The Regulatory Whisperer
This week I am talking to Michael Hufford the CEO and Co-Founder of Lygensis a company that is breaking the mold of organ replacement and enabling organ regeneration. They recently received FDA 2A clearance and additional funding and will be starting their first human trials shortly.
Michaels background has helped him master the regulatory and investment landscape providing him with keen insights that help navigate the steps necessary for funding and safely and successful developing therapeutics offerings. His important Incremental point as he describes his regulatory super power; seeing things through the eyes of the regulator or investor is critical, or put another way:
“Speak regulatory, money, or science”
Prometheus for Livers
The history of Lygenesis includes multiple publications demonstrating that we can grow organs in our own lymph nodes – our very own personal bio-reactor. The animal results in pigs showed reversal of liver disease liver cells transplanted into lymph nodes were capable of forming ectopic livers that cured all the animals of otherwise-fatal disease (also in mice kidney tissue)
The current waiting list suffers from a profound supply/demand imbalance with more than 100,000 people waiting for organ transplants, many of whom will die still waiting for an organ to become available. This number is not fully representative since many do not even qualify to get on the transplant list.
Listen in to hear Michael share the exciting progress to data that has taken the human bio-reactor of lymph nodes, something that is hijacked for use by cancer cells and instead use it for good to generate liver, and in the future, pancreas, thymus and kidney. Delivering multiple organ transplants to many people from a single donor organ through an outpatient minor procedure.
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Raw Transcript
Nick van Terheyden
Today I’m delighted to be joined by Michael Hufford. He is the CEO and co founder of lie Genesis. Michael, thanks for joining me today.
Michael Hufford
Oh, thanks for having me. It’s a genuine pleasure to be here.
Nick van Terheyden
So, for the benefit of the listeners, I think it’s always important to get a little bit of background. Tell us about yourself and your journey to this point and how you got here.
Michael Hufford
What was what what happened? Well, frankly, I’m incredibly fortunate to have been born in these interesting times, right as the old Chinese proverb goes, so I, you know, a very brief background, right, I did my undergraduate work at Purdue University, got a Master’s and PhD at University of Pittsburgh before, completing a clinical and research fellowship in the Department of Psychiatry at Harvard Medical School, was a professor for a short time, but got recruited to my first startup. I, you know, over 20 years ago now, before such things were fashionable, and got exposed to really the consulting side of the pharmaceutical industry. So at the time, I was doing a lot of patient reported outcomes consulting, but got involved in a lot of FDA meetings and scientific advisory boards. And then from there had just been very fortunate to work in a number of different really fascinating areas of drug development. So I worked on xeno biologics and ambling pharmaceuticals, worked on a number of products in development, that eventually won FDA approval there. And really ended up being very therapeutically agnostic in terms of the areas that I worked in. But what I ended up specializing in was really, that value inflection you get with positive proof of concept data in humans, right. So really helping assets get through the FDA process, and giving them the key test to either go or no go right in that phase two trial. And so that ended up being a particular area of expertise of mine. And I was just very fortunate a few years ago to meet my co founders, and we go on to form like Genesis, and it so happened that that was the hurdle facing them. So I was the one who had sort of crossed those hurdles in the past and just thrilled to be able to help them move forward now.
Nick van Terheyden
So it sounds like from your past that you you actually like all of this regulatory oversight, navigating through that process. I I’m I’m serious. I mean, it’s, you seem to relish that whole experience of driving the science through a process.
