Rezolute, Inc. (RZLT) May 2026 Investor Update Transcript

Thank you for standing by. Welcome to today's webcast, Diagnosis and Management of Insulinoma and Non-Islet Cell Tumor Hypoglycemia. As a reminder, today all webcast participants are in a listen-only mode, and the meeting is being recorded. As part of today's event, there will be two interactive polls that the audience can participate in. I would now like to hand the webcast over to today's moderator, Carrie Stearns from Resolute. Please go ahead.

On behalf of Resolute, it is my pleasure to introduce today's speaker, Dr. Heidi Del Rivero. Before I met Dr. Del Rivero, I kept hearing the term unicorn, and it really speaks to her unique dual board certification in both endocrinology and medical oncology. Among her many accomplishments and accolades, Dr. Del Rivero has been instrumental in the guideline development for NANETs, for ASCO, and MEN1 Guidelines for AIDS. And with that, I'll turn it over to Heidi.

Great. Thank you so much for the kind introduction. And it's a pleasure for me to be here with you today. And having an endocrinology and oncology background really helped me understand more about these endocrine cancers. So today we are going to discuss something that is very close to my heart just because of the different aspects of hormone excess as well as tumor biology. And to start this webinar, we're going to discuss the diagnosis and management of insulinoma and non-ILA cell tumor hypoglycemia. The objectives of this talk is to review the causes of tumor-associated hyperinsulinism, including functional pancreatic neuroendocrine tumors and non-ILA cell tumors. Describe the underlying pathophysiology of tumor-associated hyperinsulinism and insulinoma as well as non-ILA cell tumor hypoglycemia. Discuss the clinical presentation and key diagnostic considerations in patients with hypoglycemia suspected as being caused by tumor-associated hyperinsulinism. Summarize current management strategies for hypoglycemia and insulinoma as well as non-ILA cell tumor hypoglycemia. And highlight the emerging investigational therapies and ongoing clinical trials for the treatment of hypoglycemia due to tumor-associated hyperinsulinism. Now, let's discuss with a case. So, this is a 55-year-old man that presented with a five-month history of abdominal pain and unintentional weight loss. CT scan revealed a 1.8 cm pancreatic mass with multiple hepatic metastases. Liver biopsy confirmed a pancreas neuroendocrine tumor with a somatic pathogenic MEN1 mutation. Octotiotic therapy was initiated. However, the patient experienced progressive abdominal pain and tumor growth despite treatment. Due to the cis-progression treatment with lutetiant, 177 dotate was initiated. Two days after the first PRT dose, the patient developed severe hypoglycemia with neuroglycopenic symptoms. Biochemical workup and imaging findings supported the insulin-mediated hypoglycemia consistent with insulinoma. So as we can see here, these are the laboratory findings. We have plasma glucose that was low and elevated insulin, C-peptide, as well as pro-insulin, all consistent with hyperinsulinism or tumor-associated hypoglycemia related to insulinoma in this situation. And in this case, the hypoglycemia actually worsened after the first dose of PRRT. And one of the questions was, well, this patient most likely developed tumor lysis because of the PRRT. This patient then has continuous intravenous 50 dextrose infusion through a central venous line, And despite enteral nutritional support, treatment with diaxoside, everolimus, dexamethasone, pasirotide, and glucagon, the patient remains profoundly hypoglycemic and dependent on dextrose infusions. Now, what is the most appropriate next step in the management of this patient refractory hypoglycemia? So we have the answer here, and this is, I will ask you to use a QR code so that way you can select your answer. But among the answers, we have hepatic artery embolization of liver metastasis, CAPTEND, increased IV dextrose concentration, initiate parenteral nutrition via central line, consider use of investigational therapy to treat refractory hypoglycemia or continuous glucose monitoring and the thyroid optimization with Kornstein supplementation. And with that, please select the answer. I'm going to give you a few seconds a couple more answers okay so now now let's see the results so in this situation there was a tight between a pathic artery embolization of liver metastases as well as consider use of investigational therapy to treat refactory hypoglycemia okay we're going to discuss about uh the different answers and what we think will be the best answer in this situation now let's discuss another case uh so this is a 77 year old female with locally advanced pelvic and left inguinal differentiated liposarcoma with regional nodal involvements on arable end past history is consistent with multiple hospitalizations and icu admissions for hypoglycemia managed with dextrose and high-dose steroids. She presented with recurrent and refractory hypoglycemia, requiring, again, hospitalizations for IV dextrose. For a workout of the hypoglycemia, as we can see here, it was relatively low plasma glucose or low plasma glucose, but we can see here that the insulin and C-peptide were low. Pro-insulin at that time was not available as well as the beta-hydroxybutyrate, But based on the history of differentiated liposarcoma, IGF-2 was obtained, which was elevated. Based on the clinical presentations, no I-less-cell tumor-associated hypoglycemia was considered. Now, what is the most appropriate next step in the management of this patient hypoglycemia? Initiate glucocorticoids, administer recombinant human growth hormones, initiate diaxocyte, increase IV dextrose, and initiate parental nutrition, or consider use of investigational therapy to treat the refractory hypoglycemia. So please select the answer. Thank you. More answers are coming. Okay. Let's see the results. So in this situation, so majority chose