Rezolute Inc Aktie

Good morning, and welcome to the sunRIZE Topline Data Conference Call. [Operator Instructions] Please note, this event is being recorded.

I would now like to turn the conference over to Nevan. Please go ahead.

Thank you, and good morning, everyone. We appreciate you joining us today to review the study results from our Phase III sunRIZE study for ersodetug in patients with congenital HI. I would like to start by thanking the patients, their families and the investigators for the tremendous effort in participating in the study. We are deeply grateful for the broad participation of the worldwide congenital HI community in working with us to explore the possibility of finally bringing a new therapy to this patient population, where there's a massive unmet need.

As you've seen in our press release, the primary and secondary endpoints did not achieve statistical significance. Frankly, we are shocked and dismayed by the outcome of the study. With a drug that we believe has activity, we were unable to demonstrate a significant difference compared to placebo in an outpatient study, where glucose is both the endpoint and the vital sign for patients. Again, both the endpoint and the vital sign for patients.

Notwithstanding this result, we believe that our drug works in treating hyperinsulinism, and we believe that the observed study effect in the placebo arm reflects an inherent problem in conducting studies of this type in an ultra-rare pediatric population where knowledge of glucose levels and family vigilance prevent serious hypoglycemic outcomes is critical to patient management. I want to point out that more than 50 children on the sunRIZE study are now on our therapy as part of the open-label extension. And some of those children have now been completely weaned off of other background therapies. They are on ersodetug as a monotherapy.

This represents exciting potential for the patient population, but only to the extent we can find a way to responsibly get ersodetug into the hands of other patients and their families by gaining regulatory approval. With all of that as a backdrop, we believe that the negative outcome of the sunRIZE study is definitive proof that the traditional and historical methodology of the "gold standard" of a Phase III randomized placebo-controlled study is simply not suitable for this ultra-rare pediatric indication.

Fortunately, FDA has recently demonstrated a willingness to reconsider how we study ultra-rare diseases, and we're encouraged by the statements recently been made by FDA leadership and others regarding the need to streamline clinical development, particularly where there is mechanistic possibility and an indication of real oral benefit. And we know these are not simply just empty words coming from FDA. And here's the case in point. Up until September of this year, FDA wanted us to conduct a Phase III placebo-controlled study for our other indication, tumor HI.

However, when we approached FDA to reconsider this study design, the agency recognized our success in treating tumor HI patients under our expanded access program, and they believed that the activity and the totality of evidence warranted a modification. Subsequently, just a few months ago, FDA agreed with us to streamline study design into an open-label fashion and to use glucose infusion rate as a mechanistic endpoint sufficient for registration.

We are extremely excited about the tumor HI study and the fact that we have a new paradigm to move forward to treat that patient population, and we will work on that study and complete that study next year. But as we consider congenital HI, we're not giving up. We will be engaging with FDA to hopefully find a sensible path forward for this patient population. Let me be very clear. We are not done. We are committed to the congenital HI community and getting our therapy into the hands of patients and their families.

Our commitment is based on doing what is right, doing what is right for patients and their families. And if we're going to do what is right, then it is our duty and our mission to break down all barriers, real and manufactured to achieve the goal that all of us share to improve outcomes for patients that are suffering with severe rare diseases. From a corporate perspective, we're fortunate. We still have the financial wherewithal to pursue our objectives. As of September 30, 2025, we still had $150 million in cash.

That said, we have to be conservative, and we are already thoughtfully starting the process of decreasing operating expenses, which includes an unfortunate expected reduction in force. We plan to provide additional details about these updates as appropriate. But importantly, I think we should discuss the study and the results in more detail. And to that end, I would like to now turn the call over to our Chief Medical Officer, Dr. Brian Roberts.

Thank you, Nevan. Let me continue by repeating the obvious. We are extremely disappointed and surprised by the results, which showed that the sunRIZE study did not meet the primary or secondary glucose endpoint. While we have not yet evaluated all secondary endpoints as part of this top line analysis, it's our view that the main outcomes are clear. And for that, I'd like to thank our clinical development and operations team, as well as our clinical supply team for executing a high-demand study at a very high quality.

Of the 63 enrolled participants between the open-label arm and the initial 8 infant participants and the remaining participants enrolled into the randomized controlled arms of the study, only 4 patients early terminated the study, which were due to adverse events that I'll discuss later. 59 participants who completed the study universally elected to enter the open-label extension, as Nevan has indicated, and an overwhelming majority of these remain on the OLE or open-label extension to date, with some approaching 18 months now of total treatment duration.

This is a very high retention rate in the study and into the OLE in the setting of needing to visit study centers every 2 to 4 weeks for a 30-minute IV fusion is no less than remarkable considering these circumstances and is a testament to the efforts families, study sites and our Rezolute employees made and continue to make on behalf of ersodetug in the sunRIZE study.

As I lead up to a more detailed discussion of the efficacy results during the pivotal treatment phase of the study, I'd like to first emphasize the final study demographics and baseline characteristics confirm our preliminary reporting at the Annual Congress of the Endocrine Society this past July. The short conclusion here is that we enrolled the right patients and they were well matched across the treatment arms. Amongst a total of 55 enrolled participants randomized fairly equally across the double-blind treatment arms, the average age was about 3.5 years, and the majority of patients were using one, if not more standard of care therapies for hypoglycemia management, including about 40% on diazoxide, almost 70% on somatostatin analogs and almost 40% who were using regular tube feeding regimen.

Notably, and in spite of these background therapies, baseline hypoglycemia rates were high, including an average of almost 13 hypoglycemia events per week by self-monitored blood glucose or glucometer across the treatment arms and almost 20% time in hypoglycemia by continuous glucose monitoring. Importantly, the 3 treatment groups of placebo and 5 and 10 milligram per kilogram of ersodetug were generally very well matched across these characteristics.

As we indicated in the press release earlier this morning, ersodetug target drug concentrations were safely achieved across all age groups studied. There were 2 benchmarks we used when designing the study and selecting the dose regimen. One was a model of efficacious concentration based on an EC50 derived from both in vitro and early phase clinical studies. And the other was the observed concentrations from the open-label Phase II RIZE study where reductions in hypoglycemia from baseline of up to 75% were observed with administration of 6 or 9 milligrams per kilogram of ersodetug every other week for 8 weeks.

