Actor Peter Dinklage has Dwarfism from Achondroplasia. New treatment available.

Hi, thanks for watching episode #136 of the Doctor Podcast Show, and I'm your host, Doctor Robert Sicard. Thanks for tuning in today. You'll really enjoy this program and we'd appreciate it if you could follow Doctor podcasts and also subscribe and also like and repost episodes that you like, like this one and allow us to get more great guests in the future. Today, our excellent guest is Doctor Carlos Pacino. Dr. Pacino is the chief of the genetic service at Texas Children's Hospital, the vice chair for clinical affairs in the department of molecular and Human Genetics at Baylor College of Medicine.

He's also a professor of molecular and Human Genetics and medical director of the Baylor Genetics Cytogenetics Laboratory. He's a board certified clinical geneticist with deep expertise and skeletal dysplasias. He leads the Skeletal Dysplasia program and has been personally involved for years in multiple clinical trials for achondroplasia, which we're going to discuss a lot today. And he's going to talk about treatments sponsored by companies including Ascendas Pharma by Omarin, Pfizer, Sanofi and others.

He's recently quoted by Ascendas Pharma on the landmark FDA approval of a new drug called UV well. The approval of once weekly UV well is a major step forward in the treatment of children with achondroplasia. So thank you very much for taking the time to join us today. Doctor Pacino, you're one of the world's experts on this condition, so I really appreciate your time and and sharing your wisdom with us. OK. Thank you, Robert. It's really a pleasure that you know you have invited me to your program.

I had the chance to take a look at some of your podcasts and they're excellent. So I'm very, very happy that you have asked me to participate. That's great. Thanks very much. So tell us, what is achondroplasia? How common is it? And is it caused by a gene mutation or some other issues? And why does it lead to disproportionate short stature? Yeah, so, so achondroplasia is a very common form of dwarfism. I work in clinical genetics mainly and essentially what we do is we work in many rare disorders.

So I specialize in in a number of areas, but skeletal problems is one of those. And these condition and contraplation happens to be probably the most common form of dwarf systems that happens in humans. So even though we say this is a rare disorder, but the reality is that it has an incident of one in 15,000. So are there plenty of these patients around? And you know, obviously we we receive a lot of consultation for this condition. So it costs a short stature and and we can go in more detail about it later, but not only causes the the stature issues, but also it says to be disproportionate because the limbs appear to be even shorter than the trunk and that has to do a bit about the mechanism that causes a contraplasia.

So as a result, the disproportion results in other difficults of daily living which are common in this condition, and that is is a frequent complaint of these patients. Right. So they also have spinal issues and sleep disorders because their lungs are compressed and they get other difficulties as well, right? Well, yeah, the the issue with a contraplasia is not just about stature, their number, even though the bones are the structure that is mostly affected, but it has repercussions in other systems.

So what you said is correct. They do have a lot of problems with, you know, what we call disorder breathing, which is essentially synonym with apnea that that can be also significant depending on the type of apnea there is and the disproportion we talk about. Patients with a contemplation in the early years have a lot of issues related to frequent ear infections secondary to the positioning of the ear canals and sort of the sort of recurring congestion of fluid as retaining in the middle ear. But the other more severe problems, one of those is the compression of the spine and they're essentially they are, as I will say, coming to different types early on, a significant compression can affect the cranial cervical junction, so essentially in the neck area.

And that can lead to significant morbidities, including sudden infant death syndrome. That has an increased risk during the first two years of life. And after that it improves. It's not longer. An issue of that needs to be, you know, looked around. The other problem that typically happens in adult age is a stenosis of the lower spinal canal. So I will say that stenosis of the of the spine is pretty common in a contemplation, happens in more than 90% of the cases. Of course, not everybody's going to develop symptoms or clinical issues, but the reality that is something that is present and is a great cause of morbidity.

Breathing is not an issue even though the chest is smaller, but that typically doesn't represent an impediment or these individuals do not have pulmonary issues or anything like that. It's really more about the passage of the the air through the airway and apnea. I see. Now, when you say dwarfism, how tall are these patients when they're in their full adult height? So essentially you are around 4 feet 3 1/2 to 4 feet. So that will be 132 centimeters for females, 100 and 3638 centimeters for males.