consider a use of investigational therapy to treat the refractory hypoglycemia. A few votes, they're considered glucocorticos, diaxocytes, IV dextrose. So we're going to also discuss the management not only for insulinoma, but also for non-ILA cell tumor hypoglycemia. And with that, let's first discuss what is the pathophysiology of insulinomas and non-ILA cell tumors. So the key features of insulinoma, as well as non-ILA cell tumor hypoglycemia, are different. And we're going to discuss all of that. Even though the clinical presentations may be similar, the origin or the tumor characteristics may be different. So we know that for insulinoma, it's the most common hormone associated with pancreas, neuroendocrine tumors. For non-ILA cell tumor hypoglycemia, this is a type of paraneoplastic syndrome, and it's associated with extra pancreatic tumors in this situation, most commonly associated with solitary fibrous tumors, hepatocellular carcinomas, fibrosarcomas, gastrointestinal stromal tumors, mesotelioma, as well as other cancers. Usually, the ones that are associated with this type of paraneoplastic syndrome are usually large tumors, very vasculars, that may have developed risks to this. In terms of the insulinoma, we know it's coming from the excess of insulin from the pancreatic beta cells. Insulinoma is quite rare, so it's about one to four cases per million per year. And a small percentage are malignant or metastatic. In terms of the non-insulin cell tumor hypoglycemia, it's rare, but I also feel like it's under-recognized. In terms of medical oncology practice, sometimes we see these patients with advanced disease and then they start to develop hypoglycemia. Sometimes the thought is that, well, maybe, you know, the liver is failing and because of that, you know, that's sometimes indication that not foreign therapies is indicated. But I think there is something that we need to think if this is really because of the worsening of disease or it's because maybe the tumor itself is producing these paraneoplastic syndrome. And it's something to keep in mind, and I do believe that it's under-recognized in medical oncology. In terms of familial syndromes associated with insulinoma, it's a 4% to 3%, most commonly associated with MEN1. Sporadic tumors, even though they have found some mutations in the chromatin remodeling or M-tropathway alterations, usually these mutations are not something that we can target with therapies. in terms of non-ILA cell tumor hypoglycemia, not necessarily related with Hereditary Syndrome, and usually the genetic profile, the molecular profile, depend on the tumor of origin. In terms of the tumor characteristics for insulinoma, most of them are not metastatic, and it makes sense because these tumors may produce insulin, and then sometimes with the excess of insulin they become very symptomatic with hypoglycemia. So it's because of this clinical presentation, so it's easier occasionally to detect that earlier. But approximately 10% of these patients may be metastatic, quite aggressive as well. And in terms of the selenomas, in terms of neuroendocrine tumors, we usually look at the size of the tumor. And in terms of non-functional pancreatic neuroendocrine tumors, we recommend surgery, fist-grade, and two centimeters in size. But for any functional pancreatic neuroendocrine tumors, no matter the size, direct surgery is recommended because of the symptoms. And by removing the tumor, then remove the excess of hormones and as well improving the symptoms. And non-ILS cell tumor hypoglycemia, usually they're very large tumors, as I discussed earlier. Here, the hypoglycemia for insulinoma, we know it's because of the beta cells of the tumors, endogenous hyperinsulinism, where for non-ILA cell tumor hypoglycemia, this perineoplastic syndrome is because of the high molecular expression or elevation of the high molecular wave IGF-2. In terms of the prognosis, if it's localized in the length, they have 94 to 100 percent has a five-year survival. When it's more aggressive, so then five-year survival is a 24 to 60 percent. And these patients may have more aggressive disease. And because of this hormone excess, sometimes very difficult to control. And that's necessarily something that needs, and it is an omelet need to develop better therapies and to control the hormones. And because by controlling the hormones, you can improve the symptoms related to the excess of hormones. Whereas the non-ihilous cell tumor hypoglycemia usually is poor prognosis and dependent also the type of cancer associated with this. Now, so it's important also that we're talking about insulinomas as well as non-ihilous cell tumor hypoglycemia. But the biochemical evaluation is different as well between the two of them and insulinoma. We know that this excess of insulin is also measured. Usually, whenever we suspect that this is an insulinoma, we obtain a random insulin and C-peptide and proinsulin. But then after that, if we think that this is an insulinoma, then the recommended subsequent evaluation or diagnostic test will be a 72 fasting test, but we're going to discuss more about that. But for here, it's important to know what is the biochemical evaluation. We know for insulinoma, insulin is high compared to non-ILA cell tumor hypoglycemia, which is low. C-peptide is high in insulinoma, low in IGF-2-mediated tumor hypoglycemia. Beta-hydroxybutyra is something that is suppressed in both of them, and we're going to discuss a little bit about that as an important aspect in the pathophysiology. Growth hormones in insulinoma is normal to elevate it, and IGF-2-mediated hypoglycemia is suppressed. And one of the reasons is because these tumors that produce IGF-2, this IGF-2 excess is going to suppress the growth hormones. And by suppressing the growth hormones, then it's going to then also decrease the release of IGF-1. So it makes sense that in these situations, growth hormones is going to be suppressed, IGF-1 levels is going to be low because of this excess of IGF-2. a