Developing Novel Cancer Drugs On A Budget With Iterion Therapeutics' Rahul Aras, Ph.D.

On this week's episode of the Business of Biotech we speak with Rahul Aras, Ph.D., President and CEO at Iterion Therapeutics, about capital efficient drug development in oncology and progressing a novel therapeutic with relatively small funding amounts. Iterion is a clinical stage company developing cancer therapeutics targeting the Wnt/β-catenin pathway, a known signaling target in oncology, but one that has confounded drug development efforts for decades. Rahul talks about his path from academia to company building and early work in gene therapy, Iterion's partnership strategy, and operating a biotech in the Houston, Texas clinical hub. 

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Transcript

Meet Rahul Aras, Ph.D. And Iterion

Ben Comer 0:04

Welcome back to the Business of Biotech. I'm your host, Ben Comer, Chief Editor at Life Science Leader, and today I'm speaking with Rahul Aras, Ph.D., president and CEO at Iterion Therapeutics, a clinical stage company developing cancer therapeutics, targeting the Wnt/β-catenin pathway, a known signaling target in oncology, but one that has confounded drug development efforts for decades. Rahul is a scientist by training and has previous experience building and leading a venture-backed drug company and doing it in a very capital-efficient way. Iterion is progressing its lead candidate through smaller overall investment amounts, a topic that we'll dig into during this episode. We'll also talk about Iterion's partnership strategy, the combination potential for its lead drug candidate, and what the challenges and opportunities are for launching and growing a therapeutics company outside of the big biotech hubs like Boston or San Francisco. Rahul, thank you so much for being here.

Rahul Aras, Ph.D. 1:10

Thanks so much, Ben. I'm looking forward to it.

From Bench Science To Dealmaking

Ben Comer 1:12

Yeah, me too. I wanted to start off with your background. I mentioned in the introduction that you were a scientist by training. You got your Ph.D. in biomedical research from NYU. What did you do next? Where'd you go from there?

Rahul Aras, Ph.D. 1:27

Yeah, no, I appreciate it. So yeah, PhD from NYU. We studied uh microbial pathogenesis and its relationship to gastric cancer. Uh moved from science bench quickly into the business development realm, went to Cold Spring Harbor Lab, where we uh I was at a very exciting time there when there was a lot of RNAI research that was just coming out. Actually, Alnylam was being founded and you know, siRNA was being looked at as a novel modality with a lot of the IP having been generated from some of the labs at Cold Spring Harbor Lab. So that gave me some exposure to doing BD deals and engaging in these startup discussions that I found quite interesting. Uh went from there to the Cleveland Clinic, uh, worked in the innovations group, and that's where I started my first company. So uh out of Cleveland Clinic, co-founded a company called Juventus Therapeutics. It was in the cardiovascular regenerative medicine space, uh, developing novel gene therapies to really help in the areas of heart failure and peripheral artery disease. Uh, and that's what got me started. So, you know, that company started with a Lancet paper, quite frankly, uh, very much a concept. And we took that all the way from concept through phase two clinical studies. Uh, and it really, you know, it gave me the bug to work in this startup early stage, venture-backed private company setting that I like so much.

Ben Comer 2:43

Yeah, well, I want to back up just a little bit. You must have gotten a bug before that, because after what I'm sure was a fairly difficult uh PhD program at NYU, you you jumped straight into business development. How did you, or I guess what made you decide that you wanted to be, you know, active in the industry and work in in life sciences and developing drugs?

Spinning Out Juventus Therapeutics

Rahul Aras, Ph.D. 3:07

Yeah, no, I appreciate the question, Ben. It's um it's interesting. When I started my PhD, I had already worked for a couple of years in a laboratory at Mass General. Um, so I got kind of a sense of what it meant to be a bench scientist. And I just I always loved science, found research fascinating. Uh, but ultimately I was always interested in how do you turn that into a product? And that was something that was innate from you know my early years. So I actually walked into my PhD and my thesis advisor, a fantastic guy by the name of Martin Blazer, who I ought to be the um chairman of medicine at NYU, uh, and told him, listen, I'm super excited to do my PhD. I'm fascinated by science, but I ultimately want to build that into something where it cross-sects, where it's a cross-section between business, a law, and I can bring the two fields together. And that's what got me interested. I actually, when I started out, I thought I was going to be a lawyer, um, went through the process of taking my LSAT, started applying a law school, then started interviewing for a couple of jobs with patent prosecution worms and decided, you know, that just wasn't the perfect fit for me, but was really, really interested in the concept of licensing and business development. And that's what took me into Colston Harbor Lab.

Ben Comer 4:23

And then you mentioned you went to uh Cleveland Clinic. You're part of Cleveland Clinic Innovations, I believe. Uh is that right? Um what yeah, what was the what was that job? Would you mind just describing it?

