All right. Good afternoon, and thank you for joining us on day three of Guggenheim's inaugural Healthcare Innovations Conference. My privilege to have Nevan Elam, CEO and founder of Rezolute. Thank you for flying in across the country.
Thank you for having me. Good to be here.
So it might just be helpful for the audience if we just do a quick overview of Rezolute, where you are currently, and then we can get into the Q&A.
Sure. We are a company focused on treating a disease, hyperinsulinism, which is often the overexpression of insulin, which can create a very dangerous hypoglycemic state for patients and individuals. We have two indications that we are working in that patient population. The first is congenital, so from birth, children that overexpress insulin, and we're also working in an indication that is associated with the tumor overexpression of insulin, and both of these programs for the congenital are in phase three right now, so we're in the midst of enrolling patients worldwide, and next year, we will commence our phase three study, registrational study for the tumor program, and our treatment, just by way of background, is the first treatment that's been specifically designed to treat hyperinsulinism.
So there's a lot of other therapies we use today to try to stop the production of insulin at the pancreas, but we actually operate downstream as a universal treatment, and hence our ability to treat different patient populations that actually have hyperinsulinism. And it's an antibody, and an antibody that's administered in a 30-minute infusion. And so a quick snapshot of the company.
Awesome. So given that both of these are rare diseases, help us frame the opportunity first on CHI and then more on tumor-associated hyperinsulinism.
So the opportunity begins with the massive unmet need because, again, we're repurposing existing therapies to try to stop the production of insulin. Or in the U.S. in particular, we use pancreatectomy, so removal of the pancreas as a trade-off for having a child who has chronic hypoglycemia. Surgeons and families will make the decision to actually remove the pancreas, which it would be nice if there was a therapy that would prevent that as well. And in the U.S., there are about 3,000-plus people that are living with congenital hyperinsulinism. And with the existing therapies, we think that at least half of those patients immediately would be addressable with our therapy.
Why do you say half?
Say half because today, the current first-line therapy is diazoxide. And diazoxide works in about 40% of the children to actually stop the production of insulin. But there's two things about diazoxide. One, what we do know is that it has very draconian side effects. So everything from extensive hair growth, brow line extension, syndromic-like feature changes in the face of the children. There's a black box warning for pulmonary hypertension. It is not an ideal drug, particularly to use in a pediatric population. But it's all we've had. And it does work based on genetics in about 40% of the patient population. But even within that 40% of the patient population, what we know, just looking at natural history and our last study, our phase 2 study, was an all-comer study. And we let patients enroll as long as they met the entry criteria, meaning they had sufficient hypoglycemia.
Even those patients on "standard of care" who are responsive genetically to diazoxide, we still had a third of the patients who were on diazoxide who met the entry criteria and were enrolled. There still is an unmet need even within the patient population that is responsive. We largely, just from a conservative modeling perspective, assume that notwithstanding the side effects and notwithstanding some of the efficacy challenges, that at least initially, those children that do respond will, for the most part, remain on diazoxide, except for those that do suffer with some severe side effects by taking the drug.
Got it. And on the tumor-associated hyperinsulinism, that phase 3 starts next year. How big is that opportunity? I think the feedback we've gotten from some of your core holders, they actually believe the tumor-associated market is much bigger than the CHI market.
I would concur with that, given that, to understand the dynamic in the tumor indication, there are two different types of tumors that actually have this overstimulation of the insulin receptor. The first is islet cell or insulinoma-type tumor, which is the classic presentation. These are metastatic patients, often hospitalized, severely hypoglycemic. And we believe, just initially looking at kind of the overall, starting with the incidence and the prevalence, that at least 500 of those patients a year would be ideal candidates for a therapy like RZ358. And again, that's probably conservative as we continue to learn more. But then there's also non-islet cell tumors. So these are usually solid mass tumors. Hepatocellular carcinoma is a good example. And these tumors also can overstimulate the insulin receptor, but with IGF-2, not insulin.
If it's IGF-2, the current therapies like diazoxide or the use of somatostatin analogs are really inapplicable to treating that patient population. There we know and believe that at least 1,000, just in that one tumor type of hepatocellular carcinoma, patients would be candidates for RZ358. But there are still 12 other tumor types, whether it's mesothelioma, fibrosarcomas, and other tumors that also do cause hypoglycemia that needs to be treated, where there's not today a treatment option. We're going to learn more, and we continue to learn more, which often happens in rare diseases and the unmet need. That opportunity probably is larger than the congenital opportunity.