uh and in tumor-induced hypoglycemia we also see elevated of high igf2 to igf1 ratio usually more than 10 to 1 and i can like explain before because of this igf2 then will suppress core hormones and then subsequently suppress the release of igf1 and that's the reason why we see this ratio that has to be seen more than 10 to 1 um and the timing of hypoglycemia and And insulinoma, that is usually fasting, but also it may occur any time. And non-ILA cell tumor hypoglycemia is more severe. And again, there is a very important pathophysiology factor that we're going to discuss as well. Now, in terms, again, of the pathophysiology of these tumors, whether it's insulinoma, with the excess of insulin, or when it is non-ILA cell tumor hypoglycemia because of this barynoplastic syndrome producing IGF-2, this is going to then activate the insulin receptor. And by activating the insulin receptor, then, consequently, what it's going to do is also going to express the glucose transporters. And this glucose transporters, what it's going to do is going to increase the peripheral glucose uptake as well as decrease the hepatic glucose output. And with that, that's what is going to then cause the symptoms related to hypoglycemia. Now, more important about this, the difference between insulinoma and IGF-2, non-insulin cell tumor hypoglycemia. As we discussed earlier, in insulinoma, insulin increases the peripheral glucose uptake as well as decreases hepatic glucose production. but on IGF-2-mediated hypoglycemia, despite the peripheral glucose uptake and decreased in hepatic glucose production, here in this situation, we're going to also have decreased lipolysis. We also see it on insulinoma, but not as more intense or more pronounced and tumor-induced and IGF-2-mediated hypoglycemia. And this is an important aspect to recognize between the two And why this happened? One of the reasons is because insulin, the half life of insulin is relatively short, where the IGF-2, the half life is longer. And because of that, it accumulates in the fat tissue. And by doing this, it decreased lipolysis. But this is an important aspect because in patients that have hypoglycemia, in order to obtain energy production, we're going to obtain it from the ketones. And if there is no doubt, the patient can go into severe brain estervation. And because of that, these patients, they have more severe refractory hypoglycemia. And not just that, they also have weight loss and they also have cachexia. And you have to add that on top of the already management of the cancer, which they can complicate the situation. We discussed about the different biochemical evaluations and insulin, increase insulin, increase C-peptide, and proinsulin, IGF-1 and growth hormones normal, where the non-ILA cell tumor hypoglycemia, insulin, C-peptide, and proinsulin is low, but at the same time, as we discussed, the IGF-2 is going to suppress the Croc formulas and then subsequently decrease the release of IGF-1. And even though in both of the insulinoma and a non-ILACEL tumor hypoglycemia, we're going to have a decrease in lipolysis is more pronounced in the non-ILACEL tumor hypoglycemia. Now let's discuss a little bit about the clinical presentation and management, diagnosis and management. So let's discuss about hypoglycemia and insulinomas first. So the most common clinical manifestation of insulinoma is we know fasting hypoglycemia. We always discuss about the whippetriase. The whippetriase is a low plasma glucose with symptoms related to hypoglycemia that is relieved with a high carbohydrate or sugary diet or meal. So by increasing that, then the symptoms will release or by increasing the glucose, the symptoms will release. This hypoglycemia can have a variety of symptoms, signs and symptoms. We have the neuroglycopyneic symptoms, which can cause confusion, ultimate status, visual disturbances, behavioral changes, seizures, and this is more pronounced and not either cell tumor hypoglycemia. We also have the autonomic symptoms, diphthesis, tremor palpitations, anxiety. An important aspect to recognize here is the hypoglycemia symptoms usually precede the detection of tumors, and because of that, when there is this hypoglycemia and no evidence of other, you know, history or evidence of tumors, then they can be misattributed to psychiatry disorders, cardiac, neurological disorders, and sometimes delaying the diagnosis from one to two years. Now, in terms of the approach to diagnosing insulinoma. So we discuss with post-triad, recurrent hypoglycemia. Usually we obtain a baseline or insulin, pro-insulin C-peptide. Once we see, as we discussed, the classic clinical lab of insulinoma that we see elevated insulin, elevated C-peptide, pro-insulin, and we then determine that this is an endogenous insulin-mediated hypoglycemia, the next step is to do a 72-hour supervised FAS. And that's something that needs to be in the inpatient setting. And with that test, then we measure, again, the insulin, the C-peptide, the proinsulant, the beta-hydroxybutyrate, any insulin screening, which can be all of the sulfonylureas and meticulatides. That's important. And as well, we know that this is glycemic response to glucagon. Now, once we have these lab levels, then we look at the insulin. If the insulin is low, then we can think that this is a non-insulin mediated hypoglycemia. If it's high, then we then suggest that this is an insulin mediated hypoglycemia. We look at the C-peptide. If the C-peptide is low, then this could be related to exogenous insulin. But if it is elevated, then after that, we can think that this is also related to endogenous insulin-mediated hypoglycemia, related to likely an insulinoma. Once we have this insulinoma, pancreas, neuroendocrine tumors producing excess of insulin, it's important to do localization studies. How do we do localization studies? By doing an MRI of the pancreas, multi-phase CT scans, and endoscopic ultrasound. In patients with neuroendocrine tumors, as we know, they express somatostatin