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

Good day, and thank you for standing by. Welcome to the BridgeBio webcast to discuss month 12 and 18 Phase II results of infigratinib for achondroplasia. [Operator Instructions] I would now like to introduce you to your speakers today. Dr. Ravi Savarirayan, clinical geneticist and Group Leader of Molecular Therapies Research at the Murdoch Children's Research Institute in Australia; Dr. Daniela Rogoff, Chief Medical Officer of Skeletal Dysplasia, BridgeBio Pharma; Justin To, Chief Executive Officer of Skeletal Dysplasia, BridgeBio Pharma. I would now like to hand it over to Dr. Neil Kumar, Chief Executive Officer of BridgeBio Pharma.

Thanks, operator, and thanks, everyone, for joining this call. The second webcast we have had the privilege of hosting in this past week. Today, we focus on our program for achondroplasia, hypochondroplasia, and related FGFR skeletal dysplasias. I'm grateful to be joined today by the BridgeBio team and immensely grateful to have the opportunity to hear from and to learn from Dr. Ravi Savarirayan, a pioneer not only in achondroplasia and related conditions, but indeed in rare disease with large. Today, you'll hear about a molecule designed from the outset to target this condition added source, mutated gain of function FGFR3. With the premise of doing so, we can more efficaciously, more safely and more conveniently serve children with achondroplasia and related conditions. Before we get there, I'll remind everyone that we're making forward-looking statements today. The slide deck associated with this call is publicly available and will refer to specific slide numbers as we progress the discussion. I'll start with what is always the most important slide in our documents, Slide 3, a thank you to the amazing and inspiring children and families, advocates, physicians, clinical research staff and collaborating research partners that make our work possible. Yours are the efforts that make whatever impact infigratinib is to have possible. And in turn, we recognize our responsibility to you, to move quickly, to provide this medicine to patients as broadly as possible and to continue to explore its full parameter space of usefulness. Indeed, it was the community and leader-like Ravi's push to explore efficacy beyond the primary endpoint, which matters a great deal to the children and families we have spoken to that led us to explore efficacy against proportionality. We are listening to you and when we fail, please push us. Today's findings related to proportionality represent the beginning of that exploration, which I hope will continue to expand in both magnitude and scope over time. With that, I'll turn it over to my colleague, Justin To, who leads our infigratinib efforts, to provide further context.

Thanks, Neil. Before we get into the data, I'd like to spend a few minutes on the opportunity at hand and the design rationale for this program. As a reminder on Slide 4, the opportunity for infigratinib is vast and largely untapped, with a total addressable population of up to 25,000 people in the U.S. and EU alone. The market for therapies in achondroplasia is now full validated with the continued growth and uptick of vosoritide, although much of it remains untapped due to many families concerns around daily injections for the children. Like achondroplasia, hypochondroplasia is also caused by activating FGFR3 variant and has a similar prevalence and incident out of achondroplasia. Today, we have announced the launch of our ACCEL program in hypochondroplasia. Finally, we will be planning to expand in the future to other FGFR3-driven conditions such as Crouzon syndrome, where there's tremendous unmet need. Moving on to Slide 5. When we first initiated this program in achondroplasia, we had 3 key design criteria that we believe we have now met. The first was targeting the condition of directly added source to unlock not only a new level of efficacy, but also new types of efficacy, as Neil mentioned. Second, we wanted to demonstrate a favorable safety profile, avoiding frequent injection site reaction and hypotension. We also wanted to avoid inhibition of VEGFR3, which is a liability of other FGFR3 inhibitors. Third, based on consistent feedback from the community and from advocates, we wanted to avoid the significant burden of daily injections. On average, with the daily injectable, more than 4,000 injections will be given to a child from birth until the closure of their growth place. Moving on to Slide 6 now. As a reminder, infigratinib is the only treatment and option -- treatment option in development for achondroplasia and hypochondroplasia that directly addresses both downstream effector pathways. The MAPK pathway, which impacts chondrocyte hypertrophy and the JAK-STAT pathway, which affects chondrocyte proliferation. We believe impacting both signaling pathways are key to unlocking not only maximum improvements in linear height, but also improvements in key measures like proportionality that matter to the community. With this, I'll pass it over to my colleague and our Chief Medical Officer, Dr. Daniela Rogoff to present our exciting data update today.