Got it. There is some real-time evidence data that you're collecting in a compassionate use setting. Maybe let's talk about that before we move back into CHI.
Yeah. What makes us a pretty unique company, and one thing that we're very really happy about, is the fact that we've been able to use our antibody in conjunction with investigators, with FDA approval, even before it's been approved, to treat patients today across the U.S. that are suffering with severe hypoglycemia, particularly the hospitalized patients, where unfortunately, these patients are so severely hypoglycemic, they are unable to take their cancer therapies, the radioactive label therapies. They're not candidates for surgery. And unfortunately, they waste away and are often released to hospice, and they pass away. What we've seen in the last two years in our treatment of patients is that the administration of our antibody has made a tremendous difference because the hypoglycemia, after a couple of doses, is eradicated.
They're able to get out of the hospital, able to resume normal life function, able to resume their cancer therapies, and has made a really big difference. So we've already seen the drug working in the real world in these seven cases, each one repeated presentation the same. So that's given us confidence to then move very swiftly into a registrational study. So when we approached the agency early this year and said, "We'd like to talk about what type of study we need to do," they said, "We get it. We see each one of these cases. We've seen the case reports. We know this drug is working in the real world. Just do a relatively small study as a registrational study." So hopefully, this continues to hold up, and we can eventually get this into the hands of patients as a commercial product.
Got it. And how big do you think the study is going to be?
The study itself will be very similar to our congenital phase 3 study where we're studying in about 56 patients. This study, we think, will be about 48. The very first part of that study will be open label. We'll be looking at, again, hospitalized patients. That should be really interesting as we collect that data. I hopefully would expect to see what we've already seen in real world. We'll kick that off and enroll patients targeting mid-next year. I would expect and hope to have top-line data towards the end of 2026.
From a dose perspective, how different are the doses in CHI versus in the tumor-associated hyperinsulinism?
The doses are very, very similar. Sometimes the approach in the oncology setting is to be a little bit more aggressive. These are adults. It's weight-based dosing. So the investigator or the physician is free to administer the dose, whether it's weekly initially, biweekly, monthly. It just depends on how the presentation of the individual patient and the severity of the hypoglycemia. The nominal dose that we're using is a weekly dose of nine milligrams per kg. And you can contrast that with the congenital dose, which is 10 milligrams at the top dose per kg. So very similar dosing. It's really about the frequency of dosing that may be different between the two patient populations.
Got it. So let's go back into CHI. Phase three is already underway. Walk us through the phase two experience where the data looked fairly compelling, be it slightly lower doses. You had, what, five and.
We had six and nine.
Six and nine, where you're five and 10 right now.
Correct.
Right? And maybe a slightly different sequence initially versus what you're going to do in the phase 3 study?
Yeah. So in the Phase 2 study, we really were looking, of course, first for safety as we were down to patients ages two and above. Average age in the study was about six and a half years of age. And we wanted to see efficacy. And how do we define efficacy in this space? If a therapy can change hypoglycemic events or time in hypoglycemia by at least 25% from what a patient is experiencing at baseline, that's significant. And that would be encouraging. And so based on our earlier work in Phase 2a, we hope to see around a 40%-50% improvement in hypoglycemia. What the results were and what was borne out at the higher doses at six and nine mg per kg is pulled together 75% plus eradication of hypoglycemia. So very significant reduction in hypoglycemia.
We dosed every other week for eight weeks as a pivotal treatment period. And given those results, that really galvanized the community worldwide because we've been waiting for therapy for hyperinsulinism, particularly in the congenital and in the children space. And with those results, there's a lot of interest. And we've had a lot of interest from investigators all over the world who are participating in our Phase 3 now. Coming out of that study and from just our real-world experience and even a few patients who applied for and were able to receive our drug and who have remained on our drug, the antibody, for more than two years now. And we learned that monthly dosing as a maintenance makes a lot of sense and could work. So for Phase 3 , the dosing is different, whereby we have a loading dose. The first three doses are every other week.
The last four doses over a six-month treatment period are monthly. So that's the difference between Phase 3 and Phase 2.
From a payer perspective, you're expected to show about a 35% reduction in hypoglycemic events.
We're powered to 35%. I would hope and expect to see more than that, based on our experience in Phase 2b .
Is it powered at 80%, 90%? We're not entirely clear on that.
We're powered to show a 35% at least effect, which is why we would expect to exceed it. I think we should be in good shape.
Okay. What about the patients who currently are amenable to surgery? Why wouldn't you treat them with RZ358?
