The Bioinformatics CRO Podcast

Transcript of Episode 49: Joshua Hare

Disclaimer: Transcripts may contain errors.

Grace Ratley: [00:00:00] Welcome to The Bioinformatics CRO Podcast. My name is Grace Ratley, and today I’m joined by Dr. Joshua Hare, who is a professor of medicine and director of the Interdisciplinary Stem Cell Institute at the University of Miami, as well as co-founder and chief scientific officer at Longeveron. Welcome, Joshua.

Joshua Hare: [00:00:15] Thank you so much. It’s a pleasure to be with you.

Grace Ratley: [00:00:18] Yeah. So tell me a little bit about Longeveron and the therapies that you’re working on.

Joshua Hare: [00:00:23] Longeveron is a biotech company devoted to solve diseases of aging and aging related conditions. We founded Longeveron in 2014 with a license from the University of Miami for technologies related to using cell based therapy to treat a condition called aging frailty. Since then, Longeveron has branched out to also focus on Alzheimer’s disease, the metabolic syndrome. And as every good rule needs to have an exception. Our exception is a disorder of neonates. So we’re an aging related company with most of the aging related conditions. And in a program we’re very excited about for neonatal congenital heart disease. The technology is based around a cell based therapy that is a culture expanded product that comes from healthy bone marrow. Young, healthy donors give their bone marrow. And we have shown that this product can be used as an allograft and doesn’t require immunosuppression. So that’s a very big feature of convenience because it’s an off the shelf product and therefore gives a great economic scale.

Grace Ratley: [00:01:43] Sure. And the cells that you’re working with are mesenchymal stem cells. Can you tell me a little bit about those and why you chose mesenchymal stem cells as opposed to other stem cell types?

Joshua Hare: [00:01:55] Well, first of all, whether or not they should be called mesenchymal stem cells is highly controversial in the scientific literature. And just in the interest of time, I think we can stay away from that controversy. But because of that, we don’t call them mesenchymal stem cells anymore. There are other names that have been given to them to maintain the MSC abbreviation. So two other names that some people use are mesenchymal stromal cells or even more away from that is medicinal signaling cells. So three versions of what MSC could stand for. Those of us in the field chuckle a little bit because it’s the kind of thing where whatever you call it, we all know what people are talking about, but a huge amount has been made of what to call this cell entity because of the debate really about what a stem cell is. And so some purists feel that if the cell doesn’t engraft and differentiates that it should not be called a stem cell. And I can agree with that. I think it’s really more semantics than anything else, because we’ve been using this product for decades now, literally decades, without the expectation that it would engraft and differentiate. So it’s not like we’re making something up in terms of what the mechanism of action is, but we can agree also to not call it a mesenchymal stem cell. Now as we’re a biotech company and are making a product that we’re trying to get through regulatory agencies, it has to be given an official name anyhow.

[00:03:39] And the name that our product has been given is Lomecel-B. So we refer to as Lomecel-B right now. Now, in terms of why we chose to go this route, I’m a cardiologist. I’m an expert in heart transplantation. I’ve been working on cell based therapy for 20 years now, and I started to work in the early part of last decade on this particular type of product, trying to understand particularly the immunology and then the reparative capability of the product in heart disease. I studied it extensively in animal models, and then very early on in the life cycle of human trials, I was one of the first in the United States to give it to people with heart attack. We started doing that about 2005. The reason I’ve stuck with MSC work is very, very simple and some people misunderstand this. I’ve stuck with it because the data I’ve been getting has been positive. Now, some people debate that, but the fact of the matter is I’ve done a large number of clinical trials in human heart failure, and our results have been interesting and provocative and have warranted further work in my view. Now, we pivoted away from heart failure alone to the whole body when we started to look at aging frailty. Because a very interesting observations we were making in patients with heart failure, their whole body was getting better, not just their heart. So the cells which have four basic actions that we know about, none of which is related to being a stem cell.