Thank you, Justin. Good morning, and thank you for calling in. I will be sharing the updated data on Cohort 5 for up to 18 months of treatment and assessment. On Slide 8, we have the summary of the safety in Cohort 5. Infigratinib continues to be well tolerated, with no safety concerns identified throughout the participation of the children in the study, which was up to 18 months. There were no serious adverse events or adverse events that led to treatment discontinuation. Most of the adverse events were mild in severity and assessed as not related to study drug. No adverse event on excess of growth or adverse events associated with excessive growth were reported. No hyperphosphatemia was observed and most importantly and as expected at these doses, no adverse events at the eye level were reported. On Slide 9, we have here the adverse events reported for more than 10% of the children enrolled in the study. As you can see, these are all common conditions in pediatric population and in children with achondroplasia. Moving on to efficacy now on Slide 10. We have represented a change from baseline in the annualized height velocity at month 6, month 12 and at month 18. We can see that treatment with infigratinib results in a robust increase in the annualized height velocity, which is sustained throughout the study, meaning that the effect of infigratinib persisted for up to 18 months. The change from baseline at month 12 and month 18 was 2.5 centimeters per year, which is highly statistically significant with a p-value of 0.0015 at month 18, and greater than any other treatment of [indiscernible] in development at both high points. It is important to remark that the month 12 and month 18 data is based on 11 children, as 1 child dropped out before the month 12 visit for reasons unrelated to safety or efficacy, but due to the closure of the site as the PI was leading the institution. This child was considered as responder at month 6. Slide 11 shows the [indiscernible] of the annualized height velocity up to 18 months of the treatment for all children in Cohort 5. We can see that the response to infigratinib was broad, with 10 out of 11 children having an increase in the annualized height velocity at month 18 and 73% having an increase in the annualized height velocity of at least 25% compared to baseline. Going to month -- to Slide 12. Here, we have the effect of infigratinib on body proportion represented by the upper to lower body segment ratio. At month 6, we have already seen a trend towards improvement in body proportion, which continued to show persistent decrease with longer duration of treatment reaching statistically significant at month 18 with a p-value of 0.001. This improvement in the upper to lower body segment ratio after only 18 months demonstrates strong potential for a meaningful effect on body proportionality. And to explain more about what this data means from the clinical perspective, I will hand it over to Ravi to provide the context of the results shared today. Ravi?

Thank you very much, Daniela. And it's a pleasure to be on the call. I've been working in the field of rare bone diseases for 30 years with the name of bringing new treatments that will promote health for children through rigorous science and clinical trials. Why is proportionality so important? Proportionality is crucial because achondroplasia is not an isolated short stature syndrome, it is a skeletal dysplasia with disproportionate growth of the skeleton. And in fact, the upper segment to lower segment ratio is double the average value at 2 versus 1. That is important from the day-to-day living of these children because disproportionality with a relatively large head is associated with delayed motor milestones in infancy and impaired functionality with regards to toileting, with regards to running, with regards to increased fatigue and exercises. So it's really important that as we gain height any treatment that gains height with achondroplasia also can improve proportionality. And the cumulative improvements that we are seeing in proportionality are extremely encouraging in these children because they are the unfiltered needs of parents and children who want to have longer arms and legs, so they can perform their activities of daily life with much more efficiency and much more easily. So that's why proportionality is such a critical endpoint in achondroplasia, and I've encouraged the team to really pursue this and to see that we are trending and getting significant changes at the 18-month level is extremely, extremely promising with results to enhancing these factors in the children's life. And I'll now hand over to Justin.

Thanks so much, Ravi, for taking the time to kind of talk about why we're so excited about the change in personality. Moving on to Slide 16. Here, we're talking -- we remind folks that currently PROPEL 3, our registrational Phase III program for achondroplasia is now underway with full enrollment anticipated by the end of this year. The primary endpoint for PROPEL 3 is meaning change from baseline and annualized height velocity at 52 weeks, which has been aligned with both the FDA and EMA. In parallel with this momentum on our achondroplasia program, we have also announced this morning the initiation of our ACCEL program for hypochondroplasia, with the first child consented into our observational run-in last month. I'll hand it back to Ravi to talk a little bit about hypochondroplasia, and then to Daniela to talk about our clinical development program.

