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

Greetings. Welcome to the Crinetics Pharmaceuticals, Inc. Conference Call. [Operator Instructions] Please note this conference is being recorded. I will now turn the conference over to your host, Corey Davis. You may begin.

Thank you, Schmally. And thank you all for participating in today's call. Before we start, I'd like to point out that there is a slide deck that will accompany today's presentation. It can be viewed using the webcast link provided on the Investors page of the Crinetics website. Also posted on this web page is a news release issued earlier today announcing data from the single ascending dose portion of the Phase I study evaluating CRN04777, which is the topic for today's call. Before handing it off to the Crinetics team to talk about their newly announced data, I'd like to remind all listening that some of the information contained in the news release and on this call is covered under the safe harbor provisions of the Private Securities Litigation Reform Act; and contains forward-looking statements based on current expectations, including statements about the initiation of planned clinical trials. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's businesses. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release; the company's other news releases; and Crinetics' SEC filings, including its annual report on Form 10-K. I'd also like to point out that the content of this call contains time-sensitive information that's accurate only as of the date of this live broadcast, September 15, 2021. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this call. With that, I'd like to turn it over to Dr. Scott Struthers, Founder and CEO of Crinetics. Go ahead, Scott.

Thanks, Corey. And thanks to all of you listening this afternoon. I'm joined today by Dr. Alan Krasner, our Chief Medical Officer; and Dr. Chris Ferrara-Cook, our senior medical director who has specialized in the treatment of children with hyperinsulinism throughout her medical career. Marc Wilson, our Chief Financial Officer, will also be available to answer questions following our prepared remarks. As Corey mentioned, the purpose of today's call is to discuss the results of our Phase I single ascending dose study evaluating the safety, pharmacokinetics and pharmacology of CRN04777, our oral nonpeptide SST5 agonist being developed for the treatment of congenital hyperinsulinism or congenital HI. Let me cut to the chase. We are very excited to let you know that, just like paltusotine and 4894, CRN04777 has demonstrated pharmacologic proof of concept and good [ drug-like ] properties in the SAD portion of our first-in-human healthy volunteer Phase I study. Safety assessment showed that 4777 was well tolerated at single doses up to 120 milligrams, as we saw no serious adverse events in the SAD study. Pharmacokinetic analysis showed that 777 was orally bioavailable with a dose-proportional exposure profile and a favorable half-life of about 40 hours and a tmax of about 1 to 2 hours. Finally, our pharmacologic analysis showed clinically meaningful suppression of stimulated insulin secretion with 777. Study participants treated with 4777 saw a strong dose-dependent reduction in glucose-stimulated insulin secretion and a dose-dependent reversal of the effects of insulin secreted in response to sulfonylurea administration which pharmacologically mimics congenital HI. Collectively, we believe these clinical findings provide pharmacologic proof of concept for 4777 in congenital HI and any other disease driven by excess insulin secretion. We look forward to building on them with data from our multiple ascending dose study which is ongoing. Those of you who are familiar with Crinetics know that the beauty of endocrinology drug development is the ability to follow and utilize endocrine biomarkers from preclinical studies to healthy volunteer studies, to patients. For paltusotine, we saw good hormonal suppression preclinically then in first-in-human pharmacologic proof-of-concept study, and now it is in Phase III registrational studies measuring hormonal suppression. Last month, we showed how we successfully applied this same development strategy to our ACTH antagonist CRN04894, and today, we will show you how we once again successfully replicated it with CRN04777. Before we get into the data itself, I'd like to start with some background on congenital HI. And for that, I'll hand the call over to Chris, who has a wealth of experience treating congenital HI patients and is an expert in this area. Chris?

