Day, and welcome to the Odyssey Therapeutics UEG Week 2026 Investor Webcast. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question, you will need to press star 11 on your touch-tone telephone. Please note this call is being recorded. I will pass it off to Gary Glick, Founder and CEO of Odyssey Therapeutics.
Good afternoon, everyone, and thank you for joining us. Earlier today, Bruce Sands presented an update from our phase II-A monotherapy trial of OD-001 in ulcerative colitis here at UEG Week in Barcelona. His slot was only 10 minutes long, so we wanted to give you the rest. The complete induction data set, biomarkers of colonic and systemic inflammation, and mucosal transcriptomics from patient biopsies with enough time to walk through each piece of data and then take your questions. Next slide, please. Just before we begin, a reminder that today's presentation contains forward-looking statements, including statements about the clinical development, efficacy, safety, and therapeutic potential of OD-001 and some of our other product candidates, our regulatory plans, and the timing of future milestones. The actual results may differ materially, so please review the risk factors in our SEC filings. We will also show data from other companies' trials.
Those comparisons are for context only. There have been no head-to-head studies, and the data we present today are from an ongoing study, and the trial remains subject to change until there is a database lock. Joining me today is Dr. Tony Opipari, who was recently named our Chief Medical Officer. Tony has been with Odyssey since day one, and he has led the phase II trial, so he brings real continuity and expertise to the next stage of development. I have known Tony for over 30 years, and I could not be more pleased to be working with him and having him lead our clinical work. Also with us is Collin Todd, our SVP of Strategy and Business Development. We plan to spend about 48 minutes on the scientific materials and leave about 20 minutes at the end of the presentation for your questions.
In May, we reported top-line data from this trial, 27% clinical remission at 20 mg BID. The primary endpoint was met. Activity in patients who had already failed advanced therapies and a clean safety profile. We also told you that a broad suite of biomarker and transcriptomic analyses was underway, and that we enrolled additional patients at the 10 mg low dose. Today, we are delivering on both. You will see the complete 10 mg cohort, now 15 patients in total. Additional subgroup analyses by endoscopic severity and symptomatic remission over time, objective biomarkers of colonic and systemic inflammation, and transcriptomics on paired mucosal biopsies from baseline and week 12. Let me just say this once up front. This was an open-label study, active only proof-of-concept trial, and nothing we show today replaces a randomized placebo-controlled trial.
That trial, our phase II-B, starts this year, and we will read out at the end of 2027. What today's data gives us is more confidence in three things. First, there are multiple converging lines of evidence that inhibiting RIPK2 scaffolding underlies the clinical benefit that we observed with patient-level correlations across clinical efficacy, histology, biomarkers, and transcriptomics. Second, the 20 mg BID as the lowest maximally effective dose, the dose that phenocopies a RIPK2 knockout. Third, efficacy across patient subsets with no serious adverse events, no discontinuations due to adverse events, which furthers our conviction that OD-001 can be competitive with approved and investigational UC therapies. Let me briefly start with the disease, the target, and how we drug it, and why going upstream has the potential to deliver differentiated outcomes for patients. First, IBD is two diseases, ulcerative colitis and Crohn's disease.
They differ in where they occur and how they progress, but they share the same pathogenic sequence. The intestinal barrier breaks down, gut bacteria translocate across it, and both innate and adaptive arms of the immune system become dysregulated. There are now about a dozen approved drugs across roughly half a dozen mechanisms. Despite that, placebo-adjusted induction remission rates in UC remains below 30%. Most patients do not achieve remission, and many that do ultimately lose response and cycle to the next drug. This is quite personal to me. My son has lived with Crohn's disease for 17 years, and I have watched him go from one therapy to the next, to the next. Patients need new therapies that are more effective, better tolerated, and that could change the natural history of disease. We believe that takes new mechanisms and combinations.
We are starting in ulcerative colitis because it is confined to the colon and supported provably by endoscopy, which makes trials faster and cleaner than in Crohn's. The important thing is that the biology we target is shared by both. IBD develops in three steps. In the first step, the epithelial barrier is breached. Bacteria enter the lamina propria. In step two, innate immune cells, meaning monocytes, macrophages, and neutrophils, and the like, sense bacterial cell wall components through one of two receptors, NOD1 or NOD2. RIPK2 transduces that signal, and RIPK2 activation also amplifies toll-like receptor signaling. The output of this is cytokines that you know well, IL-23, TNF, and TL1A. Neutrophils activated through RIPK2 continue to damage the epithelium, so the loop feeds itself.
In step three, adaptive immune cells, T cells in particular, are recruited to the sites of inflammation that have been activated in the gut. Let us have a quick look at where our previous late-stage drugs sit. The anti-TL1A, the anti-TNF, and the IL-23s, the JAK inhibitors, S1P1 modulators, vedolizumab, all act downstream on individual cytokine components of the adaptive immune response. OD-001 acts at the point where microbial sensing first becomes inflammation, so that rather than blocking one cytokine, the aim of inhibiting RIPK2 is to turn off several of these cytokine sources. That has two implications we will come back to. For monotherapy, the patient who has failed to develop against one downstream cytokine has never been exposed to this mechanism.