This threshold range was reached at the sunRIZE study dose regimens of 5 and 10 milligram per kilogram administered every other week initially, followed by every 4 weeks over the remainder of the 24-week treatment duration. As with the patient population enrolled, we believe the dose regimen also set the trial up for potential success. Safety observations from the study were generally favorable and in our opinion, support safe use of ersodetug in pediatric and adult patients. Two participants from the study experienced serious hypersensitivity reactions, which led to early discontinuation of study drug. The incidence of serious allergic reactions across the program is quite low compared to biologic or monoclonal antibody treatments at about 2% or less overall.

As I mentioned earlier, 4 patients discontinued early overall. And the other 2 -- as I mentioned earlier, 4 patients discontinued overall, so 2 being the serious allergic reactions I mentioned and the other 2 were also due to adverse events. One was for hypertrichosis and one a more mild infusion reaction. Hypertrichosis was the most commonly reported study adverse event associated with the study drug, and this occurred in 14 ersodetug treated patients and in 1 placebo patient.

But this is generally mild and self-limiting and reported to be much less significant than the typical diazoxide experience. And there were no other ersodetug-related safety findings in the study. Unfortunately, although ersodetug target concentrations were largely safely achieved in this enrolled patient population with demonstrated baseline hypoglycemia, this did not translate into the ability to show statistically significant reductions in measured hypoglycemia in the pivotal study portion.

For the primary endpoint, which was the percent change in the average weekly number of hypoglycemia events by self-monitored blood glucose or fingerstick glucometer, the observed reductions from baseline at the week-24 end of treatment visit were 33%, 45% and 40% at the 5, 10 and placebo treatment arms, respectively, which were not significantly different. As you can conclude, there was a significant study effect with measured events and the effect size in the ersodetug arms was not meaningfully more than this for this endpoint.

The highest priority secondary endpoint in the multiplicity and fixed sequence testing strategy was the percent change in the average daily percent time in hypoglycemia by continuous glucose monitoring, which may be somewhat less prone to measurement bias because of its consistent nature. Although a 7% increase in hypoglycemia time from baseline to week-24 in the placebo group indicated that no study effect was observed, the observed reductions from baseline and hypoglycemia time of 17% and 25% in the 5- and 10-milligram ersodetug groups, respectively, did not reach statistical significance.

We'll continue to evaluate the impact on other secondary endpoints and report those at an appropriate future time and setting, but it should be noted that those would not be controlled for type 1 error in light of the failed primary and key secondary endpoints and therefore, would need to be interpreted with caution. Again, this is an extremely disappointing and frankly, surprising result for all involved, considering that it doesn't reconcile with past and present reports in clinical trials and expanded access in our open-label patients.

On the one hand, the explanation could be as simple as this being a controlled clinical trial. On the other hand, past experiences in congenital HI patients as well as aspects from the present trial, including learnings from the ongoing open-label extension portion of the study do merit additional investigation. As would be expected, we are conducting a thorough evaluation to gain a better understanding of the study outcomes, and we intend to meet with the FDA under our breakthrough designation to consider next steps for the program.

In spite of the setback with our congenital indication, we remain committed in our efforts to bring a better therapy to patients and families suffering with the consequences of hypoglycemia caused by congenital as well as other forms of hyperinsulinism.

And with that, I'd like to open the call up for questions.

[Operator Instructions] Our first question today will come from Debjit Chattopadhyay with Guggenheim Partners.

I have a couple. Could you walk us through the interim analysis and what could have been done differently at the interim? And then given that sunRIZE was supposed to be the pivotal for the upLIFT study, what does this mean for the tumor indication going forward? Can you file based on the outcome of the upLIFT, would you need a second study? Not entirely clear at this point.

Sure. Thanks, Debjit. Both obviously key questions. There was nothing we could have done differently at the interim analysis. It was executed exactly as planned. Please recall, we were blinded, and we reran the interim analysis. The study conclusion is one of our evaluations on the same 24 patients who finished, and we produced a result that was consistent with the decision to continue the sample size as is. Unfortunately, we were in a tiny sliver area where we were not in the [fetal] zone, but also not in what was called the promising zone that would have led to a study sample size increase.

And in a blinded fashion, I think based on, again, past results, past outcomes across the program, observations, empiric anecdotes, we hear all of it. We were optimistic, but we were blinded and we didn't know the outcome. We've confirmed that with our own analysis. We've confirmed that that's, in fact, what the DMC saw. So there was nothing we unfortunately could have done differently, and it's a disappointing outcome.

As far as carryover and what it means for the tumor program, it doesn't. As far as we can understand, this is a separate IND. The FDA and our discussions with them clearly indicated it had to be a separate IND. It's the same division. They wanted the primary supporting study in the tumor indication to be the tumor study. And so we believe that the planned study there, which is a different endpoint glucose infusion rate, an endpoint that reflects severe continued consistent hypoglycemia in a hospital setting and can't be confounded whatsoever has a high likelihood of success based on what we've seen thus far in the program.

And to further add to -- sorry, go ahead, Dejit.

Finish your thought, Nevan.

Yes. And just to add to Brian's thoughts there as well. We know that the tumor indication from a financial perspective is a much larger indication. And there's a lot of interest and excitement around that. And given what we've seen to date and the real-world use of our drug in the really dramatic change we've seen in hypoglycemia and getting patients out of the hospital and substantially changing their lives has been really impactful. And so that remains the same.

And so some could say we should be still delighted that we have a larger indication that is well intact, and we're moving forward with that. But we are really disappointed by this study result because this is about children, it's about families, the most impactful patient population you can ever imagine. And we have to do what is necessary to get this drug into the hands of children and their families. And so you can hear from the tone of our call and our thoughts that we're really dismayed by these study results because notwithstanding the fact that this is a smaller indication relative to tumor, this is extremely important.

