The Big Experiment
Ever wondered how technology start-ups, well, start-up? For most founder entrepreneurs, it is the biggest experiment they'll ever run. Like most experiments, the result isn't known beforehand and it often doesn't work first time. On a bigger scale, how do big tech companies turn innovative science into profit?
Mark Davison interviews founder scientists, executives, investors, communicators, and others in the technology start-up and corporate science ecosystems.
Learn how great ideas turned into thriving businesses (or not) from those who made it happen (or didn't). Get business tips, lessons learned, and life lessons straight from the people who know.
Inspiring, disastrous, funny: hear what life in a science-driven company is really like.
Straight-talking, no nonsense, but conversational style. All technical content is explained for the non-specialist - you don't need a PhD or fluency in jargon and technobabble.
The Big Experiment
Mike Teiler – Innovating Type 1 Diabetes Treatment
My son was diagnosed with type 1 diabetes at the age of 13.
Which is why this episode is very close to my heart. There are big life-altering challenges for the patient and their family in managing type 1 diabetes. With limitations to the current insulin therapies that make the work of my guest in the episode, Mike Teiler, all the more important.
Mike is the Chief Pharmaceutical Officer at LeviCure, a startup focused on new approaches to type 1 diabetes. In this episode we discuss the difference between type 1 and type 2 diabetes. And explore the development of LeviCure's triple therapy, which combines three existing drugs to improve glycaemic control and potentially achieve remission in type 1 diabetes patients.
A therapy that has shown promising results in both recent onset and established patients. We discuss the potential of repurposing existing drugs for the treatment of type 1 diabetes. As well as the funding required and the clinical trial process that will be undertaken to be able to launch the therapy.
“Many of them completely stopped insulin injections.” – Mike Teiler
You’ll hear about:
01:10 - The difference between type & type 2 diabetes
04:03 - The lifechanging nature of type 1 diabetes
06:40 - The LeviCure story
11:16 - The effect of weening people off of insulin
15:08 - Oral drugs that could replace insulin
18:48 - Disentangling the honeymoon effect
20:15 - The effects on established patients
25:02 - The pharmaceutical benefits of this therapy
27:58 - The intellectual property perspective
30:43 - The democratic nature of these new therapies
34:15 - What are the clinical phases?
41:08 - Making sure the therapies hit the target
43:44 - The fundraising needed
Follow Mike:
LinkedIn - https://www.linkedin.com/in/miketeiler/
LeviCure on LinkedIn - https://www.linkedin.com/company/levicure-ltd/
LeviCure - https://www.levicure.com/
Connect with me:
LinkedIn: https://www.linkedin.com/in/markdavison100/
Grant Instruments: https://www.grantinstruments.com/
Grant Instruments on LinkedIn: https://www.linkedin.com/company/grant-instruments-cambridge-ltd/
Hello everyone and welcome to The Big Experiment, a podcast that goes behind the scenes of science and business to discover the people and the stories that make new technology happen. My name is Mark Davison and my day job is CEO of Grant Instruments. We make laboratory instruments and equipment. You can go to grantinstruments .com if you want to know more, but that's the last you're going to hear about it from me. Any views I express here on my own, not the company's. So this show is about other people and it's about how they use their science and business skills to make the world a better place. Thanks for listening. If you enjoyed this episode, don't forget to like, comment, subscribe and share. Hello everybody and welcome to the big experiment. This week we're going to cover a subject that is very close to my heart and I'm delighted to welcome Mike Taylor, Chief Pharmaceutical Officer at LeverCure. They're a startup looking at new approaches to type 1 diabetes. So welcome Mike, great to have you. Thank you so much Mark, thanks for inviting me, it's great to be here. Good. Now, this is a topic that I know quite well, so I'm going to make sure that we don't go too deep too soon, but maybe you could start with the basics and explain to people the difference between type 1 diabetes and type 2 diabetes, because they're relatively different diseases, right? Yeah, absolutely. In fact, they're almost opposite diseases, which is really interesting. And you know, it's confusing because they do share the same name. Actually, the interesting thing is diabetes mellitus, the full name, really means sweet urine. And so initially, that was a symptom that was common to both diseases. The body excretes sugar in the urine, and in both cases, because there can be too much sugar in the blood. And once the kidney passes a certain threshold, it can't filter back the sugar anymore, and it excretes it in the urine. So, you know, the old joke about doctors having tasted every bodily fluid, apparently they actually used to do that and that was a way of diagnosing in the old days, that's how they diagnose diabetes. But actually, as it turns out, they're almost opposite diseases in that in type 1 diabetes, the body stops secreting insulin, right? It's an autoimmune disease, the cells of the immune system attack the insulin-secreting cells. in the islet of the pancreas, in the beta cells, in the islets of Langerhans, and destroys the capability of those cells to secrete insulin. And that's what causes the problem. Now there's no insulin in the body. The body has no way of metabolizing the sugar and turning it into energy, and quickly causes a very, very severe problem. Type 2 diabetes is almost the opposite. There tends to be too much insulin, and it's really caused by the body being resistant to the insulin that is in the body. And so it's not that there's no production of insulin, there's plenty of insulin production, even too much insulin production. The body becomes resistant to that insulin and then the cells of the body that need to absorb the sugar from the blood are unable to absorb the sugar. And that's the job of the insulin is to signal to the cells of the body that need the sugar for energy to absorb that energy. so that they can do whatever it is that they need to do. If it's the muscles that need to contract or the brain that