Thanks, Scott. Those of you who are familiar with congenital HI know it's a devastating rare disease that primarily affects neonates and children. As the name implies, children with congenital HI are unable to properly regulate insulin secretion due to mutations in the pancreatic beta cell. On the left-hand of the slide, you see a simplified explanation of the way glucose homeostasis is achieved under normal physiologic conditions. When glucose levels rise, for example, just after a meal, the pancreatic beta cells release insulin. This stimulates the uptake of glucose by target tissues and a normalization of glucose levels in the blood. Conversely, when glucose levels fall as they do several hours after a meal, insulin secretion will be suppressed and glucagon will be released. This causes glucose release from the liver and limits glucose uptake by target tissues, again ensuring the normalization of blood glucose levels. In congenital HI, one of several mutations causes dysregulation of the pathway controlling insulin secretion, which disrupts glucose homeostasis. That means that, when blood glucose levels drop in these patients, they do not have a corresponding drop in insulin levels as they should. This is problematic because it leads to the continued uptake of glucose by target tissues, further decreasing the concentration of glucose in the blood to the point where it is not enough to adequately supply the brain with energy. This phenomenon is known as hypoglycemia, and it can result in neurodevelopmental disorders and even death. Unfortunately, current treatments for congenital HI often have suboptimal outcomes and place a high burden on families. For those of you interested in access to some great resources to learn more about the disease, I suggest you take a look at the work being done by Congenital Hyperinsulinism International, which is a fantastic patient advocacy group. Now before getting any deeper into the science of congenital HI or 4777's mechanism of action, I think it's important to talk a little bit more about the unmet needs of patients and their parent caregivers. Children with congenital HI require intensive 24-hour glucose management to prevent hypoglycemia. This often includes constant [ monitoring eating ] or delivery of glucose through a surgically inserted gastrostomy tube as shown in the patient on this slide. As I alluded to earlier, this places an extraordinary burden on both patients and caregivers as they live in constant fear of severe hypoglycemia, which can lead to neurological complications including seizures, developmental delays, learning disabilities and even death. The lone approved drug across the United States for congenital HI is diazoxide and is unfortunately ineffective in about 50% of patients due to its mechanism of action, and its use is limited by its safety profile. Other treatments have limited efficacy; and often involve injections, which is obviously an issue when dealing with the disease affecting neonates and children. Complete or partial pancreatectomy may ultimately be required to effectively control the disease, and even then, hypoglycemia often remains a problem, leading to complex medical therapies and sometimes even repeat surgery. The goal of our 4777 program is to address the significant unmet medical need by providing a convenient oral treatment that is universally effective for all congenital HI patients regardless of their underlying genetic cause. It is our hope that such a treatment will allow children with this disease to feel more like kids and less like patients; and allow parents to enjoy the role of parents, not caregiver. Here on this slide you can see a more detailed overview of the treatment landscape for congenital HI. A key point I'd like to emphasize is that, other than 4777, there are no oral agents available or in development that can universally treat all congenital HI patients. While diazoxide is orally administered and can suppress insulin secretion, it is not universally effective. This is because it targets the KATP channel, where nearly 50% of patients with HI harbor a genetic mutation which renders diazoxide ineffective. Additionally, diazoxide use is complicated by its safety profile with significant fluid retention and excessive hair growth and has a black box warning due to the occurrence of pulmonary hypertension in some patients. While other drugs that are in development for use off label could potentially be universally effective for congenital HI, they each have limitations. Somatostatin receptor 2 agonists, which are used off label, only have partial efficacy and often must be co-administered with enteral dextrose delivered through a gastrostomy tube for part or all of the day. sst2 agonists also require burdensome injections and are not well suited to a pediatric patient population. GLP-1 antagonists are another class of injected drugs under development. There is also an allosteric insulin receptor antibody in development as well as glucagon and glucagon-based therapies, all of which require IV or subcutaneous administrations and do not work to specifically combat increased blood insulin levels. Finally, a strategy to treat congenital HI is to administer therapies that directly increase blood glucose levels. These include delivery of enteral dextrose for part or all of the day through a surgically inserted gastrostomy tube. As I mentioned earlier, therapies such as these are wrought with administration challenges and require intense 24-hour management while not addressing the underlying hormonal imbalances driving congenital HI. Now in our conversations with experts and key opinion leaders, we realized that the shortcomings and unfavorable risk-benefit profile of the therapies I just mentioned created a need for a convenient oral therapy that can suppress insulin secretion and effectively treat all congenital HI patients regardless of the specific mutation driving the disease. This is what eventually led to the creation of our 4777 program, which as you can see here is designed to target pancreatic beta cells to suppress insulin secretion in all hyperinsulinism patients. To achieve the goals of our 4777 program, our internal drug discovery team set out to create a first-in-class early available nonpeptide SST5 agonists. We believe that targeting this receptor in the pancreatic beta cells represents the best strategy to provide an important new therapeutic option for these patients. The rationale for this hypothesis is shown in the diagram on the slide, which gives us a view inside the pancreatic beta cell. Looking at the diagram, you can see some of the various mutations known to cause HI. While I'm not going to discuss these in detail, I will emphasize that -- a main point of this graphic, which is the location of the SST5 receptor in the insulin secretion pathway. As you can see, SST5 receptor activation inhibits the release of insulin by working downstream of the mutations underlying congenital HI. Therefore, we believe this represents the best point in the pathway to target, as activation of the SST5 receptor should effectively counteract the impact of all the various known HI mutations. Taking a broader view. 4777's mechanism of action should be broadly applicable to any disease characterized by excess insulin secretion, including syndromic hyperinsulinism. Rather than being caused by a single gene mutation combined to the pancreatic beta cell, syndromic HI may occur as part of a [ constellation ] of clinical findings in diseases where genetic mutations have pleiotropic effects outside of the beta cell. The best examples are Beckwith-Wiedemann syndrome, Kabuki syndrome, Sotos syndrome and Turner syndrome, where HI may occur in some patients in addition to other phenotypic findings that are characteristic of these conditions. Because of SST5's role as a critical downstream regulator of insulin secretion, we would expect patients with these syndromes to respond to SST5 agonism in the same way we'd expect those with congenital HI to respond. Turning our attention to this slide, I'll speak just a bit more about 4777 before handing the call off to Alan. Like all our drug candidates, 4777 was designed with the goal of incorporating optimal pharmacologic and pharmaceutical properties, including oral bioavailability. As you can see on the left hand of the slide, it potently and selectively activates the SST5 receptor. Following our overarching developmental strategy, after designing 4777, we then tested its ability to activate the SST5 receptor and prevent hypoglycemia caused by sulfonylurea-induced insulin secretion in rats. The administration of sulfonylurea acts to close the KATP channel on the pancreatic beta cell, thus mimicking the most common and severe genetic defect in congenital HI patients and serving as a pharmacologic model of the disease. As you can see on the right, 4777 was able to prevent sulfonylurea-induced hypoglycemia in a dose-dependent fashion, which is indicative of suppressed insulin secretion. We anticipated observing similar in vivo pharmacology in healthy volunteers. And after appropriate manufacturing and first-in-human toxicology studies, a Phase I healthy volunteer study was launched to test it. Those results will now be presented by our Chief Medical Officer, Dr. Alan Krasner. Alan?