So just a follow-up, if I may. Do you think the CGM data, if it was unmasked to caregivers and patients could have impacted the placebo response kind of what was observed in the [indiscernible] glucagon study?

Debjit, I think patterns are potentially consistent with that. If I can talk about a spectrum, for example, just to add to that of assessments with point-of-care self-monitored blood glucose is only a fraction of the day. It's influenced by when a patient checks. We certainly control for that as best as we can. As we discussed before results with a variety of people, we required a minimum of 4 times a day. We have patients check whenever there's a source of information that suggests a possible event. But ultimately, they're influenced by what they see when they choose to check.

And I think on the spectrum of endpoints, that's probably the most difficult. And that pattern has persisted here. And I've heard that feedback from key opinion leaders already that that's extremely challenging. They believe in this patient population and outpatients where these are the endpoints that the FDA has required to date. On that spectrum, I would say, CGM then is less prone to that. And then as you move along that spectrum, unfortunately, it's a patient population you can't study as outpatients are those that are on a glucose infusion rate.

So again, as I indicated, that is an endpoint that is pretty hard, clear and mechanistically driven. And I think that's what we see in the tumor patients, it's quite clear in our expanded access program. That is the primary endpoint in that study. And as we look for possible directions on the congenital program and have discussions with FDA, we'll certainly look at how we can implement that into a potentially additional small study, whether that's our planned neonatal study or in another form to be focused on that endpoint in a very concise fashion and see where that can go. We have to have those conversations with FDA. There's still work to be done to get there.

Our next question today will come from Maury Raycroft of Jefferies.

I'm sorry to hear the news. Maybe to start off with the upLIFT study, wondering if you're going to advance the program if FDA recommends that you switch back to your original plan for a randomized controlled study. Maybe just talk about what are the most likely scenarios there? And how could this impact your time lines to approval?

We don't anticipate that, Maury. We are in the middle of the upLIFT study. We're enrolling, and we don't expect any changes to that.

Got it. Okay. And just for the Phase III results, do you have perspective on just -- or can you comment on just the lower-than-expected reduction in hypoglycemia events in the 10 mg per kg arm versus what you observed in your Phase II?

Certainly. So I think -- I wish I had an answer for you. I covered a couple of things that obviously, everyone would want to think about in terms of explanations, including baseline demographics. We've done some subgroup analyses already. We'll continue to do that. Nothing has emerged thus far as an explanation with regards to factors that could influence results. Dosing, I talked about that we had very good exposures in the study. I've also taken a portion of the dosing period in the sunRIZE study, the first 8 weeks, which reflects biweekly dosing over the same duration in RIZE, frankly, at a 10% higher dose level, 10 milligram per kilogram versus 9.

When you look at that time point, we don't see any differences compared to the end of treatment time point on every 4-week dosing. So the explanation is not -- does not appear to be in the dose or dose regimen. So Maury, I don't know the answer. I wish I did. One possibility is that RIZE was 15 patients between the 2 treatment arms that did show that type of effect, and this was 18 participants per arm in sunRIZE in the active arms. We still think as we had indicated in RIZE that especially in this patient population on standard of care failing all therapies, a reduction of that magnitude is meaningful. Of course, the confounder here is what was observed also in the placebo arm.

Got it. Okay. And maybe last question, and I'll hop back in the queue. Just wondering if you guys looked at antidrug antibodies. And is there anything more you could say about the 2 patients who discontinued due to the serious hypersensitivity reactions? Were those due to the positive ADAs?

Those 2 patients did not have positive ADAs. I'll get back to the ADA as a whole, but the circumstances for those, one occurred at the fourth dose with some mild indications, a rash at the third dose, worsen rash and some early evidence of a systemic allergic reaction with the fourth dose. The medication was stopped and it resolved quickly on its own without further intervention.

The second patient occurred with the first dose within about 10 minutes of the infusion, similar experience and it also resolved without further intervention. But both patients were not reexposed at that point. As far as ADA, we collect those in batch and we analyze them in batch. So we don't have the full study results yet. But the batches we've run so far, we do not appear to have any meaningful antidrug antibody levels.

Our next question today will come from Peter Stavropoulos from Cantor Fitzgerald.

Nevan and Brian, sorry for these outcomes. Can you help us understand the response over time on the weekly -- average weekly hypoglycemia events? Was there a treatment effect initially that waned over time? Or was the response consistent, say, from the first dose through the end of the study?

Pete, thank you. The response was fairly consistent, not necessarily right after the first dose, but pretty early in the treatment phase and relatively consistent over the course of the study. I would say that for the CGM endpoint where, if anything, the placebo arm sort of bounced around and was generally worse, meaning an increase in time in hypoglycemia to a magnitude more than the end of treatment endpoint, which was a 6% increase, whereas the active groups, there was a pretty consistent and reduction in time in hypoglycemia over the endpoint. So the net effect at end was a little bit smaller actually than the net delta than at earlier time points in the study just because of what placebo did.

I know that you touched on it, but again, can you just sort of try to help us understand the placebo response and reduction in hypoglycemia events? What sort of drove that higher-than-expected response? And how did you actually calculate the expected placebo response?

Yes. I mean, I can only speculate. It's now the second occurrence in a controlled clinical trial where this magnitude of placebo response was observed. And I think I touched on this a little bit, Pete, but to reiterate, patients only capture events when they measure events, number one. There -- we certainly control for standard of care therapies that there was very good stability in standing or scheduled doses of therapies like diazoxide, somatostatin analogs, tube feeds, all of that.

We can't control for small -- everything patients do. And I think I hope you picked up on Nevan's comments at the beginning are critical. Glucose here is both the endpoint and the vital sign for patients. And these families, this is a serious illness where hypoglycemia has tremendous consequences. And so if there's any indication on any source of information, they do tend to react.

And that means -- that doesn't mean at a level where they suddenly increase the diazoxide, but it could mean that they're intervening around the margin with smaller interventions or acute interventions, and/or feeling that they don't need to intervene and then not checking as much. We didn't see a decrement in measurement frequency over time, which is good or a difference between treatment arms, which is good. So yes, Pete, I think it's intrinsic to studies in congenital HI, I believe, at this point and I think that KOLs I've spoken to also believe that as well.

