On October 30, 2024, Angiex CEO Dr. Paul Jaminet and founder Dr. Harold Dvorak, a leading expert in angiogenesis, presented at a webinar hosted by Force Family Office. The discussion highlighted Angiex’s TM4SF1-targeted approach to cancer therapy, with a focus on its lead antibody-drug conjugate (ADC), AGX101. Dr. Jaminet shared updates on AGX101’s ongoing Phase 1 clinical trial, emphasizing its unique mechanism of action that targets both tumor cells and the vasculature that supports tumor growth.
The webinar offered key insights into Angiex’s approach to anti-angiogenic therapy, a field in which Dr. Dvorak played a pioneering role with his discovery of VEGF (vascular endothelial growth factor). Unlike traditional angiogenesis inhibitors, which block the formation of new blood vessels, AGX101 actively destroys the vasculature feeding tumors. Dr. Jaminet explained how AGX101’s dual-targeting mechanism offers a potential breakthrough in cancer treatment, with applications for a wide range of solid tumors.
The session also provided a window into Angiex’s strategy for advancing AGX101 through clinical trials. Dr. Jaminet highlighted the company's disciplined approach to drug development, backed by support from notable investors, including Peter Thiel. Attendees had the chance to engage directly with Dr. Jaminet and Dr. Dvorak through a Q&A session, covering topics such as the potential for combination therapies, investor opportunities, and the path to regulatory approval.
The Force Family Office webinar spotlighted Angiex’s leadership in TM4SF1-targeted ADCs, reinforcing its position as a key player in the next generation of cancer therapies. The insights shared by Dr. Jaminet and Dr. Dvorak provided a compelling case for the therapeutic and financial potential of AGX101.
Transcript of the webinar
Callie Mellana: Thank you for joining us today. Before we kick this off, I do want to point out to the audience that we welcome questions. During today's discussion, you can post them in the Q&A section. Time permitting, we will get to those at the end. So now I would like to turn this over to Force Family Office's chief communications officer, Harvey Briggs, who will be moderating today's discussion.
Harvey Briggs: Great. Thank you, Callie. I really appreciate the opportunity to be here today. And I really appreciate everyone taking time out of your busy day to join this panel and hear a great discussion from two people who are doing amazing work in the field of oncology.
With me today is Paul Jaminet. He is the founder and CEO of Angiex and Paul has an interesting background. He began his career as an astrophysicist, then became an entrepreneur and got very involved in in health and diet, and then eventually um, helped found uh, Angiex.
With our other guest here, and that is Dr. Harold Dvorak, who is the founder uh, founder and scientific advisor. Interesting tidbit in his past: Hal was the first winner of the NFCR Szent-Györgyi Prize for Progress in Cancer Research in 2006 for his discovery of VEGF. Which is a hugely important piece of the puzzle.
To both of you, welcome to this discussion. Thank you for joining me.
Dr. Paul Jaminet: Thank you.
Harvey Briggs: Great. Hey, Paul, can you start out by just giving everyone a brief overview of Angiex and what the company is and what they do?
Dr. Paul Jaminet: Yeah, so Angiex was founded on a wonderful biology that was discovered by my wife and Hal uh, during their time at Beth Israel Deaconess. And uh, they were, they were searching for the best cancer target in the human genome that would allow drugs to attack the angiogenic vasculature of tumors, and they found one.
And uh, I had made a rash promise to my wife about a dozen years earlier that if she ever found a way to cure cancer and needed someone to start a company uh, to make it real that I would do it. And uh, so, after they made their discoveries, I had to start Angiex and we did that in 2015.
And we've made what we think is an extremely good drug.
We took our time. We benefited from seed funding from Peter Thiel, who was willing to be a patient investor. And uh, we were very careful. We were frugal, but we did careful experimentation and made what we believe is a great drug, and it's now in the clinic. And we've dosed four dose cohorts of our phase one dose escalation. And we're just about to get to potential efficacy. So, we're very excited.
Harvey Briggs: That's great. Hal, talk a little bit about how you got to know Paul and his wife.
Dr. Hal Dvorak: It was very simple and straightforward. She came to my office one day and she was looking for a job as a postdoctoral fellow. Now, this is like, 15 years ago. And um, she um, had a really marvelous curriculum vitae and had published a number of important papers and was um, was very, very impressive young lady. And I offered her a job on the spot.