Thank you, Chris. And good afternoon, everyone. Our Phase I single ascending dose study was designed to assess safety, tolerability, pharmacokinetics and the pharmacologic effects of single doses of CRN04777 on healthy volunteers. We administered the study drug as an oral solution and evaluated multiple dose levels in the study ranging from 0.5 to 120 milligrams, escalating the doses sequentially after a safety review of the previous cohort. By doing this, we were able to assess safety, tolerability and pharmacokinetics in healthy volunteers as a standard practice in first-in-human studies. Now as Scott alluded to earlier, what differentiates this single-ascending dose study from traditional Phase I trials is that it was also designed to establish pharmacologic proof of concept for 4777. To do this, we evaluated the study drug's ability to suppress glucose and sulfonylurea-induced insulin secretion, which should be predictive of the molecule's efficacy. We did this using 2 dynamic testing procedures in healthy volunteers. These were the intravenous glucose tolerance test and the sulfonylurea challenge test, which I'll discuss in just a moment. Moving on now to discuss the data, I'd first like to again emphasize that, to date, the study drug has been well tolerated, with no serious adverse events and only mild to moderate adverse events observed. Our pharmacokinetic analyses showed that 4777 had favorable pharmaceutical properties that support once-daily dosing, as it demonstrated oral bioavailability with dose-proportional exposure, a half-life of approximately 40 hours and a time to maximal concentration of approximately 1 to 2 hours at potentially effective dose levels. We are currently in the midst of evaluating whether 4777 absorption is affected by the presence of food. We first evaluated drug absorption in the presence of a 1,000-calorie high-fat salad meal for adults as a standard practice during drug development and recommended in regulatory guidance. Absorption was significantly reduced when 120 milligrams of the study drug was administered with such a meal. However, I should note that a high-fat 1,000-calorie meal is not the typical diet of a neonate or a child. Looking forward, we will be studying co-administration of 4777 with meals that are relevant to the patient population. Let's turn our attention to the pharmacologic analyses, beginning with the intravenous glucose tolerance test or IVGTT. The diagram on the right shows an overview of the IVGTT. As we can see, the tests began with the administration of 4777 or placebo. An hour later, we administered an intravenous bolus of glucose to volunteers and then took blood draws at various times to see how glucose and insulin levels respond to the glucose load in the presence or absence of study drug. This allowed us to assess the ability of 4777 to modulate the SST5 receptor and suppress insulin secretion. Shown on this slide are the results of the IVGTT. On the left, you can see insulin levels after the administration of 4777 or placebo. For simplicity, we are showing just a few of the evaluated dose groups on these graphs, as they are representative of what we're seeing more broadly. If you focus first on the time points around minus 30 minutes and just before the IV glucose was administered, you can see that under normal physiologic conditions, 4777 treatment led to an immediate decrease in insulin secretion and rise in plasma glucose. Looking at the rest of the curve, we can see that, when IV glucose was administered to patients receiving placebo, who are denoted by the gray line, a rapid rise in insulin secretion was observed. However, as we increased the concentration of 4777, we saw a dose-dependent decrease in glucose-stimulated insulin levels. Turning our attention now to the graph on the right, we can see the effect of these changes in insulin secretion on plasma glucose levels. Decreased insulin secretion reduces the ability of peripheral tissues to remove glucose from the blood, resulting in increased plasma glucose levels. Patients receiving the highest doses of 4777 saw the most pronounced increase in glucose levels before and during the IVGTT, which was due to the suppressive effects of the study drug on insulin secretion, which in turn results in decreased uptake of glucose by peripheral target tissues. Taken together, these 2 graphs clearly demonstrate 4777's pharmacologic activity by showing a dose-dependent suppression of glucose-stimulated insulin secretion and a corresponding increase in blood glucose levels with the administration of the study drug. To build on these exciting results from the intravenous glucose tolerance test, we then went on to evaluate the study drug in the context of a sulfonylurea challenge. For this assessment, we looked at the 30-milligram and 60-milligram doses. This parallels the sulfonylurea challenge conducted in our preclinical in vivo pharmacology model that we showed earlier. However, to conduct such a study in healthy volunteers, participants are placed on an automatic IV glucose infusion to clamp glucose levels in the normal range and prevent hypoglycemia upon administration of the sulfonylurea. On day minus 2, this was done in the absence of study drug. 2 days later, we again administered sulfonylurea to volunteers in the setting of a glucose clamp and then followed this up with administration of 4777 or placebo. As we discussed, when reviewing our preclinical data, what's particularly valuable about the sulfonylurea challenge is its ability to pharmacologically mimic the effects of a common genetic mutation in congenital hyperinsulinism. As you can see on the left side of the slide, the administration of sulfonylurea recapitulates the most common and severe form of the disease by blocking the KATP channel. This leads to insulin secretion even in the absence of increased blood glucose, which is what occurs in congenital hyperinsulinism patients. The use of automated infusion of IV glucose to maintain safe plasma glucose levels when conducting this SU challenge allows us to assess the study drug's pharmacologic effects by monitoring the IV glucose infusion rate, which is a measure of how much glucose support is required to keep levels in the blood stably within the normal range. This closely parallels the treatment used in patients with congenital HI. A higher glucose infusion rate is needed when insulin secretion is higher, while a lower glucose infusion rate is indicative of suppressed insulin secretion since, as we mentioned earlier, insulin causes the removal of glucose from the blood. On this slide, we can see the results from the sulfonylurea challenge. Looking at the top portion of the slide: The teal curves on each graph represents the data from day minus 2 before subjects received either 4777 or placebo. If we focus here, we can see that sulfonylurea requires a notable increase in glucose infusion rates in order to maintain plasma glucose above hypoglycemic levels. This is indicative of the expected increased insulin secretion caused by the sulfonylurea. If we look now at the graph on the top left, in red, we can see that a similar increase in glucose infusion rate was seen on day 1 in patients who received placebo. Turning our attention to the orange graphs in the middle and right of the top panel, we can see some very exciting data. In the middle, you'll notice that giving patients a single 30-milligram dose of 4777 dramatically reduced the glucose infusion rate or glucose support needed to maintain glucose homeostasis in the face of the sulfonylurea administration. In patients receiving the 60-milligram dose, the need for IV glucose support was completely eliminated. Remember that many children with congenital HI require IV glucose or dextrose delivered through gastrostomy tubes to prevent hypoglycemia. Therefore, reducing or eliminating the need for glucose infusion in the face of insulin secretion induced via sulfonylurea is a meaningful pharmacologic metric to demonstrate proof of concept for future patient trials. Focusing now on the bottom portion of this slide, you can see data on plasma glucose levels during the sulfonylurea challenge. Looking first at the teal curves in which no 4777 is onboard, you can see that the clamp is set to allow a small drop in glucose levels following the sulfonylurea dose, but it then kicks in with glucose infusion to keep the subject's glucose levels from falling below a set point. Both the sulfonylurea dosing and the glucose clamp procedure performed as expected. If we now look at the orange curves in the middle graph on the bottom half of the slide, we can see that the reduction in insulin secretion induced by 30 milligrams of 4777 resulted in plasma glucose levels that are mostly above the lowest allowed level by the clamp after the sulfonylurea challenge but still in the normal range. In other words, 4777 reversed the hypoglycemic effect of sulfonylurea-induced insulin secretion, resulting in normal glucose levels, which is what I would hope to see from an effective treatment in a patient who has excess insulin exposure due to congenital hyperinsulinism. At the high 4777 dose, seen in the graph on the bottom right, we see not only reversal of the sulfonylurea hypoglycemic effect but even mild elevations in glucose levels despite essentially no glucose infusion. The dose-dependent increase in plasma glucose provides strong evidence that the suppression of insulin secretion induced by 4777 is clinically meaningful because a plasma glucose rise would not occur with only minor degrees of insulin suppression. This together with the IVGTT data suggest we could have a wide range of effective doses suitable to achieve stably normal glucose levels based on individual patient need. We look forward to discussing these data with the congenital HI community during our upcoming presentation at the Congenital Hyperinsulinism Virtual Research Conference on Saturday. Additional detailed results from our study will be presented at future medical meetings. Now before I hand it back to Scott to make some final remarks, I just wanted to sum up the key conclusions from our single ascending dose data and speak a bit about where 4777 could fit into the therapeutic paradigm for congenital hyperinsulinism and other diseases characterized by uncontrolled insulin secretion. With regard to the data, single doses of 4777 up to 120 milligrams were generally safe and well tolerated. And we saw no serious adverse events, and all adverse events were mild to moderate. Our pharmacokinetic analyses showed that we achieved our target PK profile. 4777 was rapidly absorbed following oral administration, with a tmax of about 1 to 2 hours, dose-proportional exposure and a favorable half-life of about 40 hours. And finally, we clinically established pharmacologic proof of concept by demonstrating the activity of 4777 in healthy volunteers. We were able to achieve a strong dose-dependent reduction in glucose-stimulated insulin secretion and a dose-dependent reversal of the effects of increased insulin secretion in a pharmacologic model of the disease. With these data, we believe we have taken a major step toward introducing a new drug class for patients with hyperinsulinism. They show that 4777 has the potential to be a convenient oral therapy that can suppress insulin secretion, the underlying hormonal cause of hyperinsulinism, in all patients regardless of the specific mutation driving the disease. This positions 4777 to overcome the shortcomings of competing approaches. Looking ahead, we are currently in the process of conducting the multiple ascending dose portion of our 4777 Phase I program. We expect the MAD data to further demonstrate the study drug's pharmacologic effects, provide additional insights into the therapeutically relevant doses and inform the design of subsequent trials. We plan to report these data in Q1 2022. With that, I'll now hand the call back over to Scott. Scott?