Okay. Just one last question. Was there any changes in therapy during the treatment period, especially in placebo?

No.

No. Okay.

And Pete, maybe just to address the second part of your first question. I think in spite of being surprised by the magnitude of the placebo effect and in spite of Zealand having seen that previously in a controlled trial, I didn't think we would see that to the same degree we did. Nevertheless, we modeled for a placebo effect of this size. So that was built into our assumptions and our powering. So we -- I didn't think we'd see this it was reproduced. And now I think it's pretty clear in these types of studies. This is what happens when patients get on a study and you're measuring an endpoint that's very discrete and patient dependent.

Our next question today will come from Catherine Novack of Jones Research.

Just want to express my condolences to you and the patients for this outcome. I wanted to ask, was the drug lot between Phase II and -- Phase IIb and III the same? Were there any changes in the manufacturing process that might have impacted the results?

Thanks, Catherine. I appreciate that. No, there were no changes. And to our knowledge, there's nothing different in the manufacturing lots or in drug supply that would explain anything that happened in the study.

Okay. And then thinking about the standard error and the 10 mg per kg, how did that look? Do you think there would have been any different outcomes if this study were run, let's say, in a 2:1 randomization of just looking at 10 mg per kg versus placebo?

The standard deviation was actually within the model deviation for the powering as well, Catherine, so -- and 5 milligram and 10 milligram were not all that different. So certainly for the primary endpoint, the modeled placebo effect, the modeled standard deviation, we were in the ballpark with those. I think with CGM, the study was not powered for the key secondary endpoint.

We were statistically significant at a couple of time points at 10 milligram and close -- in fact, also close, if not reached significance at 5 milligram per kilogram in time in hypoglycemia at a couple of time points. But there's more variability with the CGM. So that's where we lost on the CGM endpoint is the variability in CGM. The error was greater than 35% there, which is that was not our endpoint that was powered for.

Got it. Yes. And on CGM, can you just confirm when you say that missed significance, was it nominally significant? Or was multiplicity control plan allowed for this to be significant even if the primary endpoint failed?

The p-value was 0.3 at 10 milligram per kilogram at the week-24 treatment endpoint.

And our next question today will come from Julian Harrison of BTIG.

Sorry about this outcome. On upLIFT, has the FDA communicated an expectation in regards to response rate on the primary endpoint? Also, are you able to comment on or indicate the target number of enrollment sites for that study? And how much cash runway you're expecting after top line data next year?

Julian, the endpoint is the number of patients who achieved a 50% reduction in glucose infusion rate. And so just based on exceeding the lower bound of 30% on the confidence interval, the math is that out of 16 potential patients, you'd have to achieve that in 9. So that's how that endpoint works. So just to put that in some perspective, patients we've treated in the expanded access program in the past to be clear, are not part of the study.

We feel like we need to reenroll with -- under clear protocol treatment guidelines and clear data collection. But had they been those patients, we would have already met that because patients often come off of glucose treatment completely. And I'm going to have Brian address the other question.

Yes. Thanks, Julian. So we have sufficient capital. Again, we're in a good position to get through the tumor study, and we will do so. And with our cash position just as of end of September, north of $150 million, that allows us to get through all of 2026, well into 2027 and through 2027. And that's why we're taking conservative measures now to make sure we reduce our spend, to make sure that independently without taking any action externally, we can actually hit our endpoint and be in a strong position with cash to actually then move forward. So the tumor program is not impacted by our current cash position or where we sit today.

Our next question today will come from Douglas Tsao of H.C. Wainwright.

I guess, Brian, I'm just trying to understand in terms of the placebo response rate, did you see -- it sounds like there were not changes within the study in terms of background medications, diazoxide or somatostatin analogs. But I'm just curious, were there changes relative to the prior Phase II study and sort of changes significant or noticeable changes in terms of sort of standard of care as you went to a broader set of institutions, sites for the study?

Yes. No, Doug, there weren't. The disease is managed similarly worldwide. There's no regional differences that we observed in the baseline characteristics in management, no regional differences in how they manage the background therapies on study, very stable overall. Even we've looked at sub-analyses of per protocol population. It mostly reflects the -- what used to be called the ICT, is now called the FAST population, the full analysis set that we just -- we don't see any differences.

What we don't know and never know is what smaller incremental things patients do, but it's not just about what they might -- how they might intervene, it's also how they might choose to check. So it's both factors. And I know everyone wants to always understand, well, what therapies are patients changing. We are all over ensuring stability of standing scheduled medications, and we are all over defined rescue criteria. When a rescue happens, it has to meet a certain glucose threshold and it necessarily means that it's associated with the event capture, so it doesn't confound the endpoint and a short-term rescue being short-acting doesn't affect future events or time and hypoglycemia input.

So those are not things that we can necessarily control, watch, capture or even understand or quantify completely other than what we say in a protocol. And we don't know how patients engage with their reporting of these smaller measures or whether they even check an event when there might be hypoglycemia. Those are things that are just frankly inherent to outpatient studies where to date, at least the FDA has required self-monitored blood glucose events or discrete events to be their primary endpoint.

And I guess, Brian, as a follow-up, and I know it's early, so there's like an element of sort of just a challenge, trying not to overreact or jump too many quick conclusions. But when you think about the endpoint, I think you indicated that there was more variability with the continuous glucose monitoring. But do you think that, that is ultimately a better measure of drug performance and perhaps even if there's more greater variability that you just need to revisit study size sort of in planning and powering assumptions?

Perhaps, Doug. I mean this study, arguably other studies have now shown that possibly. But I think that there are even some limitations with CGM and the FDA has not wanted CGM to be a primary endpoint. So I think that the best endpoint is mechanistic. Frankly, it's GIR or even controlled mechanistic studies or perhaps we intend to do this to very much look at our OLE extension, real-world data.

We'll see what we can do with those data and the ongoing OLE because, again, I think Nevan reiterated this, it's our belief based on what we've heard, what patients are doing in the OLE that they seem to be receiving some benefit anecdotally. They're on the drug. They're continuing to come for IV infusions. Some of them have stopped background therapy. So there's ways I think we're going to have to look at to show this benefit that we believe is there.

