Targeting the Root Causes of Metabolic Disease w/ Bob Geho, Founder & CEO, Diasome

Every year, one in five adults with Type 1 diabetes experiences a dangerous drop in blood sugar that renders them unable to treat themselves. These severe hypoglycemic events are still happening, even though many patients now use continuous glucose monitors and automated insulin pumps.

Why has this trade-off between long-term A1C control and dangerous sugar crashes persisted for over 30 years?

Bob Geho, Founder and CEO of Diasome, joins host David E. Williams to unpack the results of the company’s 200+ patient Phase 2B OPTI-2 trial of HDV™ insulin. The study was presented recently at the American Diabetes Association meeting in New Orleans.

In the trial, five patients using standard insulin experienced severe hypoglycemic events. This compares with zero such events among patients receiving HDV™ insulin. Meanwhile, HDV™ insulin matched standard-of-care A1C control.

Bob also shares how the HDV platform is being studied for its potential to reduce side effects in GLP-1 therapy and to address insulin resistance, considered the root cause of Type 2 Diabetes.

🎙️⚕️ABOUT BOB GEHO
Bob Geho is the Chief Executive Officer of Diasome Pharmaceuticals, a clinical-stage biopharmaceutical company developing portal-hepatic -targeted therapies designed to act at the source of metabolic regulation.

Under his leadership, Diasome is advancing its proprietary Hepatocyte-Directed Vesicle (HDV) platform, which targets liver hepatocytes and the portal hepatic region, where metabolic control is centered. The company's lead clinical program, HDV-Insulin, applies this approach to insulin therapy — grounded in the principle that therapies working with the body's natural physiology may produce meaningfully better outcomes. The HDV platform is also being explored across GLP-1 and serotonin programs.

Bob's work in hepatic-directed drug delivery spans more than three decades, including helping lead the first successful human clinical study of liver-targeted insulin in Type 1 diabetes patients. He co-founded Diasome in 2004 and has since guided the company through multiple rounds of financing and into clinical development. He also co-founded SDG, Inc., a Cleveland-based holding company that has supported the creation of multiple life sciences startups and strategic partnerships.

He holds an MBA from Case Western Reserve University.

🎙️⚕️ABOUT HEALTH BIZ PODCAST
HealthBiz is a CareTalk podcast that delivers in-depth interviews on healthcare business, technology, and policy with entrepreneurs and CEOs. Host David E. Williams — president of the healthcare strategy consulting boutique Health Business Group — is also a board member, investor in private healthcare companies, and author of the Health Business Blog. Known for his strategic insights and sharp humor, David offers a refreshing break from the usual healthcare industry BS.

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Transcript

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About one in five adults with type 1 diabetes has a severe hypoglycemic event every year. And that's even though many have continuous glucose monitors and automated insulin pumps. The technologies are amazing, but that really hasn't solved the problem. The trade-off between A1C control and hypoglycemia seems like an iron law. But today's guest, Bob JHO, CEO of Dinosome, is developing a product to break that trade-off. They've just reported impressive phase 2B results at the American Diabetes Association scientific meeting, and they're also leveraging their platform technology for GLP1s and beyond. Hi everyone, I'm David Williams, host of the Health Business Podcast and president of Health Business Group, where I'm a strategic advisor to Dinosome. Welcome, Bob. Thanks, David. It's great to be with you. Now, you're a CEO, but you also live with type 1 diabetes. And so you're well placed to tell us what hypoglycemia feels like and how does that affect your work? Yeah, it's a great question. So, like uh really everybody who has type 1 diabetes and most people who take insulin as a type 2 patient, the uh chronic risk of having a low blood sugar event is just always there for us. And what it means is that we have to be very, very careful about the way in which we manage our diabetes condition with injected or pumped insulin. And the reason for that is pretty straightforward. Uh insulin is life-saving. We have to take insulin in order to literally stay alive, but we can very easily and inadvertently overdose uh with insulin relative to the amount of blood glucose or sugar in our body. And the reason why that's a problem is that the brain in a healthy non-diabetic person has about a four-minute supply of sugar. The brain is the biggest user of glucose or sugar molecules in the body, and it needs, for obvious reasons, a constant supply of fuel in the form of sugar. So if I inadvertently take too much insulin and I ended up in a low blood sugar event, there's actually a fairly narrow margin of safety uh in my brain and other parts of my body from a blood glucose point of view. So the the risk of having a low blood sugar event, which can be dangerous and even fatal because I could black out, I could have a seizure, um, and or worse, is something that I just have to be routinely