CEO of IN8Bio. IN8Bio is a clinical-stage biotechnology company developing genetically modified gamma delta T cell therapies for cancer treatment. The company has three clinical candidates. The drug that the company is focused now is INB-100, that is being evaluated as a therapy for leukemia. The firm also has a second drug, INB-200, targeting recurrent GBM patients, that has also shown positive data so far in phase I clinical trial. Last week, management executed a corporate strategy to focus on INB-100 at this time. So to talk about the company's strategy for the rest of 2024 and beyond, I welcome Will to this fireside chat. Will, glad to see you again, and I appreciate you accepting to talk to our audience today.
So for starters, Will, can you help us understand what gamma delta T cells are, and what role do they really play in the immune system? And what made you decide to do this as a therapeutic cell therapy?
Great. Thanks, RK. Thanks for having me, and good to see everybody here in the room. As RK and I have actually known each other for over twenty years, so I spent many years on the sell side and as well on the buy side. And quite frankly, when we started the company, I was actually on the buy side, trying to figure out how do you go from CD19 CARs, which are autologous, meaning the products come from the patients themselves, to potentially off-the-shelf cell therapies for solid tumor cancers. I was an early investor in Fate, looking at allo therapies, but really, almost a decade ago, I recognized that the cell therapies in development came with limitations, whether they were alpha beta T cells, which have been plagued with toxicities, cytokine release syndrome, so patients have to be in the ICU.
They're dosed with tocilizumab. We've seen ICANS or neurotoxicities, sometimes which results in patient deaths, and then when we got to the NK cells, they're purely innate, meaning they're purely of the immediate immune response, and they have no persistence. The first clinical data that came out across all the NK cells, let's be frank, if not very promising. The lack of persistence prevents surveillance to prevent any residual leukemia or cancer cells to come back, and that's the advantage of the gamma delta T cell. They are a specific subset of the white blood cells. If you will, think of it as an ancient immune cell before we had specialization, and so it can do many of the features across multiple immune cell types. I like to think of them as the special operations forces of our immune cells.
Not only can they kill directly, but they also communicate with all the different aspects of the immune system, so we can call in the recruits and the other immune cells when we need to.
You know, you spoke a little bit about CAR Ts, but gamma delta T cells are thought to be different, you know, from either NK cells or TCRs or CARs. What sort of advantages can you highlight, especially in terms of efficacy, but also on the safety and manufacturing side of things?
So gamma delta T cells have unique properties. So you talked about NK cells and CARs and whatnot. So a natural killer cell, each white blood cell, for the most part, has a different function in its biology. The natural killer cell is designed to distinguish between what's you and what's not you. If it's not you, so it has signals that says, "These don't match. These are not my cells," the NK cell's job is to kill them immediately. On the alpha beta T cell side, those cells are great at identifying pathogens, things that you've been infected before, so that I have memory.
The very challenge, especially in oncology, is that your cancer cell is still your own cell, so I need to be able to distinguish between what's healthy and what's transformed and is cancerous, and that's the job that gamma delta T cells do best. And so when you look at the CD19 CARs, they don't distinguish between a healthy B cell or a cancerous B cell. They wipe out the entire compartment of B cells. But when it comes to other cancers, organ cancers, lung cancer, liver cancer, brain cancer, breast cancer, ovarian cancer, in many cases, we still need those organs, and so we have to be able to discriminate between the two, and that's what the gamma delta T cell does best. It discriminates between what's yours, what's not, and what's healthy and what's dangerous.
It keeps the healthy and safe cells and kills the dangerous cells without driving toxicities. To date, we have delivered donor-derived cells. We have not seen significant increases in graft-versus-host disease, or GVHD. We've seen no cytokine release syndrome and no neurotoxicity, and we've seen no off-tumor effects, and so that's ultimately the advantage and why we think the opportunity for gamma-delta T cells are so exciting. The challenge is the market doesn't necessarily understand them. They saw originally, the alpha beta T cells comprised about 60%-70% of all the white blood cells. The gamma-delta T cells are only one to five%. So people think, "Oh, the alpha beta T cells must be the important ones 'cause there are so many of them." Well, that's not how I think of it.
When you think of a military, the most powerful person on the battlefield is not your infantry soldier, who's there to, unfortunately, in many cases, die. It's the guy with the radio who can call in whatever I want, right? When my team's pinned down, "Hey, I need an A-10, or I need an AC-130 gunship here, now," and this is what you target... and that's what the gamma delta T cell can do. You don't need a lot of them, because they can communicate with all the different parts of the immune system to recruit the entirety of the immune response.
The program that you're focusing now on, which is INB-100, so you've been testing it in leukemia patients, especially to reduce relapse.
Mm-hmm.