For combinations, OD-001 doesn't overlap with any mechanism on this side, and it acts on the innate rather than the adaptive immunity, which makes it a natural partner for them. The case for RIPK2 rests on over 20 years of both animal and human data. In animals, colitis models require microbes. Knocking out RIPK2 reduces inflammatory cytokines and improves intestinal histology, and blocking RIPK2 signaling pharmacologically does the same. Importantly for safety, RIPK2 knockout mice are developmentally normal. In humans, the RIPK2 pathway activation is increased in intestinal tissue from patients with both ulcerative colitis and Crohn's disease. Activated, ubiquitinated RIPK2 is observed across ulcerative colitis patients, including those carrying non-function loss-of-function variants. This is not limited to genetically defined sufferers. Variants in ATG16L1, an autophagy gene, and CARD9, both linked to this pathway, increase IBD risk, and protective CARD9 variants reduce it.
Now with our phase IIa clinical efficacy data with OD-001, there is now proof of concept that RIPK2 works in ulcerative colitis. On the left now I'm showing you how RIPK2 is activated. Bacterial peptidoglycan is recognized by NOD1 or NOD2. RIPK2 must scaffold with a protein called XIAP, which is ubiquitin. That complex activates TAK1, which drives NF-kappa B and MAP kinase signaling, and ultimately inflammatory cytokines. Hold on to the MAP kinase arm, which is something that we'll come back to. You can see that RIPK2 is activated based on ubiquitin status in both Crohn's disease and ulcerative colitis, and that the RIPK2 gene signature, which we designed, tracks with clinical severity from inactive to severe disease. It's something that we tracked in the clinical trials. Importantly, RIPK2 drugs must block scaffolding to fully inhibit NOD2 signaling. This is the design principle behind OD-001.
RIPK2 is a kinase, and the first-generation programs were kinase inhibitors. In 2018, two independent groups, one from Genentech, which published in "Molecular Cell," and one from an academic group, which published in the "EMBO Journal," showed that RIPK2's kinase activity is dispensable for NOD2 signaling. What matters is its scaffolding interaction with a protein called XIAP. Kinase inhibitors that block signaling did so to the extent that they blocked this interaction. If you want to fully shut down this pathway, one must block scaffolding. That's what we set out to do from the first day of this program. OD-001 is an allosteric scaffolding inhibitor. It binds to RIPK2 away from the interaction site with XIAP, and it holds the protein in a conformation such that it reduces the affinity for XIAP.
In the middle panel, it shows you this directly as OD-001 binds to RIPK2, which is shown in the red, XIAP binding to RIPK2, which is shown in the black, falls to zero. The right panel shows you the functional consequences of this interaction in human macrophages stimulated with peptidoglycan, OD-001 blocks production of IL-23, TNF, and TL1A in a concentration-dependent way to near complete inhibition. Three of the most validated targets in IBD are all inhibited by one oral molecule. The question that we get often is whether RIPK2 scaffold inhibitors are all the same. The answer is they're not. On the left is the pharmacology describing this. This is a three-component system. The inhibitor and XIAP can bind to RIPK2 at the same time, forming a ternary complex. What determines how well a compound blocks signaling isn't simply how tightly it binds to RIPK2.
It's how much it changes the affinity of RIPK2 for XIAP once it's bound. That is the Ki on this slide. Because it's a three-component system, the result depends on how much XIAP is present in the assay. A compound could look like a strong scaffold inhibitor at low XIAP concentrations and can lose much of that effect at physiological ones. On the right, we tested OD-001 against three RIPK2 inhibitors developed by others and disclosed in the patent literature. Here we're measuring TL1A production by human macrophages stimulated with peptidoglycan as the output. OD-001 drives TL1A production to near zero. Comparators were A plateaus with most TL1A production intact, whereas comparators D1 and D2 are less potent and plateau with roughly one fifth of TL1A production remaining.
How completely one blocks scaffolding determines how completely you block signaling, and that's why we dose for maximum inhibition in the clinic. Let me turn to the trial itself. OD-001 is the first innate immune-targeted therapy and the first RIPK2 scaffold inhibitor to enter clinical development for ulcerative colitis. We designed this phase II-A to answer a go/no question, is the drug safe and active, and is the signal strong enough to justify further development? We set the bar before the trial got started. The primary endpoint was changed from baseline in three component modified Mayo score of 12, power to detect a two point change. For the key secondary endpoint, which was clinical remission, the trial was designed to detect a placebo-adjusted improvement of at least 15 percentage points over a historic placebo rate of 10%. In other words, we were looking for a remission of roughly 25%.
The dose selection for the trial came from the phase I study. RIPK2 isn't active in healthy volunteers, so we measured target engagement ex vivo. Blood from dosed patients was stimulated with peptidoglycan, and we measured TNF. On the left, 10 mg BID reduced TNF stimulated by about 70%, 20 mg BID reduced it by about 90%, and 30 mg and 50 mg added nothing further. 90% is what we see when RIPK2 knockout cells are examined in vitro. So we chose 20 mg BID as the lowest dose projected to be maximally effective. The PK on the right is consistent. At 20 mg, exposure stays above the whole blood IC90 for most of the dosing interval. So going in, 20 mg was the dose we expected to perform best, and 10 mg gave us a submaximal comparison.
Tony led the trial, and he'll take you through the design of the data. Tony?
Thanks, Gary. The trial enrolled patients with moderate to severely active ulcerative colitis with a modified Mayo score of five to nine. The trial was open at 18 sites across seven countries. We allowed up to three prior advanced therapies. Dosing was done in two parts. Part one started at 10 mg BID, so we could establish safety in UC patients at submaximal inhibition before we moved on to maximal inhibition. We expected 10 mg to be active, but its first job was as a safety branch. Part two moved to 20 mg BID. We randomized one to four between a two-week step-up from 10 mg and 20 mg from day one. Those were the two arms that we randomized in part two. Step-up was there in case we needed a tolerability strategy, which we ultimately didn't. After 12 weeks, patients moved to vedolizumab, with follow-up through week 52.
