First day, first session here at, at Mai-Britt anyway, at our conference. Thank you, guys, so much to IO Biotech for joining us this morning. Let's jump in for everybody on the webcast, hopefully, with a brief overview of the company. Can you talk a little bit about yourselves, your cancer vaccine platform, and where you're at? Yeah. Do you want to introduce yourself? Sure. Amy Sullivan, CFO of IO Biotech. Thank you for having us. Our pleasure. Yeah. Mai-Britt Zocca, the CEO of IO Biotech. Thanks also for having us. We have a very exciting pipeline, and we have a very exciting technology where we are using the T-win platform to generate therapeutic cancer vaccines. What really differentiates us from anyone else that are developing therapeutic cancer vaccines is that we are hitting hard on both the immune suppressive cell compartment and the cancer cells. What that really drives is that we have an ability to really see a much larger effect in the patients treated with these vaccine strategies. What we have seen in recent trials that have read out is quite a dramatic effect in progression-free survival in our phase III trial that read out earlier this year. We are seeing a similar effect with some of the earlier targets we have in our pipeline. It is really a platform technology where we can use different targets to hit different cells in the tumor microenvironment and thereby generate a much better effect on the tumor cells themselves. Excellent. You mentioned the phase III, so let's start there. Yeah. You announced your top line result earlier this year. It was a narrow miss on P-value. Can you walk us through, as you say, there's what looks like a substantial PFS benefit. Can you walk us through the study design, what led to the narrow P-value miss and where it went? Yeah. It was, we have been really working hard on this phase III trial the last couple of years and really been excited about both the enrollment rate that we saw with patients coming into the trial. That generated a lot of excitement at the clinical sites with the investigators. We took in 407 patients. We had an aim or a goal of 380, but we landed on 407 patients. Those patients were randomized one-to-one with the combination where we used our lead program or the lead product, Cylembio IO-102, IO-103 in combination with pembrolizumab against pembrolizumab alone. That was the control arm. It was a global study. We enrolled across the globe. What we saw as a readout was really exciting. Despite the narrow miss on the P-value, that's still a pain point. We have looked beyond that now and really understood that we have a drug. It has been discussed, of course, with several key opinion leaders and others. They are excited about what they are seeing as an effect in the patients. We came out with a hazard ratio of 0.77 or 0.76 in PFS. The study was powered for a hazard ratio of 0.65. Because there was this discrepancy between what we had set up in the statistical analysis plan and where we really landed, you know, that probably resulted in the study being just a little bit too small. Even over-enrolled as it was. Yeah. Can we talk about the assumptions that led you to the powering choice that you made and what drove those assumptions? Yeah. That was really our proof of concept study, MM1636. That is a phase one two study, single center, single arm trial that gave us the breakthrough therapy designation by FDA some years back. What we saw there was really a dramatic effect in overall response rate, 80%, and a CR rate of 50%. Of course, we have set up the phase III based on those data that we saw in that trial. We landed on a PFS value in that study of 25-month median PFS. What we see in the phase III trial really actually almost mirrors the PFS value. We have replicated that, but based on the hazard ratios, we were unable to actually hit on the P-value. Okay. You met with the agency who told you you needed to run another study. Can we talk about some of the subgroups that you saw in the phase III where maybe you had bigger effect sizes or you had especially nice results and how that can drive you into the next trial? Yeah. Of course, we want to learn as much as we can from this study. It's been giving us some very important data points. Especially if we look at the PD-L1 negative subgroup, what we are seeing there is really a dramatic effect. The patients treated in the experimental arm come out above 16 months in median PFS, where in the control arm, we have three-month median PFS. It's almost four times up in effect that we are seeing in those patients. That's really interesting to me. It jumps out at me when I saw the results for the first time because we're used to thinking of other oncovaccines as being most active in highly inflamed tumors and PD-L1 positive tumors, those being the places where the effect size is the strongest. You saw almost the opposite here. Is that fair to say? It's fair to say. It really reflects what we expect from the mechanism of action that we have in our vaccine strategy. As I mentioned in my introduction, we are going after the immune suppression. Because we are lowering and we know that we are targeting specific those cells that are helping to shield off the tumor cells, because we can target those specifically, that's driving the effect we are seeing also in the PD-L1 negative group. We have seen it in other models and also in other of our trials that we do have an effect in the PD-L1 negative patients. Excellent. What pieces do you still need to align on with the FDA to head into the next trial? I mean, we have now announced the trial design just recently that we are going after. Of course, we want to discuss that in more details with the agency here in the U.S. and also understand that we are hitting on the right comparator. That was one of