Thanks, Alan. The data discussed today are yet another important milestone for Crinetics, as now our third in-house discovered new chemical entity has demonstrated clinical proof of concept. This is a testament to the abilities and hard work of all our staff and collaborators. Congenital HI patients and their families are a source of inspiration for everyone in our company. And it's tremendously rewarding to see what we may be able to bring -- see that we may be able to bring our drug discovery and development talent to their aid. I also point out that this is Hypo Awareness Week, so the timing of our announcement couldn't be better. We're excited to continue the development of 4777 as a potential treatment for congenital and syndromic hyperinsulinisms that affects around 3,500 to 4,000 patients in the United States and, of course, many more around the world, but I wanted to be emphatic that there is more to Crinetics than just these 3 NCEs now in the clinic. Our discovery team continues its highly productive efforts to find new molecules for new indications. And we are actively closing in on novel drug candidates for hyperparathyroidism, nonfunctional pituitary adenomas, polycystic kidney disease and other important indications. Given our growing track record of success, patients and health care providers facing endocrine and related diseases should be hopeful knowing that [ remarkable, approved ] drug hunters and drug developers at Crinetics are working tirelessly to create new agents to help them better control their diseases and improve their daily lives. I hope to be able to share more details of these emerging programs in the near future. Finally, this year has been one filled with important milestones for our company, and we anticipate important additional new milestones to come soon. In addition to reporting the MAD data from this study in Q1 of '22, we also expect to achieve several milestones outside of our 4777 program as we move through the end of the year and into next. By the end of this year, we expect to initiate our PATHFNDR-2 Phase III study in acromegaly and a Phase II trial evaluating paltusotine in patients with carcinoid syndrome. In the first quarter of next year, we plan to report data from the MAD portion of our Phase I trial evaluating 4894, our oral nonpeptide ACTH antagonist, which is being developed for -- as a treatment for Cushing's disease and congenital adrenal hyperplasia. Looking into the second half of next year, we plan to advance both 4894 and 4777 into Phase II trials in patients, assuming the remainder of the Phase I programs continue to provide promising data. Collectively, we expect the execution of these clinical milestones to further solidify our innovation leadership position in the field of endocrinology. We look forward to the continued advancement of our programs and remain committed to working to improve the lives of our patients. I'm extremely proud of the Crinetics team that have brought us these data today. I'd also like to take a moment to thank the investigators and participants in our clinical studies that are so critical for the successful clinical development of new drug candidates. With that, I'd like to thank everyone for joining the call and open it up for questions. Operator?

