Good day, and thank you for standing by. Welcome to BridgeBio, Achondroplasia Educational Roundtable Event. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Dr. Neil Kumar, BridgeBio Founder and CEO. Please go ahead.
Thanks, operator. Appreciate the time and appreciate everyone taking the time today. We're privileged to spend the coming almost hour with Dr. Irving, who I'll introduce in a moment. The objectives of today's call, in response to a bunch of questions that we've been getting from many of you over the past few months, are simple and are really the following four. Number one, to better understand the unmet need associated with achondroplasia and related skeletal dysplasias. Number two, to understand the pathomechanism of this disease. As many of you know, this is a well-described disease. Number three, within that context of understanding both the molecular pathomechanism as well as the large unmet need to describe the nature and goals of the therapeutic agents, including one that BridgeBio is attempting to develop that are being trialed or are approved today.
Finally, four, to explore what the extensibility of these therapeutic agents might be beyond achondroplasia to other important unmet needs. As I mentioned, we're lucky to be learning today from Dr. Melita Irving, a Physician in Clinical Genetics at the Guy's and St Thomas' NHS Foundation Trust in London. Dr. Irving, as many of you know, has been involved with many of the seminal trials in this space, including I think being the second author on The New England Journal of Medicine paper associated with risdiplam. She's published extensively on treatment guidelines, the natural history of achondroplasia and other related conditions. As in all of our endeavors, we only operate really in these spaces thanks to the efforts of the unbelievable physicians, scientists, families and the children in the space. We're thankful for Dr.
Irving's time this morning. As a reminder, before we jump in, BridgeBio anticipates releasing the final cohort of our phase two data in early March. With that, I'll turn it over to Dr. Irving and then ultimately over to Justin To and Dr. Daniela Rogoff from our team, who leads clinical development in this area to have a discussion. Dr. Irving.
Thank you very much, Neil, for the introduction, and thank you for inviting me today to speak about this, the treatment landscape and unmet need in achondroplasia. I understand that you can all see the slides that I'm speaking to. I'm just moving to slide two to show you my disclosures, and then quickly on to slide three. Achondroplasia is the most common cause of disproportionate short stature. The depiction on the left here is to show you that achondroplasia is not a new condition. It's been around for millennia.
This is a depiction of a man with achondroplasia on the side of a sarcophagus in the Museum of Egypt in Cairo, showing, as you can see from the modern-day photograph of another individual with achondroplasia in profile, very similar physical traits. Disproportionate short stature, by which I mean the there is overall short stature comes from the trunk. Sorry, from the limbs in the main. Short legs. You can also see, therefore, that translates to short arms as well, with a relatively normal trunk size, and a larger head size. That's really well depicted in the photograph on the right, kindly shared with me by Dr. Will Mackenzie, a pediatric orthopedic surgeon, in Wilmington, Delaware, showing twin brothers, fraternal twins.
One of whom has achondroplasia and the other does not. It's a very clear depiction of the physical traits that are associated with achondroplasia. Again, that disproportionate short stature, where if you look at the arms of the boy on the right, his hands, his fingertips come really just around to his, the level of his underwear, whereas his brother's go way past that and onto his upper thigh. You can see a relatively short chest. You can see that they're standing very differently. The boy on the right with achondroplasia has extreme joint laxity in his knees, and those very short legs again, and the arms are much shorter.
There's also some constriction at the elbows, all of which make functionality, doing things for himself on a day-to-day basis, much harder than it is for his brother. Disproportionate short stature with other physical traits and therefore knock-on effects to daily life as a consequence. Again, just to show you, moving on to slide four, another depiction in historical illustration, in the court of the royal family in Spain. This is a painting by Velázquez, showing a lady in a very prominent position within the court who clearly has achondroplasia, a physical condition back then that was very much revered, as was the man with achondroplasia depicted on the sarcophagus.