And Brian, just as a quick follow-up along those lines, when will you get your first cut or first meaningful cut of that OLE data?

We haven't determined that yet, Doug. We've been so focused on the pivotal. We don't -- and I should be clear, we -- the results we released were entirely on the pivotal portion of the study. That's the data that's been quantified -- quantitative, cleaned, programmed, validated, et cetera. I don't have...

Yes. No, but just understood, but I think it is, to your point, powerful that patients are remaining in the study and if they were not seeing a benefit, right, both either the families themselves or the clinicians would presumably sort of take them off the study because these studies are not -- it's not easy to participate, they're a hassle and obviously, these patients have sort of -- these impacts their lives already.

Yes. And then just to add, as soon as feasible, I mean, we're coming into the holiday period. There's still a few things to learn here on our end. But as soon as feasible, we'll be meeting with the advocacy group, we'll be meeting with KOLs, and we will seek a meeting with the FDA as soon as it makes sense to do that to look at these various things.

Our next question today will come from Albert Lowe of Craig-Hallum.

I was wondering for the hypertrichosis, that was noted that like an unexpected effect of ersodetug or could that perhaps be reflective of maybe some of these changes on background diazoxide where [indiscernible] comment?

Yes, Albert, based on the numbers that I reported, 14 events in treated patients and 1 in placebo, there's no imbalance between treatment arms and diazoxide use. These are treatment-emergent adverse events. They exclude patients, and there are many on diazoxide who had extensive hypertrichosis noted at baseline. So the study data tells us that these are study drug related.

It also tells us, though, that they're mostly mild, the distribution of hair growth, the pattern is less extensive based on what we've heard and less concerning than diazoxide, but it does seem to be something associated with the drug, whether -- the term hypertrichosis is very familiar to the -- this indication and those that treated in patients. So it may be excess hair growth more broadly could have different causes. And if I can comment a little bit, could be when under a different term hirsutism, an indication of some attenuation of insulin and actually an indication of activity. So it seems to be active at the hair follicle without a significant safety consequence. And so -- and I think it's clear we believe it should be active at the liver, muscle and fat for glucose as well.

Okay. And maybe just to clarify something that you were saying before, for these patients that did have scheduled tube feeding for any changes there, is that data that was collected in the study?

Yes, we collected that. We followed that carefully, and there were no changes in tube feeds. So as I -- as we presented at the endo meetings, I didn't go through that in detail here. About 40% of patients were on scheduled tube feeds. Most of those were on continuous. So either 24-hour continuous or overnight continuous. Those were not changed in any material manner. And a couple of patients that had a de-escalation or a decrease in standing tube feeds, we have modified analysis to adjust for that and account for that.

Those didn't seem to have any impact at all. And it's -- again, it's a fraction of the overall patient population, extremely small. So I just -- I want to emphasize again, things that are scheduled standing, routine doses that affect not just the current single point estimate of glucose, but future glucose values were very stable over the course of the study as a whole.

Our next question today will come from Yun Zhong of Wedbush Securities.

Very sorry to hear the negative outcomes. The first question, a follow-up question on upLIFT, and apologies if you already commented on this, if I missed it, but would you consider adding some type of interim analysis into the study to, well, kind of increase the likelihood of success? And were there any discussions when you reached that alignment with the FDA back in September that you will need to do certain steps or potentially could do certain steps in the case of sunRIZE fails to confirm the efficacy of the treatment, please?

Thanks for the question on upLIFT. No, first off, the latter part of your question, there is nothing that we heard from FDA or that's related from FDA related to the congenital study. To be clear, again, these are 2 separate INDs in very different patient populations, and the FDA has been clear with us along the last couple of years through our interaction that we should view it that way.

And to that end, this study now and the clarity we have on the upLIFT study stands independently. So from an interim basis, there's nothing we really need to do, and here's why. This is an open-label study. So this is a completely different study, and this is back to my earlier point about responsible and thoughtful drug development in an ultra-rare disease where there's a massive unmet need as there is in the tumor study. These are patients that are often otherwise on the cusp of dying, and we're able to put our therapy into use and to make a huge difference.

So given that it's open label, it's a small number of patients, we don't feel the need or desire to do an interim analysis as you would do typically as we did do in a Phase III randomized placebo-controlled study. So that study, the upLIFT study is very clear, very clear pathway, and we'll be marching along that.

Okay. And just to confirm because I believe you have breakthrough therapy designation for both indications. So when you seek a meeting with the FDA to talk about congenital HI, are you going to also confirm the FDA's approach or attitude towards the tumor HI indication? Or will that be strictly limited to discussion about the congenital HI indication?

Yes. No, thank you. And discussion will be all about the congenital. We are now squarely focused as we are dealing with this unfortunate outcome of this study, engaging with FDA and again, finding the responsible and a better path forward that will be clear and direct to be able to treat children. So that's what our discussion will be about is we will be completely focused on the congenital indication.

At this time, we will conclude our question-and-answer session. I'd like to turn the conference back over to Nevan for any closing remarks.

Thank you. And again, thank you all for joining us on the call today as we review the results from the sunRIZE study and understand initially the top line results and the implications as we move forward. I just want to reiterate that we remain very committed to the congenital HI community. We have, as we've discussed, more than 50 patients still on our open-label extension study. And again, some who have been weaned off of background therapies, which is very, very significant. And we've had children now on our therapy and who remain on our therapy for a number of years, and that's very encouraging.

So we know we have a drug that has activity. We believe in our drug, and we will work with regulatory bodies across the world to make sure that we find a way to thoughtfully get this drug into the hands of patients and families, not in a clinical setting, but in the commercial setting. That's our duty, that's our obligation, and that's exactly what we're going to do. There's a reason why we've named this company Rezolute. We have to resolve, and we will do what our mission is. Thank you all for joining us, and thank you for believing in us, and stay tuned.

The conference has now concluded. We thank you for attending today's presentation, and you may now disconnect your lines.

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.