[00:05:28] So this is why I think that what you call it is much ado about nothing. But we know and we’ve documented that the cells have an immunomodulatory effect. They have an antifibrotic effect. They have a pro vascular effect, which is multifaceted and they stimulate endogenous repair. They themselves don’t engraft and differentiate, but they can create tissues that have stem cell compartments and have proliferative ability to undergo a reparative process. And we’ve known about that for at least ten years. When we looked at what was happening to people with heart failure, we saw that things like their quality of life and their six minute walk distance was improving. So there were effects that their whole body. We then went on to show that endothelial dysfunction was also improving and endothelial dysfunction is a very important part of heart failure and aging. So with all of these things we were seeing in heart failure patients, we said we got to try this for aging frailty. And there was one more important piece of the puzzle which was in our heart failure population, we looked to see if age was a factor where older people not responding as well as younger people. And in fact, we found that older people and younger people were responding the same. So it became very logical to then say, okay, aging frailty is a major worldwide problem. It’s characterized by a lot of the things that affect heart failure patients. Let’s see if we could try this product in patients with aging frailty.

Grace Ratley: [00:07:09] So tell me a little bit about aging frailty. What are some of the symptoms of that and how do you differentiate it from the normal aging process?

Joshua Hare: [00:07:18] Your question is great and hits the nail on the head. We have this unfortunate view in our minds because it’s just the lens we see through right now that aging is inevitable and that an aging decline in function is inevitable. That’s not true, by the way, but that is our view because that’s our world experience. What we also know is that some people are aging more successfully than others. We all know two 80 year olds or two 75 year olds, one who’s doing great and the other who isn’t. Everybody knows that. But we believe and we accept because the old joke, the only two guarantees in life are death and taxes. So we all know we’re going to die and we all know that we’re going to age and we all know that we are aging right now. Every day is a day we’re a day older. It’s this issue about how what our quality of life is and our functional capacity is at the end of life. And this is where their misconceptions. And so it’s a very important field in geriatric medicine, the study of aging frailty.

[00:08:28] And what’s been shown is that, in fact, some people are aging successfully and others are aging unsuccessfully. And the people who are aging unsuccessfully have a greater vulnerability to diseases. And it’s gone so far that there’s a new hypothesis in medicine right now called the Geroscience hypothesis. The Geroscience hypothesis holds that aging is the number one risk factor for all other diseases. So some are advocating that we should be focusing on treating aging as the pathway to treating heart disease, cancer, Alzheimer’s. So I’ve been familiar with this literature and this science for a long time, and it made a lot of sense to me to apply MSCs or Lomecel-B to people with aging frailty because it’s a major unmet health need, it’s biologically based and therefore it’s amenable to be treated. We also know what causes aging frailty, right? It’s low grade inflammation. It’s endothelial dysfunction, and it’s sarcopenia, which is a loss of skeletal muscle. So these are processes that are biological processes and can be addressed. And it made sense to us. What we had observed in other patient studies was that Lomecel-B might be an effective treatment for aging frailty.

Grace Ratley: [00:10:01] I am curious as to how you hope Lomecel-B will be used since aging affects everyone. What are the indications that it will be used? Like will you give it to only people over the age of 65 who meet a certain criteria? Or do you hope that it will be more of a commercial medicine product?

Joshua Hare: [00:10:20] How it will be used will be determined like every medicine’s use is determined and it’s determined by regulators. And very typically what happens is a manufacturer of a drug negotiates with the FDA or the European Medicines Association or the agency in Japan, whatever country you’re in and you pre negotiate the indications and then you have to do studies to prove that in that setting, the drug works. How I hope it will work is not really up to me. It’s up to a very open dialogue between Longeveron the company I co-founded and regulators. Now the big challenge is that these regulatory authorities have never approved any drug or any treatment for aging frailty. And because of this whole issue of the controversy about whether is it an actual disease or not. So there’s a lot of new ground being broken here. There’s huge interest in anti-aging therapies and geroscience therapies. And this is something that’s really coming to the forefront right now. Science and medicine is really shifting its attention to understanding and acknowledging that aging is a biological process and should be treated and that great benefits will accrue to society and the individuals and families who are affected. So how it actually gets used will depend on the study that we do. And what we’ve completed right now is a phase two B study. It was done in patients between 65 and 80, depending on how the FDA views that study and tells us what to do next, we’ll determine of how it’ll be used. The age range, the indications and so on and so forth.

