#452 Learning about Teplizumab

March 12, 2021Scott Benner

With Francisco Leon, MD, PhD

Enlightening conversation with Francisco Leon, MD, PhD, and the CSO and co-founder of ProventionBio, the company potentially bringing Teplizumab to market if approved by FDA. Leon is a Spanish immunologist and self-described “autoimmunity aficionado” focused on eradicating autoimmune disease through early detection and prevention. He clearly and comprehensively explains how autoimmune diseases are similar, research supporting the unexpected link between coxsackie virus and T1D in studies, and research on Teplizumab which has a BLA under review for approval by FDA for patients at risk of T1D with a PDFUFA goal date of July 2021.

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DISCLAIMER: This text is the output of AI based transcribing from an audio recording. Although the transcription is largely accurate, in some cases it is incomplete or inaccurate due to inaudible passages or transcription errors and should not be treated as an authoritative record. Nothing that you read here constitutes advice medical or otherwise. Always consult with a healthcare professional before making changes to a healthcare plan.

Scott Benner 0:00
Hello friends and welcome to Episode 452 of the Juicebox Podcast. My guest in this episode is Francisco Leone and you are not going to want to miss a word of what he has to say.

You may recall that recently on episode 433 Karla Greenbaum was on talking about trial net. And during that conversation, she spoke about a drug called, oh, Ready, here I go, to please a mob to place a mob Teplizumab. I think that's right to close them off. Well, I might not be able to say it, but you definitely want to hear about it. What's going to come next is an hour long conversation that I found absolutely riveting as a person who has family members and loved ones impacted by autoimmune disease. I hope it strikes you the same way. Please remember, while you're listening that nothing you hear on the Juicebox Podcast should be considered advice, medical or otherwise, always consult a physician before making any changes to your health care plan, or becoming bold with insulin. Alright, a little more business, and then we'll get right to it. Let's let the music do its thing first, though.

Today's episode of The Juicebox Podcast is ad free. But that is because of the support of Omnipod, Dexcom, The Contour Next One blood glucose meter, Touched By Type 1 dot org, the T1DExchange and Gvoke HypoPen. What I mean by ad free is there won't be any ads. But there will be a break in the middle of the show where I try, in 30 seconds, to get out the links to all the sponsors of the Juicebox Podcast. And I'm going to remind you of some links that'll be pertinent to this episode. We'll see what I can do 30 seconds, I'll give it a try.

Francisco Leon, MD, PhD 2:10
Good morning, Scott. Thanks for the opportunity. My name is Francisco Leon, I am the Chief Scientific Officer and a co founder of prevention bio. I am an immunologist by training, and perhaps you can tell by my accent that I am from Spain. I've been in the US for over 25 years now. My entire life has been dedicated to try to find solutions for patients with autoimmune diseases. And that's what brought me to the US. I can tell you a little bit more about my background later if you'd like.

Scott Benner 2:48
Yeah, I am interested though, before we move on. What made you focus on autoimmune?

Francisco Leon, MD, PhD 2:53
I actually came to Auto immunity from the science side. But it quickly became personal. Let me explain that. My mom lost her kidneys to very severe stone disease. She was on the waiting list for a transplant. And she had to wait for eight years. She go ahead and transplant and it was rejected by the immune system when I was a teenager. And so you had to go back to dialysis. And that that influenced me a lot because I just couldn't understand why would they immune system reject perfectly functioning kidneys and condemn that her to a life tied to a machine. So I went to medical school. In the middle of my medical training, I took time off to do research and I became a bit of an autoimmunity aficionado because back in those days this is the late 1993 the first trigger for autoimmunity was found gluten triggering celiac disease, the first antigen and I focused on that, try to understand how does our immunity start? I finished my medical education. I did my PhD in autoimmunity and in celiac. And I learned that the mechanisms that lead to celiac are identical to other autoimmune disorders, such as type one diabetes, multiple sclerosis, rheumatoid arthritis, etc. It's always the same sequence of events. A genetic predisposition towards out immunity a vital trigger the loss of immune tolerance against yourself, tissue destruction, and then symptoms and complications. So, from very early on in my career, I wanted to be able to contribute to stop in this sequence of events. I did a residency in clinical immunology to have the patient side as well, not just that the laboratory side. And then I came to the US to work at the NIH, at NIH. And from there, I went to the pharmaceutical industry to translate all the basic research into medicines or solutions. And I was really fortunate that over time, I was able to contribute to a few drugs that have made a big difference in our community in diseases like psoriasis or inflammatory bowel disease at companies like Bristol Myers, Squibb, Johnson and Johnson. Ultimately, I get a little restless, because Big Pharma is really outstanding at doing the hard work to get medicines through patients. But they focus a little bit too much on chronic disease. They wait a little bit too long, until patients have too much damage, too many symptoms before they intervene. So I learned from one of the leaders in this field Professor height, and Dr. Height is both a professor and a Johnson and Johnson leader. He developed the theory that we should be focusing early on, he created something called the disease interception accelerator at Johnson and Johnson. And I totally bought into those concepts. But j&j was too slow to implement this new vision. So I left I became an entrepreneur, I started the company with the other co founder of prevention, Ashley Palmer, we started this small company called cell immune to start testing this concept of intercepting autoimmune disease. And to do it in a fast and cost effective way.

