All right. So welcome to this next session. My name is Paul Jiang. I'm one of the biotech analysts at Guggenheim, and I'm very pleased to welcome our next presenting company, Context Therapeutics. And with us today is Martin Lehr, CEO. Marty, thanks for joining us. Thanks for having me. Great. Before we get into the details, for those who are maybe newer to the story, could you provide a brief intro to Context and the strategic focus for the pipeline on the category of T -cell engagers for solid tumors? Absolutely. Thanks again for having me. Context Therapeutics is focused on developing T -cell engagers. This is a class of antibodies where one arm of the antibody binds to a tumor antigen, preferably one that's highly enriched in tumors, and then the other arm binds to an immune activator. In our case, we are very interested in using CD3 as the immune activator, and we use high affinity CD3 across the portfolio. The idea being, if you look at where the success has been with T -cell engagers, all the approved T -cell engagers, all 12, use CD3. Why fight inertia and gravity and go with the thing that works? We are a search and development company. We do not have any in-house research. All three of our programs targeting Claudin-6, Mesothelin, and Nectin-4 were externally sourced. Two were licenses. The third was an asset acquisition. The core thesis being that there's a lot of great antibody engineering companies out there. They create way too many drugs. They're very efficient. There's always a surplus of drugs available to identify and then ultimately acquire and develop. Our three programs, two are in the clinic, Claudin-6 and Mesothelin. Claudin-6 will have data in Q2, Mesothelin in the middle of 2026. Our third program, Nectin-4, will be in the clinic shortly. All right. So then starting with Claudin-6, CTIM-76, which is your most advanced asset. The Claudin-6 space is fairly active right now with multiple modalities, mechanisms, and clinical development. Why do you think Claudin-6 is a very compelling target to you for solid tumors, and why do you think that T -cell engagers are the right approach for the target? Yeah. So I've spent my career in oncology in solid tumors. What we all search for from a development standpoint are targets that are restricted to the tumor. Typically, those are oncofetal proteins like MYSO or MAGE, Claudin-6, CT83. There's very few of them that have ever been discovered. There's a lot more that have been putative oncofetal proteins like OR-1 that were later disproven and are much more broadly expressed than people thought. If you have something that's restricted to the tumor, you can theoretically hit it really, really hard without disrupting normal cells. In Claudin-6 case, a variety of modalities have been developed against the target. That has more to do with time. As time progresses, you learn more about the target. What is Claudin-6? Claudin-6 is part of a family of Claudins. These are tight junction proteins. They help cells attach to one another, ultimately forming the architecture of tissue and organs. Claudin-6 is not an oncogene. It barely has any signaling activity. In cancer cells, we do not think it really has any at all. So a monoclonal antibody approach does not make a ton of sense. It does not internalize all that well. It is a tetraspan protein, meaning it has four pieces that cross the membrane. It is really wedged in there. It is not ideal in our view for an ADC, but it is highly expressed, stable, and does not do anything. That is a really good target to anchor against if you are developing a CAR-T or a T -cell engager. We prefer TCEs to CAR-T because of the optionality of the modality. CAR-Ts are very cumbersome, very expensive. It is a one-and-done typically. In the TCE case, you can titrate, you can make it cost-efficient for providers, and you can make it painless or as painless as possible for patients. We think it's the ideal modality to use. If you look at our targets that we're developing, from a commercial standpoint, we're focused on targets that are clinically validated by ADCs. We want to treat ADC resistance. On top of that, ideally, there's a CAR-T in existence against this target that validates the target from an immunomodulatory standpoint. Certainly, BioNTech, a well-known fact, UGER actually discovered Claudin-6 during the Human Genome Project. He's been working on it forever. They had a CAR-T that had unbelievably good data in ovarian and testicular cancer. That was sort of all the breadcrumbs that led us to a TCE against Claudin-6 and then more broadly in the portfolio. Speaking about the clinical validations from those more advanced CAR-T or ADC programs, I guess, what are the key learnings from those data