[Operator Instructions] And our first question is from Charles Duncan with Cantor Fitzgerald.

Okay. Scott and team, congratulations on these observations. One question that I had is when you -- it kind of seemed like Alan was actually alluding to this, but when you consider the results in the IVGTT versus sulfonylurea challenge, which of the two are you more compelled by in terms of predicting efficacy and translating to longer-term benefit with longer-term dosing?

Thanks, [ Chaz ]. I'll let Alan answer in more detail, but I think the important notion is we're triangulating this from multiple different dimensions and ensuring that the pharmacology is there that we expected. But Alan, maybe you want to comment on the translatability then of these 2 methods.

Sure. [ Chaz ], these are 2 different techniques to stimulate the secretion of endogenous insulin from the pancreas. One is by injecting a bolus of IV glucose, and the other is by challenging the patient with a dose of sulfonylurea. They both are very consistent with each other in the sense that, no matter how you stimulate insulin secretion from the pancreas, you can suppress it with 4777. If you ask me which I find most compelling in terms of predicting efficacy in the patients that we're targeting, I would have to choose the sulfonylurea challenge model because, again as we discussed, that's really a model for the underlying pathophysiology of the disease, at least one of the most common variants of this disease and also, as it happens, the most severe variant of this disease. So the fact that it works in both models, to me, just is sort of an internal check that this is a real phenomenon pharmacologically, but in terms of predicting efficacy, I really am excited by the sulfonylurea challenge data.