aware of. You know, I first uh heard about this and you know, uh actually in the 1970s because I was a kid and my father was a runner and he was out running, and he mentioned like he found somebody and they were like they were blacked out on the on the lawn. They've been mowing and they, you know, they blacked him, and he actually knocked on the door and somebody's dying it because it can happen. You know, this was the 70s, though. That was 50 years ago. And so you're saying it's still an issue today, even with all these devices and things that I see people having. I mean, I know you said that, but that's that this this was my first, it was a very vivid impression because my dad had been going by, and who knows what would have happened. Yeah, so the brain is is, as I indicated, really dependent upon glucose as the fuel source to run the brain. And you know, normal blood sugar is uh between 80 milligrams per deciliter and 120 milligrams per deciliter. Um, people may not think about things in terms of milligrams of something per deciliter of blood, but people are probably pretty familiar with, yeah, my blood sugar, if I'm fat, if I'm taking a fasting blood glucose test for an annual physical, needs to be at 100. Um, so that's considered in the normal range. Hypoglycemia or low blood sugar starts when blood sugar is at 70 milligrams per deciliter. That's that's considered level one, or the point at which you need to start drinking orange juice or eating a candy bar or something that has carbohydrate or sugar in it. But you still can be fairly functional at that point. But when blood sugar goes below 54 milligrams per deciliter, that's called level two hypoglycemia. And that's the point at which the brain goes into something called neuroglycopenia, which is a big long technical word. But neuro, of course, is the brain, glyco is glucose, penia is having too little of something, and that's the point at which you have so little glucose in the blood supply to your brain that you begin to actually experience or can experience many stroke-like symptoms. So blurred vision, inability to communicate, you could get to the point where you actually don't have enough control over your the way your body's functioning to even walk to the refrigerator to get a glass of orange juice. And so the situation that you described where someone's blacked out on their front lawn, that's because the brain has gotten to the point where it just simply doesn't have enough fuel to operate in a normal fashion. And the the deep challenge with that kind of situation is that person had gotten to the point where they were experiencing what used to be called severe hypoglycemia, now is also referred to as level three hypoglycemia, and that's the point at which someone can't rescue themselves. So I mentioned my dad, but your father's actually a much bigger part of this story because as I understand it, yeah, he's the scientist behind HDV, which is your product, and he'd spent decades on liver-targeted insulin delivery. So I'm wondering, you know, what did he see early on that the rest of the field had had clearly missed? Yeah, it's a really fascinating story. Um, so he was uh collaborating with a researcher at Columbia University um earlier in his career, and this particular researcher made the first fully biologically active radioactive form of insulin, not as a diabetes experiment, but as a chemistry experiment to see if he could make put a radio label on an insulin molecule and have the insulin still work like insulin in uh the body of a rat. And so he published this paper where he showed for the very first time, and this is quite some time ago, that when he injected insulin with this tracer on it peripherally into a group of rats, lab laboratory rats, uh, then they sectioned the animals and they looked for the traces of this radioactive material. And to his and everyone else's surprise, they could find the insulin everywhere in the body of these animals except their liver. So why is that important? Well, the liver is the most important organ in the entire body, whether you're a lab rat or a human being, because the liver can do two things that no other part of the body can do. It can store a lot of glucose, which it does in response to insulin during a meal. And very importantly, on the other side of the equation, the liver is the only organ in the body that can release stored glucose to prevent low blood sugar. And so that research got my father involved in well, how do we fix the problem of insulin not going to the liver? And that's the genesis of the diacome story. So just to be clear in terms of the sequencing here, this this was not a matter of you know, a father saying, hey, my son has some issue, I'm going to deal with it. This just happened to be uh this just happened to be what he was working on. I didn't I hope he didn't cause you to get diabetes. Yeah, no, no. I joke with people that uh yeah, as a type one, you know, maybe my dad took my pancreas out when I wasn't drinking or wasn't aware of it. But no, I was diagnosed with uh type one diabetes very unexpectedly when I was in graduate school. Um and that really had a big impact on me in a lot of ways. I mean, number one, I ended up with type one diabetes, which I certainly hadn't been planning on, but it also really changed my career