needs to think or the heart that needs to pump and the body, in both cases, the body is not able to absorb the sugar, but the reason is really quite different. Yeah, that's fascinating, isn't it? And we could talk all day about type two diabetes, which is a larger population of people, but we'll stick to the script a little bit for type one, which is a challenging enough disease in its own right. It's been a hundred years or so since researchers discovered insulin. And before then type one diabetes was a lethal disease, right? Patients died within five years at the most. But since then, that steady innovation in insulin delivery and blood glucose monitoring is, it's a much more manageable chronic disease now, but it's still, it's still life -changing. It's still life -changing. I mean, as you will know from your own personal experience, it's hours per day to manage the disease. And over many years, the long -term complications can be quite devastating. There are cardiovascular complications, there are complications with blood flow, which often leads, after many years, often leads to problems with blindness or require amputation because there's not good enough blood flow to the peripheral parts of the body. So there are some really devastating complications of diabetes. Of course, insulin has been fantastic and being able to give insulin over the last hundred years has really been life-saving. But still, injecting insulin externally is never going to be as well controlled as what the body can do by itself. The body is just amazing in terms of its feedback mechanisms and the way it's able to control insulin. And we haven't yet, even with all the closed -loop systems and all the great feedbacks, the CGM to the pump, which has made fantastic strides over the last number of years, it's still not as effective at managing insulin and glycemic control as the body can do by itself. So what we're hoping is that by restoring the ability of the body to secrete insulin, that will really improve the entire situation for type 1 diabetics. Yeah, fantastic. And just a full disclosure here. As regular listeners will know, I love all science. Any flavor of science is great with me, but this particular episode's got an extra dimension. So when my son was 13, he was diagnosed with type 1. And it's a really life -changing event. Clearly, it's life -changing for the patients, but it's a very tricky disease to manage for families. And it's typically a childhood disease, type 1. It's more common in younger people. So I really understand how families feel in trying to manage this issue. And it's come a long way in that. 12 years since my son was diagnosed, it's come a really long way. Closed loop systems are becoming more common. The finger pricking that was, you know, that means that kids hate to draw blood on their own fingers. Who wants to stick a needle in the end of your fingers six or seven times a day? You know, it's horrific. So that's all getting better, but it's still a very complicated multifactorial disease. And it's always been unlikely that insulin was the one thing that would fix it, right? So single molecule is never going to be the the one bullet solution to it to type one diabetes. So maybe let's loop back and think about the Levicure story and how this kind of combination therapy came up because it's almost a serendipity, a kind of medical guided serendipity, but it's an interesting story as to how this new approach came up. It is, it's really an interesting story and the inventor is a Professor Shmuel Levitt, who's a clinical endocrinologist. He's been practicing for over 35 years. He practices in Tel Aviv at Asuta Medical Centers. And he was searching for improved glycemic control in his patients. He has many type 1D patients in his practice. And he was looking for improved glycemic control. Now, he's very on top of the literature. And he was following what was going on in the world. And he saw different approaches. For example, there was the group led by Alexander Abunovitch, who was treating with cytoglyptin and a proton pump inhibitor. And he had used Lenzoprazol as the proton pump inhibitor in his last trial. So just to pause that for a moment. So proton pump inhibitors classically used for gastric issues, reflux, et cetera. Correct. Initially they were used for ulcers and today it's used for heartburn and for reflux, gastric reflux. So, you know, it's almost counterintuitive that a heartburn medicine would be part, you know, an integral part of a therapy in type 1 diabetes. Cidagliptin, which is used in type 2 diabetes, is actually contraindicated in type 1 diabetes because it wasn't found to be effective enough in type 1 diabetes in order to justify its use. But Alex Rabinovich, and he's part of our advisory team, so, you know, we're on a close, friendly basis. He believed that the two of them together, understanding their mechanism of action, could actually have a positive effect. And he saw, you know, he had really good results in animals and in cells, but when it came to actually doing it in people, the results were not good enough. Now, at the same time, roughly at the same time, there was a lot of work being done with GABA, gamma aminobutyric acid. Now, GABA is a neurotransmitter. And it's found primarily in the central nervous system, but it's also found in the endocrine system. And it's interesting that the cells of the endocrine system, particularly the gastrointestinal tract, are the most similar to those of the central nervous system. And there are a lot of similar mechanisms in those two systems. So work that was done by people like Daniel Kaufman from UCLA and Patrick Columba were showing that GABA could have an important effect in increasing insulin secretion. And again, it worked really well in the lab, but it just didn't translate to people. So Shmuel, Professor Levitte, he knew these, he was aware of what was going on in these two different schools of thought, and he thought, well, hang on a second. If I combined these two together, maybe I can get improved glycemic control. I don't think he himself dreamed of getting to the level of remission that he actually achieved in his patients. But he thought that by combining these two approaches, he could achieve improved glycemic control in his patients. And so he was using these three together, what we today call the triple therapy, in his patients. And his success, he was so successful that he