receptors, so 68 gallium or 64 copper dot of the scans is also important for localization and staging. So if you're able to localize a tumor and if it's still within the pancreas, then we do surgeries and these indications. The difference here is when it's related to MEN1. So MEN1 usually has multiple pancreas neuroendocrine tumors. Maybe some of them produce insulin, maybe none of them. And that's sometimes when we don't know if it's multifocal or we don't find the source of the excess of insulin, that's when a selective arterial calcium stimulation may be important. So, and what this test is, is that they kind of like localize the three different arteries that supply the pancreas, like the gastrointestinal artery, the SMA, the splenic artery, and then inject calcium if they see a step of insulin or wherever is a step of insulin that's important for the surgeons to then determine this this where is located and then do the surgical approach if they're unable to see it either on the anatomical imaging studies or even on the um uh dotate scans the dotate scan is a highly sensitive test for neuroendocrine tumors but there is a percentage of insulinomas that may be no positive on the dotate scans and that's the reason why there is another type of nuclear medicine scans and GLP-1 excepting that is more sensitive for insulinoma according to some European studies. Now we discussed about the biochemical evaluation of insulinoma is different than in non-ILA cell tumor hypoglycemia. Here is the differential diagnosis based on a 72-hour FAST data. So we know that the biochemical evaluation related to insulinoma when there is an exogenous insulin. So the difference here, even though we're going to have high insulin and low glucose, the proinsulin and C-peptides are going to be low. Now, the insulin antibody conditions related to insulin out antibody and insulinoma biochemically looks the same. So we have low glucose, we have high insulin, pro-insulin, C-peptide, and beta-hydroxybutyrate. But the difference between the two of them is clinically. Insulinoma, the symptoms of hypoglycemia, of course, fasting, but in insulin autoantibody or related hypoglycemia related to insulin autoantibody, that usually happens two to four hours after the patient eats. And what happens is like when somebody eats, the insulin gets released, but in the presence of insulin out on the body, these antibodies, they kind of like catch the insulin, it's like sponge, they absorb the insulin, but then it's not released until two or four hours later, and then that's when the symptoms happen of hypoglycemia. So, even though insulinomas or hypoglycemia is related to insulin antibodies may have the same biochemical profile, the clinical presentation is different. And that's kind of like where we need to, in these situations, check for insulin autoantibodies. Addressing hypoglycemia is a key treatment goal in insulinoma. So if it's localized disease, solitary tumors in the lens, usually surgery is the indication, no matter the size of the pancreas and your endocrine tumors. If the patient is not a surgical candidate, which is less than, in this situation, less than 5%, then we need to understand the stages, we need to understand where the disease is located, the volume of disease, whether it's metastatic or surgical and resectable, to then provide the best guidance to these patients. There are different therapies, front embolization, radiofrequency ablation, stereotactic body radiotherapy. There is also 177-notician dotatate if the patient is positive on 68-gallium or 64-cop dotatate scan. Like I said earlier, so there are a small percentage of insulinomas maybe negative in this type of scans, Even though we know it's highly sensitive for all neuroendocrine tumors, especially the well differentiators for the GLP-1 PET scan can be another treatment, another way of diagnosing these patients that say it's not available in the United States, more available in Europe. And as I say, if the patient has more aggressive metastatic disease, we also need to understand, again, the volume of disease. I always tell my fellows and patients as well that it's not like one side fits all. The treatment of neuroendocrine tumors is personalized from patient to patient, and what I recommend to one patient may be different than another one. And we also need to understand different clinical characteristics of these neuroendocrine tumors, including not only the primary tumors, but also to understand whether they express somatisatine receptors, what is the volume of disease, whether it's slow growing or rapidly growing, And of course, if they produce hormones, and it's important to understand that in order to guide the best therapies for these patients. And that's when even in a subset of patients that may have metastatic disease, always discuss with the surgeon, maybe there's a window to do a cytoreductive surgery and it's something that needs to be discussed. If it's unresectable, that's when our systemic therapies play a role. now hormones and and again when i talk to my fellows and we see a patient when you're endocrine tumors we i always ask you know is the tumor functional or non-functional if it's functional then there may be uh other therapies that may be not the same to control the tumor and i always ask my fellows what do we need to do in order to control uh the symptoms related to hormone excess or what we need to do in order to control the tumor growth because sometimes the management may be different from one to another. So we think that the systemic therapist may be able to treat some of the symptoms related to hormone excess by reducing the size of tumors, but we know that that doesn't necessarily happen. They still have the symptoms and their other measurements need to be implemented. So which one does? We have diaxocyte, for example, that inhibited insulin secretions, somatostatin agonist. So this is an important aspect in terms of somatostatin agonist to remember. So 4% of the somatostatin agonism