Michael Hufford
It’s funny you say that, right? Because my experience of almost all FDA interactions, as you know, you it’s typically a great deal of frustration. But that being said, I think you’re right, that what drew me to business outside of academia, frankly, right was this intersection of science and business. And at the end of the day, when you’re developing, you know, drugs for human disease, you’re, of course dealing with the FDA. And I was fortunate to work with a number of chief medical officers and chief quality officers that I guess I came to understand that just the way you tell a scientific story to investors, right to get them to invest in your technology. It’s a different type of storytelling, but you’re still really telling a scientific and quality story to the FDA, to reassure them that you’re not putting patients at risk, you know, using good listening skills to understand what their concerns are, and then reflecting that back in your programs. And I think I’ve just come to appreciate the remarkable value inflection you have in developing assets that come with meeting those FDA milestones, right? So as an entrepreneur, right, when you have those FDA meeting minutes that you can put up in front of a venture capitalist and say, Look, I know exactly what my last trial is going to be before my first in human study, because here I have the minutes from the FDA meeting, that becomes so definitive and many ways kind of stops you kind of chasing your tail, right? Like very often, in in, in fundraising, you’re sort of always chasing the next milestone and you kind of can feel like you’re on a hamster wheel, never making progress. But when you have those FDA meetings, it really can help say, Look, you’re in or you’re out. This is what we’re doing. We’re moving forward, get on board because this is what we’re doing. I’ve had the good fortune of being able to leverage that both in my fundraising for my companies in the past, and then also with you know, corporate exit the same thing, right? It’s having those those definitive FDA milestones, either lets you right decide to stop investing in an asset. Certain things don’t work, or conversely really gives you a fuel for the fire when it does. So I guess I would say I, I’m not sure I enjoy the interactions per se, but they are sort of at the fulcrum of either moving investors off of what’s that great phrase? I heard that investors live on a teeter totter between fear and greed. Right. And and your goal is as as an awkward jewelleries is to kind of shift that teeter totter from fear to greed, right? You know, it’s a bit unfair, but not entirely, right. So I think those FTA meetings can serve as a fulcrum to kind of pry investors to get them engaged. And conversely, when you’re dealing with large pharma partnerships, right, having those FDA minutes, it just eliminates all of the guesswork. So instead of the clinical team saying, oh, but the FDA might require you to say this, or that you can say, hey, I’ve met with him. We had a meeting, we discussed just this, this is what they said. And it just becomes a catalyst, I guess, right. And that’s how I see the regulatory interaction as a necessary catalyst, either to advance your your fundraising objectives, or to advance your kind of business objectives on the, you know, partnering side.
Nick van Terheyden
So, before we get into like Genesis and the origin story, I have to ask you, what, what’s your superpower? With regards to investing in the FDA? Because it sounds like you have it the hoster I’m not, it’s not a secret. But there has to be something about your approach to this, because what I get very clearly from the way that you describe it is not necessarily love. But absolutely admiration, respect for the process and the way, but I know many people struggle with it, but you seem to have navigated this and adaptive, do you have any small thing that you could give in terms of insights as to how to successfully navigate that space?
Michael Hufford
It’s a great question. It really doesn’t feel like a superpower. I appreciate the Gulf. But I would say, um,
you know,
Michael Hufford
I joke sometimes, but I think it’s true. So, you know, I got my PhD in clinical psychology. And, and, and so, you know, I have always had a kind of soft spot for the CNS indications and psychiatric disorders, certainly, but um, you know, among that training, right, you get a tremendous amount of training of listening and, and being empathetic, right. And so, while I did a very research oriented program is where it kind of focused on research. So that clinical training is valuable, right? Because I think a lot of times, it’s easy when you’re meeting with the FDA to get very frustrated for reasons I’m very sympathetic with. But if you think of things from their point of view, right, they’re looking at all these sponsors, they see what happens. left unchecked, right, patients can be put at risk. So I think regulators obviously play a key role. And if and if you listen to their concerns through kind of and try to take their point of view, and craft your regulatory documents, like folks joke about speaking, regulatory, but like a lot of it, right is writing in such a way that you’re connecting the dots, and you’re empathetic to your audience, right. So that I’ve been in meetings that folks don’t listen, well, sometimes in FDA meetings, right. And I think, you know, meetings can be won or lost in your reaction in real time to the feedback that you get. And so, you know, not being defensive, at least trying not, if it’s about know that I always succeed, but, you know, try not to be defensive in those interactions to understand where the concerns are coming from. And conversely, when you work with your scientific colleagues, so, you