Rahul Aras, Ph.D. 4:34

Yeah, it was a pretty exciting time there. So Cleveland Clinic has a pretty forward-thinking new ventures and innovations group. Um, and you know, if you think of the Cleveland Clinic, you typically think of really high-level cardiovascular, um, excellent device innovation, um, a little less notable and known for some of their biotech work. However, they have fantastic research labs there, and they do have new technologies coming out, not only cardiovascular, but in cancer and autoimmune and other areas. Uh, so it was an opportunity. They were building their team in the life sciences space. And it was an opportunity for me to go in there and really get in at kind of a ground level uh and work on some of the new innovations that were coming out of there. And we did some exciting deals. Uh, I started to get more exposure at that point to the creation of new companies and spinning technologies out of academia in an effort to bring them into new ventures and secure funding. And that's what really got me attracted to the um opportunity at Juventus.

Ben Comer 5:35

Okay, yeah, it sounds like a kind of natural progression. And I uh when you're talking about Cleveland Clinic, I think during this time period, I remember when I first started covering the drug industry, Steve Nissan, you know, was was the big name in cardiovascular, uh, who had a somewhat adversarial at times uh relationship uh with the industry, which we don't have uh uh time to completely go into. But you were in this role, you know, seeing these, you know, incredible discoveries and developments and and and companies starting to roll out. And so I guess you thought, well, you know, maybe I could take a shot at this. And that maybe just describe uh Rahul, if you would, how uh Juventus therapeutics uh came into being.

Rahul Aras, Ph.D. 6:19

Yeah, no, it's uh it's a good question. And yeah, the Cleveland Clinic, you know, it's got it's um it's got a high number of thought leaders and guys like Dr. Nissan, Dr. Topel, others. Um, the people that people listen to, right? So they they were definitely out there with their opinions and giving some perspective on what they thought of novel developments in the field. So Juventus specifically, um, it was a technology that was being developed out of a lab of a cardiovascular clinician named Mark Penn. And it was a very unique opportunity in the regenerative medicine space. So back, you know, in the early 2000s, people were really interested in understanding if cell therapy could help in areas like stroke or heart disease. Um and he had identified a novel factor that was able to activate an endogenous repair process that was stem cell-based. So if you turned on this molecule called SDF-1 in the heart, um, you had a potential to get the body to repair itself. And, you know, one of the complexities at that point was the delivery of cells itself. And so what we came forward with was a potential gene therapy that was delivered to the injured organ. And by delivering that gene therapy, which expresses SDF-1, you could basically trick the body into thinking it was time to repair itself. And it would turn on its own stem cell-based repair processes. Um, and we tried that both in heart failure and peripheral artery disease, some very early encouraging results. Um, unfortunately, as we got into phase two, studies got larger, we were not able to replicate some of those challenges. And I think what the field is seeing is that regenerative medicine in that tissue repair setting is quite complex, especially in a chronic disease setting like stroke or heart failure, some of the places we were looking at.

Lessons From Early Gene Therapy

Ben Comer 8:06

Yeah, and that was early days for gene therapy. I think that was a yeah.

Rahul Aras, Ph.D. 8:10

Yeah, I used to walk into it. It was interesting because uh, you know, it was the first company we started, and we started with investor meetings sometime, you know, the 2007-2008 window. And I remember walking into investors and we'd be like, we have a heart failure therapy, and they'd be like, We're not interested. And it's but it's gene therapy, we're even less interested, right? And we deliver it by a device, but so there was a lot of novelty in both the modality and approach we were taking. Uh, but ultimately it was, you know, it was a very interesting biology and it was something that we were able to get through some early clinical studies, and I learned a lot through that process.

Ben Comer 8:44

Yeah, and you often can't predict how um development candidates are going to perform in late-stage trials. That's the whole risk of this industry and you know, the the key challenge. Um, but you know, as we've heard many times on this podcast, uh failures of that kind can be some of the best learning experiences. And I wonder what you might say about uh what you learned and what was, I think, your your first uh your first time leading a company.

Enter Iterion And A New Target

Rahul Aras, Ph.D. 9:13

Yeah, um, it's a great question. And you're absolutely right. Like in this field, you have to be okay with missing the mark, right? And you can miss the mark frankly for several different reasons. Um drug development is incredibly hard. The indications that we're trying to tackle are challenging for a reason. Um, and the goal is to make an impact, right? Um, and so you need a lot of things to come together really nicely to be able to do that. Uh, what I learned from the Juventus experience, several things that I learned. I mean, it really was going after heart failure, one of the hardest indications for clinical development just out there, right? Absolutely. Um, then on top of that, there was a novelty of using a non-viral gene therapy with a novel target of SDF one, right? And then at that time, and still, you know, the concept of delivering it to a biologic to the heart with a device was another variable. So one of the things, frankly, in coming into Iterion, I thought very hard about was you have to minimize some of those variables so you focus on individual challenges of drug development opportunities, right? And there was just too many unknowns in that question. I think that for understandable reasons is scary both to investors as well as partners. Um, and then I think, you know, the other opportunity is making sure that in your development plan, you have near-term value inflection points or gates that you can see, am I progressing in the right direction? You know, one of the challenges with that strategy is in the cardiovascular space, we don't have good biomarkers, right? And so one of the biggest issues was hey, this might work, but you're gonna need a lot of money and a really big clinical study to demonstrate that. That's true in areas like Alzheimer's and other places, right? Where you just don't have all the tools other than a large clinical study. And that could also be scary and difficult for investors and partners to get their arms around. So I tried to take some of those things into consideration as I move beyond Juventus into other ventures and auto arteria.