really wanted to do a study in his patients, just sort of a retrospective study to see if what he was perceiving as tremendous progress. was really true. Did it really hold water statistically? So just to pause there a moment. So I just want to explain for listeners that a medically qualified doctor is more or less able to prescribe what he or she feels fit for that patient in any given circumstance, right? I don't think people realize the power that doctors have to kind of wing it in a way and actually figure out what will work for the patient, even if that indication is not on the label of the drug. Correct. If they understand the pharmacology and they know what's going on, it's, you know, that's why they have all these years of training and you know, that gives them license to be able to use drugs, even if the indication isn't necessarily on the label. Right. So you can make these breakthroughs that the science on the packet would say is not there yet. You can intuitively jump forward as a, as an individual clinician. So over time he was actually weaning his patients off of insulin. And he wanted to see how significant that effect really was. So the initial retrospective analysis that he did, he did in 2018, and he found that he was getting really significant results. And then he applied for a patent. Now, he's a clinician, he's a physician, he's not a businessman, he's not from the industry. And so, you know, he didn't really know how to go about what he was trying to go about, but he put in a patent application. And roughly at the same time, our other founders, Danil and Lucy, a married couple, had come to Professor Levitt to treat Lucy's mother for a different endocrine problem. And Shmuel saved her life. So of course, they were really impressed, and they had become very close over a period of time. And then one of Danil's close friends was diagnosed with type 1 diabetes. And he said, look, I know this amazing endocrinologist in Israel. They were actually living in Russia at the time, in Moscow at the time. And he referred his friend to Professor Levitt, who treated him with the triple therapy. And his friend over a period of time went into full remission. In other words, was maintaining good glycemic control without any insulin injected at all. And, you know, Daniel and Lucy were so impressed by what, you know, what they saw with their friend. They said, look, we have to be involved with this. We have to see how we can roll this out. to the rest of the world. How is it possible that people, you know, more people don't know about this? And they went ahead and they put a lot of their own money into doing the work that was required in order to finalize getting that patent granted. They actually worked backwards because the first results were in humans and then they went backwards and then the animal studies, which were required to prove that the triple combination was actually superior to any of the double combinations and some of these double combinations had been known. So quite rightly, the patent reviewer came back and said, well, you need to show me that this triple combination is actually superior to the double combinations. And that was done in an NOD mice study. So that's a pretty big gamble that they took as private individuals to back this clinician on a hunch, really. Well, they had seen it in their friend. And they'd already had a very good relationship with Professor Levitt. and they really believed in what they were doing. And yeah, but they did, they took a certain leap of faith and they put some money in and they did the experiment. And lo and behold, they came out with very conclusive data that it was only the triple therapy that was superior to placebo in achieving all of these results that were so impressive, not only including the fact that many more mice survived and that glycemic control was much better. that much less insulin was required and many of the mice came off of insulin entirely. They were actually, each mouse was treated like a patient. They needed to continue getting insulin because otherwise the mice would have died during the study. So the mice, once they developed the diabetes -like syndrome that NOD mice develop, they were treated with insulin. And then using a particular titration mechanism, they had a real clear algorithm as to how to down titrate the insulin, they were able to down titrate the insulin in these mice. And not only did they see the improved glycemic control, the reduced insulin requirement, but there was also an increase in C -peptide, which is the sign that it's actually endogenic insulin, insulin that's created in the body that is responsible for these results. And the increase in C -peptide was very profound. That's amazing there. Just to pause, so those are three orally available drugs, tablets, if you will, that could potentially replace injectable insulin and have the very similar results. So two of those products are available as medications today. Citagliptin is available by prescription. As we said before, the actual indication is type 2 diabetes. Omeprazole today is available without a prescription over the counter. It's used for heartburn. It's used for gastric reflux. And GABA is not available as a drug. GABA is only available as a food supplement. It's quite widely available. Most countries in the world, there is GABA available as a food supplement. I think the UK actually may be one of the exceptions to that, but it's very widely available. And so... Professor Levith was able to provide his patients with prescriptions for these two drugs and send them off to the health food store to buy GABA. And they were able to take the cocktail, the triple therapy. And he was finding over a period of a number of months, it doesn't happen overnight. It takes some time for the mechanism to kick in, but they were able to reduce and many of them ultimately completely stop insulin injections. That's amazing, isn't it? And so for those on who are type one or know somebody with type one, is this a phenomenon that is true regardless of stage of development of the disease or is this something which is only working in the first year, two years of diagnosis? So what we've seen is that, so when we did the final retrospective analysis of Professor Levitt's patients, we ended up with 19 patients that could be analyzed and we were very strict in terms of the diagnosis. parameters that we used, we used the accepted parameters of the American Diabetes Association and the European equivalent, the EASD, who strangely actually agreed on their criteria and they don't always agree across the pond on different guidelines of things. Absolutely. But they were in agreement as to what are the diagnostic criteria for type 1 diabetes and we were very strict about the inclusion exclusion criteria. And we were not selective in our patients as long as they met those criteria, we included them in the analysis. So we ended up with 19 patients that we could analyze. 