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

Good morning, and welcome to the Lumos Pharma KOL webinar on LUM-201 for the treatment of pediatric growth hormone deficiency. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the Lumos Pharma website following the event. I would now like to turn the call over to your host, Rick Hawkins, Chief Executive Officer of Lumos Pharma. Please go ahead, Rick.

Good morning, and thank you for joining us for our KOL event on pediatric growth hormone deficiency in LUM-201, Lumos Pharma's therapeutic candidate targeting PGHD. I'm Rick Hawkins, CEO, Chairman, President of Lumos Pharma. I'll be joined by 2 noted thought leaders in the field of pediatric endocrinology for our discussion. 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. Actual results may differ materially from the historical experience or present expectations. So I'm going to begin today's program with a brief overview of Lumos Pharma. Following that, Dr. Brad Miller will discuss PGHD, the therapeutic landscape, and LUM-201. Dr. Fernando Cassorla will then review in greater detail the mechanism of action of LUM-201 and the new patient data disclosed in our press release this morning, illustrating the molecule's pulsatile MOA and its potential effects. Finally, we'll close the program with a question-and-answer session with our 2 speakers, joined by Lumos Pharma's management team. So Lumos Pharma is focused on developing and commercializing therapeutics for rare diseases with our current programs targeting the endocrine space. Our lead asset is LUM-201, an orally administered small molecule growth hormone secretagogue, currently in a Phase IIb program, targeting pediatric growth hormone deficiency, or PGHD. Our Phase IIb trial, the OraGrowtH210 trial was initiated in the fourth quarter of 2020 and continues to enroll patients. This trial will evaluate 3 different doses of LUM-201 against standard of care recombinant of human growth hormone injections in 80 PGHD patients identified by our predictive enrichment markers. We will enroll these patients at 40 to 50 sites in the U.S. and internationally, and we expect data readout of our OraGrowtH210 trial in mid-2022. Dr. Miller will provide a few more details about this trial and more information may also be found in our corporate presentation on our website. So in the second quarter of 2021, we expect to initiate another trial, the OraGrowtH212 trial, evaluating the PK/PD effects of LUM-201 in 24 PGHD patients. This trial will be conducted by Dr. Cassorla at a single specialized site, where 24 patients will be randomized into 2 groups, each group receiving 1 or 2 different doses of LUM-201. While this trial is not required as part of the regulatory pathway for approval, we believe this trial will corroborate the new data Dr. Cassorla will review today, illustrating the potential advantageous effects of LUM-201's pulsatile mechanism of action. As we announced on our last earnings call, the hospital where the clinic is based, experienced a fire. While the clinic was not impacted directly by the fire, the hospital did close temporarily to address the affected area. The hospital is open again in a limited fashion, and Dr. Cassorla is prescreening patients, so we continue to be encouraged that this trial will start this quarter. Now the pediatric market for all indications currently treated by recombinant growth hormone totals about $3.4 billion globally with approximately 35% of the sales or $1.2 billion derived from the treatment of PGHD. This entire market is currently served by daily injections of recombinant human growth hormone, and we believe LUM-201 has the potential to be a platform therapeutic with ability to address not only PGHD, but also other indications currently treated with growth hormone injections and capture a significant portion of this overall market. We plan to proceed first with our program in PGHD and then evaluate the opportunity for LUM-201 and these other indications. Our management team has many years of experience in clinical development in the rare disease space to support our current and future programs. This team is also conducting due diligence on other rare disease assets for potential licensing to expand our pipeline. Our cash balance is solid. We had approximately $99 million at the end of 2020, plus we received $26 million in non-dilutive proceeds in January from our PRV sale last year. This PRV was granted in late 2019 with the approval of the Ebola vaccine developed first by us and then completed by Merck. This pro forma cash balance should provide sufficient funds to support our current development program in PGHD and the flexibility for pipeline expansion. Now as I stated earlier, we have a highly experienced management team supporting our programs, and I wanted to mention that last week, our CFO, Carl Langren, announced his retirement effective July 4, 2021, after a distinguished 40-year career as a financial executive, including over 15 years at Lumos Pharma as predecessor company. Carl will continue to serve as a consultant to Lumos Pharma thereafter for a transitory period to ensure a smooth succession process. Lori Lawley is currently Senior VP of Finance and Corporate Controller and will take over as CFO in a planned succession effective July 4, we refer to as Carl's independence day. So Lori is a CPA by training, has 14 years of experience in overseeing financial operations. Carl and Lori have worked together since Lori joined in 2015 and both were hands on in a merger process, so the transition should be smooth. Now I'd like to introduce our 2 KOL speakers. Dr. Bradley Miller is currently a Professor and Division Director of Pediatric Endocrinology at the University of Minnesota Medical School, where he is a practicing pediatric endocrinologist and published research investigator focused on normal and abnormal growth in children. He completed his fellowship in pediatrics and pediatric endocrinology at the Mayo Clinic after receiving his M.D. and Ph.D from the Medical University of South Carolina, Charleston, and has received numerous awards and recognition throughout his medical training and career. Dr. Miller is actively involved with the MAGIC Foundation for children's growth and this foundation is the global leader in endocrine health, efficacy, education and support. And Dr. Miller is also an investigator in our Phase IIb OraGrowtH210 trial in PGHD. Dr. Fernando Cassorla, our second distinguished speaker is Chief of Pediatric Endocrinology at the Institute of Maternal and Child Research of the University of Chile, a position he has held for 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 position of Clinical Director of this institute in 1990. He's authored numerous chapters in pediatric endocrinology and over 200 original articles in peer-reviewed journals. He has presented over 300 abstracts at scientific meetings, 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. Has fellowship in pediatric endocrinology at the Children's Hospital of Philadelphia. As stated previously, Dr. Cassorla is the principal investigator for our PK/PD OraGrowtH212 trial in PGHD. So now I'm going to turn the program over to Dr. Miller. Brad?