Ben Comer 11:23

Well, yeah, I mean, you clearly have a tolerance for risk. You're willing to clearly willing to take some big swings, but it sounds like what you're describing is uh a way to manage risk, you know, to make it not overwhelming, you know, when when it very well could be by kind of separating things out, accomplishing your, you know, your kind of day-to-day clinical objectives is what it sounds like you're saying. Um, and I I want to carry this into Iterion, um, but maybe we could start with just the the circumstances that landed you there.

Tegavivint’s Early Clinical Signals

Rahul Aras, Ph.D. 11:57

Yeah, so um Iterion was very unique opportunity for me. So I was um I was leaving Juventus, I was doing some work with a number of different early stage companies. Uh I knew the space that I liked to be in was in a translation translational setting, um, going after novel targets, you know, novel opportunities of biologies. Um and I got a call from Sante Ventures, which was looking to do a the first institutional seed round into Iteria. Um, and you know, at the time I had known the team, Sante Ventures is an excellent investment group, um, really fantastic um partnership there. So I was excited the opportunity to work with them. And then as I started to look more closely into the technology and the biology of what they were doing, it really was unique, right? So winter beta catenin is a pathway that's been known in oncology for 40 years. Uh, it has been targeted by almost every major drug company, and they have all failed for basically toxicity, typically in the form of some kind of GI issues or bone fractures. And so frankly, when I got the first call from them, I kind of was like, listen, there's no such thing as a winter beta cutina inhibitor. These things don't really work. Um, but as they went through the novelty of the target, which is a protein called Tibble 1, and the biology, it really did present itself as an opportunity to be able to potentially drug that pathway and do it in a manner that did not elicit the toxicities that others did. Um, and it was at a stage, you know, it was starting to enter clinical studies that some of the early data, you know, early risk was removed from the program and we really could start addressing some of those questions head on. So I found that to be very attractive. It was a very focused program around a drug called Tagavivant and demonstrating if we could actually drug the winter beta catenin pathway in a way that no one else has before.

Ben Comer 13:52

Right. Uh Tagavivent is your um your lead uh candidate. Um maybe wouldn't would you mind just giving us a kind of overview of the of the status of where that drug is uh uh clinically and and maybe a sense of um what your clinical strategy is going forward?

Rahul Aras, Ph.D. 14:10

Yeah, so we're very exciting stage right now. So Tagavivent, it's a small molecule inhibitor of protein called TIMBO1, which is the downstream target in the wind beta cutina pathway. Um, we have, you know, we had done some early work in a tumor type called Desmoid tumors, there are these rare non-metastasizing, highly fibrotic sarcomas, um, you know, occurring otherwise young, healthy individuals, but really are debilitating from a quality of life perspective, very difficult to live with, a lot of pain. We saw some very nice clinical responses in that setting. Um, but as I came in, we started to migrate into more complex tumor settings, uh, specifically hepatocellular carcinoma. So liver cancer, huge unmet clinical need, you know, third leading cause of death worldwide. Uh, and frankly, not a lot out there to help these patients. What's interesting is about half of the patients who have um hepatoulcarcinoma have a winti beta catenin-activating mutation. So it's a large population of patients for which there are no available therapies. We have just finished up phase one of clinical study in patients with advanced HCC. Um, and we are seeing some very nice responses as well as disease control in late-stage patients for which there are no available therapies right now. There's essentially failed everything out there. So, having finished that phase one, seeing this encouraging data, we're now preparing to initiate the phase two there. Um, and I think the other thing that's exciting is this is the first wind beta-catenin inhibitor that has really shown tolerability, clinical responses, and pharmacodynamic activity in a complex tumor type. That's huge when you think about the fact that about a half million cancers are diagnosed annually with some level of wind beta-catenin activation. So it opens up the door for us to go to a number of different cancers. Uh, we just recently started a clinical study in collaboration with Emory School of Medicine in patients, uh pediatric patients with recurrent osteosarcoma. And we're in the process of starting a clinical study in colorectal cancer, uh, in which about 90% of patients actually have a wink-beta-peteen activating mutation. So there's just a ton of opportunity clinically here, now that we've shown that the drug is tolerable and active.

Why Start With Liver Cancer

Ben Comer 16:28

Well, how did you select that initial uh indication? Uh heptocellular uh carcinoma. Um, you said I think 50% of those patients uh versus you know some of the other figures you just gave where it's a larger percentage, 25% of all cancers potentially are um, you know, this this pathway is active. Um, what can you say about uh making the choice for that initial indication? How'd you do that?