Grace Ratley: [00:12:24] That’s really exciting. Congratulations on your completion of that phase and I wish you the best going forward. Do you have any idea of when you might expect it to hit market?

Joshua Hare: [00:12:35] Well, we have to at a minimum do one if not two phase three studies. And we have to negotiate with the FDA what the endpoint of those studies will be. We’re not even sure that they’ll say you can go ahead to phase three. Right now, they might say do another phase two. We just don’t know until we talk to them. Our plan is to talk to the FDA with the data that we have now and make a determination. If we go to phase three, we’ll be able to at that point decide with the FDA’s advice what the endpoint should be and how long the trial will be. So the time to market depends on how big that study has to be. If we could get away with a study of just hundreds of patients, it’ll be much quicker than if it’s thousands of patients. The funny thing is I’ve been working in this field for 20 years and we keep saying it’s five years away, it’s five years away, it’s five years away. And every five years comes ticks by and we still say it’s five years away. That’s the problem with any new field. It takes a long time. A brand new idea like this can take anywhere from 30 to 40 years to get proven and accepted by the general community.

Grace Ratley: [00:13:55] So you’re collecting these cells from young, healthy donors from the bone marrow. I know there’s a general shortage of people who donate bone marrow for other uses, like cancer therapies and whatnot. How do you think you’ll overcome that?

Joshua Hare: [00:14:13] One of the great things about the allogeneic technology is that one donor can generate enough material for hundreds, if not thousands of doses. So it’s not one donor, one recipient the way it is for bone marrow transplantation, for lymphoma, leukemia. This is a culture expanded product that we culture expand in a specific lab called GMP lab, a good manufacturing process lab. We can generate thousands and thousands of doses from a relatively few number of donors. Now in the future, one of the main focuses of the company is to scale this up. If this gets approved for aging, frailty or Alzheimer’s disease, I have to tell you a little bit about Alzheimer’s disease. These are major unmet needs, and we’re going to need huge amounts of material and we’re going to have to address a scale up plan. And we are in the midst of doing that right now. I can’t tell you anything about it because it’s all on the drawing board. But if you invite me back in a year or so, hopefully I can tell you a little bit more about the scale up plan.

Grace Ratley: [00:15:27] We’ll certainly have to have you back on. But yeah, do tell me a little bit about its application in Alzheimer’s disease.

Joshua Hare: [00:15:34] Yeah. So if people really understand and study what we’ve done, they’ll see it’s very logical and systematic. I told you how we went from heart failure to frailty. It was based on observations in the heart failure population, the biology and preliminary observation. So it made sense to do it. It wasn’t just throwing spaghetti at the wall. And the same with Alzheimer’s. What we noticed was in an earlier frailty study we did. We did a crude measurement of cognitive function, which is a simple test you can give to a patient called a mini-mental score. And the Mini-mental score improved in the patients who received the predecessor version of what is now Lomecel-B. And we were like, Whoa, that’s surprising. That wasn’t expected. Then when we spoke with experts in the field, they also informed us that indeed there was a hypothesis that made sense, which is that there’s inflammation in the brain in Alzheimer’s patients, and that might go unaddressed by some of the other approaches that were being developed. That’s called the neuroinflammation hypothesis. And with all of the troubles in the Alzheimer’s field, there’s been a huge shift towards looking at neuroinflammation. So knowing how our cells work, remember I told you the four things we know about Lomecel-B, anti-inflammatory anti-fibrotic, pro vascular and stimulation of endogenous repair plus the observation in the earlier study that there was an improvement in mini-mental, it may again make total logical sense to go ahead and try it in a small Alzheimer’s study, which we did. We were very fortunate that the Alzheimer’s Association funded it under a part of the cloud grant. So I want to acknowledge them. And we did a 33 patient study that’s been published in the journal Alzheimer’s and Dementia, which is a journal of the Alzheimer’s Association. And the results were really, really interesting. Of course, they’re preliminary and provocative. It’s just a phase one study. But we did show safety, But from a preliminary standpoint, we saw suggestions of efficacy and they seem to be meaningful. So Longeveron is presently enrolling in a phase two study.