So the patients who are, and when you say surgery in the congenital, who are?
Yes. Yeah.
Who do.
Focal disease, yeah, focal disease as opposed to diffuse disease, right? Those who present with a focal disease still get surgery. But why not have an antibody when you have why do a pancreatectomy?
Yeah. I think it's a fair point. In the U.S., we use pancreatectomy a lot more aggressively than the rest of the world, and that's just a clinical practice, so there are the two different types of disease. The focal lesions that occur can be surgically curative, and so those procedures are done worldwide, including in the U.S., and that's wonderful if a surgeon can go in and remove the lesion, and the child is literally cured of the disease. That's a small minority relative to the patient population, but that's a practice that we would expect to continue because it's curative. Unfortunately, in the U.S., we, again, do a lot of diffuse surgeries, and what we know through diffuse surgeries are several things. Even with a near total pancreatectomy, these children still overexpress insulin in many cases, and two or three surgeries are required.
And often, these surgeries come with complications, which can be challenging to manage. And over the course of even a near total pancreatectomy, these patients are on medical therapies for five to seven years after the pancreatectomy. So we would hope and we would expect, and I think if you asked a surgeon who performs these surgeries, that RZ358 would replace the need for surgeries in diffuse patients because it would be a better option. I think removing a child's pancreas versus actually having a medical therapy to treat the disease, hopefully, a safe medical therapy would be the better alternative.
So when you talk about your 3,000 patients, does that factor in these patients who get surgery despite diffuse disease, or that would be on top of?
That's on top. Yeah, exactly.
What's that number roughly?
The overall prevalence today is about 3,000. And then of that, there is a breakdown in terms of those who get diffuse disease and the amount of surgery that we do in the U.S. and, again, very different in Europe. And so if we take a look at the ideal patient population, so the 60% that are not responsive to diazoxide starting there and the number of procedures in the U.S. that are done, we would hope to see those procedures significantly reduced. Take Europe as an example. In Europe or elsewhere in the world, the Middle East and Asia, the diffuse surgeries are not necessarily go-to as an elective option. And so there, we would expect to capture those patients right away.
Got it. And since you're further downstream from the insulin secretion pathway, when you think about competition from dasiglucagon or what's the other one, avexitide from whatever, how are you thinking about those two products?
So again, I think looking at our program is very unique because the antibody was screened looking for a universal treatment for hyperinsulinism specifically, unlike other therapies which are largely repurposed and, again, targeting, blunting the production of insulin as a therapy. We actually don't view any of the companies that are working in the space as competitors. We think it's complementary. Let's take dasiglucagon, Zealand's drug. We actually hope it gets approved. It may have a good use in emerging cases and acute cases, particularly in the hospital. But from a chronic therapy perspective, we don't think it is of the same caliber or would be in the same class as RZ358. Avexitide is very early still. We'll see where that goes. And that mechanism, they may be approaching that looking at a different patient population for start. We'll see.
But we really don't largely view the other companies working in the space as competitors. Hopefully, we continue to have new therapies across the board to treat these children.
Got it. And your data right now for CHI, you expect second half of 2025, not that far away. How are you thinking about where these patients are located as we start thinking about building a commercial organization, how big a sales force, et cetera?
Yeah. We are in the beginning stages of doing a lot of planning on this exact topic. We have a small commercial team today, but we'll be building that through 2025. We've done all the work to analyze in terms of sales force and infrastructure, and because it is an ultra-rare disease in the U.S. and we would absolutely want to launch this drug in the U.S. on our own, it is not a massive lift for a small company, so you're talking anywhere from an additional 35-50 individuals in the company. We know who the pediatric endocrinologists are. We know where they are, where the leading centers are throughout the country, and so we will be working actively with MSLs, et cetera, over the course of the next 18 months and, of course, anticipating filing for approval to be prepared to launch the drug in the U.S.
So it's very feasible versus some other challenges that you may encounter for small companies to actually launch this drug.
How many centers of excellence do you think there are, I mean, outside the two that everybody talks about?
You know, there are the two that everyone talks about. But there still are 10 to 15 other centers that see patients based on geography, whether it's in the Midwest or on the West Coast as well.
Got it. And one of the things that the docs continuously point to and why they think you would see a very rapid uptake is the nighttime control. It's a quality of life changing, not just for the patient, but for the family in general. In the long-term extension study, what have you sort of noted?
