All right, we're going to go ahead and get started. I'm Stephen Willey, one of the senior biotech analysts here at Stifel. I'm glad to have with us here for the next presentation, Martin Lehr, who is the CEO of Context Therapeutics. He's going to be walking us through an intro of the company. If there's time remaining, we'll have some Q&A. Feel free to raise your hands if you have a question. Martin, thanks for coming, and I'm going to hand it over to you. Thanks for having me, Steve. I'm proud to sit down. There's a podium, whatever you want to do. Oh, there is a podium. There we go. I've just been seeing people sit. Well, thanks, everyone, for coming in and listening in via the webcast. Martin Lehr, Context Therapeutics. Context is an emerging oncology company focusing on T-cell engaging bispecific antibodies. I encourage everyone to, on their own time, read our forward-looking statements and important disclosures. Context is a development company. We have three exciting programs in our pipeline. All three are T-cell engagers focused on solid tumors. The three targets for those programs are CLDN6, mesothelin, and Nectin-4. Context is very much a roll-up strategy. We do not have any in-house research. We acquire assets from either private or public biotech companies through outlicensing or outright asset acquisition, and then bring them into our organization. We started with our CLDN6 program, and then in July acquired a mesothelin program from Link Immunotherapeutics. That was an asset acquisition. Then in September, we licensed a Nectin-4 bispecific from BioAtla, a publicly traded biotech company. Context is in the fortunate position where in May we completed a $100 million PIPE financing for the company. That was led by a blue chip roster of institutional investors and really gave us the capital to expedite our growth plans, as well as to provide runway into 2027. That would directionally put us through the Phase 1a dose escalation trials for our Claudin 6 and mesothelin programs, and then the IND filing for our Nectin-4 program with a sufficient amount of runway on the back end, which directionally would be six months for each program. The pipeline illustrated here on slide four represents our three assets, as you'll see. They all have slightly different flavors, which is representative of three different companies we acquired the assets from. Moving from left to right, and I always like to provide the caveat, I don't have a favorite child. All three programs are tremendous, but they're also unique in their own perspective and applications. So our CLDN6 program is an asymmetric bispecific. That is an asset we license from Integral Molecular. CLDN6 is a really exciting emerging oncology target. It's an oncofetal protein. There aren't many of those out there. That means that the protein is expressed during the development of a fetus, but then is actually epigenetically suppressed in normal, otherwise healthy adult tissue. So we quite literally don't have CLDN6 in our bodies. It does become highly enriched in certain types of cancers. So these cancers will epigenetically reprogram the cancer cells to develop a more developmental-like phenotype to promote their growth. CLDN6 is enriched in a wide range of cancers. We are particularly interested in gynecologic cancers because CLDN6 has high prevalence. We think that we can also enroll the trial really, really well and deliver data that investors can understand, which would hopefully underwrite future investment. Our second program targeting mesothelin. Mesothelin is a target that's found in approximately 30% of all cancers, so a very large market opportunity. The challenge with mesothelin is really twofold. First, you do have some mesothelin expression in normal cells, most notably your pericardium and your peritoneum. Then also mesothelin is a shed protein. The protein itself is cleaved by six different enzymes. There are cleavage sites across the continuum of the protein. So what one tries to do is develop an antibody that binds selectively to the portion of mesothelin that's most proximate to the cell surface. And that really does help also get the T-cell very close to the cell surface. So what we bring to the table is what's referred to as a butterfly format. It is optimized to bind to that C-terminus, that proximate terminus of mesothelin. It's also avidity-enhanced, meaning that the two arms of our antibody are not particularly potent. The idea being that when our antibody sees mesothelin monomers, it has a relatively high on-off rate. And so that's a very unstable bond. When you get bivalent binding of both arms of our antibody, hopefully on the tumor cell surface, that is when avidity kicks in. And so the binding affinity, the KD, increases by almost a hundredfold. That bond goes from a high on-off rate to a thermodynamically stable bond with a really long on-rate. Or to say it differently, our antibody stays stuck to the cell surface. The second component in the butterfly format is having two CD3 domains that are sterically hindered by the Fc. And so even though this is a two by two, it functions as a two by one, only one CD3 binds to a T-cell at a time. And you typically need multiple antibodies cross-linking a T-cell, so multiple antibodies bound to a T-cell to fully activate that T-cell. And so if you think about concentration gradients, we need a lot more antibody within the