This Fireside Chat, the team from Equillium, Bruce and Stephen are on with us. Lots to cover over the next 28 minutes, so if you have any questions, I think all of you know the housekeeping rules. Just send your questions over to us, or put them into the Q&A box in Zoom, and we'll direct them to Bruce and Steve. Team, I think a great place to start off is, and we have asked every sponsor to do, is to just put into perspective their lead asset, right? Yours is EQ504, which is a differentiated, selective oral aryl hydrocarbon receptor AhR modulator, that is also very coupled with a colon-specific delivery. So maybe help us put into perspective the mechanism and its differentiation, and specifically also contrast, you know, versus Abivax's obefazimod, which, you know, also targets similar pathways.
So handing it to you, team, to kind of walk us through the mechanism and, and its rationale in IBD.
Yeah, sure. Maybe I can take that question. So it's really very simple. If you think about ulcerative colitis, it's characterized as a disease of immune dysregulation, impaired barrier function, and a lack of ability for those mucosal tissues to heal. And we've got a, you know, a number now, over a dozen of approved drugs, all immunomodulators, and they all selectively, in one way or another, target the immune system. But we're still capped at this sort of 30%-ish clinical remission rates. And clinical remission rates, the bottleneck for achieving that is mucosal healing. So it really highlights the need for molecules that will go beyond just modulating the immune system, and ones that will drive improving the barrier function and driving mucosal healing, in addition to modulating the immune responses.
And really, I think that's what sets EQ504 apart, because it's the only molecule that we're aware of that really hits all three of those important axes of disease pathophysiology. Now, if we think about AbbVie's molecule or any of the other molecules we have, there's generally a skew to targeting the immune cells, whether it's the T cells or macrophages, and they all seem to lack the ability to really drive barrier function or mucosal healing. So we really hope that this mechanism brings more coverage to a disease driven by multifactorial pathology.
That's super helpful. Maybe help us understand, you know, what do we know about this axis and its clinical validation in IBD for investors who are maybe new to this target?
Yeah. So one of the benefits we have, at least with AhRs, it's a very well-characterized receptor. It's a xenosensor that's expressed in the barrier tissues of the skin, the gut, the lung, the eye. And people have studied this for many decades and really, truly understand that its role is to take chemical signals and translate them into biological functions, whether it be detoxification of those ligand pollutants or to drive immune homeostasis in tissue barrier layers. And so people have studied this in normal, healthy volunteers. They've studied this in ulcerative colitis, but perhaps the largest dataset that we have is translationally, where if you knock out the aryl hydrocarbon receptor, you lose the ability to maintain homeostasis in those tissue layers.
But then we have a number of clinical proof of concepts, be it through tapinarof, which is an AhR modulator used to treat skin inflammation and atopic dermatitis and psoriasis. We also have the botanicals that are enriched in AhR modulators that actually have very compelling activity in ulcerative colitis.
Thank you. Is there any other companies that's pursuing these modulators in active clinical development in IBD currently?
Yeah. So despite us knowing as much as we do about the receptor, and there's entire symposia that happen each year focused on AhR, there's two big clinical challenges for the drug development of AhR modulators. The first is you need to have a potent and selective AhR modulator, and the second one is you really want to deliver this to the target tissues of interest. Now, not all AhR modulators are created the same. So AhR modulators that come from the pollutants generally induce the detoxification mechanisms, but not the immune modulatory mechanisms. And so actually finding a molecule that is potent, selective, induces the right profile of immunomodulatory pathways without having inherent toxicities, has been quite a challenge. Now, why we're quite excited about EQ504 is it's derived from ITE, which is the gold standard selective AhR modulator.
It's probably one of the most widely studied AhR modulators, and ours is essentially a more drug-like analog of this molecule, which has very strong activity, very strong selectivity. It binds to tissues, like, such as the skin, the gut, the lung. It can modulate the immune responses, and then is very rapidly cleared from the human. That contrasts to many of the other molecules that are in development by companies that are using indirubin, which is a naturally occurring but not very good drug-like molecule. And we know other pharma companies, such as Takeda, has had an active program in the past, and Eli Lilly has a portfolio of AhR agonists that it has developed through structural-based mechanisms, which are also cited to be very potent and selective.
