Crinetics Pharmaceuticals, Inc. (CRNX) Earnings Call Transcript & Summary

Good morning, and welcome to the Crinetics call on oral paltusotine for the treatment of acromegaly. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the Crinetics website following the event. I'd now like to turn the call over to your host, Scott Struthers, Chief Executive Officer of Crinetics. Please go ahead, sir.

Thank you, and good morning, everybody. Thank you for joining us. Looking forward today for an interesting conversation on acromegaly and the role of paltusotine in the future treatment of the disease. If we could go through the next slide. I'd just like to refer everybody to our -- we will be making forward-looking statements, and you can see that in our safe harbor statement or on our website or SEC filings. Next slide, please. Just briefly, I'll introduce for those of you who don't know us well already, a couple of things about Crinetics. We're based in San Diego. We're at about 85 employees. And our strategy is a fairly simple one. We think that there are a lot of endocrine patients who need much better treatment options, and we're dedicated to creating those treatment options in our discovery labs, developing them and getting them out to patients around the world. We could go to the next slide, Peter. We've been quite successful so far in growing our pipeline organically. Today, we'll focus on paltusotine, which is our phase -- almost Phase III compound for treatment of acromegaly. But we'll soon also be starting the clinical program in neuroendocrine tumors. And today's panelists, while we focus on acromegaly, both also have experience in treating patients with neuroendocrine tumors. Beyond that, we're starting the clinical program for an oral ACTH antagonist, which is super exciting in the field of endocrinology. And also CRN777 (sic) [ CRN04777 ] for the treatment of congenital hyperinsulinism, and both of these start Phase I studies with meaningful pharmacology readouts in the next couple of months. I'd like to remind everybody that all these molecules were created in-house by our discovery lab, and they're actively involved in figuring out the next set of molecules to come in and join our pipeline. Go to the next slide, Peter. So briefly on paltusotine. It is a nonpeptide drug. It is not a peptide. It is like many other small molecule drugs that one would take for hypertension or hyperlipidemias or things like that. And because it's a small molecule, it's able to easily diffuse through membranes, and this results in high oral bioavailability in the case of paltusotine on the order of 70%. And we also engineered in a long half-life of about 2 days, which means it's consistent with once-a-day dosing. We take great pride in the drug discovery and engineering of these molecules. Actually, I think it's more of a craftsmanship. If you go to the next slide, please. This is what we were trying to do when we set out to make paltusotine because it's a nonpeptide, it's stable at ambient temperatures and has a simple supply chain, relatively low cost of goods. Because it's highly potent at the sst2 receptor and it's highly selective, it's potent for GH and IGF-I suppression at low doses and without the risk of hyperglycemia. The high bioavailability -- oral bioavailability means it can be administered at home without these painful injections that we'll hear about in a few moments and also at a relatively low dose. And the long half-life, it means that you have -- you can have it once daily, but it also gives consistent exposure throughout the month with forgiveness of a missed dose. And finally, we tried to make this molecule, so that it had very few, if any, drug-drug interactions, none of we know of at this point, which makes it much easier for physicians and pharmacists to prescribe and distribute. And we don't have any strange excipients that might alter the absorption of other drugs. We'll go to the next slide. So today, I don't want to talk very much today. I think you want to hear from people who've treated hundreds of acromegaly patients each, Cushing's patients and even some neuroendocrine tumor patients. We're very, very pleased to have today Peter Trainer and Monica Gadelha. Both are international experts in the pituitary and in endocrinology in general. They're part of the leadership of this field. Peter up until very recently has been the Clinical Director at Manchester Academic Health Sciences Center, a Professor at Manchester and also the Director and Clinical Lead for Endocrinology at the Christie. But recently, he's decided to join Crinetics as a true Crinetizen as we refer to ourselves and our first staff member on the east side of the Atlantic. So very happy to have Peter join the team working with Alan to advance our endocrinology programs. And we also have today, Monica Gadelha, who is a Professor of Endocrinology in Rio de Janeiro, and also leads the endocrine -- Neuroendocrine Research Center at the Hospital Universitário Clementino Fraga Filho. Apologies for my butchered Portuguese. But she's the lead investigator on the ACROBAT program. She's also President-elect of the Pituitary Society, which is a society for those of us interested in pituitary diseases. She has more experience with paltusotine and acromegaly patients than anybody else here. And I'm sure you'll be interested in hearing her impressions. So with that, I'd like to turn it over to Peter, who's going to talk about the background of acromegaly and the measurement of IGF. And then Monica will come in and talk about the current treatment options and her experiences with paltusotine. Thank you. And Peter, I'll turn it over to you.