Rahul Aras, Ph.D. 16:55

Yeah, it's uh, and it was a very strategic choice of that, because we did a full landscape analysis. And to your point, there are a number of different indications you can go in with a winter beta-cutene inhibitor. Um, a couple of reasons. So HCC presents a very unique biologic opportunity with about 50% of patients having this mutation and knowing that the pathway is a driver in late-stage disease. So it's typically known that it's active in advanced disease and that its activation correlates with tumor progression in late-stage patients, right? So the biology all lined up really nicely. Um, the other opportunity was the clinical white space. So it is challenging for HCC patients because right now in first line, they typically get some immunocology regimen, whether that's the Tezobev, um, derbotremies recently been approved as well. And they do get some benefits from that, right? And what they typically see is anywhere in the ballpark of year and a half survival, no, maybe seven months PFS, 30% response rates. The challenge at the first line is the options drop off dramatically. So what patients are typically presented with at that point are these um pyrosine kinase inhibitors, these you know, pan inhibitors like um levant nib or cavozantinib or seraphanib, right? And the outcomes with those are quite they're modest at best, right? You get a few months of progression-free survival, less than a year of survival itself, and almost non-existent response rate. And after second line, there's nothing. So at that point, physicians are typically cycling through the TKIs or they're looking for clinical styles. Um, and despite there being a high prevalence of patients with these mutations, there is nothing really targeted in the field that's being developed. So we thought it was a unique opportunity clinically to demonstrate tolerability and hopefully monotherapy activity, which we're now showing, in a setting where, if successful, we could move very rapidly and to call it a second-line approval pathway. Either as a monotherapy in combination with PKIs that gives us an opportunity for an accelerated approval on not an enormous registration study, right? And so that was the strategic reason for going to HCC. Now that we're demonstrating that, um, it really does open the door to go into some of these large indications like CRC, where frankly, at that level, you know, most likely you're going to be combining with other therapies. You may be later stage or later lines in those indications, but where there's still huge unmet need.

Capital Efficiency By Design

Ben Comer 19:39

Yeah, that's excellent. And it I think it touches on uh something that I I want to talk to you about, which is capital efficiency for drug development. It sounds like the selection, and correct me if I'm wrong, it sounds like the selection of that indication. Also, there was an economic component to that calculus when you're talking about the size of a registrational study. Um how do you progress a drug candidate, you know, without a hundred, uh, if not hundreds, uh, of millions of dollars? Because that's not that's not your approach. That's not what you're doing.

Rahul Aras, Ph.D. 20:11

Yeah, we have been um we've been very capital efficient in our development, right? So we've gone as a company essentially from concept through human, you know, human total concept in HCC and Desmoid tumors in less than $50 million of equity capital raised. Um, we've done that a couple of different ways. So we've also been the beneficiary of about $26 million in grant funding that's come from the Cancer Prevention Research Institute of Texas. Absolutely fantastic organization, incredibly supportive of Texas oncology companies. Um, and really puts, I mean, that's they put real capital to work, right? We're not talking about $100,000 grants here. We're talking about product development money. Um and then the second component of that is tremendous focus. So every time we're going after an indication or development strategy, we had very clear questions in mind that we're trying to answer, right? And so you'll note that we didn't do the classic basket study where you enroll 150 patients followed by, you know, additional arms that look for signal seeking. We went very intentionally after desmoid first, demonstrated that the drug was active and tolerable, and then went into HCC with an intention, right? And I think doing that has allowed us to there's risk associated with that. I you know, we're acknowledge that there's definitely risk associated with that. But you know, to the extent that you can demonstrate the drug works, you get a lot further on a lot less dollars. So we're now at a point where we're looking to start a study that could enable, you know, a potential registration study after the completion of this, less than $50 million. That's that's pretty much unheard of these days.

Ben Comer 21:59

Yeah. That's very purposeful too. And you've talked about that now opening new doors to potential other indications, uh, potential combination therapy. Um, and so I I assume you it sounds like you've you thought this through ahead of time and have have potentially, you know, at least uh hypothetically established these kind of staggered clinical pathways that can get you from point A to point B to point C to point D and beyond.

Building Monotherapy Then Combos

Rahul Aras, Ph.D. 22:27

Yeah, that's the plan, Ben. Exactly right. And so, you know, ultimately as a small company with a drug, the number one thing you need to show is it's tolerable and it's actually clinically active on its own, right? It's got monotherapy activity. And we felt like there was an opportunity to do that in HCC and we've now done that, right? And um, the type of responses we're seeing in some very heavily treated patients is quite encouraging. And I can tell you, you know, we're in a parent with our physicians where just an interesting fact, when we started this study, nobody was genetically typing their HCC patients because there's no need to, right? Um, as they started to see the trial develop, all of our clinical centers are now pre-screening their patients for winter beta cutene activating mutations. And when they identify those patients, they're proactively calling us, right? And they're saying we have patients, you have slots. So by the time we were midway through the study, we would open a cohort and we would have that thing filled in about 48 hours. So now that we've shown that monotherapy activity, which is so important, it really does open the door to combinations. And that's ultimately where you have to go with any cancer therapy, right? To maximize its potential. Um, and two things are in to our advantage in that situation. First and foremost is we're seeing responses. Um the second is the drug is incredibly well tolerated. Um, so one of the things we hear from our physicians is this is one of the easiest to administer drugs that they've had in their clinic. Um, patients come in once weekly for an infusion and have, frankly, quite good quality of life between those infusions. And that's incredibly important, particularly in patients with compromised liver function, right? And it's also important because what oftentimes kills combinations is toxicity, not just lack of efficacy. So now, you know, we are looking at an opportunity in HCC where we'll go forward and evaluate the drug as a monotherapy, but we are also looking at combinations of tyrosine titase inhibitors, which would be natural. Um, as we think about CRC, you know, it is going to be essential to have good combination regimens for patients with colorectal cancer. And to do that, you need tolerable drugs. So I think we're in a very favorable position as we think about expanding into other indications and particularly into settings where we know certain things work and we may be able to add or you know enhance those responses in those patients.