Harvey Briggs: You're a leading scientist in the field of angiogenesis. What is it, and why is it important, especially to cancer?
Dr. Hal Dvorak: Dr. Google defines angiogenesis as, quote, "the process of forming new blood vessels from pre-existing ones." And it's a biological process that goes on throughout life: from birth to old age. And of course, before birth as well in the embryo.
And the reason it's important is that animals, humans depend on blood vessels to bring necessary nutrients, to, like oxygen, for example, and amino acids, to various organs and tissues of the body. And also to remove waste products um, that uh, the body makes during metabolism. So it's absolutely essential.
Every organ and tissue in the body requires um, uh, these nutrients and removal of waste products. And the same is true of cancers, because cancers behave like organs, and they require a blood supply if they're going to grow beyond minimal size. And so, they have to develop new blood vessels if they're going to grow and metastasize.
And I think you can think of this in terms of what happens when blood vessels are plugged or destroyed. For example, in the heart, if blood vessels uh, supplying the heart are destroyed, you get a heart attack. Or blood vessels in the brain, if they are plugged, you get a stroke. So, um, what happens is the heart tissue dies, the brain tissue dies, and so applying this to cancer, the same principles apply.
The problem has been, uh, I don't know if we want to go into this at a later time, but some of the approaches that have been used to destroy angiogenic vessels have not been very successful. And there are some reasons for that, I think. But basically, angiogenesis is the supply of new blood vessels to tumors and to all organs and tissues, and if they're impaired, the tissue dies.
Harvey Briggs: Great. And you've made some important contributions in this field. Can you talk about some of those that you've made in your career?
Dr. Hal Dvorak: Sure. Um, as you, as you said in your introduction, um, I discovered VEGF, vascular endothelial growth factor. We actually gave it a different name, but the name VEGF became the prominent name.
And it simply turns out to be the key molecule that causes new blood vessels to grow. Without it the um, the embryo does not mature, it dies in utero. It's that key molecule that is responsible for blood vessel growth.
Harvey Briggs: Okay. Great. Paul, talk about some of the challenges you've faced in getting Angiex up and running. And to this point what things have you encountered and how have you overcome them?
Dr. Paul Jaminet: Yeah. So that's a big question. So, there's a lot of challenges that any entrepreneur faces. So, you can think of entrepreneurship as, you're trying to build an ultimate value chain, which has a lot of different people and, but you're trying to, there's the phrase of building the airplane while you're flying it.
You have to fly the company, keep it running, but you also have to build it and you have to, make it a good deal for everybody who's participating. Every employee has to make money and every, everybody has to feel it's a worthwhile endeavor.
But in a cancer therapeutics company. Where you're not allowed to get revenue until you've reached approval and it costs 300 million dollars and 10 to 15 years to get there, it's quite challenging to keep everybody you need happy through 15 years. And to find 300 million dollars to help keep everybody happy.
And uh, you know, so of course fundraising is a very uh, significant challenge. But you have to recruit scientists and people with technical expertise.
In our case we founded the company, my wife and I, and a long-time technician of hers. So my wife is a fantastic biologist but we needed a great chemist as well. And so that, you know, was one challenge to get the appropriate expertise.
And we had to get good investors. I mentioned Peter Thiel was a very good seed investor. It's difficult in this industry because the venture funds and the private equity funds that fund things, they have limited fund lifetimes.
They want to exit in three to five years. And that doesn't match up well with either the, the time you need to do great science, or the time you need to develop a great drug. But they're the ones who have money and then if you rely upon the individuals, it's very difficult to get the large sums together that you need.
And in our case so we benefited so about half the money into the company so far has come from Peter Thiel or funds that are related to him. And about half has come from my friends and family and a very large part of those friends have been people who attended our health retreat.
So, I think you mentioned earlier first I was an astrophysicist, and I became a software tech entrepreneur. And then I started learning how to be healthy and started a natural health business with a health retreat. And we earned some credibility by writing a popular book and blog that gave good advice and running a health retreat that helped the guests a great deal.
And so a lot of people trusted us and we've ended up receiving over 30 million dollars in investments from former guests of our health retreat. You have to pull a lot of things together and so I would, and of course we needed manufacturers, we needed medical people, we needed a lot of help with all the various aspects of the company, but I would say the most challenging are investors, first of all, and then key technical experts.
