At the MedInvest 2024 October Meeting, Angiex CEO and founder Dr. Paul Jaminet provided an in-depth look at AGX101, the company’s pioneering TM4SF1-directed antibody-drug conjugate (ADC) therapy. The presentation showcased AGX101’s innovative dual mechanism of action: targeting tumor vasculature to cut off blood supply while directly killing cancer cells.
Dr. Jaminet highlighted preclinical success, noting, “We’ve never found a cancer we can’t regress, and there’s never been an adverse effect at efficacious doses.” AGX101’s safety and efficacy profile, including its unique ability to activate immune responses against tumors, positions it as a transformative therapy in oncology.
Key points from the presentation included:
- AGX101’s robust therapeutic margin, with no overlap in toxicities typical of other oncology drugs.
- The potential to enhance checkpoint inhibitor efficacy, increasing response rates from 10-20% to 70-80% in preclinical models.
- Applications beyond oncology, including angiogenic eye diseases and vascular inflammation.
The meeting provided an opportunity for Dr. Jaminet to discuss Angiex’s progress in clinical trials and engage potential investors. His compelling narrative emphasized not only the science but also the human impact of Angiex’s work, driven by a deeply personal mission to make life more fair for patients battling cancer.
Presentation transcript
Angiex is an oncology antibody-drug conjugate company. We're pioneering a novel approach. We attack the tumor vasculature, killing the tumor vascular, regressing the tumor that way. That gives us three mechanisms of action against cancer.
So first of all, killing the tumor blood vessels leads to the death of all the cells dependent upon them. So that shrinks the cancer. Vascular injury activates immune surveillance. So the immune system always surveys a fresh wound with an immunologically warm profile. And so we get to activate immunity against the cancer.
And then it turns out that tumor cells actually use the same biological pathway to invade and metastasize the endothelial cells used to invade hypoxic tissue in order to expand its blood supply. And so we have an opportunity to kill invasive and metastatic tumor cells as well.
So preclinically we've gotten robust efficacy. We've never found a cancer that we don't regress, and there's never an adverse effect at the efficacious doses.
By some measures of therapeutic margin we have the best-performing oncology drug ever. We're in the clinic in phase one, early clinical data. So far, there's been no drug-related adverse and a stable disease in our first scan. We have a very good profile in terms of commercial potential.
Our toxicities don't overlap with other oncology drugs, but our efficacy is additive, and that makes it very easy for oncologists to prescribe it either in combination or in series with the drug that has been toxic.
And the investment case is very strong. Great opportunity, we have a great team. I'm supported by some great people. I myself am a scientist entrepreneur, originally an astrophysicist. Then a founder of four companies. Successful and author of a bestselling book.
I'm supported on the executive side of the company by Ian Dukes, who formerly led BD at Amgen and Merck and then became a venture partner at OrbiMed, where he is been CEO or chairman of a number of companies.
Our Chief Medical Officer, Glen Weiss, led Phase I oncology research at one of the Harvard hospitals and then moved to industry and has CMO experience.
Our CMC leaders have led the top ADC companies on the East and West Coast. Between them, they have six approved ADCs and 70 billion dollars of company acquisitions.
Our scientific founders: top people in the field of angiogenesis. Hal Dvorak discovered VEGF, vascular endothelial growth factor, which was the basis for 100 billion of drug sales. And my wife, Shou-Ching, discovered the biology I'm going to describe.
And so the company came about when I promised her that if she discovered a way to cure cancer, I'd start a company. Make it real. And so she did, so I had to follow up for her.
The three hallmarks of cancer that we address angiogenesis, a very fundamental hallmark of cancer, which turns cancers dangerous. Everyone by age 50 has hundreds of microtumors the size of a pin where the tumor cells proliferate freely. But a tumor can't grow because it can't grow its blood supply.
The initiation of angiogenesis is what makes cancer a disease and potentially harmful. We have the potential, by obliterating the angiogenic vessels, to reduce every tumor to that pin-head size, which is harmless. In addition, as I mentioned, when we injure the tumor vasculature, we activate immunity. I'll speak more about that in a moment. And also the tumor cells invade and metastasize with the same biological mechanism.
Now, on the safety side we have the reason we have the potential for great safety is primarily that we have great tumor homing. And the reason for that is that TM4SF1, the target of our antibody, is very important in embryonic development.
And it's very important in tumors but it is basically not expressed in adults, in healthy adults. And in the normal tissue you can see on the left. Resections from the liver of a liver cancer patient by a transplant. TM4SF1 very strongly expressed in the tumor cells, in the tumor vascular endothelial cells. But in normal, not expressed at all except in the endothelial cells, and they're at very low levels. 120th level in the tumor.
And so what that means is we have great tumor homing. So on the right is clinical radio imaging data. On the far right, I've given you a PET imaging scan using Perceptin or Tristuzumab, which is the antibody for the most successful existing ADCs.
And you can see the tumors really don't stand out. On the left of that panel is clinical radio imaging with a TM4SF1-directed antibody done by Bristol Myers Squibb in the 1990s. And you can see the tumor really jumps out. And that background there and none of their organs is all background that we won't have in our drug. It's the result of their using iodinated E thiol and iodine readily falls off the antibody.
So we have a much more stable drug. With us, the tumor would really dramatically stand out. There's only been one prior TM4SF1-directed ADC. It was made by Pfizer. And it was not taken to the clinic. We improved the therapeutic margin of our drug over theirs by tenfold.