Thanks very much, Justin. Yes, hypochondroplasia is another FGFR3-driven skeletal dysplasia that is also a dominant condition. It has a similar incidence to achondroplasia, meaning there could be up to 250,000 people in the world living with this condition. And it has a greater genetic heterogeneity. And clinically, it is a milder version, although some people with hypochondroplasia have similar and overlapping features to achondroplasia. The most important thing again to point out here is this is another disproportionate short stature in which there can be functional problems as well, in which head circumference is larger than average and there can be medical complications as well. And also in this condition, it is also associated with features such as epilepsy and other cognitive features such as mild cognitive impairment. Most importantly, the condition is FGFR3-driven, and this molecule will also potentially combat this medication at its very origin as it directly targets FGFR3 signaling. Thank you very much, and I'll hand over to Daniela Rogoff.

Thank you, Ravi. And now moving on to Slide 20. We are very excited to initiate our ACCEL program, which is our program in hypochondroplasia. It consists of an observational run-in study, a single pivotal intervention study and the long-term follow-up study. We are very pleased to have the FDA and EMA alignment on our plans. The ACCEL study, which is an observational run-in will enroll the children with hypochondroplasia that will participate in the interventional study ACCEL 2/3. The study will collect the baseline data, not only in linear growth, but also in body proportions and medical complications, quality of life among others. The ACCEL 2/3 is a single pivotal study that consists in an initial open-label Phase II portion, followed by the pivotal Phase III portion that is a double-blind placebo-controlled trial in children with hypochondroplasia. All of the children participating in either the Phase II or the Phase III portion need to have completed at least 6 months of observation in ACCEL. The primary endpoint is the change from baseline in annualized height velocity versus placebo and a secondary endpoint, we will evaluate other indicators of growth, body proportions, quality of life complications described in hypochondroplasia, including the evaluation of cognitive functions that as Ravi mentioned, difficulties in certain aspects like attention complications have been described as potentially more prevalent in individuals with hypochondroplasia compared to the general population. And as infigratinib process the brain blood barrier, it has the potential to have a positive effect on this cognitive function. The study will enroll children between 3 and less than 18 years of age, with potential to grow, and they will be treated for 52 weeks. After completion of either the Phase II or the Phase III portion of the study, children will be offered the opportunity to receive treatment with oral infigratinib in the ACCEL OLE study, where the long-term efficacy and safety of infigratinib in children with hypochondroplasia will be evaluated. The observational study ACCEL is already underway, and this is the first stepping program to evaluate the potential of infigratinib as a treatment option for children with hypochondroplasia. Now I will hand it over to Justin for closing remarks.

Thanks so much, Daniela. So we're now on Slide 22. To conclude, we are extremely pleased at the continued best-in-class efficacy and well-tolerated safety profiles for infigratinib are sustained out until the end of study at 18 months. Even more exciting for us and for the community is that the statistically significant improvement in proportionality for the p-value of 0.001 which represents a functional improvement beyond just linear height. To our knowledge, this is the first clinical trial in achondroplasia, showing a statistically significant change from baseline in proportionality. We continue to make excellent progress at enrolling PROPEL 3, and are thrilled to build on our momentum by expanding to hypochondroplasia with the initiation of our ACCEL clinical program, which has been aligned with both the FDA and EMA. I'd also like to acknowledge our commitment to capturing the full potential for infigratinib as a potent and selective FGFR3 inhibitor. We will be continuing to evaluate ongoing expansion indications into not only FGFR-driven conditions with high unmet need by Crouzon syndrome, but also potentially larger FGFR wild-type growth conditions as well. With that, I'd like to thank Dr. Ravi for joining the call, and I'll stop here and I open it up for questions.

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

Congratulations on the data. So I have a couple for you. The first one is the statistical significance on proportionality is pretty exciting. So can you put this magnitude of improvement into context with the existing body of clinical data and discuss how that might improve over time? And the second one is just discussing your confidence in this 12- and 18-month AHV data holding up in a larger Phase III trial that is ongoing.