focus. Um I had been a music student in my undergraduate training, then went to business school. Um, and even in business school, when I started, I was I was really focused on um going into arts management or something like that. And the more I kind of came to grips with being a type one patient myself and learning more about the work that my father actually was doing, it's kind of like one thing led to another, and this has become a very missional part of my life now from a business perspective. So I you know I gave a story from the 70s. So let's talk about some of the innovations that have occurred since then. So you've got these continuous glucose monitors that are reading the glucose level every every few minutes. You've got these sort of closed loop pumps that adjust insulin automatically. You have better insulins, analog insulins that mimic the physiological timing. So with all of that, is there really a need for more innovation in insulin, or is it just a matter of using better what we already have? Yeah. So the answer is it it takes a variety of different strategies to get people closer to normal physiology when it comes to insulin management and type 1 and type 2 diabetes. And so it is the case that technologies like continuous glucose monitors, which I use, insulin pumps uh which I've used uh from time to time, these are critically important tools in terms of helping people live more normal lives as insulin-using people. But the central challenge that we're focused on is that when any form of insulin from any company, and whether it's injected with an old-fashioned syringe or a pen injection device, or it's pumped subcutaneously from sophisticated insulin pumps, those insulins are all distributed broadly throughout uh the vascular system because we're injecting it subcutaneously under our skin. And the challenge with that is that on the one hand, it's life-saving because it tells fat cells and muscle cells that have insulin receptors to take glucose out of the blood, which is critically important to prevent routine high blood sugar. But those cells have no capacity to release that stored glucose to prevent low blood sugar. So it's kind of a one-way glucose street in terms of how we administer and deal with insulin therapy today. And that's in direct contrast to the way in which the pancreas, which is the organ that makes insulin, delivers its insulin payload in a person who doesn't have diabetes. So, what happens in a non-diabetic person is that when they eat food, it stimulates the pancreas to produce a lot of insulin during the meal, and that insulin is put directly into the liver, and the liver uses about 80% of the pancreas, his entire insulin production as a signal to store about two-thirds of all the sugar molecules that a person eats during a meal. So the job of the liver in response to pancreatic insulin is to basically act like a sugar storage tank to prevent high blood sugar or hyperglycemia. Got it. So it's it seems like fairly well understood how the pancreas uh works relative to the to the liver, and the insulin isn't getting there when it's uh injected or you know, absorbed in the in the usual uh ways for diabetic. So why why has this limitation been tolerated in that case? Yeah, so it turns out that it's really challenging to change what we refer to as the biodistribution of injected insulin therapy. Um, when we administer insulin, it gets absorbed into the broad peripheral vascular system and it gets exposed to a zillion insulin receptors in fat cells and muscle cells before it can ever reach the liver. And part of the problem is that the liver has its own kind of blood supply that's relatively sequestered from the rest of the peripheral uh vascular system. And so just the simple challenge of getting an injected what we call exogenous material to the sequestered blood flow of the liver has has daunted the insulin industry and research for literally decades. Um it's a it's a really big challenge to actually you think about changing where insulin molecules go once they've been administered subcutaneously. Um it requires very sophisticated chemistry, very sophisticated clinical trial work. Um there are a variety of challenges that have uh impeded advances as quickly as other aspects of diabetes care. So HDV, uh which is hepatocyte-directed vesicles, what does HDV do? Yeah, so HDV is a Frisbee-shaped disc that's less than 100 nanometers in diameter. So a nanometer is a billionth of a meter. So we make these discs that are anywhere from 50 to 100 billionths of a meter uh across. And the disks are made with a very uh specific kind of chemistry that makes the surface of the disc negatively charged. So if we think about the disk as a magnet, uh magnets have either a north pole or a south pole, they're positively or negatively charged, and so they stick together if they see an opposite charge. So we make the disk negatively charged, and with the reason why we do that is because insulin molecules are positively charged. And so when we add a liquid form of these HDV discs into a standard vial of commercial insulin from any of the manufacturers, it basically binds to the free insulin molecules that are in the vial. And the insulin will essentially coat the top and bottom surfaces of this Frisbee-shaped disk. When a person then injects themselves