10 were recent onset patients. That is, they had been diagnosed and started insulin therapy within the last 12 months. And the rest were established patients, so meant beyond 12 months. And many of them had been on insulin therapy for a number of years, quite a number of years. I think the mean was about nine years for the established patients. And we definitely saw that in the recent onset patients, there was a... better chance of reaching remission. Seven out of the 10 patients in the recent onset group all reached remission seven out of 10, which was incredible. I mean, again, Professor Levitt never dreamed that he was going to reach that level of success. Again, he was looking for glycemic control. But you know, and he reached remission and in seven out of 10 patients. So it was just incredible. And clearly, so there is there is a honeymoon period after the onset of diabetes, right? So typically what happens is you're diagnosed and clearly you're sick at that point, but you have insulin. But the amount of insulin that you need in year one and the ability to control glucose with those insulin injections is much easier and gets harder over time as your remaining islet cells die off pretty much. So how are you disentangling that from the honeymoon effect anyway that kind of makes it a bit of a simpler task in year one? Well, we did an analysis of what that honeymoon effect really looks like. And yes, as you say, the honeymoon effect is well known in the clinic and in the literature, but the honeymoon effect is so much smaller. You know, we're talking about something in the neighborhood of 10 % and we're talking about something in the neighborhood of, you know, of a very short period of time of a number of months. Here, we're talking about seven out of 10 patients who are in full remission and many of those patients remained in remission. for well over a year. In fact, we have some patients that we followed up for as much as three years who remained off of insulin. Eventually, they all did need to go back on insulin, and many of those were able to go back on insulin, but at a reduced dose. So if a patient started out at, say, 12 units per day, if they had to go back, maybe they had to go back to six units per day later on. There was definitely a much more profound, you know, if you compared the two effects statistically, much more profound in the triple therapy. than what was known in the literature for the honeymoon effect. Yeah, that's fascinating, isn't it? And I think that early phase of shock of being diagnosed and that life -changing daily routine, if that can be made easier, then that's going to have a huge effect on patients' mental well -being as well as physical well -being. Absolutely. And then in established patients, we also saw many improvements. In the recent onset group, we saw an increase of nearly 150 % in C-peptide, which is just phenomenal. In the established patients, it wasn't as profound. And if you looked at the mean data, it appeared that there was no increase in C-peptide because it was very variable between patients. Some patients showed an increase, some patients did not show an increase and continued to have a decrease as the disease progressed. And our understanding is that as long as there is some existing C -peptide, in other words, there is still some beta cell activity that we're able to encourage that activity, increase the activity, increase the secretion of insulin from those existing cells, and hopefully also increase the volume of the cells in the pancreas that are secreting insulin. That's really interesting. And does that lead to a pathway for helping stem cell therapies and other therapies to take if you will, you know, that for people who've been established a long time with very little endogenous insulin left, it's really easy to augment that with a dual process. So we definitely think that there's a synergy between, you know, some of these stem cell and beta cell transplantation therapies in that what we're treating and what we've seen and we've done an extensive analysis when I say we, I mean, Lucy, Lucy, is trained, and this is really interesting, right? She's trained as a lawyer. That's her degree, but she's also working as a researcher at Uppsala University together with Helgi Schiot in the pharmacology department. And she has studied this for a couple of years already, and we've just recently submitted for publication a very detailed mechanism of action of all of the different pathologies. that are happening in type 1 diabetes. And, you know, as you said earlier, it's not reasonable to believe that there's going to be one molecule that's going to be able to address all of these dysfunctions. And what we see is that with the triple therapy, we're actually addressing both the metabolic dysfunction as well as the autoimmune dysfunction at the same time because we have the three together. And so one of the drawbacks or potential drawbacks of using these other therapies where beta cells or stem cells are used is that the immune system still continues to attack the beta cells. So as long as you're not taking care of the autoimmune dysfunction, over time there's potentially going to be a degradation of even those new cells to be able to secrete insulin as the body attacks those cells. And with the triple therapy, because we're addressing both the immune dysfunction alongside the metabolic dysfunction, we believe that that would be synergistic in with all of these cell therapies as well. Yeah, that's if that works long term, that's going to be amazing, isn't it? Because I think it will if we can find a way to help people who've been diagnosed a number of years as well as new onset, then I think that's really game changing. Yes, we're really excited about it. And as I said, we've seen improved glycemic control in our established patients as well. We believe that it's through a different