Lumos Pharma, Inc. (LUMO) Earnings Call Transcript & Summary

Good morning, everyone. Welcome back from Labor Day weekend, and thanks for joining us to listen to the KOL panel with 5 pediatric endocrinologists, to discuss pediatric growth hormone deficiency, or PGHD, in the context of the upcoming final data set from Lumos' Phase II trial with LUM-201, which would be the first oral once-daily pill for our PGHD. I want to set the stage for a discussion with our KOLs with 2 slides. The first is going to show the mechanism of action for LUM-201. That graph in the yellow box is a representation of the PK profile for the natural growth hormone and normal individuals over 24 hours, and shows what is called a pulsatile profile, is almost exactly 38 years ago, it was October of 1985, Genentech had the first FDA approval for recombinant human growth hormone called [indiscernible] tropin, to treat kids with growth hormone deficiency. And it's been the standard of care ever since. It was actually the first biotech drug ever approved. There's not lots of different brands now, lots of different versions of recombinant human growth hormone, but they're all daily injectables that simply replace the natural hormone that's lacking in these kids. But what you don't get is that pulsatile type of release. It's just constitutively high, and that's why I brought it up. LUM-201 is Lumos' oral growth hormone secretagogue, it stimulates the release of endogenous growth hormone. And as a result, it can restore that more natural pulsatile release of growth hormone, and can be subject to the natural feedback mechanisms for regulation. The big reason that Lumos is setting more moderate patients, that are included in its trials is at -- if these patients were completely deficient in their ability to release growth hormone, there would be nothing for LUM-201 to stimulate, so it wouldn't work. The more moderate patients still have some level of growth hormone secretion and therefore, LUM-201 just helps to increase that amount to more normal levels. So in terms of the data, remember, Lumos reported interim data from its Phase II trial back in November on 40 patients that expect the top line results on the full number of patients around 82 in the fourth quarter. There's 20 patients in each of 4 arms 0.8, 1.6, 3.2 and recombinant growth hormone as the active control. They'll also release data from 22 patients from their Phase II OraGrowtH210 trial at the same time. Importantly, remember, it's not statistically powered to prove noninferiority to any one of the LUM-201 arms compared to the active control. The primary endpoint is simply annualized height velocity, the very standard end point at 6 months. But they're also expecting to release data from a smaller number of patients treated for 12 months and for 18 months, at the same time of the main data release. So the second slide here is the data that was put out in November and subsequently presented at multiple medical conferences. This is the 6-month interim data with LUM-201, on 3 different doses and the control. So the 4 columns on the left are the AHV values for each of the 4 arms, at the time of the interim analysis. The 1.6 mg arm showed 8.6 centimeters in AHV, and the active control arm showed a somewhat anomalous value, and we'll talk about that in our discussion of 11.1 centimeters. Remember, these are moderate PGHD patients. And in order to qualify for the trial, patients had to show greater than 5 nanograms per ml of circulating growth hormone on a stim test. The stim test is the same test that's used more broadly in diagnosis, where less than 10 nanograms per ml is considered to be growth hormone deficient, although we can talk about that and to various cutoffs as well. Except for in this study -- are instead of using arginine or clonidine as the stim, they use LUM-201. So it's a great way to enrich for responders, and also to ensure that they are not enrolling severely deficient patients. The columns -- the 4 columns on the right, show the historical results from 4 different large databases. These are for moderate PGHD patients. So if you look at the labels for some of the approvals of the more long-acting drugs, you'll see higher numbers here. So the important point is that from these very large databases, these are in moderate PGHD patients, after being treated for recombinant growth hormone for 6 months in the first of the 4 columns, in 12 months in the other 3 of those columns. And you see the average very consistently right around that 8.3 to 8.8 point centimeters. This is the same range on the left at the interim results showing 8.6 in that 1.6 mg arm, and what should be reasonable to expect from the final results after they're unblinded in Q4. Phase III would be next, obviously, would needed to be powered appropriately, once the right dose is chosen and would simply be a 2-arm trial comparison of LUM-201 to injectable standard of care, with enough patients in each arm to support, in this case for Phase III, is statistically significant and meaningful assessment of the non-inferiority margin. And that margin is expected to be similar to all the other studies in this field, somewhere between 1.8 and 2.0 centimeters. So hopefully, that sets the stage for the discussion now and [indiscernible], we can take down the slides. I'm going to start by asking each of the KOLs to introduce themselves, their affiliation and a little background on how much of their practice is dedicated to treating PGHD, or rather than having meet much of their bios. Then I'm going to go around ask each series of questions, which should take the first hour, and we'll spend the final 30 minutes taking questions both live from the audience and in a written form. So you can start thinking now about what you'd like to ask, just type it into your dialogue box on your Zoom interface. I'm the only one that could see the questions. So I won't announce your name, unless you want me to. So don't be afraid to ask whatever you want to. So with that, why don't we start off with some introductions and have Dr. Bhangoo go first, you just introduce yourself for your affiliation and what makes you tick in the morning.

