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

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

Well, thank you, Sarah, and good afternoon, and thank you for joining our key opinion leader call for a review of our top line Phase II data evaluating our oral therapeutic candidate, LUM-201, for moderate pediatric growth hormone deficiency, or PGHD. Additional analysis not previously disclosed will also be reviewed by these distinguished leaders in the field of pediatric endocrinology. Now as a reminder, this conference call is being recorded. In addition, certain statements made during the call are forward-looking statements on the U.S. federal securities laws. Please see Lumos Pharma's website for more information regarding our programs and related forward-looking statements. So before we get started into the discussion of data, I first introduce the speakers on this call. I will then provide a brief overview of Lumos Pharma's programs, the data to be presented today and our upcoming clinical milestones. Today, we're pleased to have three key opinion leaders from the field of pediatric endocrinology on the call who will review the top line Phase II data for our oral growth trials. Our first speaker is Dr. Fernando Cassorla, personal investigator of our mechanistic PK/PD OraGrowtH212 trial, who will be followed by Dr. Andrew Dauber and Dr. Leslie Soyka, two investigators for our dose finding or OraGrowtH210 trial. Dr. Cassorla will review some additional data from the OraGrowtH212 trial and Dr. Soyka will review data related to our predictive enrichment marker or PEM, strategy as well as combined data from growth -- OraGrowtH210 and 212 trials. After the discussion, there will be a question-and-answer session with instructions to follow at that time. Dr. Fernando Cassorla is currently Chief of Pediatric Endocrinology at the University of Chile and previously served as Clinical Director at the National Institute of Child Health division of the NIH. He has authored over 200 articles and numerous abstracts in his field, has been a recipient of numerous international awards for his work. Dr. Cassorla received his MD from the University of Chile and completed his residency in pediatrics at Albany Medical Center in New York and his fellowship in Pediatric Endocrinology at the Children's Hospital of Philadelphia. Dr. Andrew Dauber is currently Chief of Endocrinology at Children's National Hospital, having previously served as Program Director and a Director of Translational Research at the Interdisciplinary Cincinnati Center for Growth Disorders in Cincinnati Children's Hospital Medical Center. And prior to that her served as Assistant Medical Director for the clinical research unit at Boston Children's Hospital and as an assistant professor in pediatric at Harvard Medical School, from which he received his medical degree and Master's in Medical Sciences. Dr. Dauber has authored over 100 publications, has received numerous rewards from the Endocrine Society and the Pediatrician Society, among others. And finally, Dr. Leslie Soyka, who's currently the Division Chief, Pediatric Endocrinology University of Massachusetts Memorial Health and Associate Professor of Pediatrics University of Massachusetts Chan Medical School. And Dr. Soyka received her MD from the University of Connecticut School of Medicine, Farmington, Connecticut and completed at a residency at UMass Chan Medical School and a fellowship program at Mass General Hospital. She has authored, coauthored or reviewed approximately 40 peer-reviewed articles, poster publications and book chapters on pediatric endocrine subjects including growth disorders and diabetes, among others, and has served as an investigator in numerous clinical trials focused on disorders in this space. Dr. Soyka has also received a number of awards for her work and has been recognized locally and nationally as one of the best doctors in the field. Lumos Pharma is a clinical stage biopharmaceutical company focused on rare endocrine disorders. Our lead candidate is LUM-201 and OraGrowtH [ hormones ] stimulates small molecule that works naturally within the endocrine feedback loop and is currently being evaluated in several Phase II clinical trials for Moderate Idiopathic Pediatric Growth Hormone Deficiency or PGHD. Prior data suggests that LUM-201 has the potential to address up to 10 other growth disorders, representing a total market of approximately $3.5 billion, not including China. And currently, the only treatment for PGHD and 10 other growth hormone disorders consists of either daily oral, daily injectable growth hormone or a weekly injectable growth hormone [indiscernible] If approved by the FDA, we believe LUM-201 has the potential to disrupt this sizable injectable recombinant growth hormone market. Our top line data from our Phase II OraGrowtH210 and 212 trials met all primary and secondary endpoints and showed that LUM-201 produce growth in line with historical data from moderate PGHD patients. These data also provided preliminary validation of our PEM strategy for identifying PGHD patients likely to respond to LUM-201. We anticipate holding an end of Phase II meeting with the FDA the first half of 2024 and expect to initiate a Phase III registrational trial in the second half of 2024. And finally, we have sufficient cash on hand to get us through Q3 of 2024 and are exploring opportunities, including strategic licensing partnerships to finance our Phase III trials. I'll now provide a few high-level comments about our clinical programs. So today, we are going to be reviewing data from our Phase II trials in our pipeline. The large multinational dose-finding OraGrowtH210 trial and the single [ site ] pharmacokinetic, pharmacodynamic OraGrowtH212 trial that provide key data supporting the unique mechanism of action of LUM-201. Our two other OraGrowtH trials in our pipeline are the long-term extension trial and a small switch trial. Both trials are ongoing and support the two main trials featured today. In addition, an investigator from Massachusetts General Hospital, Dr. Laura Dichtel, is conducting a small pilot trial evaluating oral LUM-201 in Nonalcoholic Fatty Liver Disease or NAFL. Based on exciting data from a prior trial, she conducted with injectable growth hormone in that indication. And currently, we are focused on PGHD. What we do believe that LUM-201 represents a pipeline and a product with the potential to address up to 11 indications currently treated by injectable growth hormone. And if approved, LUM-201 could offer a welcome oral therapeutic alternative to patients, families and clinicians. And finally, I'd like to provide a brief summary of the findings from our Phase II OraGrowtH210 and OraGrowtH212 trials, which our KOLs will discuss in greater detail. Now I say the least, we're very excited to report that these two trials both met all primary and secondary endpoints, providing preliminary validation of our PEM strategy and support for oral LUM-201 as an effective therapeutic for PGHD. The top line Phase II data demonstrated that LUM-201 increases the pulsatile secretion of growth hormone, thereby normalizing growth hormone and IGF-1 levels. Importantly, these data also show that oral LUM-201 present -- or promotes growth comparable to injectable growth hormone at only 20% of the growth hormone concentrations daily bolus injection of growth hormone produces. So I think this is really important. So let me state that again. LUM-201 promotes growth comparable to injectable growth hormone at only 20% of the growth hormone concentrations, a daily bolus injection of growth hormone producers. Also, combined data from both trials showed a durable effect of LUM-201 on Annualized Height Velocity out to 12 months and out to 24 months in a small subset of subjects. The data from the OraGrowtH210 and 212 trials support the selection of the 1.6 mg per kg a day dose of LUM-201 for our Phase III clinical trial. And we look forward to our end of Phase II meeting with the FDA anticipated in the first half of next year and to the initiation of a registrational Phase III trial expected in the second half of 2024. With that, I'd like to turn the call over to Dr. Fernando Cassorla. Fernando?