that have been reported, and how does that inform how you think about your forthcoming update next year? Yeah. BioNTech has really extraordinary data in ovarian and testicular cancer. We wanted to focus on those subtypes in our phase I trial. Claudin-6 is also highly enriched in endometrial cancer. There is less clinical data out there, but that is something we wanted to include given the prevalence. There is also an ADC from a private biotech company named TORL Biosciences. They, like many other ADCs in ovarian cancer, had about a 50%-55% response rate, which we think is tremendous, but they use a very high cutoff for Claudin-6 expression. For us, that gives us an opportunity to use a different modality. T -cell engagers are typically 100-1,000x more potent than ADC. We do not need that really high cutoff for activity. We have a very low cutoff to screen patients. We can have CAR-T-like efficacy, but treat a much broader patient population than TORL. That high cutoff becomes a problem if you want to drive these drugs in the earlier treatment lines where Claudin-6 in particular is prognostic. The more severe your disease, the more Claudin-6 you'll have. You want a lower cutoff to push in the earlier treatment lines. I see. Okay. CTIM-76 has been in the clinic now for, I believe, over a year. Last week, you had a very early update on the data with your earnings report. Can you review what you sort of reported at that time and what you saw for early safety and efficacy? Yeah. Maybe a step back. Historically, T -cell engagers took forever in phase I. The most recently approved T -cell engager in a solid tumor, Tarlatamab, spent seven years in Odyssey during phase I. There is a little scar tissue with investors. From the time we enrolled first patient to now enrolling cohort five, it has been nine months. It is still slower because you need to have sentinel patients. You dose the first patient, then you have to wait a couple of weeks. It is getting closer to an ADC-like development path. We've been really happy with the trial. We're enrolling cohort five. We noted that in an early cohort, in cohort three, we had an ovarian cancer patient who was heavily pretreated, including prior exposure to Mirvetuximab, the folate receptor alpha ADC, who had a confirmed partial response that was super deep and continues to be on treatment. We wanted to give the investment community and our shareholders confidence that things were going well, which they are with that particular program, and really orienting people to the second quarter. At that point, we'll have more wholesome data on cohorts one through five, maybe even a little bit of cohort six, and provide guidance around what phase I-B would look like, how we're going to think about doses and dosing frequency, and when that trial would start. On safety, it looked like the update initially was quite good with the early reads, but I'd like to get your perspective on how cytokine release syndrome could be managed given you're using a very high affinity CD3 domain in all of your programs. How do you think about the target profile you'd like to see for CRS, onset, resolution, overall management, et cetera? Yeah. So we have a dual challenge with Claudin-6. We have CRS because it's a T -cell engager. Claudin-6, even though it's only found in the tumors, the binding domain has very significant overlap with Claudin-3 and 4, which is found in your liver. You want to make sure you're not having profound CRS, and you're also not hitting three and four and causing the liver enzymes to spike. In the case of Claudin-6 on the CRS side, you were right. We're using high affinity CD3. What we've learned over the last few years is that clinicians have gotten very good at managing CRS. Some of the technologies have helped as well. The reality is, in our view, the reason CRS rates have plummeted is clinicians know how to manage patients on the front -end, which would be step dosing. You start at a low starting dose, and you increase the dose over time so the immune system can adjust to the higher dose. Second, you prophylactically give a steroid. It does not matter if it is dexamethasone or prednisone. You do it at direction an hour before first treatment. That has had a profound impact on CRS, which is typically occurring in the first or second dose. You give a steroid before each one of those doses. If a patient should break through and have grade two or higher CRS, you then can give an anti-IL-6 therapy, most often tocilizumab, which helps resolve the CRS rapidly. Almost thinking about it as like a rescue therapy. On the liver side, we do anticipate all Claudin-6 drugs to have dose proportional liver enzyme elevations. Where we think we will differentiate is