Let's go ahead and get started. My name is Nicole Gabreski. I'm a biotech research analyst here at Piper Sandler. It's my pleasure to introduce iTeos Therapeutics. Joining us today, we have the company's President and CEO, Michel Detheux, and CFO, Matt Gall. Welcome, guys. Just to go over the format, we have a couple of minutes of introduction from the company, and then we'll go into a fireside chat format, with some more detailed Q&A. Without further delay, Michel, I'll turn it over to you. Hi. Good afternoon, everyone. My pleasure. To introduce iTeos, I would start by the fact that we have spent the 10 last years to build an expertise in tumor immunology in order to select relevant targets involved in tumor immunosuppression with multifaceted mechanism of action and develop differentiated assets, what we consider to be best in class today. Then we have today 3 programs in clinics. The most advanced is a TIGIT antibody partnered with GSK, and we have two programs targeting adenosine pathway with a novel angle and really a way to approach adenosine pathway in unprecedented way. To come back to TIGIT, we have today 4 phase two ongoing, where we test different doublets in different indications, and we have 3 phase one B, where we are testing triplets with novel combinations. For adenosine pathway, we have a randomized, phase 2 ongoing in second-line lung, chemo-naive post PD-1, and we have a new target in the adenosine pathway, where we are currently going into a dose escalation in phase 1. Perfect. Thank you for that. So we have just over about 20 minutes or so for Q&A, and we will look for participation from the audience. So feel free to speak up or raise your hand if you have questions. And with that, we'll dive into Q&A. So I guess where I wanted to start was with belrestotug, your anti-TIGIT antibody. So before we dive into the specifics with that program, I guess I wanted to back out and kind of get the 30,000-foot view, just given the various updates across the TIGIT landscape over the last year. So maybe just help frame why it's a good time for people to be paying attention to this space now. Indeed, this is a fascinating situation. Two or three years ago, many people were thinking that TIGIT will be the next PD-1, that could be used in multiple indications in combination with PD-1, and that there were a series of antibodies moving forward, all similar. What is really fascinating today is that the last data that we have seen this year is showing this is not the case. First, every antibody is different, and we believe that we are very well positioned with a very strong PD-1 coming from our partner GSK, and a potential best-in-class TIGIT. Second, indication matters. Some people started, or some companies started, clinical trials in multiple indication with a very weak biological rationale, and we believe it's super important to be data driven and to be driven by the biology. This is what we are doing in our partnership with GSK. Third, and following the accidental leak by Roche of their phase 3 data in August, the design of the study is super important, and we believe it's an added value for us. We were behind some of our competitors, and we have been able to leverage this information from the competitor design in order to refine and optimize our clinical trial. Perfect. So I guess maybe just diving into belrestotug a little bit more. So maybe for those not as familiar with the story, I guess, can you remind us maybe how this molecule is differentiated, just, from your competitors and why you believe it could potentially be best in class? Yes. And today, if we consider the most advanced program, there are five players. Four companies, iTeos, Merck, Roche, and BeiGene, are developing an IgG1, an active isotype, which is able to engage Fc gamma receptor in addition to the binding of TIGIT. And one company, Arcus, is developing a silent isotype. If I'm starting with the silent versus active isotype, all the preclinical models have shown that you have a better antitumor effect if you use an active isotype that will show multifaceted mechanism to engage TIGIT on one side and different immune cells on the other side. Interestingly, Arcus claim that a safety profile could be better for a silent isotype. So far, thousands of patients have been dosed with an active isotype, and there was no safety signal which has been recorded. Then we don't believe there is any downside to develop an active isotype, and we believe there's, in fact, an upside by having this multifaceted mechanism. Now, if I compare the four players developing the active isotype, we have reported the best phase 1 data so far, with one confirmed partial response and 45% stable disease in the 20-patient dose escalation. More importantly, we have been the only one showing that at any dose of the antibody that we have dosed in patients, we've observed a massive Treg depletion in the tumor microenvironment of the patient dosed with the antibodies, showing that we have a very efficient antibody to engage Fc gamma receptor and show a multifaceted mechanism. Great. So you guys had announced the agreement to co-develop and co-commercialize belrestotug with GSK back in mid-2021. And you have various development programs ongoing with combo dostarlimab, like you had mentioned, as well as other candidates targeting the CD226 axis. So I guess, can you maybe just remind us why GSK is the ideal partner to bring