Thank you very much, Scott. I thought what I would do is just make a few comments about my background and what's made me move to join Crinetics in the last week. So I was practicing endocrinologist for the last 37 years, last 22 in Manchester in the U.K. as the clinical lead. Christie is the busiest single center -- cancer center in Europe, and that meant that we were seeing 150 new neuroendocrine tumors per year, was looking after approximately 200 patients with acromegaly and a plethora of other endocrine hormone-secreting tumors. In parallel with that, I did research. The most rewarding research for me was always while I was engaged with the discovery scientists. And that led to me become a Director of Academic Health Science System, which is an amalgam of the university, the local, small biotech companies and the major health care deliverers in trying to accelerate that time between the bench and bedside, trying in my role to take discovery through development and then deployment. And the attraction for me at Crinetics is they're a discovery company. And I can -- I enjoy engaging with the basic scientists and want to help driving development and deployment. And they didn't ask me to be a square peg to fit into a square hole but actually have given me a terribly interesting challenging unit, and I just want to start off then by describing acromegaly, a condition I've been looking after for many years. Its name reflects the fact that it's recognized by the -- it's the appearance it causes, large extremities, great extremities, great height. So this is the condition, its phenotype, is how it's diagnosed. Legend is full of acromegalic giants, so he can develop tumor before puberty is finished and your bones are still growing, you'll get precociously tall. History is full of legends of giants. Literaturist, Hilary Mantel's recent novel on The Giant, O'Brien describes the life of one Irish-born giant who made name for himself while living in Ireland. And most famous is Goliath. In some ways, taller size is the problem. Goliath was a giant. He had a pituitary tumor, tumors in the pituitary, squashed eyelids, you lose your peripheral vision. So he never saw David's stone coming and hitting on the temple. His healthy pituitary being damaged, so he was caught with all the fishes and more prone to get unwell and that was his downfall. This is another picture, which tells us something about societal prejudice. These are 2 identical twins and the question is, which one was taken to the doctor by their mother. And the answer was the healthy boy of normal stature, who was -- his mother's consent that he wasn't growing as well as his brother. The truth, of course, was that brother had a pituitary tumor causing accelerated growth, which may have pleased the parents initially but in the longer term comes with a price. The majority of patients, who develop growth hormone-secreting tumors in the pituitary, do so after their bones are fused, after they've stopped growing, after puberty, the typical age of presentation is in the 40s. And the features there are rather different. So normal height, but thick and soft tissues, so you get frontal bossing, you get changes in the jaw, grease in skin, changes in shoe size and the diagnosis is often delayed because of the insidious nature of onset. And here is a slide that illustrates that one. This is a rare disease. There are 3 to 4 new cases per 1 million of the population per year. So a prevalence of 60-7 (sic) [ 60-70 ]. It's one of the few endocrine diseases, which is equally balanced between men and women. And as I said already, the average age of diagnosis is in 40s. Most primary care physicians will only ever meet, at the most, one patient with acromegaly during their entire career. So when patients have rather nonspecific symptoms such as fatigue, sweating, headaches, it doesn't necessarily ring any bells. The diagnosis is often delayed until the penny drops in summer. So here's an illustration of a young man, here he's a boy. He joined the Navy. And at 27 years of age his acromegaly was diagnosed. So you can see the gradual change in his facial appearance. And one -- it's opened speculation, when did he develop the disease? Well, as I said, not during puberty because he wasn't tall, probably somewhere around 20, 21 years of age. So he has 6 or 7 years of active disease before the diagnosis was made and that would have caused some irreversible damage, particularly to his joints. So the earlier we can diagnose the better. And this just again illustrates that the pathophysiology behind the disease and the changes in appearance of phenotype. So you're looking here at slides through, on scan, here is the tongue to oriented people, there is the tongue. There's the spinal cord. And you can see here illustrating in the red, the base circle, the pituitary tumor. The eyelash, they're somewhat scorched at the top of this tumor. And you can see the white here which is the contrast in the carotid artery. So this tumor is a butt in the carotid arteries, which is something the surgeon has to recognize and avoid going near the carotid arteries. The tumor secretes growth hormone, so it's both the active hormone and, in a sense, the tumor marker. And I illustrated the liver because growth hormone acts on growth hormone receptors. They are widely spread across most cell types, but most circulating IGF-I. Endocrine IGF-I is generally found in the liver. And that IGF-I is responsible for the phenotypic changes. So you can see macroglossia, the large tongue, obstructs the airways. It causes dental problems. Overgrowth of the lower jaw causes prognathism, dental malocclusions. One can get the soft tissue thickening. This happens in the feet. So you get not longer feet, but broader feet. The male often notice their collar size is changed. Wrist watches become too tight or rings have to be cut off the fingers. If it occurs in the younger age, it causes gigantism. And this is a patient that I looked after who was 7-foot 6 in height before the diagnosis is made. Moving on, what are the long-term consequences of acromegaly. It reduces life expectancy. It reduces life expectancy because patients are more prone to cerebrovascular events. They're more prone to cardiac problems, particularly dysrhythmias and cardiomyopathy. The soft tissue swelling of the tongue, the airways -- the upper airways causes sleep apnea, which is a major cause of morbidity. And there's also evidence that patients are more prone to get serious respiratory infection. The risk of colon cancer is increased in patients with acromegaly, and we know that they suffer from more fractures. Growth hormone is in some ways are badly named hormone because it does much more than encourage linear growth. It's a growth -- it's an instant antagonist, so higher growth hormone levels, the more insulin resistant you are, the more prone to diabetes. And the thing that dominates many of our older patients' lives is they get premature arthritis, particularly of the spine because they damage their joints when the disease is active. And even when we have apparently cured them, they can still run into problems with arthritis. Growth hormone is the hormone produced by the pituitary. 