tumor microenvironment to have bivalent binding, as well as to potently activate the T-cell to stimulate that T-cell to kill the cancer cell. And that should provide, based on our pre-clinical data package, a really nice therapeutic window where we would have efficacy against the tumor without material side effects. And the most notable side effect with this therapeutic class is cytokine release syndrome. Our most recent asset acquisition is our Nectin-4 program. That's a really new program. You can see it looks very similar to mesothelin in its butterfly structure. However, Nectin-4 is a little bit different than mesothelin, so you have Nectin-4 on some normal tissue, including keratinocytes, hair follicles, and placenta, and so this asset is avidity-enhanced for Nectin-4, just like mesothelin, so it's a weak Nectin-4 binder, and only when you get bivalent binding do you get avidity enhancement in a thermodynamically stable bond, and then the Fc, just like the mesothelin program, prohibits dual binding of the CD3, so only one CD3 can bind at a time. The other elegant technology included in this antibody is pH dependence, and so cancer cells are different than normal cells. Cancer cells derive their metabolic needs through glycolysis. That creates a lot of lactic acid and a protonated tumor microenvironment. Protonated tumor microenvironment results in the acidification of that tissue area. And so when those protons bind to proteins, they can slightly shift the conformation of the target protein. And so these antibodies are affinity-enhanced for that low pH microenvironment. And so in particular, with the CD3, we get localized activation of the CD3 relative to normal tissue. So there's three unique components to the antibody: avidity enhancement, CD3 steric hindrance, and then pH dependence. We bucket those concepts and technologies in something we refer to as logic gating. Companies use a variety of logic gating approaches to drive the therapeutic activation of this class, T-cell engagers, to the tumor microenvironment. So it can include pH dependence, avidity enhancement, and can also include masking and other new emerging technologies. So we have three great programs, two of which are either in the clinic or about to be in the clinic. CLDN6 is in the clinic. Several sites are open, and we're screening for our first patient. Mesothelin is moving very quickly, and we could have our first site open shortly and targeting first patient early 2025. And then Nectin-4 is on track for an IND filing in mid-2026. So how do we get this pipeline? I mentioned at the beginning we were fortunate to complete a $100 million PIPE. We used a portion of that capital to acquire the assets. Given what's going on in biotech, you see massive investment in the moment in ADCs. You see it in metabolic and I&I, but a lot of other therapeutic areas are searching for capital. And so that creates an opportunity for companies like Context to acquire assets given the limited competition and scarcity of capital. And so we focused in a really narrow area, those being T-cell engagers for solid tumors where the target is clinically validated by an ADC. And I'll talk a little bit more in a minute about why ADCs matter to us. We're also using high affinity CD3. That's a very aggressive payload for this therapeutic class. We think that is critical to driving therapeutic activity and optimizing efficacy for these various products we have, all of which use high affinity CD3. We want best-in-class assets. We think we have a portfolio that certainly has that potential. And then as the target requirements necessitate, we will use increasing amounts of logic gating. If a target is very clean, like CLDN6, that doesn't require a lot of technology. If the target has a little bit broader expression, like mesothelin or Nectin-4, where you want to avoid on-target off-tumor activity, you then bring in some of these technologies like avidity enhancement. I talked a little bit about the timelines. From a business development standpoint for the mesothelin and Nectin-4 assets, we spent about $15 million upfront. We have very modest milestones from a pre-approval standpoint due over the next two to three years and a very low royalty rate. So on a blended basis, it's about 5% between the two programs. So importantly, none of the milestones ever create, in our view, a potential financing overhang for the company. So that's the pipeline and our approach to how we build it. But now to talk a little bit more about our thesis and strategy and why someone should care overall about T-cell engagers. T-cell engagers are antibodies where one portion of the antibody binds to a cancer cell, preferably a target on the cancer cell that is highly enriched in the cancer cell and absent from normal tissue. That way you can minimize your side effect risk, and then the other portion of the antibody binds to an immune cell. You can target a variety of different immune cells, T-cells, gamma delta T-cells, and NK cells. In our view, a vanilla T-cell with a high affinity CD3 is probably the best approach to maximizing outcomes in these patients. There are a variety of other approaches like detuned CD3 or co-stims like CD28 and 4-1BB, but we really do think that binding a clean tumor-associated antigen on the cancer cell and a high affinity CD3 is the best approach. For those of you familiar with T-cell engagers, you'll