Harvey Briggs: So let's talk about what Angiex does what specifically you've identified. This unique pathway you're developing a new treatment. Talk more about that and what specifically you do here and how it's unique.
Dr. Paul Jaminet: Do you want to start, Hal?
Dr. Hal Dvorak: No, I'm sorry. I'm happy to.
Dr. Paul Jaminet: I'll start, and you can fill in.
We make antibody-drug conjugates. So that's a two-part drug, which has an antibody, which homes to the tumor. And then it has a conjugated drug or chemotherapy, which is what brings efficacy within the tumor. The antibody endows the chemotherapy with targeting to the tumor, and the chemotherapy endows the antibody with potency against the cancer.
And so our antibody is directed to TM4SF1, which is a special protein that my wife Shou-Ching discovered and that she and Hal investigated for oh, a dozen years or so, at Beth Israel Deaconess. And that just has a very special biology, which we can get into that's extremely favorable.
In adult cancer patients, about half of all the TM4SF1 is in the tumors. And that's unique among, all the proteins of the human genome. So there really isn't any other gene known in which more than about 4 or 5 percent of the antigen is in the tumors.
So that right there is a unique advantage for our antibodies. We get a lot more delivery to the tumor and a lot less delivery to normal tissue than other antibodies do. And then we have a special internalization biology which enables us to use the chemotherapeutic payload, which is not what in the industry is called drug-like.
And so, drug-like molecules are molecules that can go all over the body. They can cross membranes. And the cell uses a lot of membranes to protect itself from toxins and bacteria and viruses and pharmaceutical drugs. And typically, you need to design drugs with these drug-like properties in order for them to be potent. But when you do that, they can go all over the body and cause lots of toxicities.
And that's why chemotherapies are so famously toxic.
But we have the advantage. We don't need drug-like payloads, so we can make things that won't go anywhere in the body. They just get excreted harmlessly. And so the only way they can affect the cell is when our antibody first delivers them to that cell.
And so, as a result, we've been able to make a drug which is pretty much adverse-effect-free. There's no effect... no effect the patient would notice, outside the tumors. And so that's it's really the first drug which achieves that. So, we're very excited about that.
And so, we have to learn how to dose it and how to achieve efficacy. But it's an extremely exciting opportunity.
Harvey Briggs: Great. Hal, can you talk more about that TMS4, TM4SF1. Yeah. Yeah, sorry. And just talk a little bit more, more about the biology and why it's special.
Dr. Hal Dvorak: Let me just go back to Shou-Ching's discovery of this molecule.
There are millions of molecules that are expressed by different cells. And we were looking, I was interested, she particularly was interested in finding a molecule that could serve as a target that was expressed both on tumor cells, and on the blood vessels supplying the tumor.
She did a couple of screens, one from our lab, and one that she had used before, and after this screen of many thousands of molecules, she found this one, TM4SF1, that was uniquely expressed, as Paul mentioned, on tumor cells. And he said about half of all human tumors express it in large amounts. And also on the blood vessels supplying these tumors.
Now there are a couple of things worth pointing out. One, this molecule is expressed on many cells, but is much greater expressed on the tumor cells and on the blood vessels supplying them. And what is unique about the expression on the blood vessels is that it is expressed, overexpressed, on the large vessels leading to the tumor.
Now, most of the angiogenic drugs that have been used in the past target molecules that prevent the formation of new blood vessels. But what TM4 is, is a target that, when it is hit by the antibody conjugate that Paul mentioned, it destroys the blood vessel or the tumor cell that expresses it.
And this is particularly important because it expresses this molecule is over-expressed. On the large vessels that lead to the tumor.
And this is an analogy would be if you were trying to turn off the water in a house it, you could do this most advantageously by turning it off where the large pipe enters the house, it would be far more efficient and effective than going around and have to turn the faucet off in every room in the house.
And that's why this is such an important target on the vasculature. Because it is over-expressed on the large vessels that lead into the tumor. And not just, it's also expressed on the small vessels, but in particular, it is over-expressed on the large vessels, the arteries that lead to the tumor. So here you have a target that is dual-expressed on tumor cells and on the large vessels and the small vessels that lead to the tumor.
Harvey Briggs: Great. So, let's talk about your lead drug candidate, AGX101. It's, you said it's in the clinic, you're dosing patients now. What kind of drug is it? How does it work? And talk a little bit about the potential to treat different types of cancer.