Thank you, Rick. These are my disclosures. I've been working now with Lumos for quite a while on the 212 study, and I'll give you some information about our results. If you look at the goals for all hormone replacement therapy, they are to normalize hormonal levels. The primary aim of endocrine therapy involves several key aspects. The first one is it concentrates on reestablishing hormonal equilibrium through oral replacement treatments, a well-established practice observed with cortisol, thyroid hormone, and gonadal steroids. Extending this foundational principle to growth hormone therapy emphasizes the importance of natural secretion, IGF-1 production and the restoration of typical growth patterns, advocates the avoidance of supraphysiological recombinant human growth hormone dosing whenever feasible. And number four, it emphasizes the acceptability and convenience of oral therapies to reduce the caregiving burden, particularly in cases when extended data is necessary. I think we should stop here for a minute and think about this. In general, when we, as endocrinologists give therapy to patients who lack a hormone, we give the hormone usually once a day and the hormone levels achieved with that particular treatment are quite stable. Let's think about thyroid hormone, for example. You got the pituitary that produces a stimulating hormone, TSH, that goes to the target gland, in this case of thyroid that produces T4 is a hormone with the biological action. But in the case of growth hormone, there's something different. In the case of growth hormone, there is no target gland. In fact, the gland that produces growth hormone is a pituitary. It doesn't produce the stimulating hormone like TSH. It produces the actual hormone that has a biological action. And that produces kind of a situation in which we got both a challenge and an opportunity. What do I mean by this? The principles of LUM-201 therapy is that the objective of this therapeutic approach isn't solely to achieve rapid catch-up growth, followed by a decline in growth rate due to growth hormone usage, but rather to achieve a sustained improvement in growth velocity that leads to the normalization of final height. Moreover, the strategy is likely to support the physiological increase in endogenous growth hormone or execution during puberty, thereby facilitating a more natural progression of growth. The [ cartoon ] you got on your right indicates that when you give an injection of growth hormone as shown in the blue line, the hormone levels actually be go to very high supraphysiological levels for a while, then they came down during the next hours, and they end up quite close to almost undetectable levels by the end of the 24-hour period. But when you look what happens in a normal child shown here in the black line, actually, in normal child produces growth hormone in a pulsatile fashion, particularly at night. And we can't produce that at all with an injection of growth hormone that essentially gives us supraphysiological level of growth hormone for a few hours and then essentially nothing. And when you look at the patient who has growth hormone deficiency, in the dotted black lines, you can see that actually this trial has maybe a couple of minor pulsatile patterns of growth secretion, but it's not nearly close to what happens in normal child. So in fact, the challenges, how do we attempt to reproduce the normal physiological pattern of growth hormone secretion in normal children when we give a bolus of growth hormone and injection of growth hormone that actually will lead to very high levels for a few hours and then essentially [ that will do nothing ]. In fact, we don't. And that's where the challenge comes. It's difficult to do that. It's also an opportunity because if we could, in some way, stimulate the pituitary gland to produce growth hormone a pulsatile fashion, we will be very much mimicking, reproducing what the normal physiology would do in any growing child. Now the drug that we have working with essentially is the oral growth hormone secretagogue that acts both at the level of hypothalamus and the pituitary, stimulating [ solo ] receptor to produce growth hormone in this pulsatile fashion because we are stimulating the pituitary to produce growth hormone. We're not giving growth hormone. And therefore, the pituitary, will [indiscernible] respond by producing growth hormone the way that pituitary knows how to do it. That is in a pulsatile fashion. And we believe that, that has a very important physiological significance in growth hormone secreted by the pituitary will stimulate the production of IGF-1. Some of it may have some -- effects on bone, but ultimately, long bone growth will take place as a consequence of the production of growth hormone by the pituitary. Therefore, the idea behind this is that we will have a growth hormone stimulated growth hormone [Audio Gap] by natural IGF feedback mechanism and this would be a very different mechanism compared to exogenous injection of growth hormone that actually would not have any kind of feedback mechanism that will be preserved. So that is in a way, the opportunity that this sort of therapy would provide for children who are not producing growth hormone [ adequately ]. Now the OraGrowtH212 [indiscernible] which I am involved has recruited a total of 22 patients. This is an open-label study for moderate pediatric growth deficient patients who are growth hormone treatment naive. They never received treatment. This study is being conducted until they achieve near-adult height. It's being conducted at a single specialized clinical site in Santiago. And the important thing that we believe has helped us to understand the mechanism of action of this particular drug is that we're able to assess growth hormone secretion by sampling our patients, these 22 patients with samples obtained every 10 minutes over 12 hours after randomization before they were allocated to either 1.6 milligram per kilo per day of this drug or 3.2 milligrams per kilo per day. And after 6 months, we repeated the Q10 minute sampling in order to see whether the pulsatile pattern, the profile of growth of growth hormone secretion would actually change after 6 months of therapy. The study endpoints were to assist LUM-201 effect on endogenous growth hormone pulsatility and Annualized Height Velocity to evaluate PK/PD in children and to confirm prior PK/PD data in adults and subset of Merck 2022 trial (sic) [ Merck 020 trial ] and to support