Thank you. Today, I'm going to talk about the future of therapy for growth hormone deficiency. These are my disclosures. I am an investigator in a number of clinical trials for children with growth disorders. The information I'll be providing today will include the discussion of off-label use of medications since these medications are currently in development, including LUM-201, which is an investigational compound. I'm going to start today by talking about the growth hormone in IGF-1 axis, focusing in the upper left corner on the hypothalamus and pituitary that are regulating the growth hormone secretion. Growth hormone released into the blood supply will then head to both bone and liver. At the liver, it's going to stimulate the production of insulin-like growth factor I and IGF binding protein 3, which is then going to facilitate the transport of IGF-1 to the target tissue, the growth plate. And at the growth plate in the bone, in the long bones, we're going to see the action of growth hormone and IGF-1 on growth. Today, we'll be focusing on growth hormone deficiency, a condition that we, as pediatric endocrinologists, see quite regularly in our practice. About half of the new visits in our clinic are for children with growth failure. Growth hormone deficiency is defined as a combination of growth failure, decreased pituitary growth hormone production and low growth hormone actually causes low levels of IGF-1 in the blood. At the bottom, you can see the spectrum of pediatric growth hormone release, which is on the left panel, the pulsatile secretion in a child with normal growth hormone production. The middle panel showing limited growth hormone release in a child with partial growth hormone deficiency or mild growth hormone deficiency and to the right, very limited or no growth hormone release. When we look at the number of children that are seen for growth hormone deficiency, a study in 1994, looking at all children less than the third percentile in a school system evaluated for growth hormone problems, the incidence was predicted as 1 in 3,500. The majority of those children have idiopathic growth hormone deficiency with a smaller proportion being organic or congenital or acquired. The actual incidence in practice is not known, but it is definitely above 1 in 3,500 as that would represent about 20,000 children in the United States receiving treatment for growth hormone deficiency based upon recent census data, but we know that the numbers for that are much higher. We'll talk today about the range of secretion insufficiency that we see in growth hormone deficiency patients. And in clinical practice, this is a really important factor for deciding how a child is going to respond to treatment. And so it's well-established that we have a wide range of severity that there are variability in the responses to growth hormone therapy with those who are more severely deficient, responding better than partially deficient. And in the graphs on the right, the top 1 shows that the IGF-1, the change in growth based upon how low the IGF-1 is at the start is an important predictor. And on the bottom panel, we can see the growth hormone response to stimulation tests. Again, the more severely deficient child is, the higher their response to growth hormone therapy. And so this has been shown in numerous publications using daily growth hormone. In the response models developed by Michael Ranke, the growth hormone response to standard stimulation test has been the most important predictor of the first year growth response to growth hormone therapy. And if you add in the baseline IGF-1 that strengthens that model. And then again, recent publications showing that about 60% of total pediatric growth hormone deficiency is in that moderate category, showing that there's quite a few children that are treated for growth hormone deficiency that have moderate growth hormone deficiency. Now in my practice of 18 years at the University of Minnesota, I've only experienced the use of daily growth hormone. It's been available since 1985. It's FDA-approved for growth hormone deficiency and a number of non-growth hormone deficient conditions in both children and adults. And we have a lot of safety data. The pros of daily growth hormone are that we have more than 500,000 patient years of safety data. The adult height with treatment is near the mid-parental target height for children with growth hormone deficiency. The cons are that it is a daily injection, and it's an expensive medication. So those are 2 issues that we have with daily. When we think about daily growth hormone, I want to compare to what does the physiologic response of growth hormone in the body look like? So growth hormone is naturally cleared by glomerular filtration, receptor mediated uptake and probably also extracellular proteases. In the graph on the right, you can see that after an IV injection, there's a rapid decrease in the growth hormone in the blood with a half-life of somewhere between 14 and 19 minutes, which is slightly faster than what we see after endogenous pulses of 25 minutes. The circles -- the dark circles extending over the 24-hour period represent what an injection looks like after subcutaneous -- what clearance of growth hormone looks like after subcutaneous injection with a half-life of about 2 hours. In this next slide, we can see that the 24-hour serum profile of a child receiving a daily injection in the large parabolic curve on top, seeing a large peak followed by clearance of the medication. The growth hormone deficiency mean is actually the dark triangles or dark diamonds showing very few pulses and overall area under the curve is lower and somewhat growth hormone deficiency. And then you can see the pituitary secretion with normal pulses of a child. And the importance of this slide is to show that daily growth hormone injections that we currently provide patients are not physiologic. So the current challenges with daily growth hormone therapy primarily are related to adherence. And the famous quote that drugs don't work in patients who don't take them is quite relevant. And adherence has been a concern in children receiving daily growth hormone therapy. And in the bottom panel, we can see 3 different studies from around the world that talk about the noncompliance in growth hormone deficiency patients with about 10% missed, greater than 15 injections per month in the U.S. study. New Zealand, 66% missed more than 1 injection per week. And in Spain, the moderate-to-poor adherence category was present in 1/3 of patients. And in the bottom row, we can see that, that impaired adherence actually impairs the growth response to growth hormone therapy. And so I think it's important that as we think about daily growth hormone that is a daily injection that the need for that injection over time leads to poor adherence and poor health outcomes. And when I talked to patients in clinic, one of the first things that I get is this look from families, when they hear that growth hormone is only available as an injection. And I think that's when they're facing growth problems for their child and realizing that a treatment is available, the shock about an injection is one of the big things that's real for families. The administrative burden of daily growth hormone. This is a study by Dianne Kremidas from the MAGIC Foundation, looking at injection experience of patients, and it includes the patients and their parents showing that the majority of families have some sort of complaint related to the injections, whether it's bruising, stinging or pain. So because of