Great. Good morning again, everyone, and thanks for joining us for our next fireside. I have Collin Todd here, Senior Vice President of Strategy and Business Development at Odyssey Therapeutics, to walk us through the story. Maybe I will kick it over to Collin to sort of give a quick overview of the company, and then we will get into a Q&A. Collin, over to you.
Great. Well, thank you, Alex, and thank you to Stifel for having us on the fireside today. I am Collin Todd, Head of Strategy and Business Development for Odyssey. Odyssey was founded in 2021 with the idea of delivering transformative therapeutics to patients that are suffering from autoimmune and inflammatory disease. Today, we will obviously discuss several of our pipeline programs and upcoming catalysts, but I think first it is good to touch on some of the organizing principles of how we put the company together. First, all of our programs are homegrown. Everything that we are working on are things that we have started since 2021. Second is that we are using two validated modalities to advance our portfolio, small molecules and protein therapeutics. Then the third is ultimately our goal is to, for medicines that we advance, to be the first or second to the market.
Great. Maybe starting with your lead program, your RIPK2, can you walk through some of this genetic and mechanistic rationale in IBD? Then we will walk through the data that you have generated so far.
Yeah. First, I think it is important to note that all of IBD starts with the breakdown of the epithelial barrier. In this case, when the gut barrier is broken, the bacteria that are present in all of our GI tracts ultimately becomes exposed to the host immune system, and in doing so, it sets off the downstream inflammatory cascade. This is something that we have seen, RIPK2 ubiquitination, both in patients with ulcerative colitis as well as Crohn's disease. This is something that we see as ultimately being applicable to all patients within the inflammatory bowel disease space. With respect to genetic rationale, there are different mutations that are related to RIPK2 sensitivity or activation. These include CARD9 and ATG16L1.
Both of these ultimately increase the risk of patients developing inflammatory bowel disease. We think supports the concept using human genetics of going after this target.
Yeah. I guess, as always the case with small molecule development, human genetics is the start in a lot of ways. But then, designing a molecule that works is a whole other challenge, right? For OD-001, what are sort of the key elements of designing a proper RIPK2 inhibitor, and why have others been unsuccessful?
Yeah. I think first you really have to start with the biology that you're looking to block. Many of the first-generation approaches going after RIPK2 were targeting the RIPK2 kinase function. It was back in 2018 that there was a definitive series of papers that actually illustrated that the kinase function was not necessary for downstream signaling activity. What was actually important was the scaffolding function. From the very start of when we worked on this program, we set out to create a RIPK2 scaffolding inhibitor. What our molecule does is it binds to RIPK2 and holds RIPK2 in a conformation that reduces the affinity of XIAP. XIAP is essentially the scaffolding protein that when it binds to RIPK2, it ubiquitinates RIPK2, and then produces the downstream cytokines that you see, such as TL1A, TNF, and IL-23, which themselves are all validated targets.
We have some materials in our corporate presentation that actually outline our molecule and how we approach this. Looking at this with respect to the XIAP binding affinity, what this ultimately means for RIPK2 scaffolding inhibition, whereby we were able to achieve 100% scaffolding inhibition, and then achieving the most robust inhibition of downstream inflammatory cytokines, which we think is ultimately what leads to the clinical activity that we saw in our phase II study.
Yeah. Let's walk through the phase IIA. Can you talk a little about the monotherapy design dose selection here? I want to get into the data specifically.
Yeah. Of course. I think first it is important to note, this was the first time a RIPK2 scaffold inhibitor has been taken forward into ulcerative colitis.
Our first goal here was really to make sure that we had a safe molecule that was well-tolerated and learn as much as we could about the potential efficacy profile and confirm that this is a mechanism that we wanted to invest further capital behind. At the time that we started the study, we had three-month toxicology results, and therefore, we were limited to only being able to dose for 12 weeks with our molecule during this study. As an inducement for patient recruitment, we also offered vedolizumab as a maintenance treatment, essentially because this is critically important for both investigator and patient interest in any kind of modern IBD trial. We took forward two doses, a 10 and a 20 milligram dose, and this dose selection was informed by an ex vivo TNF stimulation assay that we did in phase I.
What we did is we were going through the MAD cohorts. We would take the blood from the patients, and we would stimulate it with peptidoglycan, which is a component of all bacterial cell walls and is ultimately what activates RIPK2 after it binds to the NOD receptor.
What we observed is that at doses of 20 milligrams BID and higher, we were able to achieve maximal inhibition of RIPK2 signaling. We define that as what you observe in a RIPK2 knockout cell, which is 90% inhibition. That was the high dose that we took forward. Going back to my initial point, we really wanted to understand if there was a potential for any kind of dose response and how maximally do you have to inhibit the target to have activity. We also use the 10-milligram BID dose, which achieves about 70% coverage of the IC90 during the dosing interval. That allowed us to test two doses. Ultimately, we expected both doses to be efficacious, and we saw activity with both of these doses in the trial.