191 amino acids, 22 kilodaltons is produced unsurprisingly at greatest quantities during puberty when people are growing fast. But growth, adults still need growth hormone, it's still significant during adulthood, the levels fall with increasing age. You can see on the left-hand side here, a profile of growth hormone secretion in a normal individual. So normal adult will have 5 to 6 pulses of growth hormone. And in between times, growth hormone levels grow essentially down to undetectable levels. And as all children are told by their parents, "Go to bed, get a good night sleep if you want to grow up to be tall." Most growth hormone secretion occurs at night, and that's because that's when you fast, you have less insulin. When your insulin is low, your growth hormone is high. And vice versa, after a meal, insulin levels are high, growth hormone levels are low. If you look at the acromegalic profile here over 24 hours, the levels aren't necessarily peaking and is higher in the healthy volunteer. The peaks maybe the same, the difference is the lack of troughs. The growth hormone levels never descend to be undetected because it's perpetually being produced by the tumor. So when you're coming to diagnose acromegaly, a single random high-growth hormone is of a little diagnostic value. A low value, undetectably low, is good at and it's against acromegaly. But I'll come on to how we actually diagnose the condition in a moment. Growth hormone drives to the growth hormone receptor, the generation of IGF-I, insulin-like growth factor-1. So named because it's structurally similar to insulin and has a hypoglycemic effect. It's a smaller molecule, 70 amino acids, molecular weight 7.6 kilodalton. Growth hormone receptors expressed on virtually all cells, that all cells are making IGF-I, either autocrine working within the same cell, paracrine working within neighboring cells or in case of the liver-generated IGF-I, an endocrine action where it circulates, and that accounts about -- the liver accounts about 70% of what we measure in the blood. Its virtue in terms of clinical practice is a single measure of IGF-I gives you an overview, a measure of integrated growth hormone secretion. So it overcomes those problems of pulsatility and having to -- difference between day and night, circadian rhythms. But like growth hormone, there's an age-related decline in the secretion. When it comes to diagnosis there, as I said earlier, the big problem is that -- is someone thinking of the diagnosis. So the ones that's been thought of, it's easy usually -- easily it's confirmed biochemical. And it's one of those diseases where all doctors get a sense of satisfaction when they suddenly recognize the diagnosis, but are often embarrassed how long it took me to make it. It's not long ago since some orthopedic surgeon wrote me to say, he was just admiring a patient's risk where he operated on carpal tunnel syndrome in both hands. And I looked up at the patient to complement himself and how well he done it and looked at the patient and realized the reason she had carpal tunnel was acromegaly. And once the penny dropped, we were able to do a glucose tolerance test and in a normal individual growth hormone falls to undetectable levels after that exposure to glucose. In subject with acromegaly, it fails to suppress. And they will, at the same time, have an elevated IGF-I level. And by elevated, I mean that was above the upper limit of normal for their age. We don't consider this in terms of mass units nanograms per mL, and I'll explain why in the next slide. So this is data looking at normal healthy individuals from several European countries, 15,000 of them, where the IGF-I has been measured by the IDF iSYS system. This is regardless the gold standard IGF-I assay, particularly because of the bigger with which the reference range has been defined. And what you can see is the rise in IGF-I levels during puberty. If you superimpose these puberty at close early in girls, so that the peak occurs a bit earlier than in boys, post pubertal, IGF-I levels fall, but IGF-I is still present through until late -- throughout life. And so that if we simply quoted results in nanograms per mL, it would be in a poor way of judging patients across different age ranges. So you can see this man with an IGF-I of about 450, he's either -- if he's acromegalic, he's well controlled. He's safe and in the normal range. 30-year-old with the same value 450 nanograms per mL would be an uncontrolled acromegalic or an undiagnosed acromegalic. So this is why when we talk later slides about results for IGF-I, we're going to do it in terms of the upper limit of normal. This patient is more probably 50% above the upper limit of normal, 1.5x the upper limit of normal. This is the goal standard of IGF-I passage and this one will be usually in the future studies. So again, the goals of therapy is to lower IGF-I down into this age-related reference ranges, and secondary endpoints to bring down growth hormone secretion. We want to see patients' symptoms improvement and there are tools for assessing symptoms in patients with acromegaly, and secondary endpoints such as improving their glucose tolerance, getting rid of their diabetes. This is data noted from New Zealand, small country, very good at keeping COVID out of the country, very good at capturing the data on every patient with acromegaly. So this is a series of just over 200 patients, and you can see compared to general population in black that acromegalics overall have a reduced life expectancy of about 10 years without adequate treatment. If you have diabetes and acromegaly, the prognosis is worse. If you have diabetes and acromegaly and heart disease, that prognosis is, again, significantly worse. So this disease, without adequate treatment, reduces life expectancy. The good news from the same population is that when they broke patients down into those where IGF-I hormone was controlled with treatment and those uncontrolled, restoration of IGF-I to normal restores life expectancy back to that of the background population. This is New Zealand data. There's now many other sets of data bringing home the same message, the importance of vigorous treatment. This reliance on IGF-I, one does have to come with a few words of caution, not all assays are the same. So the technology for measurement varies in quality, but particularly in the reference ranges. And that's why the [indiscernible] IDS iSYS reference