Okay, perfect. That's exactly what I was driving at, Alan, and that's helpful. Second question is related to the dosing. I guess this is less relevant given this last answer that you provided, but in the IVGTT analysis, it just looks like when you double the dose, going from 27 to 60, there is a lot more daylight between that and the effect than when you double the dose between going to 60 and at 120. Is that because -- or does that suggest that you are going to hone in on, say, a dose somewhere between 30 and 60 mgs?

Alan, do you want to comment on that? Yes.

I would -- sure, sure. Charles, I think what I would say is that, that does suggest we may be reaching the top of the dose response curve. And that's really the goal of the single ascending dose arm of a Phase I study. It's hard to translate that into what you would see with multiple dosing and, of course, into patients, but what I would say is these data are incredibly valuable. Once we have this plus the MAD data, our modelers will get to work on it and help predict what we should expect to see therapeutically in the patient population.

Okay. And then last question is that next step, say, as you move into patients with the Phase II. Can you give us some sense of the dosing duration that you would like to deploy to be able to show an effect? And do you think that the development program -- this is way, way out in advance of where you're going right now, but do you think that the development program can be driven by biomarker analysis? Or would it require some development milestones to be evaluated?

Well, [ Chaz ], I think you see from the data we show today that the effects of 777 on these models of hyperinsulinism are almost immediate. So you would expect to see very rapid results in patients is what [indiscernible] then trial designs then become a matter of statistics and dose selection, but of course, we also want to explore doses or the effects of this in a longer-term setting so that we ensure that there's long-term safety and tolerability. But Alan, maybe you want to comment in a little more detail about just our broad thinking on the late-stage studies in patients.

Yes. Actually it's interesting because -- getting to your biomarker question, [ Chaz ]: In a sense, that's pretty much what we do in endocrinology. And the key biomarker from the patient's perspective is their plasma glucose level. These patients get sick because their glucose drops to dangerously low levels. That's hypoglycemia. And our goal is to prevent that hypoglycemia, so in a sense, that's our key biomarker. And yes, that's what we would be measuring in our patient trials. The actual end points that we would -- there's different ways to assess the impact of glucose on patients. And there are different patient populations we may want to approach as we go into Phase II and Phase III. I'll ask Chris to actually fill in some detail here, but in general there are patients with this disease who are oftentimes very young and amongst the sickest population and are oftentimes in the hospital receiving IV glucose support, so the amount of IV glucose they require to prevent hypoglycemia is going to be a key metric someday in that patient population. And then there are also patients who are managed as outpatients with this condition, and the frequency with which they experience hypoglycemia as an outpatient is another metric. So Chris, I don't know if you want to add, if you'd like to add any more ideas regarding those 2 patient populations and what we might measure in those populations.

Alan, I think you did an excellent job. Just with respect to the amount of glucose support, that's not just isolated to patients that have an IV glucose requirement, which tends to be the newly diagnosed neonates, but it also would apply to those patients that are dependent on enteral dextrose delivered through that surgically inserted gastrostomy tube and are really bound to having a glucose delivery system with them at all times. For them also, reducing the amount of glucose support is a very important metric of efficacy.

And our next question is from Joseph Schwartz with SVB Leerink.

Let me add my congratulations. You guys are on quite a roll. I was wondering if you could talk a little bit about how you'll be going about undertaking a MAD study for 4777 now. What will that trial look like in terms of the dose levels you'll be testing, the time period you're looking at and the measurements you're taking? Is it too simplistic to think that it's simply an extended version of the SAD study? Are there any special considerations given what you're asking healthy volunteers to sign up for?

Alan?

I don't think it's too simplistic to think of it in those terms actually. So the idea for the MAD is, instead of a single dose in 1 day, we would have healthy volunteers come out, come in, in sequential cohorts. They would be receiving a daily dose of the compound versus placebo for 10 consecutive days. And given the pharmacokinetics of -- that we've observed with the single dosing, I'm confident that we'll be able to reach a steady state pharmacokinetically within that kind of time frame with daily dosing. Of course, we measure safety and we assess safety and we measure pharmacokinetic profiles over that period of time. And we also will be following the glucose and insulin responses, as you can imagine, very carefully. One additional metric that would be of interest in the MAD that we're planning is a very simple test which is actually sort of simulating the real world of eating meals and glucose levels before and after a meal. It's sort of another kind of challenge test. It's called the mixed meal tolerance test. I think that will be a very interesting aspect in the MAD, and I'll ask Chris to maybe elaborate on that a bit.