the things that we discussed in the earlier meeting we had with the FDA. We are just going back and just reiterating some of the points that we already have discussed with them at the earlier meeting we had some weeks ago. The comparator arm is a particularly interesting question, right? Obviously, in melanoma, we've got a couple of different combination therapies that are almost neck and neck in terms of current market share. PD-1 monotherapy also still has meaningful market share. Can you recap maybe the conversation that you had with the FDA about the comparator arm first? Tell us a little bit about how you're deciding on the appropriate comp arm for the next trial. Yeah. There is no doubt that ever since we started our own phase III trial that just read out, anti-PD-1 monotherapy was definitely a standard of care that has changed quite dramatically since the approval of anti-PD-1 LAG-3 combinations. For example, the Opdualag, which is now driving like 30%-35% of the first line metastatic melanoma market, especially here in the U.S. There is a difference in Europe where there is a different label approved for Opdualag. Of course, given that change in the landscape, now we are looking at a different type of standard of care in the first line settings. That is what we are adjusting ourselves to. I noticed you don't mention the CTLA-4 combinations, which do also still have meaningful market share despite all of their limitations. Yeah. Only a hair below Opdualag currently. Yeah. It's still a fantastic drug for patients that can actually benefit from it and tolerate it. We see that the toxicity that goes hand in hand with that is actually not beneficial for most patients. We want to come in and add as much as we can on efficacy without adding any toxicity. Therefore, the Opdualag is much more interesting. You would be thinking about a combination on top of Pembro, not on top of Opdualag versus Opdualag. It would be head to head with the combos. It would be head to head Opdualag in combination against Opdualag, yeah. In combination with Opdualag. Can we talk then about the combination of the or the choice of the mechanisms? Do you expect that LAG-3 would dovetail more neatly with the vaccine mechanism than CTLA-4? Yeah. I think anti-PD-1 is one thing we already know. We have great effect in combination with anti-PD-1. Adding LAG-3, you're adding just more of the same type of mechanism of action as anti-PD-1. Just, of course, works on different subtypes of T cells. What we expect is adding effect. We're seeing that already in an investigator-initiated trial that is running currently at Memorial Sloan Kettering in New York, where early data have shown us that we have reasons to be excited about the benefit we can drive in this combination as well. Let's talk about that investigator-sponsored trial then as well. That trial is still running. It's still relatively early. What have you seen and what do you expect the market to be able to see before we start thinking about the phase III? The data are still early. Probably during next year, we will see some announcement of the more mature data. What we are seeing right now is a PFS benefit in the combination with Cylembio and Opdualag that goes beyond what you would expect from either one alone. Is that a single arm study? It's a single arm study, yeah, running at three different centers all under the umbrella of MSK. Do you know how many patients they'll have? Altogether, 43 patients will be enrolled. Currently, we have the data of 32 patients where we have seen. It's a pretty reasonable cohort. Also, given the history of the phase III design challenges you've faced, I imagine you'll be a little more conservative with the design on this phase III. We have learned a lot with the data that we have gotten out. Of course, the first phase III trial we ran was based on a single arm, single center trial. We were excited about what we are seeing. We're still excited about what we are seeing. We are seeing a clear effect, clear drug effect. Now we have much more to put into our assumptions. I'm confident that we will hit success with this one. Yeah. What about patients who have previously seen PD-1, maybe in the adjuvant setting in melanoma? Yeah. Those patients, of course, we have looked at also in the current phase III that just read out. We are seeing if we are excluding them that we actually have a higher benefit in the rest of the portions of patients that were enrolled. A better relative because obviously people who have previously exposed, you would expect them to do not as well. On a relative basis, you're also not seeing the same benefit. Yeah. We will enroll them in the current trial as well, the new trial, just with a cap on. We are stratifying against that. That observation is interesting to me as well because given you have a larger relative benefit in PD-L1 negative patients, I would have maybe expected to see something mirrored with patients who had prior exposure, grouping them together in some sort of nebulous way that they're less inflamed or less responsive to checkpoints. We're still looking for the answer there. It's still early days, I think, to treat patients that have been treated in neoadjuvant settings and to understand what is really the impact on the immune system and why it might be changing compared to if patients come in and they are naive in the front line settings. We will stratify against prior treatment and see. Are you capping enrollment on those patients as well? Yeah. We are still working on the clinical trial design. I will be giving a better answer in some weeks or months from now. All right. We'll ask you next time, I guess. Yeah. Thank you. What about the EU? I mean, obviously, the FDA asked for another trial. They were very adamant about the lack of feedback. They