Ben Comer 24:52

How and I may regret asking you this because uh it'll get over my head very quickly on the science. But uh, you know, you mentioned earlier in our discussion that toxicity was the real roadblock for other companies who are developing therapies to try to target this particular pathway. Can you at maybe at a high level explain how you were able to avoid that toxicity and still target this pathway?

Precision Targeting To Avoid Toxicity

Rahul Aras, Ph.D. 25:17

Yeah, then it's a and it's um a super important evolution in the science around the beta-catenin pathway. Right? So the challenge with the pathway is that the effective protein, the protein that's actually driving the oncology of the cancer-causing activity, it's called beta-catenin. It itself is undruggable, so you can't make typical drugs that typically bind to beta-catenin. So historically, what companies have done is they've gone higher up in the pathway of a receptor ligand level. The challenge there is if you turn off beta catenin that level, it has really important functions in the membrane and the cytoplasm that are necessary for normal cellular function. So you shut down the whole machinery, and not only are you shutting down the oncogenic activity, you're shutting down this normal cellular function activity that's necessary. So there's this next generation of companies, we're one of them, that has really identified novel ways to focus specifically on what's known as the canonical pathway for winter beta-catenin. That is the transcriptional oncogenic activity, the cancer-causing activity, and to do that by sparing any of the upstream activity. Right? So when we bind to Tibble 1, we bind to that protein, we prevent a complex from forming with beta-catenin. And that complex is absolutely necessary to drive cancer gene transcription. It is not involved in any of the normal biology that beta-caten is otherwise involved in. So we have a very specific bullet that goes after tibble one. We shut down beta-catenin transcription, we lead to the grace degradation of nuclear beta-catenin, and we don't touch any of the cytoplasmic or membrane-bound pools of beta-catenin. So they're free to continue to do their normal cellular function. And so it it's very much, you know, it's a very elegant biology story where that's what was shared with me when I was coming into the company, and we've now proven it out. And it really does seem you can shut down, you can cause a lot of anti-tumor activity without inducing toxicity by being downstream.

Ben Comer 27:24

So, right. So it's a more precise targeting of the pathway and also downstream uh in a very bay, in a very basic way. Okay, got it. Um, I, you know, you've just talked about uh a number of different opportunities across uh several different indications. And I wanted to ask you about Iterion's um partnership strategy. Are are you actively seeking, you know, like a co-development partner or other kinds of collaborations? How are you thinking about that?

Partnering And Combo Strategies

Rahul Aras, Ph.D. 27:54

Yeah, so as a small venture back company, right, um, partnering is typically going to be part of a longer-term strategy. Uh, and now that we're showing that the drug is well tolerated and active and complex solitaries, I can tell you those discussions have ramped up significantly. Um, so for example, on the HCC side, we have a yet-to-be announced clinical collaboration with a large pharma on which we'll be partnering to develop the TKI combination. Um, we're in similar discussions with other pharma companies around potential combinations. And there's just overall a good amount of interest in the data that we're developing because it is the first drug in this pathway to be able to demonstrate that type of monotherapy activity in a complex treatment. Um, so I think the next couple of years is gonna be exciting as we develop that data. Um, and ultimately, you know, with where we are, we could envision, you know, this opportunity to go alone and to continue to finance this, but also to partner with companies that have more expertise on bringing compounds like this to market.

Ben Comer 28:59

Yeah, I was gonna ask you that. Is the thinking about the population, the HCC population, that is some, and if you were to uh proceed with a monotherapy, that is something you could potentially commercialize uh by yourself, you think?

Rahul Aras, Ph.D. 29:13

That is a that is an indication that a small and mid-cap company could definitely advance on its own. But it's okay, it doesn't require a you know 800 person per arm clinical study that's gonna you know take three years to finish. Um but ultimately I think what we'll do is we'll focus on generating the data. Um, and basing that strength of the data, I've got some very good investors on board and we'll do what we think is best for the drug ultimately, and then you know, the shareholders as well.

Ben Comer 29:45

Right. Um, the the oncology development and treatment landscape has changed a lot uh in the last several years. Uh there's a big focus on precision oncology, uh, modalities like immuno oncology, ADCs are still very hot. Um, how does Itereon fit into that evolving landscape?