or gives themselves a bolus from a pump, the HDV disc is targeted to specific cells in the liver because we embed a form of the vitamin biotin as a liver cell targeting system into the HDV disc surface. And the reason why we use biotin is very simple. Um, the liver is the biggest user of biotin molecules in the entire body. So if you put biotin on a disc and it has insulin attached to it, it's going to be especially attracted to the cells in the liver that need insulin. Got it. So, you know, this type of approach or thought to try to break this trade-off between A1C control and hypoglycemia has been around for a while. And Eli Lilly, which is uh you know, the big player in this space, had a program maybe 15 years ago, I think it's called Peg Lyspro, and they were working on it, and you know, they ended up discontinuing it. Now, uh I understand it's because of liver toxicity, and a lot of drugs have liver toxicity, and it sounds like when you're trying to jam something extra into the liver, that's likely to happen. I mean, is is HDV insulin is different in some way that uh that that's not an issue? Yeah, so uh I mean Lily really was at the vanguard of making what is called hepato or liver preferential forms of insulin. And as you say, David, they were very successful in demonstrating uh improved HVA1C levels and reductions in hypoglycemia because they were able, with their chemistry, to put more insulin in the liver, which is exactly what diacome does with the HDV system. The difference between HDV and the PEG LISPRO system is really in the chemistry of the liver targeting system itself. So the Lilly system used uh a form of insulin that was put together with polyethylene glycol molecules, uh so-called PEG technology. And PEG has been used and continues to be used uh in a wide range of pharmaceutical applications because polyethylene glycol will increase the circulatory time of uh of a drug molecule in the blood. It basically blocks uh receptor uptake for a longer period of time than the native molecule would itself. The challenge uh of PEG Lyspro was, as you say, for probably a variety of reasons, uh caused increases in liver fat. And um that hasn't really been explored a lot after Lily terminated that program. Uh but there was the hepatotoxicity was related to increases in liver fat. The HDV system is very different from polyethylene glycol. So it takes a lot less HDV material to uh have the liver effect that we need because it is a much more specific, in our opinion, form of liver targeting. And the raw materials that we use to make HTV are specifically designed for chronic daily entirety of a person's life use without uh causing liver toxicity. And so across the many different human studies we've run, including two double-blinded six-month dosing trials where people were taking a dose of HTV insulin before each meal for 180 straight days, we've never had any liver toxicity signals of any kind. So we feel very confident about the safety profile of HTV. Let's talk about the Opti-2 trial. It was recently completed. It's a phase 2B trial, and the results were exciting enough that uh the uh investigators landed a prominent speaking role at the uh ADA meeting in New Orleans. So, what was this trial designed to prove, and what did it show? Yeah, so opti-2 is a really exciting advance, we think, in clinical care and type 1 diabetes with insulin. The study was what we refer to as a phase 3 dress rehearsal, so it's a phase 2B trial, but it was a six-month double-blind uh controlled trial where we compared standard insulin LISPRO, so that would be like Eli Lilly's hemolog insulin, to that same insulin that had HDV added to it. And the patients didn't know which form of insulin they were on, their physicians and clinical teams didn't know, and we as the sponsor didn't know. So it was a fully blinded clinical trial. And all of the subjects wore continuous glucose monitors from DEXCOM throughout the entirety of the six-month trial. So they could see every five minutes what their blood sugar level was. And the focus of the study was to try to show for probably the first time that you could reduce the incidence or risk of dangerous low blood sugar, really focused on level two hypoglycemia, which I talked about a little bit ago, without enabling people or causing people to have higher HBA1C levels. So A1C is the 90-day marker of overall glycemic or glucose control in the body. And one of the easiest ways to reduce low blood sugar risk is to take less insulin because insulin raises the tendency of hypoglycemia risk. But if you take less insulin, almost inevitably your HBA1C is going to rise, which is not permitted by FDA if you're developing a new form of insulin. So the goal of this trial was to very simply show that you could have equivalent A1C control to the control insulin, which is standard of care humolog insulin, but with a dramatic decrease in low blood sugar risk because of where we're targeting insulin with HDB. Got it. So, you know, you had this unusual binary, primary endpoint at week 12. And, you know, as easily, you narrowly missed that one. Um and yet when we look into the maintenance period, uh, you know, there's very, very interesting and significant uh results there. Why why is the maintenance period uh more important? And where is the right window for