We made the drug both more potent and safer. We tripled the MTD in both monkeys and mice. And we found a number of improvements that are non-obvious and specific to TM4SF1-directed drugs and they've been able to give us a strong patent portfolio.
Just to illustrate how the vascular mechanism works, I'm showing two models here. In the middle is a tumor model and on the left and right are models that have tumor-like vessels, but no tumor cells. So that's generated by injecting an adenovirus that expresses VEGF into mouse ears. And these show the effects of the drug at successfully escalating doses.
So at low doses of our drug we kill some of the endothelial cells in the vessels in the angiogenic vessels. We don't harm normal vessels. That vascular injury has the effect of depriving tissue of nutrients and oxygen. So in the tumor, it can't grow for a while. And it also activates immunity. So the immune system, when it sees, injured vasculature goes in and investigates, looks for germs, anything foreign to regress.
As we go to higher doses, we start obliterating vessels, and you can see that among the vessels we can destroy are the feeding arteries, draining veins to a tumor. So you can think of that as shutting off the water supply to a house with the main valve. We shut off nutrients and oxygen to the tumor that leads to necrosis in the middle of the tumor some survival around the edges of the tumor but significant tumor shrinkage. And then as we go to very high doses, we can completely obliterate tumor blood vessels and all the cells and then upon them die.
It's a chemical surgery; without ever breaking the skin of the patient the tumor goes away. That's not necessarily the optimal way to treat a cancer patient, so you probably want to regress the tumor a little more gradually, give the patient some time to heal between doses.
But it does mean that we have no shortage of efficacy.
And then the immune activation, how does that work? There's a lot of parallels between the tumor-healing process and the wound-healing process. It's been found in cancers that there are basically two immune profiles that you commonly see: an immunologically worn profile with cytotoxic T cells, antigen presenting cells and that profile, those tumors are responsive to checkpoint inhibitors, but only about 12 percent of patients have that profile; eighty eight percent have an immune suppressed profile that does not respond to checkpoint inhibitors.
And those profiles also occur in the wound-healing process. So when you have a fresh wound, you get that immunologically warm profile where the immune system is looking for germs or anything foreign.
And then as the wound-healing process matures, after the vasculature is healed, the immune profile shifts to the immunologically cold profile, where the immune system actually helps the normal cells proliferate the complete tissue here.
And so this paper hypothesized if you could injure the tumor vasculature, you could switch the immune profile back to one and make the, make tumors responsive to checkpoint inhibitors.
We have the drug to injure the vasculature. So we tested that hypothesis and indeed we can increase the response rate to checkpoint inhibitors from 10 to 20% to 70 to 80%. Big opportunity to increase what is already a $45 billion-a-year market.
And then I mentioned tumor cells, very commonly expressive because it seems to be required for invasion and metastasis. And we can go after the invasive and metastatic tumor cells and that means that we can, through tumor cell killing, have an impact on essentially every late stage cancer.
And so this shows a number of models where all of the killing is through tumor cell killing. There's no vascular mechanism, here we have human tumors in mice and our antibodies do not cross react, so the human drug is only attacking the tumor cells. And you can see we get excellent results. And we tested several dozen models and the drug always works.
And on the safety side because of that great tumor homing, we can find a broad range of doses where there's no significant impact on normal vessels.
So Paracelsus's rule else is here: "The dose makes the poison."
A low dose of a toxin is not poisonous can be harmless, and that's where we aim to be in regard to the normal vasculature. But even while we're not harming the normal vasculature, we can be at lethal do levels in the tumour.
And on the left, you see here by exposure, 40 milligram per kilogram is a no observed adverse effect level in monkeys, and this lower exposure is effective at regressing cancers in mice. And the tox profile is also, from a clinical perspective, dose dependent, so the patients will heal if you give them enough time.
Where are we in the clinic? We've dosed safely at the lowest two dose levels. We're now dosing at a dose level where we think we'll see efficacy.
The commercial potential is very high because we do not have any tox in the places that oncology drugs normally have tox.
So no hematopoietic tox, no digestive tract tox, no liver tox, no neurological tox, no lung or ophthalmologic tox. So, and our efficacy is additive in the tumor. So a prior drug that had a similar profile, but with much less efficacy: this is Avastin. And Avastin sold over 91 million, despite very little efficacy.
And then we also activate immunity against the tumor. So I mentioned, in combination with checkpoint inhibitors, we get efficacy on the first or second dose in 70 to 80% of mice. We'll have a couple of combination arms, starting with pembro and ipi or lung. But even as a monotherapy with repetitive dosing we should have a significant immune-mediated efficacy.
We'll learn about that and in comparison to the checkpoint inhibitors, we may have negligible immune-related adverse events because we don't lower the threshold of autoimmune protections. We just focus the attention of the immune system on the tumor and help it ignore the rest of the body.
So just a final note. The incidence of cancer has risen recently. There's a high unmet need and lot of people are dying. One who did die was my mother. She was diagnosed with cancer while she was pregnant with me. And she died when I was 10. And when I was young, whenever I would complain that something was unfair, she would have no sympathy for me. She would just say, oh, life is unfair. And quite sternly. And I didn't realize how unfair it was to her until after she had died.
And now we have an opportunity to make life more fair for a lot of people.