Grace Ratley: [00:18:12] And one of the things that is really amazing about cell based therapies is the safety of it. Can you talk a little bit about that?

Joshua Hare: [00:18:22] So I have a general prediction, and I believe that over the course of this century and it’s always good to look back a hundred years and sometimes it seems like not much changes. But if you look at medicine over the past hundred years, it’s been incredible the changes. We didn’t even have antibiotics 100 years ago and now we’ve got hundreds of different antibiotics and heart failure drugs. I mean, there’s now 8 or 9 different classes of heart failure drugs, cancer chemotherapy and so on and so forth. My general prediction for the 21st century is that cells are going to become much more commonly used as medicines. We’ve already started. That process has already begun with a type of cell therapy called Car-T therapy, which is a very effective way to engineer T cells and use them to kill a variety of cancers and leukemias and lymphomas. And these are approved. I think cells are going to generally be used as medicines for a whole host of indications. And one of the main reasons is safety. I think if you have a situation where you could cure a disease with medicines or you can cure it with cells, the cells are going to win out over the next four, five, six decades.

[00:19:44] Why? Because I think cells are going to be much safer to use. Think about it as a smart bomb or addressing something surgically than with a sledge hammer. So I’ve told you these four things that the MSCs do. The cell is a living thing. It doesn’t just go in there and do that everywhere. It just goes to the area of injury and just does what’s needed to be done at that site. So that gives it a balanced action. And also they have a very long standing action. So, for example, in the Alzheimer’s trial and in the frailty trial, we gave a single dose of the cells to people at the beginning and followed them for nine months in the frailty and 12 months in the Alzheimer’s. And those effects from the single dose were still accumulating 9 or 12 months later. So incredibly safe, incredibly effective, long lasting. I think it’s going to overtake medicines in quite a few areas once we really figure out how to engineer the cells better for each specific thing we want them to do.

Grace Ratley: [00:20:57] Yes, I’m very excited about it as well. I hadn’t learned very much about these therapies before this interview, and at first I was a little skeptical. I was like, That sounds kind of ridiculous, like injecting cells into someone’s blood and just seeing what happens. But the more I learned about it, I’m really excited about it. So let’s get into a little bit about you and your journey to Longeveron and into science. So tell me about when you first became interested in medicine.

Joshua Hare: [00:21:30] I became interested in medicine very, very early on in my life, around the time I was 13 years old, when I was in the ninth grade. I always loved science. As a kid, I loved science, I loved chemistry and electronics and biology. I was fascinated by animals and I put it all together by the ninth grade saying, hey, medicine is the thing for me because it combines science and the human condition, the human experience. And so I decided very early that that’s what I was going to do. And I wanted to be a research doctor, not just a medical doctor. So I pursued that very early. I worked every summer at the National Institutes of Health in Bethesda, Maryland, starting from the summer I graduated high school all the way through college and into medical school. I published my first papers out of those summer experiences. Then I went to Johns Hopkins Medical School, which was fantastic and really research institution where research was highly valued. And very early in medical school, I decided I wanted to do cardiology. So I’ve always been very lucky that I’ve been able to know what I wanted to do early.

Grace Ratley: [00:22:52] That’s really wonderful. I’m glad that you had those experiences at a young age and really guided you to where you are. So then you went into academia?