will cause hypoglycemia. In my experience, usually I have seen that with octreotide, that with landreotide. So you have a patient that has insulinoma, and usually landreotide is my preferred choice just because I see more, you know, hyperglycemia with landreotide. Maybe somebody else may have a different experience. Also, if it has somatacatin receptor, the PRT is another one. Everolimus is another systemic therapy that is used in patients with pseudinoma because the side effect of Everolimus is that it also produces peripheral insulin resistance, and with that, it can also have hyperglycemia. There are other supportive cares of hyperglycemia, which can be frequent snacks, not only feeding, high glucose. But as we can see, There are some patients that can be quite refractory despite all these therapies, and that's when we need to, this is going to need to develop therapies, and that's also important to know, you know, what is available. So now let's discuss a little bit about the clinical presentations of the and I know the management of non-ILASL tumor hypoglycemia. And clinical presentations is tumor-associated symptoms like weight loss, abdominal mass pain, dyspnea. They can also have neurocognitive symptoms. And we discussed earlier, you know, how this happened. There's a decrease also like polys is more pronounced that we can see than insulinomas. They can have a variety of symptoms as well, very refractory as well when this is related to a paraneoplastic syndrome. There are other rare symptoms that can happen with these situations, like acromegalic skin changes and other features as well related to acromegalic features. And as we know, how this happens is because the tumor is producing this excess of IGF-2, and it can also cause the activation of the insulin receptors and cause hypoglycemia. as well. So we also confirm the symptoms related to the Whipple triad, and then it's important to know what are the next steps. Usually in those patients, we know that they may have a non-historic cancer. And in these patients that we think that, you know, they have either a liposarcoma or gastrointestinal trauma tumors, or these sarcomas, epastolecular carcinoma, and so forth, and they have hypoglycemia, then we need to know whether this could be related to this paraneoplastic syndrome and do the biochemical evaluation need it. Usually in those patients, a 72-hour supervised pass is not needed, but in the sense of knowing if there is any history of cancer, sometimes they can provide some information. Again, the difference of insulinoma versus non-ILASL tumor hypoglycemia is different in terms of what we're looking and what we measure as well. And insulinoma, high insulin versus low insulin and non-hylisole tumor hypoglycemia. Sometimes this may happen in patients that have a non-historic cancer, but if this were to be the biochemical evaluation, then we need to understand whether there's any underlying malignancy. And we need to measure as well the levels of IGF-1 and IGF-2. We discussed earlier about the ratio of IGF-2 versus IGF-1. usually greater than 10 to 1, and thus, usually, we consider that a gold standard diagnostic biochemical testing. We call it like more a biochemical clinical gold standard testing, but also the Western blood can also be important. That says it's not widely available, and we say that this Western blood will be more of a biological gold standard test. I think most institutions may have these levels of IGF-2 versus IGF-1, and that is sufficient to make the diagnosis. But in the case that you may have a Western blood, so maybe that could also help confirm it as well. So in terms of the treatments in this situation, so first we need to understand the tumor type. Every cancer that may have this baroneoplastic syndrome is treated differently. We need to understand the type of cancer, the type of therapy is related to that, but also the hypoglycemia management in this situation besides supported care that we already discussed. Medical management is different than insulinoma. Usually steroids is important here. High doses of steroids, sometimes recombinant human growth hormones can also be given, but this is an expensive type of therapy and doesn't necessarily work for everyone. And an important aspect that we need to know here compared to insulinoma is that dioxazide and nocturotide doesn't necessarily work here compared to insulinoma. And one of the reasons, because of dioxazide, we know it works with the potassium channels and the level of the cells in the pancreas, which we know in this type of parinoplastic syndrome That doesn't necessarily be the case, and that's something important to recognize. Octetite also don't have much role. Sometimes in some patients, you know, it's very difficult to control. We can use it, but I don't think there is much effect on that. And again, this has become an unmet need as well to treat these tumors. Important to know there is a significant patient burden with the current treatment options, And also understanding that these type of tumors, because of the symptoms related to hypoglycemia, can significantly impact the life of patients as well as the caregivers. These patients can have acute symptoms related to hypoglycemia, with the neuroglycopenic symptoms, with cognitive impairment. This can also put somebody in danger because you have the one drive and then having a piece of hypoglycemia, and then that can cause accident injuries because of the effect of the neurocognizant symptoms. It can also have seizures. It can go in coma, the cardiovascular event, the cardiovascular event. So these are most of the acute symptoms that can be quite debilitating for patients. The long-term is the fear of hypoglycemia, the autonomic symptoms, the cognitive decline, the impact of tumor-directed therapy, the quality of life. Some of these patients may even are afraid to go out. They need to have multiple snacks or meals throughout the day, and that can also certainly impact quality of life. Now, in terms of