Dr. Paul Jaminet: Yeah. It's an antibody-drug conjugate. So, an antibody is a very large molecule and the conjugated chemotherapy is a very small molecule.
And when the drug is initially made, that chemotherapy is hidden. It's concealed inside a little hydrophobic pocket in the middle of the antibody. So the antibody just looks like a normal antibody and the chemotherapy has no effect as long as it's attached to the antibody.
And so we infuse that through an intravenous infusion to the patient and it circulates through the body and it looks for TM4SF1 and about half of the TM4SF1 is in the tumor.
So, when we get to high enough doses, approximately half of the infused drug goes to tumors.
And then in the tumor the TM4SF1, it serves a transport function. So, it enables the cells to respond to VEGF. So, vEGF, when it binds to its receptors on the cells, it activates a number of cytosolic proteins.
So, it changes them chemically so that they become active. And those activated proteins are shuttled along the cell membrane to these micro domains where TM4SF1 is abundant. And you can think of the TM4SF1 as the locomotive and these microdomains as the freight train. And they load up their freight cars with these growth-factor-activated proteins.
And then when the train is loaded up, it internalizes to the nucleus along the microtubule network. And when it gets to the nucleus, then it drops off its cargo. And all these growth-factor-activated proteins are able to regulate gene expression and turn on this genetic program for blood vessel formation.
And so one thing we found: Shou-Ching made knockout mice that have no TM4SF1. And the embryos don't form any blood vessels, even though the VEGF level is seven times normal, seven times the level in other embryos. And, and that's just because the VEGF is binding the cell and creating all these growth-factor-activated proteins, but they can't get from the cell membrane to the nucleus and they don't turn on this gene expression.
So, our drug, the antibody, is just like a hobo hopping on the freight train. It finds a little epitope of the TM4SF1 that's sticking out into the blood and it just binds there. And then when the microdomain gets around to carrying its growth factors into the nucleus, it carries our drug along with it.
When our drug gets to the nucleus, the nucleus has its own proteasome that removes all foreign proteins, everything that doesn't belong in the nucleus. And it very quickly recognizes our antibody as something that doesn't belong. So it degrades it down to its amino acids, and that happens in less than an hour.
And when it does that, then it releases this conjugated chemotherapy, which was hidden within this hydrophobic pocket of the antibody. But once the antibody is gone, then it's released, and then it can go find its target.
But we have this further advantage of our drug that its target is not in the nucleus, it's in the cytosol. And so this drug is trapped in the nucleus until the cell attempts to commit cell division, and then the nuclear membrane breaks down, and the drug can find its target. And when it does that, then it causes the cell to die during cell division.
And we have a lot of advantages in terms of safety. So first of all, we get this preferential homing to the tumor. This nuclear delivery is preferentially turned on in the tumor. And then our payload is only potent against dividing cells-- that gives us some extra therapeutic margin.
So, we were able to make a drug that's very safe. to the normal blood vessels but very potent in the tumor against both the tumor cells and the tumor vessels.
And so, once we get to high enough dose levels to be killing the tumor cells, then we expect to get, quite impressive efficacy to go along with the very impressive safety that we've already been demonstrating.
Harvey Briggs: And because of that homing, that, does that affect dosing and how much or how little you have to use?
Dr. Paul Jaminet: In some sense it does. So we have an effect at very low doses. But until we get above a certain dose level, about three milligram per kilogram, all of the effect is on the blood vessels. The vascular antigen of TM4SF1 is a diffusion barrier.
So we start by with an intravenous infusion and then the antibodies are very high affinity. So if there's any TM4SF1 on the blood vessels, they find that and they never have time to go into the tumor cells.
And so we have a very potent drug and the result is that we start killing the endothelial cells of the tumor very early.
We have an issue: the body has evolved to fix vascular injuries very quickly. So it doesn't want to have the tissue die because it's been slow healing any vascular injury. As soon as you injure the vasculature, the body's healing process rolls into motion and it fixes it. And it does that even in the tumor. So we've been going up in these dose levels and we've been essentially wiping out the tumor vasculature in a few hours.
But also our drug goes away in a few hours because the dose levels are too low, and then the body heals the vessels. And so we haven't yet demonstrated efficacy, even though we've been killing all the tumor blood vessels because they keep getting healed and coming back.
So we're just about to get to the dose levels where we'll regress the tumors and we're very excited about that, but we haven't reached it yet.