the challenges with daily growth hormone therapy, there's been quite a bit of effort recently developing long-acting growth hormone therapies, which I'll review just briefly. And one of the questions that I have is, will long-acting growth hormone therapy actually be superior to daily growth hormone therapy. Currently, we have daily injections that are inconvenient, painful and distressing, leading to a lack of adherence that can result in reduced efficacy and increased health care costs. But long-acting growth hormone, if it is able to increase the overall treatment outcomes by improved adherence, superior serum IGF-1 levels and superior metabolic actions that we could actually see better outcomes because of improved adherence and compliance. And the non-physiologic profile with long-acting growth hormone may be beneficial because like daily, it is non-physiologic, but there could be some different side effects related to long-acting growth hormone, including prolonged levels of IGF-1 that are elevated compared to the natural state. I just want to briefly review the landscape for long-acting growth hormone. In this slide, we can see that there are 6 different molecules in different stages of development for treatment of children with growth hormone deficiency. Jintrolong in China has been approved and marketed for a number of years. Eutropin, similarly in Korea. And TransCon and Somatrogon have completed their Phase III trials and are awaiting FDA approval, sometime this year should expect to hear back from the FDA on their application. And Somapacitan has received FDA approval for treatment of adult growth hormone deficiency and is currently in Phase III trials for growth hormone deficiency in children. So I'd like to shift the discussion to growth hormone secretagogues and talk about where would that fit in the current treatment of children with growth hormone deficiency. So these secretagogues are molecules that stimulate the growth hormone releasing hormone, growth hormone or both. And so basically, they're trying to turn up the volume of production of growth hormone by the system naturally. And I already talked a little bit earlier about the spectrum of growth hormone deficiency and the importance of the pulsatility. So we can see on the left, the normal growth hormone release is the patient's own waves of pulsatile secretion with differences in the limited growth hormone release and very limited or no growth hormone release. So how does LUM-201 fit into this category? It works on receptors in the brain to stimulate the pulsatile production of natural growth hormone. So LUM-201 is a secretagogue that promotes growth hormone release by stimulating the growth hormone releasing -- growth hormone secretagogue receptor 1A. Growth hormone -- I'm sorry, LUM-201 is not an injection. It's actually in a pill form. It's a small molecule that stimulates that secretion, taken once-daily in small tablets that are easy to swallow. And in the right panel, we can see the size of the pills that are currently being used in the Phase II study compared to a baby aspirin. So how do we decide who's going to respond to LUM-201 is using the predictive enrichment markers. And so in the left, you can see moderate growth hormone deficiency in someone that's able to respond to the predictive enrichment marker by increasing their growth hormone production and increasing their IGF-1. But in the right panel, we see those who have a negative response to LUM-201 with severe growth hormone deficiency such that they are not able to secrete more growth hormone in response to secretagogue. How many patients is this going to represent? While the baseline characteristics based upon recent studies published in the Journal of the Endocrine Society show that children with severe growth hormone deficiency make up about 38% versus 60% in the moderate category, and their heights are more severely affected, and their responses in the first year of treatment are better. The moderate category, they still have an excellent response to growth hormone therapy and have less severe growth hormone -- or less severe growth impairment. Looking back at post-hoc analysis of initial studies using LUM-201, looking at the Merck Study 020, we can see that children that receive LUM-201 at different doses compared to placebo, grew in a dose responsive manner. When we looked at all subjects on the left, and then we separate the PEM negative in the PEM positive group, we can see that the PEM negative group did not respond to LUM-201 in a dose responsive manner, but in the PEM positive group, they did. The doses were 0.4 and 0.8. And the 0.8 group was the closest to the daily growth hormone group, though it was statistically lower. It was not -- I'm sorry, it was lower, but it was not statistically lower. And then if we look at the dose response of the PK/PD for LUM-201, we can see that 0.8 is actually not the highest dose that is likely to -- that a child is likely to respond to. And so in this pharmacokinetic profile, we can see the different doses on the left. The 0.8 that was used in that study is represented most closely by the light blue line with the darker lines above it, showing that we can expect to see a better dose response with higher doses. In the panel on the right, the plateau is possible, but it ends up being at a very high dose of LUM-201 that where you actually see a plateau in the response 201 in terms of pharmacokinetic and pharmacodynamic responses. But importantly, the question is, if you are giving them 201 over time, will there actually be a diminished response or a tachyphylaxis? And in adults that were studied with LUM-201 over a prolonged period of time, we can see in the slides, both with 24-hour growth hormone levels on the left and the IGF-1 levels on the right, that there is a sustained response at 12 months to LUM-201's treatment. So this is the rationale for the current clinical trial that I am an investigator in, where 80 children are going to be randomized to 4 different groups after they have been selected by predictive enrichment markers, a growth hormone stimulation test to show that they have growth hormone deficiency. And then treatment-naive patients will be randomized to 3 different doses of LUM-201, 0.8, which was the lowest dose in the previous studies and then 1.6 and 3.2 milligrams per kilogram per day compared to an arm of daily growth hormone injection in children. The objectives are to prospectively confirm the utility of the PEM management strategy -- PEM strategy, confirm the reproducibility of the PEM classification and determine the optimal dose for Phase III as well as showing annualized height velocity outcomes in this 6-month trial. So to summarize, I think that LUM-201 stimulates pulsatile secretion of endogenous growth hormone and has the potential to improve growth in the majority of children with growth hormone deficiency, but also a number of nongrowth hormone deficiency growth disorders. The use of the predictive enrichment marker should identify those children that are able to respond to LUM-201. And due to the presence of intact feedback systems in children able to respond to LUM-201, it is unlikely that elevated levels of IGF-1 will occur during LUM-201 therapy. And I think that due to the pain of injections in oral medication for the treatment of growth hormone deficiency and nongrowth hormone deficient growth disorders is a welcome alternative to injectable growth hormone therapy. And now I would like to turn it over to Professor Cassorla to talk about pulsatile secretion of LUM -- related to LUM-201.