At the start of this trial, we had three months of chronic toxicology, which limited OD-001 dosing to 12 weeks. An approved therapy after this made the trial attractive to patients and investigators. We've since completed six and nine month toxicology, and future studies will dose OD-001 continuously. Because the trial was open-label, we built in several features known to reduce potential placebo response. An endoscopic sub-score of at least two and active rectal bleeding were required at trial entry. We used centrally read blinded endoscopy. We capped steroids at 20 mg of prednisone equivalent. We ran the trial with Alimentiv, a CRO with deep IBD experience, and our team was directly involved at every level in the investigation. We often get asked why we ran this study as an open-label study.
This was the first time a RIPK2 inhibitor had been tested in ulcerative colitis, and with so many approved and effective therapies available, it's a challenge to enroll patients into a placebo-controlled phase II study with a mechanism that has no efficacy data until that point. Investigators told us that an active-only design would let them enroll efficiently. The trial was built to answer one question, is RIPK2 active in ulcerative colitis, and should we keep investing time and money behind it? It wasn't designed to estimate a precise placebo-adjusted remission rate. That's the job of phase II-B. Next slide. The participant characteristics are shown here. Here is the baseline of the group of patients that we enrolled, alongside a comparator of recent UC trials. What you can see is that our patients are generally similar.
Beyond the overall data that we'll be showing, we'll also break out two key subgroups, patients with prior advanced therapy experience and patients with the most severe endoscopic disease and MES of three. Now to the data. What's new, then biomarkers, efficacy, and safety. The induction portion of this trial was complete. In May, we reported to you 49 evaluable patients, 8 at 10 mg, 41 at 20 mg. Those first 8 10-mg patients performed well, so we made a decision to enroll more patients at 10 mg to find out whether that signal held in a larger sample. We now have 56 evaluable patients of the 61 enrolled, 15 at 10 mg and 41 at 20 mg. five patients were not evaluable, all for reasons unrelated to OD-001, t hree discontinued early, one relocated, and one failed to report study data at the endpoint.
New today are efficacy by segment and over time, biomarkers, and transcriptomics. The takeaways are on the right. The greatest efficacy is at the dose that maximally inhibits RIPK2, 20 mg BID. Tolerability remains favorable, with no discontinuation due to OD-001. The inflammatory biomarkers show a concordant dose response, which indicates clinical activity is driven by OD-001. Blood and biopsy biomarkers are valuable here precisely because they give an unbiased, objective measure of the clinical effect. On the next slide, four markers of inflammation are shown here, baseline versus week 12 and by dose. Starting on the left, fecal calprotectin is a marker of colonic inflammation. It trended down across all patients at 20 mg. hs-CRP, a systemic biomarker, fell significantly at 20 mg. Serum albumin, shown next, rises as systemic inflammation falls and the mucosa heals. This increased significantly at both doses.
Finally, on the far right, neutrophils, which express RIPK2 and drive barrier damage, fell significantly at 20 mg. Laboratory-based measures, including these, alongside endoscopy and histology, are how you understand whether a drug is reducing inflammation locally in the colon and systemically, and whether there's a dose response. Here, albumin improved at both dose levels, which tells us 10 mg is active in doing something for the disease. But across all the other markers, it isn't doing as much as 20 mg. hs-CRP and neutrophil come down at 20 mg, but not at 10 mg. The same separation you'll see in the clinical endpoints. That's a comparison we simply couldn't make in May. With eight patients at 10 mg, we could see biomarkers track with outcomes, but now what's happening between the two doses?
With the full cohort, we can, and 20 mg is significantly stronger on the relevant colonic and systemic markers. Next slide shows efficacy at 12 weeks. The trial met its primary endpoint at both doses and on a consolidated basis. There was a mean reduction in the modified Mayo score of 2.4 points, which is a p-value less than 0.001. Looking holistically across the efficacy endpoints, 20 mg delivers a better response. At 20 mg, clinical remission was 27%, symptomatic remission, nearly 50%, clinical response, over 60%, each well above the historic placebo benchmarks from contemporary UC trials that are shown as gray bars. In May, we had eight patients at 10 mg, small number to make a dose decision on. In our phase I pharmacology, as Gary Glick showed, told us that 20 mg would be better.
We ran the experiment, doubled the number of patients at the low dose. Of the seven additional valuable patients, one reached clinical remission, one had endoscopic improvement, and five had no response. With this larger cohort, along with the other efficacy measures and biomarkers I just showed you, the answer is clear. Going back to look at additional patients was the right decisions, and 20 mg is clearly the best dose. That conclusion doesn't rest on one or two patients. It rests on the totality of the data that I've shown. It's what the pharmacology predicted. 10 mg covers about 70% of the target and is partially effective, while 20 mg covers about 90%, essentially the maximum inhibition achievable, as in the RIPK2 knockouts. All in all, it's a very competitive profile, multiple lines of evidence all converging around 20 mg.