This is a very well-known and established physical condition. Here on slide five, I'm showing you the manifestations that may occur as the consequence of the abnormal bone growth that occurs in achondroplasia that is not just restricted to longitudinal growth and to body habitus, but also to a number of complications associated with abnormal bone formation in achondroplasia. The one that we worry about most of all, right from the word go, is depicted in the top left panel, which is showing you an MRI scan, looking at a child from the side. On the right-hand side of the panel is the back of the head, and the left-hand side of the channel of the panel is the face and the mouth. Within the center is the foramen magnum.
That's Latin for big hole. There's a big hole at the base of the skull through which the brain becomes the spinal cord. That hole is formed by a ring of bone, which is abnormal in achondroplasia. There is some narrowing and constriction around that hole in everyone with achondroplasia, all infants, but it can become very narrow and therefore squeeze off the spinal cord. That in itself is associated with an increased risk of sudden infant death, that is very concerning for us as clinicians who look after these children. We seek that out as a monitoring test to look out for foramen magnum stenosis.
The panel to the left and in the middle that shows that same that same profile on MRI scan, shows the different levels of stenosis that can occur. We worry particularly about the two on the right, which we know is score three and score four, the most severe forms of foramen magnum stenosis, at which there is a much higher risk of neurological complication and even death associated with the complication. Looking to the right, the cartoons there showing the airways on the on the two panels at the right top. The one on the left shows the airways, the one on the right shows the middle ear. These are all channels created by bony, yes, bony channels that are all implicated in abnormal bone growth associated with achondroplasia.
The result of that on the airways is sleep apnea or sleep-disordered breathing, for example, obstruction during sleep. Even a slight increase in the size of the tonsils and the adenoids at the back of the throat can obstruct the airway that are already narrow in children with achondroplasia because those bony channels are different. That can cause again, a significant increase in infant morbidity and even mortality because of the sleep-disordered breathing. Glue ear is very common in children with achondroplasia because again, the middle ear is constructed by bony channels that are also involved in achondroplasia. Hearing loss and ear, nose, and throat complications are very common.
The little cartoon in the middle there of the baby, one lying prone on its tummy and the other sitting up is depicting the fact that the spine is also involved in achondroplasia. In the younger kids, the L1 vertebra, the lumbar vertebra, which is roughly in the center of the back, is wedge-shaped. If children are placed in a sitting position before they are able to sit and support themselves in that position, then there is a kink in the spine or a gibbus, or as we call it, a kyphosis, which can become permanent if the spine is not looked after carefully in those very young days. Can cause, again, compromise of the spinal cord by compressing the spinal cord around the area of the kyphosis of that gibbus.
Later on in life, multiple levels of spinal stenosis and narrowing within the canal through which the spinal cord passes occurs. That too can cause neurological complications such as paralysis, and pain and functional implications as well upon adults with achondroplasia. Adults and older children or young people. The spine is also very much involved in achondroplasia. At the bottom left there, the child in the wheelchair with the metalwork is showing external fixation following a limb lengthening procedure in which the long bones are broken, they are fractured.
A frame is applied to either side of the fracture, and as callus forms to heal that fracture, the ends of the frame are pulled apart to make a fracture again, which then heals with the callus formation, pulled apart again, heals with the callus formation. That sequential process then causes an increase in longitudinal bone growth through maximizing that callus formation and extending the length of the long bone. It takes a long time. It's painful. It's very restrictive for that child. If you do one leg, you do the other. If you do the lower part of the leg, then you need to do the upper part as well. Sometimes the upper limbs are done as well.
It's very invasive with a high complication rate, often, and an extremely invasive procedure for young people. Just moving on to the next slide, where we drill down a little bit into some data generated by QED in the PROPEL natural history study, which seeks to establish what life is like normally for children with achondroplasia before they're exposed to any interventions. We saw a very high surgical and medical procedure burden in these children. In fact, 67.4% of children had undergone, when they were questioned at the point of being recruited to the natural history study, a surgical or medical procedure. That equated to roughly three procedures per child, with some children just having one, but some receiving up to 11 different interventions.