part of the mechanism of action, not necessarily working only through increasing insulin secretion or through increasing insulin secretion, but by suppressing glucagon, which is another effect of the triple therapy. And by suppressing glucagon, which really has an opposite effect to the insulin, we feel that that's probably where we're getting the improved glycemic control in our established patients. The interesting thing is, Mark, that about a third of established patients still have residual C -peptide levels, meaning they do still have some activity in their own beta cells. And so we believe that those patients will also be a good target population for the triple therapy and that they could benefit from the triple therapy. Yeah, that's fascinating. So Mike, you're formerly of Teva, huge global, global generics company, or at least known for generics amongst other things. And this brings me on to the kind of practicalities of drug development here. So repurposing and reformulating existing drugs that have been taken for years has huge benefits, doesn't it? Because you have that proven safety record of millions of patients having taken the drugs. You know what the side effect profile is. You need to do some work on the combination therapy, clearly. But you know that these drugs are not going to kill people stone dead most of the time. So explain from a kind of pharmaceutical perspective, the benefits of this combination therapy as a starting point. So exactly, as you say, Mark, I mean, we're talking about drugs that are already known and already proven as safe, although in other indications, but we know, you know, how many how many drug development programs, you know, die after tens of millions of dollars, and I don't know how many years have been spent in the lab, only to find that, you know, it's killed too many mice, or it's caused a, you know, a tumor in, you know, in a kidney or in the liver of a particular species and that all gets washed down the laboratory sink. That gets all washed down the laboratory drain. Whereas these drugs are already proven as safe and just like there's no such thing as a drug that has an effect and doesn't have a side effect. While drugs can be very selective, they're also going to have an impact in other places, which is why every drug has warnings about its potential side effects. An example that I use frequently is look at that antihistamine. that causes you to be drowsy. Well, then later, you know, that was used as a drug to, you know, for people with insomnia to help them sleep. But the spot the side effect was it kind of dried you out. So what is the desirable effect? And what is the side effect is often in the eye of the user, right, as according to what it's used for. And the famous example there is Viagra, I suppose, which is research for a completely different indication. Absolutely, right? Yes, Viagra started out, and Viagra is an interesting story because while it started out as a cardiovascular medication, and then during the clinical trials, they had this reported side effect that Pfizer found was very interesting and was potentially another use for the sildenafil. And in fact, then it became the only approved use for sildenafil. And then later, it was repurposed again back to pulmonary hypertension. which is again back to the cardiovascular system where again it was approved under a different brand for treatment. So yes, there's tremendous potential and today with the databases that we have, the electronic medical records that we have globally, Israel has many but you have them in the UK and you have them in the US and the ability to use machine learning to analyze some of this data, we're slowly finding that there are all kinds of really interesting applications for medications that you never thought could be used in a particular indication. And yet we're finding that they're very effective in these other indications. And that tremendously reduces not only the time and cost of development, because you don't have to show the safety all over again, but it also decreases the risk, because you don't have to worry that it's going to get washed down the laboratory drain after a lot of time and money has been spent. Yeah. And I think that that's a sword that cuts both ways, isn't it? Clearly, you have the benefits of drugs that are out there and known, but from an intellectual property perspective, explain how you put a ring fence around that and make a commercial gain because clearly the patents on those are usually expired or there is no longer a material composition of matter on those individual molecules. How do you get the benefit as a corporation? Right. In terms of composition of matter, which is the term that the patent agents like to use for a molecule patent. You're not going to get a molecule patent. The molecule patent is already there. It's going to be in place for 20 years. There are extensions that can bring it up to 25 years so that when Pfizer repositioned the Viagra for use in pulmonary hypertension, they still had some patent life on the molecule. But obviously, another company trying to take a generic drug, a molecule that's already gone off, or that they don't own the intellectual property to, there are other means of protection. So you can get intellectual property around method of use, the use of a particular drug, or in our case, the combination of drugs for a specific new indication. You can get patents on specific formulations and there are other patents that can be used in order to create a nice portfolio of intellectual property protection around these. Now, to be perfectly honest, from a business proposition, it gets a little bit dicey because the big pharma companies really only trust a molecule patent. They really only trust composition of matter. As you said, I was in the generic industry for about 30 years. I was at Teva for 24 years. I was at Sun Pharma for another six years. And over all that time, I don't think I ever No, I can tell you, I never saw a molecule patent defeated. Whereas almost every other patent can somehow be defeated, either invalidated or circumvented. And so there's a great, there's a level of risk at least perceived by big pharma, and they really want to see the molecule patent. So for a startup like us, that can prove to be a bit challenging in trying to express the value proposition that we have to present to partner companies. Yeah. And again, I think