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spk03: Greetings and welcome to Krenetics Pharmaceuticals conference call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn this conference over to your host, Mr. Thomas Galassi with LifeSite Advisors. Thank you, sir. You may begin.
spk01: Thank you, Operator, and thank you all for participating in today's conference call. Before we start, I would like to point out that there is a slide deck that will accompany today's presentation. This slide deck can be viewed using the webcast link provided on the Investors page of the Kinetics Pharmaceuticals website. Also posted on this webpage is a news release issued earlier today announcing top-line data from the multiple ascending dose portion of the Phase 1 study evaluating CRN 04777, which is the topic of today's call. However, before we get to discussion of the Phase I results, I'd like to remind all listening that some of the information contained in the news release and on this conference 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 business. 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 Crenatix's SEC filings, including its annual report on Form 10-K. I'd also like to point out that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, March 30, 2022. Crenatix takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. With that, I'd like to turn the call over to Dr. Scott Struthers, founder and CEO of Krenetics. Please go ahead, Scott.
spk05: Thank you, Tom. It's my pleasure to be speaking with you and all of those listening this afternoon. I'll be giving today's presentation with our Chief Medical Officer, Dr. Alan Krasner, and I'm also joined by our Chief Financial Officer, Mark Wilson, who will be available to answer questions following the prepared remarks. The primary purpose of today's call is to discuss new data from the Phase I Multiple Ascending Dose Cohort studying CRN4777, or I'll just call it 777, the investigational oral nonpeptide SST5 agonist that we are developing as a treatment for congenital and syndromic hyperinsulinism. Though we also reported our 2021 fourth quarter and year-end financial results today, we won't be talking about these during the prepared remarks. Those interested in our financials can find the relevant details in our earnings press release issued earlier today. Allow me to start with the key takeaways. I'm extremely pleased to announce the top line results from our multiple ascending dose study build on the pharmacologic proof of concept data previously reported for our single ascending dose study and its support advancement into clinical trials in patients later this year. Specifically, safety results show that 777 was well tolerated when administered daily for 10 days. We observed no serious adverse events in the trial, and all adverse events were considered mild or moderate. Pharmacologic data showed dose-dependent decreases in fasting insulin, corresponding increases in fasting plasma glucose after the first dose of 777, which was sustained with repeated daily dosing for 10 days. Additionally, we saw clinically meaningful suppression of sulfonylurea-induced insulin secretion at day 10. This pharmacologically mimics the most common form of congenital hyperinsulinism or congenital HI. These results were dose-dependent with the highest dose of 777, leading to elimination of the need for supplemental glucose support in most subjects. These findings mirror what we saw in our SAD study, which is precisely the results we were expecting. Finally, pharmacokinetic analysis from the multiple ascending dose trial were also consistent with expectations based on our single ascending dose trial, as 4777 was orally available with a half-life of approximately 40 hours. These favorable PK results support a once-daily oral dosing regimen, which we view as a potential major advantage considering congenital HI's patient population is made up primarily of neonates, infants, and children. Taken together, we believe the top line data from our phase one program provide pharmacologic proof of concept for 777, not only in congenital HI, but potentially any disease driven by excess insulin secretion. The next step for 777 is to meet with regulators so that we can discuss our data and the specifics of our planned clinical program in patients. We also believe we are now positioned to head into our clinical studies in patients with 4777. We were able to achieve proof of concept in these early developments thanks to one of the most favorable features of endocrinology and the chronetics drug development strategy that assesses the molecule's pharmacologic activity with evolutionarily conserved biomarkers that have the potential to translate all the way from our animal models to healthy volunteer studies to patients. We pioneered this strategy with paltucetine, which is now in Phase III registrational programs. Primary endpoint for phase three there is based on normalization of IGF levels, the same hormone we measured in preclinical animal models, phase one healthy volunteer study, and our phase two acromeg leak patient studies. We're also applying this strategy to our 4894 ACTH antagonist program and plan to take a similar strategy or similar approach with our recently unveiled PTH antagonist program. This efficient approach to endocrine drug development is a central component of our corporate strategy for bringing an entire next generation of therapeutic options to patients with endocrine-related diseases. With that intro, I'll hand it over to our CMO, Dr. Alan Krasner, to discuss how we are working to address unmet needs in congenital HI and other forms of hyperinsulinism with our 777 program. Alan?