know over the last 20 to 30 years, they really have not been all that successful in solid tumors and in many cases have been written off. And there are several reasons for that. First, most companies would get stuck early in development and run into toxicity. For this therapeutic class, the primary dose-limiting side effect is cytokine release syndrome or CRS. You want grade one or grade two CRS with these products. That is on mechanism. You need to activate the immune system to kill the cancer cell. But you don't want grade three and four CRS, which can be dose-limiting, which would inhibit your ability to get to a therapeutically relevant drug exposure to maximize outcomes. And that's where most companies tripped up historically. But something interesting happened over the last year. On this slide eight, we highlight five companies, five different products, different targets, different technologies, different tumor types. Some with very restricted expression, some with very broad expression, some with very low target copy number, some with high. A real mix. But what's consistent across all of them is the fact that they all have very low rates of grade three or four CRS. And there are some technologies that may be contributing to solving that particular issue. But in our view, it probably has a lot more to do with clinicians. And so clinicians have been working with T-cell engagers as well as CAR T therapies for a long time. Over the last couple of years, they figured out that if you do two things, first, give a priming dose, so a low dose of your drug to warm the immune system before you give the full dose. Then if you give a dose of prednisone, which is a very potent anti-inflammatory, that can have a remarkable impact on CRS, which is typically a first dose phenomenon. If you can dose through CRS, you can then start optimizing outcomes in patients. We started seeing really interesting data across the landscape. My favorite piece of data here is from Innovent, which is a Chinese biotech company. This data was presented at ASCO in June. Innovent has a Claudin 18.2 by CD3. 18.2 is enriched in gastric cancers. It's also expressed in your normal gastric epithelium. I highlight this because nothing really works in pancreatic cancer, right? It's been a graveyard of drug development. I'm not saying this data is perfect, but it's really intriguing that in Claudin 18.2 high patients, Innovent had a 38% response rate. My hope is that if you can show good data in the hardest-to-treat solid tumor, it's just a matter of time before clever people and clever companies figure out how to apply T-cell engagers to all solid tumors. Over the last year, we've also seen renewed investor enthusiasm for the space, as well as enthusiasm from large pharmaceutical companies. This winter, Merck acquired Harpoon Therapeutics for $680 million based on a phase 1 data set. Janux, following that, reported very preliminary clinical data in 30 patients for targeting PSMA and a separate product for EGFR. Their stock went up dramatically as a result of that data. For us, that provides really nice external validation that there are interested parties, investors, and pharma companies if one shows promising Phase 1 data. Lastly, Amgen in May had the second-ever approval for a T-cell engager in solid tumors with tarlatamab, which is now branded as Imdelltra in small cell lung cancer. What's not often talked about with these three companies is the fact that all three used high affinity CD3. And so we don't think it's a coincidence that the companies that have had the greatest success in our therapeutic area are using the most potent payload. And the analogy we provide people is if you were developing an ADC and you could manage the side effect profile, a DAR of eight will almost always beat a DAR of two. The same idea is true for a T-cell engager. If you can manage the CRS rates, an aggressive payload, a high affinity CD3 will almost always be superior to a detuned CD3, a CD28, or a 4-1BB. So what is our actual strategic approach here? Historically, as I mentioned in the beginning, T-cell engagers have not worked in solid tumors. That starts with poor antigen selection. So the historical antigens 20 years ago, people were looking at things like EpCAM, CEACAM, HER2 are expressed broadly across your body. That's a lot of substrate for a T-cell engager to bind to. And not surprising, those drugs would run into CRS. Once they hit CRS, people would say, "Oh, well, this is a big issue, and CD3 must be the culprit. And so we're going to detuned the CD3 or use a co-stim." And then not surprisingly, the data with those weaker immune activators produce weak clinical activity and poor durability. We have a very different approach. We are going to focus only on targets that are clinically validated by ADCs. There's a strategic and a scientific reason for that. Strategically, large pharma has made considerable investments in ADCs. Three to five years from now, they're going to be in the life cycle management phase of those investments. There are a variety of theses out there about how one develops a drug for ADC resistance or can be used in combination with an ADC. A T-cell engager is one of those potential promising approaches for addressing ADC resistance or developing an ADC combination. Scientifically, our view is this makes a ton of sense. An ADC and a TCE are sort of a yin to a yang. ADCs