our Claudin-6 selectivity profile. We are more oriented to six versus our competitors. That will be something, particularly as we go to higher doses. If you compare our drug to theirs, I think we will have a significantly cleaner safety profile. What are some of the adverse events you're trying to avoid with the other Claudins? For three and four, they're in your liver. Those would be ALT, AST elevations, for example. Claudin-9, which also shares homology in the binding pocket, that's in your ears. Patients will present with tinnitus, which is ringing in your inner ear should you hit that target. As long as we don't have those side effects or if we do, they're very low grade, it doesn't impact the patient's life, then we'll be in great shape. Okay. Then, yeah, you alluded to a more fulsome interim update in, I believe, the second quarter of next year. How many patients could we potentially see? What dose levels do you think you'll be at? How many of those will be in what you think will be the active dose range? Yeah. We had previously guided in our corporate deck that cohort four would be the target dose range, which we define as the EC50 for our drug. T -cell engagers are very different than kinases, for example. Cogent's popular in the news today. You would never want an EC90 or an EC99 or an IC in their case. You will exhaust all the T cells or cause all the T-cells to kill one another. You want to optimize the dose somewhere between the EC50 and the EC75. We think that will happen somewhere between cohorts five and six. Strategically, and I think it contrasts very much with how ADCs are currently being developed, T -cell engagers are very binary. They are very potent. If you can manage the safety and they work, they work really well. You do not need a ton of responses to know you have a drug. I also think with competitive tensions coming out of China with drugs, it makes sense to do your phase I- A as fast as possible. Make sure there is a signal in three, four, five patients, and then move into phase I- B as fast as possible to expand that signal and also play with your dosing frequency and push it out as much as you can, which can be beneficial both for patients from a quality of life standpoint, but then also for the sponsor. Sometimes the data is better because you have less T -cell exhaustion. We want to move as fast as possible into I- B. What is the range of dosing frequencies that you're going to explore potentially? Yeah. We have to nail that down, but we are very interested in dosing every two weeks or three weeks. Currently, it's dosing every week. Okay. Okay. It seems like if you see a signal in a particular tumor type, you might move pretty rapidly into that phase. What would, in theory, be the next steps? If you see something, for instance, that's encouraging in ovarian, how quickly could you move that into a more pivotal type study? Quickly. Quickly. We'll provide more parameters around that in Q2. I- B, the main gating items would be you have to make your commercial batches. We do have a Claudin-6 diagnostic that we would have to make the kit for, but those would be the only gating items. You can move quickly. The nice thing, particularly if we go into ovarian, is there is a very clear market need. This will be foreseeable for the next half decade, which is ADCs look great in ovarian, particularly with TOPO payloads as they get pushed in earlier lines. What are you going to give after an ADC? We think that's a large patient population. We have found it's very easy to enroll those patients, and you don't need a very large phase III. It's about 360 patients. From first patient to top line, you're looking at about a two-year time horizon, which is something we think is palatable to investors. Great. All right. I wanted to talk about the other program you have in the clinic, CT-95, the mesothelin CD3 T-cell engager. Mesothelin, obviously a very well-trod space, but yet to be successfully drugged with many different modalities having been tried. Why has this target been challenging, and how is your approach possibly differentiated? Yeah. I always like to remember, we always get the question, which of your drugs are the favorite or most valuable? We have three great drugs. I've never had that in my career. It's really cool. Mesothelin's a hard nut. There's been a lot of failure in the space. The reason people keep going after it, it's found in 30% of all cancers, right? It's a very, very large and interesting market opportunity. It's heavily enriched in some severely underserved cancers like pancreatic and colorectal. It's a righteous target to go after. The challenges are twofold. One, it is a processed protein. Tumors release proteases. They cleave Claudin-6, excuse