actually assessing hypoglycemia? Yeah, so a series of great questions uh and considerations embedded in that. Um number one, it's important to note that for phase three purposes, the long-standing FDA primary endpoint is what's called A1C non-inferiority. So a novel form of insulin can't be any worse than the standard of care comparator insulin, and that's measured by looking at HBA1C, and you can't be inferior, meaning you can't allow A1C to rise over the course of a six-month study. We intentionally added on to that very typical primary endpoint by saying, in addition to that, so we raised the bar intentionally, in addition to that, we also want to show superiority in terms of reducing the risk of low blood sugar or hypoglycemic events. And we intentionally chose the primary endpoint analysis to be at the midpoint in the six-month study, so at the end of the third month, which was the end of what's called dose optimization. So in the OPT-2 trial, for the first 12 weeks of the study, the patients were seen by the clinical site team every week for 12 straight weeks. The prior three days of their blood glucose values measured by continuous glucose monitors were assessed, and then their insulin dosing regimen was tweaked or so-called titrated for the next seven days, and they did that cycle every week for 12 straight weeks. FDA requires dose optimization along those lines because they want to make sure that you're not showing a reduction in hypoglycemia because you're basically allowing people to become more lax in their overall insulin care. So you have to prove to the FDA that you're being very diligent in managing uh insulin dosing. And so uh at the 12-week period where we were looking at both A1C non-inferiority and hypoglycemia superiority, we very clearly met the A1C non inferiority endpoint. So we're clearly um as good as the humolog comparator. And we missed on statistical significance for hypoglycemia superiority. So everything was directionally. I think 14 out of 15 of the measurements favored HD. Insulin compared to the control insulin, but we weren't able to achieve strict statistical significance. But as you indicate, when we look at the next several weeks in the study, what was called dose maintenance, we ran the exact same hypoglycemia measurements, and there we did achieve statistical significance across many different measurements in the trial. So that's actually viewed as the more relevant time period by FDA because they want to know that the study effect is durable when patients are kind of put back into the wild, as they say, and are able to kind of just live their lives in a more real-world experience. And there we showed both A1C non-inferiority and really substantial statistical significance across these major endpoints. I think that's why certainly bodes well for phase three. And also I think one of the reasons why the ADA reviewers are so excited to actually present this. Okay. There was another finding that struck me in a very stark way. And it actually goes back to the start of the podcast when I was recalling the situation with my father coming upon some person uh that was you know not on the on the lawn. And that was that there were, when we look at the severe hypoglycemia events, there were five in the standard LISPRO, as I understood it, um category, and that's just over 100 patients, you know, over the six-month period, five severe um events and zero on the HDV insulin. Now, I don't know how that all fits in terms of statistical significance or clinical significance, but I'll just say that's what struck me about it. What are you am I am I over overreading it? No. So that is one of the most remarkable aspects of a lot of remarkable findings in this trial. Um the long-standing FTA focus has been on the incidence level of severe hypoglycemic events and long-term clinical trials of novel insulins. Um it's very, very typical for there to be uh a number of severe hypoglycemic events. So these are the kinds of things where, for instance, one of the five uh cases that you mentioned, uh someone blacked out and drove off the highway and hit a telephone pole. Thankfully they weren't killed, but they could have been. And then there were four other incidents where ambulances need to be needed to be called, uh, people needed to be taken to the emergency room, or someone had to be rescued with a glucagon injection, which is the way you bring someone out of a low blood sugar event. So these are serious, potentially life-threatening incidents. And in the trial, in the standard of care control arm, there were five of these documented cases. Remarkably, there were zero in the HTV uh test group. And we weren't necessarily anticipating that, but it very much fits with a more physiologic form of insulin that's actually working in the body where insulin should be working. So we're super excited about that finding and has really generated a lot of interest and enthusiasm from our clinicians. So I had mentioned before, you know, a number of innovations that have occurred over the past decades and the uh CGM being an important part of that. Let's look ahead and say, you know, if these results are replicated and the product gets on the market, what does it mean for CGM? Does it make CGM obsolete? Does it make it more effective? What changes there? Yeah, so the way we view the future, if HDV uh can be added to commercial insulins, is that number one, people will be able to be more intentional and perhaps even more aggressive with their insulin therapy to bring their A1Cs closer to normal levels without the chronic recurring fear of hypoglycemia. CGM is a part of assuring themselves that they're actually seeing that benefit. So we don't see HDV insulin as obviating the need for or desire to use CGM. But what it will do is make people less somewhat less dependent upon it from a minute-to-minute perspective. Um, so instead of looking at their CGM uh, you know, every every 20 or 30 minutes, uh, or trying to manage looking at CGM when they're exercising, playing tennis, you know, you know, on a sailboat in the middle of you know the ocean or a lake or whatever, you know, just kind of living a more normal cadence to life, even with CGM in the background. So we we view them still as very complimentary, but the point of HTV insulin is to help people just be less dependent upon some of the technology aspects of living with diabetes. So I want to ask you now, going you know, beyond insulin and beyond diabetes, because as exciting as what you've just described there, there's uh there's more to it as I understand HTV's potential use as a platform and not just for insulin. Is that correct? And uh how do we think about HDV as a platform and not just uh something that's you know that's part of the you know something that works with the existing insulins on the market? Yeah, exactly right. So you know the the liver represents uh basically a central repository of all kinds of very important molecules like insulin in the body. Um the liver's job is to be the central regulator of both glucose and actually fat. And what's interesting is that you know the liver uses about 80% of all of the pancreas's insulin supply, but the liver is also the recipient of the GLP1 that is produced in the intestines. So 95%, you know, everyone hears about GLP1 today. 95% of the body's GLP1 is produced in the intestines. And that GLP1 drains into the same blood flow that feeds the liver. And there's all kinds of interesting biology and physiology that happens in and around the liver where insulin, GLP1, and another molecule called serotonin, which is also primarily produced in the intestines and drains into the liver, are all kind of converging. So there's a vein called the portal vein that drains blood from the pancreas and from the intestines. And it's basically a protein and peptide superhighway that goes right into the liver, and the liver then reacts to these very important, very powerful molecules to manage sugar and fat for the entire body. And so we're really excited about the potential application of HDV as an improvement for things like GLP1, because we want to be able to get GLP1 into that so-called portal hepatic region, uh, which is where the liver, where the intestines puts it. And we think we're gonna be able to show, for instance, reductions in side effects from GLP1 and improvements in efficacy. And serotonin, we think is a really important molecule for treating uh insulin resistance in type 2 diabetes, and that requires a liver targeting system as well. So the HTV system has three programs right now insulin, GLP1, serotonin, and they're all equally exciting to us. So let's talk about GLP1 a little bit because you know, with insulin, one of the one of the issues there is that um that's not really a big growth market. You know, people don't just decide to take insulin for the most part. And also if they're not completely satisfied with it, they you know, they stick with it. And let's contrast that with GLP1s, which are you know, people take it because they have some objective in mind. It's not that they'll you know they're gonna perish if they don't, if they don't have it. But then a lot of people they get that dramatic effect of a weight loss. And yet it's difficult to tolerate from a you know gastrointestinal standpoint, and then also muscle loss is a concern. So you're thinner, but you can't climb the stairs anymore, uh, et cetera. And so a lot of people go off of it, or if they don't, um, you know, they may get some impact, but then there's a side effect, or worse, that's uh that's that's a problem. So are you I mean, I would anything that any technology at hand, I would try to apply it to GLP1 since it's such a large market and there's a lot of players that are trying to get in there and to differentiate. But does HDV, is it just a matter of convenience, or is it that it could actually address some of those central issues with the GLP1 drugs? Yeah, we're we're excited that it could address uh certain central issues. Um the liver actually processes GLP1, and the there are all kinds of GLP1 receptors in the portal blood flow that feeds the liver and drains from the intestines. Um that part of the anatomy is is directly involved in what's called the gut brain axis. So GLP1 has a role to play in triggering things like a feeling of fullness or so-called satiety, um, along with dealing with serotonin release from the intestines, um liver glucose, liver fat, all these things. And so we think that using HDV to specifically target that part of the anatomy for GLP1 could, for instance, cut down on side effects, just make it more effective, make