future regulatory filings and commercialization. So this is the way the study was conducted. We are now in the second part of -- beyond the 6-months -- the initial 6-month period. Many of these children have completed 1 year of therapy and some are actually getting close to 2 years after the initial treatment period. Now these are the baseline demographics of our patients. They were allocated randomly. They are [ pretty way ] balanced in general. These are children who are prepubertal about 8, 8.5 years old. Their height are about minus 2-point-something standard divisions below at the mean. They've got an IGF-1 level that is about minus 1 standard deviation below the mean. The mid-parental height is about minus 0.8, minus 0.7 for the two groups here on the left panel, you've got the 1.6. On the right part, you got to 3.2. The bone age delay is about 1.5 years, more maybe 1.5 and 2 years. And their BMI that is the nutritional status is actually pretty normal. So in general, we believe that even though there is some minor differences in age and maybe potentially in mid-parental height, the groups are pretty well balanced. Now when we start looking at the results, what happens with these children when we treat them with this particular drug over 6-months. On the left panel, you've got the 6-month data. On the right panel, you got the 12-month data. And you can see that for the 1.6 dose over the 3.2 dose, at either for 6 months or 12 months, there's a significant increase in height velocity during this period compared to baseline. Now this is not mine. Having a child who is growing at about 4, 4.5 centimeters per year during prepubertal years, going up to maybe 7.5 or maybe 8 centimeters per year is quite comparable what you would see for pediatrics for patients with moderate growth hormone deficiency. These are not patients with severe growth hormone deficiency. This will be explained in some detail by the following speakers, but we are selecting patients who have response pituitaries. They are not growing well, they don't produce very much growth hormone, but they can respond to the stimulation with this particular drug by producing more growth hormone out of their own pituitary. When you look at the right part of the panel, you can see that there's a durable effect that actually this doesn't change very much at 12 months. They still remain at about 7, maybe a little bit over 7 centimeters per year compared to what they were at the beginning. And therefore, we believe that there's an increase in growth from baseline that there is a durable effect up to 12 months that there is a minimal drop of in annualized high velocity between 6 and 12 months and we did not observe any material difference between the 2 dose cohorts at 6 and 12-month. It wasn't as if one of the dose was much better than the other one, they were actually quite comparable. Now when you look at IGF-1, IGF-1 is a marker hormone action. Therefore, you expect the IGF-1 levels to go up during the period of treatment. And you can see in the 6-month cohort on the left panel and in the 12-month cohort in the right panel that there is a substantial increase in serum IGF-1 levels with either dose 1.6 or 3.2. The changes are quite similar. You go up by gaining about maybe one, may be potentially even up to 1.5 standard deviations of serum IGF-1, a substantial increase in IGF-1 levels that is concordant with the changes that we see in height velocity. Now if we look at another market of growth hormone action, that's IGFBP ratio, this ratio is a valuable indicator of growth hormone action because it's not [indiscernible] looking at IGF-1, but also at its binding protein. And you get an increase in this ratio, the kind of speculation is that you would get more IGF-1 action because you would get free -- a higher concentration of [ free ] IGF-1. And you can see that actually these increases over a period of 6 months in the left panel and 12 months in the right panel, again, indicating that there's not only an increase in height velocity, there is an increase in serum IGF-1, but there's also an increase in the ratio of IGF-1 to BP3. And that this effect is durable after 12 months of therapy, as you can see in the right part of the panel. Now let's -- let me show you an example. You got one patient that was treated with 3.2 milligrams per kilo per day. So the serum IGF-1 baseline was 48, the area under the curve by looking at the analysis over the 12 hours that growth hormone was measured in these patients with samples obtained every 10 minutes was about 253 and the height velocity was 4.4 centimeters per year. And the right panel, you can see the actual pulsatile, the possibility that you can observe in this particular patient, indicating that you've got one peak here before therapy, that is significant, but then the rest of the time, relatively minor peaks. But what happens once you treat this patient for 6 months. In that particular case, in the blue line, you can see that there's more peaks and there's a higher amplitude to the peaks compared to what you observed before therapy of patient. And when you look at the IGF-1, it goes from 48 nanograms per mL 211. The change from baseline is, therefore, 131%. The area to the curve goes up from 252 up to 481. The change from percent change of baseline is 91%. And the height velocity more important, goes essentially doubles from 4.4 up to 9.4, indicating that we are being successful in changing the pulsatility pattern of the patients on pituitary that is producing growth hormone when stimulated appropriately much better than what the patient was able to do before we gave this drug over 6-months. Now we not only look at the actual concentration of growth hormone, but we have made an analysis of deconvolution. Deconvolution is an analysis that is based upon the identification of peak growth hormone concentrations and looking at the following features. A rapid increase represents secretion described by Gaussian curve, a slow decay represents elimination based on the half-life of growth hormone in the circulation .And this generates episodes of growth hormone secretion expressed nanograms per mL per minute as opposed to concentrations that are just nanograms per mL. And the distribution volume of growth hormone plasma is used to define secretion over 12 hours per mL of blood, which is then converted into secretion from the pituitary as micrograms per kilo body weight over 12 hours. And that's the beauty of the system that you go