this is a feature or a bug depending on which way you spin it. The plus side of that is that you should be able to keep the costs of the medicine down compared to the costs of insulin and all of the paraphernalia that goes with the normal way of doing things. One of the big issues, as you well know, is not so much the drug, it's the supply chain for the drug. And if you've ever been as I'm sure you have as well, but when I've been to developing world countries, just the presence of a refrigerator is a medical breakthrough in some villages. So the ability to keep things cold long enough to get to the patient to inject, to help themselves, an insulin needs to be kept in a reasonable temperature. That can mean that patients don't get the treatment they need. So I explain how these oral therapies might just be a bit more democratic, if you will. Right, and that's part of the beauty of our therapy. We have an oral therapy. All three of these drugs are stable at room temperature, at ambient temperature, so they don't need cold chain storage. They don't need the cold chain delivery. We don't need refrigeration as long as you can keep it at 25 or probably under 30 degrees Celsius will be sufficient. So we should be able to make it available globally, whereas insulin that really does have to have that refrigeration is not necessarily available. throughout the world. And so we're very optimistic that we'll be able to provide therapy globally with the triple therapy, because we're talking about three oral drugs that we'll be formulating maybe in our own way. But these will be stable at room temperature and should be available globally without any cold chain. And of course, as you say also, because these are known molecules, the cost will also be much more reasonable. Yeah. And I think that's going to benefit a huge number of people, isn't it? Fundamentally, what medicine is about is making sure that the largest number of people benefit the most. And I think, you know, that's an admirable goal to be aiming for. Is there any interest from some of the philanthropic foundations, Gates Foundation, President's Fund, et cetera, in helping you to reach those markets? So we've been in touch with, you know, primarily Diabetes is funded by a couple of philanthropic organizations, primarily JD, well, they used to be called JDRF and they just changed their name to T1D Breakthrough. Sorry that I had to think about that for a second. They've just recently rebranded. And so we've been in touch with them. They had done some due diligence on what we were looking for in terms of fundraising. And while they won't take a lead role, they will support us. if we find a lead investor. Also, but you know, it's really important to say that a lot of the basic research that was done by the people that I mentioned earlier, Daniel Kaufman with GABA and Alex Rabinovich with DPP4 like Cytoglyptin and a PPI like Omeprazole, you know, a lot of the basic therapy and research was funded by what was then known as the JDRF. So we owe them a great deal of thanks for funding that basic research, because without that, we wouldn't have been able to have this invention where we were able to take these two things that seemingly don't go well together, but then actually gave us this breakthrough type of therapy. Yeah, they've done great work. And I think a lot of the work on closed loop systems with glucose monitors and glucose pumps has been catalyzed by JDRF as well in kind of de -risking. those procedures for physicians and for drug companies, just trying things and seeing what works. So your triple combination therapy is now at the process of nearly entering phase two clinical development. So maybe just explain for the audience the clinical phases and what the ability to leap to phase two means in terms of the risk and the cost. So normally till a company reaches phase two, it takes quite a number of years. First, you need to show what's happening in cells and you need to show what's happening in different animal studies. You need to show a lot of safety and preclinical safety and toxicology data. And then there's phase one data in humans in order to do some very basic understanding of safety of the dosing levels. And that's usually done in healthy subjects, not in patients. Because we're using known drugs and we were able to rely on the safety data that's already lodged with the agencies. And we've only been to FDA. We went to FDA for a pre -IND meeting back in July of last year. And because we had this, we were able to rely on the safety data for both sitagliptin and for omeprazole. And because we were able to present quite a lot of data on GABA, primarily from the literature. we were able to get a green light from FDA to go straight to phase two without any additional safety testing, without any additional preclinical testing. So, you know, that's really a huge time saver in going forward to that, you know, to phase two, where phase two is really, if you want to call it that, say a proof of concept, just before going to our pivotal study, which would be a study which we need in order to actually get final drug approval. Right. So phase two is figuring out. dosing and the kind of the basic parameters of how you're going to deliver this molecule to the patient before you go into the big phase three study where you actually prove that against a comparator regime that it actually does what you think it does. Correct. Exactly right. So, and what's the target date for starting that phase two trial? We'd like to be able to start that phase two trial towards the end of 2025. We're currently raising the money that we need in order to be able to submit the IND application. The IND application requires quite a bit of data, not only the medical writing and the full protocol, but also what's known as the CMC section, chemistry, manufacturing, and control. So we'll actually need to go ahead and manufacture the clinical supply and have the data on the three different drugs and the three different placebos that we need to go into that trial. So if we're successful with this seed round, we should be able to raise the money. towards the end of this year, start the development of the GABA API because you know, something that you know, people aren't so aware of is that in order to do a clinical trial, you have to have material that's been manufactured under GMP, good manufacturing practices, or CGMP. You can't just take a food