me, mesothelin, and the portion that's left on the tumor is very short. It's very hard to develop an antibody against that region. We have one that can do that, and Pfizer with their ADC has one. To our knowledge, that's it. The problem is the other portion that's cut off where our competitor's drugs bind, that shed piece of mesothelin. If you're binding to the shed portion, that means your drug's taken out of circulation. To have therapeutic activity, you have to saturate the shed to hit the tumor. That means you're driving up the dose that's being given. If you do that, you then have and introduce the second risk, which is 3% of your lung cells express mesothelin. Those are not exposed to tumor proteases. Our lungs are a very sensitive tissue to inflammation. If you're giving a high dose to overcome the shed, you're going to hit the lung, and that's where the tox comes in. Our antibody is really neat. It's a very clever idea in that it binds to that nub that's left over, and it's also a pretty weak mesothelin binder. Only when both arms of our antibody, it's bivalent, bind the mesothelin, avidity kicks in, and only at that point does our antibody stay stuck to the tumor. It will have a localized component to it when it works. That will help overcome both the shed and then the lung-mediated side effects. Okay. You alluded to 30% of maybe solid tumors. What are the main areas of immediate focus for you in terms of enrollment of patient types? Yeah. So we're enrolling pancreatic, ovarian, and mesothelioma. Pancreatic is overwhelmingly where we're currently enrolling and where we think that will go in the foreseeable future. A very aggressive cancer. Patients are very sick, so it's not without challenges. But we do know T -cell engagers work there. Innovent had over a 30% response rate in pancreatic with their Claudin-18.2. So we think that a T cell engager can work there. And with the use, particularly in the US, of KRAS inhibitors in pancreatic, there's now this clear unmet need for patients who progress on a KRAS to take something else. How are you incorporating mesothelin expression and screening into the clinical development strategy? Do you have a cutoff that's similar to the Claudin-6, for instance? Yeah. In both trials, we developed IHC diagnostics. 10% of the cells have to be 1+ positivity for staining. It is a very low bar. Mesothelin is interesting in that pancreatic, ovarian, and mesothelioma have such high levels of mesothelin, you do not need to screen prospectively for them. We do screen prospectively for non-small cell lung, which is about 50% of patients, and colorectal, which is about a third. Got it. Okay. The study is also enrolling. What have you guided to in terms of the initial clinical update next year? Could you set some expectations for what we'll see at that time? Yeah. Mesothelin is a much lower bar for expectations because no one with a T -cell engager or a CAR-T has ever shown activity in that population. A couple of responses would be huge. Currently, we're enrolling cohort three. We've guided that cohort four would be the target dose level. The hope is by summer, we're sharing data from cohorts three, four, five, and getting people excited about that program. What would the next steps be for this program, assuming you see some encouraging signals? It's probably going to be a little bit of a longer road than Claudin-6, just given the inherent risk with the lung. We need to adjudicate that risk. Our hope is somewhere towards the end of 2026, we'd be wrapping up I- A and then progressing to I- B from there, most likely in pancreatic, but we'll have to see about that. Got it. Okay. Then I just wanted to spend the last couple of minutes on the Nectin-4 program, CT202. This is also a target that's been dominated historically by ADCs, one ADC in particular. What do you see as the key advantage or disadvantages of ADCs for this target, and why do you think that the T -cell engagers offer a compelling alternative? Yeah. I do not actually think of it as an alternative. I am rooting for all the ADC companies. I think the newer ones, in particular with the TOPO payloads, are looking super exciting. The challenge is, as everyone consolidates into a TOPO payload, we learned over this weekend in breast cancer that TOPO resistance is real. You cannot give, in all likelihood, TOPO payloads sequentially. What are you going to give after a Nectin-4 ADC? Frankly, there are Nectin-4 radiotherapies being developed as well. We think those agents do a very good job of debulking the tumor. Part of the reason that the durability for PADCEV, the only approved Nectin-4 ADC, is so poor is they put selective pressure on the low and medium expressing cells to propagate. They