Harvey Briggs: Let's talk about the potential targets that you're talking about: solid tumor cancers here. What are you looking at specific cancer types in these trials?
Dr. Paul Jaminet: Yeah, so, actually that's an extremely interesting scientific question of, which cancers can we address? We're going to learn that.
But one thing that we've learned from preclinical studies is it appears that TM4SF1 is required for invasion and metastasis. It looks like tumor cells invade tissue the same way that endothelial cells invade hypoxic tissue to expand their blood supply. If you think you have an hypoxic tissue and it needs a greater blood supply, the endothelial cells have to tunnel a tube into it in order to increase its blood supply.
And the tumor cells also need to tunnel in the tissue in order to invade. And they seem to use TM4SF1 to do it. And they also to metastasize, they need to extravasate into the blood and then intravasate into tissue. And that seems to be a TM4SF1-dependent process.
So, the result is it appears that all invasive and metastatic tumor cells express TM4SF1 at high levels and they may be sensitive to our drug.
So, we have the potential to, as we get to high levels and start killing tumor cells, to kill all of the invasive and metastatic tumor cells and potentially convert malignant tumors into a more benign phenotype.
So, there's a there's a great potential to really benefit patients. And in animal models we've gotten quite high rates of complete responses, when the tumor cells are sensitive to our drug. The tumor cells can be resistant either because they don't express TM4SF1, in which case they're not invasive or metastatic or because they're resistant to maytansine, which can happen. Maytansine is our chemotherapeutic payload.
And we'll see if there are resistant tumors, but we think we can help just about every cancer patient.
Harvey Briggs: Yeah, Hal, why don't you weigh in on that, weigh in on that as well. Talk about, is there a potential for this to be almost a universal treatment for solid tumor cancer?
Dr. Hal Dvorak: Yeah, I certainly think there is, but defining universal first means that they have to be developing new blood vessels, which overexpress TM4, and second, the tumor cells ideally would also be expressing, overexpressing TM4, so that you have two targets within the same tumor.
Now, I think this is unique. I don't know of any other therapy that, that is able to do that.
One other point, and Paul mentioned this, but I want to just stress it. The TM4 is expressed on the surface of the cells so that the antibody is able to reach it very effectively. If the drug is circulating in the blood, it can come across the blood vessel endothelial cells that line blood vessels and hit them directly.
Many other types of drug that have been used, especially antibody conjugates that target the tumor cells only, have to cross the blood barrier and get from the blood into the tissues. And that can be very hard to do. That's a big barrier that has to be crossed.
So, there's a great advantage to this particular target as a good target for antibody treatment.
Harvey Briggs: Great. So, if you had to, is there a comparison to anything that's out there in the market now? Or is this really opening up a new opportunity in cancer treatment?
Dr. Paul Jaminet: I think it's very much a new approach.
There have been anti-angiogenic drugs, which are mostly antibodies against VEGF or its receptors. And all they do is reduce the amount of VEGF that is reaching the endothelial cells. So they can slow down the growth rate a little bit, but they don't shrink the tumors and the clinical benefit has been pretty small.
They have sold well because they combine very well with other cancer drugs. So they've been safe and they combine well with other drugs. And we think we'll have the same benefits.
We have a very safe drug and we'll combine well because we have none of the tox that other cancer drugs have. We have no hematopoietic tox to bone marrow, and no digestive tract tox, and no tox in most of the other places that oncology drugs have tox.
But what differentiates us from those is we're not acting outside the cell. We're acting inside it and we're not relying on our antibodies to be potent; we're delivering a custom-tailored payload. And we have the choice. We're not restricted to one payload. We can deliver many different payloads. In future drugs, we can deliver drug cocktails to these cells. We can take advantage of this biology to figure out how to bring tremendous benefit to cancer patients.
Harvey Briggs: So talk about the investment opportunity here then. Obviously, you're bringing something new to this market. It's a huge market. Why should people look to come on board and help you guys push this thing through the clinic and into the market?
Dr. Paul Jaminet: Yeah, I think, first of all drug developers are always in need of investors and money.
As I mentioned, you need quite a bit of money to get to approval. In our case, we could potentially get to submission of our license application in as little as three years. And we have the potential because it is potentially almost a universal therapy.