Cell immune was successful, we were acquired by Amgen, and that gave us the resources to then start prevention. Cell immune focused on celiac, but for prevention, we wanted to go all in into our community by tackling multiple targets upstream in the cascade of the immune events, the T cells, the B cells, the innate immunity, those are the three legs of the stool of autoimmunity. And we were very fortunate that our T cell drug plus a map was so successful at intercepting type one diabetes. That is what really put prevention on the map and the reason we are talking today, but I do want to mention that we continue working on celiac disease we continue working on B cell autoimmunity for example lupus as a Basal model disease. And we are the first company that has declared Our goal is eradication of autoimmunity by working upstream working in the early stages of the disease. So, we are now in a in a privileged and highly responsibility inducing position for us to lead this new era in medicine

Scott Benner 8:52
is the is the simple idea that you do screenings, find antibodies that say that this thing is likely to come for you and then jump in ahead of it.

Francisco Leon, MD, PhD 9:04
That is one of the main ideas you you could even go earlier than antibodies, you could go to the genetic predisposition as well. So as you know, Scott, were screening at birth for over 250 monogenic diseases and babies when they take a little bit of blood. Why not screen for autoimmune predisposition as well, it will just add a little bit of cost. But it could tell us if that baby is going to be predisposed to autoimmunity. And then parents could monitor you could try to avoid the triggers. But also you could try to be educated so that if disease does appear, and you can monitor that with the antibodies as the second test, you can react quickly and you can do intercepted before there is damage to the organs.

Scott Benner 10:03
Can I ask you? Do you know, are autoimmune issues becoming more prevalent? Or are there just so many more people on the planet that we see more of it?

Francisco Leon, MD, PhD 10:15
Both, they are truly becoming more prevalent as societies become cleaner. I don't know if you've read about this hygiene hypothesis, which now is no longer a hypothesis, it's proven. Back in the day, there were a lot of helminth infections. helmets are basically worms. There was a day in America when people had ring worms and things were not as clean as they are today. And the immune system has basically two types of responses, one type of response goes against one's and scolded th two response. And there is another type of response that is geared towards killing infected cells. And that is the th one response and they're balanced. Once the worms were eradicated, the th two arm was weak. And the th one arm began to dominate our responses. And that created the great susceptibility for the development of autoimmunity. And this is so fully proven. I'll tell you a very interesting anecdote. There's this region in Finland called Cordelia garden is a huge place that was split in 1945. Between Finland and the Soviet Union. In the Finnish side, as industrialization hygiene took over autoimmune diseases began to double every 20 years in terms of prevalence through prevalence. In the Soviet side, it remained flat. And the only difference was hygiene, it was the same genes, the same food, etc. So that led to research that finally proved the increase in auto immunities due to industrialization.

Scott Benner 12:17
Okay, I have to make sure I understand is the idea that we've done such a good job of cleaning things up that there were benefits we were getting from some of this, that we're not getting any longer?

Francisco Leon, MD, PhD 12:31
Exactly. us as we lost an enemy to the immune system, the immune system has began to turn against ourselves more often.

Scott Benner 12:43
Can I call you or Francisco? Of course, yeah, Francisco. Are you Are you married?

Francisco Leon, MD, PhD 12:48
I am. Alright.

Scott Benner 12:49
So I've noticed I've been married a long time that when my wife is mad at somebody else, she's nicer to me. Is that what we're talking about right now? You mean, our auto immune, our immune system has nothing to do so it's bored. And it's like, hey, let me take a shot at that pancreas.

Francisco Leon, MD, PhD 13:04
It is it is the case. The immune system has a finite set of resources. And when it is distracted with with an external enemy, it doesn't pay as much attention to the internal self.

Scott Benner 13:22
So George Carlin was right. you've ever have you ever heard the comedian George Carlin say that when I was young, we used to swim in the river with people's feces and I've never been sick a day in my life. That

Francisco Leon, MD, PhD 13:32
it is it is true. I know this, this sounds almost funny. But again, let me go back to Finland. Finland is the leading country in the world in terms of autoimmune research because they have the highest hygiene in the world together with Japan. and Japan is terrible. Now in terms of a topic dermatitis, things like that affecting 40% of the population as well, they are having similar problems there. So the Finns are really tackling this problem. First, they began to follow all consecutive newborns in the country. They did the genetic screening. And then they they started to look for auto antibodies. So imagine imagine doing that in the US all newborns, right. That's something that requires a national effort, but the fence did it. This is a study called deep and the IP stands for diabetes, interception and prediction study. So they identified hundreds of patients with D one d. m, because they had collected samples from those children and even from their mothers for over 20 years. every three months they collected samples. They found that there was only one commonality to all Have those patients, they have an infection by coxsackie B virus in the six to 12 months preceding the onset of T one D. And those children who did not have any other infection have no worms, nothing, everything's clean, they're there, their immune system over reacted against that coxsackie infection. And later it was found coxsackie infects the beta cells of the pancreas directly. The receptor for coxsackie is expressed inside the insulin granules is like a Trojan horse for coxsackie. So the immune system of those children over reacted against coxsackie destroyed beta cells. And in those who have predisposition to autoimmunity, they developed to 1d. And if the mothers had immunity against coxsackie virus, the children have 50% less to one day. That was the genesis of our vaccine project. That's how prevention started our first project was, we need to develop a vaccine for coxsackie B virus, because then we can reduce the incidence of T one T. The second step was okay, what kills those infected beta cells? That is that T cells, the activated T cells. So how do we stop those T cells in people who already got the infection, that is the police map. And that's why we began working on these two areas. Just to complete the finish story. Once they realized what was going on, in Finland now that our companies that sell Dirt, dirt from farms that are not clean, they put it in the baby's bonnets, in the socks. It's in little pouches. And then the baby gets exposed to that diversity of antigens, that distracts the immune system. Now, in the immune system, just like in life in society, diversity is very important. If you don't have diversity of exposure, that's when the immune system focuses on just one thing, and that's never good.