Thank you, Brad. We will move on now to my presentation, and I work at the University of Chile in South America. And I've been involved with studies of this sort for many, many years, and -- I hope you can see my first slide.

We can see.

There we are. So the title of my talk is effects of the oral growth hormone secretagogue LUM-201 on pulsatile secretion and linear growth in children with moderate growth hormone deficiency. These are my disclosures. I hope you can see them because I somehow cannot see them.

We can see your next slide, Fernando.

Clinical studies at the University of Chile, and I have previously acted as consultant for several drug companies. The rest of the disclosures are right there. Next slide, please. Got to have the next slide there. So we published this paper many years ago, previous slide, please. We published this paper several years ago, looking at the effects of this particular drug on the growth hormone-insulin-like growth factor I, in growth hormone-deficient children. This is kind of a proof-of-concept study, trying to demonstrate whether this drug could stimulate growth hormone IGF in growth hormone deficient children. We studied 18 prepubertal most of them in South America, as you can see from the authors, of which 4 of us are authors in this particular paper, including our nurse, Alejandra Avila, who is a key member of our team. And these patients were randomized to either 0.2 milligrams per kilo of this particular drug, 0.8 milligrams per kilo for 8 days. And on the day 15 of this particular study, they got the final dose of the oral secretagogue. Now on this next slide, you can see that actually, the changes in peak growth hormone response to placebo on the open circles and to the drug at 0.8 milligrams per kilo on the black diamonds. You can see that there is a group, these are 18 children, 9 of them on the left, 9 of them on the right, and they're divided and classified based upon their baseline IGF-1 levels. Either equal or below 15 milligrams per ml, or above about 15 milligrams per ml. And you can see that on the panel on the right, many of the patients actually had a response in the peak growth hormone to 0.8 milligrams even though originally they had relatively low dose as in respond to placebo as expected, indicating that your base of an IGF-1 level had a lot to do with your potential response to this particular drug, reemphasizing the point that Brad just made, that those patients with severe growth hormone deficiency are unlikely to respond to the drug, whereas those patients who have moderate growth hormone deficiency are more likely to respond with peak growth hormone levels that are actually some of them quite high, going up to 40 or 50 nanograms per ml. Next slide, please. Now as indicated before, the actual mode of action of this drug has to do with that it is an oral growth hormone secretagogue that acts on the receptor that is both localized in the hypothalamus and the pituitary. And you can see that the drug will stimulate the production of growth hormone, which in turn, will go to the liver and other tissues to produce IGF-1, which, in turn, will stimulate linear growth. So this is a cascade of events that in this particular case is stimulated by this oral secretagogue. Now when we started the studies, we didn't know what was the endogenous ligand for this orphan receptor. And then we learned that the stomach produces ghrelin, and these are the native ligand for this receptor that stimulates both growth hormone release and also increases appetite. So in the old days, when we did these studies, we didn't know that the ligand came from the stomach. We did observe that some patients had an increased appetite during the administration of this drug. And then we learned that actually the endogenous ligand was, as I say, ghrelin, and this is a hormone that comes out from the stomach. Next slide, please. You can see that then with this background, we ask the following questions. Does LUM-201 augment endogenous growth hormone pulses in patients with moderate growth hormone deficiency? Will increase growth hormone pulses improve height velocity? And three, can these responses be predicted from the baseline testing? Next slide, please. Now we then observed that there is this predictive enrichment markers for patients with functional but reduced growth hormone secretion already explained by Brad, in which you can see on the left, patients with moderate growth hormone deficiency that have a functional, but reduced pituitary axis, in which this drug, LUM-201 can stimulate this receptor to produce growth hormone and IGF. Therefore, these patients are able to secrete some, but insufficient growth hormone. They are expected to respond to LUM-201, and they represent over 60% of the patients. While on the right, you can see that patients with severe growth hormone deficiency should tend to be excluded from these trials because this drug, even though it would stimulate the receptor, both at the hypothalamus and the pituitary, it will be enabled to secrete growth hormone response to the secretagogue. They would have a nonfunctional pituitary axis. They would be unable to secrete growth hormone. They would be not expected to respond to LUM-201, and they would represent a smaller fraction of all patients with growth hormone deficiency. Therefore, we believe that predictive enrichment markers demonstrate that the growth hormone response to a single LUM-201 dose and baseline IGF levels have the potential to distinguish these populations among the ones, who will respond, on the left, and the