My name is Amrit Bhangoo. I'm a Pediatric Endocrinologist in Children's Hospital in Orange County in California. I'm also Associate Professor of Pediatrics in UC, Irvine. My practice -- actually, my duties are a mix of clinical duties, administrative and research. And in our practice, we see about 30 to 40 patients with stature issues, and not everybody is a growth hormone deficiency, but I would say about another 1/3 or 1/4 of that slice of short stature we see is growth hormone deficiency. And yes, looking forward to a nice discussion today.

Great. Thanks, Dr. Eugster, why don't you go next.

I'm Erica Eugster. I'm a Professor of Pediatrics at Riley Hospital for Children in Indianapolis. I've been here for 26 years. I came here straight out of fellowship, and I think I have the best job I could possibly have here at Riley as a pediatric endocrinologist. I am a generalist. I do general endocrinology, meaning that I do as little diabetes as possible, and I see a large number of patients with concerns of growth. Looking forward to the discussion.

Thank you. And Dr. Diaz.

My name is Alejandro Diaz. I'm the Chief of Pediatric Endocrinology here in Niclaus Children's Hospital in Miami, an Associate Professor of Pediatrics for Florida International University. Our practice, we are 10 members. 10 [indiscernible] and I do mainly growth and thyroid. We see -- we do 1 to 2 global mono-stimulation tests every day, and also looking to go through this discussion. Thank you.

Thank you. Dr. Misra?

I'm Madhu Misra. I'm the Chief of the Division of Pediatric Endocrine at Mass General Hospital, and I [indiscernible] the Professor of Pediatrics at Harvard Medical School. Like Erica, I've been here for a long time. This is my 25th year at Mass General. I will be moving on to UVA shortly. But as off now and until November I'm still here. I specialized in pituitary and bone disorders. And I would say that maybe about 5% to 10% of my patient population, probably has moderate growth hormone deficiency.

Great. And Dr. Reifschneider?

My name is Kent Reifschneider. First, I welcome her to the state of Virginia, because she'll be joining me here shortly. I am here at the Children's Hospital at King's Daughters in Norfolk, Virginia. I have been here for about 14 years. I'm an associate professor affiliated with the Eastern Virginia Medical School. And I do predominantly general pediatric endocrine, but I'm also the main researcher here at this institution, and been involved in Phase II and III studies over the last 8 to 10 years. My other background involves -- my affiliation with the human growth foundation and turn this all due to my mentor, Steve Turner second fleet back [indiscernible] from Cincinnati Children's, where I performed my fellowship 15 years ago.

All right. Thanks, everyone. All right. I'm going to start off talking about diagnosis and current treatment patterns with Dr. Bhangoo. Can you give us a clinical definition for a diagnosis of PGHD, and are there severity subtypes that are used both during diagnosis that you see in your practice?

Pediatric growth hormone deficiency typically presents as extreme short stature, which is height usually is below the 2 standard deviations below the mean. And also, it depends on the mid-parental height, how the parent's side is. So we always have to correct for that. You always have to look at how the growth is, especially over the last year. And if so, would the last 2 years are also important to how the growth has been. And there are some typical classical features of growth hormone deficiency. So not only it causes a slowdown in height, you would see increase in weight and the BMI goes up and the height is not going up. So there is some other classical features that are associated with classical growth hormone deficiency. But as far as the severity of the growth hormone deficiency, as described by the stimulation test, that's not very concrete. It's not been well described or used in clinical practice that much. And also in my clinical practice, we usually do not go by mild, moderate or severe growth hormone deficiency. If the growth hormone values are below a level of 10, for example, on a stimulation test, just that you mentioned in the introduction, that would be considered to be a growth hormone deficiency, and then treatment is pursued for these patients.

Great. Thank you. Dr. Eugster, am I pronouncing that correctly? I want to make sure I get it correct.

That was perfect, Corey.

The typical patient, how do they find their way to you? Are they referred from a pediatrician or do you take self referrals? And before that referral, what types of basic laboratory and imaging tests are performed, if any? And how many do you need to redo?

Yes. So we do require a referral, and we have a huge referral base. We have a referral base of over 5 million. We get a tremendous number of referrals every day, because we are essentially the only 2 brands hospital in the state of Indiana, to speak of. So we also get referrals from a huge range of providers, not only pediatricians, but many, many, many physician extenders, such as nurse practitioners, physician assistants, also family physicians. So you name it. And unfortunately, I would say the norm is that often tests are done that are not indicated, and the tests that are indicated are not done prior to the referral. So the kids end up having to be poked twice. And our strong preference would be to have no test done, to just have the physicians and the other providers refer the patients and let us do the work up based on our history and physical exam. In addition, often, they will obtain, for example, a bone age x-ray. Well, we read all of our own bone ages. We do not rely on the radiologists. In fact, we did a study where we found that we disagreed with them 68% of the time. So unfortunately, this then requires us having the bone age done elsewhere, pushed to the cloud, so that we can access at remotely and takes often a large amount of time on the phone, with our MAs trying to reach the other facility to get the bone age uploaded to the cloud. So it's not perfect, but that's sort of the day-to-day.