So that that will be your your average. I see. So that's small stature. Now what causes this condition? Can you explain the cause of it? So yeah, it's like in a nutshell, bones are developed as a result of number of genetic instructions that are involved in development of different parts of the bone. The achondroplasia is caused by a genetic instruction that deals mainly with chondrocyte proliferation. What chondrocytes are as many of the people in your audience now our cells that are very important to differentiate the bone and to allow the bone to grow during, you know, from embryonic stage to to full development in the bone.

You have instructions that make the bone grow and sometimes make the bone rest, you know, so it's just essentially the the process of normal growing, you know, different phases of movement forward and then rest until you know happens again. Imagine that FGFR free is a gene or it's also known as fibroblast. Fibroblast growth factor receptor free, that's why we call it short for FTFR free is the signaling that puts a break in Contra cyc proliferation. So if you have the bone that is growing and it now needs to rest, the FTFR free comes in to function and activation of the gene causes a decrease in the Contra cyc proliferation.

So it's a break on bone growth and quadracype proliferation or endocontrol ossification is pretty much the most important and most common form of bone formation. So most of our bone lung bones are spine Reed are essentially formed by endocontrol ossification. The only exception to the rule is part of the clavicle and the skull. So these phenomena, these genetic change causes an over activation of the EPFR free gene. So in other words, instead of having the gene that comes and puts the brake every now and then, now the brake is constant.

So it's like you have you, you have the pedal on, on brake all the time. So and that's essentially what causes all of the symptoms and there is a a total imbalance with respect to the other genes that regulate growth all. Right. So basically you have a a mutation in this gene, the FG FR3 gene, and this gene signals the bones to stop growing prematurely instead of growing to normal adult size. That is correct. That is totally correct. So. Right now, what role do advocacy groups like Little People of America play?

And how has the public perception of dwarfism changed over time? I know that in the older days, decades ago, that these people used to be made fun of. Sometimes they were in in circuses. And how has that changed now? Yeah, thanks God. This is this is gone a long way and it's changed a lot little People of America is an organization that now creates all type of people with different conditions. A contemplation happens to be common, but different forms of dwarfism and and has been a great organization for advocacy.

So fortunately, what you said, a lot of the what has been considered detrimental views and, and related to short statue and Dorf systems, which I, I don't think are different to any stigma that they're put on. People who are considered different are certainly getting better, not just because of political correctness, but I think that people are understanding that these are individuals like any other and, you know, and they deserve to be respected, you know? Right now, can you share examples of some famous actors or public figures who have achondroplasia?

For example, Peter Dinklage, who's one of my favorite actors who played Tyron Lannister in Game of Thrones is is known to have this condition. How has he and other people who have this condition helped make people aware of it and what causes it, and to break the stereotypes and the discrimination that we had in the past? Correct. I think that this is the great example probably I think it's one of the most visible cases of someone that has reached so much pain. So playing the such a great and positive role on the community.

I personally know physicians and nurses. I there is, I remember there was a Councilman where I live in Houston that actually was, was considered a force to reckon with and he was a Councilman for, for free terms here in Houston. And I can also mention one of the most reputable neurosurgeons, you know, that also deal with with bond problems is someone that works such on Hopkins University doctor Michael Haines. So, you know, I think that there's so many examples of very accomplished people that have achieved, you know, pretty much any, any type of position fame.

And this condition is associated with growth related problems and bone related problems, but not with brain related problems. So there is no no limitation in that sense. That's great to know, very important. Now, what advice would you give parents who who just received a diagnosis of achondroplasia for their little baby? And so, you know, any time obviously a contraplasic and many other genetic diagnosis families are typically very scary. You know, they start looking at information on the Internet, they start seeing postings on social media.

And by the time they get to you, they're they, they just don't know what to do and where to start. So our function in as the physician, as a geneticist is essentially informed. There are a lot of really good sources of information, including from the advocacy group and also publications that have been done by many of my colleagues that are part of guidelines written for the pediatric societies. And much information that now is available through long term studies that can give them a good idea what is going on, what to do, what to expect, what can be done.

