Click here for Part I & Part II

Developing cures for HIV, PKU, and liver cancer with groundbreaking genetic medicines

Jeff Galvin is the founder and CEO of American Gene Technologies, a biomedical company focused on developing and commercializing genetic medicines. Over the past 10 years, AGT has developed a drug delivery platform that targets major lentiviral (from the Latin root lente-, meaning “slow”) diseases such as HIV/AIDS, Phenylketonuria (PKU), and liver cancer. This year, the company will begin a Phase I human trial for its functional HIV cure, potentially solving one of the greatest health crises in the world. According to Jeff, curing HIV is only the beginning for this revolutionary new technology.

Jeff Galvin spoke to Guy Flynn, a partner at DLA Piper, for this interview.

GUY FLYNN: You’re particularly involved with HIV, and I’m going to quote you again on a couple of aspects of that: “AGT hijacks the hijacker, re-regulating gene expression to mitigate disease, using HIV to cure HIV.” Talk to us a little bit about where the company stands with respect to HIV, and what the technology is—and what the effect of the technology is on the HIV disease.

JEFF GALVIN: Let me go ahead and tell you how we’re solving HIV. If I start it from the beginning about how viral vectors work, I think it’s a very interesting story that anybody can understand, but it really cuts to the core of what gene and cell therapy is. HIV is a great example of that.

This is going to blow your mind. These viral vectors that we are talking about, specifically something called the lentiviral vector, which is what most of our technology is based on, is derived from HIV—human immunodeficiency virus. Now, on one hand it’s this horrible, scary virus. On the other hand, it’s an incredibly clever delivery mechanism for a genetic payload, which is the disease. What scientists have discovered—and what viral vectors is all about—is we can now take any virus, really, we can crack it open, we can scoop out the disease, and we just end up with an empty delivery vehicle. It still has that same ability to install genes into your cells, but is no longer carrying a disease. HIV isn’t HIV—that’s why we call it a lentivirus. It’s basically the delivery capability of HIV with AIDS erased. The other thing that we erase from it is we erase its ability to replicate, because for safety reasons when we make a virion, we don’t want it to get into your cells and produce additional virions. We want to be able to treat you with enough virions to go ahead and change your programming in the cells that we want to get to, but we don’t want to risk this thing starting to replicate, moving all over your body or even escaping your body. You could potentially start a new virus that way.

This is extremely safe, what we’re doing. We’re modifying HIV so that there is absolutely no way that you could get AIDS from it, and there’s no way that it could create a new disease, but we’re preserving in it that allows us to go in there and implant new genes in your DNA, just like HIV does.

Well, what kind of genes can we put in there? We could just put in a gene that you’re missing. There are a lot of diseases out there that just boil down to that you’re missing some enzyme or some protein that is made by a specific gene in your DNA and that gene in you is defective. We call those autosomal disorders. They’re usually inherited diseases. You just have the inability to make this particular protein. It could be something mildly inconvenient like lactose intolerance, or it could be something really serious like hemophilia or beta thalassemia or phenylketonuria—things where it’s a huge painful disease to have, sometimes even deadly.

But it all boils down to the same thing: you’ve got a gene that is not doing what it’s supposed to do. What’s the simplest application of having this delivery vehicle that can deliver anything? We just go ahead and get one of those genes pop it into our empty stealth bomber of a hollowed-out HIV capsule, piece it together—we have to replicate these things, that’s our manufacturing process—and then we go ahead and treat cells in your body, and guess what? You start making that gene product. And if you now have the enzyme, or you now have that protein, that disease might go away. That’s the theoretical basis of what we are doing.

Now, these genes that we put in there could be genes that we turn on, like I just described to you, but they can also be genes that are synthesized to make what are called short interrupting RNA—siRNA. What those things do is they can bind with the messages from genes that you do have and effectively shut down those genes, so we’re not cutting that gene out. Let’s say you’ve got a gene that’s driving a disease state—cancer is actually oncogenes that are turned on—we could shut off that oncogene by putting an siRNA to that oncogene message, and effectively it turns off that gene. Essentially, within this delivery capsule we can put something that either turns on a gene, up-regulates a gene; or turns off a gene, down-regulates a gene. We can edit your gene expression. It’s incredibly powerful, so we can shut off things that shouldn’t be firing, like oncogenes, or we can turn on things that should be firing, like the phenylalanine hydroxylase that you need to have so that you don’t develop the disease phenylketonuria.