Thanks, Alan. The mixed meal tolerance test is actually of a lot of clinical relevance for this patient population, as that will be assessing not only glucose stimulus but also the stimulus to insulin secretion from incretins which are released by the gut. And we know that the pancreatic beta cells in these patients with congenital HI tend to be more sensitive to incretin-induced insulin secretion, so this mixed meal tolerance test will allow us to evaluate that in healthy volunteers and the effects of 4777 to suppress incretin-induced insulin secretion as well.

Okay, great. That's very helpful. And then could you put the pharmacodynamic data that you've generated here into some context for us considering the magnitude of effect that you saw on glucose and/or insulin in healthy volunteers relative to what's known about these levels in patients with CHI for the different -- for the range of doses that you saw? What does that imply? How much room do you have to, I guess, go down in dose, it looks like, just given the magnitude? And I know you didn't quantify the suppression necessarily, but obviously these curves are pretty striking, so -- and these patients have very low glucose, so can you kind of help us marry the two?

Yes. Chris, maybe you could talk about some of the patients you've dealt with over the years and what these types of glucose infusion rates mean both biochemically but also from a just patient life point of view.

Absolutely. So the glucose infusion rate, I don't like to think of it just as an IV delivery, but also it can be delivered as continuous enteral dextrose through a G tube. And above a certain glucose infusion rate, a patient is considered not medically manageable and would need to be considered for surgical therapy or removal of part or all of the pancreas. So even moderate or mild reductions in the glucose infusion rate can dramatically change a patient's care trajectory. And so we're very encouraged by the data from the sulfonylurea challenge. We saw essentially an elimination of the need of IV glucose, but then also in the dose that we tested, the highest dose we tested, the 60 milligrams, we saw [ an expected ] increase in the blood glucose, telling us that we even have a further window of opportunity to suppress insulin secretion in patients that may have more severe forms of congenital HI.

And our next question is from Jessica Fye with JPMorgan.

I've got 3, so I'm just going to rattle them off. And first, can you please describe the most common adverse events and whether there was any imbalance between the treated volunteers and the placebo arms? I know you mentioned they were mild to moderate, but was there any dose dependence that you saw? Second, going back to the food effect you mentioned: Is the data in the slides from dosing patients in a fasted state? And can you elaborate on the food effect's magnitude on the PK exposure you observed? And lastly, thinking about the development path beyond the MAD, how much dose ranging work would you want to do in patients ahead of a total trial? Or is that something you could wrap into a single Phase II/III pivotal?

Thanks, Jess. That sounds like questions for Alan.

Jess, in terms of the AEs, nothing consistent. No signal regarding safety was reported. Imbalances with -- between placebo, I don't believe so, but we will be presenting complete AE tables in scientific fora. Nothing concerning, no other kind of safety signals to date with regard to objective laboratory testing. Food effect: Yes. These studies, the way these studies are done is you give a very large high-fat meal just prior to a test dose. And we used the 120-milligram dose in this case. There was a significant reduction, in that context, of absorption. And again in this situation, this is a difficult thing to translate to pediatric patients who do not -- especially the youngest pediatric patients, who do not eat anything like that, so we don't know that that's at all clinically relevant in our target patient population. We will, of course, be testing more relevant kinds of nutritional intakes in conjunction with ingestion of the compound and we'll report back again when we have that data. Dose ranging, yes. I mean, we, of course, need to get the MAD data together and unify it with our existing PK/PD information. And our modelers will do the best that can be done to predict the kinds of doses that would be useful in the patient population. It's likely, though, that we'll have to do some element of dose finding in the actual patient population. Of course, we're very excited about this data. And we don't want to unnecessarily delay the development programs and so that the patients, if they could benefit from this, could get it someday. So of course, we'll be having conversations, discussions with regulators to discuss what is the most efficient development pipeline -- or development pathway to go forward, some dose finding, I'm sure, but again the effect here, if it's anything like we're seeing in these healthy volunteers, if there's anything like this in patients, it shouldn't be a subtle response. And it should be fairly -- as Scott said, it shouldn't take long to see these responses in the patient population. So I'm hoping we will have an efficient path forward in later development.

And I think, Jess, also just a working assumption is that these are going to have to be to some extent individualized dose optimization. I mean, if for nothing else, you've got a 7-pound neonate and a 50- or 60-pound 10-year old, so we're going to be addressing a range of sizes and disease severities, but the good news is that you can see the pharmacology at home. And these parents are used to measuring glucose levels many times a day. And many of the patients are now getting on continuous glucose monitoring, so it's not like it's -- you're trying to optimize dosing for some very slow-to-react marker. It's a very easily accessible, rapidly changing marker.

And our next question is from Douglas Tsao with H.C. Wainwright.

Congratulations on the results.

Thanks, Doug.

I guess my question comes to mind just given sort of the robustness in terms of the ability to suppress the insulin levels. Is there -- how do you think about sort of a once-daily pill and being able to manage the normal fluctuations you see of glucose levels around meals? And is there a risk that you potentially have some episodes of hyperglycemia? Or how do you think about managing that potentially with dose with your drug?