All right. Good afternoon, everyone. I'm very happy to be here with the CEO of Rezolute, Nevan Elam. This is Kelly McCarthy from the Morgan Stanley Healthcare team and really excited to have you at our conference. I know you got a great schedule of meetings, and we're excited to talk a little bit more about the Rezolute story.

So before we get into it, I'm going to read this quick disclaimer. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative.

So with that, Nevan, Rezolute is focused on treating hyperinsulinism. It's a rare disease in the congenital and tumor setting. Can you provide us with a brief background on the disease and how it's managed today?

Sure. First off, thanks, Kelly, for having me. It's good to be here, and thank you all for attending to hear our story and to share where we are in our stage of development. As you said, we are focused on treating hyperinsulinism. And specifically, we have an antibody that is designed to serve as a universal treatment for all forms of hyperinsulinism.

When we think about hyperinsulinism, it's not just the overstimulation of the insulin receptor, but it is a dangerous hypoglycemia that's a byproduct of that condition. And one area starts at birth, there's congenital forms of hyperinsulinism. So these are children based on a set of known and still unknown genetic defects where they overproduce insulin and overstimulate the insulin receptor, causing the body to uptake glucose excessively, which then creates the dangerous hypoglycemia.

From that to the other side, you can have something similar happen with tumors where a tumor can overproduce insulin or insulin-like substances, overstimulating insulin receptors and causing a similar phenomenon for patients that are suffering with certain cancers. Our antibody that we have is a therapy that is designed to modulate insulin binding and signal affinity. So we don't try to block insulin, but instead to modulate it in a dose-dependent fashion and target tissues, liver fat and muscle.

Okay. So the program you're developing is really to be a universal treatment for HI. So can you give us kind of an overview of kind of how it works in addressing multiple forms of HI and kind of how you're sizing up those 2 different markets in the congenital and tumor groups?

Yes. What we've seen in our clinical work, we're now in Phase III for both congenital HI as well as tumor HI. And in our earlier work as well as in real-world settings where we've treated patients under our expanded access program, we've seen our antibody have a pretty profound effect in correcting glucose values, restoring individuals back up to normalized glucose by modulating insulin by means signal activity. And that's exactly how it works in a dose-dependent fashion.

And because it's working downstream, not at the pancreas or specifically, that's why it's a universal treatment. So all forms, if anything overstimulates the insulin receptor, then our antibody works to counteract it. In terms of those 2 indications as our core focus, there are approximately 3,500 individuals, we believe, who are living with congenital HI in the U.S. And we're still doing a lot of work to understand on the tumor side, the overall prevalence, because we're talking about more than 15 different tumors.

Some are easier to quantify and understand like insulinomas as well as hepatocellular carcinoma, but there are a variety of tumors that produce insulin. And we estimate that the tumor market may be about twice as large as the congenital, but we're still learning a lot more.

Okay. So just getting into some of your clinical development plans for the drug. Last week, you actually had an important update on achieving alignment with the FDA on the upLIFT study, and that's going to be a streamlined Phase III in the tumor HI group, right? I know that was an update you were waiting for and quite excited about. Can you provide just some updates on how significant that is in terms of timelines and impact for the program?

We believe it's a pretty significant development. And really, we're impressed to see FDA aligned with us in our view of the path forward for this indication. And what I mean by that specifically is given that in the last 2 years, all across the country from the East Coast to the West and the South, we have treated patients who are severely compromised in the hospital. Nothing can be done. Their bodies are overproducing insulin are severely hypoglycemic and nothing literally can be done because they can't take their radioactive label therapies and are often left, unfortunately, to hospice.

And what we've seen is a pretty substantial change after they're dosed on our therapy, where in these patients, after a few doses, they're often out of the hospital, quality of life dramatically changes.

And that's been embolding, I think, for us as a company as well as for FDA to look at that in the last 2 years to say, well, do we really need a placebo-controlled study in this case for Phase III as the gold standard? No, we don't because we already see what's happening in the real world. And so I think in the new FDA's view and generally speaking, the idea of trying to move where appropriate faster, particularly in rare diseases, this is a prime example of that.

So when will you actually have data to share from that study? What's the timeline for that?

So the study itself went from a 48-patient placebo-controlled study to now about a 16-patient study. And what we want to show is a 50% reduction of glucose infusion rates, which is what is the standard that these patients are on, in at least half of the patients.

So I think probably next year as we plan for success on the congenital HI program, which we'll have data in December on. I think we'll probably likely as we're filing the BLA and updating the world, we may very well have an update on that tumor program and how that Phase III has progressed.

Okay. So you just mentioned the data that's upcoming from your Phase III program, the sunRIZE study in congenital HI, which is your next big catalyst. You recently presented patient demographics and baseline characteristics from that study. Can you give us a little bit about what you presented?

Yes, I'd be happy to. And I think just describe a little bit more about the disease itself. It is a nightmare disease. Clearly, if you have a tumor and you're overproducing insulin, then nothing can be done. It's literally potentially the end of life.

And for children that are born with this disease, as you can imagine, as a parent, 24 hours a day, you're obsessed with making sure your child has adequate calories, nutrition and the ability to stave off hypoglycemic events 24 hours a day. And so that's why it literally is a nightmare disease. And there's never been anything really developed to treat this disease. So I think that understanding that as a baseline for the disease itself is really important as we think about how our therapy will fit into the treatment paradigm.

Okay. So when we look toward December 2025, what do you plan to show? What do you view as a successful outcome there and what people can expect?

Yes. And even before I get to that, just to finish off on your question in terms of baseline characteristics with that nightmare disease, we are very careful to enroll patients in our Phase III study. And what we've seen, if you can imagine, is, on average, about 20% of the time the children that we enrolled in our Phase III are hypoglycemic, 20% of the time. That's a lot.

40% of the patients are on the standard of care that works in about 40% of the patients, which is diazoxide. And yet they still meet our entry criteria to enroll in the study. On average, about 15 events a week. So these children are really suffering. And so we hope to show and demonstrate with our therapy a significant change between being off therapy on "standard of care" and then being on erso our therapy. And specifically, we want to show a 35% difference between placebo in each of the treatment arms at 5 mg per kg and 10 mg per kg.