The most common interventions and surgical procedures in particular were ear, nose, and throat related, so adenoidectomy, adenotonsillectomy, and tonsillectomy, being very common. Ear-related procedures, so treating glue ear, for example, often requiring repeat surgeries. Spinal or cranial decompression, addressing the fact that there is a high incidence of the severe foramen magnum stenosis. Later in childhood, the spinal stenosis, which can affect different segments throughout the spine at multiple levels. Infections and respiratory issues are also very high in their incidence, with 53.5% questioned in the study having a history of infection, infestations. Most common again being ear, nose, and throat related, so ear infections. Recurrent acute otitis media and glue ear.
A history of respiratory disorders, again in almost 50% of children, with sleep-disordered breathing occurring in 40%. A history of significant musculoskeletal issues as well. The most common of which was the kyphosis, that kink in the spine, and spinal stenosis occurring in 10% of children. This is something that we have seen happening more commonly in adults, but it certainly starts in children to the point that they can need surgery early on in life. Moving on now, we're onto slide eight.
Just to give you a bit more of an idea about the extent of the other complications associated with achondroplasia affecting acquiring a hearing implant because of the associated hearing loss in 17% and disorders of the central nervous system occurring in 20%. Sometimes the children develop hydrocephalus, which is a condition in which the ventricles, the fluid-filled spaces in the brain, become too fluid-filled. They become very full, and that fullness can then impact the surrounding brain tissue and compress that brain tissue with neurological consequences. That's called hydrocephalus, and so they can be shunted.
In other words, you can put in a shunt to drain away the fluid from the ventricles, and let it drain into the peritoneal cavity, so down into the abdomen to relieve that high pressure. Two children had spinal cord compression, so that severe manifestation of the spinal stenosis that occurs at multiple levels. There is significant rate of complications in these children, and they are all related to the abnormal bone formation. Moving on now to slide number nine. We have established, through a different, natural history study, that the shorter you are, the harder it is to undertake the activities of daily living.
We have a number of different questionnaires that we can administer to parents and caregivers, as well as children who are of a certain age and able therefore to complete the questionnaires by themselves. These questionnaires can look at the different domains impacting or reflecting daily life. Here in the PedsQL questionnaire, we ask about factors relating to emotional, social, school, psychosocial, and physical well-being. And we can see that these the answers can be compared at different height Z-scores. A height Z-score that is of a minus number is moving away from the mean and moving away from the average. The bar that is depicted here as blue is a height Z-score of less than -6. The normal range would go down to -2.
All of these children with achondroplasia have height Z-scores well below what we would expect for an average stature child. But less than -6 is the lowest that we have here depicted. For each of the domains, we can see that the score is worse, depicting that it's harder for children to do these things, or there is a greater impact across emotional, social, school, psychosocial, and physical well-being the shorter the children are. The children with the blue bars showing a much greater impact of daily living than the children who are represented by the red bars, which have the higher Z-scores. Those children are taller than the blue children.
The greater the height deficit, the harder it is for the children to do these things day-to-day basis, as measured by health-related quality of life tools. Just showing you here on slide 10 that there are a number of complications associated with achondroplasia impacting multisystem, you know, across the body, all relating to the impact of abnormal bone growth in children with achondroplasia. Impacting multiple systems, including the neurological system, orthopedics, ENT, dental, respiratory system, growth, neurocognitive development or developmental profiling, activities of daily living, and psychosocial impacts as well. Slide 11 shows that achondroplasia is a genetic condition, by which I mean it is caused by a pathogenic variant, a damaging change on one of the genes, the instructions to the body to grow and develop.
In particular, we're concerned about the FGFR3 gene, which makes a protein called FGFR3 or fibroblast growth factor receptor type III. A protein which is expressed in the growing ends of the bones in the growth plate, which is a slither of cartilage at both ends of a longitudinal bone. For example, the femur bone in the upper leg, it has two growth plates, one at either end. This is where FGFR3 is expressed in particular and has a role, therefore, in bone growth. The majority of people with achondroplasia have no family history of it, so it's genetic, but it's not inherited. That's the case for 80% or four out of five individuals with achondroplasia. There is no prior family history. It's a new event or de novo event in them.