ranges in 15,000 is an order of magnitude better than previous reference ranges. And as reference ranges have got better, the upper limit of normal has tended to go down. So the upper limit of normal for most assays is lower than it used to be. There's also -- as my next couple of slides will illustrate an intrinsic biological variation in IGF-I. So one doesn't want to make a definitive decision that some one is well controlled or cured based on a single sample. And that phenomena is not confined to just patients with acromegaly. And acromegaly is a long-term chronic disease where it doesn't need to make zap decision based on a single sample. But here are 2 studies done in 2 different populations of bond of healthy individuals. So this first study on the left was in British athletes, amateur athletes, the women average age 20, the men average age 22. And this is part of an attempt to develop means of detecting growth hormone dopers, athletes that are cheating by taking growth hormone. And what this slide shows, these individuals who came along once a month or 4 months, there was no evidence of doping in and they're amateur athletes, but there was -- most patients' IGF -- in subjects, IGF-I is reasonably stable, but in some patients, individuals, there were quite dramatic changes in IGF-I, and that can be nutritional, fast it will cause your IGF-I, intercurrent illness or viral illness, potentially alcohol excess. So there's an element of biological variation. On the left -- on the right-hand side now, this is a study that was done to look at the epidemiology relating IGF-I levels to risk of cardiovascular disease or cancer. This is a cohort of 89 individuals between 50 and 90 years of age, sampled on 2 occasions. And what you can see is the second result compared to the first can be up to 36% lower or up to about 34% higher. This is biological variation. And therefore, this is not a black and white issue where one IGF-I will say an acromegalic is definitively controlled or definitively uncontrolled. One has to rely on accumulation of data. How do we treat acromegaly? So the best therapy, if possible, is surgery. Transsphenoidal surgery has the prospect of curing in the best hands, a small tumor, which means a microadenoma less than a centimeter in size, 90% of patients. The worst published series, the cure rate is only 30%, and I'll come back to reasons for that. Macroadenomas are tumors bigger than a centimeter. The bigger they are, the more adherent they are to the carotid arteries. The more they're wrapped around the carotid arteries, understandably the poorer the cure rate. So the cure rate there reflects surgical scale and the size of the tumor. Radiotherapy is an option, I'll talk a little bit more about that. And then medical therapy, which is going to be the focus today, there are essentially 3 categories of medication: the dopamine agonists; the somatostatin analogues, also called somatostatin receptor ligands; and the growth hormone receptor antagonist. So this is transsphenoidal surgery. You see on the left illustration, and I want you imagine, if you lie on your back looking up at stars, and what the surgeon does, it's something akin to the size [indiscernible] introduce through the nostril, runs through the back of the nose, slowly into the sphenoid sinus, normally filled with air, out of the other side and into the pituitary, going straight down, guiding himself here to identify the tumor and avoiding the carotid artery there, and there -- because he doesn't want to damage the arteries. One of my previous roles that I was Chairman of the British National Acromegaly Register. We had a register of 3,000 patients. And during my Chairmanship, we published this paper looking at the outcomes of surgery in different centers in the U.K. And you can see why the centers wanted to remain anonymous because center K wasn't very proud, but the chance of being cured if you were operated there was only about 1/3 of the prospect being cured in surgery, inside the cube. I was in Manchester for 22 years. Manchester had nothing to quote about in this regard. We are -- I have the distinction, I won't say the honor, the distinction of having published the worst outcomes for acromegaly surgery in the literature, where only 30% of patients approximately were being cured by our surgeons. And the point was we had 8 surgeons all doing 1 or 2 operations a year. And what we all know and we want 1 surgeon doing lots of operations. And so for the time, we didn't send all our patients back maybe to our local surgeons. We sent them 4 hours up the motorway at the three-way to Glasgow, where there was a very good, very experienced surgeon and nothing focused the mind of our local surgeons who reorganized to have 1 dedicated surgeon and the embarrassment that patients were all traveling to Scotland. So -- and since we did that our cure rates in Manchester are 90% in macroadenomas, up there at world-class by having one busy experience pituitary surgeon. But even the best surgeon can't cure everybody. So radiotherapy is an option. It's an option that's particularly effective by controlling tumor growth. So if there's a large residual tumor after surgery often starts to regrow, radiotherapy is effective. It will also lower growth hormone secretion. But that is slow. It doesn't take many years to reach the target range. IGF-I falls even more slowly. So the patients that have radiotherapy are still going to require medical treatment until that radiotherapy has lowered their growth hormone and IGF-I. And I just want to mention the somatostatin receptor ligands. So somatostatin is a naturally occurring peptide out of 14 or 20 amino acids, it binds to a family of 5 somatostatin receptors. A way to think of it, it used to be nicknamed the endocrine cyanide because it switched off many hormones. So not just growth hormones, it switches off potential insulin, TSH and many of the other pancreatic and gastrointestinal peptides. The disadvantage was of it as a drug, it has a very short half-life of 3 minutes and it binds all the receptors. So if you're developing a drug for acromegaly, you want something that binds predominantly to somatostatin 2 receptor and has a much longer half-life. And therefore, octreotide and lanreotide have been in common endocrine practice for 30 years because of their specificity to somatostatin receptor 2 and they're longer half-life. They are the gold standard for medical therapy. There are the go to for patients that are not cured by surgery. They now for about 20 years promise once monthly parenteral preparation either developed -- delivered intramuscular subcutaneously. And with that, I'm going to pass over to my colleague, Dr. Gadelha, who is now going to talk a little bit about some of the new innovations. Monica, she will now have the control of keyboard.