We also show a dose response based on disease severity. In patients with moderate endoscopic disease, shown on the left panel, and having an MES of 2, remission was similar at both doses. In patients with more severe disease on the right, an MES of 3, the doses separate. None of the eight patients at 10 mg reached remission, compared with 16% at 20 mg. That fits the biology Gary Glick showed you. More barrier dysfunction means more microbial exposure and the need for more complete RIPK2 inhibition. As you can see on the right, MES 3 remission rate at 20 mg is competitive to what obefazimod recently reported in their phase III program. Looking at a different cut, this is one of the findings that we consider the most important. Most UC therapies lose activity in patients who have already failed an advanced therapy.
You can see it on this slide. Obefazimod goes from 31% in naive patients down to 12% in AT-experienced patients. In the ABT-581, upadacitinib goes down from 37% to 24% in consolidated phase III data. At 20 mg, OD-001 remission was 29% in advanced therapy patients and 23% in advanced therapy-experienced patients. The experienced group is 13 patients, so the confidence interval is wide, and I'm framing the finding conservatively. We did not see the drop-off that most therapies show. Against a historical placebo of 3% in experienced patients, that's a strong signal of effect. Mechanistically, this makes sense. Patients fail drugs against a single downstream cytokine or T-cell trafficking, and OD-001 acts upstream. Gary Glick will show a few slides transcriptional data that bear onto this. The speed of onset matters for patients and for physicians.
At 20 mg, about one in five patients was in symptomatic remission by week two. It's rising to 37% at week eight and 49% at week 12, with no plateau over the course of treatment. Alongside our data are two oral agents in late-stage development, like icotrokinra, an oral IL-23 receptor antagonist, which reached 42%-53% at week 12 across doses against 19% on placebo, and obefazimod, roughly 38%-40% at week eight against 19% on placebo. The read is that patients feel better fast on OD-001. It's competitive with two of the most exciting late-stage oral agents in development and keeps deepening on an upward trajectory through week 12. In May, we showed you that safety was very good, and it's still very good with complete data set.
Across all 61 patients at both doses, no serious adverse events, no serious infections, no liver signal, no discontinuations due to drug-related adverse events. The most common drug events were fever and headache, both resolved on their own, and no patient needed to stop treatment. The one grade three event of anemia was in a patient with pre-existing anemia, and this was unrelated to OD-001. For this drug, safety is central to how we intend to use it as a monotherapy, as long-term maintenance, and as a backbone for combinations. To summarize the clinical findings, 20 mg BID. OD-001 has an efficacy profile that's competitive with approved and leading investigational therapies. 27% absolute clinical remission with rapid onset and efficacy across patient subgroups, which supports potential for broad use.
Greater reductions in colonic and systemic inflammatory markers at 20 mg, the dose projected to be maximally inhibit RIPK2, support the efficacy conclusions and the objective endpoints and biomarkers. All of this being concordant, aligning with the significant symptomatic benefit. It's oral. There are no SAEs, no discontinuations due to OD-001 at either dose. Gary, I'll hand it back to you.
Thanks, Tony. The clinical data tell us that patients got better. The tissue data tell us what the drug did in the gut. These are direct measurements in patient tissue from baseline and after 12 weeks of treatment and augment our understanding of the mechanism and potential for future differentiation. We took mucosal biopsies at baseline and week 12 and ran RNA sequencing, an unbiased look at roughly 20,000 genes to see what OD-001 does in the tissue. We asked three questions. What changes occur in the tissue? Whether those changes track with clinical outcome, and whether there are effects specific to OD-001 when we compare with approved therapies. This is the whole transcriptome view in a 20 mg cohort, 40 patients with paired biopsies. Blue genes went down from baseline to week 12, orange went up.
The boxes on the bottom go back to the pathway I showed you earlier. RIPK2 signaling and the innate host defense signaling responses are down. The cytokines immediately downstream of RIPK2, IL-23, TNF, and TL1A are down. T cell responses, particularly effect the effector T cells, TH17 and TH1 are down. Importantly, fibrotic signaling is down, and epithelial homeostasis, a marker of mucosal healing, is up. This is exactly what one would want to see. Concordant changes from the target through the cytokine to controls to the T cell responses in the tissue. The drug is doing what we designed it to do. Now, the same signature split out by outcome at 20 mg. In patients who reached clinical remission, the RIPK2 gene signature falls significantly, and so does signaling through IL-23, TNF, and TL1A, the validated disease cytokine I showed you earlier, all of which RIPK2 regulates.
Patients with clinical response move in the same direction. You see it's obviously a heterogeneous disease, and no therapy works in every patient. We're doing more patient-level work across the data set, and our upcoming trials will keep testing it, which may teach us more about who responds to OD-001 and who doesn't. The same effects that we saw in cytokine cells for effector T cells, TH17 and TH1 signatures decline significantly in patients reaching clinical remission with a trend in responders and no change in the non-responders. Acting upstream, OD-001 also quiets the adaptive immune response that sustains disease. This is important for our combination strategy. OD-001 dampens T cell activation in the gut at its source, while vedolizumab keeps T cells from trafficking into the gut.
Two complementary ways to reduce the same pathogenic T cell burden, which is one of the reasons why we are excited about the combination. The next slide shows you a distinct set of inflammatory genes that are modulated by OD-001 and that are not addressed with existing therapies. When gut bacteria activate NOD1 and NOD2, RIPK2 signals through two arms. One produces the cytokines TNF, TL1A, and IL-23 that anti-cytokine drugs block. The other directly activates the MAP kinase pathway, which turns on a transcription factor called AP-1. AP-1 is relevant across many inflammatory diseases. AP-1 related genes are increased in inflamed tissue in IBD, rheumatoid arthritis, psoriasis, MS, and asthma.