... in these patients. So before you talk to us a little bit about the data that you have achieved so far with this molecule, what's the salient feature of INB-100?
So INB-100 is taking donor-derived or allogeneic cells and giving it to a patient. The advantage of donor-derived cells is it comes from a healthy individual. Tomorrow's my birthday.
Happy birthday!
... I'm getting closer and closer to 50. Unfortunately, the 22-year-olds' immune cells are stronger than everybody's in this room, I guarantee it, right? And so it allows you to take cells from a healthy, younger individual who's potentially more potent, higher cytotoxicity, and has greater efficacy in killing. We designed our trials the way that we did because we were the first to take a donor-derived cell, to give it a gamma delta T cell, to give it to someone. And the FDA said, "Great, you have to prove to us in the most risky population, that you're not going to cause graft versus host disease." So that means it was in a patient population who was prepped for transplant, who has their entire bone marrow ablated, who has no natural killer cells remaining, 'cause that's the greatest risk.
We designed a study in leukemia patients who are undergoing transplantation, to give a bolus of these gamma delta T cells to try to prevent relapse. The original protocol we designed was actually created by a gentleman named Dr. Leo Luznik at Johns Hopkins, and his data demonstrated that 50% of these patients would relapse at one year. We have demonstrated so far, 100% of our patients have remained in remission through that year. Today, after almost 19 months of follow-up, we have enrolled eight AML patients. Every single AML patient remains in remission to date. The reason is the gamma delta T cells. We have demonstrated that we can create persistence, in vivo expansion or proliferation, out 365 days. The gamma delta T cells are there to hunt out residual leukemic cells.
The only path to a cure for leukemic patients is to transplant them. It's a disease of the bone marrow. The bone marrow is dysfunctional. It produces leukemic cells, and so the only way to a cure is to replace that bone marrow. But invariably, patients have residual leukemic cells. They come back. If half of the patients are relapsing, it means that almost all of them have residual leukemic cells. So what we did is we infused these gamma delta T cells to act as sentries. They are there to act as surveillance. As long as we can keep pressure on the leukemic cells, when one pops up, it's killed. Another pops up, it's killed. As long as we keep that pressure long-term, the patient should remain in remission.
Today, we have patients over four years out with complex AML, who should have relapsed and, in fact, died in the first year, who remain in remission. We have a patient lost to follow-up. After three and a half years, she said, "I'm done with this. I'm fine. I'm actually moving to one of the Rocky Mountain states, and I'm going skiing," and that's the ultimate goal of cancer treatment, what we call Cancer Zero, the safe elimination of all of the cancer cells and the continued surveillance to prevent relapse, so that patients can be out walking around, continuing their lives, one, two, three years, and even beyond.
So, in terms of this study, when would we... Or what is the next catalyst, or when would we see the next data set?
So we do expect to present, continue to present updates. We've been pretty regular in presenting updates. I think the next update will likely be around ASH. We had a restructuring last week. We unfortunately reduced our headcount by over 50%. We indicated to the street that we are focusing on this particular AML trial. Look, we got feedback. We did a Type B meeting from the FDA this summer, and the FDA gave us specific guidance on what the registrational path will look like, and so we know what the registrational path will look like. Unfortunately, in the current market environment, if you do well as a biotech and you continue to progress, that invariably means that your cash expenses are going to explode, right?
A registrational randomized control study costs money, and so feedback we got from investors was, "Look, I still have some concerns." And I just flat out asked. I, I've been in the industry for a long time, I asked a bunch of people, "Okay, so if you have concerns, what kind of data will drive the interest and the risk reduction required to fund," excuse me, "a registrational trial?" And so, look, our first ten patients that we treated, we had two eventually relapse. All 100% stayed in remission beyond one year. We still have eight in remission. And the concern is, as many investors, "Well, it's a small N." It's like, "Great, so what number will drive me to interest?" "Well, maybe 20-25." Okay, so we announced we're going to expand the study to 20-25.
Well, you don't have a control arm. Historically, people didn't run control arms in randomized-
Yes.
... controlled phase I studies in oncology. They're typically supposed to be safety studies, and so I said, we, we asked people, "Well, what if I have retrospective matched controls, right?" I said that. If you go and look at the press release we wrote last week, we actually said, "IN8Bio and our investigators believe the patients in our trial who received INB-100 outperform those who get allo transplant without receiving the therapeutic." We know the data, right? We're confident the data sits within historical control, historical data, which is about 50% will relapse at one year, and about 40% will die at one year. We sat at 100%, and so our goal is to get to data that de-risks it to such point that people will be comfortable to fund the registrational trial.