supplement, for example, you can't just take a food supplement that might let you do it in phase one. But once you get to phase two, the the agencies definitely do not promote that do not support that type of work. The Europeans are even stricter about that than the Americans. And so we're going to have to develop our own GMP source of GABA API, and then in parallel, do some formulation work and create the placebos. And all of that work together, we're hoping we can complete within about a 12-month period, submit the IND, and then towards the end of 2025 or the beginning of 2026 to be able to get to our first patient study after raising additional money to do the clinical trial itself. Interesting. And maybe just take a very small detour into placebo control and what that means in practice, because I'll let you explain in detail, but the fundamental point being that the taking of a pill is often enough to create a clinical effect, even if that pill is chalk or glucose, right? So your placebo needs to look like everything except have the active ingredient in it. So that's challenging sometimes for placebo tablets. Yeah, exactly right. So You know, we actually have very impressive data from Professor Levitt's own patients. But people are going to be skeptical of that because as you rightly say, Mark, it's actually been shown that the placebo effect, especially in certain indications like say, you know, pain, which is a very subjective indication, placebo effect can be as high as 40%. So if you take a group of people that all have headaches and you give half of them a headache medication, and you give half of them a dummy medication that has just say maybe lactose in it or talc or no active ingredient, no medication at all, 40 % of those, up to 40% of those who are getting the dummy medication are actually going to feel relief and report, yeah, this worked really well for me, thank you very much, I feel great now, thank you, I'm on my way. So the standard, or at least one of the standards for many years has been It's not good enough just to show that your drug has an effect, but you need to compare it to someone so that that psychological effect, that we call the placebo effect, can actually be taken into account. And so we're going to have to go ahead and duplicate the three actives that we're looking to test with identical looking dummy tablets. And we're going to divide our group of patients into two groups. The current randomization that's planned is a one -to -one randomization where half of our patients will be getting the active ingredients of the triple therapy and half of the patients will be getting placebo. Of course, everyone is going to be still receiving their insulin and we're going to be closely monitoring those patients and as they can be titrated off the insulin, they will be titrated off the insulin. But yes, we will have to be doing a placebo -controlled randomized trial so that and double -blinded so that neither the patients nor the physicians treating them know and can, so there's no psychological effect and even the doctor can't hint to the patient, you're gonna have, don't expect much, don't expect much. Or yeah, you're gonna have a really good outcome because you're getting the real thing. They don't know themselves, so there can't even be any body language that suggests whether or not the patient is getting a placebo or the actual active investigational product. And one of the other issues around multiple tablet therapies, of course, is patient compliance with the therapeutic regime. You ask people to take one tablet four times a day, they're going to forget. You ask them to take three tablets, you know, that's another complication. How are you addressing that issue with co-packaging and other things to make sure that those three therapies are all hitting the target? Right. So You know, there's good news and bad news. And the good news is that two of our components, sitagliptin and omeprazole, each for different reasons, are actually once daily drugs by themselves anyway. So those are, those we're talking about once a day. GABA, unfortunately, is a totally different situation where it has a very short plasma half -life. And within, and that plasma half -life is about five hours. So if we want to make sure that we're getting continuous exposure to the GABA throughout the day, And what Professor Levitt did in his practice was, you know, he was giving patients twice and generally three times daily dosing. And as you rightly say, Mark, that causes a problem with compliance and what's today called adherence to the therapy. So we wanna do a couple of things. But what we're going to do in the immediate stage is we have devised a formulation strategy for the GABA so that we can turn it into a once daily dosage form. So the GABA. the GABA as well will be given once a day. So although it's three, they'll be given once daily. And we're still debating as to whether we actually put it in a sleek wallet where we can give all three together in a single pack and then you just pop out the three, each from its individual blister, or if we're going to be required to put it into three separate bottles. But still in any case, it's one time a day. And the other thing that we're going to be doing is we're going to be using some of these cool technologies that you can put either on your own telephone or on a device that you're provided by the clinical site that'll provide reminders and enable the patient to say, it's time to take your medicine. You'll get a reminder to take your medicine. Did you take your medication? Click here. And just with a single click, we'll be able to get that compliance. We'll be able to get that notification. So we'll really be able to follow up with our patients and try to avoid as much as possible using diaries. to record whether or not they've taken their medication, what their glucose levels are, what type of insulin dose they were required to use, and use as much technology as possible in order to get much more robust results within our clinical trial. Yeah, that's crucial. But I think still the advantages outweigh the disadvantages of that approach to just the sheer convenience of having room temperature drugs versus needles for one thing, but also that refrigerated component is going to be game changer if we can make it stick, which brings us on to the next stage, which is fundraising. I mean, for those people who've never