Because it sits downstream of RIPK2 and MAP kinase, it was one that we thought would be worthwhile looking at, and in fact, we see an effect. On the right, we compare endoscopic responders on OD-001 with endoscopic responders in published patient-level data sets for infliximab and vedolizumab. These are all the patients whose mucosa improved. In OD-001, AP-1 subunits and the AP-1 target genes are significantly down-regulated. In infliximab and vedolizumab responders, they are not. I am not saying that AP-1 is driving the clinical effect. What I am saying is that OD-001 blocks a well-known inflammatory process that other agents do not block. In a study without a placebo control, it is helpful to show that this effect simply does not come along with mucosal improvement. All of these patients are responders, so it tells you that this is a pharmacologic effect of OD-001. Next slide, please.
Fibrosis is the natural course of IBD. Surgery remains common despite advanced therapies, and there are no approved anti-fibrotic treatments. In patients who achieve remission on OD-001, two fibrosis gene signatures, an inflammatory fibroblast signature and a penetrating fibrosis signature, fell significantly. At the same time, the epithelial homeostasis signature rose significantly in both remitters and responders. These are gene expression signatures and an early signal, but it is the kind of signal one would want to see from a drug with the potential to change the natural history of disease. Let us go to the next slide. Thank you. Here is another piece of supporting evidence. We applied the same penetrating fibrosis gene signature to a published golimumab trial that biopsied the placebo arm. The goli responders showed a significant reduction. Placebo responders, even though they improved clinically, do not.
OD-001 responders showed a significant reduction, similar in depth to the goli. This suggests that the responses on an effective treatment run deeper on this measure than placebo responses, and OD-001 shows this depth of response. Let us go to the next slide, please. What I am showing you on this slide is patient-level data. Each line is one patient at the 20 mg BID dose. Orange are patients in the clinical remission, blue are non-responders. Each column is an independent measure. RIPK2 and TH17 signaling, two fibrosis signatures, histology and MAGNIFI score, and fecal calprotectin. Below zero is improvement, above zero is not. What you see is consistency. Patients in clinical remission are not improving on one measure. They are improving concordantly across inflammatory signaling, fibrotic remodeling, histology, and mucosal inflammation. Non-responders do not. Just want to point out two blue lines that are worth noting, mark one and two.
Both of these patients were advanced therapy-experienced patients who didn't meet the clinical remission criteria, yet they improved with the remitters on the transcriptional measures. One had a histologic response, and the other had on the hard endpoint, they got better too. This suggests that with continued dosing, these patients might also achieve clinical remission. On this slide, what I'm showing you is a comparison of differential gene expression of OD-001 with that that was reported with an anti-IL-23 therapy known as mirikizumab. IL-23 is a downstream cytokine of particular interest and one we believe is predominantly driven by RIPK2 in the disease. On the left, we correlated each of the gene changes with improvement in disease activity of the 20 mg cohort. The genes most tightly linked to improvement included IL-1 beta, IL-23, and IL-17.
On the right is the same analysis Lilly published for mirikizumab, the approved anti-IL-23 agent. What you can see is extensive overlap between the IL-23 mediating genes and the genes regulated by OD-001. That's consistent with RIPK2 controlling IL-23 signaling in IBD tissue, and it shows both OD-001's tissue response resembles that of an approved and effective drug. Beyond the IL-23 comparison, we identified public data sets with patient-level data for infliximab and vedolizumab and ran the same type of comparisons. I'll summarize the data on the next slide. One finding that isn't on the next slide, however, is that OD-001 regulates the majority of the published 34 -gene mucosal signature associated with poor responses to an anti-TNF. That's a rationale for the efficacy Tony showed in the advanced therapy-experienced patients. OD-001 acts on biology associated with patients not responding to a downstream anti-cytokine therapy.
Some biology is shared between OD-001, infliximab, and vedolizumab. Fewer inflammatory monocytes, lower TNF, lower TH17 and IL-6 signaling, and higher epithelial homeostasis. You'd expect that in any patient who improves. The more informative rows are the next two. OD-001 shares reductions in inflammatory cytokine and IL-23/TH17 programs with infliximab, but not with vedolizumab. It shares reductions in fibrosis and collagen remodeling pathways with vedolizumab, but not infliximab. So why does this matter? General mucosal improvement, as might occur in a placebo responder, should look like the shared row and nothing more. Instead, OD-001 overlaps with each approved drug on a mechanism-specific biology the other drug doesn't touch. The pattern suggests the drug effect of OD-001 goes beyond general mucosal improvement you'd expect with a placebo response. With this, let me wrap up.
The phase II-A clinical proof of concept for a best-in-class oral RIPK2 therapy and the biomarker and transcriptomic data that we talked about today link RIPK2 inhibition to the clinical efficacy we observed. The efficacy biomarker and transcriptomic data support 20 mg BID as our therapeutic dose, and 20 mg clinical remission rates were similar irrespective of prior advanced therapy, and symptomatic remission began as early as two weeks and increased through week 12. There was no serious infections, no discontinuations due to adverse events, and a profile that would support OD-001 as a backbone for combinations and long-term maintenance. The differences between OD-001 and vedolizumab in the transcriptomics are consistent with complementary mechanisms and the potential for additive or synergistic effects in combination. I'll be very direct about what these data add up to. In May, we said this drug was active.