And education is, is really, really important. It can also prevent complications that may be serious. So I think that education that we do with the parents and also education we do to other providers that are not so accustomed to see children with a contraplation is quite important. That's great. Now tell us how this was treated in the past or if there were any treatments and tell us about this new treatment that you worked on in the clinical trial that is by Ascendis Pharma. Can you tell us about this new treatment?

So yeah, this this treatment is interesting because it resulted from knowledge that was back in the 19891990 by chance, a group of Japanese researchers found out that there is a drug called CMP or cartilage natriuretic peptide. As you know, natriuretic peptides are a group of peptides 1 is for the heart, one for the brain, one is for the cartilage. These the one that is for the cartilage was found randomly that it caused changes in the growth of video culture. So once they look at that and they try to also compare will that happen with the brain or the cardiac 1?

And those had no effect that the CMP had an effect on the bone and the long bone. And when they look at it is essentially looked at the effect was at the end of the bones were essentially where the growth plates were located. So that understanding sort of led to what if you know, this is something that can be manipulated and that maybe can be used for to help with certain conditions. Understanding what happened there was also important because as it turns out, the CMP acts on a different receptor in the cell.

So the fibroblast growth factor receptor is in one place and that sends the signaling for the bones to to stop growing or to reduce growing. There is a a receptor called the MPRB on natriuretic peptide receptor B and that actually is a specific for the CMP and what it does is actually activate guantineal AMP or or GMP and and and since a different signal that actually counteracts with these pathway of the APFR free. So essentially to make the story short, this this track that was discovered by chance, it's it has a downstream effect on the brake.

So it breaks the brake. So once you stop the brake from interfere with the chondrocyte proliferation that brake that these tracks give the bone allow the chondrocyte proliferation to increase or to breathe. Now you know we can grow so. So basically kind of interferes or inhibits the the mutant gene in achondroplasia. Correct. And yeah, the downspring cascade of the Milton G study. What's the name of this drug by Ascendas Pharma? So it's called the the the formal name is navipicritite the now the the name, the commercial name is going to be UV well.

UV Well. Which is kind of a catchy name, so, right? And what makes UV well by Ascenders Pharma a true first the it's I understand it's the only once weekly treatment and the only one that provides continuous systemic CNP exposure over a full week. Is that correct? So yeah, that's correct. There is some going back to what you said before, what do we do for treatment? Well up until these drugs were available the only way you can go is essentially dealing with the more comorbidities or complications.

Or if you have cranial cervical junction compression then you need to do a craniotomy. If you have bowing of the lower limbs, you will do surgeries to restore alignment. So essentially dealing with over disorder breathing. You do sleep up, so you treat the symptoms they we're doing. Supportive care, basically for complications. And so approximately 2 years ago another company came up with the daily drug test Biomarine, but that requires daily subcutaneous injections. The difference with UV, well this is a is not the CMP directly applied is the prodrug is is they they have these unique that drug protrac with a cross linker that contains the CMP.

So essentially they inject this protrac that it starts to release the CMP slowly and has a long half life. So therefore can actually act over a week so. It's certainly more practical to do an injection weekly that an injection daily. Right. And the injection is given under the skin subcutaneous. Subcutaneous. That's correct. Right now, at what age should these injections of UV well be started once the diagnosis of achondroplasia is made? So the UV well has been approved for using children over 2 years of age.

So anytime a patient is 2 years and older up until the growth plays are completely done. So typically that happens anywhere between 15 to 17 years, you will be able to continue with the drug treatment, right? And how does this affect the height and stature? You mentioned before these these patients can be under 4 feet tall. Let's say you start treating the patient at age 2 years and you continue to treatment every week. Does the patient regain normal stature or close to normal? How does that work?

I That's a great question. That's also what parents typically ask the the drug treatment will add a significant increase, probably in the order of 10 to 10 to 12 inches on on average. It could be, it could be more. So essentially we'll put in that old height. I will say it around 4 from 4 to 4 1/2 feet. So it doesn't restore completely. You know, you have to also keep in mind that the bone changes already happened from the prenatal time. So some of those changes are difficult to refer, but certainly that some of that can be rescued with with these therapies.