Scott Benner 17:26
I have to thank you. You're not going to see this coming. But my daughter is almost 17 years old, and she was diagnosed with type one when she was two, I am a stay at home dad. And I was at that time. And she had coxsackievirus right before she was diagnosed with type one. And I spent a lot of time. You know, I think like many people do, wondering what they could have done differently. And I always thought, I wonder if I didn't wash my hands enough before I made food. Like it was a ridiculous thought. But it's all I had to try to understand it. And you just made me feel better over. I really appreciate that. Thank you.

Francisco Leon, MD, PhD 18:05
Well, I didn't know Scott that she had coxsackie. You couldn't have done anything. coxsackie is a tremendously common infection. And it's just under recognized, because in most people, it only causes a very mild disease. It's an enterovirus, it causes some gut disturbance, respiratory disturbance. But over time, now we know it is not just a very likely cause of D one D. It's also a very likely cause of celiac disease, myocarditis, heart failure and heart transplant costs due to coxsackie, the number one cause of viral myocarditis, and recently also, potentially congenital heart defects in babies. So where we are now in the middle of our first clinical trial for this vaccine. And I think that's thanks to thanks to folks like you, educating people because most people don't know about coxsackievirus I hope that the trials will work and will be able to provide this vaccine so that people will have no infection by coxsackievirus

Scott Benner 19:25
Well, this this conversation alone leads me to believe that I can direct my children to in you know, when this vaccine exists one day to use it for their newborns and and hopefully they'll get to skip this diabetes hellscape that we live in. I have to tell you, we figured it out. Because, like we were we are, you know, as positive as we can be as a family that the coxsackie caused ardens type one or precipitated it because she got it and it seemed to go away but it didn't and then suddenly It was back again. And I remember our pediatrician saying that strange, you don't get this twice. So it was almost as if it never was gone. And then we started focusing on the other issues she was having, and sort of lost track of the coxsackie. And then in that it burst out again. And that's then then the the diabetes came in, of course, we lost track of the takasaki for a while, but then in retrospect, it just seemed obvious if it was a something that people get, it's so normal, and it's, you know, sort of like chicken pox and that you get at once you don't get it again, it must have never been eradicated from the first time as what we thought is that

Francisco Leon, MD, PhD 20:37
that's correct. That's correct. coxsackievirus almost never gets cleared fully. And that's 60% of children with T one D who had the good Sankey infection. Before the diagnosis, there has been a study in donors cadaveric donors, people who donate their pancreas for research when they die, and it's the same 60% the virus is still in the remaining beta cells, it's something you cannot get rid of. So, so here's how things are gonna change Scott in the future, because there's a lot of hope, come in, for Arden, and for Arlen kids as well. So a whole new future. First, we'll be able to screen for genetic risk, the the markers are already known, so that their babies will be identified as high risk for this disease that disease and then you can use a knowledge to reduce the risk secondaries, vaccines will help prevent these triggers and reduce the incidence. But then third, for those who still will be exposed to other viruses, because coxsackie is probably not the only virus that causes the one the as I said is 60%. So there's something else other viruses probably. So what happens next, you screen with antibodies, all you need to do is to screen two to three times in a person's life to catch those patients with early disease, H 223, h five to six, nine to 10 or perhaps in puberty, because once the immune system reaches puberty, there is a general resetting of the immune system. When the genital organs appear, there are new antigens. And the immune system takes a break to allow new antigens to appear. Otherwise, nobody will have genital organs, they will be destroyed by the immune system. So during that resetting, the risk of autoimmunity starts to go down. Right. And that's why the peak of diagnosis of T one D is age 1213, just before purity. So if we can get people past purity, we're gonna reduce to one the lot. And then what happens to those who still will develop it because somebody will still the immune system will restart and develop it. So we will have immunomodulatory drugs like the police map and other drugs in development. If and when these drugs are approved, they can be given to people who have the antibodies, because the antibodies indicate the disease is already ongoing. It's just that you still have enough beta cells that you don't have symptoms. But do you want these truly a continuum? Once you get the infection, you break tolerance. Once you break tolerance, you develop antibodies, you start losing your beta cells because the T cells kill the beta cells. And it's a countdown. Once you have two or more auto antibodies, there are four total different auto antibodies is no longer a matter of if but when will you develop clinical q&a. And that's when the countdown starts for us to intercept as well. The sooner we intervene, the more beta cells the patient will have. And we can even prevent insulin dependency if we rescue enough beta cells. And I will tell you in a minute about the results of our clinical trials at risk to illustrate this concept of early prevention, but I just want to complete the continuum but by talking about what happens once you develop clinical t Wendy what happens if somebody has lost all of their beta cells? Is there a hope there?