generally require internalization to release their chemotherapy payload. To get sufficient internalization, they almost always need very high target copy number on the cells. That increases the probability of protein recycling and pulling the antibody into the cell. Because the payload is chemotherapy, they also generally require a rapidly dividing cell. Conversely, a T-cell engager, which is often 50x to 100 x more potent than ADC, works in low, medium, and high expressing cells. There's a gradient. It does work better in high, but it can also work in low. And generally speaking, prefers a cell that maybe is not dividing as rapidly as an ADC. So the two approaches in ADC versus a TCE, different mechanism of action, different AE profile, different resistance pathways. So we want to focus on clinically validated ADC targets. There's about 20 of them. We think Claudin 6, mesothelin, and Nectin-4 represent incredibly large market opportunities. I always like to remind people, if you compare Nectin-4 to PSMA, it's probably four times the market opportunity as PSMA. And what gives us confidence that our drugs will work clinically? Clinicians have greatly enhanced the probability that one will not see grade 3 and 4 CRS. They do that in a very cost-effective manner with step dosing, pre-medicating with a steroid. If you don't have to worry about or worry less about the primary side effect, you can dose harder. That optimizes the clinical activity. We do that through high affinity CD3. T-cell engagers do have monotherapy activity. The durability data actually looks reasonably good. But to enhance durability over time, companies are exploring really two avenues. The first is checkpoint inhibitor combination, not to deepen response, but to improve durability. Pembrolizumab is very good at helping with T-cell persistence and T-cell fitness. And so that can improve PFS over time. The other approach is ADC combinations. We really, and Steve and I have talked about this in the past, we thought that was two to three years out. That changed dramatically in the last six to seven weeks. So in August, Merck announced the first ADC-TCE combo. It appears now that Merck bought Harpoon, not just for the DLL3, but with this strategic goal of combining it with a B7-H3 that they have partnered with Daiichi Sankyo. That followed with Gilead combining Trodelvy with Marengo's T-cell engager agonist platform. And then in October, Amgen quite literally mimicked what Merck did with Daiichi Sankyo, doing a DLL3 T-cell engager and a B7-H3 ADC. And so for most T-cell engager companies, the bar for engaging in partnership discussions and business development discussions with large pharma historically was restricted to later stage trials because people were worried about CRS. Our view is these BD deals are really important. It lowers the bar for engaging with pharma. It also, if you think about it from a competitive standpoint, there are many, many more ADCs out there than there are T-cell engagers. And the T-cell engagers are limited to a small number of companies and very different than ADCs where each week there seems to be a new one coming from China. The Chinese companies really had focused on a co-stim 4-1BB and placed their bets there. 4-1BB turns out to be a very weak immune activator. CD3 does appear to be superior. And so there's a real scarcity of these T-cell engagers using CD3, particularly those with high affinity. So I know we're running down to seven minutes. I do want to leave it open to questions. And so I will jump back to the pipeline side and leave it there for any questions that people may have about our programs or company. Any questions? So maybe you can just talk a little bit about Claudin 6 and maybe just the historical development efforts that have existed around that target. I know it has a very kind of exquisite expression profile that almost looks kind of DLL3-like in terms of the gradient. Yeah. So in cancer drug development for cytotoxics, you're always looking for targets that are truly restricted to the tumor. So that way you can avoid normal cells. There aren't that many. And even those that have previously described as people develop better analytical tools, oftentimes they find out that they're much more broadly expressed than one would hope. Claudin 6 does truly seem to be very restricted to the tumor. And that's really exciting because then you could theoretically dose very hard and effectively kill the cancer cells. It's upregulated in a wide range of solid tumors. We are most interested in how they gate in gynecologic cancers, those being ovarian and endometrial. The challenge with Claudin 6, though, is, and there's always a challenge, right? It's part of a family of proteins. We have about two dozen Claudins in our bodies. They serve as what's referred to as tight junction proteins. So these help cells attach to one another, maintain cell permeability for those cells. And so Claudin 6 has homology to Claudins 3, 4, and 9. So they look similar. 