of 0.41 in the treatment arm from -- as a change from baseline and a placebo-adjusted value of 0.32, which is also the highest across the trial. So this contextualizes the change in the height in its relation to the population. Justin?

Yes. I think something I'll also add, what's remarkable about the height Z-score other than the magnitude is actually kind of the speed of the separation too. I think we were able to reach kind of like a milestone like plus 0.2 and plus 0.3 faster than any other [ therapy ] in the space, and we're the first to ever get anywhere close to plus 0.4 in the treatment arm. Now what does this actually mean, especially in terms of AHV, to your question around AHV as well. We have basically effectively normalized AHV to the group of the average stature population at this highest value seen across any trial at almost 6 centimeters per year. And really, it kind of leaves, based on that simple math, like a 0.04 center per year room for improvement to kind of get back to that wild-type level of growth. So especially given the safety profile today, I think there's really not much room for improvement here.

Your next question comes from the line of Ellie Merle with Barclays.

Congratulations on the data. You mentioned that there were some other indications beyond hypochondroplasia and achon that you were thinking about. Can you maybe elaborate on the biology and some of those indications and which you think might make more sense for an FGFR inhibitor versus which diseases the biology might make more sense for CNP? And then a second question, just for hypochondroplasia. How are you thinking about the increase in AHEV that we should expect to see there relative to what we would see in achondroplasia? And any differences from a dosing perspective around how the dose response might compare between achon and hypochon?

No. Thanks for the question here, Ellie. So yes, we're really excited about some of the work we're doing in other indications outside of hypochondroplasia and achondroplasia, such as Turner syndrome and SHOX deficiency. And I think, again, in that -- in those cases, there's actually a kind of developing body of literature kind of showing high between those conditions and gain-of-function and activity in FGFR3. And so actually, there's actually a mechanistic rationale for exploration [ that's been for granted ] in those indications. And if you think about how the CMPs are kind of trying to play up that type of angle there, it's actually really through inhibition of the MAPK pathway, which obviously, if you kind of target upstream of the FGFR3 pathway, you would actually expect the same results and actually with the benefits of having the oral form factor as well. So kind of more to come there. With regards to your question around hypochondroplasia, I think we published a few months ago really, the consistency of the in vitro data between the mutations in the hypochondroplasia setting compared to achondroplasia. So we really kind of don't expect any differences in dose or efficacy between achondroplasia and hypochondroplasia population. But more to come there, and something really we're really excited about.

Our next question comes from the line of Anupam Rama with JPMorgan.

Congrats on the data. Just a quick broader question here. Like maybe for Matt, how do you think about the size and scope of the sales force here in the U.S.? And can you comment on synergies with ADH1? And then comment on how you think about a European build-out here?

Yes. Thanks for the question. I mean, I think the nice thing is it's a fairly concentrated market, but it is a large market. I mean I mentioned in some of my earlier comments, right now, it's $5 billion globally. These kids are all over the world, and we are planning to launch this ourselves outside of Japan. So we're in the process of building all of that out now. I don't think you would expect to see like an ATTR-CM size sales force for something like this. I think that's also similar to ADH1. I think you can cover the centers and the doctors very effectively with a small, really good sales force. I think the nice thing, too, is the messaging is fairly simple. It's the best data that's been shown to date, and no more shots ever. So this is not a complicated sell. It's not a lot of physicians and health care providers that you have to hit. And the data is very clean and very easy to comprehend and looks amazing. So I would expect that this will be a fairly straightforward launch.

All right. And that concludes our call. Thank you, everyone.

All right. That concludes the Q&A session and today's conference call. We would like to thank you for your participation.