Yeah. An open label study obviously comes with lots of caveats for interpretation, but when you look at the totality of your data, what gives you the most confidence in the clear signal here?
Yeah. I think there's two components. I think that there's a very well laid out approach to running a modern IBD trial. First, w e worked with a company that's been in the space for decades, Alimentiv. They've been involved in the development of nearly every single IBD therapeutic over the last 20 years. We use their site level information, their investigator level information, ultimately make sure that we're going to the right sites that are enrolling real IBD patients and understand how to run these trials.
All the patients that we enrolled required a Mayo Endoscopic Score of two or three, required rectal bleeding, and importantly, we use centralized and blinded endoscopy reads. This is critically important to make sure that you're not having any types of investigator biases. In addition, our team was involved in all the site and investigator selection. Those are the things that we did to ultimately design the trial to give us confidence. But now that we have the results actually in hand, I think the most important thing that we see is you see concordance across all the endpoints that we've discussed.
You see a nice stepwise function as you move from the most rigorous definition of clinical remission through endoscopic improvement, symptomatic remission, and then finally, clinical response. In the patients that we see having either clinical remission or clinical response, we see a nice decrease in fecal calprotectin, which is a validated biomarker of ulcerative colitis severity. Then, we also see very nice activity in the anti-TNF-experienced patients.
With respect to, I think, the most definitive data set that came out of it when we share this data with investors or with key opinion leaders, is the strength of the signal that we saw in the anti-TNF-experienced population, because the placebo rate in this group is commonly in the low single digits. Our 25% rate there is something that people were quite excited about.
Yeah. How would you put this activity data into context with what we have out there today that you see?
I think this is where the mechanism of the drug is very interesting, because this is the only innate targeted therapy that has actually been advanced in ulcerative colitis to date. What that does is it allows us to get above where all of the adaptive immune system is being activated.
Yeah.
Instead of targeting a single cytokine, we have the ability to depress multiple signals that are ultimately likely to be involved in any particular patient. When you look at what we observed here, we essentially saw equivalent activity between the treatment-naive and the anti-TNF-experienced patient population. I think this carves out an interesting opportunity for us both to be used with newly diagnosed patients, given the safety profile that we observed as well as the oral profile of our molecule, but also something that can be used in the anti-TNF-experienced population, where traditionally you see a 30%-50% reduction in clinical activity in this group.
Yeah. I guess, you're going to have more data at UEGW coming up in a month or so. What should we expect to see there?
I think you can imagine this is a common question we get from the investor base.
Yeah.
As I noted, we tested two different doses in the Phase IIA.
Yeah.
Based on the results that we observed, which we've shared to date, we saw similar activity with both of the doses.
Yeah.
What we ultimately did is after we had this data in hand, we went, and we backfilled at the 10-milligram dose group, so that way, we can further understand any kind of dose-response relationship. At UEG, we will have an additional seven patients at that lower dose, taking the total set there to 15, which can be compared more fully to the 41 patients that we had at the 20-milligram dose. In addition, we will also be sharing additional data cuts from that study, and then also a whole suite of biomarkers and other assessments that we have been doing over the last several months.
Yeah.
I think as you appreciate, it takes a lot of time to get all the samples in, assess all the samples, and then ultimately assess that with regards to all the variables that can ultimately be evaluated. So that will be on October 20th. Dr. Bruce Sands will be presenting that on behalf of the company.
Great. Yeah. So obviously, a lot more going on beyond the phase IIA. Can you talk through the phase IIb, and then also I want to talk about the combination study as well.
Yeah. So we really see combinations as the future of IBD treatment. What we intend to do coming out of this study is actually start two different trials in the second half of this year. One of them will be a Phase IIA combination study. This will be a combo that we are doing with vedolizumab versus vedolizumab plus placebo. This will be an active only trial.
This will ultimately assess the potential benefit of being able to combine our agent with an adaptive immune therapy to break the therapeutic ceiling. Despite the fact that we have a half dozen different mechanisms that are approved, pretty much all patients are somewhere between a 15% and 25% absolute clinical remission rate. If we really want to change the treatment paradigm of IBD, we see combinations as the best way to do that. So that trial, we will actually have a poster outlining the design of that trial at ACG. That will be about around October 13th, I believe. So we will lay out a lot of the additional information for that trial there. With respect to the Phase IIB monotherapy advancement, we have not released the final design of that trial, but we will do so in the future.
Yeah, I guess sort of back to the combo, definitely agree on combination in IBD generally. I guess why vedo as the partner to start?