it more physiologic, putting GLP1 back in to the part of the blood supply that the intestines does. And so we think we could have something to say that would be beneficial both in terms of increased efficacy and decreased side effects. I heard uh ambulance in the background there, Bob, which makes me think that's somebody that uh did not yet have access to HGV uh insulin. Uh what's up? Yeah, hopefully not. We're we're located uh near the Cleveland Clinic main campus, so I think uh something was going on. Got it, got it. All right, let's come back and talk about you know, you mentioned insulin resistance and you mentioned serotonin. How do those two things well, what is insulin resistance? How does it go together with serotonin and what's the relevance of HGV there? Yeah, so um 95, as I said, 95% of the body's serotonin is produced in the intestines. Um and that serotonin is released into the same blood supply to the liver when we eat food that has sugar in it. So it is analogous to the release of insulin from the pancreas. Um we have really interesting data, some of which has been published, that shows that insulin and serotonin work together to cause the liver to store glucose in a normal fashion. And there's evidence data and evidence, not only from diosomes research, but from other research, that serotonin can modulate the amount of insulin required to control the amount of glucose that we eat and how it gets managed in the body. So our thinking is that it could be that type 2 diabetes and insulin resistance uh as a key part of type 2 diabetes could be in part the result of decreasing serotonin release from the intestines due to overuse. You know, we all eat too much carbohydrate, um, you know, advancing age, genetic things. And as serotonin release in the intestines goes down for one or more reasons, that could cause the pancreas to try to compensate for that missing signal by overproducing insulin. That would then manifest itself in a person, for instance, with prediabetes, uh metabolic syndrome or type 2 diabetes as classic insulin resistance. You know, it takes more insulin than would be normal to handle the amount of glucose that you eat when you have a meal. And so our thinking is if we can replace serotonin in the liver with HDV in the same way we're replacing insulin in the liver with HDV, we might be able to decrease the body's requirements for insulin from the pancreas, which would then manifest itself as hopefully a reduction in insulin resistance in the person. Great. It all sounds very exciting. Now, there's also these programs are uh you know are for drugs that are not yet on the market. Um, takes a lot of resources, financial resources, human resources, scientific resources, and time to get there. And I'm wondering about uh what your plan is to go to market and if this is something you plan to do all by yourself as diasome, or you know, to work with others on it. Yeah, so you know, obviously the there are there are large global insulin manufacturers, there are large global GLP1 manufacturers. The GLP1 space, as you've indicated, David, is a very crowded space because of the size of the potential total addressable obesity market globally. Um we think that HDV has a role to play inside diasome in terms of our own independent development paths across these three platforms for insulin, GLP1, and serotonin. But we also think that we can be very helpful to innovators in the diabetes and obesity space because the side effect profile for insulin and GLP1 are really important and really tricky problems to deal with. And we think we have something uh that can be very um important and helpful to other innovators. So we're open-minded right now in terms of pursuing a go-it-alone strategy for the time being, but also be being open to potential partnering and other forms of collaboration with other drug innovators in the space. Do you have a goal for where a diastome would be, let's say five years from now, or pick your time frame? Yeah, our overarching goal um starts with the insulin program. So five years from now, we want everybody who takes insulin to have HDV-targeted insulin and have less of a hypoglycemia risk. Just very simply, that's central to our mission and has been since diastome was founded. Five years from now, we'd like to be close to approval, if not already approved, for a more physiologic form of GLP1 therapy. So people have all of the efficacy in terms of glucose control and uh weight maintenance and weight loss, but without the onerous side effect profile that GLP1 drugs have today. And then we'd like to be very far down the path, uh, you know, even into phase three, five years from now, for an oral HDV serotonin that can go directly at insulin resistance in the global type 2 uh population. So we really want to be um, you know, a pivotal platform uh strategy for cardiometabolism and obesity using you know hepatic, oral hepatic targeting. Terrific. Well, that's it for yet another episode of the Health Biz Podcast. I'm David Williams, president of Health Business Group. My guest today has been Bob Gho. He is the CEO of Diasome. We have been talking about HDV, insulin, GLP1, serotonin, insulin resistance, and what the future may bring. Bob, thanks so much for joining me today. Great to be with you, David. Thanks for the opportunity.