Yes. Thanks so much, Tyler. This is Justin. I'm happy to address both parts of the question. With regards to proportionality, as Ravi mentioned, disproportionality is a key clinical measure of achondroplasia. And we've been hearing from the community and some clinicians that it's important for a treatment option to show efficacy beyond just improvement in AHV, and so we're excited to see if there is a significant change in such a short period of time. At 18 months, I think we kind of saw a change from 2.0 to 1.88 and I think we believe other trials around 18 months have only seen a 0.04, 0.05 change. So we're effectively not seeing more than 2x the effect on proportionality as other treatment options in development for achondroplasia at this time. And then the fact that the proportionality should also be cumulative and now we continue to grow over here. So we're really excited for what this means. And as a reminder, change in proportionality is the key secondary on our Phase III trial. And so today's results gives us more confidence that we could potentially hit that and be the first product on achondroplasia with a label for not only improvement in linear height, but also potentially improving proportionality as well. With regards to your second question around kind of the confidence that today's results give us for the Phase III, I think we're really pleased to see the continued durability of our AHV response from month 12 and month 18, where we've seen some other kind of Phase II trials diminish a little bit during that time interval. And it's also kind of magnitude of dispersion, the standard deviation kind of coming around a bit as well. For other Phase II trials, we've seen that their month 18 results mapped quite nicely through the Phase III results. So I think seeing today's durability of 2.5 really gives me confidence that would be kind of potentially around that for a Phase III.

Our next question comes from Salim Syed with Mizuho.

Great. Congrats on the data. Just a couple from us on the proportionality and also just the commercial landscape here. So maybe for Dr. Ravi, just curious...

Sorry about that. It's just going to be just us off on the Q&A. Dr. Ravi had to jump off.

Okay. I apologize. Okay. I still love your opinion. So I guess on the proportionality, Justin, just -- I know [indiscernible], but just how are you thinking about clinically meaningful changes? Is there a particular number that the physician community or the patient community look like as clinically meaningful change in proportionality, and just how that number changes over time? Do you expect this to be an increase as time goes on and more sort of like a linear change? And just on the commercial side here, just curious, I guess this is for Dr. Ravi, but I know -- I just want to get your view, just curious, what is the theoretical argument now in your guys as you speak to physician, why anybody would take Voxzogo or are you positioning infigratinib also to switch patients from Voxzogo or just new patients?

Yes. Thanks for these 2 questions. With regards to proportionality, in terms of just kind of staying in the context, as what Ravi mentioned, children with achondroplasia typically have an upper to lower body ratio of about 2 and children of average stature kind of closer to 1, 1.2 range. And so being a meaningful change, there would be kind of a decrease of 0.1 or so what I think we are already kind of clear. But what would you like to see over time is the significance of that response and that effect should be cumulative as well as we've noticed in other kind of trials with achondroplasia. So what we expect from here is that the longer the fall of the kind of more deepening of the response and proportionality that we should see. So we should expect that it would be cumulative. With regards to the potential commercial stores here. I think really, we're starting to see a very compelling target product profile for both clinicians and community, having a -- potentially faced daily oral with best-in-class efficacy at AHV, but most importantly, changes beyond just linear height such as disproportionality. And so I think that would be very compelling for not only new families diagnosed with achondroplasia, but also existing family [indiscernible].

Got it. And just on the -- just a quick follow-up, if I can ask. Somebody asked me to ask you. Are you guys planning to release the patient-level data or just these absolute AHV dotbots? Any kind of color on the change?

Yes. No. So we did share the dotbots which kind of shows some of the individual local data. Based on feedback report from community and clinicians, we're not kind of releasing exact individual local data at this time, although we might explore doing so at a later time, but that's kind of some feedback report from the community, which is why we kind of chose to show the dotbots this time around.

Okay. Got it. Congrats again.

Thanks.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on the data. Maybe following up the comments that were just made right now. I'm wondering if there's still a plan to have a detailed publication in a journal later this year? And to the extent that you plan on sharing some of these data to the Phase III investigators near term, I know enrollment is going well, but I'm wondering if these data could further kind of accelerate your enrollment time lines?