Joshua Hare: [00:23:03] Yeah, I have not left academia. I think academia is the most exciting thing there is to do. I feel like I started academia on day one of medical school because I went to a research institute and I’m still a professor of medicine at the University of Miami.

Grace Ratley: [00:23:21] I think in a lot of academic settings, it can be difficult to learn about opportunities to take your research to market or to actually take research and apply it into populations. I think a lot of scientists working in academia, they’re doing their basic research and they’re really passionate about it and they’re writing these grants like, yes, this could be used in cancer, but they’re maybe hoping that someone will just take that idea and do it for them. So how did you get into biotech?

Joshua Hare: [00:23:54] Yeah, you’re absolutely correct that there’s a lot of, I would say, cognitive dissonance between basic science and the laboratory and what’s called technology transfer. One of the major things that was done in the United States and this goes all the way back to 1980, was that the Congress of the United States recognized that there was a problem and that intellectual property was being squandered. Because if a scientist made an inventive discovery and published it before they filed a patent, they would obviate the intellectual property. Because once something’s in the public domain, you can’t patent it and then everybody can access it. Now, what everybody recognized at Congress and on the business community that it’s intellectual property or IP that drives commercialization because an investor isn’t going to invest in something that’s in the public domain because then they can’t get a return. The other thing that’s important to know is that all medicines are generated through industry, not through academia. Universities are not for profit entities and they are not set up to become companies and take on the risk that a company takes. So there’s still a lot of tension between this. But in 1980, there was a law passed by Congress called the Bayh-dole Act. And this was very, very important because you always have to remember that in the United States, the NIH funds billions and billions of dollars of taxpayer money every year to research universities.

[00:25:33] Now, the taxpayers of the United States want treatments as a result. So the law was passed that universities can and should patent their discoveries before the results are published, and that they should set up technology transfer offices and go to investigators at the university, particularly the ones who have NIH grants, and make sure or help or assist that patentable material is being patented. Now the law holds or I’m not sure if it’s the law, but it’s what’s done. The university owns the patent, not the investor, not the investigator. And their job is to license it and make sure that that it gets put into the right hands. Now, that’s not as easy as it seems, because you still have to convince investors to invest. And they’ve got a lot of different choices. There’s a lot of stuff coming out. But the long and short of it is the Bayh-dole Act provides for universities patenting inventions and for universities, licensing them to industrial partners and gaining royalties that can be ploughed back into the academic mission. That’s what’s supposed to happen. Now, in my case, I became the inventor. And to an extent the investor, because I helped start the company and I sought the investor. Now that’s also okay. And a university professor can and the laws and the rules do allow so long as the person is disclosing. And if you look at any of my papers, you’ll see I disclose in every one of my papers that I am a founder of Longeveron and own equity in Longeveron.

[00:27:22] What made it all work was that I was the person who made the inventions and then became the person on the other side who became the licensor. I raised the money from investors to start the company as well. So that’s the reason I think why it’s worked well. There’s a lot of start ups that really never get off the ground because they’re undercapitalized in the beginning or the right relationships between the inventors and the company aren’t there. The companies that are really successful, if you look around the world, in the country, there’s some very successful startups. A great example is Moderna. Moderna, the company that made of the COVID vaccines is only ten years old. It’s a startup. It’s a startup that licensed technologies from universities and commercialized them and the licenses and the patents and the IPS to use RNA as a drug. And they figured out it could be used as a vaccine. The companies that made CAR-T therapy were all startups. The ones that are really successful are the ones that engage with the inventors and have the proper relationship with the universities. That’s going to be a win win situation for the company, the university and the inventor.

Grace Ratley: [00:28:51] And I think that is done better in some places than others. So of course, San Francisco and various places in California and Silicon Valley, Boston and Miami. Miami is a definitely a growing hub for biotech. And I think universities in those hubs tend to maybe encourage investigators more or educate them more about these opportunities. How have you felt being in Miami in this biotech community?