Yeah. There is a lot of different reasons.
Yeah.
I will try to attack them as linearly as I possibly can. The first thing when you are trying to think about a combination partner, particularly with an investigational agent, is starting with what are agents that are currently approved? If the agent is not currently approved, you have to go back, do preclinical tox.
Yeah.
That takes out the opportunity for things like TL1A, which is something that we think would be interesting in the future. Second, you want to have something that is well-characterized, safe, and broadly used across the field. Vedolizumab checks all of those boxes. It is essentially a first or second-line therapy in most Western societies. Then the third is something that we think has a good chance of success as far as the various mechanisms. RIPK2 is targeting the upstream innate response, and vedolizumab in targeting T-cell trafficking is really targeting the most downstream step of the adaptive response. Mechanistically, that gave us a lot of confidence and interest in testing this. We have actually been able to see a few combination studies using vedolizumab, which have read out over the last year. One of them was a study by Takeda, the EXPLORERGEM 4 study.
In that they were able to combine vedolizumab with tofacitinib, achieved over a 50% clinical remission rate. This also tracks with what we have seen in other case series that have been published. Very good precedent for it. We think there is good mechanistic rationale for it. It is also something that investigators are quite interested in for patients.
Great. Maybe pivoting to 002 and SLC15A4. It is another immune biology target. Super interesting, I guess. Can you place SLC15A4 in the context of how people are thinking about this space in rheumatology in particular with targets like TLR7, TLR8 or an IRF5?
Yeah. I think it is really important to think about the totality of the pathway because we have a lot of benefit of significant validation that has occurred over the last 5 or 10 years.
Yeah.
At the very top of many autoimmune and inflammatory diseases, you have pathogenic signaling that is being driven by either RNA or DNA. The RNA will signal through TLR7 and TLR8, and the DNA will signal through TLR9. Both of those ultimately converge on SLC15A4. SLC15A4 adapts with another protein called TASL, and then TASL is ultimately what activates IRF5. What we get by intervening, at the point that we are doing so with our SLC15A4 inhibitor, is the point of convergence block IRF5 that ultimately, you could have a potential to have a variable indication selection between SLC15A4 inhibitor or an IRF5 blocker. To selectively block the signaling that we want to in the diseases we are going after, we think SLC15A4 is a great way to do that.
Going to the more downstream end of this after IRF5, activation of IRF5 leads to production of interferon, which we obviously know works in several diseases with the approval of anifrolumab. It can also control pathogenic B-cell activity. That is actually some of the data that we have added into our presentation that we think is really compelling here is instead of just thinking about this as blocking TLR7, TLR8, and TLR9, this actually gives us a potential to have a selective B-cell modulator in a pill.
Yeah. I guess maybe could you sort of compare and contrast SLC15A4 to TLR7 and TLR8 upstream? We have seen proof of concept, obviously, from that biology. What is unique about hitting it at this node versus upstream?
Well, so we know that these diseases are driven by both RNA and DNA signaling.
Yeah.
Let's take SLE, for example. We now have the benefit of both seeing afimetoran, the molecule that Biogen is developing, having a positive top-line result in SLE. We've seen the enpatoran results now which have shown positive top-line data in phase II and is now in phase III. So, we have validation from both of those TLR7 and TLR8 blockers. But if you look at patients who have, for example, SLE, there's also a significant component of the disease that is being driven by autoantibody production, which essentially has this feed-forward loop of inflammation. And one of those is our DNA-driven antibodies.
Yeah.
What we show is that our molecule is actually able to reduce the production of that feed-forward mechanism, whereby if you only use a TLR7 and TLR8, we don't observe that phenomenon.
Yeah. You are going to have some more data on this in November at ACR?
We will have a poster discussing this program further at ACR and laying out more of the reasons why we are very enthusiastic to take this approach forward and really teasing out some more of the B-cell biology, because we think this is an incredibly compelling molecule, kind of given where the B-cell depleter space has been going over the last 12 months.
Then maybe for the molecule itself, can you talk about some of the preclinical properties so far and sort of your path forward from here?
Yeah. The molecule is incredibly potent, single-digit nanomolar potency. We have essentially been able to phenocopy knockouts in vivo, again, showing that we are able to achieve robust target inhibition to a degree that we think is ultimately going to be very meaningful. Very high selectivity and I think similar to the rest of the small molecule approaches we work on, we really try to have a pharma-grade molecule at the end of it. Our projected once-daily human dose, sub 20 milligrams. It is actually very important when you take the step back and think about long-term commercial use. The most successful immunomodulators of all time have all been relatively low-dose therapeutics, and that is because that reduces the xenobiotic burden over time and reduces the risk of developing any AEs and tolerability issues.