This brings us to HIV. What is HIV? It’s AIDS genes that are implanted in your cells, and this is where originally I got the idea that, “Hmmm, maybe that delivery capsule since it can down-regulate genes—could we down-regulate those HIV genes?” I asked one of our PhDs and it was like, “Sure, why not?” The other thing that I had learned about HIV is that the entry point on your T-cells for the HIV virion is something that requires a surface receptor called chemokine receptor number 5—CCR5. They know this because there are certain people in Europe that are born immune to HIV—they can’t contract HIV—and it ‘ because they have a rare disorder called delta-32 mutation, but basically that is just fancy talk for some reason they are born without working alleles that make CCR5. Their T-cells are absent, and since the HIV virion needs to hold onto CCR5 in order to penetrate the T-cell, when it doesn’t have that handle, it can’t get in. So, that was the next thing I asked the PhDs. When I read about that, I was like, “Could we shut off CCR5 in T-cells?” They were like, “yep,” and I said, “Would that actually get rid of it off the surface?” Yeah, it turns out that if that gene is not firing in the T-cells, then those CCR5 receptors on the surface of the T-cells will go away, so we can simulate a delta-32 mutation in anybody.

Well, that’s our drug. We shut off the HIV genome by down-regulating conserved regions of HIV. If a cell that we go into has HIV, it can no longer function, so it can’t make more HIV virions. And then, even if there are cells in your body that are not making HIV virions, they can’t get into T-cells. What we do is we take out a little bit of your blood—actually, only a half a liter or even less than that: 400 milliliters of blood—we do what is called a leukapheresis, and that is we strain for all of the T-cells. Then, we amplify—it turns out that even if you’ve never been exposed to HIV, you have HIV-specific T-cells that are waiting around like a flu T-cell or a cold T-cell that you’ve never seen the flu or the cold—it’s waiting around because you have this infinitely diverse set of T-cells that are prepared for almost anything. We take out those T-cells and we amplify them, so we have more of them, and then we treat them with our lentiviral vector to erase the CCR5 off the surface, so they can no longer be penetrated by HIV.

Why is it that HIV ends up taking over your body? It’s really simple: The T-cell that was designed to wipe out that HIV virion, while it’s trying to eat that virion, the virion infects the T-cell. It becomes the beachhead for the infection because in fact that T-cell, now having been excited, goes back to your lymph nodes and replicates. That spreads HIV all over your body. Now, it can take its time taking over the rest of your T-cell population. Now, if we go ahead and we take somebody that is well controlled on antiretroviral therapy, guess what? They have HIV-specific T-cells again. So, you would say, “Why aren’t they immune to HIV at that point then, if they’ve got T-cells that are all ready to go?” Well, as soon as you withdraw that antiretroviral therapy, one of those T-cells will meet a virion and the viremia will rebound within 21 days, which is the normal rebound. Why is that? Because that virion will just reinfect that HIV T-cell, it will deplete those HIV-specific T-cells again, it will utilize that T-cell to spread around the body, and it will completely re-infect the patient. We take these people that are well controlled on this antiretroviral therapy, they have those HIV T-cells—and we’ve tested this, we know that they have them; we already have blood in our labs where we’re processing the blood—and we’re able to get them to a critical mass of HIV-specific T-cells that are impenetrable by the HIV virion, and they are therefore rendered immune to HIV for life. That’s the HIV cure in a nutshell, and it all comes down to the fact that we can down-regulate the HIV genes, and we can down-regulate the CCR5 gene, and we can re-program these T-cells to be impenetrable by HIV, and we can remove the one advantage that HIV used to have over your body.

GUY FLYNN: Now, is that conceptual revolution that you dreamed of and came up with specific to HIV, or is that replicable theoretically to other diseases?

JEFF GALVIN: It’s absolutely applicable to other diseases. Now, of course, when you look at AGT’s platform, we have the HIV project, which is an infectious disease. We believe that there’s a whole bunch of different infectious diseases that can be treated this way. We might go after hepatitis B or HPV, Ebola, Zika—there are a lot of different ways that we can enhance the immune system in a safe way, where we could render you immune to certain infectious diseases. We think that that’s got a future, but HIV is already a big accomplishment in that area, and that’s going to prove out the whole platform.

But the platform—there’s more to it, because our ability to re-regulate genes also works in these autosomal disorders. You know how many incurable autosomal disorders are out there? Somewhere between 7 and 10 thousand. Did you realize that 21% of the morbidity in the healthcare system is attributable to these monogenic diseases? We’re spending 20% of a 10 trillion dollar market just on palliative treatments for people that have these autosomal disorders. We’3re doing our first autosomal disorder as something phenylketonuria. We’re replacing this phenylalanine hydroxylase gene. And it’s more complicated than just replacing it. It turns out there are some nuances—and I call this the creative and engineering aspect of what we do, because we take this basic technology and then we solve some problems along the way—just like if you are building the Golden Gate Bridge: yeah, you can have a great plan, but you encounter a whole bunch of challenges as you’re actually putting up those towers and stringing those wires, and this is what the engineers solve to really make that bridge come alive. Well, we’re making bridges to these cures the same way. And that’s the way that our PhDs look at themselves. They look at themselves as sort of artists, creative artists coming up with new ways to combine these technologies to address what we call low-hanging fruit in disease categories, and then they’re engineering has some of the problems that you inevitably encounter as you try to actually build one of these bridges to a disease cure. So, that’s going to be our first in the monogenic category, but you can see that has a huge life ahead of it as well, so that’s another big area for us.