know, I have a great fortune to work with some brilliant, both, you know, academic physicians, as well as academic researchers. And very often, I think folks get tripped up because you’re not speaking the same language. And and, and so it’s a matter of almost translating, you’re trying to translate on the one hand, the deep science into something that’s digestible do we regulator that isn’t deep in that time? conversely, you’re trying to translate the regulatory concerns around patient safety to your colleagues that may not understand kind of where that’s coming from, right. I mean, understand it intellectually, but not always sort of the form it takes from the FDA. So I guess, like, a lot of what I see myself is doing is translating, and being a proactive translator. And, and I think if if you do that, well, you can engender a lot of trust, and that reflects itself in the requirements in your program and everything else. So I think it’s just oftentimes a breakdown of folks talking past each other in some of those regulatory interactions. And, and look, the FDA doesn’t make it easy, but I also You know, tell my academic colleagues imagine trying to run an organization where you’re all who is routinely 1000s of FTP. He’s down from where you need to be you’re always under budget, you’re always overworked. You can’t pay people what you’d want to pay him, right. I mean, it’s, those are real challenges to running that agency. And so like, you just have to approach it with an appreciation that man, you know, if people are doing the best job they possibly can, under a crushing workload, chronically short staffed. And that ways, right, I think, in many ways, resemble their academic colleagues in some respects, right, where you are oftentimes understaffed and always fighting for the next grant. Yeah, I think fantastic insights and, you know, helpful to others to sort of think about it in those terms, and, you know, the other elements versus the, you know, from that lens and perspective for the FDA, ultimately, you know, approving something to be used. They don’t get quite the same cue points as you know, preventing a disaster from occurring. And you know, that’s hanging over them all the time. And I think people forget that. So, but we need to get to like Genesis or Yes, like Genesis is incredible technology. So help people understand what it is some summarize what like Genesis is and how it came about. Sure. Well, look at the highest level, like Genesis is is a cell therapy company that uses the lymph node as an in vivo bioreactor to regrow a functioning ectopic organ. And, and really, what that literally means is that we use the natural biology of the lymph node as a bioreactor right, naturally meant to bio react T cells, right to help you fight infection, we wouldn’t be here if it wasn’t for having four to 500 lymph nodes as the Sentinel bioreactor spread through our body right to help fight infection. So these things have evolved to be incredibly efficient at developing T cells to fight infection. Of course, cancer hijacks that biology, right cancer, the lay public’s aware that when you get cancer into a lymph node, it’s a bad thing. And it’s a bad thing precisely because that is both a conduit for its spread, but also a conduit for the formation of tumors because those bio reactors are so efficient at growing cells. And the fundamental insight from a Chief Scientific Officer is that that biology could be leveraged to a therapeutic effect. So the way cancer hijacks the biology to form a tumor, Dr. Eric le gas or Chief Science Officer, realized me over a decade ago now that that same biology could be used to regrow functioning tissues, and he started with the liver. It is since now expanded to our platform includes the ability to regenerate a ectopic liver but also a pancreas, fineness and kidney. But taking the liver as one example what what Eric has showed in his laboratory, starting with small animals going through the large animals now and starting our first clinical trial here soon, is that if you inject hepatocytes, liver cells into lymph nodes in the abdomen, over time, those hepatocytes are very happy to be in the lymph node, they find it a very hospitable environment. And in the context of a diseased liver when the liver is emitting dozens upon dozens of biochemical signals, trying to get hepatocytes to regrow, but advanced liver right with fibrosis a has become a very inhospitable environment. So these hepatocytes and lymph nodes detect those signals begin to engraft proliferate vascularized. And eventually, the lymph node disappears and what you’re left with, we have some great pictures of this in our nature biotechnology publication, are these ectopic livers that exert life saving effect and animals that would otherwise die in a matter of days or a few weeks from, in small animals, a genetically induced disease called tyrosinemia type one, that we can rescue those animals from otherwise fatal liver disease. So that was, that was Eric’s fundamental insight a decade ago. And to his credit, he doggedly pursued that line of research through he studied almost 400 mice. By the time I had met him, he done to replicate studies in pigs, one at the Mayo Clinic, one at the University of Pittsburgh and different models. And literally when I met Eric, you know, you get a chance I was an entrepreneur in residence at the time you get a chance to meet a lot of brilliant academics. And as an academic researcher, to his credit, you know, he kept trying to get it not to work and he literally couldn’t get it not to work and he, you know, the cells and grafted over and over again because the environment of the lymph node was so hospital Right. And so it was remarkable that by the time I met him three years