I think that as we learn more about some of the younger children that have been treated with with these drugs and get to older age, we will know better what will be the the full range because that data is not yet available. Right now, I was I was going to ask you why not start earlier once the diagnosis of achondroplasia is made, Wouldn't it be better to start right away rather than waiting two years when it may be a little late to start? So the reason why UV Well is labeled to start at two years of age has to do with the clinical trial that they have performed.

So the clinical trial was done on children 2:00 to 11:00 and the patients that received UP well were found to grow approximately 1.49 centimeters over the expected growth for chondroplasia. So that is on top of what they they were expected to grow. That is the only reason why is labeled for that, because now there is another clinical trial that is for infants, for children, newborns to two years of age that is currently in place. And until that data is out and and shown to be positive or not, they cannot present that information to the FDA.

So that approval may take a longer, I'm not sure how much longer, but it could be probably a year or two more. All right, looking forward to that. Now what about if if parents have a 5 year old now who has a chondroplasia? This drug was just approved by the FDA a few weeks ago in February. Is there a problem in in starting treatment at age 5 or 6? No, there is no problem whatsoever. In fact, many patients that came into the clinical trials were 5 or 6 or even older and they gain you know height with those with those treatments.

So they issue the drug was approved about maybe 4 weeks ago. So it's still I believe that the commercialization part takes a little bit of time. So I will hope that this is available in the next 4 weeks or so. So you know, label is out, but I, I don't think that the drug is, is out there very soon hopefully. Right. Yeah, It was just approved a few weeks ago and I think on February 26th. So takes some time to get it out there. Now, in addition to increasing the height and stature, do we have data to show that it will reduce some of the other complications we talked about from achondroplasia like the Yeah, and.

I think that we can go back to some, I think that some of the critical comments that have been made to to the companies coming up with these products is that we only talk about grow or we talk about height. And, and even, you know, for many of the families, they don't like to be defined as just a high issue more as you know, as you say, you know, things related to comorbidities or medical problems. So this proportion could be like Boeing could be spinal stenosis. So those are the things that these population is more worried about.

So I think that we we have some early data that shows that was from the other drug that is already approved that if you give it to children who are less than six months of age, there appears to be improvements in the area of the cranial cervical junction. So that is still to be confirmed. But you know, as more data will come, I think that that will be extremely important. In the case of UV, well one of the the things that were study is alignment of the legs. And actually there was some interesting piece of data that shows that some of the a Boeing that is normally present in a contraplation that in some cases can worsen over the first few years of life.

And there was an improvement in what is called the tibio femoral angle. So rather the needs to be sort of going outward, there was a tendency for the needs to come back in improving that angle. And also there is a discrepancy typically between the TB and the fibula. So what happens in the contrablaze is the fibula has overgrowth with respect to the vivia. Exactly why that happens. You know, there are two bones, they're completely different in thickness in in size. So, but that typically causes some arching of the lower extremities.

And one of the things that was also seen with UV well is that the alignment of the tibial fibula is better. So it they appear to grow more in harmony. So that's an interesting, you know, if this tends to be the the, you know, the case in the in the future, it certainly could improve the mechanical alignment and obviously help with gait and avoid surgeries, etcetera. Although you know, I'm going, you know, provided all of these, you know, stays the same. Right now, every medication we use has potential side effects and issues with in the clinical trials.

Were there any severe side effects that occurred or or moderate or mild side effects? Could you go over those? The the side effects that we're seeing for these drugs were very mild. There were no no significant side effects related to bone or bone problems of fractures. They as you know, this is a natriuretic peptides. So these drugs tend to have an effect on on blood and circulation, so decreasing blood pressure. However, the blood pressure changes have been minimal and not significant from the clinical standpoint and not symptomatic.

Some patients have developed some brightness around this site of infection, but that's typically very short lasting and it's a really small number. We are talking about .5%. So it's a very overall, it's a very good and very well tolerated drug. This drug whenever is given, the families also are instructed to hydrate the child to do this, you know at a certain time of the day when they can, you know, give a few oz, two or three oz a place of liquid before they they go on to have the injection. Right now, do you know if this is going to be covered by insurance because it's it's a weekly injection for for many years.