Thank you very much, Peter. Have we managed the hand off? Click. There you go.

Thank you, Peter. Thank you, Scott. Peter, do you think that I'm able -- I'm not being able to pass these slides. Can you allow me to do that, please?

I think you've got it. There's just a time lag. That's you moving the mouse. There, you go.

Yes. So in the next minutes, I will be speaking about the experience with paltusotine in the ACROBAT Phase II studies. Here, you can see my disclosures. So as Peter mentioned, first-generation somatostatin receptor ligands, SRLs, and I will be calling them SRLs, I mean octreotide and lanreotide are the first-line medical therapy for the vast majority of the patients with acromegaly. So how about the efficacy of those medications. So here is the efficacy of octreotide and lanreotide in almost 200 patients treated in our center. You can see that 30% of the patients are controlled with these medications. What I mean by control, GH less than 1 and normal IGF-I. 59% of the patients have partial response. They decreased the GH or IGF-I more than 20% in comparison to baseline without normalization. So in this group of patients, the drugs are good, but they are not enough. So I will have to add another medication as cabergoline or pegvisomant or they may change for another monotherapy as pasireotide or pegvisomant. And in only approximately 10% of the patients, we get no improvement in terms of biochemical response. So GH and IGF-I exhibits a reduction less than 20% of the cases. So we may say that in almost 90% of the patients, these drugs, octreotide or lanreotide, do provide a beneficial in terms of biochemical response. So there is no doubt that these medications are efficacious, and we know that the safety profile is very good. So what are the drawbacks with these medications? So first, as Peter mentioned, these medications are of parenteral use. So regarding octreotide LAR, the octreotide is a monthly deep intramuscular injection that should be administered by a trained health professional. So monthly and health profession. So this means that the patients loses independence because of the chronic injection. And when I say chronic, it's a life-long injection because this treatment is not only for 2 or 3 months, it's lifelong. And in addition, the patients lose also workdays. That is very problematic. In addition, you can see the needle. So these 2 grey and green are the regular needle for intramuscular injection. And this is the octreotide one that is thicker and longer. We have the same issues with lanreotide. You -- again, there is -- the injection is subcutaneous here, but it's deep. And you can see the needle that in comparison with a regular subcutaneous injection is much thicker and long. In addition to that, Dr. Geer and co-workers published very recently, now in 2020, the patient-reported outcome data from acromegaly patients treated with injectable SRLs in routine clinical practice. So the authors evaluated 105 patients that completed an online questionnaire. And what are the results? So many patients experienced site -- injection site reactions. You can see that 83% of the patients reported pain at the injection site during injection, 68% several hours after injection, 49% even several days after the injection, 45% bruising, 47% swelling, 63% nodules and almost 50% scars and hardness. The symptom occurrence. So on the top, you can see the percentage of patients that exhibit some symptom. In dark grey, is the percentage of patients that exhibit the symptom constantly. And in light grey, the symptom only at the end of the cycle. I mean, before the next shot. So we see that there is persistence of symptoms. So it's clear that these drugs, octreotide and lanreotide verifications in a huge number of patients, the safe profile is good, but there is a need for new formulations. So I am going to show you the results of the Edge study. So this was a global clinical trial conducted at 45 clinical sites in 13 countries. The key eligibility criteria were patients not controlled, I mean IGF-I greater than 1 and less the 2.5x the upper limit of the normal range on monotherapy with octreotide and lanreotide. During the screening period, the patients received the last shot of the long-acting SRL at week minus 4. And the last dose of adjuvant medication cabergoline, for example, at weak minus 2. The baseline IGF-I was composed by the average of these 3 measures. So after the screening patients -- the screening periods, patient is started on paltusotine. So the initial dose was 10 milligrams and then potential dose increases to 20, 30 or 40. If his third drug were tolerated and previous IGF-I was more than 0.9x, the upper limit of normal at week 2 and 5 or more than 1x the upper limit of normal at week 8. And after the paltusotine treatment, there was the washout. What was the primary endpoint? So it was the change in IGF-I at week 13 versus baseline. And the primary hypothesis was that we would not see a change in the median IGF-I at week 13 versus baseline. During the washout period, the magnitude of paltusotine effect was evaluated also. An expansion phase called 05 Advance Study is available to patients who complete Edge and Evolve. The group of population. So Edge has 5 groups and Group 1 is the prespecified primary analysis population. So in the next slide, we will be focused on Group 1. Group 1 is composed by patients uncontrolled on monotherapy with octreotide and lanreotide. This population was chosen because they represent a huge number of patients in clinical practice. In addition, the primary hypothesis was that the group would show no change in the median IGF-I at week 13 versus baseline. Exploratory populations, 2 to 5, so choose combination therapy with cabergoline uncontrolled patients and Group 3 to 5 controlled patients, 3 on combination with cabergoline, 4 pasireotide monotherapy and Group 5 SRL plus pegvisomant. So the patient disposition. As I said, I will focus on Group 1. So 8% to 9% of the patients completed the study. Group 1, 88% did complete the study. So regarding the patient characteristics, the median age 52, 44% female, 12 out of the 25 were on lanreotide and 13 out the 25 were on octreotide treatment. Most of these patients uptitrated to the higher dose, that means 40 milligrams, as you can see. All patients start on 10. But at the end of the paltusotine treatment, you can see that 18 patients were in 40, 2 on 30, 2 on 20 and only 1 on 10-milligrams dose of paltusotine. The IGF-I levels. So you can see here the IGF-I levels on screening. That was keep at very similar during paltusotine treatment and then increased during the washout period. So in