from secretion -- I mean, from concentrations to actual secretion. And again, if we look at some of the data and some of our patients here as an example, on the left panel, you got growth hormone concentrations. And you see that this patient has a couple of very significant peaks here that are clear over the 12 hours of the patients were sampled. But when you perform this analysis, deconvolution analysis, you can convert that into basal and pulsatile growth hormone secretion. The basal doesn't change very much, but the pulsatile actually change quite a bit. And you hear can see that following the changes in growth hormone concentrations, you can get to the growth hormone secretions that the patient is actually producing as opposed to the growth hormone concentrations that also depend on elimination. So it's not as good a marker as growth hormone secretion. So that, we believe, is a very important factor to address the issue, does this start actually change growth hormone secretion. Well, here you've got some data showing what happens with the 1.6 and the 3.2 milligrams per day, both at baseline and after 6 months. And you can see that the number of secretory episodes is not very different, 6,6 both before and after, from 3.2 about the same thing, and the combined cohorts, essentially no change. But when you look at the pulsatile release, and that is actually how much growth hormone gets produced by the pituitary in these patients once they are stimulated with this particular oral secretagogue, well it essentially goes for the 1.6 from 25.5 up to almost 41 for the 3.2 from 24 up to 55. And for the combined is essentially a doubling of the pulsatile release of growth hormone as assessed by deconvolution. So we believe that this is an important tool to assess growth hormone secretion by the pituitary. Now when we look at what happened with growth hormone secretion as a stress by the deconvolution, you've got three key panels here. You've got basal on the left, pulsatile in the middle and total in the right. And you can see that the basal changes with a 1.6 dose and with a 3.2 dose. The pulsatile changes are also [Audio Gap] in the middle panel and any biological process. You get some patients in which the increase isn't that clear. But actually, there is a major change in most of them and the mean actually changes quite a bit. Now when we look at what happens in normal children? Well, we did not, for obvious ethical reasons, perform the study in normal children because we would have been forced to obtain samples every 10 minutes in totally normally growing children. This would have been difficult, and it wasn't done. So we have to compare this with the [indiscernible] . And you look in a blue part of the table that are actually the 12 hour growth hormone secretion at baseline for our patients for the 22 patients was 1.3 [indiscernible] after 6 months therapy -- here to the [ literature ], where there's a paper by Zadek published a number of years ago. It's not exactly the same way of doing this because they didn't give samples every 10 minutes. They rather obtain samples to a continuous withdrawal pump over 24 hours, and they change the tools of collection every 30 minutes. So it's not exactly the same. But essentially, you can see that over 12 hours, remember that we did this over the window of daytime production of growth hormone that is likely to be less than what we see during the night for obvious logistical reasons again. And you can see that the 12-hour for the untreated growth hormone deficiency is 1.1, it was 1.3 in our patients. And with normal healthy again, measuring growth hormone with a double antibody technique that is different from the ones that we're using now, it tends to show higher levels of growth hormone compared to our levels. Ours goes up to 2.6 and in normal [ healthy ] about 3.3. And if you try to extrapolate this over 24 hours, well, actually, because then we have to double this using a ratio between day and night, you produce more [ chloroform ] at night. So we have to then convert our 12-hour sampling period and say over 24-hours, this would have been a little bit more. And it actually is a little bit more. It would have been close to 3.3, plus/minus 1.8, to 4 depending on which ratio you use. That is, again, quite similar to what you would see in a normal child. Essentially, again showing, even though the comparison is not perfect, and we are the first to understand that here the same technique was not used in the sense that this is constant withdrawal and it's measuring growth hormone at a different assay, we approximate a production rate that is actually quite similar to what you see in normal healthy children. Now if you look at what happens with growth hormone treatment in this particular case, a paper by Albertson-WICKLAND from Sweden, published a number of years ago, you can see that actually the levels with the typical replacement dose at [ 234 ] micrograms per kilo per day of injectable growth hormone, you get a 24-hour [indiscernible] that would be close to maybe 20. So that's almost 5x higher than what we are obtaining, but we again believe that this is based upon the fact that you are having super physiological levels for a number of hours and then you're getting values that are very low during the hours prior to the next dose. So all in all, this indicates that we can achieve growth hormone secretion rates that are very similar to what you would see in normal healthy children and much less than you would see with exogenous injectable growth hormone therapy. Now we summarize the study by saying, all the primary and secondary endpoints were met that the increased 6 and 12-month Annualized Height Velocity meaningfully change from base that [indiscernible] normalized serum IGF-1 levels within 6-months of treatment with a dual effect after 12 months that LUM-201 stimulates an increase in pulsatile secretion of growth hormone approximating normal physiological levels. And finally, an increase in 24-hour pulsatile secretion LUM-201 achieves comparable growth to daily exogenous injectable growth hormone with only 20% concentration levels. So we believe that this represents an advantage because we are achieving profitable growth with the pulsatile secretion growth hormone by the pituitary of the same patient rather than giving a supraphysiological concentration of growth hormone by an exogenous injectable drug. I'll turn over the floor over to Andrew Dauber for the next presentation.