Once they have it, there is a 50/50 chance that they can pass it on to the next generation, and it's immaterial whether you're male or female. There is a same chance of transmission from the generation above for those in which the variant is established. There's a cartoon here on slide 12 just showing you where FGFR3 is expressed. If you look at the panel on the right, there's a cartoon here showing the growth plate. It's a cartilaginous sliver that is comprised of different cells or cells of different maturation that make cartilage. There are tiny cells at the top or the resting chondrocytes. Chondrocyte means a cell that makes cartilage.
As the cells become more and more mature, there is a differentiation between cartilage to bone. Right there in the middle of this active site is the FGFR3 gene expressing from the chondrocyte, the FGFR3 protein. That tells us that FGFR3 is fundamental, has a fundamental role in bone growth in the growth plate. Bone growth that comes from a growth plate is called endochondral bone ossification. The problem that occurs with endochondral ossification stems from this activating pathogenic variant or as was known as a mutation in the FGFR3 gene. There's a very specific change within the FGFR3 gene, which is pretty much in 100% of people with achondroplasia, a recurrent finding.
The G380R variant reflects the fact that the genes make proteins, and proteins are made up of amino acids, the building blocks of protein. An amino acid 380 should be a glycine, as depicted here by G, but it is replaced by an arginine. That, that change, that one letter change in the genetic code within the FGFR3 gene that converts a G to an R, a glycine to an arginine at position 380 is responsible for achondroplasia. Ordinarily, the panel on the left shows you that FGFR3, the fibroblast growth factor receptor type three, sits on the membrane of the chondrocyte, the cell that produces cartilage in the growth plate. The receptor looks for a signal. It receives the signal.
The signal it receives is from a ligand, something that links into it called the fibroblast growth factor receptor. When the fibroblast growth factor receptor slots into the, when the ligand slots into its receptor, two receptors come together, they dimerize, and it's that bringing together of two separate receptors that causes a signaling pathway to be fired off. The job of that signaling pathway or the FGFR3 signaling pathway is to inhibit endochondral bone growth. FGFR3, its job is to inhibit endochondral bone growth. What happens in achondroplasia is that that variant, the G380R variant, causes dimerization of the receptor even when it's not been told to do it, i.e., in the absence of its ligand.
The FGFR3 signaling pathway is activated, and the result of that is a constant inhibition of endochondral bone growth. Where is endochondral bone growth most important? Well, in the long bones, in bones that have the growth plates. The growth plates are constantly signaling to stop endochondral bone growth, which is why they grow so slowly. FGFR3 is not just expressed in the long bones. It's expressed in many other bones in the body, which is why achondroplasia is a condition that affects every part of the body in which there is bone. We're moving to slide 14 now just to show some different strategies that can counteract that activation in the FGFR3 signaling pathway, so ways to try and dampen down that abnormal bone growth.
The red blob at the top on the left there is a ligand trap that can try and mop up the ligand. It is also stimulating the receptor that's stimulated by the pathogenic variant. The blob at the bottom is a strategy to dampen down the FGFR3 signaling pathway after it's been fired off. An example to tackle that particular strategy is something like C-natriuretic peptide in development by BioMarin and by Ascendis Pharma. QED's product is depicted in the middle on slide 14, which is a tyrosine kinase inhibitor. Tyrosine kinase is the particular domain of the FGFR3 protein which straddles the receptor and which is fundamental to activation of FGFR3 receptor and therefore the FGFR3 signaling pathway.
Infigratinib is designed to inhibit the receptor, right where it is activated by the variant. In summary, achondroplasia is a medical condition with lifelong multisystemic complications. These complications are secondary to abnormal bone growth, which itself is the consequence of a recurrent genetic variant. I'm summarizing on slide 15. Interventions to attempt to restore skeletal growth present encouraging opportunities to improve not just quality of life, but also to reduce the burden of complications significantly. Addressing age-specific morbidities that can be life-changing and life-limiting as well. That's the end of my presentation. I'm happy to bring into the discussion now Justin To and Daniela Rogoff.
Thank you, Melita, for the excellent presentation. We have a few follow-up questions that we are sure the audience will be interested in learning more about. You discussed about the pathogenic variants in the FGFR3 gene that result in the overactivity of the receptor and the downstream signaling pathways. Can you speak about the importance of hitting the FGFR3 receptor directly with a drug like infigratinib?