Today's data make us more confident that the activity comes from OD-001, that 20 mg BID is the right dose, and the right next step is a randomized program, which we're starting now. The placebo-controlled answer comes in the second half of 2027, and we've designed trials to deliver it cleanly. Here's how we're taking OD-001 forward. We will advance in parallel as a monotherapy and in combination in ulcerative colitis and establish it in UC before expanding into Crohn's disease or other inflammatory conditions. Potential future indications include spondyloarthritis, for example, comorbidity in IBD. The phase II-A combination trial pairs OD-001 with vedolizumab, an orthogonal combination that addresses upstream activation and downstream immune cell trafficking to the gut. It's randomized and double-blind, comparing combination induction with VETO plus placebo. After induction, all patients enter 001 monotherapy maintenance, with results expected in 2028.
We presented the design several weeks ago at the ACG conference. The phase II-B is a randomized double-blind testing multiple 001 doses against placebo designed to support advancement into phase III, and we'll share further design details in the future. We're running these trials in parallel because the phase II-B establishes monotherapy efficacy against placebo, which is what supports advancement into phase III, while the combination trial tests whether adding an innate inhibition to an adaptive therapy can lift the efficacy ceiling ulcerative colitis drugs run into today. Both trials initiate the second half of this year, and both placebo-controlled induction trial readouts remain on track for the second half of 2027. Beyond RIPK2, OD-002 is a program we're very excited about. It's an oral inhibitor of SLC15A4 that blocks pathogenic signaling from TLR7, TLR8 , and TLR9, which gives us potential for selective B-cell modulation in a pill.
We expect to file the CTA for this program this year and begin dosing healthy patients in the first half of 2027. The phase I includes an ex vivo stimulation assay of the type that has translated to efficacy with the TLR7/8 antagonists in multiple lupus trials, with the results expected from this in the second half of 2027. The phase II portion of this trial will study multiple inflammatory diseases, including a cohort with cutaneous lupus, with phase II readouts and multiple indications through the second half of 2028. We look forward to sharing more on this program. Our OD-003 program, our TNFR2 antagonist is finishing IND-enabling studies, with completion projected in the first quarter of 2027. We're also watching carefully TRex Bio, which recently went public and expects efficacy data from its TNFR2 program in the middle of next year.
If their data are positive, we believe that bodes well for ours. Lastly, the company had $433 million in cash as of June 30th, which we expect to fund operations into the second half of 2028 through the OD-001 phase II-B in combination readouts and the phase I readout of OD-002. With that, operator, we're ready to take questions.
Thank you. As a reminder, if you would like to ask a question, please press star one one. If your question has been answered and you would like to remove yourself from the queue, press star one one again. Our first question comes from Tyler Van Buren with TD Cowen. Your line is open.
Hey, guys. Good morning, and thanks so much for the robust presentation. Just to clarify, did you say that you were testing multiple doses in phase II-B? Because given the incrementally improved efficacy observed with 20 mg OD-001 compared to 10 mg, just curious what gives you confidence that 20 mg could be the right dose moving forward and you should not test higher doses like 30 mg and go for 95% or greater inhibition given the strong safety. The second question is just given the robust biomarker results presented, why might OD-001 have greater durability of effect and prevent relapse relative to something like vedolizumab, as we have seen in past case studies?
Thanks, Tyler. With respect to your first question, testing multiple doses is an FDA requirement. The reason why we have elected not to go above 20 mg, when we look very carefully at the data that came out of the ex vivo stimulation assays in the phase I study, along with other preclinical in vitro data, there really does not appear to be any benefit or one does not gain further inhibition by going higher. So, 20 mg really is the lowest maximally effective dose, and we do not expect to see any more efficacy from going higher. With respect to your second question, we are really excited about the transcriptomic data that came out. There is a lot to chew on. Mechanistically, RIPK2 is, by acting so upstream, it is thought to block what is referred to often as smoldering inflammation.
Even though patients may be symptomatically in remission, there is still microscopic inflammation ongoing. Because RIPK2 is able to block that, in principle, that should lead to a more durable, longer-lasting response. There is also some evidence in the literature that downregulation of AP-1 is related to relapses, or upregulation, I should say, of AP-1 is related to relapses. So, there are a number of different potential mechanistic features that we think RIPK2, even as monotherapy, can lead to a more durable response, and certainly on top of vedolizumab, which takes out the T cell component.
Thank you. Our next question comes from Eric Schmidt with Cantor. Your line is open.
Well, thanks for taking my question, and thanks for the fascinating scientific presentation here. Appreciate you going over it in great detail. My question is on the non-responders. Do we know if OD-001 is inhibiting RIPK2 and downstream AP-1 and other signaling in all patients? If not, why not? Then maybe a related question on whether, Gary, you've been able to find any baseline predictors of response, upregulated RIPK2 gene signatures, for example. Thank you.
Yeah. To start with your second question, or the last part of your question first, we are actively looking at individual genes on a patient-level in addition to other analytes that may inform a patient selection stratification strategy. That's work that's ongoing, obviously. No one has been able to achieve that for any UC drug. If one is able to do that, it's a real game changer. Remarkably, the non-responders have almost no transcriptomic changes that are easily measurable. It's actually a very benign drug from an off-target perspective as it relates to the transcriptomics. The one thing that Tony didn't mention, which is a null hypothesis question, is that the PK across all trial participants is similar, so we can't simply ascribe non-responders to a PK effect.