Fitting Into Modern Oncology

Rahul Aras, Ph.D. 30:08

Yeah, it's a great question. I think the benefit we have right now is we're going after a core fundamental biology that has been known to play a role in cancer for you know decades. Right. So if you think about the four classic undruggable targets, um, there's KRAS, there's MIC, P53, and went to beta-catenin. Right. And what's exciting is if you look at just over the last couple of years, KRAS is not so undruggable anymore, right? Right. It's druggable. And I think that is exactly where we are with beta-catenin right now. Um in the next couple of years, I think we're turning an undruggable target into a very druggable target. And ultimately that pathway is involved in cancer, regardless of the other modalities or combinations you need to bring in to maximize the effect. And it comes back down to we combine very nicely. So I'll give you an example. So um immune oncology, right? So obviously it's taken a forefront in a number of different cancers, but there's also a lot of unmet need where it just can't have an impact. We know that the winter beta-catenin pathway is intimately involved in immune evasion. And there's tons of studies across several indications that show patients with active winter beta-catenin signaling don't respond very well to immune checkpoint inhibitors. Right. So there is a natural uh combination, a collaborative strategy in that setting. Um, all of these cancers have compensatory redundant mechanisms where if you turn off one gene or turn on one pathway, oftentimes another one comes into play. And so we're actually doing a study right now in collaboration with the Ohio State in patients with EGFR-positive non-small cell lung cancer. Um, some very exciting work out of David Carbone's lab there showed that patients do quite well in OSAMerton, it's to grisso from AstraZeneca, right? Historically. Uh, but in response to um EGFR TKIs, you get an upre-regulation of winter beta-catenum signaling. And that serves as a resistance mechanism. It serves as a signal for drug persistor cells to be able to survive and ultimately drive resistant. So the theory there is if you combine an EGFR TKI with a winter beta-caten inhibitor, you can prevent the development of that resistance. Right. That's very similar to a story that we have in um osteosarcoma right now, where we have shown that in patients with recurrent osteosarcoma, winter beta-catenin signaling becomes a major driver for aggressive disease. And importantly, also as a signal for potential resistance to chemotherapy. So there we're combining with gemcytaine in patients with, you know, advanced recurrent osteocarcoma to see if we're going to provide a greater benefit. So, regardless if you're looking at like old school chemo, if you're looking at some of the novel precision precision technologies like KRS, some of the modalities like immune alcology, this wimp beta cotina pathway plays a role. And there's an opportunity for us to combine every one of those settings.

Ben Comer 33:17

Uh, with uh uh I should have asked this earlier in our conversation, um, but tegaviven, um, where did that technology come from? And I I think it's a small molecule, is that correct?

Origin Of Tegavivint’s Chemistry

Rahul Aras, Ph.D. 33:28

Yeah, it's a it's a classic small molecule. Um, it was discovered initially through a phenotypic screen. So they we did not know the target at the time. We didn't know it was Tibble 1. They were looking specifically at inhibitors that could target or modulate the winti beta catenin pathway. Um, and you know, out of that screen, there were several known drugs like tancarase inhibitors and porcupine inhibitors, and this one series that was, you know, very potent and was a completely novel chemical construct. Um, and as that got developed and it was later elucidated that Tibble 1 was a target, became obvious. It was known that Tibble 1 played a role in the biology for some time of, you know, wind signaling, but it just wasn't known that it was druggable. Um and it's not your classic druggable target. Uh so what that's done is given us a very unique position, whereas the biology around Tibble One is well known for a couple of decades. The fact that it's druggable is recently new. That's really giving us quite a head start in development, and that is a novel target. Got it.

Ben Comer 34:35

All right. Um, I wanted to ask you about um operating out of Houston, Texas, uh, as well, Rahul. Um, and maybe we could just start off with the the benefits and and challenges uh of you know a market that I guess is is smaller and to some extent a second-tier market compared to something like Boston, you know, or or San Francisco. Um yeah, let me start there. What what are some of the benefits? Uh and then what are some of the challenges? What do you like about being in Texas?

Rahul Aras, Ph.D. 35:07

Yeah, usually what people point out is the benefit is wonderful winters and the challenges are terrible summers. But beyond that, yeah, beyond that, I mean, from a drug development perspective, it it is unique to be in, you know, what you kind of consider a second market. Um, you don't have the major thing you're missing here is the investor infrastructure. What you do have is absolutely fantastic academic centers, great knowledgeable clinicians. You have very talented scientists, right?

Ben Comer 35:38

And you have also a world-class academic medical center, it's right.