been involved in clinical trials like we have, they probably don't believe the nosebleed levels of funding that you need just to get a trial off the ground. So what are you looking to raise and by when? So in this current round that we've recently launched, we're looking for $6 million. to do the clinical supply, all of the medical writing, everything that's required to submit the IND application to FDA and become a phase two ready company and go forward with that phase two trial. The next stage is going to be to raise something like $19 million. In other words, the total that we need to get through the phase two trial is about$25 million. And that's going to cover, so the $6 million will cover all of the clinical supply. any medical writing, any regulatory consultancy that we need in order to take this whole thing through the FDA process. And then we're going to need close to another $20 million to actually run the clinical trial itself. We're talking about a multi -center trial, a multi -country, multi -center trial in order to get the number of patients we need. Type 1 diabetes, while it affects nearly 9 million patients globally, about 8 .9 million I think is the latest number. of patients globally, we're targeting recent onset patients for the trial. And because we want to be as risk averse in our trial as possible and have the greatest success, we really have one arrow in our quiver mark. And this, when we fire this arrow, it really has to hit the bullseye. So we're being very, very careful. We're doing a lot of risk management in terms of how we plan the trial. And in order to get the number of patients that we need, recent onset up to six months since diagnosis, we're probably going to need something like 20 different centers over a number of countries. Hopefully we can limit it to three or four countries in order to perform the trial and be able to finish it within a reasonable period of time. Yeah, and that patient recruitment and all of those other things are a huge challenge. Like you say, it does just soak up money like like you wouldn't believe. So when that 25 million is still a drop in the ocean compared to a new molecule program starting from zero in terms of time and money. So, you know, it's a lot, but it's not as much as it could be, I guess, right? Well, you know, if you look at Pharma, the big Pharma, the US big Pharma industry organization, they estimate it's over a billion dollars to bring a new drug to market. And they estimate about 12 years, we're looking at much, much lower numbers, you know. or at least in order of magnitude less than that. And time -wise, we're also looking at something that's years, years, years less. Hopefully before the end of this decade, we can be ready with our first product in the market. Interesting. So what's your target date for launch? I mean, it's too early to give that in detail, but what's in your head as to when this might be available for patients? To an extent, it depends, Mark. What we're really hoping is that it'll be recognized by FDA. as a breakthrough therapy and that we'll be eligible for accelerated approval. That was indicated in the pre -IND meeting, but it really depends on the results of our phase two trial as to whether we'll be able to get that designation and be eligible for that. If we are eligible for that, if all the stars align and everything works really perfectly, we're talking about 2029. If Murphy comes to dinner and Murphy always comes to dinner, it'll, you know, it could be as much as a year or, you know, a year or even two longer than that. But even having said that, you know, compared to the amount of time that normally takes to bring a drug to market, that that's super, you know, that's super fast. That's really abbreviated timelines. Yeah, worst case, that's, that's half the time of a standard development program. So that's, that's going to be game changing. And of course, the sooner it comes to market, the more patients benefit. the more lives are impacted and so on. So yeah, that's going to be great to see that progress. And what's your funding pool? Are you looking for international money from wherever you can get it? Or is there a specific type of funder that is going to be the most suitable? So we're somewhat agnostic. We are focusing on the US and European funds, but we're not married to that. And if monies can come from other geographies, I can tell you that in our previous funding round, which was a much, much smaller round, and we've been extremely efficient with our money, all the money that we've raised has gone to research. Everyone on the team is working on sweat equity, which is a term we use a lot. In other words, we've been working without salary, only on option schemes up until now. And everything that we've raised has gone into the research or funding the intellectual property protection. And we have quite a nice portfolio of intellectual property protection as well. So all of the money that we've raised has gone there. As I said, the initial money really came from the family. And then the second raise came from people within the community. So we did reach out, and that was very international. We had investors from Asia, we had investors from Israel, we had investors from Europe, we had investors from the US. And so we had a really nice pool of investors. representing, but primarily people within the community. So people who either they themselves had type 1D or someone in the family had type 1D. And we've really gotten tremendous support from within the community. For the larger raise, we don't think that we can rely just upon that. We are looking at companies that have a track record of investing in type 1 diabetes. And once we have a lead investor, it'll be, we'll also be able to hopefully raise some money from these foundations who don't lead. but we'll follow and we'll support. Right, right. Well, listen, Mike, I could literally talk all day on this subject. It's been fascinating and I wish you every success, both on a professional and a personal level. I think it's going to be a fascinating story to watch. And it just shows you what can happen when doctors follow intuition and investors back their hunch and things come together. So best of luck and thanks again, Mike. Thank you very much, Mark. It was a pleasure. Thanks for listening. Hope you enjoyed that episode. Don't forget to like. subscribe and share if you did and we'll see you next time