Dr. Diaz, during this diagnosis process and even after treatment starts, how often are you testing for IGF-1 and for stimulated growth hormone levels, and also kind of set the stage for the audience, just as a reminder why we should and need to do that. And then after the diagnosis, how do you decide on a treatment option? And does this severity of PGHD, play a role in your selection of options?

The important thing for me is that I live in Miami. In Miami, everyone wants to be tall. Most of the patients I see in my office are not short. They usually are late bloomers or they have familiar short stature, and those are by far the most common causes of short stature. However, no one wants to pay for growth hormone treatment, and growth hormone is expensive. Then when I see a short side, [indiscernible] on the short side of the normal range, I always call the labs. In those labs include IGF-1. IGF-1 is a market of growth hormone production, and it's not so sensitive or specific, but it's the only way to do a random test to have an idea of the growth hormone production. I do IGF-1, [ IGF-83 ] and I have a panel of labs that I do. And when the child is shorter than expected and the IGF-1 is less than minus 1 standard deviation below the mean, that's when I decided to do growth hormone stimulation test. Most of the time, I do the growth hormone test, just to be able to get the growth hormone pay by the insurance, because it's expensive. Then I do clonidine and glucagon the same day. The normal value is more than 10, but we know that more than 7 or more than 5, indeed, can be considered normal. It's a tricky part. But to the point that I only do MRI of the brain when it's -- the level is 7 or 5. But again, growth hormone deficiency happens in 1 in 4,000 to 1 in 10,000 children. Therefore, if someone is below the fifth percentile, only 1 of 200 to 1 of 500 are going to be deficient. And therefore, I treat, I would say 90% of the kids in 3 with growth hormone are not deficient. And when I find someone who is deficient, usually, we know the child has the problem when they open the door, when we see them the first time. They have some features that are characteristic. And we look at the growth chart, also the growth chart is telling us that the child has a problem. And in those cases, I do -- I order a lower dose of growth hormone. I usually order 0.2 milligrams per kilo per week. And I start -- have the dose for a week. This is something that I do just because sometimes they develop pseudotumor severely, headaches and I believe doing a lower dose for a week, it may do a difference. And I don't have a way to prove that, but that's more or less what I do. Those kids who have normal -- more than 5, more than 4 or I think they are normal, they have normal growth hormone production or very mild. I do 0.3 milligrams per kilo per week, and more or less, that's my modus operandi.

Thank you. Dr. Misra, given that all of these are injectables right now, this question kind of gets to how much resistance is there to the injections? And if you had an oral option, all else being equal, how much easier would it be to convince your patients to start treatment? And how would this influence your practice?

Yes. So that, I think, is the easiest question thus far. And If there is an oral option to an injectable option, I'm sure that's going to influence practice greatly. So most of my patients, when they come in to see me, are either not aware that growth hormone is given as an injection, or that it's given usually as a daily injection, although we have the weekly long[indiscernible] preparations now becoming more available. When they hear -- and this is -- I'm talking about after they realized that they may need to be on growth hormone because of the stimulation tests that have been described already. When they realized that this could be an injection, that this is an injection, that the majority, I would say, are not super happy about this. I would say about 20% of my patients are really unhappy about the injectables. And having said that, because we do not have an oral option thus far, most of the patients will come around to the idea of getting the daily shots, and we'll get started on the daily injections. So that's the beginning of treatment. Now there is an issue with adherence to growth hormone injections. And when you look at the data out there, it appears that -- and again, the data are very variable. There are some studies that have shown that adherence can be 75% to 95% of the time. There are other people that show that adherence ranges between 5% to 85% of the time. This certainly appears to be enough data to show that about 2/3 of the patients will miss at least 1 to 2 injections a week. And this relates to the inconvenience of injections, as well as the pain of injections. Self-administration is a problem also when it comes to our teenagers and at least the older children that can give the injections themselves. There are issues with the device and so on. So -- and also more recently, there have been issues with just availability of the injectables. So all of these does lead to reduced adherence, and I suspect that with oral growth hormone -- an oral option, that is going to be less of an issue. So if safety, efficacy and costs were all equivalent, then I think it would be the easiest thing in the world for patients to prefer an oral version to an injectable version.

Dr. Reifschneider, so this idea of different subclassifications of PGHD. Do you use those during diagnosis, if at all? But where this question is really going is, even if they're not formally placed in one of those types of categories, mild, moderate, severe, do you see differences in those patients' responsiveness to growth hormone? And second part of that question, the third part is differences to the responsiveness to growth hormone over time.