Joshua Hare: [00:29:26] Biotech is just a burgeoning field in Miami. It’s nowhere near Boston or the Bay Area. But there’s a lot of smart people here. There is the University of Miami that has a lot of investigators and a lot of NIH funding. So there is a lot of opportunity here. But there’s also not being in Boston or San Francisco, it can pose challenges to a startup. There’s a lot of interest in this city from the mayor’s office and the governor’s office to see South Florida become more of a biotech hub. And I think it will. There are lots of areas that are growing and it’s a huge part of the economy. It’s a huge part of the investment base. Investors or their investment firms are just specialized in biotech and study and understand biotech. I think it’s very exciting. I think Miami’s got a bright future. We’re proud of the fact that I think Longeveron is, if you just look at it on the basis of market cap, let’s say one of the most successful, if not the most successful spin out of the University of Miami. And so having something like Longeveron based in Miami hopefully becomes a catalyst for other companies to also successfully launch and then go all the way to a public offering. So Longeveron went public February of last year.

Grace Ratley: [00:30:56] And this isn’t the first biotech you’ve founded. Correct? You have also founded Visteon and Heart Genomics. Can you tell me a little bit about those companies and your experiences there?

Joshua Hare: [00:31:08] It shows in my view how hard it is to get all of the pieces right. So some people think, Oh, all we need is a patent and if the patent is good, it will just automatically attract money and attract people. Like everything in life, everything requires hard work, connections, experience, nothing that’s worth anything just happens by itself. So Visteon and Heart Genomics were sort of my early attempts to learn how to do this correctly. And in both instances we raised money, licensed the patents, but unfortunately never got to the point where a Longeveron is, where the capitalization at Longeveron and the infrastructure that was developed and the plan was just much more successful. So Visteon and Heart Genomics still exist. I wish them the very, very best, but they haven’t become as successful as Longeveron. They didn’t get to the point of being able to go public. They do have really good technologies, really good technologies, and I think there’ll be opportunities to advance those technologies.

Grace Ratley: [00:32:28] What did you learn from those early experiences? What were the most significant pieces of information that you would give maybe to a new founder who is looking to patent their technology and try and take it to market?

Joshua Hare: [00:32:46] You have to go into this understanding that anything you do, it requires a lot of hard work and that it just doesn’t happen by itself. The other thing that’s really important to understand is it’s just as scientifically rigorous. You have to go through all of the same steps you do just in your academic lab, which is raise money and build a team and build a facility and take the technology forward. So it’s very, very difficult. And you have to also learn and understand how investment economics work. You have to take on some knowledge of business and how things are valued. I always joke that I missed the finance lecture in medical school. Well, of course they don’t have a finance lecture in medical school, but you do have to understand finance. So the Bayh-dole Act got us so far to say, it’s okay to patent, but then the people at university still have some misconceptions. First of all, they still have somewhat of a stigma against it in some quarters. Some research professors feel that, Oh, it’s dirty to go into the commercial space and they don’t want to do it, that there’s something wrong with it.

[00:34:07] And then there’s another side where people feel that they have just incredibly unrealistic expectation of what something should be worth. So you’ve got to be able to understand the economics of that, and you’ve got to seek out the right people to invest. And you’ve got to understand enough about the deal terms that the deal terms are fair and reasonable and will allow the idea to grow. Because at the end of the day, in my view, the key endpoint is the advancement of science. We worked all the way in the university to advance the science and we’re working on the other side in the technological sphere to advance the science because it’s only through correct science and accurate science that we’ll get to effective treatments. The truth always wins out. So if anybody has falsified anything or cut any corners at any point of the way, it’s going to come out. Rigorous responsible science is critical at every step of the way.

Grace Ratley: [00:35:15] That’s some really awesome advice and some great wisdom that you’ve shared with us today. Thank you so much for joining us today. I learned a lot.

Joshua Hare: [00:35:21] Wonderful, wonderful.