We think the field is heating up now because of more of the clinical validation, but there are still hurdles in terms of identifying the right molecules and the right drug-like properties.
Then maybe also, Stephen, for investors who are new dialing in, like, just maybe give us sort of an overview. What is the depth of the preclinical data that has been generated? What are some of the key findings from those datasets? Before we go into kind of think about, you know, obviously, you guys are very focused on the phase I study, human study that's gonna be starting out mid this year, so... But maybe we can spend a little bit of time on the preclinical data package.
... Yeah, so one of the, I think, interesting things about the preclinical data is it's sort of well translated all the way through humans. So if you take an animal or a tissue, and you remove AhR from it, in the animal, they develop pneumonitis, so, dermatitis, gastroenteritis. They, they develop inflammation of the barrier tissues, and those barrier tissues fail to function, and the immune cells that are resident there also become overactivated. And we know that we can modulate AhR, and we can improve those signals. And you can use AhR knockout models, you can use AhR antagonists, and we can modulate that biology in a sort of on/off switch or even dose responsively.
From those animal models, we know that if you activate AhR, you can improve skin inflammation, GI inflammation, lung inflammation, and it induces activation of AhR, and the typical biomarker for this is CYP1A1. So it's a cytochrome P450 enzyme that is a target engagement marker for AhR. But then commensurately, depending on the cell you're in, for instance, in the skin, it's skin cells and immune cells, and in the gut, it's mucosal cells, and we can see that those pathways are activated. We see improvement of barrier function. We see regeneration of the skin or mucosal cells, and we start to see the inflammatory signals go down and the immune homeostasis restored. Now, we can see that in animals, and you can do exactly the same study and test in humans, and people have done that.
A good example would be VTAMA, the tapinarof molecule. So this is an AhR modulator applied to the skin, and when it's applied to the skin, you can see induction of AhR by CYP1A1. That's the target engagement biomarker. And then you see a reduction in inflammatory signals and an improvement in skin barrier function. And people have also done this with the botanicals in ulcerative colitis patients, where you give the botanical, it activates AhR in the mucosa. You see increased levels of CYP1A1 as a target engagement biomarker, and increased levels of IL-22, which is an important cytokine for protective function in the mucosa. So you see this nice, cohesive set of data, everything from the preclinical translational into humans.
Stephen, with this depth, and thank you for kinda also concluding sort of the translation to humans is, where is the program currently in terms of IND filing, IND clearance? And then maybe would love to kind of talk about sort of what's the rate limiting step to start the phase I studies that's expected mid this year?
Yeah, so all of the key IND enabling studies have been completed. Really, the rate limiting step sitting between us and dosing our phase I normal, healthy volunteers is the formulation. So that sort of gets to the second part of the challenges in drug development, 'cause AhR is ubiquitously expressed, and once you activate AhR, it triggers mechanisms to digest the ligand, to metabolize the ligand in situ. That turns the signal off, and so it makes a lot more intuitive sense to go directly to those cells expressing AhR in disease. Now, with the skin, the gut, the lung, and typical barrier tissues, you do have the opportunity to drug those tissues directly, and that's been shown in multiple other different disease areas.
For something like ulcerative colitis, where the cells of interest to us are the damaged epithelium and the resident immune cells that sit just underneath that epithelium, we believe that we could have a drug with, you know, improved pharmaceutical properties and improved safety and tolerability by directly targeting those tissues in the colon. So we're developing an enterically coated system, so it'll be mini tablets or spheres that are then coated with this polymer that then dissolves when it gets to the colon and then dissolves through the colon. What that allows you to do is give a nice distribution of the drug to the colon tissues, and that allows us to more optimally engage the receptor in the colon with lower systemic exposure.
The benefits of that with any drug, this is a truism for all drug development, is if you can get more drug to your target tissues and less in the systemic exposures, you've got a much better chance of having improved safety and tolerability. Now, I would say that there's no level of AhR in the systemic or specific toxicology concern that we're worried about. We just believe that it's just more efficient, given the drug's metabolism in situ, is to get the drug immediately onto diseased tissues and then allow it to titrate into the systemic, versus giving it systemically and expecting that then to diffuse out to the colon tissues. So we're in the current stage of doing our testing of the prototypes. We'll then scale up those through GMP manufacturing.