3, 4, and 9 are in critical organs in your body, including liver, pancreas, gut, and ear. And so it is very hard to develop a selective Claudin 6 binder. That's where we think we are really differentiated. Claudin 6, even though it's a new target, is a recently clinically validated target. It's clinically validated with two different modalities, each with opportunities and challenges. The first is from BioNTech with BNT211. That is a CAR-T that at ESMO this year showed really exciting data in testicular and ovarian cancer. The durability in testicular was quite good. The durability in ovarian leaves a little bit to be desired. But the response rates were tremendous. Fortunately for us, CAR-T is validating, but it's very hard to scale up CAR-T to actually effectively run solid tumor trials that are large and randomized. And so we don't view BNT211 as inherently competitive to what we're doing, but it does provide a guidepost as far as which cancers we may want to go into over time. A second company, TORL BioTherapeutics, which is a private biotech developing TORL-1-23, is developing an ADC using MMAE as a payload. They had about a 45% response rate in ovarian cancer. We think those were in ovarian cancer patients that had high Claudin 6 expression, which is about 12.5% of the overall Claudin 6 market opportunity in ovarian cancer. TORL is using a very high dose of their drug, typically at doses above 2.4 mg/kg. With MMAE as a payload, you start to run into significant tox, namely hematologic. So this is a drug that's co-administered with G-CSF to address the neutropenia issue, and then separately, it does have a fairly high grade of fatigue. That's 20% of patients grade 3 and/or higher fatigue, which is quite a bit different than published literature around prior Phase 3 trials with MMAE, which typically had a 4%-6% rate, and so that's a drug that appears to have a little bit of a heavy side effect profile. But for us, we're sort of supportive and indifferent all at the same time because, again, we view a T-cell engager can be used after an ADC. And then separately, we do view a combination potential for all of our strategies. And so in the case of Claudin 6, it's co-expressed with Cadherin-6. Merck just moved their Cadherin-6 into phase three. For our mesothelin program, it's co-expressed with folate receptor alpha. And there's an FDA-approved FR alpha ADC from AbbVie. And then for Nectin-4, it's co-expressed with TROP2. And there's Trodelvy, which was approved recently. Okay. Interesting. And then in terms of defining expression, right, not only for Claudin 6, but for each of these targets, how do you think about doing that philosophically as you go through clinical development? Do you want to have a defined expression level for each patient of the target within each tumor type so that you can kind of maximize risk-benefit? Or do you think there's a scenario where maybe you take the Seagen approach with Nectin-4, where you just go into all urothelial or bladder cancer agnostic to Nectin-4 expression? Yeah. I view it as what is the underwriting probability. For investors, it's how do you determine the underwriting probability for your investment. For us, it's how do I determine underwriting probability for doing harm to a patient, right? Patients come first. Our development strategy is you have to have a diagnostic. I do not want to be in a position to give a potent drug and the target not present. If you think, in the case of Padcev, they have developed an agnostic approach. Only 60% of urothelial cancer patients have high levels of Nectin-4. And so they quite literally rolled the dice on the phase three and they nailed it. But as we all know, there haven't been other Padcev approvals in other tumor types yet. And so in similar approaches with TROP2, Immunomedics had the first approval, but then AstraZeneca subsequently failed with their TROP2 agnostic approach. I think one does want to enrich for your particular target as a starting point. We do from there take a wide aperture. So we have low stringency for our trials. So for example, and this is in the public domain for Claudin 6, we use a 10% cutoff for our IHC-based test. So 10% of the cells have to be 1 plus. From there, hopefully that data looks good and we have a large market opportunity. If we need to refine that and tighten the stringency criteria for high expression levels, we can. But as a baseline, we want all of our patients to be biomarker positive. Okay. So they will all be biomarker positive as you go through dose escalation? Yes. And most likely for the future as well. And then you'll have the capacity to retrospectively move that around based upon the efficacy data. And do you think, and so you kind of talked about the juxtaposition between the TCEs and the ADCs where the latter requires very high density of target expression in most cases. I would imagine where you set that cutoff for a TCE will be a lot different relative to where the ADCs have been, correct? Yeah. A lot of this is informed by the experience of the DLL3 products. So HPN328 and then tarlatamab for Amgen. What is interesting about DLL3 is it's very low expression. So there's 4,000 copies per cell. You contrast that with something like HER2, which can be 50-200,000 copies or 250,000 copies per cell. And so that type of level, and you compare it to something like Nectin-4 where there's published papers that that would be Nectin-4 negative in some cases. And so the potency advantage of a TCE enables you to hit those lower expressing cells. And also you don't need internalization. You're working through, and I think it's often forgotten, T-cell engagers work through bystander effect, right? And so they literally bathe the tumor. There's no internalization. And so that's a huge advantage versus ADCs.