Do we know what the insurance status is yet? So I hope that they will be OK and I say that not that I just go on hold, but the other drug that is available currently for a contraplasia has been widely approved by private and you know, and, and also some state or federal insurance, public insurance. So it has not been a problem. I hope that this is the case. You know, once I think that once the the drugs are approved by the FDA and they showed that they can, they can work, I think that that is not an issue.

Obviously cost can always be a problem. These drugs are, are are not, you know, more cheap. So, you know, that's kind of an issue for some probably small insurance providers. Right now looking ahead, how do you see pharmacologic options like UV? Well changing a long term outlook and conversation about achondroplasia for for the next generation. So right now they seem to be quite a bit of interest and that's one of the things that we haven't talked about. There are also other drugs coming after this one, other companies looking at other parts of the EPFR free signaling pathway.

They, they're a group of drugs, they're called tyrosine kindness inhibitors and have been widely using cancer probably you're, you may be familiar with them, liver cancer, bladder cancer and these drugs have an effect over that particular break that the FGFRP chain has. So now there are drugs that are called paninhibitors. There are others that are coming up after that they're specific FGFR free FG for your FGFR two inhibitors. So essentially are now putting

inhibiting that that break directly. So and and there are also some, some additional like molecules like aptamaris that are also being researched. So as I always said, I like competition because I like good things coming to to my patients. So ultimately, you know the best one. Well, we also ascend this is is starting the clinical trial combining the CMP with pro hormone. So a lot of different things are are happening and that ultimately will lead to to better results and you know, and better hopefully you know, life,

life, quality of life. Sorry I couldn't find the word. Right. Are is there any data comparing UV well to the once a day injections in terms of outcomes or or there we don't have that data yet? Well, the the data they, they, they have some they have similarities. The one day one daily injection, the average growth is 1.57 centimeters per year over the expected growth on children over five years of age for UV, Well, it looked like it's it's around 1.7. So they're they're fairly close. So I think that when, when you look at data from the different manuscripts, you can see some, some of the number go a little bit down, a little bit go up.

But, and that's the average for children over five years. We, we know that children under five years of age, they tend to grow at slightly lower rate. So I'm not sure why but that that happens with the the daily injection and with you'll be well as well. Right, that sounds like a good number. Plus, there's a great advantage in that parents only have to inject the child once a week as opposed to every day. Correct, correct. And I and I know 1 whatever question the parents have and I always tell them that the Contra cyproliferation happens everywhere in the body.

So we do hope that that is also going to help other areas that may not necessarily be looking at, you know sort of more carefully like the spine or or some of the areas you know related to comorbidities, ear infections, apnea. So a lot of that most likely these drugs are going to help in that, but it may take time until the data is properly collected that we will know for sure. So I think that hide is the proxy that is the quickest proxy you know to use in some of these. Now, if somebody's in Texas, obviously they're, they're going to see you for treatment for this 'cause you're the expert, you're in the clinical trials, you know all about it.

What about people in other parts of the country? How do they get access to this drug? Is is it going to be available and all pediatricians can give it or do you have to go to a specialist to get this? So right now historically for interesting reason that a contemplation is a genetic disorder and has been sort of a classical condition known well by geneticists. Many of children and adults with contemplation are followed by geneticists. Having said that, with the advent of these tribes, it has become clear that we alone cannot do this.

So a lot of the the people who have also been involved in some of these clinical trials and are are pediatric endocrinologist and they're very capable of handling these patients. So I feel that the regular pediatrician may not be as comfortable with these. Those patients will still be followed by the pediatrician who has very well established guidelines of what to do and not to do. But probably the treatment will be more in the hands of the clinical geneticist or the endocrinologist. And they're more endocrinologist than us.

We are a small group, you know, compared to facial. So that's good to know. If parents have a child with achondroplasia and they want to have access to UV, well, they should see a pediatric endocrinologist wherever they are in the country. And there are many sub special sub specialists in that area all around the country. So that's great to know. I want to thank you very much for sharing this knowledge and information with us about UV Well and achondroplasia. And hopefully you'll work on some more clinical trials that'll find a way to treat this even better or maybe in the future eliminate it completely.

So thank you very much for your time and sharing this with us. Thank you, Robert. Thank you for giving me the time. Bye, bye, bye.

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