Scott Benner 24:58
Alright, you ready? There. Second Let me see what I can do here and go check out the Dexcom g six continuous glucose monitor at Dexcom comm forward slash juice box learn more about the Contour Next One blood glucose meter at Contour Next one.com forward slash juice box get a free no obligation demo of the Omni pod tubeless insulin pump or see if you're eligible for a free 30 day trial the Omni pod dash at my Omni pod.com forward slash juice box support the T one D exchange T one d exchange.org. forward slash juice box. Do you want to check out the glucagon that my daughter carries? g Vogue glucagon.com forward slash juice box? And of course always throw your support behind touched by type one.org Would you like to learn more about the company we're hearing about today? prevention bio.com pr o v n t i o n bio.com all these links are available at Juicebox Podcast comm or right there in the show notes of your podcast player. And if you're looking for those diabetes pro tip episodes that you've heard so much about, they're in there, too. They begin at Episode 210. And you can also find them at diabetes pro tip.com. I do. Let's look hold on I started at 2506 and went to 2556. I was like 50 seconds. Alright, so not 30 seconds, but not bad. And no full ads, right? Please support the sponsors when you can they keep episodes like this going, they keep the show free. They keep your juice box flowing. Let's get back to Francisco. There's a lot more coming. It's a really great episode, I thoroughly thoroughly enjoyed making this for you.

Francisco Leon, MD, PhD 26:49
Is there hope? The answer is yes. As you have seen recently, tremendous progress has been made to generate pancreatic beta cells from stem cells. So there's going to be an opportunity to replenish beta cells in our them and in other people who need beta cells. But we still need to overcome one issue. When you transplant beta cells into a patient, this is a transplant, the same thing is gonna happen that happened to my mom, the transplants going to be rejected by the immune system. And this is called Allo rejection. It means a reaction against something foreign. The second issue is if you have to and the and the cells are truly beta cell looking, they are going to be destroyed by the auto immune attack. So you have two problems. Again, that's where these immune modulating drugs are going to be helpful. Because they will stop the outflow and the auto attack. We have already data that shows that the police map reduces both Alo and auto attack of beta cells. So in the future, and I'm not talking 50 years from now I'm talking five to 10 years from now, it will be possible to transplant stem cell derived beta cells and give the person map or another immune modulatory drug at the same time to induce tolerance against those cells. And then we will be able to start talking about the cure 41 D, D one D is going to be the first autoimmune disease to be eradicated by vaccination by early screening and detection by early treatment, and finally by replenishment of beta cells.

Scott Benner 28:56
So you'll you'll put the beta cells back, and then you'll protect them from being attacked. And then you'll stop the body from doing what it did the first time with the plus map

Francisco Leon, MD, PhD 29:10
with the plus map and with other approaches. It's just that the plus a map is the first

Scott Benner 29:15
is encapsulation one of those ideas the idea of putting the cells inside of sort of a packet that's protected.

Francisco Leon, MD, PhD 29:22
Yes, so encapsulation will help. The problem is, so far it hasn't worked. Because when you put cells inside the capsule inside the body, there is something called the foreign body reaction. And it's another immune attack is a bit different. This attack is not specific against the beta cells because the immune system doesn't see the beta cells once they are in the capsule, but it reacts against the capsule. And it It causes something called fibrosis that surrounds the capsule with a material that makes it difficult for insulin. When to come in and out. So there are groups now working on better capsules, and we certainly root for them. But in our opinion is gonna take multi pronged approaches here to succeed, okay, perhaps a capsule that is semi porous, it allows some transit but not not a lot of so that you have some protection afforded by the castle. But still immune modulation to have a more specific reduction of the reactivities.

Scott Benner 30:38
It's kind of fascinating how well your immune system works, but that how stupid it is at the same time, isn't it like that a foreign body could be in your in your inside of you. And that your immune system could look at it and say, well, we can't kill it. So we'll surround it so well that it can't pass in or out of what we surround it with. But it can't look at your pancreas and go, hey, that's ours. Let's not do that. It's um, it's fascinating how strong and yet unguided it can be.

Francisco Leon, MD, PhD 31:08
Yeah, it? Well, the problem is it's it's this trigger, the trigger is what fools the immune system, because the immune system is programmed to attack cells that are infected, so that the infection doesn't propagate, right. And we're just unlucky that certain viruses have learned to infect the beta cells, because they are generally well protected. The beta cells are normally the last thing the immune system attacks, think think that in our entire body, there's only one gram of beta cells is so precious, is it has some mechanisms called immune privilege. And that's why the viruses hijack it and go inside because they know if I'm, if I'm inside the beta cell, I have a high likelihood of survival here. But eventually, the immune system finds a way to kill the cell, kill the virus, but then the collateral damage is type one diabetes. So

Scott Benner 32:08
the coxsackie hides in the beta cell, because it's such a protected spot. And the auto, your and your immune system does such a good job of rooting it out that eventually it gets to it.