this antibody forward? And maybe just a little bit about the rationale behind seeing dostarlimab as the ideal combo partner for belrestotug. Sure. So there were three major facets to the deal that were really attractive to us. One is the economic packaging deal structure that went along with it, $625 million upfront, $1.45 billion of milestones, GSK paying 60% of all development expenses. In an area where, as Michel already alluded to, a number of large pharmas are already playing, going alone would have been challenging. But being able to keep half of the U.S. market, as well as the attractive economics made the deal make a lot of sense in it. Specifically to GSK, the quality of dostarlimab, going in with a high quality at the time, already approved PD-1 to launch a quicker path to phase 2 and phase 3 studies. GSK's unique commitment to what you call the CD226 axis the TIGIT axis, where despite a high quality PD-1, they needed something of a reset of the PD-1 market to be competitive. There was a recognition they were never just gonna run, you know, a long series of head-to-head pembro studies to try to claw back market share. They were late to the game there, and it was gonna take that type of TIGIT reset for them to gain meaningful market share. The other components they have that would be highly synergistic to a TIGIT, the PD-1 and the CD96, already on the shelf. Because they were already on the shelf, we're already in a clinic with both of those triplets right now to see, are there indications where having the additional antibody providing a boost is gonna make a difference, whether it's in a competitive indication or an indication where TIGIT wouldn't be successful on its own. Yep, makes sense. So maybe we can dig into some of the studies that are ongoing. So for the phase 2 lung platform study, I believe this is now referred to as GALAXIES Lung-201. So this is a randomized open label study, and PD-L1 high frontline non-small cell lung cancer patients. I guess, can you talk a little bit maybe about the study design? And, I believe that the study does include a pembro monotherapy cohort. So maybe just talk a little bit about the rationale for including that. Sure. So let's give a little bit of an overview of the study. This is the largest phase 2 study run in the TIGIT space. It's gonna be 300-400 patients when all is said and done, and it's gonna... As you mentioned, you're gonna have a pembro monotherapy arm, which is gonna be important for comparison. It's great to see that in the PERLA study, dostarlimab has already gone head-to-head with pembro and had very good results. But it's another opportunity to show how both dostar compares against pembro, as well as how the doublet compares against pembro, is a preview to what our phase 3 design would include. It's gonna have multiple arms of the doublet, of pembro plus belrestotug, to satisfy all the requirements of Project Optimus. As well as show a really neat cut of data as to how the doublet performs versus both PD-1 monotherapies. And then there's also gonna be the first place we take a triplet into a large randomized study. So, a big chunk of data starting to roll in in 2024 publicly, and really useful as we make our big phase 3 investment decision. I know we're expecting an update from the lung platform- Mm-hmm. - trial next year. And just as I think about it, I'm guessing most people will try and probably comp the data to KEYNOTE-24 or KEYNOTE-42. Those are the studies for pembro. Mm-hmm. So I guess, do you see those studies as maybe framing the success bogey, or how do you and GSK think about maybe setting a bar to confidently move into a phase 3 registrational study? First, what is super important compared to existing data, which has been generated in the past with TIGIT, we are doing a phase 2 where we compare to pembrolizumab, and we will be able to compare directly within our trial the performance of pembro with dostarlimab as a monotherapy and the doublet with our belrestotug antibody. We indeed believe that, the different data generated with PD-1 in lung will set up, the bar. We are expecting a response rate, increased by at least 15%, compared to the monotherapy. Then we could consider that a good response rate for a PD-1 of quality is 40% in monotherapy. PFS should be, north of 10 months, and OS should be north of 25 months to consider that we have something really promising. Perfect. And then I guess maybe on the competitive front, earlier this year, we saw overall survival data from the second interim analysis from Roche's Phase III SKYSCRAPER-01 study for tiragolumab in first-line non-small cell lung cancer, after what appeared to be an inadvertent data leak. So, the final OS results from that study are expected in Q1 of next year. Maybe just, walk through your view of the data from the second interim analysis and how you think about the read-through from the final, OS analysis to the belrestotug program. And then just maybe more broadly, walk us through the competitive strategy as we think about the setup for belrestotug and dostarlimab in this setting. ... Well, we believe that this interim look was excellent news. It validated TIGIT as a target, showing that there is an added value of 6 months in OS compared to atezolizumab. One major limitation of this study is the fact that they don't use pembrolizumab as the control arm. Again, you need to make note of these comparisons. However, they've