comparison with the baseline value, you can see here, IGF-I, GH so baseline end of paltusotine treatment and no statistically significant difference. So here, you can see that the primary endpoint of the study was met. And when paltusotine was stopped after the end of the wash period, you can see an increase in IGF-I and also in GH. In this graph, you can see the individual patient percentage change in IGF-I at the end of treatment versus baseline. So 20 of the -- 20 out of 23 patients, I mean, 87%, who completed their dosing period achieved IGF-I levels at the end of this study that were 20% of baseline or lower. Only 3 patients were above. In addition, at the end of the withdraw phase, 18 out of 22 patients, who completed the study, showed a meaningful more than 20% increase of these patients here from baseline in IGF-I four weeks after withdraw. Before I move to Evolve, I would like to show some results of the exploratory population in Groups 2 and 3. Remember that Group 2 were the patients that were treated with SRL plus cabergoline but was not controlled. And three, the same combination therapy, but the patients were controlled on this medication. So we think this [indiscernible] after, in comparison with baseline, the IGF-I at the end of paltusotine treatment increased. And this is problem because cabergoline was stopped. So this increase we call the cabergoline contribution. But we can see very clearly that after the withdraw of paltusotine, IGF-I increases. So this is the paltusotine contribution for IGF-I graft. So let's move to Evolve. So Evolve was a randomized, double-blind, global clinical trial conducted at 44 clinical sites in 13 countries. The difference here is that the eligible criteria was based on patients controlled on octreotide or lanreotide, different from Edge. So the study design patients during the spring received the last shot at week minus 4. The baseline IGF-I was composed by this average of 3 measurements. During paltusotine treatment, patients were started on 10 milligrams with the possibility of drug increase, but only up to 30 milligrams, not to 40 milligrams. After this paltusotine treatment phase, patients that were controlled, I mean, exhibited IGF-I less than 1x the upper limit of the normal range were randomized so to paltusotine or to placebo. And after this, there was the washout period. The primary endpoint of this study was the proportion of responders versus placebo at week 13. But Evolve enrollment was discontinued on April 2020. And why was that? Because Edge enrollment was completed at this time, and interim results were very positive. Discontinue Evolve enabled data to be available for the end of Phase II regulatory interactions on Edge time line. The 13 previously enrolled patients were allowed to complete participation in the study. The reduced sample size did not allow for meaningful statistical comparison between groups in the randomized and the placebo. Exposure response data were analyzed in conjunction with Edge Group 1 patients. And these patients enrolled in Evolve may also had available for them the 05 Advance Study. So you can see at Evolve that most patients did not reach 30 milligrams. So all patients start on 10 milligrams, but at the end of paltusotine treatment only 3 patients were on 30 milligrams. It's important to say that in both Edge and Evolve, the dose escalation was determined by a central reader based on tolerability and the IGF-I. The site staff, patient and sponsor were all blinded to the dose. And Evolve patients did contribute to dose response data. But as I mentioned, most of the patients did not titrate to a more effective dose level. So let's focus here in the randomized withdraw period. So here, the patients that were controlled were randomized to placebo, and you can see the increase in IGF-I or to paltusotine, and you can see the decrease. You can see why this is different from this because here we have both uncontrolled patients that were not randomized and patients that were controlled and were randomized. Because of this we see the difference. So even in a small number of patients, we can clearly see that IGF-I increased in the placebo group and decreased in the paltusotine group. So the post-hoc analysis of Edge and Evolve provide evidence of a dose response. On the left, you can see the results from switching to paltusotine, so change in IGF-I from baseline to steady state at indicated dose. On the left, you can see the magnitude of paltusotine activity, the change in IGF-I from the steady state to 4 weeks after withdraw. Regarding the safety profile. So paltusotine was generally very well tolerated across both trials. Here are the common acromegaly symptoms, the common SRL side effects and other. So no study discontinuation due adverse events, no patient required rescue treatment, no safety signs seen with vital signs, no safety signs seen in clinical labs, and no treatment-related SAE. Only two nontreatment-related, one kidney lithiasis and headache. So regarding our center experience on the open label extension study, Advance. All our 13 patents included in Evolve and Edge were transferred for the open label extension study, Advance. All the patients were very happy to continue on paltusotine. No patient experienced clinical worse of acromegaly at the end of studies, both Evolve and Edge. When questioned, all patients stated that they preferred paltusotine to injectable somatostatin receptor ligands. And for the vast majority of patients, fasting was not a problem. And now I would like to show you some centers when the patients were asked about the preference between the use of oral paltusotine versus injector somatostatin in our center. So the needles made me feel bad. I feel more comfortable taking the medicine every day as a tablet than the monthly injection. I feel better with the oral. And it's much more convenient. So -- and with this, I would like to conclude saying that first generation SRLs are the first-line medical treatment for the vast majority of patients with acromegaly, with efficacy, with safety profile. However, the patients report significant burden of this treatment, including incomplete control of their symptoms and injection site reactions. So there is an unmet need for new first generation SRLs formulation for patients with acromegaly. And in this context, paltusotine is a once-daily oral medication. The ACROBAT EDGE trial show that paltusotine may be an effective option for patients with acromegaly that respond to injectable SRLs. Side effects and compliance issues related to injectable SRLs may be avoided with paltusotine treatment. And with this, I thank you for your attention.