ones who will not respond, on the right. Next slide, please. Now following this initial proof-of-concept study, we embarked on a much larger multinational study with approximately 70 patients that received this drug during a much longer period of time, and that was 6 months. The original study was only 8 days, and we also increased the dose from 0.2 up to 0.8 milligrams in some of these patients, even though others received 0.4. So these approximately 70 patients were divided and randomly assigned to receive either placebo, 0.4 or 0.8 milligrams per kilo per day during 6 months. And you can now see here an example of 3 patients in which we performed the Q20-minute sampling for growth hormone secretion to look at pulsatility over these 6 months from baseline, to the 6 months finish of the study. And these 3 patients shown on this particular slide indicate that the 3 are males. They're all relatively young and prepubertal. Their height velocity is quite low, below 4 centimeters per year, that's actually pretty poor for a child of this age. The standard growth hormone stimulation tests were different in the sense that patient A went up to 8.3, but patients B and C only went up to 1.3 and 1.9, respectively. And as peak growth hormone response to a single LUM-201 dose, this predictive enrichment marker kind of indication was very different, too. Patient A went up to 102 nanograms per ml, where patient B only to 5 and patient C only 1 to 1.9. Under IGF-1 levels, these are baseline IFG-1 levels were also quite different. Patient A had a reasonable IGF-1 level. Patient B had a relatively low IGF-1 level and patient C had a very low IGF-1 level. So the idea here was to try to find out whether there were changes in height velocity in these patients during the 6 months of treatment with this drug at the dose of 0.8 milligrams per kilo per day. Next slide, please. You can see in patient A, shown in this slide, that the baseline pulsatility study indicates that there's a number of peaks in this patient. Let me indicate that here, the scale goes up to 30 nanograms per ml. The scales are going to be different for patient B and C, much lower. So this patient has a relatively healthy number of peaks before they received the drug. And after, next slide, they received the drug for 6 months. You can see that there's a change in the serum IGF-1 level that goes up from 182 to 231, and the mean growth hormone level from 3.4 up to 6.3. The area under the curve from 75 up to 137. And the height velocity, very importantly, goes up to 7.9, doubling -- more than doubling actually the height velocity that the patient had initially. And in addition to this, you can see in the blue lines that actually the secretion of growth hormone over 24 hours increases quite a bit compared to the baseline pulsatility study in gray compared to the post therapy pulsatility in blue. So this patient, A, demonstrates that there's a period of 6 months, you can see a change, both in the production of growth hormone and in height velocity in a patient that had a relatively hefty response to the initial dose of p.m. of LUM-201. Next slide, you can go on to patient B, and patient B actually is a little different. Patient B has a lower serum IGF-1 one level of 53, a mean growth hormone level over 24 hours of 1. The area under curve is 17, and the height velocity is also low at 3.5. Here, you can see that the scale has changed, it goes up only up to 3. And there's relatively small number of peaks, but there are some peaks in this patient that after 6 months of therapy with LUM-201 at 0.8 milligrams per kilo day. Next slide, you can see that there's a change, significant change in the secretion of growth hormone following the 6 months of therapy, and the patient actually has more peaks, and they are much greater amplitude than what they were at baseline. And again, the serum IGF-1 level increases up to 72. The mean growth hormone rose from 1 up to 1.3. The area under curve goes up from 17 up to 25, and the height velocity in this case almost triples with this 6 months administration of LUM-201. The interesting thing to note is that you can see peaks here in growth hormone, following almost 18 to 19 hours after the administration of the drug, indicating that this drug can restore pulsatility many hours following the administration of the drug, not only after -- a couple of hours after the administration of the drug, but in this case going up to 18 or even 20 hours after the drug was given. The third patient, patient C, is an example of a patient that is not responsive to this drug. Next slide, please. And you can see that this patient has a lower production of growth hormone. Here, the scale goes down even further. Now going up to 1.2 nanograms per ml, relatively few peaks, but they are of very diminished amplitude. This patient has a very low serum IGF-1 level, low mean growth hormone level over 24 hours, the area under curve is much lower than the other 2 patients and the height velocity is extremely low, only 1.1 centimeters per year. Next slide shows what happens after 6 months of therapy in this patient, in which you can see that actually, there's no change in the pulsatility or the amplitude of the peaks to this drug following 6 months of administration, indicating that serum IGF-1 level did not change. The mean growth hormone level again didn't change. The area under the curve, again, did not change, and the height velocity did not change significantly, indicating that patient C has an axis and is not responsive to LUM-201, and therefore, we could anticipate that this patient, based