Yeah. Makes sense. Your plans moving forward are for a basket study. I guess, what's the rationale there? What kind of indications are you thinking of moving forward?
Yeah. We're really approaching this with a basket because we see the opportunity to develop this in multiple places. You can see many different indications are being pursued by B-cell depleters. Anifrolumab is an agent that's been approved, and we now see that expanding into other indications.
Yeah.
Ultimately also following the lead of what we've been able to see with TLR7 and TLR8. That's what's leading to the basket design. It's really we see a number of opportunities. The only indication at this point that we have committed to in this study is cutaneous lupus.
Yeah.
This is really to ultimately get the initial proof of concept results for this, with something where we know TLR7 and TLR8 works as well, potentially tease out some differentiation opportunities. Also use skin biopsies to help understand the mechanism of the molecule, because that is something that will be incredibly valuable as we move forward into later stage development and pursue indications where that might not be feasible.
I guess, what's the level of data or the quantum of data you would need to expand beyond CLE, get confident in the molecule, and think about other indications?
Well, we're going to be doing the other indications at the exact same time. We're not going to be sequencing this or staging this in any way. Again, CLE is used there as one of the proof of concept indications, but we plan on having data from these around a similar time point, and then we'll ultimately decide on the path forward from there with all that information in hand. The one thing that we will be doing, though, that I think is important is in the phase I, again, building off of the precedent of what we've seen with TLR7 and TLR8 blockers, all of these use an ex vivo stimulation assay in their phase I trial, and all of these ultimately correlated to later-stage efficacy, whether, again, it be with the enpatoran molecule, afimetoran, or an Eisai molecule , which is also being advanced as well.
Yeah. Maybe let's pivot to OD-003. At a high level, I guess, why should we all be excited about Treg biology?
If you think about potential applications on inflammatory and autoimmune disease, there's really not many that a better Treg might not be able to treat. This is something that gets to the root of disease, by being able to have Tregs that traffic to the site of disease, Tregs that have better immunosuppressive properties. You really have a potential to treat a pretty broad swath of indications. The first tier of development that's been ongoing is in dermatologic diseases. This has really been done by Nektar and others in the field, but we show some of this data in our prospectus, using an EAE model, which is essentially a murine model of neurologic disease. We're actually able to see Tregs trafficking to the brain.
We're actually able to see efficacy in a therapeutic setting where we don't see that with IL-2, which was also used as a comparator in that study. There's a lot of opportunity with this agent, and we think that TNFR2 really gives us the opportunity to build on this first layer of validation that we're ultimately seeing with IL-2 based approaches by not just expanding Treg number, but improving their function and improving their immunosuppressive properties and the stability as well.
Yeah. How would you characterize the key difference between TNFR2 agonism and low dose IL-2 or rezpeg?
We view IL-2 as really providing some of the initial proof of concept for being able to use Tregs. But it's important to note you're fundamentally activating a completely distinct program within these Tregs. IL-2 is entirely focused on expanding Treg number, whereas TNFR2 does expand Treg number, and we can see some of this in the TRex Bio prospectus that was recently published, as well as data that we've published. But in addition to that, given the fact that you have this novel program that you're activating, you do improve immunosuppressive function. We've shown that with various surface markers. We improve the ability to traffic to tissues, both by counting Treg number, but also homing markers such as CCR8. And you're also able to initiate a tissue repair program.
There's a factor called BATF, which is actually linked to the ability of Tregs to repair damaged tissue, and TNFR2 agonism increases BATF as well. We really see this as an opportunity to build on what we've learned with IL-2, but potentially make this a much more broadly applicable mechanism.
Yeah. You alluded to some of your EAE data that you generated pre-clinically. What's the status of OD-003 at Odyssey, and where do you think about indication selection from here?
Yeah. IND enabling studies are ongoing. We expect to complete those in the first quarter of next year. In the middle of next year, we also expect to see the first efficacy data from TRex Bio. Based on what we see from them, as well as what we see from our ongoing IND enabling studies, and then also IL-2, we'll decide on the best path forward for the molecule.
Great. In the last couple minutes here, can you talk about your current cash runway and what the embedded assumptions are there?
Yeah. Everything I have talked to you about today with respect to the RIPK2, SLC15A4, and TNFR2 program are included in our base runway assumptions. We have $433 million in cash as of June 30th of this year, and that capital will ultimately fund us into the second half of 2028. That will allow us to achieve both of the readouts that I talked to you about for the RIPK2 program with respect to the phase IIB as well as the phase IIA combination. It will also allow us to complete the SLC15A4 inhibitor phase I, which we intend to file the CTA on later this year.
Great. Well, Collin, thanks for joining us. Really appreciate it.
Thanks a lot, Alex. Thanks for the time.