Okay. You mentioned diazoxide in the CHI patient population. There was recently a study published on the real-world effects of that drug. So what was significant about that paper? And sort of what is the current understanding of the standard of care for CHI?

So diazoxide is a vasodilator and it can work to help suppress insulin. And depending upon the genetics that a child may have, again, about 40% can be responsive to diazoxide. But even as we say 40% are responsive in our Phase III study, we have 40% of those children still with that level of severe hypoglycemia who are enrolling.

So it's efficacy, one is a question. And then two, what we also know and now we can be a little more vocal about because it's all we've had largely to treat the children are the side effects and some of the problems associated with the drug, notably facial changes, syndromic like facial changes in the children that are on the therapy such that you can actually recognize those children that are taking diazoxide, which leads to social trauma and a lot of other issues potentially.

So it is not an ideal drug. It's a black box label for -- black box warning for pulmonary hypertension on the label. And if there was a better safe alternative, I know for sure, starting with my own children, if I had young children, I would want them on that therapy.

Okay. You alluded to the expanded access program that you've continued to enroll in for congenital HI. What have you learned from that group that you've actually seen some data out of there?

Yes. We have learned as we have a few children that have been on our therapy now for going on 3 years. That's really nice to see our drug working in a young patient population over a course of time and really correcting hypoglycemic values. And we've also seen what treating patients across the country and in Europe on the tumor side, what's actually happened to transform quality of life from literally end of life to being out of the hospital and living a much more normalized life.

And the testimonials from the families and the individuals who've gone through this with the emotional roller coaster of being closer to death and then resuming normal activities in life is powerful. It's actually very moving. And we hope to share more of those stories in the coming months.

Okay. So assuming success, you hit your benchmarks in December, what does the regulatory path do you think look like from there? I know this is a registrational study. What do you -- kind of what has your interaction with the FDA been around the path forward?

Well, we're fortunate this year to have received breakthrough therapy designation, both on the congenital side of the equation as well as the tumor. And we've used that to rigorously interact with the agency.

And so what we would expect is to file our BLA mid-2026, which then would put us with a PDUFA date in the early 2027-time frame. And we would expect to do exactly that. I think the question will be how the tumor program, now that it's been significantly truncated, how that will slot into that timeline.

So there's still may be favorable developments there, but I won't speculate today other than to say it will be a fast follower. The approval that we're looking for is back to the original equation is a treatment for all forms of hyperinsulinism. That's what this is. So I think that the tumor program can definitely be a fast follower.

So just to be balanced on my question, let's say, for any reason, there was an issue with the sunRIZE readout. Do we feel like that would directly read through to upLIFT? Or could there be concerns around the potential in HI? Or do you view those as kind of 2 separate paths? I know it's -- you mentioned that it's a fast follower, but...

Yes, they actually are 2 separate paths. They're 2 separate INDs, 2 different patient populations. The agency views it that way. We do look at the underlying disease. But I think that's why our announcement last week was a significant further derisking event for the company because each program stands on its own.

There's supportive clinical evidence that comes out of the congenital side. But the tumor program, we've already seen what's happened dramatically with 10 patients, and we would expect to see that continue as we do the small Phase III open-label study. So they do stand separately.

Okay. And I know the receiving support from KOLs and from the advocacy community is very important in rare diseases and in ultra-rare diseases. What sort of feedback are you receiving from KOLs and from the patient advocacy community in CHI?

I think it's fair to say that there's now a lot of excitement because we're talking about decades where there hasn't been a therapy. And now there's the potential, finally for a therapy to be commercially available to patients and their families.

So as we talk to physicians from all over the world, literally [indiscernible] who are treating these children and interacting with the families, as we see the families at the family conferences in different parts of the world, I think there's excitement. And that's really the word I would describe because hopefully, we can change the paradigm of how we treat these children.

And does that apply to the tumor HI population as well in terms of that engagement with -- I feel like this is a disease area where you're really defining and creating that market. So how are you thinking about approaching that patient set and actually finding those patients?

It's a great point, Kelly, because you're talking about, again, 15-plus different tumors, different patient populations. So a lot of it will be education. And even as we know from our expanded access program at the sites across the country, there's a lot of sharing amongst physicians about what their experience has been.

And those referrals have been triggered other requests for our drug. So I think we'll be doing a lot of -- spending a lot of time with a lot of education with clinicians and awareness that if our therapy is successful in Phase III, that there's now a therapy to be able to treat hypoglycemia regardless of what tumor it is that's creating the issue of overstimulation of the receptor.

Okay. I want to talk a little bit about the commercial opportunity. I know you sized up the market a little bit for us. But when you think about the combined markets for congenital and tumor HI, how do you think about the commercial path in each? You're talking about 2 different call points, of course. How do you think about the U.S. opportunity versus ex-U.S.? Maybe you can talk a little bit about what you would do commercially.

From a commercial perspective, we believe that we are in a sweet spot in metabolic disease with pediatric rare disease pricing. We can bracket that. And with the patient population, it may be a price that may be a little lower in Europe, as we all know.

But there are other regions of the world that we also are paying attention to where there's high prevalence like the Middle East, where we plan to definitely be active as well from a commercial perspective. So the drug itself, we would expect to have the pediatric indication approved and priced. And based off of that, the tumor HI indication would follow weight-based dosing.

So with weight-based dosing, we would expect to be able to command a pretty robust price for that patient population. And again, this is really making such a substantial difference in these patients and families' lives that we don't expect much pushback from a payer reimbursement perspective. And even some of the work we've done has confirmed that.

So overall, when you think about this patient population, just taking the U.S. itself, a core addressable market and which will grow, particularly on the tumor side, if we put the 2 together of at least 3,000 patients, this is a very attractive commercial opportunity. And then when you layer in geographies like Europe as well as the Middle East, it gets even more attractive. So we think we are definitely sitting in a sweet spot.

Does the weight-based dosing cause -- present any unique challenges to thinking about pricing or [indiscernible].

No, no challenges other than effectively, you -- depending upon the weight of the individual, they're going to use more drug. And so that's why it is a positive impact for us as a company from a commercial opportunity.