Francisco Leon, MD, PhD 32:19
Exactly. Wow.

Scott Benner 32:20
So it's like a crab trying to hide in a shell under the ocean and the fish that go by and just sift, sift, sift, and eventually hit one and there it is.

Francisco Leon, MD, PhD 32:28
Exactly. Wow,

Scott Benner 32:29
no kidding. I did not expect this to go this way. I'm having a good time. And at the same time, I hope you'll forgive me, I'm much more emotional than I usually am. While we're doing these things. So I feel a little flush at the moment. I don't want to I don't want to lose track of what I'm supposed to be doing here. Okay, so how close so I have people from trial net on whenever they want to come on, because I love obviously what they do. And it's starting to, to please them ABS an interesting name, because it's a word that used to get thrown around years ago, like, oh, there's a drug, you know, and now all of a sudden, it's like, hey, this drug might be coming and it is coming. And like, where are we at? And what's the application real world without the rest of the stuff needing to be figured out yet? Like what can we do right now?

Francisco Leon, MD, PhD 33:17
Right? And thank you, Scott, for mentioning trialnet because they are the heroes in this story. Prevention is standing on the shoulder of giants. Here we are the last cog in the wheel. We take all of this research, and we translate it into a drug that can be brought to patients right then I don't mean to minimize our hard work and the team's hard work. The prevention team is amazing. But it's been 25 years since academic folks like Jeff bluestone, Kevin Harold and the trial net group, Carla Greenbaum Bama trial net, and everybody it's hundreds of people who have been doing one study after another after another. And things not always worked. And that's what you were referring to at some point, the prisoner was considered the failed drug. Because one trial failed the primary endpoint. The newly diagnosed protege study failed the primary endpoint. But prevention, we recognize that the trial failed the drug. It was a problem with the endpoint. The drug still did the same thing how you have always done it has always shown protection of beta cells. That's what we acquired to place a map and then try on that conducted the at risk study tn. While we are conducting a repeat of the protege study in newly diagnosed patients so that way, we can cover both sides of the coin. The at risk data will help us If the FDA agrees, provide this drug to patients who have early disease, the so called at risk, which just means early disease, and then the the new study, it's called protect, will help us provide the drug to newly diagnosed patients, but with the same exact mechanism, protect the beta cells from the outer immune attack. So you ask the question, what can we do now? So it's it's coming, it's coming. The so called producer date, which is the technical term for the date when the FDA is going to opine on the blizzard app is July the second. So it's imminent, in just a few months, we are going to know if the FDA considers that the data merits approval. And if they don't, they will tell us what else is necessary. But we're hoping that we should be able to provide this drug to patients in the very near future so that we can stop intercepting disease. The other thing that we need to get out is the need for screening. Because if we have the drug, but folks don't know that they have the preclinical disease, the pre symptomatic disease is not going to help them. So we need to get out to families, and, and just show families that if they get screened, they can prevent disease in other family members. And it's not just the children, sometimes the parents develop the disease years after the children. So everybody needs to get screened. And now there are great initiatives in place to facilitate this jdrf has to one detect, do you want detect is an amazing program, it's at home to just go online, you sign up. If you haven't students, you pay $55 that is covered by students, if you don't have incidents, prevention has subsidized this program, we provided the grant, and you only pay 10 bucks to get all the auto antibodies done the panel, you take a drop of blood from your finger with a little Lancet, put it on a filter paper, send it on the mail, in a prepaid envelope. And then a few days later, you get your results at home in a secure email. And it will tell you if you have at risk of developing clinical T one D or not if you have auto antibodies or not. So this is a huge, advanced national program offered to everybody. Obviously, families are the most aware. But even the general public should start to think about this, it doesn't really hurt to get tested. And if you're negative, you have that peace of mind, if you're positive, now you have knowledge that might help you stop the disease.

Scott Benner 38:05
That's excellent. No, I can't, I can't say enough of what I think of what everyone's doing. I and your date is July 2, so you're coming up by so say this happens, then I send in my paper and you find antibodies. And it's past July 2, and the FDA said okay, I start taking the drug and it does what.