The last area for us is immuno?oncology. Immuno?oncology is the idea of getting your immune system to turn on the cancer—in other words, to be more effective against the cancer. There are a lot of approaches to this, but we have a really unique one that we call Immunotox. Instead of treating your immune system and hypercharging it to go after cancer—and that’s what CAR T is all about—we treat the cancer to lower all its defenses against your natural immune system, without even treating the immune system, and then we convert that cancer into a little factory that creates stimulatory peptides that actually increase the attractiveness of the cancer to your immune system and stimulate the natural specialized cancer surveillance cells that are clearing cancer from your body every single day. In reality, everyone walking around has some cancer, but we don’t call it cancer because it’s a natural occurrence in cells where they will actually just get so stressed out that they’ll turn cancerous and then the specialized immune cells eliminate them like they’re nothing. As a result, [there’s] a normal immune system and a normal amount of this cancer occurring in your body, and you would never actually get what we tend to think of is cancer.

What we think of cancer is when the immune system gets a little bit behind the cancer and it grows to a critical mass point where it gets to a condition where it can’t be handled naturally. In fact, when it gets to that critical mass point, the cancer is very clever and evolved. What it does is it actually has ways to camouflage itself against those immune cells that would have normally eliminate it when it was a 1- or 2- or a 3-cell occurrence. It puts out what are called checkpoint inhibitors—a famous one is PD-L1, and there’s a very well-known drug called KEYTRUDA, which blocks that PD-L1 receptor and so it doesn’t fool your immune system into thinking that that cancer is what? The cancer makes itself look like an organ in your body. It utilizes something that your heart utilizes also to make sure that your immune system never goes after your heart. And so when you block that PD-L1 in the cancer, voila! That cloaking is gone and at least the immune cells can help in your cancer therapy.

In what we’re doing, we’re not just dropping the camouflage_dropping the cloaking—we’re putting a neon sign on this thing and saying “free lunch here” to the natural part of your immune system. You know what we’re finding in the animal tests? These specialized immune cells will eat the cancer at 300–600 times its normal rate. That primary tumor just melts away.

And here’s the kicker: These immune cells have to circulate to your lymph nodes in order to replicate and bring back an army of themselves to fight that primary tumor. Guess what they pass on their way back and forth? The metastases and the secondary tumors. And we’re seeing evidence that it cleans them up as well. This concept that we’ve developed and patented may be a natural and safe way to treat even late stage cancers.

This is what my hope is. I think the first application of this is going to be in liver cancer, and I hope what we’re going to find is that we can melt away those liver tumors and get rid of the metastases at the same time. The primary tumor goes away and we find out that it doesn’t just all of a sudden and pop up somewhere else, because these natural immune cells in this highly stimulated state that are circulating all over your body—they’re enough to clean up all of those things. As a result, you might get five extra years of life out of maybe a $100,000 treatment that formerly a $100,000 would have only bought you a month or two. Now five years, that’s good utility, right? This goes back to my original point in why this is so disruptive.

GUY FLYNN: Now, people watching this program are going to want to know: How quickly to market are these technologies? In terms of clinical trials, talk to me about the clinical trial timeline for the HIV aspect and for some of these other diseases that AGT is working on.

JEFF GALVIN: HIV is the lead for us right now. Our three projects are HIV, phenylketonuria, and liver cancer. HIV had its pre-IND meeting last year, and the IND document, which is everything we agreed on with the FDA to provide to them to evaluate the safety—or to prove the safety, because we pretty much approved it with the data that we gave them in the pre-IND document, but we have to re-prove it with clinical grade materials in a very formal style; that’s what the IND document is—we expect that to go in at the beginning of the first quarter of 2018, so in about four months from now we think that that will be submitted. The way that the FDA works is that document is the agreement that we came to a year ago with them, and so they have 30 days to evaluate that and see that we actually provided everything that we promised and that they specified. In fact, if they don’t object, they don’t have to actually send us an approval at that point. If they don’t send us a notice, within 30 days, saying that “we found something wrong,” we’re free to start our clinical trials. That’s probably going to be middle of the first quarter.