I think those are all really good questions, because I think some of the families, as my colleagues alluded to, although I introduced the idea right before I do the simulation test that, hey, the therapy is an injectable, and of course, they're a little apprehensive about the idea. But once we reach the threshold that they have confirmed growth hormone deficiency, I don't know how to necessarily say I subdivide them or there's certainly not [indiscernible] out there. But personally speaking, I do kind of subdivide them, in response to the question that the parents often ask, well, how much of a response will I see, and how quickly will I see? And so I use the stimulation test response to try to help gauge that question -- or answer that question as best as possible. And my personal experience is that the more deficient you fail the test, it's inversely related to sensitivity. So if you fail the test significantly, as my colleague in Miami referenced, you can use lower doses. And not only use lower doses, but have a very profound robust response. Reversely, if they kind of have a subpar or what I would describe as an insufficiency, rather than deficiency, it does seem that the response is a little less, and they may even need a little bit more therapy. So that's how I kind of approach the question by the families as to what to expect. Now having said that, all of the categories tend to have a better response in the first year, 12 to 18 months. And then there's almost like a plateau effect, where they kind of normalize to their age and gender specific, pre- or peripubertal, depending on which group they're falling in, normal growth velocities. For the first year, 1.5 years is a very robust, almost what we call catch-up response. And the younger you are, also plays a role. A young toddler child, pre-skill aged kid does grow a little bit faster, both the normal individual and the one who's treated with nightly therapy than does, say, a 10-year-old. And then conversely, a peripubertal kid also grows faster than kind of the mid-range individuals.

Yes, somewhat paradoxical, but it's a point that we're going to come back to and emphasize, because I think it's an important point that the audience might not be super aware of. I'm going to go to Dr. Eugster next, and we will come to talk about the long acting in a second, but in thinking about the daily injectables that are on the market available for 38 years, other than the obvious, it's a daily injection. Are there other shortcomings, not just from this therapy, but just in general, what do you monitor for some concerns when you're following a child that may be problems on the safety side related to the drug?

Yes. So I think growth hormone is extraordinarily safe, and we have an incredible amount of data. I often tell families, we probably know more about growth hormone, than almost any other medication that we prescribe, because of the large databases that follow tens of thousands of children receiving growth hormone therapy. But that being said, there are a huge number of headaches, associated with treating children with daily growth hormone. And as has already been alluded to, a substantial number of children do complain of pain with the injections. All the different growth hormones come with different bells and whistles and different types of devices that don't all function as well as, say, as one would hope. There's a huge issue with insurance companies, changing which growth hormone is approved on their formulary. And sometimes, this happens to a single family 2 or 3 times a year. And every time it happens, there has to be a new prior authorization, a new file that contains reams and reams of paper, documents, copies of clinic visits, et cetera, and families just feel that they get jerked around to no end by this. As you all know and has also been alluded to already, there is a national shortage right now of growth hormone, in particular, the 3 most widely prescribed forms of growth hormone. And so insurance companies won't even allow us to prescribe the few growth hormone -- types of growth hormone that we can get that are available, because they say it's not on their formulary. So that -- and then some of the growth hormones need to be refrigerated, others still refrigerated, others don't. And so this affects certain families and their particular lifestyle and specifications. And again, families are just sort of caught in this quagmire and are very, very upset understandably. As far as what else I monitor, so by definition, children with growth hormone deficiency are at risk for additional pituitary hormone deficiencies. So I check thyroid function studies annually. And I also check IGF-1, just to make sure that it is not extraordinarily high. If it is high, I will likely hold the dose at the next visit. And I think in terms of safety, we do go through a short list of side effects that have been reported, but I also tell families that these are all extremely rare. Many of them I've not ever seen, and so it is a very, very safe drug. But again, I think we do worry about the very, very, very long-term potential adverse effects of supraphysiologic growth hormone for many decades going forward. And those data we really just do not have at this point in time.

Great. Thank you. All right. Supraphysiological high levels of growth hormone. We'll come back to that one, too. But I'm going to ask both Dr. Bhangoo and Diaz the same question. And that's concerning SKYTROFA, now that it's been out there for almost 1.5 years. Why do you think that more people are not being put on SKYTROFA and right now, are you seeing more comfort, better reimbursement, such that this could end up being the dominant product in 3 years? And Dr. Bhangoo , why don't you start?