were clear in their feedback, yeah. How has the EMA been responding to the data? We are still working on the meeting with getting in front of the EMA. We expect to have some feedback from that meeting in some months from now. We are still working on it. It's a little bit of a different process. What we know is that the guidelines are different in EMA compared to the FDA. There are some guidelines that actually fit maybe more the case that we have with the readout from the phase III. Yeah. I don't typically think of the EMA as being either more or less lenient than the FDA, but certainly a little different. Yeah. Supposing that your discussion with the EMA is positive and they give you a path forward without running another trial, what would you what are the avenues to get the drug launched there? How would you evaluate launch readiness looking forward to that? I mean, we are ready. We were ready at the time of the readout of our phase III trial. That was late summer, early fall this year. We are still ready. We will do everything that is needed to do to get the drug on the market. Of course, we have different avenues that we're working on in order to secure that. Are there any last thoughts about the phase III trial before we move on? I mean, I'm just excited to move forward. We have such a clear drug effect and with such a clear safety profile that I'm excited for what we can bring to the patients in a disease where there is still a huge need for better treatment. Absolutely. The effect size looks very strong. Especially on some of those subgroup analyses like PD-L1 negatives, it looks really quite remarkable. I am looking forward to seeing the new trial design and the data coming out there. Happy that you're sharing our excitement. Thank you. Let's talk about the rest of the pipeline and other indications then maybe. How do we move beyond melanoma? You mentioned seeing other interesting signals and other tumor types in some of your earlier work. Yeah. Cylembio is not really a drug that is just for melanoma. The antigens or the peptides we're using, IDO, PD-L1, are really expressed across multiple different cancer indications. We have already tested it in head and neck and in lung. We have seen encouraging results. This is, of course, something that is still driving our interest. Right now, we are focusing on getting a home run in melanoma as the first effort. We have other targets in our pipeline as well. We have IO-112 and IO-170. That's Arginase 1 and TGF-beta. We have just published at some conferences here in the fall very exciting data from both of those targets as well. Those two targets actually open up our abilities in the pipeline to move into other types of cancer indications, if you like. More of the colder tumor types than melanoma, head and neck, and lung. Here we could think about prostate or colorectal, ovarian, and cancer types like that. Again, this is second or third priority compared to getting Cylembio further. Understood. What's your bandwidth ability to get some of those other indications at least started to see some early data in a few months? We are not working on this right now. There are some smaller preclinical studies running. We are IND ready on Arginase 1. You're going to move on to that. We are going to wait until. That makes sense. Yeah. Maybe for you, can we talk a little bit about cash balance runway and what you would need to have to run the phase III properly? Yeah. We have cash till the end of the first quarter. We'll be meeting with the FDA this year and getting alignment on the phase III trial design. Post that, we'll be seeking to raise money to support the phase III study. The phase III, and Mai-Britt alluded to it, will be larger than the phase III that we just ran. It has a futility sample size reassessment baked in after the first 400 patients are enrolled and about 150 events on PFS are hit. At that point, there will be an assessment of how many more additional patients we would need to enroll. It seems like the numbers that you've been citing, the ranges that you've been citing, would indicate it being between 50% and maybe 80% larger than the first phase III. Yeah. Anywhere between 550 patients up to 800. Yeah. What would you need in terms of funding to run a trial of that magnitude? It's a couple of hundred million. Yeah, to get there and get it done. With a strong effect size, I would hope that you'd be able to find that money. Do you have non-equity options? Are you considering other options of financing to get that over the finish line? I think importantly, if EMA does give us the green light to file in the EU and we have a path there, there is strategic value to that, of course. I think even originally, our plan, there would be to partner in Europe. It's a big take for a small company to launch a product in Europe and commercialize. We would look to partner the asset there and bring in some non-dilutive capital that way. Hopefully, fund most, if not all, of the phase III off of that. I think the effect size, Jonathan, but also the safety profile. Bringing that effect without additional safety and costs to the system, it really is a valuable asset. Absolutely. Excellent. Last thoughts before we wrap up? Yeah. I mean, I think IOB-032 studying too. I do not know if you want to mention that, Mai-Britt. Oh, yeah. Our new adjuvant trial that has also been enrolling in melanoma and also in head and neck. We will be excited to give data from that trial during next year. That is fully enrolled now and just waiting to mature the data. Excellent. We look forward to seeing that data as well. Of course, updated phase III designs and maybe some feedback from the EMA before too long. Yeah. Yeah. Yeah. Sounds good. Excellent. I will thank you so much for joining us. Thank you for having us. Thank you.