There are probably the best data that suggest target engagement in those, and we don't have direct measures of target engagement, come from hints from some of the transcriptomic data. But it's nothing that I'd be willing to. They're not statistically significant enough for me to put in the presentation to talk about. There is a number of other experiments that we have ongoing from the biopsy samples to rule out things like variants in RIPK2 or those to prevent target binding. But none of those have ever been reported. There's something in the signaling pathway that prevents after target binding. We're looking at things like cFos levels, RIPK2 levels, and the like. But nothing has come to light at this stage that would explain the non-response.
Thank you.
Thank you. Our next question comes from Brian Cheng with JP Morgan. Your line is open.
Hey, guys. Thanks for taking our questions this morning. A couple from us. When you think about the totality of the data, can you further speak to your confidence in the durability of effect and whether we can see further step-ups in the clinical response when you dose these patients for longer period? Then we have a follow-up. Thank you.
Sure. If one looks at historical precedence, almost every, I think, UC drug gets better after the induction period. I think there are nine or 10 of them now, so there is no reason to believe that this would not be one of them. I would say the supporting line of evidence in the data we presented today is the symptomatic remission. Unlike several of the other agents, the comparers we showed on that slide, there is no change and there is no plateauing in the slope of that curve, which suggests that patients could continue to get better. If you also look at data we presented in the S-1, we also showed the rectal bleeding continuing to go down over time. So we feel pretty confident that the numbers will just improve with time.
Great. Just going back to your combo trial design with vedolizumab. As I recall that you have guided exactly what the designs look like for both studies, the phase II-B mono and also phase II-A combination of vedolizumab at the time of the IPO. Looking at the combo trial design you have laid out, you are going to test 10 mg BID with vedolizumab. Based on the profile here today where 20 mg BID is definitely the way to go, is there any potential to use 20 mg instead, combining with vedolizumab? How are you thinking about the combination dose? Thank you.
Yeah. So at the time of the S-1, we were looking at 10, but in the totality of the data, the combo trial will employ 20.
Great. Thank you.
Yeah. What we reported at ACG was 20 mg, and that will be the dose for the combo trial.
Thanks for confirming. Thank you.
Thanks.
Thanks, Gary.
Thank you. Our next question comes from David Nierengarten with Wedbush Securities. Your line is open.
Hey, thanks for taking my question. I was just wondering, I'm thinking about all the oral combinations and maybe touching on if you guys were looking at the oral alpha four beta seven integrin inhibitor. Obviously, there's none approved, but could potentially be developed with yours, and also, or of course, a JAK inhibitor. Anyway, just thoughts on adding those arms into a combination study. Thanks.
Yeah. Gilead reported very interesting data yesterday. I think certainly once we have the first look at how the drug does with vedolizumab, that opens up the possibility to combine with an oral agent such as that. As you know, we're pretty stout medicinal chemists here at Odyssey Therapeutics. So we have the ability to not only potentially partner with someone, but to also create our own. Obviously dealing with an approved agent to start lessens the regulatory and preclinical burden for the program. We're very excited about the potential to combine with something like JAK inhibitors. I think as everyone knows, upadacitinib is extraordinarily effective, but carries with it some toxicity baggage. It's possible that one would be able to lower the dose of upadacitinib in combination with something like OD-001. If one observed even an additive, it's not a synergistic effect. Obviously, there's tofacitinib.
There was recently at DDW, Takeda reported some data combining tofacitinib with vedolizumab in a hard-to-treat group of patients, and really showed outstanding data. There's obviously obefazimod coming down the line, which could be an interesting combination partner. So we have our eye on those. Then there's some interesting work here in Barcelona talking about the role of B cells in IBD. As you may know, our SLC15A4 inhibitor, which is a selective B-cell depleter, hitting the pathogenic ABC B cells. It's a possibility that's a combination we would own our own and have the ability to obviously get started on pretty quickly. We're very bullish on not only the quality of the molecule there in the SLC program, but the mechanism. So lots of different things that are open to the company at this stage.
If I could have a quick follow-up. At the presentation this morning, they commented on the fever being low grade in a couple of the patients. Could you just remind us what that means on the patient side and the results? Thanks.
Sure. Yeah. There were two Grade one fevers. The maximum in one of the participants was 38.1, maximum in the other was 38.6, and they lasted from a matter of hours to essentially about a day. There was no concomitant therapy necessary, nothing else associated with it. I'll also point out, David, that fevers like this have been observed in other immunomodulators, both that are approved or in development.
Thank you.
Thank you. Our next question comes from Jeff Jones with Oppenheimer. Your line is open.
Thank you, and good morning, guys. Question for you on patient selection in the planned phase II studies. Obviously, placebo is a very important factor in how we review and interpret these data. Could you talk a little bit about how you're thinking about enrollment criteria and patient selection to manage placebo responses? Then maybe also comment on the inclusion of patients who are AT-experienced and how you're thinking about that, and whether that's then a formal subgroup for some of your future analyses. Thanks.
I'll just make a general statement then turn it over to Tony to answer some more on the specifics. There is some trade-offs that one needs to consider. If one sort of limits or tries to restrict patient groups, it can really extend the time that these trials go. There's a balance between taking high quality patients, and that's the most important thing, getting the right patients on the trial, then taking those patients and subdividing those into this amount of steroids or advanced therapy or by MES score. What we're trying to do is really balance the sort of overall demographics as it relates to some of the parameters you're talking about, and the ability to get the trials done in sort of a reasonable amount of time. But I'll let Tony comment further.