Yes. So we have -- alluding to the growth hormone shortage, which started last year. It started with Norditropin then genotropin and then another brand. So we started to convert, I would say, a lot of patients from daily growth hormone therapy to weekly growth hormone therapy. But what has happened is, our staff has gone through a lot in the last 1 year. There's been a lot of burnout and turnover in our staff, which handles growth hormone prescriptions. And I, especially in our group, is very cognitive of that fact, even with daily growth hormone there's back and forth, insurance denies the growth hormones, which are available, which are not on their formulary or they are not on contract. So to save [indiscernible] that our staff has to go through, I personally and some of my colleagues, have not really started many patients on the weekly growth hormone that we thought or we expected that we would. So that's the reason why we did not start a large amount of patients approved, a lot amount of patients to weekly therapy. Even though in California, especially in our county, the Medicaid, which is also called the Medi-Cal over here in California, approved weekly growth hormone therapy, but we have been very cognizant about the fact and very, I would say, careful about transitioning patients over to the weekly growth hormone therapy. Of the ones that I have switched over, and I've seen them back in my clinic are the patients with SKYTROFA. And what I've noticed is, the efficacy is good, it's really good. Children grow very well on SKYTROFA, but they also tend to have very high IGF-1 levels. I had 1 patient who had very severe body ache and headaches, that I had to switch back to daily growth hormone therapy, because they were doing very well on growth hormone therapy. And we have said, no way, we are going to do the weekly. And then I had another patient who were on day 6. So we have to monitor IGF-1 levels, and we just talked about the supraphysiological levels of growth hormone, but also IGF-1 levels. We do not know what these do over the long term and also with acute effects, then acute short-term side effects, we don't know what IGF-1 levels do, but one of the goals of the therapy is to keep the IGF-1 levels within the 2 standard deviations above the mean. And with the weekly growth hormone, when we monitor IGF-1 level, we try to do it on day 4 or 5, but sometimes patients do it the next day, the second day after growth hormone therapy. I had 1 patient who did IGF-1 on day 6, and it was at 3 standard deviations above the mean. So even on the -- so what you end up doing is, you're scrambling to lower their dose very quickly, and then you realize you have to get another authorization. So you end it because it's a different strength. So SKYTROFA comes in different strengths. So it's actually leading to more paperwork. Not going too much into that. Another side effect that I do want to mention with the weekly, we have to be very careful, is it causes very severe lipoatrophy. Especially if patients are not moving their sides around, they really have to move all at least 6 or 8 locations. If they're not moving their sides around once, weekly call -- and they're only changing 2 sides, causes very severe lipoatrophy. I have seen at least already a couple of patients. Then the second one is the one which is available now with Sogroya I have written for that, but I haven't seen any patients back. But the data from the clinical trials suggest that the IGF-1 levels are not very high, with Sogroya and also they have a very good growth velocity. But I don't have any experience with that yet.

Great. Dr. Diaz, your thoughts on the same [indiscernible].

I have the same experience like Amrit. I order when SKYTROFA came out. I like the data [indiscernible] have to be impressive. I will have concerns about the IGF-1, though the studies -- initial study didn't show them significantly higher than normal. They say they go up in 48 hours, 72 hours they start coming down. Our experience is that one that we see high levels of IGF-1. But for me, the priority, where a very busy practice is to be efficient and to be functional. And SKYTROFA was not covered by the insurance. They gave some interim medication, but the process was painful, because we needed to do appeals and to do a lot of work. Basically, I can afford to go through that with the personal I have in my office, because I had a bad experience with the first patients I start giving them SKYTROFA, we decided not to do it anymore. And again, the concern about the IGF-1 is another one, but what I want is to work and to get it. That's my goal in medications. I want to the medication to be -- the patient to have access to the medication in an efficient manner, and it didn't work.

Dr. Misra, you [indiscernible] have any thoughts on that same topic, but then I'll expand the question, now that we've got the 2 other long-acting growth hormones out there that Dr. Diaz has just referred to with Novo's Sogroya that was approved at the end of April, now just starting to be available in Pfizer's NGENLA. Sorry, I knew I was going to mispronounce it. NGENLA, that was approved at the end of June, but I don't think it's available yet. So within your practice, do you see, now having 3 long-actings available, bringing in new patients? Or are you just, if you use them, going to end up taking share from the daily injectables?

Great question. So I really think that these new growth hormone preparations are going to mostly take the share of the daily injectables. We haven't really had much of an issue with getting insurance approval for growth hormone deficiency. The areas where we do not get approval from insurance or often in the realm of small participation age for ISS. And so those are different indications. But as far as growth hormone deficiency is concerned, for the most part, almost all [indiscernible] will get approval from insurance companies and patients do get started on growth hormone, even if they just like the injectables. So I personally do think that, as these preparations become more popular, that they mostly will be taking the share of the daily injectables. We haven't started using these long-acting growth hormone injections much. We do have a handful of patients on SKYTROFA. I have actually seen 1 patient that developed a lipoatrophy like Dr. Bhangoo mentioned. And I do worry a lot about the IGF-1 levels. I also worry about the sustained high levels of IGF-1 over time. Notwithstanding the fact that the levels do come back after day 2 to lower levels. It still is worrisome that the levels are high for a period of time, longer than they would be with daily growth hormone injections. The other issue that has not been borne out so much, but is a concern that and that many of us have shared is that, if somebody were to develop [indiscernible ] or hyperglycemia growth hormone with the long-acting growth hormone, you just can't take it away you right away, because you still have the weeks left of supply to get through, right. So that's an issue. So we haven't started to use it as much for those reasons, but also because we have 1 prior authorization specialist, and she's really swamped with the daily growth hormone prior authorizations at this point of time, and the many changes that are having to happen because of the shortage of some of the preparations. And we just haven't wanted to give her yet another set of prior authorizations to deal with.

Is the lipoatrophy right at the site of the injection, or is it a more generalized effect?

At the site of the injection.

Interesting. All right. Dr. Reifschneider, so we've got all 3 of these long-acting entrants, they each have a slightly different mechanism of action, but they all accomplished the same thing, right? High levels of growth hormone that are sustained, leading to higher levels of sustained IGF-1. So the question to you is the same thing. I mean, do you have concerns -- a priority in the lack of with the lack of long-term data about these kids persistently being exposed to these high concentrations?