It's, as I would characterize it, a fairly routine, low-risk activity, but one that's time-consuming in terms of developing that formulation. Now, one of the benefits of this would be having that formulation going into phase I means rapid movement from phase I to phase II, where typically coming out of a phase I, companies then take a pause to formulate their drug product.
Where are you, Stephen? Given that we are three months away from mid, I assume that the formulation optimization is almost coming to a finish line. Then, do you, can you submit your IND, or do you need that to be completed before the IND is cleared? Maybe help us understand sort of, well, that's ongoing before starting the human studies or maybe both. Yeah, sort of the timing of sequence of these events.
Yeah, I can jump in. Yeah, so just to highlight one thing. So we're, you know, we've partnered with one of the world leaders in this technology area. The technology is already validated clinically, so we're not really reinventing anything in terms of the formulation work, but it is just for to fine-tune it for our API, if you will. So we are still on track for mid-year initiation, and the high likelihood is that we'll be conducting this initial work in Australia, so we won't be actually submitting for an IND. We'll be doing the work in Australia, which has a more rapid sort of turnaround in terms of, you know, what's required from the submission standpoint there. And yeah, we'll need to complete the formulation work and then submit our package to get that opened up.
... And then team, if we could talk a little bit about, so I assume it's the first, once the formulation and once you start your phase I, this would be healthy volunteers? Would it be a more combination of healthy volunteers as well as patient, disease patient, UC patients, and maybe also some color, Stephen, around, you know, obviously it's a phase I study, so safety, tolerability, PK, and PD is going to be important, but what do you need to see in terms of key PD markers, right? Which then would give you color around what doses you would select for phase II. So help us frame up how you're thinking about the phase I POC, like human study.
Yeah, so it'll be a very typical SAD/MAD study, right? And I can give you a flavor of these, and we'll provide more guidance and color on exactly the clinical study later this year, prior to initiating it. But typical SAD/MAD studies can be sort of five SAD cohorts of a single dose, and then you'll move into MAD cohorts of, you know, week to weeks of dosing, as you sort of move through that. Now, we'll be looking at safety, tolerability, PK/PD, but we will do a flex sigmoidoscopy to these normal, healthy volunteers, and that'll allow us to actually look at tissue exposures in the colon. So our formulation should get to the colon. These, these are formulations, as Bruce pointed out, that are already deployed in ulcerative colitis drugs.
Then we'll have a look at the levels of activation and levels of drug in the tissues versus what's in the systemic. Now, if you think about this, many drugs that dose just systemically are interpreting what they see in the systemic as representative of the colon. Now, that is a large assumption. It's a big leap of faith. So I think one of the benefits is really going into the colon and saying: Are we engaging the target? Now, we did this in normal, healthy volunteers because it's been shown in the literature, and we've demonstrated, and we can provide sort of further color on this, is that when you expose normal tissues to AhR modulators, you activate AhR. You induce many of the important pathways because you're turning them on.
And by that, I mean induction of anti-inflammatory cytokines, barrier tissue integrity molecules, et cetera, a whole host of different important pathways. So we have the benefit of actually getting a lot of rich data from colon biopsies. Now, the other important element here is that we have an enormous amount of data from the Indigo Naturalis data set. So for the investors new to this story, Indigo Naturalis is a botanical that's highly enriched in indirubin, which is a very potent but not selective AhR modulator, and that's been demonstrated in multiple phase IIs to be able to achieve clinical remission rates of 40%-50%. So really strong clinical remission rates, driven by very profound mucosal healing scores.
Now, in those studies, they're able to show in the colons they can induce AhR, they turn on the AhR pathways, and one of the key cytokines they often follow is IL-22, because it's a protective mucosal cytokine. And so what we'll be looking at is, do we turn on very similar markers that have been seen in patients in normal, healthy volunteers? Now, so we'll be able to understand a little bit more about interpreting that mechanism from normal, healthy volunteers to interpret dose selection for patients. But of course, we won't be able to get any activity data because we're not looking at, improving mucosa.
But I think the benefit of being able to do this in normal, healthy volunteers is being able to do as much as possible here that drives better dose selection and then move that rapidly into patient cohorts, that I'll let Bruce comment on, that'll really start to give us some information on the, you know, benchmarking activity.