Yes. This is a precision medicine that absolutely targets the concerning factor, the FGFR3 activation. It targets the receptor itself, which is the root cause of achondroplasia. We know that the FGFR3 signaling pathway is quite complicated. There are, there's more than just one pathway that is triggered by FGFR3 activation of the receptor, and that's the STAT1 pathway and the MAPK pathway. Hitting the FGFR3 receptor itself will counteract the overactive signaling through both those pathways, not just one pathway. It really tackles the problem at the root cause.
Indeed, in preclinical models, we know that FGFR3 inhibition showed really promising results in respect of bone growth were used to demonstrate in the clinical setting the potential effects of infigratinib. That yet there were multiple readouts from that preclinical data showing an improvement in general in the way the bones grew in the mice with achondroplasia treated with infigratinib. Now, I'm speaking to the point that it tackles the FGFR3 signaling pathway at its root.
Thank you, Melita, for the very clear explanation. It is an exciting time right now in the achondroplasia therapeutic space, with options available or in clinical development. What do you think the achondroplasia and healthcare community are looking for in new treatment options in achondroplasia?
I think what I've tried to get across in my presentation is that achondroplasia is a very complex situation. There are multiple comorbidities, multiple complications of achondroplasia, some of which are serious, many of which are lifelong, many of which might not be so serious, but cumulatively, there is a very high burden of medical and surgical need for children with achondroplasia, again, extending into adulthood and activities of daily living as well. A treatment options that we in the healthcare community are looking for in respect of managing achondroplasia would be to tackle those complications and the difficulties that come with the abnormal bone formation in achondroplasia.
To reduce the medical load of achondroplasia, to improve the surgical burden, improve day-to-day activities and the quality of life, and to stop some of these very severe complications which can occur early on in life and can extend into adulthood as well. It's something that will tackle all of the consequences of abnormal endochondral bone formation and the involvement of all the bones, as I've already described. The beauty of infigratinib, of course, is that it is an oral preparation. It's taken orally as opposed to being injected, which has obvious benefits in terms of its for want of a better word, invasiveness of administration. That is one benefit of infigratinib.
The early data also suggests that it's very safe. Of course, there are ongoing trials to demonstrate to keep on demonstrating its safety profile, but also to try and find a dose that would be optimum in trying to counteract some of these complications in achondroplasia. Daniela, I probably should also point out that we do measure height as an endpoint in the trials, and that's because we can see a change in the longitudinal bone growth. We measure it accurately, we can replicate those measurements, and we see a response. To me, this isn't just about height, but measuring height tells me the bones are responding.
If the long bones are responding, then it infers to me that the other bones are responding as well, and therefore decreasing the complication, the complication load associated with achondroplasia.
Thank you, Melita, and thank you for remarking how complex this condition is and how important it is to address all the complications and not just focusing on height, but also in remarking how important it is height as well to evaluate and demonstrate those changes that are occurring not only in the long bones, but the overall skeletal that could potentially translate into benefits in other complications that are associated with achondroplasia. This is why we are also committed to continue evaluating the potential benefits of long-term administration of infigratinib in the ongoing open-label expansion study.
We will not only be collecting information about growth and final height, but, most importantly, we'll provide the opportunity to evaluate the potential benefit of infigratinib in those outcomes that matter the most, but will require longer time to assess.
Yeah.
Yeah. Thanks again, Melita. We understand that changes in annualized height velocity is not the only goal of new treatment options, as you and Daniela very eloquently put it. However, given that annualized height velocity is one of the only surrogate endpoints that can be evaluated in a shorter period of time in a clinical trial, it remains an important metric for comparison. What would you see as a clinically meaningful improvement in AHV from baseline for a new therapy option?
I'm often asked this, the question that I'm usually asked is, "Do you think that a change in annualized height velocity of 1.5 is clinically meaningful, or should that be 1.7? What do you think about 1.2?" Actually, I don't have a view on those individual numbers because actually, if you think about it, comparing a change from 1.5 - 1.7 is we're talking about 0.2 ml, or down to 1.2 -1 .5, we're talking about 0.3 ml. Well, that's not clinically meaningful at all in any way, shape, or form.