the current approaches, so we talk about some of the management, not only for insulinoma, but as well for non-ILS cell tumor hypoglycemia, in terms of the treatments to control the symptoms related to hormone excess or hypoglycemia direct therapies. In insulinoma, we discussed the diaxocytes. We see some responses. So we know that diaxes are active, so the level of the potassium channel opener. And by that, it's basically inevitable release of insulin and that some of the patients may have a response, but some of them doesn't necessarily have a response. And not just that, but they also need to recognize the side effects like edema, fluid retention, and non-ILA cell tumor hypoglycemia, as we discussed, there is no role of that. and the same with somatostatin agonist. And in insulinoma, we have some variable efficacy, as we discussed. Always keep in mind that 4% may cause hypoglycemia. As I say, I have seen it more with landreotype than other type, but in terms of, we always say for neuroendocrine tumors, the efficacy between the two of those in terms of tumor control is equivalent, but in terms of side effects may be different. Ulucocorticoids may have a limited role in insulinoma, but it's usually the mainstay first-line therapy for non-ILSR tumor hypoglycemia as well. This insulinoma is usually higher dose. It requires careful titration. It has some long-term side effects with osteoporosis, hypertension, immunosuppression. So that's important. A lot of our cancer patients, they require immunotherapy as a therapy for their cancer. So, and in this, if they have hypoglycemia, you cannot give steroids, for example. And now immunotherapy is not like the standard therapy for a lot of our cancers. So, and that's important because in that situation, glucose will be contraindicated in certain situations just because that suppress immune system. And with recombinant human growth hormones, it seems to be an option for non-I-lessal tumor hypoglycemia. I personally don't have the experience for that, but that has been used. But that said, it's costly, and usually given in combination with steroids, it doesn't have a role in insulinoma, and we know the other like IV dextrose and glucagon, which only cause a short-term stabilization, but that said, still sometimes these patients are in constant IV infusions of dextrose and so forth. So as we can see, even though we have these options, it still is limited, and every patient may response to this. And also knowing the side effects and also the interactions, drug and drug interaction that may happen with other therapies associated not only to treating the neuroendocrine tumor, but as well the other cancers that develop this type of neoplastic syndrome. Now, in terms of the tumor-directed management for insulinoma, surgical resections, cytoreductive surgery can be an option here, and certainly you remove the volume of disease that can also improve the excess hormones and symptoms. And in non-ILA cell tumor hypoglycemia, 50% of patients are not candidates. I mean, we know that some of these cancers, so like hepatocellular or certain sarcomas, surgery is not beneficial. For prognosis, you need to act more with systemic therapies. and liver-directed therapy for hepatic metastasis and neuroendocrine tumors is an option as well for non-ILA cell tumor hypoglycemia. Lutathera, OPRT with 177-lutition dotate, it can be an option as long as the tumor expresses certain receptors with the neuroendocrine tumors, not with the non-ILA cell tumor hypoglycemia. CAPTEN has been used for pancreas neuroendocrine tumors with efficacy of shrinkage in these tumor types and the mTORS we discussed because of verolimus, even though the response rate is not as significant, but is able to have some antitumor effect controlling the symptoms because of the side effects with the hyperglycemia and also having stabilization of disease, but not necessarily an effect on the non-ILASL tumor hyperglycemia because in this situation you need to treat the tumor depending on what the tumor is now in terms of the management of these patients it requires a multi-primary approach and the core care team is an endocrinologist who can understand more about uh the in the biology in terms of the insulin production and as well as the medical therapy for the hypoglycemia oncology is important because they may manage the tumor that causes this excess of insulin, manage the metastatic disease, the malignant insulinomas. Surgeons as well is important. Most of my neuroendocrine tumors, I do discuss it with my surgeon because there is a subset of patients that may benefit from surgery, and it's always important to discuss with the surgeons as well as nuclear medicine and radiologists as well whether the patient may benefit from the radioligand therapy. Supported care is also important, specialized care with nurses, nurse practitioners, dietitians. Like I said earlier, sometimes these patients may require multiple meals throughout the day, psychologists, counseling, as well as palliative care. Now, after this discussion, let's see how we do with the questions. So we go again with these questions. As you remember, this is a 55-year-old male with five-month history of abdominal pain an unintentional weight loss. CT scans reveal a 1.8 pancreatic mass, multiple liver metastases. We see a picture here of the DOTTE scans with multiple liver metastases, biopsy confirmed a net, pancreatic net with a somatic pathogenic MED mutations. After that therapy was initiated and then due to progression he received 177 nutrition DOTTE. He developed symptoms of hypoglycemia, and neuroglycopenic symptoms two days after the first infusion. We discussed earlier about the biochemical information. This patient has worsened of the symptoms, continuous intravenous 50% dextrose, and despite all of the nutritional support and dioxin, this patient received everything par serotype glucagon. He still remains profoundly hypoglycemic. And with that, let's just answer the questions that we learned here.