Thank you very much, Monica and Peter. We'll now open the question and answer, and Corey will moderate that for us. So please ask us whatever you'd like. And Monica, Peter will be able to answer. Or if it goes more into some programmatic issues, Dr. Alan Krasner, our Chief Medical Officer, is also here to help.

Thanks, Scott. Thanks, everyone. [Operator Instructions] And first, we're going to go to Tyler Van Buren from Piper Sandler.

Great. Can you hear me?

We can.

Great. Thanks to everyone for the presentation. Dr. Trainer, great to see you join the Crinetics team. I think it says a lot about your conviction on the programs, given how long you've been in practice. And you guys spoke about the spectrum of severity in acromegaly patients. But I wanted to just ask a follow-up on how you treat them with SSAs or SRLs, as Dr. Gadelha referred to it. So when you think of biochemically controlled patients versus biochemically uncontrolled, do they benefit -- have different treatment benefits from SSA therapy or SRL therapy? And then the second question is, my understanding is that most patients have IGF-I levels above upper limit of normal. So do you still treat all those patients with SSAs? And how significant, again, is the treatment benefit, specifically in those patients with IGF-I levels above 1x upper little of normal?

So shall I go first?

Sure.

So thank you. Very relevant, important question. This is -- I think the important thing to recognize is that this is not a black and white issue. Less than upper limit of normal, good; above upper limit of normal, a disaster. You have to appreciate that if patient presents, their IGF-I may be 6x the upper limit of normal. If you bring that down to twice the upper limit of normal to 1.5, they may feel -- they will feel profound benefit in terms of their symptomatology. So it's -- we want to get the IGF-I ideally into that reference range that -- below the upper limit of normal. But there's still great benefit from patients from being taken from having a very active disease, where their life is dominated by lethargies, sweating, fatigue, headaches to feeling much better. But we would always, of course, be looking to what's the next step? Can we actually improve the IGF-I and get completely normal? One also has to recognize the difference in age. So that in the younger patients, tumor's often more aggressive, the symptoms are worse, the biochemical challenge and normalizing is greater. The older patient where the phenotype is much mild and where the back chemical advantage is milder. And one has to say the life expectancy, even with the best win in the world, is shorter. There is less imperative to achieve normalization. So we'd like to achieve it, but there's still great benefit for a patient when you don't achieve it. Does that start to answer your question? Maybe Monica wants to add something.

Monica?

Yes. Thank you for the question. It's very important, indeed. Actually, as Peter said, we get control with this drug for approximately 30% to 40% of the patients, but we do get benefits in other, like I would say, 50% of the patients. So the drugs are very important. Also, of course, we're now in an era that we have the biomarkers. So we may use biomarker to predict the good candidate for these drugs. We will actually be publishing the next months our model to predict response to these using artificial intelligence. So of course, if the patient has high assay to 2, has a granulated tumor -- a densely granulated tumor, has a high [indiscernible], so many biomarkers, the patient is then a good candidate for these drugs. So we may use the drugs for better candidates. But as a role, without using biomarkers, I would say that approximately 80% to 90% of the patients do get benefits from these drug classes.

We're going to go to the next question from Charles Duncan at Cantor.

Okay. Can you hear me, Corey?

We can indeed.