Yeah, no, we're going to take contemporary, what's known as the very best strategies, and I think you hit on a number of points. At a future point, we'll describe in greater detail what we're doing with the phase II-B monotherapy design. What we've described at the ACG meeting with respect to the combination. Let me start by saying, one of the biggest impacts that we understand can contribute to these unforeseen higher placebo rates is potentially the use of corticosteroids in a way which is not reported or not understood by the sites. We're making a very concerted effort to really work with the PI, work with the sites to ensure that any use of corticosteroids is understood and can be accounted for in the trial so that's not a confounding factor.
Beyond that, in terms of the enrollment criteria, we are allowing up to four failed drugs in advanced therapies, three classes. We otherwise are using the same degree of moderate to severe criteria for mild to severe that we used in our phase II-A trial. I think that's probably the best summary of where we are.
Great. Thank you.
Thank you. Our next question comes from Alice Nettleton with UBS. Your line is open.
Hi. Thank you for taking my questions. I have two. Interesting analyses presented today. Ultimately, how does this kind of change your confidence in the probability of success for the phase II monotherapy and vedo combination studies coming up? Can you remind us what you would consider a successful outcome for each study now that investors' attention is probably going to turn to this readout? Secondly, how important do you think these analyses will be in shaping the industry perceptions of RIPK2 as a therapeutic target in IBD, particularly given the historical challenges with this target? Thank you.
Thank you. Thanks for the question. With respect to probability of success, I think we were very confident. Certainly, coming out of the trial and at around the time of the IPO, this only enhances our confidence. Having additional unbiased hard endpoints that are not patient reported across what is now an industry acceptable number of patients and showing the concordance of endpoints, showing evidence for the biology, I think just overall very significantly increases the overall probability of success. The way I talk about this internally is there's no question that the drug works. It's making sure that the next trial is run as efficiently as the first trial. With respect to the overall numbers, the number that we focus on most internally is what is the combination induction VDA? Because this field is moving toward combinations.
I think walking around here in Barcelona, that is really the thing on everyone's lips. It is what is your combination strategy and what are you looking at? I think at a 40% induction remission is really where our lowest expectations for the combo with VDA. For the monotherapy, what's important obviously is safety, the fact that obviously the molecule is oral and that we demonstrate significant efficacy. The reason why I'm not giving you an exact number there is as we've seen this morning and as we've seen over the last couple of days here and as we've seen at DDW, the potential for synergy is real, and it's just hard to project synergy from two. It's not simply additivity for a number of these mechanisms now. Having an active drug similar to what we've observed so far, I think puts us in an outstanding position.
I'm sorry, can you repeat your other question?
Yes. The question was just around how important they will be in shaping industry perceptions of RIPK2. Yeah.
It is a great question. The first set of trials started before the, I think, the seminal work on RIPK2 scaffolding was published, and that was by GSK, and they had a molecule-specific, a liver signal. I think that sort of muddied the waters a little bit around the target. I showed the slide that not all RIPK2 inhibitors are the same. A couple of the competitors came from a patent that only used below physiological levels of cIAP in their assays, so it looked really good there. But once you put it into cells, it was very clear that the molecules were not really that active.
I think the totality of these data and others starting to come out about RIPK2, I think folks, it is hard to imagine how one could not think that the promise of the target is real, the target is valid, the pharmacology is reproducible, the pharmacology is predictable, the mechanism is driving forward what the preclinical and sort of the 20 years of discovery have brought to bear. Most importantly, not only is the target safe, and I think we knew that at least from the knockout animals, but OD-001 is safe. It is hard to drug, but if you have the right compound, it works.
Thank you. Our next question comes from Thomas Deal with Raymond James. Your line is open.
Great. Hey, guys. Thanks for taking the question. Gary, you touched on this a little bit, but as you look at the biomarker and transcriptomic data here, to what extent does this also build your confidence that this mechanism should be active in Crohn's? In other words, would you expect to see similarities in kind of the differential gene expression among treatment responders in both indications? Then maybe just quickly, we saw some data from another RIPK2 compound at UEGW this weekend. Obviously, a very small open label UC trial out of China. Just curious for any early impressions there and whether you think that's kind of broadly supportive for the mechanism. Thank you.
With respect to Crohn's disease, we believe the mechanism should work in Crohn's disease. The biology is shared among both indications. From a company strategic standpoint, we want to establish our position first in ulcerative colitis before moving into Crohn's. Crohn's is a tougher disease to treat for a lot of different reasons. But we have every expectation that this mechanism will have equal or perhaps even better efficacy in Crohn's disease. We are familiar with the other trial out of China that you're referring to. Again, it was a single-site study across a small number of patients in China. We believe that is certainly supportive of safety of the target, consistent to what we've observed. There is evidence of a signal there. So I think that overall, directionally, it's broadly supportive of the target and pathway.
Obviously, we'll need further data from that study on AT-experienced, AT-naive, MES 2, MES 3, and obviously a larger number of sites in other geographies to get a sense of how the compound performs. But directionally, it's all moving in the right direction.
Thank you. This concludes the question and answer session. I will turn it back to Gary Glick for closing remarks.
Thank you. So thank everyone for their careful attention and thoughtful comments. I hope that, we have tried in this presentation to be as transparent as possible, laying out all the data we have, laying out patient-level correlations, which oftentimes you do not see and certainly do not see in data sets for a phase II-A study. We walk away more convinced than ever in the target and the pathway and look forward to reporting the data from the phase II-B studies and the phase II-A combination study next year. Thank you, everybody.
Thank you for your participation. You may now disconnect. Good day.