Yes, this is the operator. The poll is open for people to submit answers again for poll one. Thank you.

Okay, I think there is a few more people voting here. Okay. Well, so let's show the answers now. So, a good number selected, consider using investigational therapy to treat refactor hypoglycemia, and some seropathic taste for liver metastasis. We can discuss more about this. In the first patient with the pancreas, neuroendocrine tumors, and liver metastasis, an option to consider will be embolization, ablation, to treat the liver metastasis. So that's an option, especially if the patient has mainly liver metastasis without any estereopathy disease. I think embolization can be considered, and that's an option that the patient has not received. That said, we know that in these patients we're not going to cure from the disease. It may be symptom management for some time, but then we need to think about what other options do we have. So now let's continue with the next case. Okay, good. So this is the next case. If you remember, this is a 77-year-old female with left inguinal de-differentiated sarcoma with regional nodal involvement, a past history of multiple hospitalizations and ICU admissions due to hypoglycemia, managed with dextrose and high doses of glucocorticoids. She's still presented with recurrent refractory hypoglycemia, requiring hospitalizations. And we discussed about this is the biochemical finding consisted with non-ILA cell tumor hypoglycemia. and um let me see do we have the answers here okay yes let's see i mean i still believe that some are um voting still okay yes i think this patient with a uh non-ylaseal tumor hypoglycemia related to differentiated liposarcoma who already is receiving therapy for the cancer or they have received high doses of steroids and is still hyperglycemic, then if there is availability of an investigational drug that can help the symptoms of hypoglycemia, that's something that we are going to discuss next. But understanding what is the limitations of current therapies with the management of hypoglycemia and insulinoma, As we discussed, the responses are variable and sometimes are not quite effective. We know that we have also the toxicity associated not only with the treatments to control the hormone excess, but also at the same time with the various systemic therapies indicated for neuroendocrine tumors. Some of these patients may still be quite refractory, especially in the metastatic setting or on the resectable setting, and sometimes it's biased, although the other intervention still remains hypoglycemic. In terms of the non-isolation tumor hypoglycemia, we have very limited options. Glucocoricoids is usually what is the standard on these patients. Dioxoside and SSAs doesn't work here as in patients with insulinomas. These patients may have also treatment related toxicities, and these patients may have persistent hypoglycemia despite the interventions. And there is an unmet need and significantly a challenge to treat these patients and recognize not only the clinical presentations and how in terms not only on their well-being with the symptoms related to hormone excess by the same time, the treatment of the cancer itself, But with all those challenges and still unable to control the symptoms of hypoglycemia, this is definitely an unmet need. And with that, we're going to discuss what we have in the treatment landscape for tumor-induced hypoglycemia. So we discussed earlier about the pathophysiology of insulinomas as well as the non-hylocal tumor hypoglycemia. We know that this either excess of insulin or excess of IGF-2s can align to the insulin receptors and with that activates the insulin receptor cascade and with that the glucose transporate for which it's going to then increase the peripheral glucose uptake, decrease hepatic glucose production, hence the hypoglycemia. And currently there is a novel therapy. Let me just go back here because as we can see, you know, this is kind of like understanding the pathophysiology on how these insulinomas and the not tumor in this hypoglycemia binds to the insulin receptor. But if we are able to do something that can help prevent that, and that's where this novel therapy with their soft dog. This is a fully human insulin receptor antibody. It has an allostatic binding, which is important because it doesn't block the insulin receptor. So it's still kind of like have the activity for which they still, they can have normal production of insulin because insulin is needed in order to lower the glucose as well. But in this situation, these allosteric bindings, it doesn't block it. It produces an evasion of this activation of the insulin receptors. It also modulates insulin binding and significantly resulting in a reduced glucose uptake from the bloodstream and also modulates. Modulation results in a more normalized insulin state, as we discussed, because of this allosteric binding and how maintenance glucose values in the healthy range. It's administered via IV infusion weekly for eight weeks, followed by every two to four weeks. So how this was developed, and this is just an overview of the talk, initially was, in order to understand the safety, was given in a couple of healthy individuals. And then after that, a multiple phase 2 and 3 study was given for patients with congenital hyperinsulinism. And now there is a program for tumor-induced hypoglycemia, not only insulinoma or pancreatic