Okay. Super. Thanks, Scott, for hosting this call and Drs. Trainer and Gadelha for sharing your perspectives. I had a question for probably Dr. Trainer and then a follow-up with Dr. Gadelha. First of all, regarding -- or to Dr. Trainer. Regarding your recent decision to leave private practice and become an employee of Crinetics, I guess I'm kind of wondering if you could provide some additional color. On the basis of that decision, was it primarily driven by paltusotine's, call it, differentiated mechanism of action or some other considerations of, call it, the craftsmanship and how it's been designed for acromegaly or the potential for it to be used more broadly in NETs?

It was those things and more. I think if it's engaging with discovery scientists, it's always currently stimulating. And it's not just about acromegaly. The most -- just about the most challenging disease that endocrinologists look after is Cushing's. And when you say what's the attraction, it's being in the forefront of driving a completely novel type of drug. There are no ACTH receptor antagonists for managing Cushing's or for managing congenital adrenal hyperplasia, which is another rare disease affecting children and adults. So it is the ability to work alongside, great scientists who have never met a patient. You have to ask Scott one day how many patients with acromegaly or Cushing's he's met. So that there is a synergy here in relationship. And the notion of easy to take, small molecules, to save people injections is a great bonus. So I think it is the whole package that actually this company is going to generate new ideas, new pipelines, new targets, and I have the chance to be in the forefront of bringing that to patients. It's a natural progression from what I've been doing for several decades.

And if I could just correct 1 answer from Peter. I've now met many acromegaly patients. We have a very active patient community. We have a patient council. They're wonderful people we listen to all the time. But I've never had the responsibility for their individual care, which is a completely different burden that both Peter and Monica realize.

I stand corrected.

That -- Dr. Trainer, that response makes sense to me you through and a nuance though that I wanted to, I guess, ask you about, and that is easy to take oral. And I guess I'm wondering if you just think about paltusotine and its design, I guess, it seems to interact with somatostatin receptors potentially differently than, say, some of the somatostatin ligands that are out there, including an oral octreotide. And I guess as you think about paltusotine and its potentially mechanism -- differentiated mechanism or its high bioavailability and long half-life, what is the most attractive feature to you?

So from a patient perspective, the patient doesn't care about bioavailability, bioactivities, somatostatin 2 receptor. What the patient would like is a tablet that they can take once-a-day with minimal fuss. Patients with acromegaly typically have got potentially pituitary damage. So they're taking maybe hydrocortisone already. They are taking thyroxine. To take alongside their morning hydrocortisone additional tablet, alongside their thyroxine, this one extra tablet fits into the patient lifestyle. The onus, of course, on Crinetics is to show that we will have good biochemical control of their IGF-I. The patient doesn't care of the bioavailability. The patient cares about that convenience as well as its effective. I think that's my perspective on it as a clinician.

Okay. And then if I may, just 1 additional question for Dr. Gadelha, which is likely a multi-part question, as you might imagine. Dr. Gadelha, I'm wondering if you think about the Edge study in the group one patient sample, how does that compare to your broader population? You had a median age of 52, and you mentioned age being a factor in terms of potentially responsiveness. But when you -- in your earlier slides, you talked about your experience. And I guess, how do you feel the Edge study reads on the predictive value for both the controlled as well as the uncontrolled -- or usefulness in the controlled and uncontrolled patient population?

So thank you for the question. I think that the study population -- the group 1 study population Edge reflects very well the general population of acromegaly in our outpatient clinic because the 50-year-old age is very similar to other patients in our outpatient clinics. So I think that it does reflect our general population.

And then with an oral version of octreotide, why would you only get a responder rate of 60%? Could that be related to bioavailability or some other aspect of that particular drug? And then I'll hop back in the queue.

Yes. I don't have experience with oral octreotide because I was not involved in their trials. So I don't have experience. Of course, I saw the publication, but I am not familiar with oral octreotide.

Okay. I think next, we're going to go to Joe Schwartz from Leerink. And a reminder to everybody. We were supposed to finish at noon Eastern Time, but we've got a lot of good questions coming in. So I think we're going to go to 12:15. So thank you for being patient.

All right. I was wondering how necessary is it to control for the inherent variability that we heard about that can exist in individual IGF-I levels in acromegaly trials? How is this best done? And how is it done in the ACROBAT studies?

Peter, you want to start with that?

So I'll respond first then. I think the best -- the important thing to realize is that this is -- it's not black and white. This is -- and what we want to do is get a true measure of the disease and the best means of doing that. And you see that -- saw that in the value of the study, was multiple measurements. So to do the IGF-I on 2 or 3 occasions, separated by a week, a fortnight gives you a much truer measure of disease, that deviation to the mean. And we're dealing with a chronic disease. So to wait 3 weeks is nothing in the disease, which affects people for generations. So multiple measurements, both sort of entry and, ultimately, an exit of studies is probably the way of getting over that natural biological variation. I'll let Monica pick that up.

Yes, I agree. I think that we can't rely on only one measurement. So as imagined, Evolve the baseline IGF-I was evaluated by a mean of 3 measurements. So I think that it's very important to do average, as Peter said, with a week 2 or 3 of interval.

Right. Okay. That makes sense. And then just quickly, I was wondering, switching opportunity would appear to be larger and more important to demonstrate efficacy. But what about treatment-naive patients? Are there any plans to study paltusotine in this patient group?