What it says to me when we see a change in AHV, is that the bones are responding. We can infer from that it's not just the long bones that are responding, it's the other bones as well. The true power in these in the trial and in looking at the role of infigratinib in the treatment landscape is to see what the cumulative effects will be. A difference of 1.5 cm per year, well, the next year that will be 3 cm. The next year will be 4.5 cm. Cumulatively is where the value of drugs like infigratinib will come. As Daniela has already pointed out, yes, we can see a relatively quick change in AHV.
We can see that over the course of a year, the other clinically meaningful endpoints are gonna take longer to demonstrate. That's not least because these bones need remodeling. They need to take time to respond fully to the intervention. It's gonna take longer to realize the full effect of the, of these drugs. I think in respect of what is a clinically meaningful AHV, there is no answer to that, other than to say, having a response to the bones, a greater effect on the bone, is more likely to have an impact on longer term outcomes.
I think also, just thinking about, you know, other treatment landscapes here, again, I've already said that of course there is an advantage in an oral preparation, potentially over an injected preparation if they are achieving the same thing potentially. Of course, all of these studies are still in an early development, so we do not know the full impact these drugs will have. The growth is very different and bone development is very different across childhood. Children who are infants grow very differently to children who are in established childhood, who grow very differently to children who are going through puberty. For each of those different age groups, there are different sets of complications.
We don't know yet if one preparation may have an advantage over another. If there will be a benefit in combination. We just don't know all of this just yet. All we can go on at the moment is seeing a response in the bones and extrapolating what that could mean to the complication risk and the other outcomes that we think are important in achondroplasia.
Thanks, Melita. That's, I think, the perfect segue to, you know, my next question is, you know, how do you think about the different ways to measure changes in height? For instance, AHV versus Z-score in the different populations. What do you think the importance of having a baseline is when you're measuring AHV?
Well, growth is a very tricky thing to work with because there are so many different factors that come into play. If you track a child's growth, any child's growth over the course of a year, there will be times when they're growing faster, times when they're growing slower, which is why it's important. This is why we talk about annualized height velocity. We don't take a snapshot and then base our assumption on the rate at which they're growing based on that snapshot. It is averaged out over the course of a year because of those potential discrepancies. Also, growth is very different at different ages.
Children who are in infancy, 0 - 6 months, grow differently, whether they have achondroplasia or not, compared to children who are older. One of the ways that we can drill down into those differences is to look at height Z-score. Height Z-score is a reflection of normality across growth for any particular age. We have height Z-scores for children with achondroplasia, which have been developed over by several different groups over the years, but most recently and most accurately by Julie Hoover-Fong at Johns Hopkins. The height Z-score gives us a good way to compare the height of children with achondroplasia, at any particular age, with children with achondroplasia of a particular age on infigratinib, for example.
That can iron out those changes that we see based on age. Baseline is really important as well to collect because we see differences in from child to child as well. Not just in respect of growth in one child over the course of a year, but we see differences in the way children grow between from one child to the next. Of course, that's the same is true of any child, children without achondroplasia as well.
That's why there's been so much emphasis on careful collection of natural history baseline data in the PROPEL study so that we established a really valuable resource around what the baseline growth parameters and characteristics of children with achondroplasia are, so that we can compare children on treatment and later on in the clinical trial development program at home as well to see what difference infigratinib makes to the baseline growth.
Thank you, Melita. As you know, preclinically, infigratinib has shown effects not only on long bones, but on the foramen magnum and spine as well. We are currently evaluating and will continue to evaluate if infigratinib could result in improvement in significant and sometimes serious complications in achondroplasia. From an endpoint outcome perspective, what is meaningful to the community, when it comes to new treatment options beyond just height?
I think the preclinical data was really, really encouraging in respect of the effects of infigratinib on foramen magnum dimensions and spine morphology. I've already explained from my presentation about the involvement of the foramen magnum, that big hole at the base of the skull, which can become narrowed and constrict the spinal cord with very, very serious consequences and the deformity in the spine that can occur very early on as well. The prospect of having a drug that can target those concerning complications is very, very appealing in respect of the community and expectations from treatment options. It's really canceling out the serious complications.