Stephen, how do you, What is the tox coverage going to be as you're going to be looking at some of these biomarkers, you know, PD biomarkers? Like, I'm trying to visualize the math portion, whether it would be, you know, a week study or two-week study, and how soon the IL-22 axis moves to provide that color.
Yeah. So those are really good questions. So let's start with the beginning. So we've done a lot of toxicology work here, and we believe we've got adequate margins to get to the active doses, away from any of the toxicological events that have been observed. And I can characterize those as non-severe, no deaths in animals, no irreversible tissue damage or anything else like that. Now, when we do our animal models, because we can't use the formulated version, it's too big for a mouse, so we just give it systemically because we've got no reason not to. So we give the molecule systemically, and we're active in those DSS colitis models at about 1 mg per kg. So to put that into human dose equivalents, that's about 5 mg total.
Indirubin, which is the active component of Indigo Naturalis, is about 10 mg per kg, so about tenfold more potent than that. Obefazimod, just as you've asked about that in the past, that was effective in the DSS colitis model at 50 mg per kg. So we get very strong activity. Now, when we think about deploying this through the formulated version, we'll give this directly to the, to the colon. So we know when you give this systemically, what levels of activity and what levels of drug you need in the colon, and you can actually model this when you give it enterically, how much you need into the colon.
As you can imagine, giving a drug to the distribution volume of all of the blood and all the systemic versus giving it to the colon, you can get away with giving much, much lower levels of drug to the colon, and you'll see much lower levels end up in the systemic. So we believe we've actually got very adequate and very good coverage between where we believe anyone may observe, you know, the NOEL effects or any other effects of the drug at high levels there versus where we think the efficacy levels are. And I think the formulation, again, is not because we believe there's anything specific that we need to avoid. It's really that... Look, you see, as a drug is a drug development landscape and a commercial landscape governed-...
predominantly by safety, because we just don't have that many efficacious drugs. And I think the JAKs aren't that much more efficacious than our biologics, but come with a lot of safety and tolerability hangovers. To give this molecule the best possible chance, I think giving the drug directly to the tissues through enteric formulations really will give us the best possible chance of having a drug that has the best safety and tolerability profile. That allows you then to stack other immunosuppressant molecules to it, as we think about where the puck is going in terms of combinations. And ultimately, it just allows us to make sure that we're not leaving efficacy on the table by hoping that a systemically administered molecule gets out to the damaged luminal wall, by just actually going straight to the tissues of interest.
Thank you, Stephen, for the color. Do you think you would include an 1C portion of UC patients in this study, or do you think the IL-22 data would be informative enough that the next steps post that would be to embark onto a phase II study?
Yeah. So I think patient data would be very informative and very helpful to get. You know, one thing I like to sort of remind people of is, we're not interrogating a new mechanism, right? This is a mechanism that's been well established. So I don't think that the goal here would be to prove that this is a mechanism that's worthwhile. Like I said, the preclinical translational and human data is very compelling in multiple placebo-controlled phase II studies across the world. So I think it will help us understand, is any given dose going to be you know, effective in patients? But I don't believe that necessarily it's a study we have to do to validate the mechanism.
Now, IL-22 that we see in the normal, healthy volunteers, you asked a question about how rapidly we may see that. That's likely to be seen after multiple doses, not after SAD, but most likely, if we see it, it'll be after the MAD. Now, you should always see the CYP1A1. That's an activation marker of AhR, and we can very well translate that across to what we see in the ulcerative colitis patients. So we're currently working with our advisory board. We're very lucky to have, as a legacy and further bolstered the advisory board with key opinion leaders who've got deep experience in the development of drugs.
We'll be meeting with them over the next couple of weeks to months to really start to flesh out what the transition from a 1A to 1B, or potentially I to phase II may look like. And I think you could expect to see further updates from us closer to the initiation of the phase I, is what, if any, additional 1C patient cohorts you may see in this study, or whether we would move directly to a phase II post a phase I.
Then, Stephen and Bruce, like, what have you guided in terms of the timing of the phase I readout? And maybe, Bruce, what is sort of the current capital, the current cash and runway, and how much it would fund the phase II development?