There's the potential that it could save a hundred thousand lives a month. And if that comes to pass, then (a), we want to get it to approval as quickly as possible. So, we like investors to help us pay for that. But also, the potential revenue. If you think of a lot of cancer drugs these days are charging a hundred thousand dollars for treatment, and if you multiply a hundred thousand dollars per patient times a hundred thousand lives saved per month, and multiply by 12 months per year, you get to a pretty large number.
There is a, a potential for a very large investment returns. Angiex is currently valued below a hundred million dollars. And so it's if you multiply those numbers out, it adds to potential for a hundred billion dollars a year of revenue. And the drug to treat a patient costs less than a thousand dollars. From an investor's perspective, there's a very good potential. And some people speak of investment philanthropy in terms of the benefit of lives saved and helping people. That's also a very substantial reason to invest.
And that's really the reason why Shou-Ching and I have devoted, the last 10 years of our life to this company and why Hal and Shou-Ching devoted their careers to cancer research.
Harvey Briggs: Hal, talk a little bit about where you see this playing out over the next few years. What's the path forward and what are the milestones that you're looking at to see success?
Dr. Hal Dvorak: Yeah, the first thing I think is that it does not cause toxicity, and that's where we are at this point in giving the drug to human beings. So, I think that is the first step, and so far, so good.
I guess the next step is going to be defining which tumors are helped the most by this, and in this early phase one situation where we are now we take all comers, is that right Paul?
Dr. Paul Jaminet: That's right. It's an all-comers trial.
Dr. Hal Dvorak: And the next milestone is going to be able to find those tumors, human cancers, patients with cancers, that are most susceptible to the drug. And I think we go there from there. What do you say, Paul?
Dr. Paul Jaminet: Yeah so I would say, yeah, the first step is to demonstrate efficacy because people don't know how meaningful safety is until they know you can also generate efficacy at a safe dose. And so that's what is next up for us. And our thinking is that in about three months from now, we'll have evidence of efficacy. So we're quite close.
And so once we're demonstrating efficacy, as Hal says, we have to learn about, the differences between different tumors. And, any difference is relevant. Is it easier to achieve efficacy in some cancers than others? Is the efficacy more meaningful in terms of survival benefit?
Because you can do things like shrink tumors but cause other problems. Like, some tumors, the invasive tumors, are integrated with normal tissue. And if you leave a damaged normal tissue that might impair the patient as well. So there's a lot we have to learn.
We have the potential to be efficacious at many dose levels. And so we have to figure out, is it better to regress cancer slowly at low dose levels or rapidly at high dose levels?
We also combine very well. So. In preclinical studies, we increase the response rate to immune checkpoint inhibitors from 10 to 20% to 70 to 80%.
And early next year, we'll do combination arms with pembrolizumab and ipilimumab, and we'll evaluate whether those numbers translate to humans. The advantage of those combinations is we can use very low dose levels and activate, potentiate those checkpoint inhibitors.
Alternatively, we can as a monotherapy go to high dose levels where we reach the tumor cells and kill the tumor cells.
So, we have to figure out what the best way to treat, which patients should be treated this way, which patients that way. And so, there's a lot of investigation to do.
And our thinking right now is we'll probably seek drug approval in at least three indications. We might have a single high unmet need orphan designation that we can get to approval very quickly. If it's something where people are dying in six months, then it doesn't take a lot of patients to prove a survival benefit in six months.
And so, you can be quick to approval. And then probably a couple of tumor-agnostic indications, so a tumor-agnostic indication with no TM4SF1 on the tumor cells. So, we treat at a low dose, maybe in combination with a checkpoint inhibitors. And then another tumor-agnostic approval where a TM4SF1 is high in the tumor cells, and we treat at a high dose to attack the tumor cells.
And there's a lot of options that we have to explore. And another thing we want to do is create a PET imaging agent so that we can image where all the TM4SF1 is. And conceivably, there could be other conditions that lead TM4SF1 to be upregulated, and we might want to avoid treating those patients until that other condition was healed.
And so, we have to create tools to help the clinicians manage the patient study biomarkers, all kinds of other things. So, there's a lot to learn. And also to get to approval, we have to build the manufacturing supply chain and all the quality management tools that the FDA requires.
So, there's quite a bit of work to do. And of course we have to recruit the investors that will help us pay for that work.
Harvey Briggs: Do you see commercializing this on your own or are you looking for partners or even other potential exits?
Dr. Paul Jaminet: So, our thinking at the moment is that we'll manage the clinical development and the manufacturing and quality. So, we'll control the drug.