Yes. Thanks for the question, Anupam. Yes, I think as we mentioned at previous conference, our plan is still to kind of put this together for a major publication, again, exact timing to be determined depending on the review time lines. But it's our every intention to have submitted to a kind of a top journal, given excitement around its data, especially around proportionality. With regards to kind of excitement that we've heard from our investigators, we have shared this data with our investigators and they are extremely excited about the results that we're seeing. And enrollment is already going very well, and so I would expect that this would only kind of continue to feel that as well. Did that answer your question?

Yes. I'm good.

Our next question comes from Mani Foroohar with SVB Leerink.

This is CJ on for Mani. Congrats on data. A couple of questions from us. Do you have any details on the one child that did not have an increase in AHV from baseline at month 18, like did that child has FGFR variant that is unique from all other children? And the second question is whether the upper to lower body segment ratio changes at month 6 or month 12 were also static?

Yes. No, thanks for the question. With regards to the one participant who did not have an improvement in change -- improvement in AHV from baseline, there's no particular baseline characteristics or anything that would suggest why they would not have a response. I think the only thing to kind of point out is that I think, I believe they had a pretty high baseline, above 6 from the start, which is kind of on the very high end for children with achondroplasia. So the fact that we didn't see an improvement from there is not discouraging, given the fact that even potentially to maintain that would be quite encouraging given the baseline characteristics. With regards to your second question, just want to make sure I heard it correctly, again, it was around proportionality you said?

Yes, exactly. The upper to lower body segment ratio at month 6 and month 12, those are also static?

Yes. So I believe neither month 6 or 12 were static, but month 18 was static.

Okay. Got it. And then the patient [indiscernible], you said they had 6 centimeters per year at baseline, that's also the highest absolute level of the cohort rate?

Correct.

Our next question comes from Josh Schimmer with Cantor Fitzgerald.

Just have 3 of them. First, can you remind us what the AHV is that the PROPEL study is powered to detect and the extent to which that is consistent with these data?

Yes. So the PROPEL 3 study is powered to detect a change from baseline of approximately 1.3. So we kind of powered detect to be quite conservative actually, given what we're seeing improvement effect.

Right. Got it. And what is your latest thinking on potentially exploring the safety of a higher dose for kids who might need some catch-up growth?

Yes. No, thanks for that question, Josh. It's a good one. It's one we thought about. I think just given the very strong efficacy and safety profile, we seem to be both kind of best-in-class change in AHV that has taken proportionality, but also a pretty clean and safety profile as well as the kind of the feedback we've got from a community that they really want a [indiscernible] as soon as possible. We really prioritized on pushing for the 4 to 5 dose level in development right now and same for that in hypochondroplasia as well. We think it's one we really want to prioritize.

I got you're prioritizing that and that's what you're studying in PROPEL, but would you consider a separate analysis to push the dose higher and see if it's well tolerated to get some potentially stronger growth for kids who might need it?

Yes. No. Again, I think it's a really good question and one we'll continue to explore. But I think at this time, we'll be focusing our efforts at the 0.25 milligrams per kilogram dose for the time being.

It is an interesting question, sorry, Josh, like we've not thought about, as you and I have discussed, dosing all the way up to hyperphos for each child individually so that you could max out the dose and then figure out and then come down slightly. But that's not really -- not what the community physicians or regulators wanted to see. So you could imagine individualizing doses, but that's obviously not as doable when it comes to interrogating something in a clinical trial or commercially.

In the AE table, there was some pain in extremity, noted and up to around -- almost 30% of patients, maybe can better characterize that? Is there any reason to think that's some on mechanism and side effect, how severe was it? And were there any lesser common side effects that might be mechanism-related?

Thank you for the question. The pain in extremity was reported, as you mentioned, in approximately 28% of the children. Pain is one of the most common auto symptoms in children with achondroplasia. So the ones that were reported during the participation in the trial were all mild or moderate in severity and none of them were assets that's related to this study drug. I hope this answered your question.

Yes. And Josh, just to pick up to your other point here on potential on mechanism off-target effects, right? Yes, just to reiterate, we didn't see any cases of hyperphos or kind of off-run effect as well. So nothing -- pretty clear and encouraging safety profile overall.

Our next question comes from Paul Choi with Goldman Sachs.