Thank you. Fascinating data, it's really lovely to see that presented. Thank you, Dr. Cassorla. So I'm now going to be talking about the results from the 210 trial. So these are my disclosures. All right. So I think many of you are familiar with the design of the 210 trial, but just to briefly review the -- this trial was based on the idea that patients who are enrolled in the trial would be those who are going to be likely responders. And it used a strategy called a predictive enrichment marker or a PEM test. And this strategy was defined based on a post-hoc analysis of the initial Merck study that was done to evaluate this drug a number of years ago, and it distinguishes between patients with moderate idiopathic growth hormone deficiency from those with severe organic growth hormone deficiency. And the specific markers that were required for enrollment in the study were that you must have -- the patients must have a baseline IGF-1 of greater than 30 nanograms per mL. When given a single test dose of the LUM-201, they have to achieve a peak growth hormone level of at least 5 nanograms per mL. And these two factors really indicate that the patient has a functional but perhaps reduced hypothalamic pituitary growth hormone secretion as opposed to a completely absence one or destroyed one. And it's estimated that approximately 60% of the total pediatric growth hormone deficiency population would be PEM positive would fall into this moderate growth hormone deficiency category and therefore, be eligible for a trial of LUM-201. So this is the design of the study. The study was a randomized controlled trial where patients were randomized into 1 of 3 different doses of LUM-201, either 0.8, 1.6 or 3.2 milligrams per kilogram per day, and they were compared to patients on daily subcutaneous growth hormone. It was -- the study was done. Again, of course, the inclusion criteria, they must be PEM positive, and the study was done across approximately 45 different trial sites around the world. And the major objectives of the study were, one, first, to confirm the utility of this PEM strategy; second, to evaluate the reproducibility of the PEM test itself; and then third, to look at the Annualized Height Velocity in these different doses and therefore, with the goal of determining the optimal dose for Phase III. And I'm going to say this now and likely will say it again that this study was not powered to show statistical non-inferiority compared to daily growth hormone, right? This is a relatively appropriate appropriately sized but Phase II study. This is not the definitive study to show non-inferiority compared to growth hormone. And here on this slide, you can see the baseline demographics of the different groups, approximately 20 patients in each group. And you can see that these data are pretty representative of a patient group with modest -- moderate growth hormone deficiency, heights in around the minus 2.3 standard deviation range and IGF-1 in the minus 1 to minus 2 standard deviation range and some degree of bone age delay. And I think it is important to note, as we talked about this a bit last year, but you'll see now that in the full data set, the patients by chance who were randomized to the combinant growth hormone arm were slightly younger than the other groups, had slightly taller parents and also had a slightly higher BMI. And these are all factors that would predict better responses to growth hormone therapy. And that is just what happens with chance when you do a smaller Phase II studies, that not all baseline variables are always equally distributed. So this is the primary objective. And what you see here are the growth velocities on the left at the 6-month time point and then on the right at the 12-month time point for the 3 different doses of LUM-201, versus the dose of recombinant human growth hormone. And what you see is that the 1.6 milligram per kilogram arm of the LUM-201 was the best-performing dose, with growth velocity of 8.2 centimeters at 6 months and 8 centimeters at 12 months. So very similar, looking like a sustained response over the 12 months of treatment and a growth of 8 centimeters is comparable to historical 12-month growth philosophies in a moderate growth hormone deficiency population. And I'll show you a little more about that in the next slides. There was -- the growth hormone arm did have higher growth velocities of 10 and 9.7, although that 1.7 centimeter difference between the 1.6 arm and the growth hormone arm is less than has been historically used in Phase III non-inferiority margins. But again, the study was not powered to show non-inferiority. So this, I think, is a really interesting analysis. This is data looking at the patients who had full 12-month data available, showing in the 2 doses at the both, the 1.6 and 3.2 showing their growth velocities at 6 months and at 12 months. And what you can see is that there is a rise in growth velocity in almost all of the patients by the 6-month time point, and that is pretty sustained from the 6- to 12-month time points. You do not see a significant drop-off in the height velocity from 6 to 12 months, which is very reassuring at both doses and there were no statistical differences between the 2 cohorts at each of those 2 time points. Now as I mentioned, the growth hormone cohort by chance had some variables, which suggested perhaps better growth hormone response. And in fact, 2 of the patients of the 3 subjects who are under age 5 by chance, happen to be randomized to growth hormone and had extremely positive responses to growth hormone, which is skewing some of the data. And you see these 2 patients had growth velocities up above 12 centimeters per year at 6 months, 1 almost at 16 centimeters per year, and those patients happen to have factors that led to them being very responsive to growth hormone treatment. And this data is basically a much better than these are outliers compared to what 1 would expect from pediatric growth hormone deficiency. Now if we look at the data that was seen in the 1.6 arm and compare it to historical data sets, which are obviously going to be much larger than the control arm in this one Phase II study, you can see the numbers of patients in the bars, whether it's 433 in the GENESIS study, 100 in the isolated Pediatric Growth Hormone Deficiency trial or 3,075 in the KIGS study, you can see that growth hormone achieved growth velocity is more in line with what was seen at LUM-201, between 8.3 and 8.6 centimeters, slightly higher in a moderate growth hormone deficiency population taken from a recent Phase III study. So much more similar to what we saw in the LUM-201 arm in our study. Now Dr. Cassorla showed you already IGF-1 values in the 212 study. These are the IGF-1 values here in the 210 study. And you can see there was -- it looks like a dose response relationship somewhat in the IGF-1 response. And you can see that the LUM-201 was able to bring IGF-1 levels into the normal range well into the normal range, both with the 1.6 and 3.2 dose. And both of those increases, they were sustained throughout the 12 months of this study. The growth hormone arm did lead to higher IGF-1 levels. So in summary, all of the primary and secondary endpoints were met from the 210 study, the Annualized Height Velocity is consistent with prespecified targets from historical benchmarks in patients with moderate growth hormone deficiency, the 1.6 milligram per kilogram arm was within a non-inferiority margin that has been typically used in the past in Phase III pivotal trials. LUM-201 did normalize the IGF-1 SDS within 6-months of treatment. The safety profile remains extremely clean after over 1,300 patients have been treated to date with this medication. And these results support advancing to a Phase III trial with the final design that will be confirmed at the end of Phase II FDA meeting, which Lumos is anticipating to have in the first half of 2024. And with that, I will now turn it over to Dr. Soyka to give us some additional analysis of the combined data and the PEM strategy.