Okay. And then as you think about commercializing, would the plan be to just do that independently? Or is there a partnership potential for this landscape?

Given that we're dealing in the ultra-rare space, we really feel confident about our ability to penetrate the market and commercialize the drug ourselves in the U.S. We're excited to have brought on, most recently in the last few weeks, our Chief Commercial Officer. So he and our commercial team will be aggressively moving forward with all those preparations.

And we will continue to evaluate the alternatives for the rest of the world. Suffice it to say, we're not going to do anything in the near term in terms of partnering because we don't need to as we think about the rest of the world. But we'll be thoughtful in how we actually think about different regions and how we commercialize, whether it's through distribution relationships, partnering and also potentially on our own. And so all of that will continue to be evaluated over the course of the next 12 to 18 months.

Okay. You mentioned your recent hire on the commercial front, which is great and certainly builds out that muscle for you. Can you talk a little bit just about how the Rezolute team has come together over the last few years? And you think you have the right pieces in place to be successful, both from an R&D and clinical execution perspective, but also for the long run, it seems you're building out that later-stage ability in our ability set?

I think we've been really fortunate to have a very talented team that's dedicated, where we have very little, if any, attrition. We all share the excitement and enthusiasm to be fortunate to work on such a devastating disease and to be able to potentially make a difference.

And that's not often that you can do that as a small team. So whether it's our CMC and quality team, our clinical team, to your point, as well as the scientists in the company, I think there's a mission-driven and focused. And it helps when as a company, you get the chance for many of the individuals who work for the company get to interface with families and physicians and get to hear the stories and understand that we are part of something that truly will make a difference. So really excited about continuing to grow out the team and just thankful that we have such dedicated professionals.

Can you talk just on the history of the company, where erso came from, how it came to be in your hands and being developed at this late stage?

Yes. I started the company about a dozen years ago and having done a lot of work in metabolic disease throughout my career and came across XOMA, which was a development company at the time, very different company today. And they had this program as a lead program and XOMA has been developing antibodies for many, many years, just what they used to do.

And just looking at the early clinical data and the mechanism of action and the potential for this universal treatment for hyperinsulinism was really intrigued. The more we did diligence and work on it to bring this out of XOMA and put it into our hands as our really sole core focus. And that's the history. It's been great.

And I know you did have a regulatory bump in the road along the way. And it feels like you've kind of cleared that. So do you want to just give a little bit of context for how that came to be and then how you guys have put that in the rearview?

Yes. Well, clinical development is a journey starting with, obviously scientific discovery. And one thing is clear is you're going to have all kinds of bumps in the road potentially, and you have to be prepared for that. We had a partial clinical hold in the U.S. that was associated with the finding in one particular species and specifically one type of rat.

And so we worked with the agency over the course of a couple of years to realize that, that finding in one particular type of rat was inapplicable to humans and made it very clear. And so a year ago, the agency said, and particularly the pharm tox side of the division, we agree. We agree. Thank you for being patient with us. We told you we'd eventually get there, but we're aligned and please, let's go. Now let's get patients in the U.S. And hopefully, this will be a successful study, and you can get this into the hands of patients and their families.

One of the things that you have to deal with, and we all had to do it in the company is to be patient because here, you're staring at a very frustrating, seemingly ridiculous issue in late-stage clinical development after Phase IIb, but to be patient and to work through the process. And so we've done that. And now, coming on the other side of that, we've been the beneficiary of rare disease causal mechanism. Your drug appears to work. How can we go faster? And by the way, from partial clinical hold to 2 breakthrough therapy designations. So a definitely interesting twist in turns.

Well, congrats on putting on the rearview, and it seems like a very clean story ahead with a very important catalysts coming. I guess as you just view the competitive landscape in HI, anything you would highlight in terms of either -- we've talked a little bit about the standard of care and the limitations there that you're trying to overcome. But anything in terms of the competitive set, it feels like you're really at the front of this wave and probably the most attractive potential therapy that's being developed here?

We really don't view as we look out at the landscape, we don't see competitors. We see other companies developing other therapies that we're supportive and cheering them on, whether it's a new and better somatostatin analog, which can help suppress insulin.

If it's a new and better version of a glucagon that could be used in emergent and acute settings, we think that's great. We believe we're the only therapy that can be used across the board in all forms of hyperinsulinism with a durable effect that it could be and supported by chronic dosing.

So we don't really view anyone out there who's working in the space as competitors, and we're really cheering everyone else on. It helps when we have a drug that is -- so far has demonstrated such profound results.

So if we were to have you back at the Morgan Stanley conference next year, this time, looking back at the prior year, what would you like to say you've accomplished as a company in the clinic from a regulatory perspective, what excites you about the next 12 months?

Well, the next 12 months are going to be a big set of 12 months for us, given that it will really start with our clinical readout for the congenital. So we really do hope in December of this year that we have a successful study that will definitely be exciting. That will enable us then to push forward filing our BLA mid next year.

And then mid next year into roughly this time frame, we also would have an update on the tumor program. And hopefully, we can have an update that is demonstrative of, again, what we've already seen in the real world in 10 patients, which would be very exciting and with a little bit more clarity on what that regulatory path hopefully looks like on the heels of the congenital HI program. So a lot is going to happen, we think, over the next year and a lot that is hopefully going to be really great.

Agree. Yes. Very exciting time for the Rezolute team. And then maybe just for any investors or participants who aren't as familiar with the company. Anything that you want to leave people with? Anything you want them to know about the company and your mission here?

Well, I think we've largely covered it. We were a company that wasn't known a few years ago. We were quietly in the background, but I think as awareness of a lot of these stories and the impact we're having with families and the fact that we're just in late-stage development now. I think there's a lot of excitement and enthusiasm across the board and just happy that I'm part of it and as a team, we're part of it.

Well, thank you for joining me. I'm really glad to have you at the conference and hope it's a productive one and really excited to see what will come out of the Rezolute story and particularly the data in December. We're very much looking forward to that update. Thanks, Nevan. We wish you luck.

Appreciate it.

All right.