Congrats on the data. I was wondering if you could maybe comment a little bit on some of the responses by age group or age bucket? I know the majority of the patients are under 8. But just curious if you're seeing any differential based on age at baseline and just sort of what that looks like? And then my second question is for the hypochondroplasia study, I know you're going to do a bit of a run-in here, but just sort of thoughts on what dosing levels might be appropriate for this particular population? Would it -- would the amount of drug be similar to what you've seen here and required for achondroplasia and just sort of what sort of treatment frequency might look like there?

Yes. Thanks, Paul. To your first question around kind of the differences in age baseline. No, we don't see kind of any difference in treatment effect across different ages in our study. I think the only ages where there could potentially be a treatment difference is looking at very young kid, kind of younger than 3 and kind of much older kids who are kind of near puberty, over 12 or so where we don't really have them in the PROPEL 2 study. I think those really are only 2 age buckets where there could be different treatment effect size difference, but we're not seeing that -- those differences in our 4 or 5 studies. With regards to your question around hypochondroplasia, we are planning to interrogate the same dose of 0.25 milligrams per kilogram daily in our achondroplasia -- the same dose as in our achondroplasia study as well. It's kind of based on what we've done preclinically, but also thinking about the same level in additional will be quite important here. And we have got a regulatory buy-in upcoming using a single dose as well for the Phase II and Phase III program in hypochondroplasia. Did that answer your questions?

Yes, it did. Great.

Our next question comes from Cory Kasimov with Evercore ISI.

I have 2 as well. First one is, do you have any plans to evaluate infigratinib in the 0- to 3-year-old patient population or, I guess, 0- to 2.5-year-old? Is there anything about the formulation that would prevent it from being used in these younger kids? And then the second one is similar to Josh's question on safety. Can you contextualize the roughly 30% vomiting as well? I assume it's not overly significant, given there are no discontinuations and obviously, no grade 3 plus events, but any color would be helpful.

Yes, happy to take it. So I'll take the first one about infant toddler first, and I'll hand it over to Daniela for the question around the vomiting, which is really not concerning. With regards to the infant toddler study, yes, we do have plans to kind of go down to the youngest age range, the 0 to 3, which -- we've heard consistently from clinicians and from the community remains that age bracket with the highest unmet need. So we do have plans that we'll announce in the future about our request have to go through the younger ages, that remains a core component of our deployment program and one we're committed to. The administration shouldn't be an issue for kids who are about 1 to 3, and we might explore some sort of oral solution potentially for the younger kids, but just trying to be anything too difficult. I'll hand over to Daniela for the question around the 30% vomiting.

Yes. Thank you for the question. So the vomiting as well, they were considered as mild in severity. They were not associated with infigratinib, in the sense that they were not timely connected or there was no association in the intake of infigratinib and the vomiting. And as well there were other -- in many cases, there were other signs of GI dysfunction or intercurrent at the time of the vomiting.

Did that answer your question, Cory?

Yes, definitely. Appreciate it.

Our next question comes from David Lebowitz with Citi.

When you look at the design of the pivotal trial, the age range is from 3 to under 18 and the mean age for the Phase II is about 7.5. How do you see the mean age of the study and the overall distribution of patients changing with respect to what we saw in the Phase II? And how might this affect the results in the Phase III?

Yes. Your question around the achondroplasia program or the hypochondroplasia program?

The achondroplasia.

Great. Thanks for that question. One of the main reasons why we expanded the age range on a Phase III compared to the age range of Phase II, ultimately, we want to have a little bit of a broader label than just 5 and up. And as I mentioned before, and I think on the previous question, from what we've seen, there's really no impact of age differences within this particular age range on efficacy on AHV. So only when you look at the youngest kids and look at kids who are in puberty that you might have an impact on the treatment effect. So I think having a broader age range in our Phase III shouldn't meaningfully kind of change the expected impact on AHV.

And that's all the time we have for questions. I'd like to turn the call back over to Justin To for closing remarks.

Great. Well, again, thanks so much for the time and joining today, and I want to make sure we again thank the clinical trial sites, the clinicians and the families who participate in the study for kind of what we're making possible community. So again, thank you all.

Thank you for your participation. This does conclude the program. You may now disconnect. Everyone, have a great day.