Okay. Thank you. It's a great discussion. Good afternoon. So I will be discussing the predictive enrichment marker strategy and the combined data from the 2 studies 210 and 212. And these are my disclosures. So to review what Dr. Dauber was previously discussing, the Predictive Enrichment Marker strategy was designed to identify these subjects with moderate Pediatric Growth Hormone Deficiency that are likely to respond to LUM-201. So these would be the subjects with an intact hypothalamus and pituitary growth hormone axis and which LUM-201 can act as an agonist at the growth hormone secretagogue receptor and result in an increase in growth hormone. So the PEM positive subjects were defined as those with the baseline IGF-1 greater than 30 nanograms per mL and has stimulated LUM-201 peak greater than or equal to 5 nanograms per mL after a single dose of LUM-201 and 0.8 milligrams per kilogram. And again, these values would indicate the presence functional but reduced hypothalamic pituitary growth hormone axis. And that is in contrast to subjects with severe growth hormone deficiency and [ home administration ] at LUM would not stimulate a significant growth hormone response in these PEM negative subjects had a baseline IGF-1 below 30 nanograms per mL in a stimulated growth hormone peak after a single dose of LUM below 5 nanograms per mL, indicating a nonfunctional hypothalamic pituitary growth hormone axis. So the primary objective of the 210 study was to show clinical validation of the PEM strategy intended to select subjects that are capable of secreting growth hormone response to LUM-201 and therefore, likely to respond to LUM-201 based on reaching the prespecified target growth velocity. This graph shows the percent the study population, reaching the target growth velocity based on enrichment in the aside LUM-201 dosing arm. You can see that compared with the group with no enrichment, which consists of subjects with both moderate and severe growth hormone deficiency, about 50% are responders in terms of their growth, the PEM positive subjects in the low-dose arm of 0.8 milligrams per kilogram per day also showed about a 50% response. However, if we look at the PM positive subjects who are in the higher dose arms of the 1.6 milligrams per kilo and a 3.2 milligrams per kilogram per day, over 70% of these subjects met the prespecified target growth velocity. This indicates that the PEM strategy allows for enrichment of growth responders at the higher LUM-201 doses. The secondary objective for the 210 study was to assess whether the PEM test is reproducible in the study subjects. The PEM test consisted of assessing growth hormone response after a single dose of LUM-201 at two separate visits at screening as well as day 1. Result of the 2 PEM test showed a positive agreement in 76 out of subjects with a reproducibility rate of 100%, we exceeded a prespecified statistical objective. The durability of the gross response to LUM-201 was previously discussed by the other doctors, Dr. Cassorla and Dr. Dauber. This is evaluating data from the subject in both the 210 and 212 studies from the cohorts assigned to the two higher dose groups, the 1.6 and the 3.2 milligrams per kilogram per day. The graph shows the baseline growth velocity in those subjects to a growth -- baseline growth velocity data available at 4.52 centimeters per year. The 6-month data showing an increase to 8.1 centimeters per year and the 12-month data is showing sustained improvement of growth velocity to 7.4 centimeters per year, showing sustained improvement to 12 months. The durability of the growth response to LUM-201 was evaluated to 24 months in a small subset of study subjects from the 210 study who met the prespecified annualized growth velocity at 12 months as well as the subset of the subjects from the 212 study with growth data available to 24 months. And these subjects were in the two higher dose arms, the 1.6 of the 3.2 milligrams per kilo per day. And as you can see, there are 10 subjects total with the growth data available out to 24 months. The graph shows the baseline growth data of 4.5 centimeters per year in the LUM-201 treated subjects. The increase to 9 centimeters per 6 months and then 8 centimeters per year at 12 months. And as previously discussed, the annualized growth last 12 months is similar to published data for moderate growth hormone deficiency growth rate of about 8.6 centimeters per year in year 1 of treatment and published data and growth hormone treated subjects. The graph shows -- sorry, need to move ahead -- as a graph further shows sustained improvement in linear growth velocity up to 24 months in these 10 subjects, and shows a lower decrease and the percent change in Annualized Height Velocity going from year 1 to year 2 of 6.3% and this is much lower than what has been reported in growth hormone treated subjects who have almost a 20% decrease in growth velocity going from year 1 to year 2. So again, the data in this small subset of patient subject shows a durable response up to 24 months with less of a decrease from year 1 to year 2. And this is maybe due to the LUM-201 restoring pulsatile secretional growth hormone leading to normal levels of growth hormone in IGF-1. So these data show the individual growth responses of the subjects in the 210 and 212 studies that have growth data available to 24 months. And as mentioned previously, there are a total of 10 subjects with growth data out to 24 months from the two studies. And this graph shows the male subjects, of which there were 6. The male subjects growth data is displayed against a graph of age-based reference ranges for Annual Height Velocity and U.S. male children in the age range display from 6 to 12 years. And you can see the individual subjects annualized growth last year baseline 6, 12, 18 and 24 months. And the dark symbols represent subjects receiving a 3.2 milligrams per kilogram per day dosing and the lighter symbols represent the 1.6 milligrams per kilogram per day dosing arm. And as you can see, the growth velocity increased in all the subjects with the 6-month growth velocity showing the largest increase in most subjects attaining a growth velocity over 97 percentile for age initially and then followed by a sustained increase with growth velocity maintaining over 50th percentile to 24 months. And this is similar data but in female subjects, and of those 10 subjects with 24-month data, there were four females. There were all in the higher dose, 3.2 milligram per kilogram per day dosing arm. And again, their Annual Height Velocity is displayed on a background of normal Annual Height Velocity for the age of interest from 6 to 12 years of age. And again, you can see similar to the male subjects, in most subjects had an increase in linear growth velocity, often exceeding to the 97th percentile or higher, most markedly at 6 months and then a sustained improvement in Annualized Height Velocity out to 24 months with most maintaining a high velocity over the 50th percentile out to 24-months. So these data suggest that the LUM-201 in the higher dose arms restores growth velocity to normal in both male and female subjects and this, again, very small cohort of subjects to date. Okay. So lastly, I'll talk about the safety data from the combined trials. Across the top row, you can just see the number of subjects in each dosing arm. So the base number was those subjects who are at a PEM test, in which there were 129, and then about 18 in the low-dose arm 33 and each of the higher dose LUM-201 and then 20 and then [ growth hormone ] untreated arm. You can see the number of AEs was fairly large, but we're focused on the treatment-related AEs and about 6% or less subjects in the low-dose LUM-201 arm in the PEM arm had adverse -- treatment-related adverse event and then about 40% in a higher dose LUM-201 arms had a treatment-related adverse event and 25% in the growth hormone treated group had a treatment-related AE. So before moving on to the SAEs, what are the treatment-related AEs that they had. So the most frequent adverse event was an increase in appetite, which I believe we often see in growing children. And this did tend to resolve on average over about 9 months. And importantly, did not lead to a normal weight gain in the children or an elevation in their BMI. There is also some extremity pain, growing pain, again, not unusual to see in growing children, most were mild in a brief duration. The Arthralgia's were mild and typically lasted a few days to less than two weeks. There was one case of self-limited abdominal pain. In one case of elevated liver transaminases, which resolved after a few months. A review of the series of adverse events. There are a total of four SAEs across the study groups. Of these, one subject in the low-dose LUM-201 group had an SAE due to hospitalization between the PEM dose in the randomized study visit, so it was not on study drug at the time of the SAE. And similarly, one subject in the growth hormone treated group had an SAE due to a hospitalization between the PEM dose in the randomized dose. The other two SAEs in the LUM-201 groups were due to hospitalizations for events assessed as unrelated to the study drug. So in summary, to date, there are no meaningful treatment-related serious adverse events. There were no dropouts from the studies due to SAEs or AEs. And there are no meaningful safety signals observed in lab values, AEs or EKG values. And the treatment related AEs have been mild to date and tended to improve over time. So I believe at this point, we'll be moving on to questions.