spk07: Thanks, Scott. I'll start by giving some background on monogenic congenital HI, which is a devastating rare disease affecting about 2,000 patients in the U.S., the majority of which are infants or children. The disease is driven by mutations affecting pancreatic beta cells, which lead to inappropriate insulin secretion and ultimately life-threatening hypoglycemia, which means that blood sugar levels drop to dangerously low levels. You can see an illustration of this concept on the left side of this slide. Under normal physiologic conditions, the pancreas secretes insulin in response to an increase in blood glucose, such as after a meal. This leads to glucose uptake by target tissues, keeping blood glucose levels in the normal range. Conversely, a drop in blood glucose levels during fasting leads to the suppression of insulin secretion. This slows glucose uptake by target tissues, once again ensuring blood glucose levels stay within the normal range. Unfortunately, patients with congenital HI are unable to properly regulate their insulin secretion. This means that when blood glucose levels fall, insulin levels may not come down as they should. This leads to continued glucose uptake by tissues, which further decreases blood glucose levels. All too often, Blood glucose levels in congenital HI patients fall so low that the brain cannot be adequately supplied with energy. Untreated, this hypoglycemia can acutely result in dizziness, weakness, confusion, and at lower plasma glucose concentrations, seizures, coma, or even death. Years of recurrent hypoglycemia caused by congenital HI can lead to brain damage and developmental delays. To prevent these adverse outcomes, current treatment paradigms require intensive around-the-clock glucose management, yet still produce suboptimal results. For those interested in learning more about this disease, I highly recommend you take a look at CongenitalHI.org, which is the website of an outstanding patient advocacy group known as Congenital Hyperinsulinism International. Before we get into the specifics of the treatment landscape and our data, I think it's important to first frame just how significant a disease congenital HI is, not only for the infants and children it affects, but also for their families. Due to the limited efficacy of current therapies, caregivers of congenital HI patients live in constant fear of hypoglycemia and its tragic consequences. To prevent this, their children require intensive 24-hour glucose management, which includes constant monitoring, feeding, and can require glucose delivery through a surgically inserted tube, as shown in the patient on the slide, who must take her glucose backpack with her everywhere. As I'll show you in a moment, other treatments in use have shortcomings even beyond limited efficacy, including side effects, burdensome injections for children, and surgical risks. Our goal is to provide a convenient oral therapy that allows those affected by this terrible disease to live the life of a child rather than a patient. Additionally, we hope that such a treatment will allow their parents and caregivers to go to sleep every night without worrying that a hypoglycemic episode may be just around the corner. Turning our attention to the specifics of the congenital HI treatment landscape, the first category of therapies I'll discuss are those designed to prevent hypoglycemia by directly increasing blood glucose levels. Examples of these therapies include IV glucose, which may require administration through a central vein, or enteral glucose delivered through a nasogastric or gastrostomy tube. These therapies are obviously wrought with administration challenges, including procedural risks, and may require hospitalization. In slide 8, you can see an overview of congenital HI therapies directed toward the pancreas, liver, or target tissues. Of these therapies, FDA-approved diazoxide is the only agent that is orally administered, though it is ineffective in about half of congenital HI patients. This is due to its mechanism of action, which targets an ion channel, the KATP channel, that is commonly mutated in these patients. Diazoxide's use is further hampered by its safety profile, including a black box warning related to pulmonary hypertension. For the remaining therapeutic agents shown on this slide, they all must be administered via either an injection or intravenous infusion. These burdensome delivery routes are not well suited for congenital HIV patient population, which again is made up primarily of infants and children. Finally, you may notice that this slide mentions pancreatectomy, which is used as a last resort for some of the sickest children with diffuse congenital HIV. This major surgical procedure obviously carries inherent risk, including the development of lifelong diabetes. A medical therapy that obviates the need for this kind of surgery would be a major advance for these patients. It was with the aforementioned shortcomings in mind that Krenetic's team of drug hunters designed CRN4777, which we believe is the only oral product candidate in clinical development that is designed to address all hyperinsulinism patients, regardless of their underlying genetic mutation. CRN4777 is designed to activate the SST5 receptor within pancreatic beta cells. The reason we chose SST5 as a target is because of where it resides relative to the various mutations known to cause congenital HI, shown on this slide. I'm not going to go into each of these mutations today, but we'll highlight the key takeaway, which is that SST5 receptor activation is known to inhibit influence secretion downstream of all known mutations. As I said earlier, we believe this approach positions 4777 to address excess insulin secretion in any congenital HI patient regardless of their underlying mutation. In fact, we believe 4777's potential role as a downstream regulator of insulin secretion could enable its applicability to extend beyond just monogenic congenital HI to a variety of pediatric syndromes that are associated with similar forms of congenital hyperinsulinism. These include Beckwith-Wiedemann syndrome, Kabuki syndrome, Soto syndrome, and Turner syndrome. With that overview of hyperinsulinism and CRN4777, I'll turn your attention to this slide, which shows the objectives of the multiple ascending dose or MAD portion of our phase one study. Like the single ascending dose or SAD cohorts before it, the 4777 MAD was designed both to assess safety tolerability and pharmacokinetics in Healthy Volunteers, as well as pharmacologic proof of concept for the molecule. The key difference between the SAD and MAD portions of the study is that while the SAD cohorts looked at these parameters after a single dose of 4777, the MAD was designed to see if the molecule's profile held up with repeated daily doses. On the right side of the slide, you can see some of the procedures we