I do. I think that, that's why it's so critical that there is ongoing Phase IV or registries or some type of safety data collection, just as you say 30 years ago when nightly came out, more than 30 years ago. About 25 years ago, it was when our [indiscernible] came out, we had the same concerns, right? We're worried about acute long-term side effects. And we've had a lot of data to show that nightly is very safe. I even use it on a cancer survivor patient population, that's that safe. But with the long acting, that is a major concern. I think we all had the same concerns that sustained high levels IGF, what does that mean? Is there a short-term and/or long-term price paid? So these individuals certainly warrant more follow-up, closer follow-up and more surveillance. At least that's my standard of care. I do have about 1.5 dozen on SKYTROFA. It works well, but you have to use lower than what's recommended, because it works so well, and I think the idea [indiscernible] are a little higher than I'm comfortable with.

Great. Thank you. All right. I want to switch gears now and talk a little bit about Lumos' LUM-201, set the stage for the data coming in Q4 later this year. Dr. Misra. In looking at the historical clinical trials of growth hormone, I didn't show an effect going from 6 months to 12 months to 18 months, but we asked a question about it earlier, and I want to get into this a little bit more, what happens with those AHV rates at each of the time points, specifically for more moderately deficient subjects? And how does that compare to the more severely deficient subjects?

So generally, we think about children having a genetically predetermined trajectory for growth that they will follow over time. And so the further they fall from that trajectory, as a consequence of growth hormone deficiency, the more rapid the initial response will be to growth hormone therapy. And we typically think about the growth velocity being the highest in the first several months to 1 year of giving growth hormone. And after that, the growth velocity decreases over time in subsequent years. So generally, because of this predetermined genetic trajectory, and the fact that the further you fall, the more rapid your catch up is, the rate of growth tends to be more robust with more severe growth hormone deficiency. So that's -- and it also depends upon the age of the child. So the younger the age, the more rapid will be the catch-up and the greater is that annualized growth velocity at the beginning or even subsequently. So I hope that answers the question. So usually, I think about growth velocity being the highest earlier in the course of treatment and it kind of decreases in subsequent years. And it is higher when there is more severe growth hormone deficiency and with younger age, younger bone age and also with the higher dose.

Yes. No, that answers the question. I think it's worth really repeating because it's not obvious for those of us that don't do this day in and day out. Dr. Diaz, I just wanted to ask you next. And [indiscernible], if you could put those slides back up again for a second, just the second slide with the data on it. And the question is, do you think that, that expected average height velocity in that 8.0 to 8.6 centimeters is similar to what you've seen for injectable growth hormone in your more moderate patients in your practice?

Yes. I had very variable results, in general. As I mentioned, I would say 90% of my patients don't have growth hormone deficiency, real one. They may have mild forms, but there are some markers that help me to find out who's going to respond, and the easiest one is usually the IGF-1. When I see the IGF-1 on the lower range of the normal range or slightly lower than the normal range, those patients usually had that response that we see the first 6 months, 1 year are impressive and the they kind of plateau, but still growing a little bit faster than normal. However, those kids who have a normal IGF-1, usually more than above the mean, the response to growth hormone is not as good. Some of them, when they have the IGF-1 [ plus 1 ], or they usually don't respond quite well. I mean, it's variable. I use a lot of growth hormone. I try to avoid using as much growth hormone as I would like to do. But I mean, again, it's Miami. And we have a Latino population that are -- tend to be short. I learn more or less, who's going to respond or not to treatment, and based on that, the response is variable. There's -- most of them have some improvement, but the IGF-1 is, in my opinion, the best marker to have an idea. And I hope, I mean, if Lumos works, I mean, this is the perfect situation here. It's something that I've been talking for years. Right to do something that is less invasive daily injections for these kids, who are on the lower side of the normal range and want to be taller.

Great. Then Kent, I'm going to leave those data slides up, and I know you weren't involved specifically in this trial. So hopefully, you can answer this. But when looking at that 11.1% AHP growth rate in the control arm, we know that there were 2 young subjects in there that were outliers, that grew around 15 centimeters that help skew that average, when you have low numbers that has a big impact. But do you have thoughts on how big an outlier these -- that growth rate is? I mean do you ever see kids that grow that quickly in response to recombinant growth hormone.

So I think you bring up some great points, Corey. I think that, first and foremost, the power is not there, right? It's only 10 subjects. And so 2 of the 10 or 20% of them had a far above and beyond what we normally see in clinical practice. So I would say that the -- in the context of remembering, the more deficient you are, the more sensitive and more muscular response you have. So that's one thing. And then secondly, the younger kids grow faster, either nondeficient kids or therapeutically treated kids, they grow faster than the middle group kid. So I kind of categorize like preschool, then school-age kids and then pubertal kids. Those are the 3 kind of buckets of kids, and they grow differently. And so those 2 were preschool kids. So they inherently grow faster than the other buckets. Well, the middle age group, not as fast as the peripubertal kids. Two, I think that -- I don't know how deficient they were, I know that these are all moderate deficient. So they kind of fell in that moderate, but maybe they're on the lower end of the moderate, and so therefore, they are more sensitive. But 15 centimeters per year is very, very robust. I don't -- I rarely -- if I saw that individual at a follow-up for months, and the annualized speed was 15 centimeters per year, I would actually be checking labs. And also wonder, as some of my colleagues mentioned, that maybe, either my doses too much, or they're not using the delivery pen properly, and they're mistakenly getting higher doses than anticipated, thus yielding a very, very atypical response.