Thank you, Dr. Soyka. We'll begin our Q&A session. [Operator Instructions] And with that, we'll take the first question from Charles Duncan at Cantor Fitzgerald.

Yes. And thanks to Rick and team for hosting this webinar. It's been very informative. I have a question for each of the KOLs and then one for you, Rick. First of all, for Dr. Cassorla. The first question is regarding the pulsatile release of growth hormone, I've always been intrigued with this. I'm wondering whether or not you think that not only in terms of Annual Height Velocity, but also perhaps call them downstream side effects, if you will, such as long bone growth or anything else, would you anticipate that the pulsatile release might be better than the bolus strategy? I know it will take a while to show that, but what's your thought on that?

Thank you for your question. I always thought that the pulsatile release growth hormone is no accident. The best, if the pituitary produces growth hormone in pulsatile fashion, it's because it promotes growth better than just having a high concentration of growth hormone for a while and then essentially nothing. For all the metabolic actions of growth hormone, which are many essentially, there's reason to think that the pulsatile release of growth hormone fulfills a physiological role that actually it's the way the system is designed. And we are bypassing the system by giving growth hormone. Now granted that it's a very effective way of helping children to grow. But question is at what cost. I'm not talking about financial cost, but I'm talking about financials but I am talking about [Audio Gap] this happened for all endocrinologists in which -- so I believe that the fact that growth hormone is [indiscernible] in pulsatile.

Dr. Fernando Cassorla, it's Corey David [Audio Gap]

Growth-promoting effects that we believe is [Technical Difficulty]

Dr. Cassorla, can you hold pause for a second? We're having some connection issues. Charles, do you want to move to your next question? So we make sure we hear his answer, and we'll come back to it.

Yes, yes, absolutely. For Dr. Dauber, I had a question regarding -- you mentioned three things, slightly younger patients, slightly taller parents and then slightly higher BMI patients going in kind of drove if you will, a sample size imbalance. And I guess I'm wondering if you think about that in terms of a pivotal study, at what size of sample would you believe that those impact -- the impact of that might be eliminated? Does the trial -- or does the company have to power up, if you will, in a significant way or could they get there with a reasonable sample size?

I think a reasonable sample size would probably do it. Like if you remember -- so right now, the sample size essentially for the comparisons is 20 to 20, right? So that's obviously too small for a pivotal Phase III trial. And if you remember the look at the data that we did last year when we presented this with half as many patients, the effect was even more prominent because those two real outliers were already in the data, and that attenuated just by going from 10 to 20. So I think that any sample size that they're going to be -- that's going to be sufficient for a pivotal Phase III, and I don't know what that number is 80, 100, whatever it is, I'm sure that that's going to be sufficient patients to even out the outliers and the distribution.

Okay. That's helpful. And then finally for Dr. Soyka, I had a quick question. This is a multipart question. The first one is -- first part is how would you use LUM-201 if it achieves a target product profile supported -- supportive of this data in your practice, how would you use it and identify patients that might be responsive to it? And the second question is more along the data. If you just look at Slide 60 and 61 or 62, it appeared that there was one male subject and one female subject that was not responsive. And I guess I'm wondering if you're surprised that one of them just didn't start low enough and maybe that didn't help the efficacy either? Or is that a concern for you?

Yes. Thanks for the question. So I'm just going to answer the last question first, if you don't mind. So I believe that in the 212 and the 210 studies, the initial enrollment did not require a prespecified height velocity. And I believe, in some cases, and this asset -- often happens in clinical practice. We are using, in some cases, perhaps a growth point from the primary care physician, which when we either repeat or follow up, does not seem like maybe it was accurate. So I believe in the -- for the entry criteria, there was not a prespecified height velocity or maybe some question about that might have been a baseline or pretreatment -- preenrollment height velocity from a primary care and couldn't be verified or something like that. So it is a couple of subjects that didn't stand out to me, but I think there were some questions about the pretreatment height velocity, maybe not being perfectly accurate or something like that. So in terms of use in clinical practice, I mean, I think as a general pediatric endocrinologist, we're always -- the more options we have for patients, the better. So I think that every patient deserves individualized care and some subject -- some patients that we see have a real needle phobia. I can't say that there's any patients that I see that are anxious to get any medications by injection as one of the biggest hurdles that we face. So I think we would be taking into account efficacy once the Phase III data is available, patient preference, height deficit, how many years do you have left to grow would be another consideration. So I think that it's great to have as many options as possible to offer patients and families in terms of treatment.

Fabulous, you guys have been very helpful. One quick question for you, Rick, and then I'll hop back in the queue, if I may, Corey. And that is, Rick, in terms of the end of Phase II meeting end the 1H '24 versus sooner. I guess the question is, what is driving the time lines, is there any certain milestones that you're looking for, for durability, the durable data, if you will? And then could you give us any color on that long-term extension and Switch trial that's ongoing? I assume that patients are staying in, but could you provide any more information on that?

I think the patients are favorably impressed with the -- with their height velocity. I think there have been the durability of effect is actually even more encouraging to think that historically growth hormone from year 1 to year 2 drops off almost 20% versus only about 6% with our drug says a lot. And I think that will also -- when we go to recruiting in Phase III that will help the new recruiting situation. As far as timing goes, Charles, to a large extent, we don't have any control over the [ adequacy ], we'll have to go through a process that is preset in stone, we will submit in a reasonable period of time. We've guided to the first half of the year next year and we're doing everything we can under our power to be able to get that meeting and to and are excited about presenting our results for the chance of the first oral therapeutic halfway to approval with a trial to ago, we believe.