I hope I've got across that there are a number of other complications as well that are of very high incidence in children with achondroplasia, much higher than they are in children without achondroplasia, which can impact childhood. While they're occurring, they can impact day-to-day life. There are significant, there is a significant burden in respect of hospital appointments, missing school, missing out on social interactions, standing out as different in that respect because of the higher medical and surgical burden, and then undergoing those surgical procedures as well, which again, I've showed are numerous in these children. Different things happen at different ages. What we're hoping from treatments are to improve the complication rate across the board.
There's very severe complications that happen early on, improving the complication risk later on in childhood as well. I'd love to see these effects lasting into adulthood because we know that adults with achondroplasia also have significant complications of their own. Things that don't just stop happening to people because they're not a child anymore. In fact, they can often ramp up with a number of complications such as obesity, spine problems, spinal stenosis, degenerative changes of the joints, mental health issues as well. A huge number of issues. Pain. Pain is a real problem in adults with achondroplasia and sleep-disordered breathing recurs as well.
A treatment landscape I would like to see addressing the complications as they occur at different ages, but lasting into adulthood as well, when probably we're not gonna be thinking about actively treating people with drugs because what do the drugs do? They modify activity at the growth plates. What do adults not have? Growth plates. We've not really established yet whether there is a role for taking these medications later in adulthood. That being what I'd like to see and what I wish for, is that the benefits that are reaped in childhood, lasting into adulthood as well and alleviating some of those really problematic complications that can significantly impact life.
Thanks so much, Melita. I think that's a great reminder of the long-term complications and outcomes that we all wanna impact and improve beyond just height. We've been talking a lot about the development of infigratinib for achondroplasia. Could you speak to some of the other potential indications and opportunities for an FGFR inhibitor in skeletal dysplasias?
Yes, I can. We've been talking, the FGFR3, the type 3 fibroblast growth factor receptor. There are other conditions which are the consequence of pathogenic variants, the damaging changes in the gene that encodes the FGFR3 protein, not just achondroplasia. In particular, I'm thinking about a slightly milder, in respect of the effects on stature and the complications, the complication landscape, a slightly milder condition called hypochondroplasia. There is significant unmet need in those children as well. My experience is that the parents of children with hypochondroplasia that come to our clinic and people that I meet are extremely keen to for there to be a trial of an FGFR3 modifier to potentially treat hypochondroplasia as well.
Hypochondroplasia, as another example of an FGFR3-driven condition, again impacting the endochondral bone ossification, as I've described through the FGFR3 signaling pathway. The, again, one of the attractive things about infigratinib is that it's not just targeted. Whilst it is targeted, it's not just targeted to the FGFR receptor type 3. It is also potentially applicable and could be used in the context of other FGFR-related genetic disorders. There are a number. There are conditions associated with damaging changes, pathogenic variants in FGFR1, FGFR2, as well as FGFR3. Those conditions are again, associated with height deficit, but also with craniosynostosis. This is a premature fusion of the skull bones.
The skull bones are designed to be separate in children to allow for growth of the brain underneath to occur. The bones fuse to create that protective casing, i.e. the skull. If those skull bones close prematurely, then there is abnormal growth of the skull with an abnormal head shape and with compression of the brain underneath and severe neurological consequences as a result. That's called craniosynostosis. The FGFR-driven craniosynostosis genetic conditions may also be amenable to treatment with infigratinib, given that it targets the FGFR tyrosine kinase domain.
Great. No, thanks for that very detailed answer, Melita, thanks for that, wonderful overview. Again, thank you for joining us. I believe that concludes the Q&A section. Neil, I'll be passing it back to you for closing comments.
Thanks, Justin, Daniela, and thanks to Dr. Irving for taking the time today. I appreciate everyone's time dialing in. Just as a reminder, we'll be updating our Phase 2 data sometime in the first week of March and look forward to reconnecting then. Thanks everyone for the time.
This concludes today's conference call. Thank you for participating. You may now disconnect.