kill the high expressors, leave the low and mediums. The antigen burden decreases. You need something more potent. I think that's where a T -cell engager shines. We're something like 500x more potent than PADCEV. We can come in and kill those cells. We're very interested where PADCEV's approved in bladder. There are a lot of other really interesting areas like non-small cell lung and triple negative breast, head and neck, where we love to pursue Nectin-4. With all of our targets, but Nectin-4 in particular, it's co-expressed with a lot of interesting targets like TROP2 and HER3, among others. That creates very rational combination opportunities with ADCs and other modalities in those indications. All right. CT202 has a couple of really interesting design elements that are incorporated that you think could increase the target avidity and also the conditional activation pieces. Could you walk through what those enhancements are and why you think those will give you a profile that's optimal? Yeah. It's a super clever antibody. I wish I could take credit for the design ideas, but Nectin-4, if you look at total addressable market from number of patients, is top five, maybe even top three. It is ubiquitous in cancer. The challenge is that we have some Nectin-4 in our skin. You probably noticed we have a lot of surface area as far as skin in our bodies. That creates substrate that can result in CRS or localized inflammation in the skin. Our antibody is pH dependent. Tumor cells are highly dependent on glycolysis. They create a lot of lactic acid that creates a highly protonated tumor microenvironment with a low pH. Normal cells have physiological pH of 7.4. Our antibody is both affinity matured at the Nectin-4 and the CD3 to be pH dependent. There's so much dermis that you're never going to fully prevent binding to the skin. What's unique about our antibody is when it does bind to the skin, it does not do a great job of activating a T -cell. Historically, companies that have tried to develop Nectin-4 T CEs with CD3, and you'll notice if you go on the internet, we're the only one in existence to our knowledge right now that's heading towards the clinic. They all ran into skin toxicities, SINOs. What we disclosed over the weekend in SITC is we've gone up to crazy super therapeutic doses. We've never seen skin irritation in a single monkey to date, which is really exciting. I think we have the right asset to test the question, could Nectin-4 work with a TCE? We will certainly be in a position in 2026 to start answering that question. All right. Yeah, on opportunities, you mentioned well-validated in bladder cancer, but also some interesting signals and opportunities in other cancers. There were some competitor data in head and neck, for instance, cervical cancer. How do you plan to prioritize indications as you move into the clinic? That's really hard because there are, I mean, I'd love to do cervical. It's more prevalent in Asia than the U.S., for example. That may be a really good example of something we may want to partner with someone to explore who has more expertise in that particular geography. I don't know where we're going to take it. It may involve a partner just given the breadth of opportunities. Bladder, I think once you go post-PADCEV is fascinating. PADCEV took a market that was a less than a billion-dollar market, and now they're driving to a $5 billion+ run rate with metastatic bladder. That's interesting. Colorectal, really underserved. The ADCs have had very limited success there to date. Certainly, you're referring to the Corbus data and head and neck, among others. Once you have resistance to PADCEV or anything like that, this may be a very logical approach. The nice thing about a TCE, different than an ADC, an ADC you can't really combine with another ADC or chemo. The toxicity is overlapped. They're additive. A T -cell engager, and this has all been proven over the last year, whether it's a solid tumor or liquid, is an ideal combination agent for chemo, for an ADC, for a variety of other modalities as well, because the toxicity is unique, right? You're not worrying about cytokine release syndrome with an ADC. I think ultimately it's probably through combinations with Nectin-4 that we would really want to push the boundaries. TROP2 is a great example. Given the amount of TROP2 ADCs that are approved and coming on the market, it's co-expressed with Nectin-4. That's a great opportunity for us to differentiate from the Nectin-4 ADCs and to even potentially leapfrog them. All right. Perfect. That's right on cue. I think we're out of time. I wanted to thank you again, Marty, for joining us, and really looking forward to next year. Thank you so much. Thanks for having me.