But we'll probably partner with a global pharma company to market, sell, distribute the drug all over the world. And so other companies have done similarly. So, for example, Daiichi Sankyo, who's a very prominent ADC company. They developed a drug called Enhertu. And about a year before approval, they did a deal with AstraZeneca and AstraZeneca markets it, and Daiichi Sankyo did the development. And yeah, so that's the most likely model.
People say it's getting easier to build your own sales and distribution networks. Now that there's the internet and there's virtual meetings are possible, but it's not really something we're interested in.
And there are plenty of people who have built those networks and are good at it. But I think it is valuable, we're the experts in the biology and the drug. And so we should keep the things that depend on that expertise: the clinical development and the manufacturing and quality within our organization.
Harvey Briggs: Great. It looks like we have a lot of questions in the chat, and I want to give people a chance to weigh in and ask you guys their questions. So, I'm going to turn it back over to Callie.
Callie Mellana: Great. Thank you so much, Harvey.
So can you tell us how did Peter Thiel become an investor? And you also mentioned that he was a patient. Can you explain that?
Dr. Paul Jaminet: Okay. I didn't mean that he was a cancer patient. No, I meant he was a patient investor that he didn't give us a deadline to produce a drug.
Callie Mellana: Got it. Okay.
Dr. Paul Jaminet: And I think, when you're doing science, you can't always predict how long it's going to take. You do an experiment and you see the result. And if the result is unexpected, then you have to investigate more. And so it was like that with us, we had to we had to do five years of experimentation and we had, a fantastic scientist and we were very efficient. But still to make a great drug, it takes time.
And so it's very important, if your goal is to make a great drug then it's very important to have an investor who's willing to let you take the time. And Peter Thiel he's quite happy going away and not putting any money in for four years. And that can be a good thing, when you're a scientist who wants to be left alone for a little while.
Whereas investors who have funds with, need to return their money to limited partners within three years, they'll be looking over your shoulder and saying, can you hurry up a little bit? That doesn't necessarily lead to the best work.
Then how do you patent the pathway? You can't patent biology. But what you can do is patent novel and non-obvious ways of making a drug that performs better on that pathway than other drugs would. And so we've been able to file a dozen patents. And the reason we've been able to get so many patents is because the biology is so novel.
So there's nuclear internalization is unique to TM4SF1, it's different than how other drugs internalize. And so it needs a different chemistry.
Callie Mellana: Yeah. So another question that's come in what phase clinical trial are you in right now? And how would you consider licensing with positive data?
Dr. Paul Jaminet: Yeah. We're in phase one in the dose escalation. So the very first thing you do in the clinic is you start at a low dose and if it's safe and if it's safe, then you go up to the next higher dose and repeat until you get up either to finding a dose that isn't safe or to finding that you've reached diminishing returns. You've passed 100 percent receptor occupancy or which is what we think will be our limit in the future. Our stopping point.
So we dose escalate and then with the data that we get at each of those dose levels, then we can judge what to investigate next. And we will do further investigations to find the optimal dosing regimen and to find the optimal patient populations to treat.
And then as far as licensing we don't want to license. We want to follow that strategy I mentioned earlier that Daiichi Sankyo followed of we develop the drug and we'll do a deal with the pharma company maybe a year before approval.
Callie Mellana: And then are your clinical trials going to be combination therapies?
Dr. Paul Jaminet: We'll do both. So we'll do monotherapies and we'll do combination therapies and we'll figure out what's best for patients. And so as I mentioned it's likely that treating at low doses, treating patients where the tumor cells do not express TM4SF1. We'd want to treat at low doses and we'd probably want to treat in combination with other drugs to get greater potency against the tumor cells.
But on the other hand, where the tumor cells do express it, we'd probably want to treat at high doses as a monotherapy. So I think, different patients and different types of cancer will get different treatment strategies.
Callie Mellana: And then is the molecule naturally wrapped in a hydrophobic polymer or is your process doing that?
Dr. Paul Jaminet: No, it's not. We have a natural antibody and we have a hydrophilic linker, which links it to the antibody to the chemotherapeutic payload, and it's a small molecule. But all of these small molecules, traditionally they've been quite hydrophobic, and that's partly because you need that in order to have those drug-like properties that I mentioned of being able to diffuse all over the body.