upon the very severe growth hormone deficiency that he has, he was unlikely to be a good candidate for the study. Next slide, please. Therefore, we can show in the next slide that the status of the hypothalamic pituitary axis has a lot to do to whether a patient is responsive or not responsive to this drug. In the patients who are responsive, the LUM-201 will stimulate the hypothalamus and the pituitary. There will be an increase in growth hormone production and increase in IGF-1 levels, and the patients will grow a little better. The patient C, who is not responsive, has a poor response to LUM-201, did not increase growth hormone levels in response to the LUM-201 stimulation, indicating that this patient had an axis that is not responsive. Next slide, please. Therefore, we conclude -- next slide, please, that LUM-201 can stimulate pituitary growth hormone secretion and improve height velocity in children with moderate growth hormone deficiency, previous slide please, previous. Previous slide please. And improved height velocity in children with lower hormone growth deficiency. In patients A and B, the baseline IGF-1 level was over 30 nanograms per ml and the peak growth hormone response to a single LUM-201 dose was greater than 5 nanograms per ml, 24-hour growth hormone was augmented, less than twofold, but height velocity was improved. In patient C, the baseline IGF-1 level was low, below 30 nanograms per ml, the big growth hormone to a single LUM-201 dose was less than 5 nanograms per ml, growth hormone, 24-hour growth hormone there was not augmented and height velocity did not improve, indicating that in some patients, but we think that in most patients, this drug will have an effect, whereas in those patients who have very severe pituitary dysfunction, it's unlikely to have any significant effect. Next slide, please. So we believe that further studies on LUM-201 in pediatric patients with moderate growth hormone deficiency are required in order to confirm that. LUM-201 increases endogenous growth hormone pulsatility, augmented growth hormone pulsatility improves height velocity and augmentation of growth hormone pulsatility and improvement of height velocity by LUM-201 treatment can be predicted from baseline IGF-1 levels and peak growth hormone response to a single dose of LUM-201. Next slide, please. Therefore, we are embarking in a study at the University of Chile that will enroll 24 prepubertal patients between the ages of 4 to 8 years for girls and 10 years for boys with short stature caused by moderate growth hormone deficiency and naive to growth hormone treatment, will be assigned randomly to receive oral LUM-201 at a dose of 1.6 milligram per kilo per day to all patients or 3.2 milligrams per kilo per day to all patients for 6 months. 1.6 is twice the dose that we used in some of the previous studies, and 3.2 is 4x the dose that we used in some of the previous studies. Pulsatile growth hormone secretion will be assessed in blood samples obtained every 10 minutes during 12 hours, 8:00 a.m. to 8:00 p.m. at the beginning and at the end of the study, and height velocity during the 6 months of LUM-201 administration will be compared with the baseline period prior to intervention. Next slide, please. This is a cartoon showing how the study will take place. We show here, on the top panel, that the patients who will receive the drug at a dose of 1.6 dose -- 1.6 milligram per kilo per day will have a screening study that is under -- patients are undergoing the screening study even as we speak. They will have their baseline height, IGF and more importantly, Q10 minutes sampling for 12 hours to measure growth hormone peaks. And this will happen again at 6 months, after 6 months of therapy, in which we look again at height to see whether there was a change in height velocity, serum IGF-1 levels, and again, the pulsatile pattern with measurements every 10 minutes for 12 hours. And the same thing will be true for the 12 patients, who will receive the 3.2 milligram per kilo per day dose, in which we will go exactly through the same protocol, a screening study, a baseline assessment with the Q10 minute sampling over 12 hours and a 6 months assessment with, again, height, IGF and Q10 minutes sampling over 12 hours, trying to relate the changes in height velocity to potential changes in pulsatility during this period, indicating that the drug does increase growth hormone pulsatility, we believe, during treatment. What are the expected results? Next slide. We will document any increase in the height velocity of these prepubertal patients with moderate growth hormone deficiency treated with LUM-201, which may be dependent on the dose employed. Second, the improved height velocity during LUM-201 administration will be correlated with an increase in growth hormone pulsatility after 6 months of therapy with this drug. And third, the increase in growth hormone pulsatility and improvement in height velocity induced by LUM-201 can be predicted by the baseline serum IGF-1 concentrations and the peak growth hormone response to a single dose of LUM-201. Next slide, I would like to finish by showing a picture of our group at the University of Chile. We've been working in this area for many years. And in our group, we've got both clinicians and basic scientists that were involved in the original study published several years ago with this drug in clinical pharmacology, therapeutics and who are involved in this particular study, again. Thank you for your attention, and I will pass this back to Rick for the question-and-answer session.