Building Biotech In Houston

Rahul Aras, Ph.D. 35:42

Yeah, like unbelievable, right? Like we're our facilities are basically right, you know, we're surrounded by Baylor School of Medicine, MD Anderson, Texas Children's, all right around us. Um, and the other thing that plays a huge role in Texas is this Cancer Prevention Research Institute of Texas, right? They give grants everywhere from an academic setting to true product development grants that can be anywhere between 10 to 20 million dollars to get products into clinic. And that helps bridge a huge gap where, and I think places like Boston, you probably have more active feed investment or early stage venture folks who are ready to take a little larger risk or leap on those technologies. Um, the other thing you have is just a tremendous sense of community. Right. And I'm sure, you know, I'm from Boston originally. I grew up there, as I mentioned, I worked at Mass General. Um, that obviously exists in those housing those ecosystems, but you really can at any time call anybody in the Houston or Dallas life science ecosystem. They'll pick up the phone, you can have help right away. Same with every single KOL in the region. The thing that's probably the challenge is financing and getting attention, right? Like uh it's it's not that you can go down to the Starbucks and Kendall Square and bump into four investors and you know three potential collaborators. It takes a little bit more work. Um, we've been very fortunate. We have excellent investors in the company. Uh, you know, two of our largest shareholders are Sante Ventures, who has offices in Texas, but they do a lot out of Boston as well. And Lemira Ventures, who's got offices in Boston and Toronto. And then one of our investors is a group called Venture Investors who's out of Madison, Wisconsin. Right. So very little infrastructure investment coming directly from Texas. But I think because of the stage of the technology and the progress we've been able to make, we're getting that attention now.

Ben Comer 37:37

Does it matter where uh a company is based from an investor's perspective? Do you feel like uh, you know, and and it's uh I'll admit superficial, but do you think that, you know, kind of at first pass an investor is is more willing, you know, to take a look at a company that's based in Cambridge versus one that's based in Houston? And and if so, how do you kind of overcome that? What are, you know, how do you break through?

Funding, Community And Access

Rahul Aras, Ph.D. 38:01

Yeah, it's and uh maybe I'll be a little controversial here, right? Because I think the PC answers it doesn't matter. I think it does matter. Um, and I think it's if you're in Boston, it's not necessarily always that the technology is better or that the investors even have this inherent bias. It's just this natural evolution of you get recommendations, introductions from people you know, people you you know, I think about how we get introduced to some of our investors. Sometimes it's at a networking session, or you know, you bump into them at a seminar somewhere and you start talking. That's just gonna happen more naturally in a in a setting like Boston. Um, there's also a lot of co-investment with groups within that region, and they'll get comfortable with each other. Does that mean it's impossible for someone outside Boston? Absolutely not. You just have to be aggressive with your outreach. You have to find the right people who can help connect you. And then you have to make sure when you get that opportunity, you're very clear and concise on the value proposition that you're providing that. I think one of the nice things nowadays is what we're doing right now, right? Zoom. That whole necessity of being in person, having to, you know, sit across a table, it's still really important and valuable, but it's not mandatory anymore. I mean, I actually, when we closed one of our last rounds of financing, I think it was the one Lemira um led, um, that was during COVID, right? We we had not met, I had known of several of the folks in the Lemura team, and obviously they were um friendly with some of the existing investors we had in the company, but I had not met them in person between when we got introduced and conservated the deal. That wasn't possible 10 years ago. No. Yeah.

Ben Comer 39:50

So yeah, well, it what about uh are there other kind of uh offsets just in terms of of cost base? And I'm thinking about really basic stuff like office space for, for example, you know, in a in a San Francisco or a Boston or or you know, uh you name it. Is it are the cost of goods in in some respects cheaper uh, you know, in a kind of secondary market? Is that, you know, does that show up on the balance sheet? Is that real?

Rahul Aras, Ph.D. 40:18

It is. And I think that Delta is becoming more significant in the recent past, like you know, in the last five, six years. Um it is definitely more capital efficient to run a company in Houston. Um, and there is great infrastructure. Like right now, for example, we're actually in a facility that's being run by um a group called Portal Innovations. And Portal has these really high-end laboratory incubators that are set up in a couple of what I'd consider like not your core, they do have one in Boston, but also in Chicago and Atlanta and Houston, right? And I I don't have an apples to apples comparison, but I can promise you I'm paying less per square foot, especially for lab space than you typically would in a Boston setting, right? Um, and that that's flexible. And the nice thing is we find really high-end talented scientists down here coming out of some of these leading academic centers. Uh, so we're able to staff the way we need to. Um, and I do think overall we probably spend a fraction of what some of those groups do in Boston on the actual development side of stuff.

Ben Comer 41:32

Yeah, well, you know, I've talked to other leaders who have implemented various kinds of fractional employment schemes and, you know, worked uh a lot with, you know, more or less part-time consultants. Is that how do you, I guess, how do you think about your workforce and give me a sense of uh the number of uh folks that are full-time at the company?

Talent, Costs And Flexible Teams

Rahul Aras, Ph.D. 41:51

Yeah, no, it's a great question. And you do have to be resourceful in that context as well. Um so right now, you know, we have 14 full-time employees. We do have some part-time contract individuals. Um, and we do have individuals that aren't located in Texas, right? Uh, and sometimes when you start looking at your senior leadership and you need that high-level individual, and they may not be ready or to come to Texas or be in Texas, you can make things work now because of the way we're exchanging and communicating. So that flexibility is important. Um, you don't necessarily probably the other thing I would argue that investors may suggest is lacking in Texas is just a you know huge network or basket of executives who've been there, done that, sold a number of biotech companies. And if you want that expertise, sometimes you do have to bring in someone fractional or even full-time from one of the coasts.