Francisco Leon, MD, PhD 38:29
So if we get approved and you are positive for two or more auto antibodies in this at home test, you go to your doctor because we want your doctor, your endocrinologist to confirm the results and to take additional blood because when you have two or more auto antibodies, you have early stage to one day. But the question is how advanced is it? Do you already have these glycemia which is when you have abnormal glucose levels in your blood? And that's an important question. Because if you have these glycaemia you have 75% chances of developing clinical T one the insulin dependent in five years, and you have 30% chances in one year. So that means it's urgent. But if you don't have this glycemia the risk is lower is 44% in five years, and then you may is your choice, you may want to wait or you may want to act that that question is still a bit unresolved. What happens without dysglycemia our application to the FDA is for patients with auto antibodies and dysglycemia. We will recommend that then your physician considers the police map. So then the plisson map is a drug that He's given us 14 days of infusions every day between 30 minutes and 60 minutes. The reason it's like This is to prevent and minimize side effects. by splitting the dose, in very small doses that are given daily for 14 days with this has been tested over all of these 20 years of research, that if you do it this way, the safety profile is well managed. So you will receive infusions for two weeks. And that's it. The pleaser mob is not a chronic drug. And that's a big differentiation from other therapeutics that are in the market. And the reason is that we're catching the disease early and resetting the immune system. So we don't have to give this drug every month for life. as other drugs need to be given one, once you have lost your your function of your organic cetera, it's a chronic disease. Here, we're intervening early. And that affords us the ability to just those once the data is as follows. After you get two weeks of the person map, that median, the median is basically the average delay to developing clinical to end with insulin dependency is three years to three years delay, on average, after two weeks of therapy, is what the data showed that some patients will have one year of delay, the vast majority will have at least one year, some patients have eight or more years of delay. And then what happens next, that question, we don't know the answer yet, we believe we should be able to those again. And, again, they lay the disease for another number of years. But those data are not available. That is work that we are going to undertake now. But our hypothesis is that by providing the person map a few times in the life of a pre symptomatic patient, we might be able to indefinitely delay the disease. And then if you indefinitely delay the clinical disease, you're almost talking about the functional cure in a way because you never need insulin.

Scott Benner 42:36
Yeah. Wow. That's amazing. I'm see as you're talking, it keeps occurring to me that everything you know about this comes from what your mother went through, and, and how grateful I am, then everybody will be when they hear this, that her experience led you in this direction. You know,

Francisco Leon, MD, PhD 42:57
thank you, Scott. But I obviously I am I owe everything to my mother. But you you you owe more to others than to me because I'm really just less than the last cog in the wheel here. There's so many people who have worked on this for so long. Let me mention that our chief medical officer, Dr. Lenny Ramos, who is the transplant nephrologist. And that's the reason I met her because again, the kidney transplant. She actually worked with the pleasant lab many years ago in an academic setting. And she is a big part of the reason why we pay attention on the police a map and acquire the drugs. So it just cannot be under emphasized how it takes a village to do this. Hundreds and 1000s of scientists and physicians and more importantly, the volunteers, the volunteers in the clinical trials. They they take the risk to help society and it's it's they are the real heroes,

Scott Benner 44:09
we'll know for certain I mean, I'm just hearing your you know, I see your background here. And then in my mind, I'm thinking of all the just like you said, all these other people, and I wonder what all their impetus was like what what what got them to lean in this direction. Take the risk, you know, if they're going to be involved in a study or devote their lives work in this direction, it's just very, you'll never know. You know, one day when you know if if what you say is true if there's a future where my children's children can take a vaccine that stops them from getting coxsackie virus that stops them from having an auto immune response. Don't ever know how lucky they are or where all this came from. You know, it's it's really fascinating. Thank you. Thank you. I don't want to stop you because you are doing such a great job but I do have some questions. In front of me, are we at the point where I should ask them to you? Or do you have more that you want to add?

Francisco Leon, MD, PhD 45:04
Now, please, let's go with your questions.

Scott Benner 45:07
Okay, so these are all from people who listen to the podcast. One person wants to know if the effectiveness is in any way can connected to the age of the patient.

Francisco Leon, MD, PhD 45:18
Yes, there's no, we have the data is published, the effect of the blessing man was similar in children and adults.

Scott Benner 45:28
Okay, there's next question which you've covered, they wanted to know about what you would need to qualify to use the drug besides antibodies, but you've gone over that they'll need to be some world glucose testing, I guess, right, making sure that you are on your way into the process of not being able to hold back your own blood sugar anymore. Right. Do you have any plans of using this on people who have had type one forever to see what impact it has on them?

Francisco Leon, MD, PhD 45:59
Yeah, that's a great question. The answer is yes. But I need to qualify the answer. So on one hand, the low hanging fruit is the combination with beta cell transplant, in my opinion. But it is true that, you know, even in patients with long standing disease, there is always a little bit of C peptide, which is the marker for beta cells in the circulation in the blood, there is always a little bit of C peptide that can be found, comes up comes down, it seems that there are always some beta cells that start to grow, and then disappear. And the question is, is that an attempt by the pancreas to regenerate the beta cells that is quickly overcome by the immune system. And then you could potentially give the police a map at that time, when those beta cells are starting to grow, before they are destroyed. But this is purely speculation. And we don't have any data to support this other than this observation that even even after 50 years of T one D, you still have some beta cells in your pancreas.

Scott Benner 47:18
Okay, are there any side effects from taking the treatment? Either short or long term?