shown that they increase OS from 16 to 22 months with this combination. We believe that Roche has an excellent TIGIT, even if they've not been able to show any Treg depletion with their IgG1 active isotype. They still have an excellent TIGIT antibody. We believe that this interim analysis has delivered most of what we expected from this phase 3, because there is probably more than 90% of the total events that they are looking to get for the final analysis. From our point of view, in terms of competitive landscape, this interim analysis has delivered all what we need, especially, focus on the fact that the two curves were overlapping during the first 6 months, which is super important in terms of biostatistical design for a successful phase 3, and this is what we have done. The final result that will come next quarter is still an unknown and is not going to impact our strategy and our decision. It could be positive. doesn't mean that it will change the clinical practice, because again, they don't compare to pembrolizumab, and they show benefit of the doublet, which is similar to pembro alone, and it's very difficult to compare. And it could be also possible that their statistical design is not optimal for the actual data that they've seen in the second interim analysis. In conclusion, it could be possible that Genentech Roche is not able to get to registration with this data. It's still a very good news for us, and it's showing that one of the most advanced competitor could be out of the race in lung, creating a momentum for GSK and iTeos to go into this specific population. Perfect. Okay, so maybe transitioning to head and neck. So you're also evaluating belrestotug in combo with dostarlimab in PD-L1 positive head and neck squamous cell carcinoma. Just maybe from a mechanistic standpoint, why does moving an anti-PD-1 and anti-TIGIT combo into the setting make sense? And I guess, how does the setup of the tumor microenvironment maybe compare and contrast to that in lung cancer? Yes. Then head and neck is a biology which is very similar to lung cancer, and each time that we've discussed with clinician, they were telling us: Look, head and neck is really a mechanism of action for TIGIT that is highly relevant. On top of that, head and neck is a very high concentration of Treg regulatory T cells that we are able to deplete with our antibody. And we know that depending on the PD-L1 level, pembrolizumab is a limited benefit for this patient, just below 20% or around 15% for the CPS low and just above 20% for the CPS high. And we believe that this indication is a perfect fit for our Treg depleting antibody with a similar biology and mechanism action compared to lung. Interestingly, there is a limited number of trials in this indication. Roche has an ongoing phase 2, randomized phase 2, SKYSCRAPER-O9, which has been quite discreet so far. We don't know when they will have read out, and there is a basket trial from Merck where they test also head and neck. We really like this indication. We have today two ongoing phase 2, one where we compare doublet and the triplet with CD96, and one we evaluate the high CPS and the low CPS, and we'll be able to show the first data in 2024. Perfect. It's a great segue into talking about the TIG-006 study. So this is the open-label phase 1/2 basket study, which is evaluating belrestotug with a number of various combination partners. But we're expecting data from the phase 2 expansion cohort in first-line metastatic head and neck in 2024. So a data timing question, and one you probably aren't in a position to answer, but I will try to ask anyway, is that the estimated primary completion date for the study listed on clinical trials slated for January 2024? And I guess, is that kind of representative of where things stand with the trial, as well as potentially thinking about maybe an update earlier in the year, rather than in the latter back half? Yeah. So you were right in how you phrased the question. We're not in a position right now to tighten guidance on the head and neck cohorts of that study. We are committed to a 2024 data release. There's one other arm of that study that I think we think also is pretty interesting, which is the triplet with chemo. That could set up, I talked about earlier, you know, future places we could go expanding beyond stage four lung cancer. That triplet could be more relevant, so it's the first place we're exploring that as well. And that also could be data we release in 2024. Okay, perfect. And then maybe just as we think about kind of efficacy expectations for the update next year, I believe, you know, you've indicated that we'll get at least response rate and PFS data from the TIG-006 update. Obviously, cross-trial comparisons are never perfect, but as we think about maybe a potential success bar here in this study, maybe what do you see as the appropriate comp? And I guess, for example, does the pembro monotherapy in KEYNOTE-48 kind of set a bar or a floor of some sort? And then should we be thinking about wanting to see potentially pembro plus chemo-like efficacy from the doublet combo? Or you know, just any perspective around this. And again, we are currently evaluating the two population, the CPS high and the CPS low. We believe that in the CPS high, pembro would be a good comparator. Keep in mind also that, GSK has a very strong experience with head and neck, following their phase three with