used to generate pharmacologic proof-of-concept data in the MAD, which included measuring basal fasting plasma glucose and insulin levels on each of 10 days of dosing and evaluating the ability of the compound to inhibit insulin secretion in a pharmacologic model of the disease that is following sulfonylurea challenge, which I'll describe in more detail in a few moments. Turning our attention to the data, You can see on this slide that 4777 was generally well tolerated at the evaluated doses. The most common treatment-related adverse events included dose-dependent mild to moderate nausea, vomiting, and diarrhea, which are known side effects of somatostatin receptor ligands, or SRLs. Importantly, GI side effects due to SRLs generally improve over time as patients become acclimated to continuous therapy. We saw evidence of this in our MAD cohorts as the GI events usually began shortly following the start of treatment and resolved without the need to discontinue study drug. In fact, we saw no study drug discontinuations due to adverse events and no serious adverse events at all in the SAD or MAD. We also did not see safety signals with vital signs, laboratory testing, or ECGs. On slide 13, You can see that the PK results and exposures observed in the MAD were consistent with our expectations based on the SAAD data at the same doses, which is exactly what we were hoping to see. Our phase one results showed oral bioavailability, a favorable half-life of about 40 hours, and a time to maximal drug concentration of about one to three hours, which we believe supported once daily dosing schedule for 4777. Turning our attention on slide 14 to pharmacodynamic analyses, this slide shows the effects of 4777 treatment on basal fasting insulin and plasma glucose. On the left, you can see that oral administration of 4777 led to a dose-dependent decrease in insulin levels. On the right, you can see that these decreases in insulin led to corresponding dose-dependent increases in fasting plasma glucose levels, which is to be expected. Notably, these changes occurred rapidly after the first study drug administration and were sustained throughout the duration of the MAT. Together, these results demonstrated the pharmacologic activity of repeated administrations of 4777 and showed us that the study drug is behaving as intended. Here on slide 15, you can see that similar to our single ascending dose data, The multiple ascending dose portion of the study also utilized the sulfonylurea challenge to assess 4777's activity in a pharmacologic model of congenital HI. Just like in the SAD, participants were placed on an automatic IV infusion to clamp glucose levels in the normal range and prevent the sulfonylurea, which stimulates insulin secretion, from causing hypoglycemia. On day minus two, participants were clamped and given sulfonylurea in the absence of study drug to get a baseline measurement. Then, after receiving nine daily administrations of 4777 or placebo, participants again received a sulfonylurea challenge followed by a tenth dose. On the right side of the slide, you can see the administration of sulfonylurea closes the KATP channel, which mimics the most common and severe genetic mutations known to cause congenital HI. This leads to excess insulin secretion, even when glucose levels are low, which is precisely what we see in congenital HI patients. Slide 16 shows 4777's effect on sulfonylurea induced insulin secretion. On the left, you'll see that administration of placebo resulted in insulin levels that were essentially the same as those measured at baseline. Moving to the right, you'll notice that increasing the dose of 4777 led to dose-dependent suppression of insulin secretion, with the 120 milligram dose blocking insulin secretion near maximally, as shown by the solid gold line on the rightmost graph. These data indicate that with the 120 milligram dose, we have achieved our goal of identifying the upper end of the healthy volunteer dose response curve. Here on slide 17, you can see how this marked reduction of insulin secretion translated to changes in the glucose infusion rate, or GIR, of the glucose clamp. As a reminder, GIR increases in proportion to insulin secretion. as the added insulin in the blood leads to drops in blood glucose levels that are counteracted by the IV glucose support. Conversely, in the situation where there is no excess insulin secretion, GIR would remain near zero, as exogenous glucose wouldn't be needed to maintain normal levels. Focusing first on the slide's three upper graphs, you can see that the gray lines represent the data at baseline before subjects received 4777. Here, the administration of sulfonylurea in the absence of 4777 led to a substantial increase in GIR in order to maintain blood glucose levels above hypoglycemic levels. This is indicative of the increased insulin secretion caused by the sulfonylurea. If you now focus on the maroon curve in the top left graph, you will see that administration of 30 milligrams of study drug led to a marked decrease in the glucose infusion rate needed to maintain glucose homeostasis in the face of sulfonylurea administration. Moving on to the teal and gold curves in the two graphs in the top right, you'll see, again, decreases in the GIR with 4777 treatment, with the 120 milligram dose essentially eliminating the need for IV glucose support in these subjects. Eliminating the need for IV glucose support for a hospitalized patient with HI is very much a therapeutic goal in this patient population. In the previously reported single ascending dose portion of the study, a single dose of 60 milligrams of 4777 eliminated the hypoglycemic effect of 5 milligrams of the sulfonylurea glubiride. In the MAD, we wanted to be prepared to evaluate a higher dose of 4777 but because the 5 mg sulfonylurea effect was completely reversed by 60 mg of 4777, we would not have been able to detect a difference from the 60 mg dose unless we increased the sulfonylurea dose in the MAD. Therefore, the sulfonylurea dose used in MAD was double that used in the SAD. This dose of sulfonylurea effectively results in maximal sulfonylurea-mediated insulin secretion in adults. it therefore actually modeled a higher severity of hyperinsulinism in patients. The dose response seen between 60 and 120 milligrams in the MAD, if translated to the patient setting, suggests that the 4777 dose could be titrated upward, if necessary, in higher severity HIV disease states. Turning our attention to the curves at the bottom of the slide, you can see how plasma glucose levels changed throughout the sulfonylurea challenge test, both at baseline and after 4777 administration. Looking first at the gray, maroon, and teal curves in the bottom row of graphs, you can see that the sulfonylurea-induced insulin secretion caused glucose levels to drop. However, before glucose levels dipped below the normal range, which is denoted by the red dashed line, the glucose clamp kicked in and prevented hypoglycemia. This showed us that both the sulfonylurea administration and glucose clamp performed precisely as they should. Looking at the gold curve of the 120 milligram dose group in the lower right graph, you see that 4777 treatment actually led to mild elevations in glucose levels compared to baseline values. As was the case with our SAD cohorts, We view this dose-dependent increase in plasma glucose as strong evidence that the levels of insulin suppression we are seeing are clinically meaningful. Furthermore, given the wide range of doses evaluated in the study and mild degree of fasting hyperglycemia observed only at the highest dose in the study, we believe that 4777 could be useful across a broad spectrum of disease severity. and that the dose could be titrated in individual patients to prevent hypoglycemia without resulting in significant hyperglycemia. In slide 18, you can see a summary of the insulin and GIR data I just walked through, which emphasizes the dose-dependent nature of 4777's pharmacologic effect. The bars shown represent the percent change from baseline as measured by the area under the insulin or GIR curves. As you can see, the 120 milligram dose of 4777 reduced sulfonylurea-induced insulin secretion by 90%. This essentially eliminated the need for direct glucose support, as we saw a 97% reduction in GIR in this cohort despite maximal sulfonylurea stimulation. To put these results into context, I should emphasize how the sulfonylurea challenge and glucose clamp are designed to mirror the experience of congenital HI patients, like the one shown on this slide. Similar to the healthy volunteers in our study, excess insulin secretion in children with congenital HI necessitates direct glucose support to prevent hypoglycemia. However, unlike our healthy volunteers, many congenital HI patients must live day in and day out with a feeding tube to provide the support, as you can see in this photograph. We believe the kind of results we are seeing in healthy volunteers, if translated to the patient setting, could potentially enable a very sick, hospitalized child stuck with IV lines and probed with feeding tubes to discontinue the hardware and go home taking an oral liquid medication once per day. This is very much our goal. Before I hand the call back to Scott for concluding remarks, I'd like to recap our Phase I results and lay out the next steps for the 4777 program. Safety data from healthy volunteers to date show 4777 being generally well-tolerated with no treatment-related discontinuations when administered daily for 10 days. The PK results observed in Phase I support a once-daily dosing schedule for 4777 as the molecule was orally bioavailable with a half-life of about 40 hours. Finally, our Phase I program established pharmacologic proof of concept in the clinic by showing the following. First, we demonstrated dose-dependent decreases in basal fasting insulin, which led to corresponding increases in fasting plasma glucose in SAD and MAD. Secondly, there was demonstration of dose-dependent reduction in glucose-induced insulin secretion in the IV glucose tolerance tests previously performed in the SAD. Finally, we demonstrated dose-dependent reduction of sulfonylurea-induced insulin secretion in a pharmacologic model of hyperinsulinism in SAD and MAD. We believe these results leave 4777 well-positioned for further development in an effort to address the unmet needs of congenital HI patients and their families by overcoming the shortcomings of currently available treatments. We believe its PK results alone, which support its development as an oral therapy with once daily dosing, represents an attractive outcome, especially when you think about the need to deliver therapy to infants and children. Additionally, we believe our pharmacologic data supports 4777's potential to address the underlying hormonal cause of congenital HI by suppressing insulin secretion in all patients regardless of the specific specific mutation driving their disease. There are currently no oral agents in clinical development designed to do this that we know of. As you can imagine, we are also interested in exploring the therapeutic potential of this compound in additional patient populations, including those suffering from post bariatric hypoglycemia and insulin secreting tumors. With our phase one single and multiple ascending dose cohorts complete, Our next step is to discuss our data with global regulators prior to initiating a clinical program in patients. Based on our current projections, we expect to open enrollment in this program by the end of the year. And with that, I'll now turn it back to Scott for some closing remarks.
spk05: Thanks, Helen. I hope today's presentation has given everyone a better understanding of our 777 program and why we're so excited to advance this molecule to the next stage of clinical development. to evaluate its potential to improve the lives of children with hyperinsulinism and their families. Congenital and syndromic hyperinsulinism affects kids and their families around the world, and about 4,000 of these kids are right here in the U.S. If these Phase I Healthy Volunteers results indeed translate to similar reductions in insulin secretion in kids with HI, we believe 777, if successfully developed and approved, could dramatically improve both medical management of their condition and quality of life. But beyond just 777, I hope today's call has given all listening a greater appreciation of what makes Krenetics unique. While I often talk about our pipeline now including three new chemical entities with clinical proof of concept data, this is just the beginning. We have assembled a world-class team of in-house drug hunters and developers. The drug hunters in our discovery organization have now repeatedly demonstrated an ability to craft highly differentiated therapeutic candidates with well-behaved pharmacologic and pharmaceutical properties. Our endocrine drug development organization has proven its ability to enable and conduct multiple clinical programs around the world to meaningful clinical readouts that advance our pipelines. These core capabilities are integrated into a uniquely efficient endocrine drug discovery development strategy that enables early de-risking through animal and healthy volunteer studies that are designed to evaluate effects on the same endocrine biomarkers that could be used in registrational studies and management of patients in the real world. Finally, these efforts are all focused on expanding and advancing a highly synergistic pipeline designed to address diseases treated by endocrinologists and related clinical specialties. These facets of Chronetics were designed from the inception of the company, and it's with great pride that I see them now coming together to enable our long-term vision of creating the world's leading endocrine company that can help people around the world to better manage their endocrine diseases that plague them. But as I said, this is just the beginning. Chronetics is entering a new era of its evolution. We're actively pursuing multiple additional drug discovery projects and closing in on candidates for indications such as hyperparathyroidism, nonfunctional pituitary adenomas, and polycystic kidney disease. We continue to grow our discovery and development capabilities to further expand the potential impact of our science and to enable a philosophy of no good idea left behind. Endocrinology has vast areas of unexplored therapeutic targets that we can translate into drug candidates for a wide range of diseases, sometimes beyond those treated traditionally by endocrinologists. It's our intention to be the company that pioneers these new therapeutic frontiers. This philosophy was exemplified last year by our founding of Radionetics Oncology. Radionetics is based on exciting radiopharmaceutical candidates, which emerged from our core capability of discovering small molecule ligands to endocrine receptors. Building a dedicated oncology company around this aspect of our platform position us to potentially generate additional value for kinetic shareholders for our ownership in this new spinout without diverting attention away from our core endocrine focus. Finally, I'd like to provide a quick update on our anticipated 2022 milestones. The Pathfinder Phase III clinical program evaluating paltucetine for the treatment of acromegaly remains on track despite these difficult times of pandemic and war and humanitarian crisis in Eastern Europe. Prenetics is saddened by the ongoing invasion of Ukraine by the Russian military and our hearts are with the Ukrainian people. While we did not have any active or planned studies in Ukraine, our Pathfinder program did include clinical sites in Russia that were screening patients when the war began. We have since paused activities at these sites, which represent less than 10% of the Pathfinder program's clinical centers, and no patients at these sites were randomized into the trial. Given the geographically diverse nature of the Pathfinder program, which plans to activate approximately 100 sites around the world, we do not believe the pause of our Russian sites alone will have a material impact on study timing, and we continue to expect top-line data from both Pathfinder 1 and 2 in 2023. In addition to the continued progress of our Pathfinder program, we expect to report MAD data for 4894, our ACTH antagonist program, in the second quarter. I should note that the brief delay in our 4894 program was primarily due to a number of subjects in one of the latter cohorts of the study contracting COVID during the trial's inpatient portion. In the second half of the year, we expect to open enrollment in Phase II patient studies for both 477 and 4894 programs. Lastly, we expect to identify a lead candidate for our PTH receptor antagonist program and initiate IND-enabling studies throughout the course of this year. I'm proud of all the Kreneticians who have brought us to where we are today and grateful for all the investigators, site staff, and clinical trial participants who have made these accomplishments possible. With that, I'd like to open the call for questions and hand it off to the operator. Thank you.
spk03: At this time, we will be conducting a question and answer session If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary for you to pick up your handset before pressing the star keys. One moment while we poll for questions. Our first question comes from the line of Joseph Schwartz with SVP Learing. You may proceed with your question.
spk13: Hi, I'm Drury Dalyan for Joe. Thank you for taking our questions. I guess, what will you be proposing to regulatory agencies as far as next step goes? Do you think you could enter straight into a pivotal trial, or is there more work to be done in order to refine dosing further?
spk05: Hi, Drury. I'll pass it on to Alan, but let me just say that whenever you go into your initial patient studies, even in these rare disease indications where those studies may end up being pivotal, you don't ever call it that. You start a phase two program and you see what happens and you go from there. But let me let Alan address that with some specificity.
spk07: Right. Thanks for the question. We certainly are excited to talk to regulators around the world about our patient trials and we hope to get them underway by the end of the year. We We certainly have proposals in mind, and we generally divide the CHI patient population into two major groups, those that are so sick they need to be in the hospital versus those who are currently being managed as outpatients, and certainly we think in both patient segments, there is a great medical need and we have ideas to show efficacy and safety of this compound in appropriately designed patient trials. We have to have those discussions with the regulators, but I do think we have good ideas of what the trials would look like and certainly the endpoints that we believe the regulators expect to see.
spk13: Okay, great. And then in HI patients, I would imagine preventing a hypoglycemic event is important. Now, based on the data that you have, have you done any modeling work to project that taking into account any differences we should expect between healthy volunteers and patients? Thank you so much.
spk07: Yes, we have some very talented colleagues at Krenetics who are doing such modeling now based on the existing data from Healthy Volunteers, and they will help us project the doses and the dosing regimens that we'll be using in our initial patient trials. We also like to leverage existing data and newly developed data, emerging data, about the natural history of this disease in the outpatient segment as well, which will help us design that trial. So absolutely, these activities are ongoing.
spk11: Okay, great. Thank you so much.
spk10: Thanks, Jerry.
spk03: Our next question comes from the line of Charles Duncan with Cancer for Gerald. You may proceed with your question.
spk06: Hi, Scott and team. First of all, let me add my congratulations on these positives results and kind of make the remark that really beautiful dose response that you showed today. Thanks, Justin. I had a question you're probably not going to answer or provide much detail, and it's kind of a follow-up to the last one. But for the less creative on the phone, especially me, can you help us imagine what the next steps could be? It seems like in a hospitalized patient population, you could have a relatively short duration of dosing and that you might be able to show efficacy within a short period of time. And then the question is, what numbers of patients Could you imagine round orders for efficacy, but then also safety?
spk05: Yeah, I mean, you hit on a good point, Chas. You just got to put your head into the mind of these families and the kids in the most severe setting, which is in the hospital. And in many cases, they can't leave the hospital until their disease is more stabilized and they end up spending months in a NIC ICU. Sometimes they go on to a pancreatectomy. They have feeding tubes or IV glucose or sometimes a central glucose line. And so while I don't think the endpoint of a trial would be those clinical endpoints, being able to reduce or maybe even eliminate the need for those feeding tubes could have remarkable effects on their ability to go home or avoid a pancreatectomy. But still, if they go home, you need to make sure that that drug keeps working in a home setting, that the safety is true long-term, and that the efficacy is sustained in the outpatient setting. So I think all those considerations come into play. But the exact details of how that translates to a clinical trial, the entry and exclusion criteria, the dosing regimens, those are all things that we really have to have some conversations with the regulators with now that we have this data in hand. So, you know, I'm not trying to dodge the specifics. It's just that really there's a number of dimensions that need to be worked out. And I don't want to plant the, you know, incorrect assumptions at this time.
spk06: Okay. I mean, that's fair, and I understand there's a lot of moving parts. I guess one additional question that I'm going to ask that you may not be able to answer is relative to dosing. Post the last question, Alan suggested that you had a handle on dosing or will do. But I guess I'm wondering, would you anticipate a personalized dosing paradigm or some dose level that you would be able to give to most patients? And I guess, how do you think about that in terms of the normal human volunteer situation? Could there be homeostatic mechanisms that are lacking in patients that may change dose-response relationship?
spk05: Well, Alan, maybe you can answer in more detail, but just a reminder to those listening that, you know, we're talking about children who, you know, very young children who might be just several kilos to young adults who might be 60, 70 kilos. So there's going to be a range of weights regardless, as well as some differences in disease severity. But Alan, maybe you want to talk about the dosing strategy. Okay.
spk07: Yeah, no, I agree completely, Scott. And not only that, there's also a range of severity of disease I alluded to in my prepared remarks. And Chasta, I think realistically speaking, I would imagine that we would, like many other drugs, have a starting dose, again, based on the patient's weight and or size and age. And that would probably cover mild to moderate disease for most kids is my guess. And then if they happen to have more severe disease, that dose could be titrated upward to effect. Endocrinologists are very used to and comfortable titrating medications to biochemical markers, and I suspect that's what we would be doing with this as well. The data in Healthy Volunteers just gives me a lot of comfort that there's such a wide dynamic range where we have efficacy and toleration to choose from. So I'm confident that when we translate those to the pediatric doses, we'll be able to kind of see the same thing in the patient population.
spk05: To add on to that, remember, they're already measuring their glucose many times a day. if they're not already on a continuous glucose monitoring. So there's no better way to guide dose adjustment or selection than that.
spk06: Right, than that quantitative information. Last question is relative to safety. And thank you for taking all the questions. The nausea, I guess I'm wondering if, Alan, you characterized the severity and timing. But just to make sure I heard it correctly, it did not get worse over the 10 days. And in fact, maybe it became less severe over the 10 days. And was it even something that you would necessarily see in a patient population?
spk07: No, you're right, Chas. So generally these episodes were mild to moderate in intensity. They generally started right after study drug was initiated and And as is typical with SRLs, typically waned with continued dosing. Nobody needed to stop the dose because of this. This is a pretty typical time course and profile for this class of drugs, SRLs in general, like octreotide and lanreotide. And, you know, octreotide and lanreotide are currently used in this patient population. And this is off-label use, of course, but these patients generally do okay from a toleration standpoint on these drugs. So I don't think we're seeing anything here that would be different than what these endocrinologists who treat this disease are already used to with this drug class.
spk06: Thanks for the added color. Congrats on the results. Thank you.
spk03: Our next question comes from the line of Monica Marchandani with Evacor. You may proceed with your question.
spk02: Awesome. Thanks for taking the question. Congrats on this data. This is a very quick one on slide 14. I think the insulin levels were post-fasting, but could you talk about how the levels kind of changed during the day, like throughout the study before the the sulfonylurea challenge, if you have that data, and how important it is to replicate the normal fluctuations to also prevent any potential cases of overshooting and hyperglycemia. Thank you.
spk10: Al?
spk07: Yeah, so, you know, during the day, these are volunteers in a metabolic unit, so they're eating, you know, their meals during the day. These are the fasting pre-meal and pre-study drug dose values we're seeing here and we're seeing dose-dependent reductions in fasting insulin and those corresponding increases in fasting glucose. We don't do 24-hour profiles because it would be affected by meals and other such things. We do see a sustained effect with daily dosing. In fact, the onset of that effect is very rapid, and you can see it really starting at day two. I don't expect to, as I alluded to in my prepared remarks, I don't expect hyperglycemia would be a difficulty that couldn't be managed by appropriate titration of the dose in individual patients. Certainly, these patients did not experience significant hyperglycemia even at the highest dose. And it's only at the highest dose that I would even characterize this as even mild hyperglycemia. Again, these doses were assigned to these healthy volunteers. These weren't optimized doses for an individual patient's case of HI. So I'm actually very pleased with the fact that a wide range of doses suppress insulin secretion and reduce the hypoglycemic effect of esophageal urea. But we really aren't seeing much in the way of hyperglycemia so far. And of course, the true test will be in patients, but in healthy volunteers, I think it looks pretty good.
spk02: Yeah, that makes sense. And just given what you described about kind of the range of patients and their weights, what would you consider a weight-based dosing approach? in the next study or are you thinking start with a fixed dose?
spk07: Yes, I think we would consider weight-based dosing in our patient trials, yes. That is still being evaluated exactly how we achieve the equivalent pediatric doses of these adult doses you're seeing here. but it's very typical for pediatric drugs to be based on weight, particularly when we are looking at a wide range of age in the pediatric population, a wide range of body size as well. So I would not be surprised if we end up with weight-based dosing in our trials, yeah.
spk11: Got it. Thank you. Our next question comes from the line of Jessica Fye with JPMorgan. You may proceed with your question. Hey, guys. Good afternoon. Thanks for taking my questions. I'm curious. Could the next trial be a single-arm study?
spk09: And if not, would the active control be glucose support? And what would the endpoint involve? Would it be being able to back off of glucose support in the experimental arm or... Should we think about an endpoint being kind of like glucose levels? And then second, sort of related to future clinical development, on the safety side, what do you anticipate the FDA would want to see in terms of either patient numbers or duration on treatment in addition to efficacy to support approval? It seems like this is a kind of situation where you may be able to generate an efficacy result fairly quickly, so not sure how much additional kind of safety follow-up you might need.
spk10: Thanks, Jess. Yeah, Alan, do you want to take a stab at that?
spk07: Sure. Let me address your second question first because I actually think that's very, very relevant and helps to answer your other questions. So, yes, in the inpatient population, children who are in the hospital almost by definition, are in the hospital because they require ongoing IV or enteral glucose infusions, just like our glucose infusions in our CLAMP studies in Healthy Volunteers. So, yes, I do think in that patient population, showing a reduction in glucose infusion rate is very likely to be the endpoint in the inpatient patient trials, and there is a precedent for this. And we anticipate that would be our endpoint. And you're absolutely right to say it shouldn't take terribly long to see that, especially if our adult healthy volunteer data carry forward into the pediatric population. And as you can imagine, for a hospitalized population, we would have a limited number of days to work with. So you're right. I think the duration of treatment in such a trial would be fairly limited. Now, in an outpatient setting, it would probably be by definition, be a bit longer so you can demonstrate outpatient hypoglycemic event reduction. But even there, you know, I don't think we're talking about months and months of treatment duration, potentially even a month or so at first based on precedent. Could we do a single arm trial? Well, let me just, I don't want to speculate, certainly, I see your point that, you know, do you really need a placebo or a control arm to see an effect like we're seeing here in the adult volunteers? Generally though, as everyone is well aware, the regulatory community and the FDA in particular, are generally in favor of placebo-controlled trials. And we will be having that kind of discussion going forward. So I'd rather not speculate on what the exact trial design would look like at this time. How many patients? Wow, that's another discussion we'll be having, of course, with the regulators. But in general, you need a reasonable number. This is a very rare disease, but you would need a fair number treated for at least a few months and some treated generally for an FDA approval up to a year. Certainly, we hope to have, in addition to our upcoming patient trials, we would always be working to have readily available an open-label extension trial for any patients who complete parent trials to feed right into an open-label extension to have that longer-term data as well. So that's my current understanding just of the situation.
spk09: Okay, great. And then on the side effect profile, can you tell us what the rate of nausea and vomiting was with the 120 milligram dose and how it compared with the lower doses, i.e., is this a dose-dependent side effect?
spk07: Yes, the GI side effects are dose dependent. The table on this slide shows the overall results across the cohorts, but clearly it's at the higher dose range that you see that kind of thing. And that's another reason I'm quite optimistic and why we have no concerns about going forward, because the efficacy as well as the toleration can be managed using dose titration. Recalling that in general, for this kind of medication, I would expect to start with a low dose and slowly march up on the dose as needed for effect. Generally, that's a very effective way to deliver SRLs in general, true for octreotide and lamreotide as well. And in general, most patients tolerate it very well.
spk11: Great, thank you.
spk10: Thanks, Jess.
spk03: Our next question comes from the line of Douglas Sao with H.G. Wainwright. You may proceed with your question.
spk08: Hi, thanks and congrats on the data. Thanks for taking the questions. Just maybe as a starting point, given the importance of the pediatric patient to this market and the fact that this is a lot of patients, as Scott, you described in the NICU, how young do you think you can go in your initial patient studies and what's your thoughts in terms of being able to ultimately get to those patients in the NICU?
spk05: Yeah, I think generally that you do want to start with at least a few older patients who can talk to you. And that's kind of the general way of doing pediatric development. But we do want to move rapidly into the youngest patients who have the most severe needs. But Alan, maybe you want to add a little detail to that.
spk07: Yeah, I mean, so this disease affects children beginning from birth all the way generally through approximately age 12 or 13. Interestingly, a lot of these children tend to outgrow this disease in a sense by the time they're in their adolescent age range. Oftentimes the hyperinsulinemia spontaneously improves or even completely resolves. So this really is a pediatric disease. The goal is to tie them over safely so they can avoid hypoglycemia until they get to the place where they sort of outgrow the disease. So a priori, I wouldn't rule out any age category here in the pediatric age range. Certainly we'll be having those discussions with the regulators, but as Scott was alluding to, generally you'd like to have some safety data first and some older children, and then assuming that is okay, then you would subsequently dose some of the much younger children.