We will be able to get safety data out of this within a matter of months and I think efficacy data within a matter of months after that. By the end of 2018, I hope to be able to come back to you and show you a cohort of cured HIV patients. In other words, people that had HIV, who no longer have to take antiretrovirals every day, have no chance of developing AIDS, have no chance of spreading HIV to anybody else, and are immune for the rest of their lives—so they can’t even re-contract it. They’re actually better than cured; they’re permanently immune, like you expect to be from the virus. That’s very exciting. That’s all going to happen. I think you’re going to see a lot of news on that by summer of next year.

We’re looking at preliminary data because we already have a clinical trial site contracted. We’re already getting patient blood that we’re putting through the entire treatment protocol. The only thing we’re not doing so far is re-infusing it into patients. We know that there’s this critical mass point of protected, HIV-specific T cells—that, when it’s in your body, gives you immunity to that virus—and we’re exceeding that by manyfold. We are feeling cautiously optimistic—or I could say, since I’m not the scientist, I’m feeling extremely confident—that we’re going to have a good outcome to that study.

Now, PKU and in hepatocellular carcinoma, commonly known as liver cancer—we expect to have the pre-IND meetings in 2018, then get the INDs out, and get into the clinic in 2019. Those two drugs are sort of other bullets in the gun, and that was part of our strategy: we didn’t want to bank on one thing in case we hit some hiccup. Keep your fingers crossed we won’t hit a hiccup on that, but these other diseases are looking equally good in terms of their path to the clinic. It’s just a matter of how much resources do we have to progress things all in parallel. Those things are looking very promising as well.

GUY FLYNN: So Jeff, my last question for you has to do with safety, and part of your answer has probably been subsumed in some of your other answers, but viral vector safety—is this is ultimately a safe technology?

JEFF GALVIN: I believe it is. And the reason that I believe it is is that viral vectors have actually been around and have been used now for about 40 years. In fact, lentiviral vectors are on third- or fourth-generation depending on who you talk to. Call them third-generation lentiviral viral vectors. They’ve had a huge amount of experience in the clinic. They’ve had an even much larger amount of experimentation in laboratories around the world. The basic building block of the lentiviral vector, when properly used, I think is very, very safe. I think its safety has been largely established. and now it’s a matter of “Are atoms safe?” It depends on how you use it, right? Radiation leaks? Not so good. Every powerful technology needs some maturity in order to utilize it within a safe zone and I think that there were some early misfires in viral vectors, where people were over exuberant with this new toy and they used them in manners that they didn’t really understand, and it led to some adverse consequences, which actually threw a pall over this whole industry in the late 1990s and the early 2000s. But we’re in a more developed, more matured technology,—and matured in terms of our use of that technology—phase of this, and I feel that it’s very safe.

There are several hundred gene therapy trials on clinicaltrials.gov right now. There’s a variety of different viral vectors that are all safe in different types of uses. I don’t see anything out there that I feel is really—not that I’m an expert in this, I mean you would really want to talk to PhDs that are at the heart of this research to say “Is anybody doing something that is pushing the envelope too far?”—but I’m very comfortable about how AGT utilizes viral vectors, and I think that we’re staying well within that practical zone that is well understood and safe.

GUY FLYNN: AGT really is at the forefront of personalized medicine, wouldn’t you say?

JEFF GALVIN: Depends on what you think of as “personalized medicine,” because people use that term in a variety of different ways. In one way—and I think what’s really getting the most gravity or traction in terms of personalized medicine—is the idea that by getting information about you, your genomics, we can determine which existing treatments are most likely to work for you. Where does AGT fit into that? Since we don’t have an existing therapeutic, we might not really fit into that model, but I think that what you’re going to see is, coming out of this whole revolution in big data in genomics, you’re going to find a lot more information about the underlying drivers of disease, which we can action on viral vectors and we can start to create new therapeutics. It doesn’t matter if you take a genomic test and it tells you that you have a 30% greater chance of having disease X—if there’s nothing you can do about it besides worry. The key to really actioning this whole idea of genetic medicine—of personalized medicine, in my mind—is this amazing geometric growth that I expect to see in therapeutics that are based on re-regulation of genes and editing of genes, and really all of the genetic technologies that we’re at the forefront of, but still really at the beginning of a road of discovery and development that will ultimately make what we’re doing right now look pretty crude.

GUY FLYNN: Phenomenal. Well, Jeff this has been a terrific discussion, and to many people this sounds like the stuff of science fiction, but guess what? The future is now in many respects. We wish you all the best with AGT and with all the tremendous, groundbreaking work that you and the company are accomplishing. Thanks for your time.

JEFF GALVIN: Thank you.

Connect with Jeffrey on LinkedIn

Edwin Warfield, CEO of citybizlist, conducts the CEO Interviews.

If you're interested in reaching CEOs, please contact edwin.warfield@citybuzz.co

Connect on LinkedIn