Sure. So yeah, thanks for that question. So as mentioned, we're currently tracking to a study initiation mid-year. We would expect sort of a reasonable timeframe for data from the SAD, MAD level sometime during the first half of 2027. As Steve mentioned, over the next few weeks, we're gonna sort of start to pin down what we will do following that, and determine what makes the most sense in terms of getting to patient-level data. In terms of the runway and financing, as you know, we announced in August a $50 million financing. Some great investors came in to support our efforts in advancing the program. That was Adar1, Janus, Adage, Woodline, and Coastline were the syndicate that came together around that.
The financing included a $30 million investment upfront, and a second tranche of $20 million that will be triggered when we start our first clinical study. So, we would expect that to come in, you know, shortly after study initiation. The public guidance we have only reflects the $30 million we've received already, and our guidance is that the cash on hand should get us through towards the end of 2027. And obviously, the additional $20 million tranche will extend that runway, well into the 2027-2028 timeframe. So certainly, through the SAD/MAD program, and we believe we should likely be able to get to some patient-level data as well. Again, we'll come back to the street with further clarity and updates around that sometime when we're stepping up to start the study.
Thank you. Sorry about the... Sorry, a little head over there popping in. That was my three-and-a-half-year-old, who is on winter break - had to be like, "Mommy, Mommy.
No problem.
I saw two of my friends.
No problem.
In his little area, so he, that was him-
All good
making a comeback.
All good
Saying hello to all of you.
All good.
Yeah.
A budding biotech analyst.
Yes, that's right. That's right. He definitely is, he's a character.
Yeah.
But, team, how does-- as we think about this mechanism and its validation, I assume that your interest would be-- obviously, you see as a full, full-front, most important indication expansion. But what else, is there are other opportunities for this mechanism beyond IBD, that you would be pursuing? And again, appreciate any color if there is some thoughts around not only this asset in UC, but also broader pipeline expansions.
... Yeah, so it's already been well validated in the skin. The gut and the lung are two other really important areas. Now, the gut, like I said, has a ton of clinical validations. That makes the most obvious place to start. But more recently, folks have been looking at the role in lung tissues, and we know AhR is really important to the lung. And so one of the things we like about EQ504 is its properties. It's very potent, very selective, but it has water solubility. Now, that's really important for something like colonic delivery, where the colon is actually very low in fluid volume, so you do need some solubility there.
But the other benefits are, you could essentially nebulize this molecule, and you could potentially go after other indications in the ILDs, be it COPD, IPF, a number of other lung manifestations. Now, I think that's an enormous opportunity for AhR modulation because it's really, again, it's the damaged alveoli and the immune cells that are sitting resident. And there was a nice paper published by Novartis, I think it was last year, about modulation of the inflammatory and fibrotic component by AhR modulators. So I think that just sort of opens up another axis that we'll, you know, turning our attention to in the latter part of this year, once we've gotten the phase I going, is really where else we could take this molecule.
I think it diversifies the program because it is mutually, you know, it's independent of what we're doing in UC, but it really could open up another area for where AhR modulation could go. Now, of course, we could turn our attention to skin, but I think with VTAMA there, and, you know, my view on psoriasis is that we-- it's a very crowded area. There's a lot of other good molecules, be it in the biologic space. So I think for us, our next focus for AhR modulation will be to take a look at lung. But we could also think about opening up our formulation to hit higher up in the GI tract to go after Crohn's. That's another opportunity.
Now, historically, in Indigo Naturalis, Crohn's was not an area where it showed its strengths, but it could be, once again, it could be some limitations of Indigo Naturalis, and that more likely distributing drug to the lower GI tract. So I think there's a lot of different places we could take this. I do believe this is sort of a, you know, dare I say it, a, a pipeline and a product. And we'll be moving our thoughts and attentions to different indications here, I think once we get the clinical study up and running, which of course, is a huge priority for the company in terms of meeting a valuable inflection point.
Wonderful. Well, Steve and Bruce, thank you so much. I can't believe we came, we covered a lot in the 28 minutes. So thank you again for being part of our Immunology Day, and very much looking forward to talking to you soon. So thank you for finding time on your busy schedule.
Thank you.
Yeah, thanks, thanks so much for having us. Really appreciate it.
Thank you. Bye.