Erica, I'll ask you next. So I'm going to leave this slide up and just refer to the slides and refer back to this one, that profile for the PK of normal growth hormone in that yellow box, do you believe that LUM-201, because of the mechanism, has the potential to restore a more normal growth to these kids? And implicit in that question is whether or not you and other physicians are going to care that it has this profile, and recombinant can induce a super physiological growth because of not having that pulsatile release.

Yes. So I think it's just inherently very attractive to have something that simulates normal physiology. And I think for pediatric endocrinologists, we always have a bias toward getting as close as possible to normal physiology, because mother nature didn't evolve the way she did by coincidence. There is a reason why the body works the way it does. Same for all hormones. If we can have endogenous hormone production, rather than giving hormones, it's always going to be far superior. So I think this is one of the most exciting and positive things about LUM-201. And again, getting back to the issue of safety, getting back to the issue of long-term effect of very high IGF-1 levels, I think that LUM-201 really is in a different class altogether, because it appears that it would be much less likely to have very high IGF-1 levels. And getting back to the whole discussion about catch-up growth, I mean that all happens for a reason. It happens, because as Dr. Misra mentioned and several others, every child has a set point for growth. And if you look at their growth chart, it's just beautiful, and I point this out to my trainees all the time, that despite the same milligrams per kilo per week of growth hormone, what a child will do is cross channels and zoom up to a particular percentile and then grow parallel along that percentile, because that is where they are destined to grow. And so I always tell families, our goal with therapy is to allow your child to fulfill their genetic potential for growth. I'm not trying to make them any taller than they would otherwise have been. And I think the whole mechanism of action here is a strong positive.

That's a great point. Okay. [indiscernible], we can take the slides down now. Dr. Bhangoo, I don't have a slide for this, but I know you've taken a quick look at the IGF profile for LUM-201 from their interim Phase II results and just in general, can you comment on the safety profile, specifically with respect to IGF-1, and tie that into the mechanism for LUM-201 that allows for more normal feedback inhibition.

Yes. I have looked at the IGF-1 levels on the 2 doses, which was used, and there was the 1.6 milligram and the other one was 2.3 milligrams. And the IGF-1 levels on both of these, before and after the treatment, both in terms of absolute IGF-1 and IGF-1 standard deviation scores, significantly improve after 6 months of treatment. And they seem to have gone up by at least 1 standard deviation on the 1.6 milligram dose, and around approximately 1.5 standard deviation change with the 3.2 milligram dose, which is -- and also it's important to note, although it's a small number of patients, it does not seem like these patients have superphysiological IGF-1 levels from the Phase II data that we have. So it seems like very safe, but safety then, again, will be more importantly, study in the Phase III trials as well.

Okay. I'm keeping an eye on the clock, and I want to make sure we get time for questions from the audience. So I'm going to ask 1 more round of questions from each of the panelists, and then go to the audience. Kent, I think you said earlier, you have about 18 patients that are on SKYTROFA now, but as a percentage, what percentage is that roughly? And where do you expect that to be in 3 years? Is this something that you would expect, you would take to a very high percentage or the daily injectables always going to have a place in your practice?

That's a great but very difficult question. In part, as many of the colleagues already alluded to, what has made this such a challenge for us for the last 9 to 12 months is the shortage. And so we're often having to bounce around to try to find what we can and grab it when we can, and that leads to a lot of inks and paperwork, both on the family's behalf and our staffs behalf. As a consequence, SKYTROFA, because they have abundant supply, they've been able to kind of take advantage of that opportunity. And so I would say I'm about, I don't know, 10% of my patients are on SKYTROFA, because they're able to take advantage of the shortage and use that as an approval process. I don't know if that's sustained. That will be based on one of the biggest barriers we have is insurance, what they're willing to pay for, what they approve and pay for, that's what dictates almost all of our actions, unfortunately. We may have a preference for a particular product, but at the end of the day, insurance and the policies the families have really dictate what choices we use. Does that answer your question?

Yes. Nobody's got a crystal ball, but it helps qualitatively. Dr. Diaz, what percentage of your patients now would you categorize as having that moderate GHD? I get that it's somewhat of a artificial label that we're using, because of the nature of the mechanism for LUM-201. But what we're trying to get at is, what segment of the population would LUM-201 be appropriate for? And remember, I said at the beginning that the stim test with LUM-201 had to be above 5 nanograms per ml, but that equates to 3 nanograms per ml on a standard stim test.

Yes, I would say that 90% of our patients had more than 3 nanograms per milliliter. And I would say more than 70% of our patients had more than 5. As I mentioned before, those patients who have real growth hormone deficiency, you see them quite straight forward and also the growth chart helps you a lot. But most of the patients that we see here in our practice are moderate or mild growth hormone deficient.