Thanks, Doug. Chris, do you want to communicate about your thoughts on potential for hyperglycemia and what the families might think of that?

Well, I can tell you that the biggest concern in this patient population is the [ fasting hypoglycemia ]. And even with the therapies that we are using, we do accept a minimal amount of hyperglycemia, especially after meals. We've shown, though, that -- with our Phase I data that we are able to have a dose-dependent effect on insulin secretion. And we're able to achieve insulin suppression in that 30-milligram dose in the sulfonylurea challenge without causing the hyperglycemia. So we'll be exploring this in our patient studies. And then we also will be exploring the glucose levels before and after meals in our ongoing Phase I study to help address some of those questions.

And I think -- go ahead, Doug.

And I guess just as a -- no. Go ahead.

No, I was just going to say that, just in the daily risk-reward question, hyperglycemia long term is obviously not good. You can generate diabetic-like states, but it's not going to cause developmental disorders that night or seizures or -- that is a very, very manageable question. And I think most parents with CHI kids would love to worry about hyperglycemia instead of hypoglycemia.

[indiscernible] -- yes, totally understood. That's preferrable. And I guess, when you think about Phase II, do you anticipate incorporating like some kind of CGM component and looking at time and range as part of some of the end points?

I think CGM is a wonderful tool for these patients. And it's not widely enough available, yes, but that also brings into play regulatory conversations about the use of CGM. So I think it's an important tool that will be part of our studies. Whether or not that's a registrational end point or not is something we'll talk about later.

Okay, great. And congrats on the data.

Thanks.

And our next question is from Catherine Novack with JonesTrading.

Congrats on the data.

Thanks, Catherine.

I guess [ my question ] is on as you look toward the Phase II population and thinking about target patients. At the moment, real opportunity seems to be patients who have potassium channel mutations, who would be considered diazoxide failures. Is that kind of how you're thinking about it? And then in terms of age, you mentioned dosing neonates, so is it -- are you expecting to be able to go into that population initially? Or is that something you're considering down the line?

I think we want to develop this for all the kids that have HI because there is just -- all have very high unmet need, but Chris, maybe you want to talk about some of the specifics.

Well, as you mentioned, the diazoxide nonresponsive patients tend to make up the majority of patients because of the mutation underlying them, but there still is an unmet need in those patients that are diazoxide responsive that have other mutations in the pancreatic beta cells. Diazoxide [indiscernible] oral therapy does have a significant side effect profile. The fluid retention is significant and requires co-administration with a diuretic. And just based on the mechanism of action of 4777, we think this is going to be broadly successful in all patients, and so our trials are considering all comers. And with respect to the age, that's going to be conversations with the regulators, but of course, we are targeting those patients that are at the most unmet need within this population, which will include some younger patients, but those are ongoing conversations.

Yes. I think, Catherine, if you think about what these families [ say ], the most severe challenge is after a kid is born and they're trying to gain control of glucose, and they may be facing months in the pediatric ICU or the potential of a pancreatectomy. So I want to get to those patients as soon as we can, but there is also going to be a lot of patients out there and -- at home with -- hooking up to G tubes or just half a dozen glucose finger sticks a day. Imagine -- I have 3 grandkids, and I can't imagine chasing them around trying to get glucose sticks every day. There is going to be a lot of improvement in the life of kids and mothers and fathers if we can avoid all that.

Yes. No, that makes sense. Definitely, treating this severe phenotype population in neonates is going to be an important differentiator and an important unmet need. My second question that I had was in terms of mechanism of action. If you're comparing this to something like RZ358, which is working downstream on insulin receptors, how do you see differences in terms of clinical benefit?

Do you want to comment on that, Chris?

Of course. So they're extremely different mechanisms of action. And 4777 is targeting the beta cell and is therefore stopping kind of the primary pathophysiology for these patients, which is the excess insulin secretions. And another contrasting feature is just the oral administration. And as Scott mentioned, these patients are checking blood glucoses sometimes up to 10 times a day by finger sticks. Octreotide and lanreotide, which are the sst2 agonists that are used off label, are injectable therapies. And so these patients are just calling out for a therapy that's oral and universally effective. So that's another contrasting feature that we have.

Got it. And that makes sense. One last question: Did you -- have you done -- tested for any drug-drug interactions? I know you mentioned dietary restrictions, but...

Yes. We always work to minimize potential for drug-drug interactions in part of the discovery program. We like to say we'd want to make well-crafted drugs, but you eventually do have to characterize a bunch of those clinically. And we've not started any of those studies yet.

And being that it looks like there are no more questions, it looks like we have reached the end of the question-and-answer session. And I'll now turn the call back over to Scott Struthers for closing remarks.

Thank you, everybody, for joining us on the call today. We'll be sure to keep you updated on our progress and look forward to continued advancement of the pipeline. Stay safe. And hope to see many of you as soon as we can. Take care.

And this concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation.