Rezolute, Inc. (RZLT) Earnings Call Transcript & Summary

Good day, and welcome to the Rezolute Investor Event Conference Call. [Operator instructions]. This event is being recorded. I would now like to turn the conference over to Christen Baglaneas, Head of Corporate Affairs. Please go ahead, ma'am.

Thank you, operator. Good afternoon. Before we begin, as a reminder, the information discussed during this call will include forward-looking statements, which represent the company's view as of November 10, 2025. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events, except as required by law. Please refer to our filings with the SEC for information concerning risk factors that could cause actual results to differ materially from those expressed or implied by these statements. Joining us today are Rezolute Founder and CEO, Nevan; Chief Medical Officer, Dr. Brian Roberts; and Chief Commercial Officer, Sunil Karnawat. In addition, also here with us are 2 leading hyperinsulinism experts: Dr. Mansa Krishnamurthy, Pediatric Endocrinologist and Staff Specialist in congenital hyperinsulinism at Cincinnati Children's Hospital Medical Center and Assistant Professor, Department of Pediatrics at the University of Cincinnati; and Dr. Azeez Farooki, attending Physician and Clinical Member on the Endocrinology Service at Memorial Sloan Kettering Cancer Center, where he is an expert consultant on tumor-related endocrine complications and Associate Clinical Professor at Weill Cornell Medical College. Following the presentation, the speakers will be available for questions. Now, I would like to turn the call over to Nevan, who will provide an introduction and overview of Rezolute.

Thank you, Christen, and thank you all for joining us. As Christen noted, I'll provide some opening remarks about Rezolute, and then we'll discuss the flow of today's presentation. As many of you know, we are a rare disease company focused on treating severe and debilitating hypoglycemia associated with hyperinsulinism. The advancement of our antibody, ersodetug, or erso, as we like to call it internally, represents the first time that a novel therapy has been developed specifically to treat all forms of hyperinsulinism. Erso is now in late-stage clinical trials, and we believe that we are on the cusp of potential approval in 2 indications. Importantly, in both the real-world setting as well as in clinical studies, erso has shown the potential to substantially eradicate hypoglycemia and improve the quality of life for individuals living with hyperinsulinism. What makes erso special is its unique mechanism of action, which is designed to treat hyperinsulinism regardless of the underlying cause. I mean, simply put, if the insulin receptor is overstimulated by excess insulin or other insulin-like substances, our antibody works to modulate insulin binding and signaling at target tissues in a dose-dependent fashion to help maintain glucose values in a normalized range, a mechanism of action that we believe is a very elegant way to treat and manage several related diseases under the overall umbrella of hyperinsulinism. Our lead indication is congenital HI, where we are studying erso in children ages 3 months and above in a Phase III randomized controlled trial. And we are expecting to announce top line results mid-December of this year, so in just about 1 month from now. Our Phase III study builds upon our Phase IIb study, which demonstrated a profound correction in both hypoglycemic events and time in hypoglycemia. And we are optimistic and excited about the upcoming Phase III readout. In addition, having successfully treated more than 10 individuals suffering with hypoglycemia due to tumor HI caused by pancreatic insulinomas and nonpancreatic tumors under our expanded access program, we are now pursuing a small single-arm open-label study as confirmation of the efficacy that erso has already demonstrated, prior to filing for approval in this indication. The real-world impact that we've observed for patients and their families has been profound. In short, this is a very exciting time for us at Rezolute as well as for the patients, families and treatment providers that we serve. We are getting closer to becoming a commercial entity and getting erso into the hands of treating physicians and most importantly, being able to offer patients and their families a new paradigm in their journey living with hyperinsulinism. Today, we are fortunate to be joined by 2 distinguished physicians who will provide perspective on the 2 indications that we are studying. First, I'll ask Dr. Mansa Krishnamurthy of Children -- Cincinnati Children's to offer some remarks on congenital HI, and then Dr. Azeez Farooki from Sloan Kettering will provide some insight into tumor HI. After that, our Chief Medical Officer, Brian, will provide some color on our clinical programs, and then he'll turn the call over to Sunil, our Chief Commercial Officer, who will provide an update on the overall commercial opportunity across both indications. Finally, Christen will conclude the prepared remarks for today by sharing some feedback that we've received from patients and families under our expanded access program. We will then open the call to questions. And with that, Dr. Krishnamurthy, I'd like to turn the call over to you.

Thank you very much, Nevan. It's great to be here. So, I will be talking about congenital hyperinsulinism, specifically the unmet needs in this patient population and end the call with a call to action. So, what is congenital hyperinsulinism? This disorder results from dysregulated insulin secretion from the pancreatic beta cell causing persistent hypoglycemia. The estimated incidence varies geographically, affecting one in 22,000 patients in the general population and can be as high as 1 in 2,500 live births in populations with high rates of consanguinity. There are typically 2 forms of congenital hyperinsulinism, both a transient form and a permanent form, and it's the permanent form that affects patients' lifelong and is considered to be a chronic disease. On average, patients with potassium ATP channel mutations are affected with hypoglycemia for approximately 15 years. The treatment options in this patient population include medications such as diazoxide as well as another medication called octreotide. Many patients are aggressively fed often through a G tube or an NG tube and in patients where medications don't work effectively, a pancreatectomy is performed, which is surgical removal of the pancreas. As I shared earlier, there is a significant unmet clinical need in this patient population. Patients are often born with severe persistent hypoglycemia, which can be the key clinical presentation. Hyperinsulinism is the most common cause of hypoglycemia in infants and children, and many of these patients present within the first month of life. The low blood sugar places these patients at high risk for seizure, coma and death, and neurological damage is a very big concern, affecting 50% of patients with hyperinsulinism. The reason why the brain is so affected with hypoglycemia is because the brain is highly dependent on glucose as the primary energy source and repeated low blood sugars in this patient population can result in decreased brain volume, cognitive impairment as well as developmental delays. Patients and caregivers and families take significant effort to avoid hypoglycemia, and this negatively affects their quality of life. They spend a lot of time constantly monitoring blood sugars. Patients are often aggressively fed, which results in abnormal feeding patterns. The socialization of these patients and their families is also negatively affected and regular things that we take for granted, including sleep and work, are impaired because of the amount of effort that goes into caring for these patients. This really speaks to the importance of early detection of hypoglycemia and the need for better treatment options. Unfortunately, many of the available therapies have suboptimal efficacy or severe safety concerns. Diazoxide is the only FDA-approved medication for hyperinsulinism and is only useful in some patients. It's considered ineffective in about 60% of patients that have potassium ATP channel mutations, which we call diazoxide unresponsive. Diazoxide also has serious safety risks, including a black box warning for pulmonary hypertension as this medication results in fluid retention in the patient population, causing things like puffy hands and feet, swelling of the face, trouble breathing and can also place these patients at risk of heart failure. The medication is poorly tolerated and parents will often complain of excessive hair growth in abnormal places, including the body, the arms, the leg and face. And many families will notice that the faces of their children are changing and they have a syndromic appearance. Finally, diazoxide is probably one of the worst medications I have ever tasted and can suppress appetite for a long time, and this often exacerbates the underlying feeding versions that already exist. A second-line medication are somatostatin analogs frequently called octreotide or lanreotide. And this line of medication is not very effective at controlling insulin secretion or low blood sugar and often requires aggressive feeding regimens that are either given continuously or semi continuously through a G tube or an NG tube. These medications also have pretty significant side effects, suppressing hormone secretion in the body, including thyroid hormone and growth hormone, which can negatively affect growth in these children. These medications are not approved for children under the age of 6 months because of the high risk of necrotizing enterocolitis or bowel obstruction, and many of these children often -- or these medications often affect secretion from the liver and gall bladder and place these patients at high risk for developing gall stones. While these medications fail, patients are often considered for surgery to either have a partial or near total pancreatectomy. Patients that have diffuse disease will undergo 98% removal of their pancreas and will eventually have insulin-dependent diabetes. They also lack enzyme secretion from the pancreas, which causes exocrine pancreatic insufficiency. Unfortunately, undergoing these surgeries does not prevent persistent hypoglycemia from occurring, so patients may continue to have ongoing hypoglycemia after surgical removal of their pancreas. So, these surgeries are considered palliative and not curative. I'll finish with a call to action. Across the country and even globally, there's an urgent need to standardize protocols to quickly and effectively diagnose patients with hyperinsulinism. There's also a strong need for referral networks and improved access to specialized centers with the experience in managing patients with hyperinsulinism, and this includes a multidisciplinary model of care. There is a need for improved therapies that are better tolerated long-term for patients with hyperinsulinism as well as interventions to reduce neurodevelopmental consequences and improve the quality of life for patients and their families. Many of these patients struggle with access and insurance coverage for glucose monitoring technology, including continuous glucose monitors, which needs to be addressed. And finally, we need to develop improved standardized protocols for follow-up and neurodevelopmental monitoring as well. And now, I would like to hand the call over to Dr. Farooki.

Thank you, Dr. Krishnamurthy. Good afternoon, everybody. I'm going to talk about tumor hyperinsulinism. So, this is caused by 2 types of tumors, broadly speaking. One is the insulinoma, which is located in the pancreatic islets. And the second is a non-islet cell tumor. So, this can be from a variety of tumors outside of pancreas. These types of tumors both cause hypoglycemia due to overactivation of the insulin receptor. And surgery and debulking therapies are commonly utilized, but there is a need for chronic medical management in many, many of these patients with therapies that treat the hypoglycemia and prevent the hypoglycemia from happening. And as we'll get into, the hypoglycemia is very detrimental to quality of life, can increase morbidity and mortality. And basically, the multifocal or malignant tumors are the ones in need of chronic therapy. For insulinoma, we have therapies like diazoxide, corticosteroids and somatostatin analogs. These therapies can be effective in congenital hyperinsulinism, but in insulinoma, a lot of times these are not effective. I can tell you in practical experience, they just -- we'll get into this a bit more, but they really have significant limitations. And in NICTH or non-islet cell tumor hypoglycemia, this is -- can be thought of as a paraneoplastic production of a substance that acts like insulin. So IGF-2 is the substance, sort of a slightly bigger form of the IGF-2 molecule. And again, the treatment options here are pretty limited. I mean, steroids are basically the only game in town, and they definitely have limitations, which you can get into. There's a lot of adverse effects from steroids that can occur. Diazoxide is really not a therapy for NICTH. So bottom line, we don't have anything that's a targeted therapy that targets the insulin receptor to block this very significant serious life-threatening hypoglycemia that can occur. And we want something that allows the patient to get what they need with the oncologists to do what they need to do to try to treat the tumor without having significant hypoglycemia to impair their performance status and their ability to receive therapy. We'll go to the next slide. So here, we talk about pancreatic tumors, neuroendocrine tumors, if you want, or you can say islet tumor or you can just call it insulinoma, basically talking about the same thing. Hypoglycemia in this context is caused by too much insulin, and that activates the insulin receptor and causes hypoglycemia through a variety of mechanisms. And what we're trying to do here as endocrinologists is -- the oncologists would defer this treatment to endocrinologists. They don't want to -- they have enough to worry about. They don't need to get into this. So, they would send them that you guys fix the hypoglycemia, send them to endocrinologists working at a cancer center -- a major cancer center, that's the way it happens. And for insulinomas, 90% the teaching -- 85%, 90% are considered benign and solitary and can be cured surgically and 10% of patients have malignant or multifocal tumors. And these, you might imagine, can't be cured that easily and require chronic therapy. Of the benign tumors, actually, I want to make the point too though, that some of them cannot be localized. They're very small tumors and hard to find in various places in the GI tract. -- and the pancreas. And maybe, let's say, roughly 10% of them would not be able to be localized even with very advanced imaging techniques that we have nowadays. The -- going to the malignant case, the 5-year survival, I'm going to -- there's -- that's -- there's data on this, but I'm going to let the company get into it a bit more. I mean it's not great. Basically, that's the bottom line is that you have rough estimates here. And it's on an individual basis, though, because each patient is different and some people can live a long time, other people do -- really don't do well at all. So, you see some estimates there are about 2 years for malignant tumors. There's high hospitalization rates. Sometimes people need to be admitted for intravenous glucose because despite what we're giving them, they just get refractory hypoglycemia, some of these malignant patients. And so, you see the bullet here that greater than 50% do not respond to standard-of-care to try to treat the hypoglycemia. And in the case of diazoxide and steroids, both, the side effects are pretty common. And we'll go to the next slide. Hypoglycemia is basically the defining characteristic here, and these patients have spells is what we would learn in medical school and residency endocrine fellowship, that they have spells of these symptoms of not feeling well and nobody can quite put their finger on it. So, in some cases, the diagnosis is delayed if you have a benign tumor, for example. On the other side of the coin, if it's a malignant situation, it will declare itself with spread to the liver, et cetera. But the symptoms of hypoglycemia are basically fight or flight symptoms, so shaking, sweating, feeling, shaky, palpitations, all these type of things. And that can -- that's the early warning symptoms. So what that can progress, however, into more severe symptoms, which are called neuroglycopenia. And in that -- in those symptoms, it's more like you can lose consciousness, you can get a seizure, you can really -- it can be quite dangerous. You can pass out, if you will. okay? So, the diagnosis, again, can be delayed, but the way we confirm this is through a fasting procedure. And the patient may have to fast and be admitted to the hospital or for safety reasons. And so, what we do is we wait until the sugar falls below a certain threshold, glucose. And at that point we draw the labs that we need to make the diagnosis because it is very inappropriate for a patient to have elevated insulin levels or insulin breakdown products, C-peptide levels as well as a bunch of other labs sitting a certain blueprint -- fingerprint, I should say, in the context of a low sugar. So, this can be a bit of a challenge to get the patient to become hypoglycemic, but for patients that have a serious situation, their sugar will drop like a rock. For more of the benign patients, it may take up to 72 hours. And finally, the localization of the tumor, once you've identified biochemically that they have true hypoglycemia and this clinical picture called Whipples Triad is met, that is that they have the symptom, they have the low sugar and it gets reversed when you treat it, the symptom does get better, Whipples Triad is met and then you localize the tumor. So, you can localize the tumor, but again, in at least 10%, 15% of patients, the localization can be challenging. Next slide. The insulinoma treatment landscape is detailed here on this slide. So, the -- again, the multifocal and the malignant patients are the ones that really are a challenge for us as endocrinologists to protect them from hypoglycemia. And the best case, you have a solitary insulinoma, it can be localized and it's taken out. So that is -- and then the patient gets better and they don't have to require further therapy to prevent hypoglycemia. But on the other side of the coin, you can do surgery and debulking therapies. And these are not -- do not directly treat hypoglycemia. Sometimes what can happen is the hypoglycemia gets better for a temporary period, like if you do a chemoembolization of liver metastases, the insulin levels go down and the patient is better for a few months, let's say. But that -- often these patients recur and they have a chronic disease, let's say. And -- so, you need to do something to protect them from hypoglycemia, these multifocal malignant disease type patients. And especially even if they do need a surgery -- any surgery, we need to try to prevent hypoglycemia, and that might involve intravenous glucose infusion, but oftentimes, some patients are even refractory to that. So, we need something to protect these patients -- and the one option is this drug called diazoxide, which is listed here. But the response to this is not great. It's probably less than 50% of patients respond. And diazoxide therapy has side effects that can cause hirsutism in women, that means extra hair growth. It can cause significant fluid retention, and that means swelling in the legs and just overall too much fluid in the body. And for some patients with advanced disease and liver disease, this is a disaster. It just causes a fluid overload in the whole body called anasarca and not a situation that is good for the patient medically or for their quality of life, actually. Final point here is that many patients like this are treated at NCI cancer hospitals, not all, I'm sure, but many of them are. Next slide, please. Now, let's move on to NICTH. This is caused by something that is an insulin-like substance. So IGF-2 refers to insulin-like growth factor 2. So, this is a bigger version of IGF-2, and this can cause very severe hypoglycemia, again, by over activating the insulin receptor. These tumors are large generally and can be found by -- initially, before there's hypoglycemia. And there's a variety of tumor types that we'll see that can cause this syndrome definitely. The incidence is interesting. It's been thought historically that it's more rare than insulinoma. But, because of the fact that you have 15 large tumor types and other factors listed here, lack of physician awareness, maybe, there is some data that Rezolute may -- has gathered that show you that it's surprisingly much more common based on claims and machine learning and whatnot. So, I'll leave that to them to discuss. 60% of these tumors are malignant, 40% are benign. And there are definitely high hospitalization rates and poor outcomes with standard of care here. The standard of care is really steroids, and that is about it in this disease because diazoxide really targets insulin secretion from the pancreas, and that does not work here. So, these patients can have severe hypoglycemia. And there you see the neuroglycopenic symptoms of hypoglycemia listed seizures, loss of consciousness, even death. Next slide. So, these patients may present with hypoglycemia, but it could be either way. It could be before or after cancer diagnosis. They could wind up in the ER. They could be having spells like we said, which nobody can figure out what's causing while they're driving, for example. And again, this requires a lab workup in the presence of a low blood sugar to diagnose this problem. The goal here, again, is to manage the hypoglycemia and get the patient to get whatever tumor-directed therapies, whether it be chemotherapy, targeted therapy to help treat -- extend their life and quality of life. So definitely, oncologists and endocrinologists co-manage these patients and the oncologists would again say that, no, you guys take care of the hypoglycemia. And that is our -- yes, that is what we want to do for these patients. So, we have multidisciplinary care involved at cancer centers all the time in these patients. And okay, next slide. These patients, again, require pharmacologic therapy. There's really not much to offer these patients. The standard of care therapies, as I just said, are not effective in terms of diazoxide. We don't use somatostatin analogs much at my center. Honestly, we don't find them effective for insulinoma or for NICTH. However, they may be helpful for neuroendocrine tumors and not for hypoglycemia, but for other paraneoplastic secretions and whatnot. So here really, corticosteroids are the only game in town. And they have quite a bit of adverse effects. They can cause increased risk for bone fractures. They can cause profound muscle weakness on a steroid-induced myopathy, they can make your skin friable and nonhealing. They can give you insomnia. They could even give you psychosis, believe it or not, in the high doses that are required to treat the tumor-induced hypoglycemia. This is not a trivial dose of steroid that's given to these patients. It's often a very high dose that's required. So that's about it. And that with debulking of some kind chemoembolization, as I mentioned, might be helpful if it's feasible. Yes. No, that is the end of my remarks, and I'd like to hand the call back over to the company, to Rezolute. So, thanks for your attention.

Hello, everyone. It's great to have the opportunity to present today, and I'd like to thank Dr. Farooki. We really appreciate your insights as well as those of Dr. Krishnamurthy. There is clearly a significant unmet need for better therapeutic options for hyperinsulinism, both the genetic and acquired varieties. As many of you know, we have 2 ongoing Phase III studies for hyperinsulinism. And today, I'd like to take a few minutes to give an overview on the nature and status of both of these programs. On the next slide is an overview of our program in congenital hyperinsulinism, which is our lead program. And we're at the tail end of an ongoing global multicenter randomized, double-blind, placebo-controlled Phase III study to examine the safety and efficacy of ersodetug in patients 3 months and older with congenital HI who have inadequately controlled hypoglycemia on existing standard of care. In the pivotal treatment period of the study, eligible participants are randomized to one of 3 parallel treatment arms to receive either 5 milligram or 10 milligram per kilogram of ersodetug or matched placebo by 30-minute IV infusion as add-on to existing standard of care for a controlled treatment duration of 24 weeks or approximately 6 months. The first 3 doses in the pivotal period covering about 6 weeks are administered every other week and thereafter during the pivotal period, dosing is every 4 weeks. This is the most rigorous study design and duration conducted to date for a therapeutic in this indication, either existing or in development. The primary endpoint of the study is the change in the number of average weekly hypoglycemia events for which we powered the study with 16 patients per arm and expect to observe at least a 35% difference between each treatment arm and placebo, which is highly clinically meaningful for this patient population. The key secondary endpoint is the change in average daily percent time in hypoglycemia and several additional secondary endpoints will evaluate other hypoglycemia metrics and their related impacts such as on the patient-reported quality of life outcomes. Following their completion of the pivotal treatment period, patients may roll over into an open-label extension for continued access to ersodetug. And to date, we have had a very high percentage of patients do so and remain on treatment. We completed enrollment of 63 participants midyear, which exceeded our enrollment targets and included patients from key treatment centers in the U.S., both Western and Eastern Europe, Asia and the Middle East, and as a result, are now poised to announce top line results next month. On the next slide, I'm providing an overview of the patient demographics and baseline characteristics from the fully enrolled study, which we presented at the recent ENDO conference in San Francisco. We were very pleased to share that the baseline demographics and characteristics are very similar to what we observed in our previous Phase IIB RIZE study. Notably, and on average, the patients that we enrolled are having about 15 hypoglycemia events per week and are spending about 20% of their time in the hypoglycemic range. Like in the Phase II study, this magnitude is significant and demonstrative of the high unmet medical need with current standard of care. On that particular point, it is noteworthy that about 40% of the eligible and enrolled participants are using diazoxide with an inadequate response based on meeting the hypoglycemic entry criteria. And as you'll hear from Sunil later in the presentation, diazoxide [indiscernible] responsive patients may represent an addressable patient segment that we generally don't account for in our initially addressable commercial model. Roughly 2/3 of the patients are on somatostatin analogs and a significant number are using aggressive feeding and carbohydrate regimens administered directly into the stomach by a tube, which tends to exacerbate underlying feeding issues observed with these patients, but is nevertheless, unfortunately often required in an attempt to avoid life-altering hypoglycemia, particularly in diazoxide nonresponsive patients. In summary, we believe that the baseline characteristics reflect the serious nature of the disease and that the study is poised to be able to rigorously demonstrate the efficacy and safety of ersodetug on managing hypoglycemia in this setting based on the patients enrolled. Switching gears, I'm now going to provide an overview and the status of our Phase III upLIFT study in tumor hyperinsulinism. Our second program in tumor HI to be filed as a supplemental BLA is in treating hypoglycemia due to tumor HI caused by pancreatic neuroendocrine tumors or insulinomas or non-islet cell tumors that mediate hyperinsulinism through paraneoplastic production of IGF-2 variants or other insulin-like substances, as you've just heard from Dr. Farooki. Regarding our Phase III upLIFT study, we recently announced a streamlined study design and Phase III program, stemming from alignment with FDA on the back end of their granting of our breakthrough therapy designation for this indication. Given our experience under our expanded access program and the relatedness of the congenital and acquired indications, the agency agreed with us that an additional randomized and controlled clinical study was not necessary for this indication. Instead, in this revised pivotal study design, we'll only need to evaluate the efficacy and safety of ersodetug in single-arm open-label fashion in a relatively small sample size of up to 16 highly addressable patients who are requiring continuous glucose infusion through an IV in the hospital because of severe and persistent hypoglycemia. The agency also agreed that the comparison can be to baseline. In other words, randomized within study placebo-control or other external control groups are unnecessary. As such, the primary endpoint is the number of patients able to achieve at least a 50% reduction in glucose infusion rate compared to baseline, and the study is powered to demonstrate clinical and statistical significance if 9 of 16 patients achieved that outcome. We think that this represents a very significant step forward and reflects trends at the agency in streamlining development pathways in rare diseases where there is mechanistic, and in our case demonstrated clinical plausibility both in the congenital HI program and in the real-world setting in tumor HI patients. We also think that this outcome is very achievable based on what we have observed thus far in our EAP experience. We expect to complete enrollment next year, which will enable an announcement of top line results in the second half of 2026. To conclude today, I'd like to review the significant accomplishments and milestones from 2025. As I'm sure you'll agree, this has been a really impactful year for us as a company. We were able to secure 2 breakthrough designations from FDA for both the congenital HI and tumor HI indications. Further, our clinical operations and clinical development teams have done an amazing job of completing sunRIZE enrollment midyear and continuing to execute the study while we gear up towards last patient in the pivotal phase and subsequent database lock and top line results shortly. As part of our post breakthrough designation meeting with FDA, the agency confirmed that our proposed nonclinical and clinical data packages would support filing of the BLA in congenital hyperinsulinism. And finally, on the regulatory front, we were also able to achieve alignment with FDA on a streamlined Phase III program for tumor HI with an adequate and well-controlled but open-label Phase III study combined with our expanded access program, as I just presented. During these negotiations, our clinical operations and development teams have maintained an aggressive start-up and enrollment time line. And with preplanning and adaptation, we recently announced the initiation of the Phase III upLIFT study. I'm extremely grateful to all those who helped facilitate these accomplishments, including our CRO partners, patient advocacy organizations with whom we partner, physician experts and their study teams and most importantly, the patients who carry out this important research by way of their feedback and participation in our trials. I'm very excited to be able to report sunRIZE top line data to all of you next month. With that, I'd now like to turn the call over to Sunil, who will provide an update on the commercial opportunity for ersodetug. Thank you.

Thanks, Brian. Good afternoon, everyone. I'm thrilled to be here today with you all. I joined Rezolute a few months ago, and I would first and foremost like to recognize the incredible work that this team has already done in analyzing the commercial market for ersodetug. My first task as a Chief Commercial Officer was to validate the current market assumptions, and I can confidently say that not only has this team hit the mark, but we are now, as I will share in this presentation, realizing an even greater market opportunity than initially expected, based on our latest analysis. I have had a chance to delve deep into the claims analysis where the underlying business rules were validated by KOLs to ensure we are identifying the appropriate patients for both congenital HI and tumor HI. We also identified where these patients are being diagnosed and treated, which will help us further understand the most likely HCP audience, commercial efforts and investment required to launch these 2 indications successfully in the coming years. Next slide, please. The latest claims data indicate that congenital HI occurs in approximately one in every 22,000 births, higher than previously published estimate of one in every 28,000, translating to about 165 new cases each year in the U.S. What's important to understand is how highly concentrated the treatment landscape is. Over 80% of patients are seen across 90 major children's hospitals in the U.S. and almost 2/3 of these patients are further concentrated in less than 40 centers, which, of course, includes the 2 designated centers of excellence in the U.S. Roughly 400 pediatric endocrinologists treat the majority of these patients at these centers. As expected, the mix is overwhelmingly pediatric. 90% of patients are under the age of 18 with 3/4 under the age of 10. From my perspective, this is a highly concentrated market and represents a perfect opportunity for a rare disease company like Rezolute. Specifically, the dynamics of this market will allow us to launch ersodetug in a very focused small sales team of 10 people to engage with a relatively small number of pediatric endocrinologists and the centers that see the bulk of congenital HI patients. On the next slide, I will walk you through this funnel schematic to explain how we determine the initially addressable patients for congenital HI at launch. These numbers represent the current prevalence, whereas the future addressable prevalence is likely to grow with the availability of a potentially safe and highly effective therapy, resulting in possible shifts away from current practice patterns, including use of pancreatectomy and diazoxide as a primary methods of treatment. We began by identifying patients in the claims database using stringent selection criteria to find patients with congenital HI based on the occurrence of multiple diagnosis scores for hypoglycemia and who are also treated with therapies known to be used in hyperinsulinism such as diazoxide, somatostatin analogs and pancreatectomy. Since there is no specific ICD-10 core for congenital HI, we applied the above logic across multiple claims databases over 7 years, resulting in about 3,000 prevalent congenital HI patients shown at the top of the funnel. We then removed 40% of the current prevalence equating to diazoxide responsive patients as well as the cumulative patients whose hypoglycemia would be expected to have resolved as a result of focal or near total pancreatectomy over this time period. Given our focus on pediatric endos at launch, we arrived at approximately 1,500 initially addressable pediatric patients. Having said that, I want to reiterate the noteworthy potential upside to these numbers based on our conversations with physicians and patient communities. The many side effects of diazoxide are widely recognized as well as the black box warning for pulmonary hypertension. Based on the target product profile, many physicians have reported that they would switch most, if not all, their diazoxide-treated patients to ersodetug, particularly as we learned that many diazoxide-treated patients presumed to be at least partially responsive, often have residual hypoglycemia. We believe that 1/3 to half of diazoxide-treated patients will eventually transition to ersodetug. This dynamic occurs frequently in rare diseases, where positive HTP experience builds momentum. In addition to gaining adult patients over time, we also believe that virtually all physicians and patients will forego near total pancreatectomy in favor of ersodetug. We believe that at peak, we could reach substantially more than 50% of the 3,000 prevalent patient population. Next slide, please. As I mentioned earlier, the congenital HI care ecosystem is highly concentrated. Roughly 80% of patients are managed at 90 major children's hospitals, a small targeted network that allows for focused commercial engagement. There are 2 centers of excellence in the U.S. and around 35 large academic hospitals that have the bulk of experience managing these patients. At launch, both our medical and commercial teams will focus on targeting these 90 centers. At the same times, our patient affairs and marketing teams will continue to implement patient engagement strategies to identify individuals affected by congenital HI and expand awareness across care centers not yet engaged by our field teams. On that note, last Friday, we launched the patient disease state website called [ reachinghigher.com ] to inform, support and connect families affected by congenital hyperinsulinism. Our market research with physicians and caregivers demonstrate a clear readiness to adopt ersodetug once the therapy is available. Every physician we surveyed said they would use ersodetug as a second-line option and nearly 1/3 said they would consider it first line, which speaks further to the potential market upside above our core addressable assumptions. From the caregiver side, we saw even stronger enthusiasm. 100% said they would ask about the therapy and 80% said they would be willing to try it. Families are motivated by the potential for highly effective treatment, monthly dosing and the chance to reduce hypoglycemia episodes that can lead to significant neurologic complications if not identified on time and properly managed. These insights give us high confidence in early market receptivity. Our medical team has already been active in engaging with key centers, including understanding the number of patients currently under their management. In this next slide, I wanted to walk you through the patient infusion journey. Ersodetug is given by infusion every 4 weeks once patients reach a steady state. We have mapped a detailed patient journey tailored to the patient's age and preferences. We have learned that many patients and caregivers would prefer home infusion, which is not surprising to me as this is very similar to the experience I had with other therapies such as Ultragenyx's drug Crysvita. In the next slide, I would like to highlight our key learnings from extensive payer research. Our payer research reinforces the high perception of unmet need that we have heard across the clinical community. Payers recognize Congenital HI as a serious rare disease with limited therapeutic options. They view ersodetug favorably due to its strong differentiating clinical efficacy profile compared to diazoxide and anticipate typical ultra-rare pediatric pricing aligned with other ultra-rare treatments. It's also worth noting that approximately 90% of Congenital HI patients are covered through commercial or Medicaid insurance. Now let's pivot to Tumor HI indications. Starting with insulinoma, a rare insulin secreting pancreatic neuroendocrine tumor where persistent hypoglycemia is the presenting and characteristic feature. This is a clearly defined market with an established diagnostic code and a well-understood prescriber base. Adult endos are generally consulted for these patients since hypoglycemia is the presenting and characteristic feature of insulinoma and the primary focus of treatment. In malignant insulinoma, outcomes related to hypoglycemia remains poor. Hospitalization rates are high and existing treatments, including tumor-directed therapy and diazoxide, often fail to control hypoglycemia. There is also upside potential in perioperative management for benign or solitary tumors where the tumors can be located or surgery is contraindicated due to the location of the tumor or comorbidities. The following slide highlights the market opportunity based on a robust claims analysis that identified approximately 3,000 new cases of malignant insulinoma patients per year using disease-specific ICD-10 codes C25.4 and E31.21. So to restate, this is an incidence model in which we subsequently derive prevalence based on a projected treatment duration. From the total annual incidents, we removed approximately 60% of patients who respond to the current standard of care, namely surgical removal or debulking or pharmacological treatments such as diazoxide, leaving us with approximately 1,200 addressable patients who are refractory to current therapies. Since most of these patients are treated at National Cancer Institute's NCI designated academic medical centers or non-NCI academic medical centers, we took an additional cut in terms of where we can focus to find these patients who are managed by adult endos at these centers at launch. This gives us a conservative initial addressable patient base of 750 per year, which is significantly less than what we believe is the true market opportunity, representing the 1,200 refractory patients. However, at launch, we are focusing on 750 incident patients in academic medical centers managed by adult endocrinologists. We assumed a treatment duration of approximately 2 years based on the reported 5-year survival rate of 50% in malignant insulinoma and substantiated based on our overall EAP experience. By projecting a treatment duration of 2 years, we believe we will have approximately 1,500 patients who can benefit from ersodetug each year managed in approximately 300 academic medical centers. Now, let me briefly discuss the NICTH market insights in the next slide. As previously highlighted, this is an underrecognized paraneoplastic syndrome caused by a variety of tumors that produce IGF-2 variants or other insulin-like substances, which activate the insulin receptor. It is important to recognize that the key characteristics of these patients are persistent uncontrolled hypoglycemia irrespective of tumor type. Somewhat in contrast to insulinomas, these tumors are generally large and diagnosed before the onset of hypoglycemia. The current management of NICTH has a two-pronged approach. The goal of tumor-directed therapies is to cure or debulk the tumor burden, whereas the goal of medical management is to eliminate hypoglycemia. Since typical insulin-focused drugs such as diazoxide or somatostatin analogs are ineffective in these patients, most patients are treated with steroids. These patients are co-managed by oncologists and endocrinologists, but generally, the hypoglycemia treatment decisions are made through consultation with an adult endocrinologist. On the next slide, I'm showing you a similar funnel schematic that allows us to arrive at the estimated initially addressable patient population in the U.S. To identify potential NICTH patients, we conducted an audit of confirmed NICTH patients and based on the insights gained from these patients, developed specific business rules, which were validated by KOLs. We applied these business rules to multiple large claims databases to ensure the validity of the output. These analysis identified 6,000 new NICTH cases annually in the U.S. As with malignant insulinoma, this is an incident model in which we subsequently derive the addressable prevalence using a projected treatment duration supported by literature reports. From the total annual incidents, we then removed patients who responded to current surgical or pharmacological treatment similar to what we did for insulinoma market evaluation. We further refined this analysis to identify the subset of patients who are hospitalized and treated with IV glucose to manage their hypoglycemia, indicating highly addressable patients. Like the insulinoma funnel, we took an additional cut of patients who are managed at NCI designated or non-NCI academic medical centers. This gave us an annual incidence of approximately 1,500 severe refractory patients who fit our target profile at launch. We have assumed a treatment duration of 1 year based on varying 5-year survival rates for 15 or more tumor types that NICTH represents. So, in the case of NICTH, the addressable annual incidence equals to the addressable prevalence. Again, we believe the true market may very well be the entire refractory population of 2,400, which represents a significant market expansion opportunity. However, at launch, we will focus on adult endocrinologists at centers with considerable patient volumes. The following slide explains where we can find Tumor HI patients. Because of the severity of the disease, malignant insulinoma and NICTH patients are often treated within academic medical centers. Across this ecosystem, there are 66 NCI-designated academic centers, each managing between 20 to 40 patients. Initially, we will focus on 66 NCI-designated academic medical centers because of the high awareness of hypos. Typically, the most severe cases at these institutions are referred to multidisciplinary tumor boards, which comprise both oncologists and adult endocrinologists, to make treatment decisions. Tumor HI patients are typically older with an average age of 60 to 65. As expected, almost 50% of the payer mix for Tumor HI is Medicare, with the remainder split between commercial and Medicaid insurance. In these last couple of slides, I will conclude by summarizing the combined market opportunity across the indications we have just reviewed. Starting with an explanation of weight-based dosing of ersodetug. The vial presentation for ersodetug is 80 milligram per ml. The usage of the drug is weight-based and most patients with Congenital HI will use 10 milligram per kilogram, while most patients with Tumor HI will use 9 milligram per kilogram. Hence, weight-based dosing applies to both indications with Tumor HI requiring at least 2 to 3 times the number of vials as Congenital HI due to weight differences between the populations. To reiterate this, patients receive infusions every 4 weeks, totaling 13 infusions per year, which translates to 39 vials annually for a 24-kilogram pediatric patient with a Congenital HI. An adult weighing 80 kilogram with Tumor HI would then use proportionately 3 times more vials per year based on a 9-milligram per kilogram dose. We understand that a loading dose can be given at more frequent intervals. However, for modeling purposes, it is reasonable to assume a steady dose at every 4-week interval for both indications. In closing, we believe both Congenital HI and Tumor HI represent a significant commercial opportunity in the U.S. for us. In terms of commercial build, we will take a step-wise approach. We will start with 10 salespeople for the Congenital HI launch focused on pediatric endos at the major children's hospital. We will augment these with an additional 10 salespeople as we prepare for the Tumor HI launch with an initial focus on insulinoma and NICTH patients at the NCI designated academic medical centers, specifically targeting adult endos. As we grow and develop the market, we may add 10 additional salespeople to identify insulinoma and NICTH patients at approximately 200 non-NCI academic medical centers. In short, we will gradually build field sales, medical and patient support teams as we continue to expand beyond our core treatment centers. The U.S. market represents a substantial commercial opportunity with approximately 4,500 patients across both indications. For ex-U.S. markets, our strategy prioritizes key markets that can deliver a faster time to approval with a relatively high price point and a concentrated market for rapid commercial uptake. Our priority will be to focus on the GCC countries, such as Saudi Arabia, where a large population of Congenital HI patients exists due to consanguinity. In Europe, we'll focus on Germany, France and U.K. due to potentially high price points and familiarity of ersodetug at 5 COEs based on clinical trial experience. Lastly, I would like to share why I joined Rezolute a few months ago. The combination of people, purpose and potential of ersodetug is extremely unique. The Rezolute team is among the most capable and mission-driven I have encountered in my career, united by a shared commitment to transform care for patients living with devastating hypoglycemia. What drew me most was the unique opportunity to redefine what's possible in Congenital and Tumor HI. These are communities that have waited far too long for a meaningful therapeutic innovation. The science behind ersodetug, combined with Rezolute's deep clinical expertise and focus, has the potential to fundamentally change lives, what we all dream about in the drug development. I have had the fortune to launch drugs in rare and ultra-rare diseases in the past. Each of these launches has taught me valuable experience that will help guide me at Rezolute to capitalize on the incredible market opportunity that lies before us. It's rare for a company to be able to apply a highly compelling compound to have multiple indications in rare diseases. I am proud to be part of this team as we work to bring this therapy to the people who need it the most. Now I would like to hand the call over to my colleague, Christen.

Thanks, Sunil, and good afternoon, everyone. Before moving to Q&A, I'd like to briefly highlight the real-world patient benefit we've observed with ersodetug through our expanded access program. To date, as a result of unsolicited and word-of-mouth physician requests, we have treated 13 patients with Tumor HI, many of whom were hospitalized or in hospice-bound condition due to severe hypoglycemia. In many instances, the patient's tumor-directed therapies have been deferred due to severity of their hypoglycemia. Following the administration of ersodetug, these patients experienced substantial improvement in hypoglycemia as indicated by the discontinuation of intravenous dextrose with no significant side effects reported. In several cases, these improvements enabled discharge from inpatient to outpatient care and resumption of tumor-directed therapies. The feedback from patients has been encouraging. Following what some have expressed as a feeling of hopelessness upon initial diagnosis, patients described a renewed sense of optimism and improved quality of life reflected in their ability to resume everyday activities such as walking, driving, traveling and even having the opportunity to attend milestone events for loved ones, such as weddings, children's birthdays and welcoming grandchildren. We are fortunate to have a therapy in late-stage development where we have already observed in the real-world setting the meaningful difference it is making to improve the lives of patients and their families. We have also been encouraged by our constructive dialogue with the FDA, which took the real-world impact from this early access program into consideration in streamlining our Phase III Tumor HI study. We remain committed to improving the treatment landscape for the HI community and look forward to continuing to share our progress. Thank you all for taking the time today to learn about the commercial opportunity and clinical development of ersodetug as we progress in our 2 Phase III studies in Congenital and Tumor HI, respectively. We will now turn to Q&A.

[Operator Instructions] And our first question for today will come from Ry Forseth with Guggenheim.

Setting this up. I really appreciate it, and I'm here representing Debjit today. A question for Dr. Krishnamurthy. Could you comment on the baseline characteristics of the sunRIZE study and how we should think about the likelihood of spontaneous improvement in hypoglycemia event rates for subjects that have an inadequate blood sugar control on standard of care? And two, could you help define what it means to have an inadequate blood sugar control on standard of care in your practice?

Sure. So I think patients that undergo standard of care, whether it's diazoxide or somatostatin or have had a pancreatectomy and after that are either treated with feeding therapy and somatostatin analogs, they continue to have ongoing hypoglycemia, and we sort of accept the fact that, that is going to continue. And so we try our best to make sure that the blood sugars are as normal as possible. We use a cutoff of 70, but we kind of hit a point where we just don't -- we can't do anything else to be able to normalize the blood sugar. So, aggressive feeding therapy only works so much. Somatostatin analogs only work so much and the pancreatectomy also only provides that much benefit. But at one point, you kind of are stuck without any additional options. So we go ahead and optimize everything we can. But unfortunately, we still have patients that still present with significant time below range, and we're sort of out of luck, and we don't have anything else that we can offer, which is where a drug like ersodetug can absolutely have a lot of benefit in being able to treat patients that have such refractory hypoglycemia despite everything that we throw at them or everything that we treat them with. So I think when we look at the sunRIZE data that has been -- or the RIZE data, at least that I have seen, we absolutely can see that the time and range definitely improves for these patients, if not absolutely completely normalizes. And so I think that just speaks to the fact that ersodetug is a very viable therapy for this patient population.

Maybe just to address though for completeness, Ryan, your total question. I'll ask Brian to also comment on the sunRIZE study and I think the baseline characteristics, which I think are very informative.

Yes. So as was indicated in my presentation, the sunRIZE baseline demographics are very similar to Phase II, and as Dr. Krishnamurthy indicated, reflect the severity of the disease in this patient population. So we had almost 20% time in the hypoglycemic range and about 15 events per week. So that's encouraging that we're seeing this patient population look very similar to a study where we already know in open-label fashion that ersodetug was highly effective. The rest of the characteristics were similar too, as I went through on the call today. In terms -- just to round out the question regarding the likelihood of spontaneous recovery, again, as Dr. Krishnamurthy said, this is a patient population who's already failed everything, including pancreatectomy in some instances. So spontaneous recovery or some sort of study or placebo effect are highly unlikely in this patient population. They've really been exhausted on all measures, including often, as we shared from the baseline characteristics, being on aggressive tube feeding regimens as well. So while it's unlikely, we have modeled for a potential treatment or placebo effect, study effect, if you will, up to 35%. So even if we did see that, which is not expected, we are powered nevertheless, to demonstrate the 35% effect size that has led to the sample size calculations in the study.

The next question will come from Pete Stavropoulos with Cantor.

Congratulations on your new position, Sunil. So first question is for Dr. Krishnamurthy. In your clinical experience, in what proportion of your patients is diazoxide effective, defined by complete control or high control? And knowing the side effect profile of diazoxide versus ersodetug to date as well as the efficacy differences where patients either partially or do not respond to diazoxide or, say, somatostatin analogs, would you consider using erso as a frontline treatment? And knowing the outcomes of young patients, including irreversible neurological outcomes, can you speculate if payers will give you a significant pushback if you chose to go first line with Rezolute?

Sure. So I currently probably treat -- 70% of my patients are diazoxide responsive or partially responsive and about 30% of our patients are not and have had to have pancreatectomy to control their hyperinsulinism. 100% of my patients have not responded to somatostatin unless they had a pancreatectomy. So our protocol is to try diazoxide first if they fail to try somatostatin alone. If they fail, which 100% of my patients have, then we would move forward to pancreatectomy and try somatostatin analogs after the pancreatectomy. So, if you were to ask my expert opinion, I think despite my -- 70% of my patients being on diazoxide, we do have several of them. I'd probably say 20%, 25% of them have serious side effects, including pulmonary hypertension. They may be syndromic and have abnormal cardiac function or cardiac abnormalities at baseline. So again, using diazoxide is very difficult. And then almost 100% of my patients complain of hair growth and facial changes, et cetera. So, I would absolutely feel comfortable offering ersodetug to my patients as a first-line treatment if the parents agree. And so I feel comfortable kind of offering either diazoxide or ersodetug on an equal level. And I think I can't -- I don't know how to answer the payer question, because again...

Actually, you don't have to answer that one. I'll ask Sunil to answer that one because I know that's not your world. So that's Sunil's world. So I appreciate that. Sunil, please?

This is Sunil. So the question was about how would payer respond to diazoxide or the first line for ersodetug. We have done a lot of payer work and the payer research. I think what we have heard consistently from the payer, and this is very typical to the rare disease, right, where if there is a current approved therapy, very likely payers will want to step through that. And we don't think that is a big issue because a lot of these patients have tried diazoxide before. So it's there in the [ chart review ] for most of the physicians. So we think that's a very small hurdle to basically demonstrate to the payer that the patients have tried diazoxide has not worked and get the approval for ersodetug. So we don't really think it's a big issue from a payer perspective. Even if it is a first line or a second line, most likely the payers will go for it just because these patients have tried diazoxide before.

Okay. And just one question for Dr. Farooki. Can you just give a little bit of detail on diagnosis process? And is it really -- is it easy or difficult to sort of diagnose NICT patients with hypoglycemia? How easy is to identify those patients? And the company is initially focused, or at least I believe they're initially focused on hepatocellular carcinoma. Are there other tumor types that drive hypoglycemia and that could possibly be addressed by Rezo's mechanism of action? And if so, how often do you see those tumor types?

Yes. Thanks. I could speak to that. So the mechanism of NICTH is common. It's this overproduction of the substance called IGF-2. And there are a lot of tumor types in this bucket. I mean there are carcinoma, [ they're ] hepatocellular carcinoma, there are carcinoid tumors and just a bunch of others. So -- and your question was -- sorry, the first part of the question was what again?

How difficult is it to identify?

Diagnosis. Yes. The diagnosis -- these patients tend to have pretty severe hypoglycemia. I mean they are -- they have a lot going on with their tumor therapy. So when the sugar comes back at 40 or 50 or something there, it is a significant issue. It might get ignored in the context of a sick patient, but it is definitely a red flag that needs to be addressed and does get addressed at academic centers, I would say.

And just one last question for Rezolute. How exactly are you thinking about pricing? Like what benchmarks should we be using? And as you mentioned through the presentation, as you go from child-based -- or child-based basically pricing on a kilogram basis or a unit basis, you're going 3 times higher for adults. So by our calculations, pricing starts to sort of balloon up. And do you expect to cap the price or somehow have a mechanism in there for pricing for adults?

Yes. No, thanks for the question. Yes, so the way we are thinking about the pricing, it's a definitely ultra-rare pediatric disease. So we have a lot of analogues to think about in terms of how we would price the Congenital HI. And in the presentation, I also showed that the tumor is likely to be at least 2 to 3x of Congenital HI based on the weight-based dosing. Really good analogue to consider potentially would be Crysvita, which I had a fortune to launch at Ultragenyx, and it also has a 2 indications for XLH and TIO. It was a very similar weight-based pricing. So that's one proxy to think about in terms of how the price will work. I mean for the most part, tumor will be, of course, 2 to 3 times Congenital HI, but all the payer research we have done, it never really had any issue in terms of the price point because it's such a ultra-rare disease, particularly the insulinoma as well as NICTH. So we don't really see a lot of issues in terms of the pricing for Tumor HI. And will there be a cap? Potentially, there could be a cap, but it really comes down to specific population and the payer. And if it gets to that point, we'll definitely talk to the payer. But at this point, given what we know, we don't really see a big issue in terms of the price point for Tumor HI given that it's such a ultra-rare disease.

The next question will come from Maurice Raycroft with Jefferies.

Maybe one for Dr. Farooki. Should we think about ersodetug as potential frontline treatment in NICTH and as a second-line plus treatment option for ICT, given that steroids and SSAs are not that effective in NICTH? And maybe you or the company can talk about just the proportion of these patients that you think would get erso in frontline or second line?

Yes. I think the existing therapies have such limitations. It's just -- I think we're -- as an endocrinologist dealing with this, we would love something that's targeted and non-toxic and so forth. So I think for both, I mean, it would be a reasonable thing. Now whether the payers will agree to that or not, that's, again -- Sunil can speak to that, I think. But yes, I think diazoxide is not an easy drug to tolerate for insulinoma. And we do try that. In insulinoma that can have some success. And in NICTH, I mean, the diazoxide, as I said, is not effective. So then we're left sort of trying to [ pummel ] the patient with high-dose steroids. And we endocrinologists really don't love doing that because we know very well the problems that can cause in terms of bone loss and muscle loss and quality of life problems, as I said. So, yes, I think in both situations, it would be nice if we could just use the targeted therapy that was approved to treat the hypoglycemia rather than doing other maneuvers. So both, I would say, is the answer. I think that I would like to use it in both, if I could.

Got it. So probably high proportion of your patients, and are all your patients -- you kind of assume that?

Yes. I think a high proportion, I mean, case by case, of course, but I just think it would be a very good fit to solve this problem.

And then maybe one other question, too, just with what you're looking for in the upLIFT pivotal trial that could support widespread adoption, would you want to see a 50% reduction in glucose infusion rate from baseline? Would that be sufficient? Or would you want to see near or complete weaning off of IV glucose? And then for other endpoints, how important are time to discharge from the hospital and CGM? How important are those for adoption?

Yes. . .

Go ahead, sorry.

I was going to ask Brian to comment, but if you want to comment, Dr. Farooki, please go for it.

You go ahead, Brian. It's okay. I mean I was going to say just the 50% reduction, that is a clinically meaningful endpoint. I mean we'd like to get the patient off the insulin drip and get them out of the hospital. But I think these are complex patients. So the selection of that 50% reduction was a reasonable endpoint to get the ball rolling in that direction.

Yes. And this is Brian. I would just add, remember that patients on a glucose strip are having one long severe hypoglycemic event. So if we're able to achieve that in the hospitalized setting, that translates to the same reduction in outpatient events. So a 50% reduction in event rate certainly equates to or even exceeds the -- what's viewed as clinically significant, for example, in the sunRIZE study. So remember, this is an endpoint in the study, but would translate directly to very pronounced impact on clinical benefit in the outpatient setting as well.

The next question will come from Catherine Novack with Jones Research.

My first question is for Dr. Krishnamurthy. So when you discuss the treatment duration for CHI, can you help us understand why patients grow -- why there are no adult patients that you're treating? Are they growing out of the disease? Or is there something else that's happening that's changing the course of the disease as these patients grow up?

Yes. So I think it is absolutely true that patients when they're first born with hyperinsulinism, they're secreting very, very high levels of insulin. And so, over time, whether they're on treatment or not on treatment, the natural evolution is that the pancreas just can't keep up anymore. So initially, they secrete a ton of insulin and hyperinsulinism becomes a very big problem with hypoglycemia when they're very young. But as you sort of follow them, they undergo a period of what we call burnout where the beta cells just cannot keep up anymore. So there's a small possibility that without treatment, some patients actually just kind of normalize and then that burnout eventually could mean that they will have diabetes. Of course, we intervene at that point where these babies are secreting so much insulin having hypoglycemia, that's the time in which we're trying diazoxide or somatostatin analogs or proceeding to pancreatectomy to protect the brain and the brain is sort of like our very -- is probably the most -- is given the most priority at that time. So of course, we don't just kind of -- we couldn't just sit back and just let the natural evolution happen. But this is why you sort of don't see as many patients that are older that are on diazoxide. I can't say there are none, but I would say that as you approach age 18, 20, 23, 25, the diazoxide requirement significantly goes down or they're not on diazoxide at that time.

Got it. And then switching gears to talk about tumor hyperinsulinism. You mentioned that you still have less than 50% of Tumor HI patients responding to diazoxide. And we've seen, I guess, with the sunRIZE trial, how even so-called diazoxide respondent patients are experiencing hypoglycemia. But can you help us understand why so many Tumor HI patients are not responding to diazoxide?

Sure, Catherine. Thanks for the question. I'll ask Brian to go ahead and comment.

Catherine, so diazoxide, firstly, we don't -- I don't know that we know definitively, but there is a tendency for suboptimal response of diazoxide. And some of that may just be because these tumors can secrete very large amounts of insulin. They're also often differentiated, and that does explain the lack of response generally to somatostatin analogs. They just -- they will stop expressing the normal receptors. And as a cancer, they stop behaving normally. So the response to some of these agents may be even less than it is on the Congenital HI side. And I would just add to Dr. Krishnamurthy's response on CHI as well. And she characterized the kind of evolution of disease in diazoxide patients well. Remember also that right now, we have a practice pattern for non-diazoxide responsive patients that often involves a near total pancreatectomy. And that, of course, influences the patient journey and the life -- the expectancy of disease duration. So with a highly effective medical therapy that does not require removal of the pancreas, particularly in those diazoxide non-responsive patients that are very severe and the disease tends to be very long lasting, the duration of the disease is likely to be longer or the treatment needs anyway.

The next question will come from Julian Harrison with

On diazoxide, I'm wondering if you could put the pulmonary hypertension and broader cardiovascular risks in more context for us? How often do patients have to discontinue diazoxide due to these side effects? And is it typically reversible after patients stop? And then on a related note, I'm wondering if there's a chance that erso could be used perhaps preferentially in CHI and maybe Tumor HI as well just based on diazoxide's cardiovascular risks alone?

Thanks for the question, Julian. Maybe I'll ask Dr. Krishnamurthy to go first. And then Brian, if you have any additional thoughts, that would be great.

Sure. Thanks for the question. So I think the pulmonary hypertension that happens with diazoxide, the risks are definitely higher if there are children with hyperinsulinism that have an underlying cardiac defect. So you may see this primarily in syndromic patients, patients that have Kabuki syndrome, Turner syndrome, in which those syndromes have higher rates of hyperinsulinism compared to other rare syndromes. And also in patients that have hyperinsulinism that is maybe transient initially in the NICU, the standard of care guidelines, is to try diazoxide in that patient population. And in neonates, the pulmonary vasculature is very, very sensitive to changes in fluid, whether you have diazoxide on board or not. And so when you add diazoxide as a treatment, which is at this time standard of care for what we call sort of perinatal stress hyperinsulinism, that absolutely exacerbates any kind of underlying cardiac abnormalities and makes it very difficult to manage these patients. So I would say that those are the more like at-risk patients that have pulmonary hypertension due to diazoxide use. But I would also say that sometimes we put patients on diazoxide that are healthy patients in which we assume there's no cardiac risk. And of course, they're all screened before we start diazoxide. But randomly out of the blue, some of these patients will have pulmonary hypertension even without any of those risk factors. So it's a little difficult to predict who is going to have it and who's not as a consequence of diazoxide use. But I would say that the at-risk patients for sure that are syndromic or that have what we call perinatal stress hyperinsulinism are the patients that definitely are more likely to have pulmonary hypertension from diazoxide use.

Okay. Great. And then a follow-up, if I may, for management. Home infusion seems like a really nice proposition in CHI for patients who are old enough. Curious if this setting requires a human factor study? And would you expect that setting of use to be available upon initial approval potentially?

Yes. So in terms of -- this is Sunil. So in terms of the infusion journey, right, as I mentioned in my slide, we have done a lot of work understanding how the patients will get treated. I think it's fair to assume that the new born that typically would get a couple of infusions in hospital setting -- and once the patients stabilized in a hospital setting, then they would go into the outpatient and eventually after outpatient, they would go into the home. My experience with Crysvita is that almost at steady state, we had almost 80% of the patients getting the infusion at home. So we could see the same pattern here as well for ersodetug. Now as you mentioned, right, the older patients potentially could start in the outpatient setting and then eventually to the home. And then definitely, the more older patients will probably start at home. And as you know, payers also prefer home setting just from a reimbursement perspective. So we'll be ready to launch in all 3 settings, and we would basically meet where patient wants to get treated. But eventually, we do think that a number of these patients will transition to home setting.

Your next question will come from Yun Zhong with Wedbush...

So the first question on Tumor HI, streamlined design for the pivotal study is very encouraging. But I'm just curious, have you got any confirmation or indication from the FDA that the type of patients enrolled in the study on continuous glucose infusion is not going to be affecting the label that the approval or in some way limited to only those type of patients? I know that in the market research that you presented, it looks like you have already taken account this type of patient in the NICTH market estimate, but what about the insulinoma patients, please?

Thanks. Appreciate the question. I'll let Brian go ahead and comment.

So, as part of the streamlined design, we certainly got alignment with the FDA regarding that design. I would say, again, I'm going to put my endocrinologist hat on and Dr. Farooki can feel free to comment as well. Although we are evaluating the drug in the inpatient setting, the need for continuous glucose infusion is a direct representation of a severe and prolonged hypoglycemic event. So there would be nothing to indicate that, that response should we see it, and we're confident that we will -- would be different in the outpatient setting. Remember also that in parallel, or actually preceding it, we will have the outcomes from the sunRIZE study, which are randomized, double-blind, placebo-controlled in the outpatient setting on events. So we believe with these -- hopefully, it's come through today, these indications are very related. They're all hyperinsulinism and the mechanism is relevant to all, and that is another data point to support continued use in the outpatient setting. It's difficult to imagine that the drug would be stopped or that the regulatory bodies would require it to be stopped in the outpatient setting. And I would add to that one last thing. We hope, and based on the expanded access program, expect that many patients will be able to come off the drip and be discharged, and we will continue to follow hypoglycemia directly, both in terms of hypoglycemia time and events in the outpatient setting. So we will have a body of data that supports the use, and there will certainly be a weight of evidence argument for a broad label. And I think we were -- we'd be optimistic that we would achieve that.

Okay. And then a question on congenital HI and maybe for Dr. Krishnamurthy, please. So I saw that 13% of the patients in the Phase III study had already undergone pancreatectomy how -- what's the percentage of patients still having hypoglycemia after the pancreatectomy? And I believe that virtually all patients will eventually develop diabetes. So the erso treatment, would that further increase the risk of diabetes development?

Sure. So I would say that about 30% to 40% of patients that undergo pancreatectomy still have hypoglycemia after the surgery, which is why we say pancreatectomy is more palliative than it is curative. And then, I think from the data that we have so far on erso, the hypoglycemia or hyperglycemia excursions where blood sugar was higher than target occurred in blips, but I don't believe that things like hemoglobin A1c, which we target for diabetes, I don't believe that any of those were high enough that they were even of concern for the patient population. So while there is obviously a theoretical risk that blood sugars could be higher with ersodetug use, I don't believe that it's high enough to cause concern that it would cause diabetes. And you are absolutely right that after pancreatectomy, patients could have diabetes after their surgery. If the surgery is performed when babies are young, they usually don't come out with diabetes consistently. There is a period of sort of hyperglycemia and then eventually normal glycemia. But it's the patients as they age that have pancreatectomy that are much younger as the insulin requirements over time increase in anybody's life as you sort of go through puberty and beyond, that's the time in which diabetes is more likely to be diagnosed in patients that have hyperinsulinism.

This concludes our question-and-answer session. I would like to turn the conference back over to Nevan Elam for any closing remarks. Please go ahead.

Thank you, and thank you, all, for joining us again today. Really appreciate you taking the time to learn a little bit more about the treatment landscape, the disease state and of course, the commercial opportunity. I would particularly like to thank Dr. Krishnamurthy and Dr. Farooki for taking time out of their day. It's very important, I think, that we all have the awareness about hyperinsulinism and how erso may be used in the treatment landscape. I'm also really excited that Sunil is on board as our Chief Commercial Officer, and his team is growing rapidly and as we prepare, planning for success to commercialize erso and get it into the hands of patients. And with that, I would say we'll see you all next month, which will be an exciting time for us as a company as well as for treatment providers and patients and looking forward to that. The feature of next month will not be me or Sunil or others, but it will be Brian's show as we unveil top line data for sunRIZE. Thanks again. Wishing you all a good afternoon.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.