ago, he had done the majority of the ind enabling work really without meaning to I mean, without intending for that regulatory purpose, but by the time I met him, I’ll never forget our first meeting. I mean, the hairs on the back of my neck stood up, as he showed me, the mouse data was incredible. He’s great pictures, just jaw dropping stuff. And I thought, look, that’s fantastic. What about large animal work? fully expecting him to say, Oh, well, we’ve not gotten to the large animals, or Oh, you know, it didn’t work. And so he’s like, Oh, yeah, we’ve got to replicate studies in pigs, we rescued those. We’ve rescued tyrosinemia pigs, we use a porter cable shunt, which is a surgical procedure to mechanically induced liver injury, we rescue those pigs, you know, and so you just think, holy cow. I mean, this is, you know, as you well know, right. So often in drug development, you’re, you’re pushing against biology, you’re, you’re trying to either trick the body or get it to do things that it doesn’t naturally want to do, right? So you’re always dealing with unwanted side effects, or, you know, off target effects. And here it was, it was really the opposite was like, the body wants to do this. We can’t get it not to if you get the cells in the lymph nodes, the biochemical signaling is so powerful, right? The Greeks realized 5000 years ago that the liver would try to regenerate that was, you may recall the myth of Prometheus. Right? Prometheus has the legend right? stoled fire get it from Zeus gave it to man. And so Zeus punished Prometheus by chaining into a rock. And the Greek myth was the eagle would come and eat his liver every day, and it would regenerate and then he be tortured by having the eagle come and eat his liver again. So I joke the folks the Greeks had a right 5000 years ago, the liver tries to regenerate. There was this fundamental insight that we were able to use the lymph node as an in vivo bio reactor, this kind of made that a reality today.
Nick van Terheyden
So for those of you just joining, I’m Dr. Nick the incrementalist and today I’m delighted to be joined by Michael Hufford, the CEO and co founder of lie Genesis, we were just covering the incredible concept that you essentially describe the potential to turn our own bodies, in this case, the lymph nodes into actual organs that, you know, we have tremendous challenges with in healthcare, we understand the concept of transplants. But we have this massive shortage. Yes. For the benefits of those listening, just clarify where that stands in terms of, you know, lost opportunity, available organs?
Michael Hufford
Well, there’s really dual tragedies, when it comes to the transplant was the first tragedy that people are aware of that there’s more than 100,000 people in the US currently on the waitlist for a transplant, right? So there’s the supply demand imbalances, absolutely profound, there is far more demand than there is supply. And that’s true, whether you’re talking about hearts or livers or lungs, you know, kidneys, some wait times are longer than others. I think the average wait times for kidney is almost two years now. liver is, is still under a year, but you’re on the list a very long time. And so look, the reality of that means dozens of Americans die every single day, waiting for an organ that never comes. up I said it was jewel tragedy. That’s the first tragedy. The other tragedy, is what a lot of people don’t realize is to even qualify for the transplant list means that you have a lot going for you, right. And so in some diseases, advanced liver disease being a good case, you know, it can be a one to one to two to one ratio of the patients that don’t even qualify to make the list. So the double tragedy is that while many Americans are aware and hopefully sign up to be an organ donor, which, you know, they absolutely should I think the fact is, many patients are so sick because of either cardiovascular comorbidities, or, or you know, past cancer diagnoses, your whatever the specific indication is for that organ. The fact is, many patients never even make the list, right. And so at the highest level, what we’re trying to do is, you know, hopefully one day eliminate waitlist altogether, at least for some of these organs. And I think you are technology because you know, today a single donated organ can treat one patient using our technology, a single donated liver taking that as an example, has enough liver cells, these hepatocytes using our technology to treat 75 or more patients. So you want to talk about that’s a complete disruption of the supply demand calculus when it comes to organ transplantation. We graph those cells using an endoscopic ultrasound procedure. So instead of What’s usually one of the most risky, you know, surgeries you can have in terms of transplant transplant surgeries. I’ve gotten obviously very good and, and don’t get me wrong, very safe and reliable as times gone, but so the major surgery of your and that’s why many patients don’t qualify for it using this endoscopic ultrasound procedure, this would be an outpatient procedure under light sedation. Right. So you’ve decreased the medical risk, you know, today in the US transplant liver costs on the order of $800,000. In terms of the costs, you know, an endoscopic ultrasound is build it, you know, 10 $15,000, right. And so when you think about the just from a business perspective, right, the return on investment, transplant is so expensive and relegated to actually, in many cases, a minority of the patients that needed our technology’s ability to disrupt the supply, demand calculus, and in graph T cells using using an outpatient less risky into scopic ultrasound procedure. That one two punch right is one of the things that I’m personally most excited about.