spk05: Yeah, and just philosophically, I mean, I know you've got young kids, Doug, but think about the choices these parents are making. You know, you have a young baby a few weeks old in a NICU, And you're thinking about scheduling a full pancreatectomy that's going to impact them the rest of their life. And you're thinking that versus a drug that initially there's very little experience with. So we need to move very cautiously in that realm. But I think we need to give people a better choice than the ones they have.
spk10: Yes, we can.
spk08: No, absolutely. And I think to your point that that choice, you know, starts to become pretty obvious, you know, especially, you know, to as Alan said, you're sort of bridging patients over because it is a condition that, you know, most patients do eventually outgrow. Just as a quick follow-up in terms of the GI tolerability, and I know you have somewhat limited experience, but did you find that those GI symptoms were fairly persistent or was it sort of somewhat ephemeral as patients had more time on drugs?
spk07: Most of them were quite transient, despite continuing the dose of study drug. And that is the case with SRLs that are approved and used in various conditions on the market today. So it's just a very consistent pattern.
spk08: Okay, great. Thank you so much. We'll be back again. Thanks, Doug.
spk03: Our next question comes from the line of John Wallaben with J&P Securities. You may proceed with your question.
spk04: Hey, thanks for taking the questions and congrats on the data. I might have missed this in the prepared remarks, but did you say how many patients at the 120 milligram dose were able to eliminate the need for glucose during the challenge?
spk07: No, we didn't boil it down to number of patients, but most of them completely came off the need for exogenous IV glucose, and I think it was two of them in the cohort required a very small trickle. So essentially, even in those who had some ongoing very little amount of glucose was needed even in them. So most of them were completely stopped on their glucose.
spk04: That's helpful. And then thinking about next steps, are there any other boxes to check in terms of your non-clinical or tox package before you kick off a phase two? or is it simply getting alignment with the regulators on, you know, more so the design features?
spk05: Yeah, we do have a little bit more talk work to finish up between now and the patient studies, and particularly want to be sure and enable those long-term open-label extensions because that's a really important part of the patient program. You don't want some kid to come into a clinical trial, get a great response on the drug, and not be able to offer them an extension.
spk04: Got it. That's helpful. And one more, looking at slide 17 on the challenge, is there anything we should read into on the infusion rate for the 120 milligram dose? It looks much lower on the early time point versus the 30 and 60 milligram dose. Is that a function of the higher challenge you discussed, or what should we think about that difference we're seeing?
spk05: Yeah, just what it turns out, and we monitored PK of the sulfonylurea too, but there's some significant variability in the sulfonylurea exposure and significant variability in the glucose or the insulin response to that. So you're seeing some of that play out. So our best guess is it's just kind of a random thing that the a little bit less insulin secretion in the 120-milligram cohort than what appears to have happened in the 60-milligram cohort.
spk10: Got it. All right. Thanks for taking my question. Congrats again. Thank you.
spk03: Our next question comes from the line of Catherine Novak with Jones Research. You may proceed with your question.
spk12: Hi. Thanks so much for taking my question. Congrats on the data. Question on the phase two. Given the heterogeneity of disease and different relevant endpoints, I'm wondering if you anticipate conducting two separate trials, one for inpatient and one for outpatient CHI. And then for the outpatient population, I'm wondering about how you intend to monitor the hypoglycemic events. Would that be via continuous glucose monitoring or some other method? Thanks.
spk10: Thank you. Alan?
spk07: Yes. My current baseline assumption is this would be two separate trials, one for each patient population. As you can imagine, there's a lot of different procedural elements in the two different patient populations, and the endpoints would probably be different too. As I mentioned earlier, in the inpatients, we'd probably be looking at IV glucose infusion requirements as a quantitative measure of efficacy. In the outpatients, we expect to be looking at hypoglycemic event rates. What most of these patients have to do is have their finger stick glucose measured on a regular basis to monitor for potential risk of hypoglycemia at home. And those measurements generally would be used to define hypoglycemia in a trial as well. You mentioned continuous glucose monitoring, which is another very important technique. Yes, we would very likely be also measuring CGM, both in the inpatient and outpatient. But in the outpatient realm, to this date, my understanding is CGM data wouldn't be able to be used by the regulators as a basis of approval. They would, I believe, be looking for finger stick glucose meter readings as to define hypoglycemia. That being said, I think CGM data would be important supplemental secondary data. And yes, we would fully intend to capture 24-hour profiles in that way as well in those studies.
spk11: Got it. Thanks so much. Congrats.
spk10: Thanks, Catherine.
spk03: Ladies and gentlemen, we have reached the end of today's question and answer session. I would like to turn this call back over to Dr. Scott Strutters for closing remarks.
spk05: Just thank you all once again for joining us. It was my pleasure to present this update on our 777 program, and I look forward to giving you additional updates on our pipeline in the near future. Look for us at upcoming scientific meetings, and thank you all for your time.
spk03: This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation. Enjoy the rest of your day.
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