Francisco Leon, MD, PhD 47:25
Yes, all drugs have side effects. So with the prism app, the observations are related to the mechanism. It's an immune modulating drug when it gets into a patient's body. And it deactivates that T cells that killed the beta cells, that the activation results in something called release of cytokines for a few days, when the cytokines are released. About a third of patients experienced a skin rash. Just like if you had like analogy is a bit itchy. It only lasts a few days, and it resolves by itself. The second observation, the patient doesn't see this, but the doctors will see that about two thirds of the patients have a change in the white blood cells in the circulation, changes in the numbers. And those changes also are limited in time, everything's going back to normal within four to six weeks. And because the plasma is given just as a two week infusion, we haven't seen any side effect long term, we have data up to seven years, there hasn't been an increase in infection, there hasn't been an increase in anything else. So at this time, we'll feel comfortable as a company presenting this data to the FDA for their evaluation, and we hope that they will agree with our assessment.

Scott Benner 48:59
Excellent. This is the show has a worldwide audience and their people are wondering outside of the US is are you working on getting approvals in any other countries.

Francisco Leon, MD, PhD 49:12
Indeed, we are actively discussing with the European regulatory agency and now with the British regulatory agency as well after Brexit and with countries in the Middle East, Israel etc. We are trying to do as much as we can. But let me also mention that we are a small company. And the biggest thing that we believe could help us bring this drug worldwide will be a partner. We are actively seeking partnership with a big pharmaceutical company so that they will help us expand access outside of the US. In the US we can manage but outside of the US We will need the partner.

Scott Benner 50:02
Yeah. Well, um, I don't bring this up very often. But my wife is a drug safety professional for her entire, like, adult life. And she's incredibly good at it. And if I let her hear this episode, she's gonna want to come work for you. So

Francisco Leon, MD, PhD 50:20
all right, let's talk.

Scott Benner 50:23
It's really amazing. Well, you have to reach back to your old friends now. Right? You didn't burn any bridges leaving j&j did you?

Francisco Leon, MD, PhD 50:29
know, I didn't, I didn't know this. I am. I am doing what what they told me to do. Yeah. So suddenly j&j is a wonderful company. As you know, they are now really, really busy manufacturing hundreds of millions of doses of COVID-19 vaccine. So that that actually is impacting a little bit of progress in other areas. Yeah, yeah. Everybody's logically focused on COVID, the FDA, the pharma companies, but I think we're all seeing the light at the end of the tunnel with COVID. And then we should be able to focus on these other problems. And actually, as you know, COVID-19 affects predominantly people with diabetes, and COVID-19 can trigger diabetes. So

Scott Benner 51:20
we had a gentleman on a couple weeks ago, who got sick, had a stroke, develop type one diabetes and needed a five way bypass. Terrible.

Francisco Leon, MD, PhD 51:30
Hope he made it.

Scott Benner 51:31
He's doing well, actually. It's fascinating. Yeah. Listen, if for people who can't believe what you just said, my wife just stood in the kitchen and explained to me the other day, the reason we got through the vaccine so quickly, is because companies really did put aside a lot of their other work and focus their employees on just one thing. And I can personally attest the fact that she's been sitting in my dining room for 12 to 18 hours a day, working on this for the last year. So it,

Francisco Leon, MD, PhD 51:59
thank thank you to her and all others who who have given us throughout time.

Scott Benner 52:06
Yeah, no, but I, to your point, like we do also need to get back to looking at other things like this. Just real quickly, as I go to the next question. Claire would like you not to forget Australia, she says Australia always gets left behind and type one diabetes. So

Francisco Leon, MD, PhD 52:18
yeah, we are looking, we were talking to Australian folks as well. It's such an innovative country, and they have a great system there for screening. Again, going back to screening, that is the key. And Australia is one of the few countries in the world with with a screening program, a screening program that we don't have in the US in the US, it's only trialnet and a few other programs, ask in Colorado, etc. So we all need to enhance screening lobby, so that this becomes more of a national effort.

Scott Benner 52:52
What ages did your FDA submission cover?

Francisco Leon, MD, PhD 52:56
Our current submission is h seven and above the trial started at above age seven, so eight and above to 45. But we probably will. If we believe that the drug should at least get approved age eight, and above, okay,

Scott Benner 53:19
is an there's always the sign um, I know you're not you wouldn't be telling anybody to do it. But doctors could see the value and use it off label or no,

Francisco Leon, MD, PhD 53:30
we can certainly not recommend that. But a doctor can always use judgment and look at the scientific data, look at the clinical data, look at the label, and then determine what's best for their patients. And that's something that we as a company, all we can do is to continue doing trials. So we have now in place, all the plans to study age zero and above children from from birth and to expand into other populations as well and do combinations and with beta cells, etc. Expand the label to maximize access.

Scott Benner 54:12
auto immune markers, like you said, you need to have to Is there any efficacy change if people have more markers?

Francisco Leon, MD, PhD 54:21
Yeah, that's another great question. We have cut the data in so many ways to try to answer that question. And the FDA has done that as well and clinicians. And at this time, what the caveat is that the study, the pivotal study, at risk, TN is a small study. So when you start cutting the data in many different ways, you end up with very few patients in those groups. And it's a bit hard to make conclusions, but our conclusion is that the drug has the potential to help every patient as long as they have beta cells. So the only group with may not see benefit is when the C peptide is undetectable that those patients may or may not have enough beta cells to protect. But as long as you have detectable beta cells, given that the mechanism of disease is similar in everybody, it's all driven by the T cells. We see benefit in across the board. Wow.

