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

Good afternoon, and welcome to the Lumos Pharma KOL Event. [Operator Instructions] As a reminder, this call is being recorded and a replay will be made available on the Lumos website following the conclusion of the event. I'd now like to turn the call over to Rick Hawkins, Chairman and Chief Executive Officer of Lumos Pharma. Please go ahead, Rick.

Thank you, Sarah, and good afternoon and thank you for joining us for our KOL event to review the interim data from our 2 Phase II trials evaluating oral LUM-201 in moderate idiopathic pediatric growth hormone deficiency. I'm Rick Hawkins, CEO and Chairman of Lumos Pharma and will be joined by 2 noted thought leaders in the field of pediatric endocrinology for our discussion. Now before we proceed with our program, I'd like to remind everyone that certain statements made during this event are considered forward-looking statements under U.S. federal securities laws and the actual results may differ materially from historical experience or present expectations. I'm going to begin today's program with a brief overview of Lumos Pharma. Now following that, Dr. Dauber will review the mechanisms of actions of LUM-201 and discuss interim results from our Phase II OraGrowtH210 trial. Dr. Fernando Cassorla will then review interim results from our PK/PD OraGrowtH212 trial, including additional pharmacodynamic data not previously released. I'll then make a few final remarks. And we'll close the program with a question-and-answer session with our 2 speakers, joined by Lumos Pharma's management team, of course. Lumos Pharma is focused on developing therapeutics for rare diseases with our current program targeting growth hormone disorders with our novel oral therapeutic LUM-201. Injectable therapies have dominated this space for over 40 years. We believe that as an oral therapeutic, LUM-201 has the potential to disrupt the $3.4 billion injectable market for growth hormone disorders, not including China, whose market is estimated at around $1.5 billion. Our initial indication targeted is pediatric growth hormone deficiency or PGHD, which represents approximately $1.2 billion of the injectable market. The interim results our KOLs will review today are from 2 Phase II trials. OraGrowtH210, a study in moderate, naïve-to-treatment PGHD, is ongoing worldwide at about 45 sites; and OraGrowtH212, a single site PK/PD trial. Prior analyses indicate that the moderate or idiopathic PGHD patients we're targeting represent approximately two-thirds of the total treated PGHD patient population. And as we previously announced, our OraGrowtH210 trial over 80% enrolled at the end of October with 66 of the targeted 80 patients randomized. At the end of Q3, we had about $74 million as a cash balance, with a cash runway into Q2 2024, which is beyond the full read-out for our 2 OraGrowtH trials in the second half of 2023. Now I'd like to introduce our 2 KOL speakers. Dr. Andrew Dauber is currently Chief of Endocrinology at Children's National Hospital and specializes in growth disorders. Dr. Dauber served as the program director and director of translational research at the interdisciplinary Cincinnati Center for Growth Disorders at Cincinnati Children's’ Hospital Medical Center. Additionally, he was the director of their Genomics First for Undiagnosed Disease Program and served as associate professor or pediatrics at the University of Cincinnati. Dr. Dauber also served as assistant medical director for the clinical research unit at Boston Children's’ Hospital and as an assistant professor in pediatrics at Harvard Medical School. He has authored over 100 publications and is an active member of the Endocrine Society, Pediatric Endocrine Society, among others, and has numerous awards from these organizations. Dr. Dauber received his M.D. and Master's’ of Medical Sciences from Harvard University and he's also an investigator for our OraGrowtH210 trial. Dr. Fernando Cassorla, our second distinguished speaker, is Chief of Pediatric Endocrinology at the Institute of Maternal and Child Research at the University of Chile, a position he has held for over 25 years. Previously, Dr. Cassorla conducted research at the NIH, serving as Senior Investigator at the Developmental Endocrinology Branch of the National Institute of Child Health and Human Development, rising to the position of Clinical Director of this Institute in 1990. He has authored numerous chapters in pediatric endocrinology in over 200 original articles in peer reviewed journals, and he's presented over 300 abstracts at scientific meetings and has received numerous international awards for his work. Dr. Cassorla received his M.D. from the University of Chile and completed his pediatric residency at the Albany Medical Center in New York and his fellowship in Pediatric Endocrinology at the Children's Hospital of Philadelphia. And as previously stated, Dr. Cassorla is the principal investigator for our PK/PD OraGrowtH212 trial in PGHD. Now I'm going to turn the program over to Dr. Dauber.

Thank you, Rick. So I'm going to begin by reviewing the interim data from the Phase II OraGrowtH210 trial. And just to start, I'd like to give you a little bit of background. These are my disclosures. As Rick mentioned, I am a site investigator for the Lumos OraGrowtH210 trial, but I do not receive any personal compensation from Lumos for my participation. So I think many of you are aware that this trial is looking at a new agent called LUM-201. And there's an interesting background story to this agent. A number of years ago actually, Merck was attempting to find molecules that could increase endogenous growth hormone secretion. And they did this by screening a number of drugs in cell-based system and ultimately found this agent, LUM-201, that bound to what's called the GSR-1a receptor, also known as the growth hormone secretagogue receptor. Subsequent to that, it was found that the endogenous hormone that binds this receptor is something called ghrelin. In any case, LUM-201 binds this receptor at the level of both the hypothalamus and the pituitary. And once it does that, it induces signaling which increases the amplitude of growth hormone pulses made from the pituitary. And an important concept to understand that differentiates this from giving exogenous growth hormone is that there is an intact feedback loop between growth hormone and IGF-1, right? So in this situation, the pituitary is releasing larger amount of growth hormone. Growth hormone then goes and works via -- primarily via IGF-1, which is produced both at the liver and directly at the bone. That IGF-1 then feeds back in a negative loop at the level of the pituitary and hypothalamus to inhibit further growth hormone secretion. So the idea is that this medication can restore growth hormone to a natural normal state, but you won't be able to have excessive IGF-1 levels due to that inherent feedback. So what we're going to discuss today is the Phase II study, which is currently ongoing, comparing 3 different doses of LUM-201 versus daily recombinant growth hormone. And it's a 24-month study in prepubertal individuals with mild growth hormone deficiency. And there's another very interesting aspect to this study, which is that in order to enroll in this study, you have to meet what is called a predictive enrichment marker. So where did this idea come from? Well, in looking back at that original study done by Merck, comparing growth hormone to a single dose of LUM-201, it was found that the subcutaneous growth hormone appeared to be more effective in the entire cohort. However, in a subsequent analysis, they divided the group of patients into 2 groups. One was a group of patients with severe organic growth hormone deficiency. And one was a group with moderate or idiopathic growth hormone deficiency. And if you look at these 2 groups, the severe was around 40% of the population. Those were individuals who had more severe short stature, lower peak growth hormone dose -- lower peak growth hormone in stimulation testing, lower IGF-1 levels, lower growth velocities. And these are likely people who do not necessarily have an intact hypothalamic-pituitary axis and therefore were unable to respond adequately to LUM-201. On the other side are the patients with the milder growth hormone deficiency who did actually in that post hoc analysis have just as good of a response with the LUM-201 as compared to growth hormone treatment. And when you looked at characteristics that define these 2 populations, they came up with this term called the predictive enrichment marker, which was looking at the baseline IGF-1 level in any -- the people who were good -- better responders -- had IGF-1 levels above 30, and their stimulated peak growth hormone to a test dose of LUM-201 was greater than or equal to 5. So taking advantage of this concept, they now -- Lumos has designed the current Phase II trial, the OraGrowtH210 trial, which is enrolling 80 subjects into the 4 different groups and only including the patients who had a positive predictive enrichment marker. So in order to get into the study, you will have to be somebody who will likely respond to LUM-201, presumably with an intact hypothalamic-pituitary axis. The patients have to be naïve to growth hormone, and you heard about the current enrollment status. And there are 3 doses that are being tested, 0.8, 1.6 and 3.2, which is a higher range on the PK/PD curve compared to what had been tested previously and comparing that to a single dose of daily growth hormone using a dose typically used in children with growth hormone deficiency. And of course, the primary outcome is looking at the annualized height velocity. So before we get to the actual results, I think it's very important to put into perspective the expectation for what types of growth velocity we're expecting in patients who meet those PEM criteria who have moderate growth hormone deficiency. And to get to that expectation, there are a number of ways to look at it, but these are 4 different data points. So one is the patients who are treated with growth hormone from that prior Merck study. And the others are either from other studies of patients with milder, isolated growth hormone deficiency or data from the KIGS database, which is a large post-marketing surveillance data set study from Pfizer. And you can see that all of these numbers are pretty similar that historically for patients who meet the clinical criteria to be in this trial, you would expect them to grow around 8.5 centimeters a year with daily recombinant growth hormone therapy, approximately that. So what did we see? So this is the interim data of 41 subjects at 6 months. So this looks at the annualized height velocity. And the yellow bar in the middle is the 1.6 milligram per kilogram dose of LUM-201, which showed the best response in the study, exactly at the expectations of around 8.6 centimeters per year for the annualized height velocity. The 0.8 arm was a bit lower, the 3.2 arm was also a bit lower compared to those groups. What stands out as very different from the expectations, though, was the recombinant human growth hormone arm that grew at 11 centimeters per year, which is much higher than one would have expected for daily growth hormone therapy in patients with these types of clinical characteristics. And looking into that a little bit more, there were some good reasons why there were these differences than expectation. So the patients who were treated with the recombinant growth hormone, just by chance, by statistical fluctuation with small numbers, ended up being younger, having lower IGF-1 scores, having taller parents and having higher BMIs. These are all predictors of positive responses to growth hormone therapy. So that skew in the baseline data may explain some of the improved and higher-than-expected growth hormone rates in the recombinant growth hormone arm. And just to show you, 2 of the patients who were really outliers in their growth hormone response, where 2 of the 3 subjects under age 5 in the entire study happened to be randomized to subcutaneous growth hormone. The third was randomized to the lowest dose of the LUM-201. And actually, that 1 patient the star, all the way the highest one, close to 16 centimeters per year is actually a patient from my site, one of the youngest patients in the trial who also happened to have pretty significant growth hormone deficiency, just meeting the cutoffs for inclusion in this trial and has had a really remarkable response to growth hormone therapy. Now looking at the results of the LUM-201 across now the length of the study, the 9 months and 12 months, It appears, as you can see, that this increased growth rate in that 8 to 8.5 centimeter per year range is sustained from 6 months to 9 months to 12 months. It is important to note that the number of subjects at the 9-month and 12-month time points is smaller, 6 subjects, 4 subjects in the 1.6 arm. So we still need to accumulate the rest of the data of the trial to be really more confident in where these estimates will lie. From a safety perspective, the safety profile has been extremely reassuring. Data available now for 58 subjects at the time of the interim analysis. There have been no serious adverse events during the ongoing portion of the trial. All of the treatment-related adverse events were quite mild and nothing -- no concerning safety signals in the laboratory values either. So in summary, the growth of 8.6 centimeters per year on the 1.6 milligram per kilogram arm of LUM-201 is exactly in line with our expectations for what patients -- how patients should respond to growth hormone in this clinical scenario. The 9- and 12-month data do look encouraging for LUM-201, but again, the sample size is still quite small. And the interim safety data appear very comparable to growth hormone treatment and overall quite reassuring. And with that, I'm now going to turn it over to Dr. Cassorla to tell us about the results from his OraGrowtH212 trial.

Thank you, Andy. I will present data on our own study with this particular drug, but looking at pulsatile growth hormone secretion and linear growth in children with moderate growth hormone deficiency. So this is another study, Phase II that's being done with this particular drug, attempting to look at potential mechanism of action for this particular growth hormone [indiscernible]. Now here are my disclosures. And I've been working with this particular drug now for several months, actually more than a year at the University of Chile, and I've acted as consultant for several other pharmaceutical companies on different drugs and different areas. Now the questions that we would like to ask during this presentation are which is the potential effects of this particular drug in pediatric patients with moderate growth hormone deficiency by presenting 3 questions. Does the oral administration of LUM-201 at the doses of 1.6 or 3.2 milligrams per kilo for 6 months increase height velocity? Part of that question has already been answered by Andy. We'll show you our own data. Second, is a change in high velocity correlated with changes in growth hormone pulsatility? That is to say, what is the mechanism of action that this drug appears to have? And third, is the increase in growth hormone pulsatility and height velocity induced by LUM-201 dose-dependent? Now the design of our OraGrowtH212 clinical study is being done in naïve pediatric patients with moderate hormone growth deficiency. We have recruited about 21 out of these 24 prepubertal patients between the ages of 4 to 8 years for girls and 4 to 10 years for boys with short stature caused by moderate idiopathic pediatric growth hormone deficiency and naïve to growth hormone treatment that have been randomized to receive LUM-201 at a dose of 1.6 milligrams per kilo per day and n of 12 or 3.2 milligrams per kilo per day with an n of 12, too. Pulsatile growth hormone secretion has been assessed in blood samples obtained every 10 minutes over 12 hours from 8:00 a.m. to 8:00 p.m. at the beginning and after 6 months of LUM-201 therapy. It's important to indicate that we have done this over the window of the day, 8 a.m. to 8 p.m. We'll talk about that a little later. And the samples are being drawn every 10 minutes in order to get an idea of what is the pulsatility of growth hormone secretion during this period. And height velocity during the 6 months of LUM-201 administration has been compared with a baseline prior to intervention. In that sense, the study is also a little different, because here, we don't have a growth hormone arm. We're just comparing 2 doses, and all patients are being treated, all 24, 12 with one dose, 12 with another dose. And their height velocities are being compared what they were before we started to administer this particular drug. Now the design of the study is shown in this slide, which got one arm with 1.6 milligrams per kilo per day, another arm with 3.2 milligrams per kilo per day, all patients have gone through a standard growth hormone stimulation test. And we have done the same peak growth hormone to a single LUM-201 administration that Andy was talking about, the PEM kind of stimulation test before they are started on therapy with the drug over 12 -- 6 months. Now during the baseline period, we measured height, we measured IGF-1, and we established a protocol whereby we measure growth hormone secretion over every 10 minutes, over 12 hours in these patients both before and after 6 months of intervention, measuring again height and IGF-1. And the same thing is done with the group that has received 3.2 milligrams per kilo per day. So in this particular study, every patient has gotten therapy. All of them have gotten their oral secretagogue at 2 different doses, and their height velocities has been compared with the height velocities that they had before therapy. Now here are some details regarding the first 10 patients, in which we have data up to a little more than 6 months. And all of them are prepubertal. And here are the ages, from 5.2 years, 5 years and 2 months up to 10 years. 6 of them are boys, and 4 of them girls. This is not unexpected in terms of the referral kind of scenario that we get from patients who are short. The doses of the drug administered are shown here, according to the randomization schedule. And here are the heights of the patients before therapy, all of them less than minus-2 standard deviation scores according to the CDC data. And here are the results of the clonidine test that is a stimulation test to define whether they are or not candidates for the study. All of them have levels between at least 3, that's patient 103, and 9.9, 10 essentially for patient 110. So the inclusion criteria required they have a stimulation test between 3 and 10, and all of them have. And here are the results of the stimulation test with LUM-201. And I want to stop here for a second or kind of emphasize the fact that the responses to this stimulation test with this oral secretagogue are much higher than what we see with the clonidine test, so the patients are way above the cutoff point of 5 nanograms per ml that would be defined as a positive PEM responder. The lowest one was 19.5, and the highest one is 40. So essentially, we're getting either tripling or quadrupling of the responses that they have to clonidine test, a classical growth hormone stimulation test with this oral secretagogue. So this -- even though this study did not include -- I mean we had -- we did not have the exclusion criteria of having patients who would not respond to this drug. In fact, all of our first 10 patients, and in fact, all of the second 10 patients going up to 2021 have responded in a very robust fashion to this secretagogue, indicating that the responses to LUM-201 -- acute responses are much higher than the responses that we see with clonidine, a typical growth alone stimulation test. Now here are the height velocities before and after 6 months of administration of this drug. Here has shown the 10 patients before therapy and after 6 months. Each patient is already shown with these 2 points that are united by a line. And you can see that the slope of the curve is quite similar. That is to say the changes in height velocity that we see with this drug are quite similar for most patients, even though some of them received 1.6 and others received 3.2 milligrams per kilo per day. Now if we look at the bars for the same kind of data, we have here a nano 5 for 1.6, and a nano 5 with 3.2. And we do see some slight difference in terms of the height velocities over the first 6 months for the group that received the higher dose in this particular small group of individuals who were seen and measured again 6 months later. Now if we go beyond 6 months and we go to 9 months and then 12 months, we see that the response with a higher dose tends to decrease somewhat. So the differences between the low dose and the high dose are less marked at 12 months than what they were at 6 months. But let me caution you that the number of patients that we have at 12 months, 2 patients with a 1.6 dose and only 3 patients with a 3.2 dose indicate that one should not over-interpret this information until we have more data. But there seems to be a difference between the 2 doses in our study, at least at 6 months, that doesn't quite remain in place at either 9 months or 12 months. Now we then answer the first question by saying, does the oral administration of LUM-201 at the doses of 1.6 or 3.2 over 6 months increase height velocity? The answer is unequivocally, yes. Now the second question that we posted in this study was, is a change in height velocity correlated with changes in growth hormone pulsatility? And is the increase in growth hormone pulsatility and height velocity induced by LUM-201 dose-dependent? And those are the questions that we'll answer in the next few slides, indicating that from our previous study we assist pulsatility in gray before, that is baseline; and in blue, after 6 months of administration of this drug at a dose of 0.8 million per kilo per day. That's lower than the doses that we are using in our study. And we see that the gray pulsatility data is lower than the blue pulsatility data. That indicates that over 24 hours, this is day on the left and night on the right, measured every 20 minutes. We measured in this current study every 10 minutes for 12 hours. There is a difference there. There appears to be an increase in growth hormone pulsatility in this previous study that measured growth hormone pulsatility over 24 hours, obtaining samples every 20 minutes. Now what did we see in our study? Well, the current study shows that when we use 1.6 or 3.2 milligrams per kilo per day, the numbers of patients are small, but that we get a mean change in growth hormone area under the curve compared to baseline of 34% with the 1.6 milligram per kilo per day dose and 197% with 3.2 milligrams per kilo per day. So there's a major change in growth hormone area that occur from baseline, whether we use the 1.6 dose, but certainly much more with the 3.2 milligrams per kilo per day. Now I want to show you a couple of patients in which we show this graphically. Patient 105, who received a dose of 1.6 milligrams per kilo per day, you can see here the baseline pulsatility data over 12 hours during the day with samples obtained every 10 minutes. And you can see that the baseline data indicates that the height velocity is below 5 centimeters per year, the area under curve is about 273 and the serum IGF-1 is 110. Then when we move on to what happened after 6 months of therapy, you can see that IGF-1 goes up from 110 up to 185. The area under the curve essentially triples, going from 273 to 724. And the height velocity increased about 50%, growing from 4.6 centimeter per year up to 6.8 centimeters per year. This is with 1.6 milligrams per kilo dose. And you can see here in graphic terms with the gray data showing the pulsatility before therapy and the blue data showing the pulsatility after 6 months of LUM-201 administration that there is a significant change in growth hormone pulsatility. And that's why the area under the curve essentially triples. But what happens when we move on to a patient -- we present data on a patient who received 3.2 milligrams per kilo per day. Well, again, the baseline IGF-1 is on the low part in the cycle. The area under the curve very similar to the previous patient, and the height velocity a little lower, 3.4 centimeters per year. And when we look at what happens after 6 months, you can see that we get more than a doubling on IGF-1. We get almost a sevenfold increase in area under the curve for the growth hormone over 12 hours with samples obtained every 10 minutes. And the height velocity increase is about 2.5x, going from 3.4 centimeters per year up to 8.3 centimeters per year, indicating that the blue data that we obtained here after 6 months of therapy is much greater than the gray pulsatility data that we obtained during the baseline study period. Now what happens with serum IGF? Here, I show the data from our study, indicating that the baseline serum IGFs were about 100, 115, 120. But after 1 month, it got quite a bit with both the low dose in orange and with a high dose in blue essentially doubling, almost doubling at 1 month. And the differences appear to be a little more clear 3 months with slightly higher levels with a higher dose. Same thing is towards 6 months, but then that kind of attenuates, a difference after 12 months. But again, the number of patients is quite small at 12 months. So we would be cautious about suggesting that actually there is a change in IGF-1 level that is dose-dependent. There appears to be a change in growth hormone pulsatility that is dose-dependent. But in terms of IGF-1, it's a little less clear. Now what do we conclude there? That we have documented an increase in the height velocity compared to baseline in this particular study of a group of patients who are prepubertal with moderate growth hormone deficiency that were treated with 2 doses of LUM-201. The improved height velocity during LUM-201 administration appears to be correlated with an increase in growth hormone pulsatility after 6 months of therapy with this drug. In this limited sample size, these preliminary findings suggest that the changes in height velocity and growth hormone pulsatility induced by LUM-201 may be dose-dependent. I would like to finish by showing a picture of our group here at the University of Chile. All of us, pediatric endocrinologists, many of them trained up in the U.S. or in Europe. And I will turn over the podium now to Rick to give some insight into what these findings mean.

Yes. Well, thank you, Dr. Dauber and Dr. Cassorla. And I wanted to spend a few minutes reviewing the data from both trials. And now you can see here on Slide 39 the mean annualized height velocity achieved at 6 months on LUM-201 is similar across both trials. Now we're pleased that the OraGrowtH212 trial corroborated our findings in the OraGrowtH210 trial, and anticipated increasing the sample size from further enrollment of each trial will strengthen these results. And we believe that a Phase III pivotal trial will support these results even further. So on Slide 40, we have combined the growth data from the OraGrowtH210 and 212 trials for further analysis to determine an optimal dose for our Phase III trial. And as you can see, the mean annualized height velocities at the 2 higher doses of LUM-201 are similar across the 6-, 9- and 12-month intervals and demonstrate a durability of response up to 12 months on LUM-201. With these findings, we believe the combined data from the selection, a 1.6 mg per kg day of LUM-201 dose for a registrational Phase III trial. And now to summarize, we are very pleased that growth on the 1.6 mg per kg a day dose of LUM-201 met expectations and established by a large data set in our targeted moderate PGHD patient population. And recall, this is for the enriched population we identified through our predictive enrichment marker or PEM strategy for selecting these moderate PGHD patients with the potential to respond to LUM-201. In addition, LUM-201 demonstrated a durable response out to 12 months and showed a favorable safety and tolerability profile. And in addition, we believe these data support the selection of 1.6 mg per kg a day of LUM-201 dose for our pivotal Phase III trial. And our -- the company is proceeding with advanced planning for that registrational trial. And finally, I want to mention again that our molecule's unique mechanism of action and oral administration, we believe these data support the potential for LUM-201 to disrupt the injectable growth hormone therapeutic market worldwide. And so now we'd like to proceed to a question-and-answer session.

[Operator Instructions]. So our first question comes from Yasmeen Rahimi from Piper Sandler.

My question is directed to the fantastic physicians who presented here. Can you maybe allude to us now looking at the totality of the data from 210 and 212 and help us understand [Audio Gap] secretagogue in terms of its utility in the current marketplace for patients with pediatric growth hormone deficiency? So assuming this data could be shown very similarly reproduced and strong in the total cohort group, I think we would love to hear your thoughts on the positioning and use in patients. And what percentage of your patients currently on growth hormone injections you would switch over to this oral growth hormone secretagogue and why?

[Audio Gap] try to answer this. This is a very interesting question because it has 2 dimensions to this. One of them is cost. And the other one is the simplicity of actually treating the patient. And those are 2 very important issues for most families. Even though third-party payers will essentially cover growth hormone therapy for patients who have classical growth hormone deficiency, there is a raging controversy as how do we define growth hormone deficiency in different countries. In my country, for example, and in most of Latin America, and I would say certainly large parts of the world, the cutoff points for growth hormone [Audio Gap] 10 nanograms per ml kind of growth hormone levels. That means that there is a group of patients who currently in many countries in the world have responses of 7 or 8 nanograms per ml, but do not qualify for growth hormone therapy, because in these particular countries, that cutoff point is not low enough. So there's one dimension to this. And that there's a universe of patients out there [Audio Gap] and third-party payers' reluctance to cover compared to patients who [Audio Gap] for the most part get this particular drug, growth hormone. So this dimension means that there's a universe of patients out there who are partial growth hormone deficient, we want to call them moderate growth hormone deficient, mild growth hormone deficiency that we think are the patients who will respond [Audio Gap]. Some of these patients are either not getting growth hormone. Or if they are, they are getting it with the inconvenience of daily injections [Audio Gap] that growth hormone has. So a short answer to your question is, yes, I at least believe [Audio Gap] patients out there who would benefit from this therapy because it's simpler and it's likely to be less expensive than what growth hormone currently costs. So the potential for being able to treat patients who have this partial growth hormone deficiency with this drug, in my view, is huge.

Yes. And maybe I can build off that from the U.S. perspective [Audio Gap] in the United [Audio Gap] more than 50% of patients who are treated with growth hormone would meet the criteria for inclusion in this trial [Audio Gap] positive, right, in terms of having the milder idiopathic growth hormone [Audio Gap] there's no doubt, and the data shows this also. These are not [Audio Gap] with abnormal brain MRI [Audio Gap] subcutaneous growth hormone is the correct treatment for those. But those are by far the minority of patients who are treated with growth hormone in the United States [Audio Gap] very large percentage of the market who could [Audio Gap]. The second question that -- the second part that you asked was about switching. So I think that there's a different consideration for starting new patients [Audio Gap] so with other therapies that come down the line. So for [Audio Gap] hesitant or nervous to start an injection therapy for obvious reasons [Audio Gap] alternative, they would clearly prefer an oral alternative. [Audio Gap] starts would prefer to start on the oral drug. And this would be [Audio Gap]. In terms of patients who are already on therapy, the majority of them actually do fine. Like once they're on it already and they're on daily growth hormone therapy [Audio Gap] especially those who are having a good response to injection therapy, I don't think [Audio Gap] for sure who the kids fight and hate their injection [Audio Gap] if given an oral alternative. I think that answered most of the aspects of your question.

Yes. No, no, no, that was fantastic. And if I may ask one last question. So after the interim data, I think a lot of investors are just eager to [Audio Gap] likelihood that and the remainder of the 20% of patients that Lumos is planning to enroll, we may see an outlier in the growth hormone injectable [Audio Gap] But now looking at that, as we're at the last chart of the trial, just your comment [Audio Gap] at Lumos and how confident you feel that growth hormone will perform [Audio Gap].

Yes. Well, first of all, I think that you have to remember that a Phase III trial is [Audio Gap] evidence of superiority or non-inferiority in any one dose or treatment [Audio Gap] subjects in each arm. That's still not a very large number of people. So what Lumos did, and they can probably chime in if they wish [Audio Gap], which are based on age as well as based on severity of growth hormone deficiency. So those [Audio Gap] how the math happens, it will even out over the course of [Audio Gap]. Now that 3/4 of the patients have been enrolled versus half the patients with the interim data [Audio Gap] happen mathematically based on stratification. So I think that, that number [Audio Gap] 6 months and the growth -- even in those outliers, like my patient who had the amazing response, the first 6 months is always the best. And by 12 months, [Audio Gap] it's not going to be as extreme as you saw for the first 6 months. But that being said, honestly, [Audio Gap]. Like even if the growth hormone arm in these 20 patients comes out a little bit higher [Audio Gap] at 12 months or like at the final readout [Audio Gap] each arm. Like if the 20 patients in the Lumos arm hit 8 centimeters a year, right, [Audio Gap] because now you've got an oral therapy in patients with mild growth hormone deficiency that's giving them around an inch extra of height a year, right? Like I can't tell you how many patients knock down the doors on my office asking, hey, [Audio Gap] that's a really -- right? Like I mean just think about that, right? That's the reality of what we're dealing with. So to me, that's still very encouraging. And then the Phase III study will do what it's going to be designed to do, which is to actually tell us the comparison. [Audio Gap]

I would agree with what Andy said. [Audio Gap] we are kind of at the very beginning of these 2 trials [Audio Gap] until final height [Audio Gap] after 5 years, that's a lot of additional height that you [Audio Gap] that patients [Audio Gap] of growth hormone therapy are very unusual. Even for young children, we [Audio Gap] based upon the data that was presented, the curves indicate [Audio Gap] per year with growth hormone appears to be really very good [Audio Gap]. Some patients will only grow 5 or 6 centimeters per year during the first year [Audio Gap] there in the response. So [Audio Gap] we're seeing patients who respond [Audio Gap] a small group of patients. We will see how it evens out. We'll see what happens at the year and 2 years. But I wouldn't be surprised if during the second year, this patient is growing [Audio Gap] to maybe less than 10 during the second year. The growth [Audio Gap] to attenuate on outpatients [Audio Gap]. And this is likely to happen with both growth hormone and potentially with LUM-201.

Great. So our next question comes from Charles Duncan from Cantor Fitzgerald.

Thanks for hosting the call and to doctors Dauber and Cassorla, thank you for your perspectives today. I had a question regarding the compounding variables that the company has identified in those outliers in terms of the age or parent phenotype, BMI IGF levels. I guess I'm wondering, maybe going back to Yasmeen's question, do you feel like those are variables that will be reconciled within a larger study of Phase III? Or would you recommend to the company that they keep track of any one of those variables and stratify for them?

So I think in the larger trial with a sufficiently powered trial, those variables will even out much better for sure, I think that you're kind of asking like how many different stratification factors would you want in a big trial. And like would you necessarily want to stratify by initial IGF-1 levels? And honestly, I don't think so. I mean they're already stratifying by age and by peak growth hormone level, which are probably the 2 best predictors. So I think that in a big enough sample size with those stratification criteria, you're going to be fine. Yes, I think that this was just like a chance occurrence, that 1 of the 10 subjects that we show so far or 2 of the 10 happen to be very good growth hormone responses. The probability that happens this is really low, but it did.

Got it. Dr. Cassorla anything to add?

Well I'm all in favor of individualizing treatment for patients who are short with the current growth hormone therapy. That is to say there are these parameters that are important to keep in mind regarding the age of the child, the BMI, the mid-parental height. How growth on efficient are they? We take into consideration these things when we decide the dose of growth hormone that we're going to use in a particular patient. So I'm not surprised by the fact that there are differences in the response to some of these drugs in these patients. And we need to make sure that we don't have kind of a uniform approach to all patients who have partial growth hormone deficiency. Some of them will be quite severe, that is to say, partial, but pretty close to classical growth hormone efficiency. And others are going to be pretty close to idiopathic short stature with responses to stimulation test already close to the cutoff point of 10. So I would say that we must, in our daily practice, look at these characteristics of patients in order to decide what do we do with current doses of growth hormone even now. And it's possible that in the future, we will also have to look certainly as to whether the patient responded to the acute simulation with LUM-201. We want patients who have a robust response like we observed in our study. Those are the patients that I think will respond the best. And we don't want the patients who will have a tiny response to the acute simulation. So in essence, the answer to your question is, yes, I think that -- some of these criteria are considered to define doses of growth hormone with the classical treatment that we have right now. And it's possible in the future, we will have to decide, if this drug becomes available, which is going to be the patients that will respond the best to this particular drug compared to patients who are slightly different. Certainly, the patients who have classical growth hormone deficiency with very hyperfunctioning pituitaries are not the patients that will respond to this drug. But out of the large population of short children, who will ask Andy and myself about what are the chances of increasing the height of my child by giving them an oral medication, we are essentially bombarded by this every day. It's likely that in this particular group, the patients who have this partial or mild growth hormone deficiency, who are the largest population of short children will benefit from this drug.

Yes. And if I can add to that, I could see a future, and I think that this is obviously a number of years down the road. But I could see the future where there's a practice topline or a pathway where it identified patients with mild growth hormone deficiency, start out with oral treatment trial, right? And those who -- like as a first step therapy, those who respond well, great, you keep them on that. Those who don't, then find maybe you escalate to subcutaneous growth hormone therapy. I think some of this will, as Dr. Cassorla alluded to earlier, depend on the cost and the availability and stuff like that. But I don't think it always has to pose as either or as much as also a step-wise progression. And I really could see a role of this becoming the first step prior to a trial of growth hormone therapy.

Got it. If I may ask one additional question, and then I'll hop back in the queue. And that is related to the mechanism, I'm quite intrigued with the pulsatility of the secretagogue. And I guess I'm wondering if you see there being any inherent value in that versus just, I guess, flooding the system with growth hormone. And then would you anticipate that the responsiveness would be retained over time? I think that you, Dr. Cassorla started to allude to this, I understand there may be a, call it, denominator function, and that growth kind of settles out over time. But would you anticipate there to be any change in the rate of, call it, tachyphylaxis with the pulsatile mechanism versus, say, the daily injection. Does that question make sense?

Sure. There's 2 questions there. Question clear. The first one has to do with patients who part of this drug will essentially show a decrease in response over time. But we don't see that. That is to say, at 6 months, the pulsatility data that we've seen so far does not seem to show that it really goes down. That is to say that we are saturating the system with so much growth hormone that essentially the feedback mechanism ends up shutting off endogenous gross on secretion, such that the response and the pulsatility becomes quite attenuated at 6 months. We haven't seen it yet. We may see it in the future. There might be an argument that with a higher dose and with the IGF-1 data that we show, there is a tendency for a slight decrease in IGF-1 serum levels after 6 months with a high dose compared to the 1.6 dose, suggesting that maybe this does a little bit too high. I would be very cautious about interpreting that kind of data at this stage of the game in that sense. It's possible. So we understand that in this particular setting, the feedback loop remains active. And therefore, if you have more growth hormone, it's possible that you will shut off, I say eventually IGF-1 production and that your IGF-1 levels will go down. Now regarding the kind of the concept behind giving a growth hormone secretion as opposed to giving growth hormone, I think there is a clear advantage of trying to reproduce physiology. When we give growth hormone, we get a huge amount of this hormone that remains circulating in the blood for a period of time with levels that are super physiological and that then come down to essentially nothing before the next dose is given on the following day. So one has to think about the least physiological way of trying to produce growth hormone secretion, this will be the one. Flowing the system with a huge amount of growth hormone and then essentially having levels that are going to be very low over several hours of this 24-hour interval. So in answer to your question, it may make sense to me. That's why I think we, practicing pediatric endocrinologists, are interested in the field is that we are attempting to reproduce physiology. And certainly, giving this drug tends to magnify growth hormone pulsatility that remains quite pulsatile in fashion. That is to say, it doesn't remain as a huge plateau that then goes down to essentially nothing, as you would see with injectable growth hormone. So we all think that nature has designed a system in the somatotropic access that includes pulsatility as a key component of growth hormone secretion and then potentially of action. This is no accident. This happens for some reason. And certainly, by giving growth hormone, we abolish that. Now with this drug, we are attempting to reproduce physiology. We seem to have data up to now that indicates that pulsatility remains quite robust with the higher dose and even with the lower dose after 6 months, suggesting that the potential tachyphylaxis doesn't seem to be that clear at least to pulsatility studies that we conformed after now in the small number of patients.

And allow me just to add that, as you also know, [ not a referral ], in the Merck studies, which went out in adults for 2 years, even after 2 years of dosing with the -- essentially the 0.8 dose, there were still increases from baseline in both growth hormone and IGF-1, really putting the tachyphylaxis issue to rest pretty much.

If I may to give just a slightly different perspective though. While I agree and in general, I'm a big fan of trying to mimic human physiology, I would note that daily growth hormone the way we've been doing it does work well. And then even now long-acting growth hormones that you give once a week, which are even far less physiologic are showing equivalent responses to daily growth hormone in terms of response. So while I don't disagree what Dr. Cassorla said, I wouldn't make too much out of that in that non-physiologic ways of growth hormone replacement still are effective. And the last point is, while I think this comes back to the point of who's going to respond or not respond, I could see that there are some patients, as Dr. Cassorla alluded to in this spectrum who are, let's say, less growth hormone deficient than others, right? And one of the benefits of growth hormone therapy is that you can push the dose and push the IGF-1 level to maybe a super physiologic range and some patients will respond better to that. And probably for those patients, LUM-201 might not be as ideal. So just to give a little bit of the other side, I think that this all has to do with the right patient selection, who's going to respond. And that the -- it's good to have more than 1 option out there.

So our next question comes from Lelan Gershell from Oppenheimer. Looks like Lelan is joining now.

Lelan, you may be on mute.

You go to the next question, [ Tara ], until we get this resolved.

So our next question comes from Ed White from H.C. Wainright.

Sorry, I had some connectivity issues. So I hope this question wasn't already asked. But perhaps both the doctors can talk about compliance in their practices in the impact of patients for noncompliance? And then also your expectations for compliance with an oral.

Well, let me go first, Andy. This is a major issue with all therapies, whether they be injectable, parenteral or oral. This has been studied at length. And we know that patients, particularly children and a little worse for adolescents may have poor compliance, particularly with drugs that are injectable. On our daily practice, and I'm going to speak for myself, my experience at the NIH and then in Chile over the last decade -- a couple of decades is that some families are very disciplined. And the children follow the kind of the indications of the parents, and they're very compliant with therapy, in this case, with growth hormone therapy. Many, unfortunately, are not, many. And there are several studies published in the literature, Wayne Cutfield from New Zealand and others that have shown that a substantial number of patients miss their daily injections with growth hormone. And this has an effect on growth hormone velocity, on height velocity. And this has been published in several groups. There's a nice review by [indiscernible] and others that indicate that actually this is a problem. Now we cannot exclude that there will be compliance issues related to an oral medication because there are when we have patients with hypothyroidism, which we need to give them a small little pill or levothyroxine, some of them don't get the pill as frequently as they should. Remember that we are treating children. Children tend to be a little less compliant than adults, particularly during the adolescents period. So the short answer is that compliance is an issue with injectable growth hormone right now as extensively published in the literature. And this affects height velocity. And therefore, one can have the best intention of treating a family in a patient with growth hormone during several years. Remember, these are very long periods of treatment. And the responses tend to decrease over time. You start measuring IGF-1 levels and they are lower. And then this information is very hard to come by. As you ask questions about compliance, most patients and families will say, "No, no, no, he gets the hormone every day. We're very careful." Whatever. But the fact is that many patients do not. Now from a theoretical point of view, it would seem that an oral medication would have a slightly better chance of improving compliance compared to an injectable drug. That is something that is intuitively kind of easy to accept. Now we will still have some patients who will not take the oral medication as planned. That has happened. But my perception, my kind of guess is that there would be less issues of compliance with an oral medication compared with an injectable medication. And that may be one of the advantages of actually providing this form of therapy for children with partial growth hormone deficiency.

I agree. I have nothing to add. I completely agree.

Okay. And Rick, perhaps a question for you. I'm just curious as to why not wait for the full data to inform the Phase III dosing instead of calling the dose now with the 1.6? Just looking at the 212 data, that appears to favor the 3.2 dose.