Thank you, Fernando. Thank you, Brad. I think we're open for questions and query. You want to take over.

[Operator Instructions] And then I'll turn it over Corey David of LifeSci Advisors to moderate the Q&A.

I will go right now because we've already got a number of questions in the queue here. So thanks for sending them in and keep them coming. The first question is going to be from Chaz Duncan at Cantor, a couple of questions, but let's start with this one. Is there anything about the patient phenotype that you've seen in some of these earlier studies that would make you less confident in the predictive value of this particular sample to the broader population?

I can answer that. There is a clear phenotype for the patients who have severe growth hormone deficiency and that they are very short, sometimes minus 3 standard deviation scores. And with a very delayed bone age, with a poor height velocity. Patients who are growing extremely slowly, who are very short, who have a delayed bone age, even clinically are most likely not to be the candidates for this particular drug. I think this will appeal to the vast majority of patients, who are not that short, who are patients who come to the clinics because their parents are maybe short, and they went through some difficult times when they were young. And some of these patients are, let's say, minus 2, minus 2.2, standard deviation score. And this is the largest segment of patients that we see in our clinics. So we believe that the phenotype will certainly help you, even before you measure an IGF-1 level, or you do a growth hormone provocative test. If the patient is extremely short, and isn't growing almost at all, it's very likely that patient has severe growth hormone deficiency, and if that's the case that's the cause for the short structure. And in that particular case, the patient will not respond adequately to this drug. But as I said before, the vast majority of patients who come to our clinics and Brad will, I'm sure, agree with this, are patients who are not that short. We see a number of patients who are close to 2 standard deviations below the mean. And these are the patients who are looking for kind -- some kind of therapy. Some of them end up with vitamins or things of some other sort. If they fail a growth hormone provocative test, they may be treated with growth hormone. But these are the vast majority of patients, so phenotype will certainly help.

I just want to echo that from Professor Cassorla. In Minnesota, everybody's above average, including height. And so we see a lot of children before they fall off the curve. They're having significant growth failure, but they're not yet below minus 2 standard deviations. And I think there is a clinical phenotype that you can see the children that have growth hormone deficiency clinically and pick them out. In that gray zone of children that we call pediatric partial growth hormone deficiency, it's a spectrum between their and idiopathic short stature that I think people don't really have a good sense of where should we exactly divide that line based upon provocative testing. And I think the predictive enrichment marker will show that some of those children will respond to treatment with a secretagogue, just like they would respond to treatment with daily growth hormone or other growth hormone products. So I think it's that phenotype with the predictive enrichment marker, I think is helpful to say, can this child respond to treatment or not? Not everybody responds to daily growth hormone either. There are some children that are resistant to a growth hormone where this is not going to help them. So -- but that fraction is very, very small.

So a second question from Charles Duncan. There are a couple of them like this, but it gets to the pulsatile mechanism of action and the possibility of efficacy and/or safety advantages over the current standard of care? Is there evidence to suggest that it may be better in terms of efficacy or safety?

We do a reasonably poor job by treating patients with growth hormone and that we don't mimic at all the pulsatile secretion of growth hormone that occurs in normally growing children. We give them a 1 per day dose, soon to be 1 per week dose in which we essentially have very high levels of growth home for some time. They're not pulsatile, and they go down slowly over several hours. So in essence, we are not restoring at all pulsatility for growth hormone during growth hormone treatment. All we do is essentially give a huge amount of growth hormone that circulates in the body at a relatively constant rate, and there's a decay over several hours, but there's -- we do not restore pulsatility at all. So there would be some reason to think that restoring pulsatility, something that is physiological and helpful for children, that's why growth hormone secreted in pulsatile fashion will occur with this drug much more so than what it will occur with growth hormone in which essentially we do not restore pulsatility at all.

And I'll follow-up on that. I think there -- when we look at the growth response, the pulsatility doesn't seem to have as much import related to that in that. Your growth hormone levels, your IGF-1 levels ultimately dictate your growth. I think the biggest impact of the pulsatility is likely to be on the metabolic body composition components of growth hormone, which as Professor Cassorla said, we're not mimicking with our current therapy. Interestingly, in the adult literature, we do see some improvement in metabolic outcomes with adult growth hormone deficiency replacement therapy with both daily and recently, the once-weekly studies. But I still think that pulsatility is missing in those and has the potential to improve both efficacy and safety. On the safety side, there's an ongoing theoretical discussion about IGF-1 levels and what will happen when they're elevated. In the daily growth hormone group, we are targeting an IGF-1 level based upon our dosing to some degree. People are measuring it either as a safety outcome or an efficacy outcome, and trying to target an IGF-1 in the normal range. With the secretagogues, I think that you're going to see some feedback, intact feedback of IGF-1 feeding back to the brain, saying, we have enough growth hormone, I don't need more now. And so that intact feedback mechanism, I think, will limit the excursions of IGF-1 in response to therapy. I think that needs to be shown in the clinical trial, so we need to confirm that. But in the long-acting growth hormones, we know that we are accepting a period of time of super-physiologic IGF-1 levels, followed by return to baseline with the different once-weekly products. And so there is a parabolic curve of a peak IGF-1 and average IGF-1 and a trough IGF-1. There hasn't been any safety adverse events connected with those high IGF-1 levels, but theoretically, there's still a concern that those higher IGF-1 levels could be connected with long-term safety outcomes. So I think theoretically, the LUM-201 provides that benefit of not seeing those wide excursions of IGF-1.