Dr. Cassorla, I'll try this one more time to go back to you because your answer to Charles' first question got lost regarding the pulsatile release not being an accident. And if you want to try to finish that answer for the physiological role for that.

Yes. I believe, again, that the fact that growth [ secrete in ] a pulsatile fashion is no accident. And therefore, when we think potential [indiscernible] of providing hormone growth for children will have benefits, not only in terms of growth [indiscernible] But also usually in terms of its metabolic effects. To be true, we haven't shown it after now. But the reason to provide growth hormone in this pulsatile fashion is likely to have beneficial effects in several areas, including metabolism.

The next question comes from Leland Gershell at Oppenheimer.

Thank you. Thanks, Rick and the team and the key [ panel leaders ] for holding this very illuminating session. A few questions from me. First, with respect to the use of injectable growth hormone. To what extent do you -- is there a concern that too much growth hormone and therefore, superphysiologic levels of IGF-1 may be exposed to these children and patients as they get older? Is that -- is it more theoretical? Or is there a reason to have a motivation to use a therapeutic that may avoid those elements?

Dr. Dauber, why don't you start answering that one, but I think we should hear an answer from each of the three of you.

Sure. So listen, recombinant human growth hormone has been available since right, the mid-1980s and it has been used in tons of patients. And the accepted clinical practice by most pediatric endocrinologist is to try and keep the IGF-1 level within plus 2 standard deviations. And sometimes people will allow that in certain situations to drift a little bit higher. Now that guidance is based really mostly on theoretical concerns. And those theoretical concerns arise from a few different sources. One is that in the general population, not patients with growth hormone deficiency or treated growth hormone, just in the general population, individuals with higher IGF-1 levels and individuals of taller stature have higher rates of certain types of cancers, right, colon cancer, breast cancer, prostate cancer are associated with taller stature in the general population. Second, we know that if you have a growth hormone producing tumor, that's not healthy for you, right? So if you have acromegaly, right, that has all types of negative cardiovascular effects, cancer risks of that. Those are the basic data that gives people theoretical concerns that long-term sustained increases in growth hormone can lead to increased risk. However, I think to be fair, there has never been shown that in children treated with growth hormone for growth hormone deficiency who are not otherwise at increased risk for cancer, right? You don't have a cancer predisposition syndrome, will haven't previously been treated with -- for cancer that there is an increased risk of cancer. There's one study -- there were some studies that raised some cardiovascular risk type questions, most of which have been refuted. There was a recent study from Sweden, which did show a slightly increased cardiovascular risk in the patients treated with the highest just -- growth hormone, not necessarily growth hormone deficient patients, but more SGA patients. So all that being said is accepted practice is, let's try and keep the IGF-1 level pretty much in the normal range because of these theoretical concerns, how concerned individuals are about those theoretical concerns varies greatly by physicians and by patients. So -- but just to echo Dr. Cassorla's comments, what we do now is not physiologic in any way. And there's reason to believe that human physiology was created a certain way by evolution over the many years for a reason. So I mean I think it's theoretically nicer to restore human physiology, whether that practically leads to any tangible increased risk is not known.

Dr. Soyka, additional thoughts?

Yes. I agree with all of those comments that generally is a theoretical risk, but we generally like everything to be as normal as possible. I do personally have patients with acromegaly that have a lot of significant growth and health concerns. So targeting that IGF-1 avoiding a high level is part of my practice. I do think the practice varies. I do you think the level of parental concern does vary as well. So again, it's theoretical. I do think there is a live -- patients are consumers now. Their parents are consumers. There is a desire to have things that are physiological and not excessive preference for many families. So I do think that, that is a concern. When I start a patient on biosynthetic growth hormone, the visit takes an hour at least to go through the medication and possible side effects and provide reassurance because, again, it's not physiologic. So I do think it is something that we think about and are concerned about and need to monitor that those levels do not get too high.

Dr. Cassorla, anything else on IGF-1?

Minor point. One problem is that not every physician will measure IGF-1 at regular level -- regular periods during growth hormone treatment that actually there are some patients that will get this drug and they will not get ticked for IGF or an issue that has to do with how often do we do it and how much attention do we pay to it. We should, but it's all always done. And then number two, it has to do with the age span of these children. Now some of these effects may take decades to become obvious. Remember the [ diploid ] cells problem, in which pituitary growth hormone was given in the 60s and in the mid-1980s, several patients, both in Europe and the U.S. became ill with this fatal condition. And therefore, one should not underestimate how long it takes for some of these effects to become clearer. And we may be -- because we're not checking IGF-1 levels as frequently as we should, except in -- for most people who work at [indiscernible] centers. We shouldn't be having there a problem that will become obvious in the future because of the latency, the time that it takes for some of these effects to become obvious. So I would urge caution,the fact that we sometimes serum IGF-1 level are two standard deviations above the mean. And there's a tendency to give us slightly higher doses because it's most likely going to benefit high-velocity, maybe a kind of a negative incentive for therapy that is supposed to be replacement. It's not replacement.

That's very helpful. And as we look ahead to LUM-201's the Phase III and its perspective use in patients commercially. I'm wondering how we have this -- on the one hand, this drug that's a daily oral, it's easy to take, well tolerated, looks like greater durability versus recombinant GH better alignment with the normal physiology and the PEM testing has -- what appears to be 100% consistency. At the same time, it looks like about 70% or a bit more of those who tested PEM positive met the prespecified target growth in OraGrowtH210. So that would imply that maybe better quarter patients didn't do so. So with the potential for a 1 in 4 chance of a patient who may be considered for LUM-201 not achieving those growth expectations, what does that sort of hold for you as a physician and maybe for the parent of a child? And would you expect that rate to be recapitulated in the Phase III? Or would you expect it to differ by much?