I'm going to jump to Erica for a second. If you had an oral drug that did show non-inferiority, statistically to daily growth hormone, but it was, therefore, met the criteria for FDA approval and was approved, but it was consistently assuming, 1 centimeter less, all else being equal in terms of safety, how widely would you expect to use it in your practice in this moderate PGHD population?

Yes. Centimeter difference in height would not bother me in the least. The safety and physiologic mechanism of action would trump, easily trump, a centimeter. And we know from a lot of studies, right, that height does not dictate success or happiness, and the children's quality of life is equally good, if they happen to be short. So I personally am very conservative and to me, that would absolutely not be a problem.

Dr. Eugster, I'm sorry, that excludes people from Miami.

Yes. So I gather, Alejandro, and I feel bad for you because that's tough. And we see a lot of Burmese patients, a lot of hispanic patients, that are referred for short stature and they're absolutely normal for their families. And I don't treat them, but I'm in Indiana.

And Miami is very peculiar.

And I'm only 5 feet tall. So, hey, some families say that means I'm not qualified, but I beg to disagree.

It's a mixed bag.

Yes.

Dr. Misra, maybe ask you the exact same question. If you had LUM-201 with the profile as posed here, how compelling do you see that?

I really like the more physiological aspect to how it stimulates growth hormone secretion and the positive secretion of growth hormone that results, and it's really very attractive. I also like the fact that when you have that feedback loop in place, potentially, the auto regulation will prevent very high IGF-1 levels and will allow for some maintenance of safe IGF-1. So I think it's very compelling.

Dr. Bhangoo, final question before we go to questions from the audience, regarding the types of doctors that treat this disorder in the future. If -- do you ever see pediatricians getting involved, given that they're kind of the first line of contact? And if we had an oral option, is it something they could ever treat or always going to stay with the [indiscernible].

No. Pediatricians do not treat growth hormone deficiency or short stature. If they would, then we would not get so many referrals just like Dr. Diaz said. But here's the thing, we started thinking about pediatricians using specialized endocrine medications when Ozempic and especially when Wegovy came out, we thought some of the community pediatricians are going to be really hands on. And they really don't want to do it because they realize there's so much paperwork authorization, and they need to hire extra people on the staff. So they push that to the pediatric endocrinologist. Also in the past, many pediatric nephrologists used to use growth hormone for renal failure, short stature and at least in our practice and the places that work there's been also -- that's also in the realm of a pediatric endocrinologists now. There are other growth promoting medications. We are not talking about growth hormone, which geneticists used to see, for example, achondroplasia. And we are -- the pediatric endocrinologist are also starting to take care of patients with achondroplasia, because of the same reasons their staff is not experienced to handle these authorizations and paperwork that endocrinology offices are.

Thank you, Dr. Bhangoo. Okay. Tara, why don't we get a question from the audience, and we'll take some orally first.

Great. Thank you, Corey. Please hold for a brief moment while we pull for questions. So our first question comes from Charles Duncan from Cantor Fitzgerald.

Yes. Corey, really great set of questions, very nicely sequenced. Thanks for hosting the call. I had a couple of questions that were really quite similar to a few of those that you asked. The first is for Dr. Bhangoo. You mentioned early on in the call regarding this stimulation test that he doesn't use it or doesn't really consider patients mild, moderate or severe. And I guess I'm wondering if you have a drug like this one, like LUM-201, that may work best in a moderate patient, would you start to incorporate a stimulant test? And would you start to kind of classify your patients differently as mild, moderate and severe?

Yes. So we do -- so the patients that we are serious that they have clinical criteria for growth hormone deficiency, and we want to treat them, we do the stimulation test, and there are many different regions. But in clinical practice, at least, we don't look at the severity just like you've said. But yes, if there is a specific FDA indication, for example, for LUM-201, our oral product, which is approved for moderate, I think the community of pediatric endocrinologists will start to look at it, and perhaps also treat differently. Yes. So the data is there, but there is an easy transition and a possibility to look at the data differently.

Okay. And then my second question is for any one of the KOLs and you've all been very helpful. I really appreciate your perspectives. But when you think about the target product profile, as Corey mentioned, towards the end, it was noninferior. It seems to work well in certain patient population. How would you sequence the use of it? What would be the biggest determiner, and let's forget about whether or not it's paid. Let's assume that it's reimbursed. So what is it in the clinical data that you you'd like to see? And how would you sequence LUM-201 versus the daily injectables or the long-acting?

I was just going to say that -- I am sorry, Corey?

I was going to say, why don't we hear from everyone on that answer, but go ahead, Dr. Misra.

No, I was just going to say about the fact that this is an oral preparation versus an injectable preparation is a big deal. And I think that's going to be a major driver of decisions, for an indication where this would be a logical choice. I think it's a no-brainer that any child [indiscernible] would prefer an oral preparation to an injectable preparation, with everything else being the same.

I agree. This is a pediatric population we're talking about. And by definition, that is a huge advantage.

And any dissent?