Yeah. Coming out of the phase two study, there's some anecdotal feedback that we got where responses like, "My child slept through the night. My child woke up hungry," things that were not normal in the average daily occurrence with these children who have the disease. And we're capturing all that data in phase three. We would expect that this makes a huge difference, hopefully, in these patients' lives because, as you can imagine, the psychosocial burden of the disease is tremendous. Parents are obsessed 24 hours a day of making sure that their children have adequate glucose on board, particularly as it relates to the brain. We know that at least 50% of the children who have the disease suffer from neurological complications. It is really difficult to capture every low. So for a new parent with a child, trying to manage that hypoglycemia is extremely challenging.
If RZ358 continues to bear out the clinical efficacy that we've seen and the nice safety profile that we've seen, this would make a big difference in patients' lives. And so that's why we're probably a little conservative about excluding the patients that are on diazoxide because I know, for one, if this was a safe and effective drug and it was my newborn and given the side effect profile of diazoxide, I would not want my child on that drug. I would want my child on a new, better drug.
What kind of hoops do you have to jump through to, I mean, I'm guessing this is going to be a pre-auth given that diazoxide is a generic, et cetera. What do you need to convince the payers that you can't put this patient on diazoxide? This is a better alternative.
I think as we educate, it's really hard to bash a drug when it's the only thing that we have largely. That's somatostatin analogs, tube feeds, enteral feeding. It's hard to really complain about the side effects of a drug when there's no alternative. With an alternative, and we're hearing it even now in the community, and people recognize the significant limitations of diazoxide, we believe that with continued education of the risks of using that drug, including the black box warning relative to a safe alternative and partnering with the advocacy group here in the U.S., which are very vocal and a really good organization, often as there are in rare diseases, to recognize if there is a safe, better alternative, that that really needs to be put forward, particularly when diazoxide is not really intended for pediatric indication and was never designed for this particular indication.
So we'll see how that evolves. But again, we're being conservative now in terms of how we think about the market. But I would expect in this well-organized community a flurry of activity, assuming that RZ358 continues to be safe and effective.
Could you sort of define the market in terms of these patients are diagnosed pretty much post-birth? Is there a spectrum of disease? Maybe after, say, 15-16 years, they don't need therapy. In the current prevalence, what's that distribution?
There is a wide range of presentation of the disease itself depending upon genetics. So it turns out that those that respond to diazoxide tend to have less severe disease. And some of those patients will age out, whether 10, 12, or 13 years of age. The disease will resolve itself, which is nice. And those with more severe forms of the disease, which are not responsive to diazoxide, largely because either the KATP channel is missing or broken, those children, they tend to have more severe disease that lasts for longer. So it can be 10, 15, 20 longer periods of time. So I think when you say 15 years, that's probably a good 15-20-year bracket in terms of treating this patient population as a chronic therapy.
Got it. And plans for expanding it into Europe and stuff, given that it's a global study? So you already have experience in Europe.
Yeah. From a commercial perspective, we'll be thoughtful as we evolve here. For the U.S., our blueprint is clear. We will plan to launch this drug for sure. I think we've seen a lot of hiccups for small companies trying to launch in Europe on their own. We do have a plan that we can do that, and we'll be continuing to evaluate that. Other regions, like the Middle East, where there's a significant prevalence of the disease, we would use most likely distribution relationships and would plan to launch there as well, and in certain areas, partnerships may make sense, and particularly as we evaluate Asia and the rest of the world.
It's a weight-based drug. Do you think you're going to get you'll price it on a weight-based basis because the mathematics changes very quickly as the patient ages and?
We do, and we think that that is one of the interesting things about the market as well because it's weight-based dosing, so as the child gets larger, of course, there's more drug that's needed, and in the tumor side, it's weight-based dosing, and you're talking about adults, larger adults, and so we think from a commercial perspective, that's a good opportunity for us.
From a pricing perspective, any ballpark?
Oh, we're just sitting down. So anyway, let's finish on the pricing.
I would say competitive, good, rare disease pricing, and I think we can all look at the analogs that there's a significant market here for us, both across the congenital indication as well as the tumor indication. Rare disease pricing, but on a weight basis.
Yes.
So your actual price might be much higher than what you.
Absolutely. There's analogs for that today. You can take a look.
Yeah. Sarepta is a great analog for that.
Sarepta, Ultragenyx, Crysvita. So two different populations, weight-based dosing. So exactly.
Awesome. Thank you for your time, Nevan.
Thank you.
Good luck.
Appreciate it. Thanks for having me.
Thank you.
All right. Thanks.