Scott Benner 55:27
Wow, that's amazing. I have one more here. It just slipped away from my eyes. Oh, are there any unknown drug interactions?

Francisco Leon, MD, PhD 55:36
No, because this is a biologic drug, a monoclonal antibody and biologic drugs. They typically don't have drug interactions. They're highly specific. So actually, in terms of FDA approval, you don't even have to study this because it's well known that biologics don't have drug drug interactions

Scott Benner 55:57
are things really moving that way. Like ideas like stuff like Xolair for asthma or chronic urticaria, stuff like that, that that's a biologic as well. Do you think the industry is paying more attention to that now? Or do we just understand more so we can, can work in that space better?

Francisco Leon, MD, PhD 56:18
I'm both, I think there is a lot of progress in the design and manufacture of biologic drugs, which are more specific than oral drugs, pills and tablets. There is a place for both, right? The problem with biologics is that they have to be injected. And some people don't like injections logically. So there are instances when appeal or a capsule can get you through a disease and there's no need to go for injections. But if you are looking for something highly specific and safer, because it doesn't have these kind of interactions, and something that can be given less often. Because the biologics typically have very long effects, then biologics are a good solution.

Scott Benner 57:13
Yeah, I suffered low iron a year or so ago, and the I and the the oral just was not doing it for me. So I took an infusion a couple of times, to bring my ferritin levels up. And it was amazing how quickly it worked, compared to what what was happening with the oral meds?

Francisco Leon, MD, PhD 57:33
Well, Scott, let me make a plug now, for celiac disease, because celiac disease is the number one cause of low iron anemia in the US of unknown origin, and is highly associated with with Type One Diabetes. So just like folks need to screen for d&d Auto antibodies, family members of d&d patients should also take a celiac test, if they have any of these unexplained manifestations, as the same is just a finger stick and and looking for auto antibodies against the celiac antigen.

Scott Benner 58:12
And that celiac can can be present and impacting you in ways without you feeling sick to your stomach when you eat food. That's correct.

Francisco Leon, MD, PhD 58:21
It's not common. It's not common, but about 20% of patients with celiac don't have gastrointestinal symptoms. Okay.

Scott Benner 58:29
That's interesting. Well, okay, is there anything that we missed, or we should have said that we didn't, I don't want to leave anything out.

Francisco Leon, MD, PhD 58:38
I really appreciate this opportunity to get the word out, because raising awareness is the most important thing now. so that people can benefit from these advances we've discussed. So just thank you for all the work you've done to educate your audience. And if anybody has any questions, we have our info at prevention bio.com if you have any questions, we'll make sure to address them

Scott Benner 59:10
I'll put a link in the show notes so people can get to it I just genuinely appreciate you doing this. And that and that you were able to make it work in your schedule because I was I was so tight I didn't know where to put you and I really wanted to have you on so thank you for for being flexible like this.

Francisco Leon, MD, PhD 59:25
No, thank you Scott.

Scott Benner 59:30
Huge thanks to Francisco for coming on the show and doing such a great job of explaining to please a map that I get a pleasant map I have it I might not have it. Anyway, I found everything about this hour to be incredibly uplifting and hopeful. I hope you did as well. Thanks also to on the pod Dexcom touched by type one the T one D exchange, Gvoke glucagon and the Contour Next One blood glucose meter. The advertisers make the show possible. They give me the time and the freedom to do these recordings, edit them and get them to you. So all my thanks to them, please, if you have a need for any of those devices, and you'd like to learn more, use the links that are provided in the show notes, we check them out. It'll help keep the show free. Before I go, let me thank you some really amazing reviews were left recently on Apple podcasts for the show that I greatly appreciate. Thank you so much to everyone who takes the time to rate and review the show so positively. I want to remind you again, about prevention bio.com. If you go there, I've been doing this this morning and click on their pipeline, you can read about the drugs that they have, and what they're hoping to do with them and where they are along the process. It's very, very interesting. It's fascinating worth a little bit of your time. The show has resources that we hope you use, and by we I mean me as I'm the only one here. The diabetes pro tip episodes, as I mentioned earlier, begin at Episode 210. And they're also available at diabetesprotip.com at that same link, you'll find all of the defining diabetes episodes. Of course, you can always go to Juicebox Podcast comm to find those things. And if you're on Facebook, and you're looking for an incredibly supportive group of people talking about type one, you're looking for the listeners of the Juicebox Podcast. That group is called Juicebox Podcast type one diabetes. It's a private group. It has about 10,000 people in it, and the conversations are just there. Excellent. I hope you enjoyed the show today. I really enjoyed bringing it to you. Next week, we'll be talking to someone who eats low carb, who has type one diabetes, we'll be talking to Elizabeth, the founder of touched by type one, and much more. If you're listening in a podcast app, please press subscribe. If you're loving the show, please share it with someone else. And if you're listening online, that's not how the kids do it anymore. You can if you want I'm not going to hassle you but your apps on the phone way better ways to listen to podcasts. Thanks for listening. Thanks for subscribing. I appreciate it when you share the show with others and review it. I hope you enjoyed today's episode. I really enjoyed bringing it to you. I'll be back soon with much more