Next question comes from Yasmeen Rahimi from Piper. And there's a 3-part question. I'm going to ask the first 2, first, and let you answer that, sticking with the pulsatility theme. How does the growth hormone pulsatility change over time as the kids grow? And the second part, is there a difference in the pulsatility pattern between males and females?

We have published paper several years ago when I was at the NIH, in which we studied a large number of normal children, remember, the NIH has a normal volunteer program in which, through this office, children who belong to churches or schools can apply to participate in studies of the sort. The first author of that study is Susan Rose. It's published in JCEM, Journal of Clinical Endocrinological and Metabolism. And we looked at children between the ages of 5 years and 18 years at a different stages of puberty. And measuring growth hormone pulsatility with samples every 20 minutes for 24 hours. And we saw that there's an increase in the secretion of growth hormone slowly during late childhood and certainly during puberty that becomes more pronounced when children reach their peak height velocity for boys at about titer 4, for girls about titer 3. That is to say that growth hormone secretion and pulsatility in normal children increases slowly during childhood and more pronounced during puberty, mimicking, to a certain extent, to what happens with height velocity in these normal children. And I might add, the interesting thing is that even in the prepubertal girls, growth at the age of 8 or 9 with no predevelopment, there was already an increase in the pulsatility of growth hormone before puberty actually started, indicating that these changes in growth hormone secretion are quite kind of exquisite in the sense that they change over time in physiological terms, even before puberty starts, and they certainly go up much more during the time of puberty. So certainly, there are differences between boys and girls. Girls tend to have the increase in growth hormone pulsatility before boys, just like they do with their height with a peak growth velocity. The growth in spurt in girls occurs a little earlier in puberty than what it occurs in girls -- in boys. So there is an association between the 2.

Dr. Miller, anything to add?

I leave it to the professor.

Excellent. The third part of Yasmeen's question is asking you to comment on the applicability of these predictive enrichment markers in the real world. Do you routinely place your patients into each of these buckets moderate to severe while you're treating them? Or is this largely a function of a clinical trial setting that may not be directly applicable to everyday practice?

Brad, do you want to?

I'm happy to. So I think this is a new paradigm in terms of being able to say this child is going to respond to this particular therapy. We're already doing that to some degree with the growth hormone stimulation tests that we are using. So it's not that different from what we're currently using. But we haven't had a situation in the past where we give a medicine and then see how are they going to respond to exactly that medicine. We use it to a small degree in children when we're concerned about growth hormone resistance. So the IGF-1 generation test of giving growth hormone for several days in a row and seeing how much IGF-1 you're able to generate is a similar thought process if you can make enough IGF-1 in response, then, yes, you are likely to be a responder to therapy. But currently, our separation of children is based upon the growth hormone stimulation test, which has similar philosophy or similar science behind it, but not exactly the same.

Let me just add that when we see these children, the likelihood that they will enter a form of therapy that is injectable that will last many years is a major issue. And therefore, we don't take this lightly. We don't kind of perform just a serum IGF-1 level and a bone age and then prescribe the drug. We go through some studies like the growth hormone stimulation tests. And after we have all of this information together, we make a decision as to whether the patient should or should not be treated with, in this case, growth hormone. The predicted enrichment markers for this are not really all that different. In the real world, we would measure serum IGF-1 level, basically on these patients, who are not growing well, not very invasive, not expensive, and certainly done all the time. And the only thing that would be different would be the response to the actual drug, the kind of acute response to LUM-201 in which we would expect these patients and ones who are a good candidate, so the drug to respond to this acute administration of the drug. So I do not think that this represents a major departure from clinical practice, baseline IGF-1 levels are measured all the time. Performing acute LUM-201 study doesn't seem, in my view, to be all that invasive in order to decide whether the patient should or should not receive this drug. So in sum, I do not think that this represents a radical departure from what's typical medical practice in children who are candidates for growth hormone treatment.

And John McKew, do you want to add anything to that?

I agree with Fernando completely.

Okay. One more question on pulsatility. I'm asking you to comment on this observation, and if you agree with this observation which is, it appears that these data showing a modest increase in the growth hormone induced in a pulsatile manner are able to increase the height velocity while maintaining normal physiological levels of growth hormone and IGF-1. So do you agree with that statement and the effect of 201? And any other comments on that observation?