Ben Comer 42:51

Yeah, I think that's also true of South Florida. I went down and did a series of uh of uh podcasts, in-person podcast episodes uh a few weeks back there. And it's similar, it's an incredible location, lots to recommend it, uh, but some of that kind of senior level expertise and investors as well are uh is the kind of missing piece. And I think that you know they're grappling with that um as well. Excuse me. Um uh that's excellent, uh Rahul. Thanks so much. Um I I wanted to ask, maybe finish with uh some of your key priorities and goals for the rest of the year. Um, you know, what are you most focused on right now and uh what do you hope to accomplish uh later this year?

Rahul Aras, Ph.D. 43:36

Yeah, no, I appreciate it, Ben. So a lot going on in the company right now. Um we have finished our phase one HCC studies, as I mentioned. So we are very focused on getting the phase two up and running and hope to have that enrolling soon. Um, and the data from that is going to be quite exciting because we'll be looking at both monotherapy as well as combination um in patients who fail. First line HCC, but really, you know, in need of some major benefits, specifically focusing obviously on patients with winked pathway mutations. So that's the number one focus for us. As I mentioned, we also have recently started clinical studies in osteosarcoma, pediatric osteosarcoma, as well as colorectal cancer. So the clinical data from that's going to be exciting as well. You know, we're actively, we're always actively engaging on both the investor and partnering side to be able to move these um programs forward. But I think, you know, we're looking at in the very near future being able to potentially engage the FDA regarding an end-to-phase two meeting around our HCC program and providing a novel therapeutic option to patients who frankly have nothing in this area right now. So that's where our focus is and what we're most excited about.

Ben Comer 44:50

Would that pediatric uh indication qualify you for a um uh uh pediatric uh rare disease voucher, potentially?

Near-Term Clinical Priorities

Rahul Aras, Ph.D. 44:58

Yeah, thank you so much for putting that up. That's a yeah, it's a great point. So we do have rare pediatric disease designation. Oh, you do, okay. Osteosarcoma. Um, obviously, you know, big news that that program was renewed. Absolutely and completely critical because I think, you know, it is challenging and it's somewhat heartbreaking to uh see people resistant to development of pediatric indications because of things like market size and other issues that are very real and you know things that have to be put into consideration, but it doesn't make the unmet need any less, right? Right. And so those are the kind of value creation tools that can really allow people to get excited about something in a pediatric indication. Um so we have that opportunity for sure. And the other thing that's I think incredibly exciting is that I mentioned we're doing this with um, you know, Emory School of Medicine, Children's Hospital out of Atlanta. Um, and it is fully philanthropically funded by what's known as the Peach Bowl Legacy Fund. Right. So it's it is challenging to be able to raise capital in the pediatric cancer space, but through these collaborations with academia, clinical centers, industry, and philanthropic groups, it's really possible to make an impact.

Ben Comer 46:15

That's excellent. Yeah, the listeners of the uh of the podcast will know that it's been one of my hobby horses to to you know see that that that uh priority review voucher program was reauthorized. So I was really, really happy to see that uh happen as well. Um Raul, thanks so much for oh, you know what? Before I let you go, there's one thing I I wanted to ask you that I I forgot to. What does the manufacturing look like for this product? Are you doing it um through a CDMO or can you give me a sense of what the the manufacturing is for this?

Rahul Aras, Ph.D. 46:47

Yeah, it's a relatively um straightforward process, which is nice. As I mentioned, it's delivered as a once-weekly IV, it's a suspension. Um, we do work with C DMOs. The drug product is actually manufactured in Pennsylvania. Um, so it's and it's um it's a process over which we have a lot of oversight control. The great thing about the drug is it's got you know, four-year stability now uh that we're backed out potentially longer. So very straightforward manufacturing, classic small molecule strategy. Um, and one that I think will provide us some advantage also as we go in. You know, there's a lot of as exciting as a lot of these novel biological modalities are, there's also just complexity in the development and cost structure, getting those forward. Uh that's one of the attractive advantages of being a small molecule in the setting.

Ben Comer 47:36

Yeah, absolutely. Um, all right. Well, uh, thank you again so much for coming on the show and uh sharing your experiences with us, Rahul. I really appreciate it.

Rahul Aras, Ph.D. 47:45

Yeah, Ben, I loved it. This is a fantastic conversation. I appreciate it.

Pediatric Pathway And Voucher

Ben Comer 47:49

We've been speaking with Rahul Arras, uh president and CEO of Rahul Arras PhD, I should say. Uh, president and CEO at Iterion Therapeutics. I'm Ben Comer, and you've just listened to the Business of Biotech. Find us and subscribe anywhere you listen to podcasts, and be sure to check out our weekly video cast of these conversations every Monday under the Business of Biotech tab at life scienceleader.com. We'll see you next week, and thanks as always for listening.