Nick van Terheyden
That’s just truly incredible. I mean, you just think about the amplification of the available organs, solving problems. And in fact, addressing that second part of the tragedy, the people that don’t qualify us won’t qualify for this because you’re talking. I can’t describe it as anything else, but a minor procedure.
Michael Hufford
Yeah, I mean, that’s right. And certainly relative to full blown transplant. And my chief medical officer, Dr. Paolo, Fanta, as you know, has spent his life as a transplant surgeon and worked at the University of Pittsburgh, and then the stars will center has treated 1000s of patients, you know, he personally was the one who would tell patients Look, I’m sorry, your loved ones never even going to make the list. If they made the list, he was the one who transplant them, right. But giving those patients some hope, right is something that very much drives us forward. And as I mentioned, so livers are lead clinical indication, we have Prop, we have proof of concept data, though, in animals showing that we can regenerate kidney, we can regenerate the pancreas to potentially address issues and type one diabetes, as well as the thymus that isn’t very exciting indications potentially for aging, as we age, our thymus in volutes, and, in fact, disappears over time.
And so
Michael Hufford
the ability to potentially regenerate the thymus has some very exciting longevity, and anti aging applications as well.
Wow.
Michael Hufford
Let’s talk about a superpower. So we got a couple of minutes left. Tell us where you are. And when we’re going to start to see you you’ve you’ve had approvals you’re marching through, give us some some estimate of the sort of timeline and the next things coming up. Now, you have some great questions, we’ve been working very hard, we received our clearance from the FDA to begin our human clinical trials late last year, we’re starting to phase two a trial in patients with end stage liver disease, we hope to have that first patient in here in just the next few weeks to a handful of months. So we’re getting very close to starting enrollment. That’s extraordinarily gratifying. As a drug developers, we’re very excited about that, that two way trials can be a dose ranging trial. And and then depending on the outcome of that we will proceed with a more, you know, more traditional, like placebo controlled trial with the FDA as input but the FDA have been very helpful. They’ve given us some great input on the design of our to a trial, and we’re looking forward to getting started. Wow, that’s really exciting. So you know, starting human studies, yes, you think about it from you know, the original insight and innovation. We’re talking many, many years to get to this point. Yeah. But I can imagine from your perspective, this is everything that you know, the organization you’ve been working for. I know you’ve been working on this for a long time. Yeah, no, three years in real. We’re incredibly gratified, can’t wait to get this to the bedside to help patients. And yeah, just you couldn’t ask for anything more than the exciting science, great colleagues and fed great engagement from the FDA and very supportive investors, event driven essence, longevity vision fund, a number of folks have been early supporters continue to support us. So those folks have been instrumental as well.
Nick van Terheyden
Fantastic. Well, as usual, we’ve run out of time, but I think, you know,
I can’t help but be excited about this. I’m fortunate I don’t sort of live in the world. But I’ve certainly experienced and participated in that world. I’ve seen the disappointment. You know, it is an astoundingly difficult problem to address because we know what to do. We just lack the raw material in who you are creating amplification for the raw material. So just excited to watch this. And very grateful that you were able to spend the time and share the details. So thanks for joining me on the show, Michael. Oh, thanks. So much with real pleasure.