ICOS. That could be also very useful for us in terms of data comparisons. They've used pembrolizumab as the control arm in this previous study. For the CPS low, I agree with you that pembro plus chemo would be a better comparator in order to evaluate the benefit of our doublet. Okay, perfect. And then maybe just, as we kind of think about moving into a phase 3 study for head and neck, I guess, you know, in the lung cancer setting, based on your pipeline chart, you know, preparation looks to be underway for the phase 2 registrational study in frontline PD-L1 high non-small cell lung cancer. But maybe talk a little bit about the data you still need to generate before feeling comfortable making a go, no-go decision around moving into a registrational study in frontline PD-L1-positive head and neck cancer. Well, we hope to learn a good amount from the SKYSCRAPER-01 data that Michel released. When we put TIG-006 together, it was meant to be a very targeted investment to see can we see similar benefits in CPS low as seen in CPS high, and then we'd leverage essentially Roche's balance sheet to learn about the indication in SKYSCRAPER-01. I think that's, that's still the case. That data is going to be very informative to our decision-making process. GSK is also running GALAXIES-202 head and neck to generate more head and neck data. So we'll have a number of data points to make that decision to make sure we remain data-driven and we're following a rational, prudent investment course before we launch a large phase 3. Perfect. Okay, so with the time remaining, I wanted to switch gears to inupadenant, to talk about that program a little bit. So, I guess as many know, there are a few different approaches to targeting the adenosine pathway, but maybe just walk us through or remind us why targeting the A2A receptor specifically, in this case is ideal. This is the perfect example to illustrate our expertise in tumor immunology. This pathway has been super frustrating for many companies. There have been different trials, most of them being negative. There is a positive read out by AstraZeneca in a phase 2 COAST, in stage 3 lung, where they combine a CD73 antibody, the enzyme that generates adenosine with durvalumab. In fact, when we started this, when we started considering this pathway, we started with the first hypothesis that there are multiple way to produce adenosine. Then if you block one pathway to produce adenosine, you could have compensation mechanisms that will generate adenosine into a different way. Then we decided to target the end point of the pathway, which is the receptor expressed on the immune cell. The high affinity receptor with the highest level of expression is the A2A receptor. Several companies have tried to target the A2A receptor with a classical competitive antagonist, and many companies have repurposed a compound that was initially designed for Parkinson's disease. We believe it was a mistake, because in the brain you have concentration of adenosine around 1 micromolar. We've been the first one to show that in the tumor microenvironment, you have concentration of adenosine well above 100 micromolar. Then we have designed the first and the unique compound, which is able to compete with any concentration of adenosine found in the tumor microenvironment. This is our inupadenant compound, which is today into a randomized phase 2 in second-line lung. On top of that, we've identified 2 potential biomarkers that could help us to select a specific patient population. And we have also identified a novel mechanism of action for the A2A receptor in immunosuppression. We have shown that it's playing an important role to inhibit plasma cell, which can play an important function in the tumor microenvironment to generate antitumor antibodies. And finally, we believe that we are in a unique position because we have identified a novel mechanism in this pathway that we are targeting with another program called EOS-984, which is also at the endpoint and it's controlling the proliferation of immune cells in the high adenosine microenvironment. Perfect. So maybe, just real quick, for your randomized, phase 2 study, in lung cancer, you're doing some additional dose, ranging work with inupadenant there. I guess, can you talk a little bit about the rationale for that? And then, we're also expecting an update from the study in late 2024. So I still... I know that's about a year away at this point, but maybe any additional color that you can provide maybe around what we can expect for that update. Then we are taking into account, the expectation of the FDA for Project Optimus and the dose justification. This trial is the first trial where we combine inupadenant with chemotherapy. We have completed this dose escalation. We are now moving to the randomized part of the study in early next year. There is no, I would say, historical data which can be used as a control for such a design. This is almost the only, phase two ongoing in this specific population. And we have determined by comparison with similar, design, that the six months PFS will be the relevant endpoint. And this is the reason why we have currently this, schedule of releasing data in the second half of next year. Great. Okay, I think we are almost out of time, so I will stop there. But lots going on and lots to look forward to next year. So thank you guys so much for joining us today. Thank you. Thank you very much.