Now, anytime I was a bystander, I can pull any number I want, it'll look fantastic, and people will come back and tell me, "Well, it's retrospective. How do I not know you weren't cherry-picking?" You should look at our data. We weren't cherry-picking. The median age was 68. We had multiple lines of therapy. One patient failed seven prior lines of therapy. We had, including CAR T, we had patients who had, you know, deletion of chromosome 7, trisomy of chromosome 8, concurrent IDH, concurrent FLT3 inhibitors, who got no maintenance therapy. These patients generally have a 80%-90% relapse at one year, and yet remain. That, those two patients, three and a half and four years respectively in remission. You're doing something.
And so we thought, "Great, what we'll do is we will prospectively try to enroll patients who undergo standard of care, and then prove it to people." And so that's our goal. We'll have data at ASH. We'll present additional data next year. We will present the retrospective meta-analysis of matched controls. We're also looking at CIBMTR data, and in the meantime, we're looking to expand the patient population and enroll controlled data.
Right.
I believe our drug is active. If you ask our investigator, we had a conference call when we presented the data at EHA. People asked, "Don't you expect that you could get 10 patients who all remain in remission?" They said, "Yes, but not 10 in a row.
So, last week, at the same time, you know, you also paused the development of INB-200, you know, the drug which was being developed for treatment for GBM-
Yep.
... even though you were, you had success with that drug in the clinic, so can you help us understand the reasoning behind that decision?
Look, it is a sad time for biotech, in my opinion. We are more than three years out in this downturn, and it is an incredibly difficult time to raise additional capital, especially for innovation and anything that's new. Look, we know the history of glioblastoma. We went into glioblastoma because of the biology, and it was likely the first indication that anybody would see success for solid tumor cell therapy. It allowed us to maximize the concentration of cells in a box. That's the advantage of brain tumors. Your head is a box. I can put my soldiers, our cells, onto my battlefield, and they're not somewhere else, right? And so that's why we went into brain, but the investor feedback was, "I don't care," right? "It doesn't matter how long the patients are out. Right now, in this market environment, I don't care." We started...
We've actually had comments, "It's uninvestable." We started a phase II trial. A phase II randomized control trial is a significant burn on your cash position, so given the investor feedback was, it didn't matter what data we produced, and I think the data that we have produced to date is good. We at ASCO announced we have a patient over 38 months in remission with a brain tumor, went back to work. We have patients who have what they call MGMT unmethylated disease. That means they have a cancer type that is unresponsive to chemotherapy, does not respond. We those patients typically relapse between four and five months.
At ASCO, we had patients who had partial resections, which means the tumor was located in a position in the brain in which you could not operate, and yet, patients are out nine and a half, twelve months, remaining in remission, and yet, from the investor's standpoint, it didn't matter. It's a difficult decision, but we made the decision to suspend that trial, and we'll continue to follow up the phase I trial on INB-200 to look at the tails. Hopefully, as the tails get longer, because we think we're seeing a dose response now with patients out, as far as we've seen, that we can drive interest either in a strategic partnership or funding from an investor base one day.
You kind of took the lead on the next question. In terms of INB-200, not only INB-200, but you also have other assets, like non-signaling CAR and other preclinical candidates, so what's the strategy there, and do you think there is some appetite for your other molecules?
Yeah. So we are experts in gamma-delta T cells. That's what we focus on. We have CAR T constructs that we have demonstrated can kill the tumor cell while leaving the healthy tissue alone. We have what they call iPSC, or induced pluripotent stem cell-derived, gamma deltas. We are one of the few that have been able to create specific immune cells from iPSCs, and quite frankly, we even have an engager created by accident. We were trying to create a specific CAR, and it precipitated. It's in solution. That's early preclinical, so it's not very meaningful right now, but our goal is to take our preclinical assets and try to partner it. We remain in some ongoing discussions. I will say it's been an incredibly difficult environment in pharma as well. You've seen layoffs. You saw Genentech kill their immunology program.
You saw last week Astellas kill a cell and gene therapy facility down in San Francisco. Takeda laid off 250. J&J last year had a, you know, a change in their head of R&D, and so you've seen a lot of changes across pharma, not just biotech, but difficulties in pharma, too. But we will continue to execute. What we did last week, we laid off more than, unfortunately, 50% of our overall team, or about 50% of our overall team. We focused on maintaining know-how and the skills to continue to execute both our manufacturing, which we do all in-house, as well as many of these preclinical projects that don't cost as much for us to push forward.
So finally, what sort of a cash position do you have now, and you know, what sort of a runway can you get from that?
Yeah, so we haven't given a public update. The last update we gave was at the end of the second quarter. We, at that point, said we had just over CAD 10 million in cash into the beginning of next year, and we'll look to provide an update, I guess, around the end of the third quarter finances. And we continue to execute and have discussions with potential investors.
Thanks, Will, and good luck.
Thank you.