So anything that was originally developed as a chemotherapy, it's hydrophobic, because that way it can be a little bit soluble in water but it can also be dissolved into the cell membranes, the lipid membranes. It's equally happy being in the lipid membranes and the water, and then it's equally happy going from the membranes to the cytosol, and then and so on to the nuclear membrane and then into the nucleus.
And so that's how people traditionally made chemotherapies. And so we have this hydrophobic payload. And oil and water don't mix. The lipids like to be with other lipids. Hydrophobic things like to be with other hydrophobic things.
And the antibody has patches where, some amino acids are hydrophobic, some are hydrophilic. And it has patches that are hydrophobic. And so the hydrophobic payloads will tend to associate with those spots. And so part of the art of designing an ADC, you make the linker that has just the right nature and length to let the payload go in a good spot. And you conjugate it to be anybody at a good spot.
So you have to, you know, search. So there's actually a lot of variables in ADC development and to make a really great drug, you have to optimize all of them. So it's quite a complex drug development process.
Callie Mellana: So have you received any non-dilutive funding such as NIH or government grants?
Dr. Paul Jaminet: No. We did receive some non-dilutive funding to do an experiment on the International Space Station, and that was quite a bit of fun. We got to take our son to Cape Canaveral, to watch the launch, and there are some videos on the web you can see of the astronaut doing our experiment in space.
And that was fun, but that's more that's maybe more of a problem than a something to brag about. It's more of a CEO who's got too much time on his hands and inflicts work on his scientists. I probably shouldn't brag about that. But anyway, it's no, we we applied for some grants from NIH but didn't receive them. And Hal can speak to the problems he and Shou-Ching had getting funding for TM4SF1, but basically no one else has worked on it.
Hal and Shou-Ching, for the last 20 years, this team of three has been more or less, almost the only, people in North America and Europe working on it. And some Chinese have started working on it in the recent years, probably because my wife had some Chinese investigators in her lab who took knowledge of it back to China. But yeah, there's only 150 papers in PubMed about TM4SF1, and so no one has worked on it, and no one knows anything about it.
Callie Mellana: And when you submit a grant, all the reviewers say, "I've never heard of this. What reason do I have to think it's important?" And so they don't rate it highly enough to get a grant. And so I think we just decided after a while, it just wasn't worth our time to keep preparing these grant applications and submitting them. It's better to just push ahead and make a drug. Okay, great. And so can you talk about the current offer to any new investors?
Dr. Paul Jaminet: Our lawyers would tell me that I shouldn't talk about offers. So I would just say as a general rule, most investors can assume that cancer therapy startups are going, are likely to be in need of money. And if you go to their website and find the contact page or the email then you may find a way to write to them and you can ask them, are you open to accepting money? And if you reach out to them, then they can reach back. But they typically don't want to make public offerings of securities.
Callie Mellana: Okay, great. Yeah and for anyone in the audience everyone has my email address. I'm happy to facilitate an introduction to Paul and Angiex. And in turn, he will have all of your information as well. I do want to turn it back over to you, Paul and Hal, for any final words before we close out.
Dr. Paul Jaminet: So I'll just say I want to thank Hal for all of his work and it's been a great pleasure. I think we first met at least 20 years ago and it's been a great pleasure. So I've been able to work closely with Hal and my wife Shou-Ching throughout this. And they're both magnificent scientists.
I was a scientist myself. My thesis advisor was a Nobel Laureate in physics. I worked with seven Nobel Laureates, so I know what very good scientists are. And it was a, it's always been a pleasure to work with them and I think great scientists are very rare, so we talked about how difficult it was to get funding.
Most scientists, they'd rather, if you think of the old joke about the drunk who searches for his keys under the streetlight, even though he lost them in the dark. And so if you think of the light as money, most people would rather, search where the money is raining down on them, than search where the scientific keys are.
And Hal and Shou-Ching are two people who search in the dark for the scientific keys. And we'll forego the rain of money. And that I think is very special. And it's been a privilege to me to able to know them and work with them.
Dr. Hal Dvorak: I would just add quickly that Shou-Ching and Paul are honest. They are fantastic people. They have enormous integrity and you can trust their work. And one question that sometimes comes up is. Why aren't more people pursuing this target? And I guess it would be like asking me why I didn't invest in Nvidia two years ago.
Callie Mellana: Perfect close. So thank you, everyone for joining us today. Thank you Paul, Hal, and Harvey, and I hope everyone has a great day.