neuroendocrine tumors producing insulin, but also for non-ILA cell tumor hypoglycemia. There is also evidence of expanded access in these patients for which they were able to establish the preliminary efficacy as well of Erzodotoc. There is currently an ongoing phase 3 study of Erzodotoc for hypoglycemia due to insulinomas and non-ILA cell tumors. The inclusion criteria is patients older than 18 with the diagnosis of either neuroendocrine tumors producing insulin or non-ILA cell tumor hypoglycemia. The HAT failed the current therapies that is given for hypoglycemia requiring IV infusions, and the exclusion criteria is evidence of active infections, treatment with another investigational drug, and they need to have a washout period, so any clinical significant abnormal lab value screening, meaning maintaining a good organ function. Primary endpoint is the number of participants achieving at least 50% reduction from baseline in IV glucose requirements. And the secondary endpoint is changed from baseline and average daily total of IV glucose and time to complete winning of IV glucose administration after initiating an air dose attack. So as earlier discussed, this treatment is given IV infusion once weekly for eight weeks. Patients will continue their standard of care therapy for either the tumor-induced for non-ILSR tumor hypoglycemia related to perineoplastic syndrome or for insulinomas. They can continue the standard of care or therapies for the cancer itself. And subsequently, these patients can have an open-level extension up to three years. So just in one aspect, we have this study available at the NIH. We're about to open soon. We're excited about this. And how can you get access to this drug? Knowing that this isn't an ometony, knowing that this is an orphan disease and the rarity of these tumors, there are different ways that you can obtain Erzodotoc. One is in the clinical trial enrollment, but in some patients where they may not be eligible for this or there are certain restrictions based on the clinical trial enrollment, They can be enrolled in the expanded access program as well. They still, all of those, they have an informed consent, an IRB oversized, and reporting to the FDA. But in some patients that maybe it's difficult to travel, some of these patients may be continuous IV glucose infusions, very difficult to treat. Maybe the patient itself doesn't want to travel. Maybe it's difficult for the family. you can always obtain the drug via single patient expanded access via compassion use. And all of that, whether it's a clinical trial, an expanded access program, a single patient expanded access, there are different ways that you can get this drug wherever you are. I think it's important that you know this, and then we can discuss different ways how to get access to the drug. And again, we have this available at NIH. I'm very excited about this. and if there is any questions, please, you know, let me know and be in touch with the sponsor. In summary, we know there is distant etiologies of tumor-induced hypoglycemia, whether it's insulinoma or non-i-less cell tumor hypoglycemia. They have a shared downstream pathway by activation of the insulin receptors and with that, we know that that increases peripheral glucose uptake, suppressed hepatic glucose, suppressed ketogenesis, and in a patient with cancer, that's important because that can also be the source of carcaxia. The diagnostic approach we discussed about confirmed the WIPOS triad, obtained insulin, C-type proinsulin, beta-hydroxyurea, sulfonylurea screen, and confirmed with a 72-hour supervised FAS, and non-ILA cell tumor hypoglycemia, the diagnosis with the ratio of IGF-2 to IGF-1, gradient and want, or detection of big IGF-2. We discussed about the management limitations, and we know that diapsis and SSAs may be more effective in insulinoma, non-ILA cell tumor hypoglycemia. For those patients, steroids is usually the main-state therapy. We don't have until now an FDA-approved agent that targets this patient population. It's certainly a clinical burden, and it's a substantial clinical burden. Because despite all these interventions, the hypoglycemia may still remain refractory. These patients require prolonged hospitalizations, continuous IV dextrose, multiple systemic therapies, and in spite of all of this, it still has severe hypoglycemia for which that can certainly, in terms of quality of life, disrupt the quality of life. And it's important to not meet. And this tumor-associated hypoglycemia is quite complex because, as I say, you don't only treat the tumor itself with different systemic therapies, but also the symptoms related to hormone excess. And it's important to have a team that can be familiar with all of this to provide the best answers to the patients. And now that we have this novel therapy with our study talk, I think that can certainly help the patients. And so I'm excited about that. And with that, I would like to thank you for your attention. Thank you so much.

We just want to thank you for sharing your clinical perspective and a wonderful presentation, Heidi. For those interested in learning more, you've seen the QR code throughout the presentation to contact our clinical team, or you can visit upliftstudy.com. I'd like to hand it back to the operator.

Thank you, Carrie. And I would like to thank everyone for attending today's webcast presentation, and you may now disconnect your webcast lines.