All right, we can go ahead and get started. Thank you everyone for joining us at this year's 46th Annual TD Cowen Healthcare Conference. I'm Spencer from the investment banking group based in San Francisco. Pleased to welcome Context Therapeutics and CEO Martin Lehr today to lead the presentation. With that, I'll turn it over to the company.
Thank you very much. Appreciate everyone coming in, for those who are viewing. Martin Lehr, CEO of Context Therapeutics. Like to orient everyone to our public disclosures and encourage them to read that on their own time. Context Therapeutics is a company focused on developing T-cell engagers. This is a class of antibodies that forces the immune system that otherwise is cloaked from finding cancer cells in our body to interact directly with those cancer cells. Think of T-cell engagers as matchmakers, literally bridging the gap between our immune system and cancer cells. We try to take advantage of certain markers that are on cancer cells, these are called tumor antigens, so that we can specifically get the immune cells to bind to those cancer cells. Context is a search and development company. We do not have any in-house research.
All three of our programs that I'll introduce shortly were discovered externally. We think this is a very efficient capital model. Really we focus on is deploying our capital in the clinical advancement of our pipeline assets. We have three programs, two of which are in clinical development, Claudin 6 and mesothelin. We refer to these programs as CT76 and CT-95. A third program that will actually be in the clinic shortly, targeting Nectin-4, which we refer to as CT-202. All three of our programs are focused on solid tumors. For Claudin 6, we are most interested in ovarian, endometrial, and testicular, and increasingly over time, ovarian. For mesothelin, pancreatic, ovarian, and mesothelioma, increasingly focused on pancreatic.
Nectin-4, we'll disclose shortly what that clinical trial design looks like and the specific tumor types there. Nectin-4 is broadly expressed in triple-negative breast cancer, bladder cancer, non-small cell lung, colorectal, just to name a few. Context is at a really exciting inflection point where this is the start of a really data-rich couple of months and actually years for the company. In Q2, we'll have our first significant public disclosure on our phase I data for our Claudin 6 program. We are really focusing on enriching that dataset in ovarian, hopefully getting to somewhere between 10 and 12 ovarian patients at target dose levels, which will be a really nice dataset for people to evaluate. On the heels of that, about a quarter behind, will be our mesothelin phase I data.
These trials started in January and April of last year, respectively, that is the sequencing of these trials. Nectin-4 will be in the clinic, hopefully Q2. It will provide a cadence where you're basically looking from Q2 onward of almost quarterly updates for our clinical programs, which we think as a publicly traded company is a great place to be. Philosophically, for those of you who are experienced in T-cell engagers, you can notice our antibody format's at the bottom of this slide four. We are big believers in high-affinity CD3. This is the most potent mechanism by which one can activate immune cells.
If you're more familiar with ADCs, think about it as using a topo payload and a DAR of 8 versus competitors who are using an MMAE payload and a DAR of 2. The risk there is that you will have with such a potent payload, cytokine release syndrome, which historically has been the primary dose-limiting toxicity for this modality. We think that clinicians have done a wonderful job of mitigating that risk through step dosing and steroid prophylaxis, and as a result, it's no longer the primary dose-limiting toxicity. TCEs are starting to look more and more like regular drugs, where you have to, over time as you dose up, keep an eye on on-target, off-tumor liabilities. In the case of Claudin 6, we keep a close eye on the liver, in the case of mesothelin, the lung, and then Nectin-4, the skin.
That's ultimately what we believe determines your therapeutic window, and what you have to optimize for in phase I development. Strategically, we are in the short term developing our pipeline to address resistance to standard of care and developing our drugs as monotherapy. Over time, and what peer companies have shown, is that T-cell engagers are a wonderful combination modality. T-cell engagers typically have, if they do have toxicities, or adverse events, it's typically in the first two doses of the drug, and then after that, adaptation mechanisms kick in, and you rarely see complications from T-cell engagers from dose three onward. In the case of other modalities, like antibody-drug conjugates, toxicities typically accumulate over time. What makes an T-cell engager such a great combination agent is that there is an inverse relationship between toxicities for combination products.
T-cell engagers are a different mechanism of action and then different resistance pathways. We've seen wonderful combination data with topotecan-based payloads, with other forms of chemotherapy, particularly in the heme space, such as CHOP and R-CHOP, and then even recently with ADC combinations. If you look at strategic investment by large pharma companies, it's been heavily oriented to ADCs and PD-1/PD-L1 bispecifics. We think that T-cell engagers really are an ideal combination agent. If you look at just the amount of money and assets in development for ADCs and PD-1/PD-Ls, it would not be surprising that many of these become commoditized over time. There's a real scarcity of T-cell engagers, and we think ultimately that's where the strategic value and the strategic premium for these assets come in over time.
With that, I'll spend a little bit of time just talking about T-cell engagers more broadly and then ultimately, talking about specifics of our pipeline. Slide seven is how T-cell engagers work, where our antibodies force the interaction between a T-cell, highlighted here in blue, and a cancer cell in orange. On slide nine, T-cell engagers are still a new modality. There's been 10 approvals over the last 10 plus years. You'll notice here the bulk of the approvals are in the last couple of years. What often happens is a drug like Venclexta is approved in 2014, catches people a little bit off guard, it becomes a blockbuster, everyone starts noticing, and then you see the investment in the space.
What I like to show in the bottom right is the 2024 revenue. This is a little bit old, but the reason it's important is it shows you hopefully that there's rapid adoption of T-cell engagers. If you look at launch profiles of TCEs actually versus ADCs, TCE adoption rates and sales typically surpass, in almost every case that we could find as a company, ADCs. That's a really exciting development. The vast majority of these approvals are in liquid tumors, but increasingly we're seeing approvals in solids and actually great data in solid tumors.
Some of those solid tumor datasets are highlighted here on slide 10, showing that even in historically cold tumors like small cell lung, pancreatic, ovarian, and prostate, that you not only have robust response rates in late line patients, but you actually have very good durability. There are some companies that talk about durability challenges with T-cell engagers. We just don't believe that's the case. I think the data here proves it. Also anecdotally, you have cases like Amgen's drug tarlatamab on the far left that has a 14.9-month median overall survival in small cell lung cancer. That was unprecedented and that led to the accelerated approval of that drug.
The reason that the overall survival was longer than people expected is that once you activate T-cells for a long period of time, you can have a memory effect where those T-cells continue to surveil the patient long after the patient has gone off therapy. The other classical example people point to are in the liquid tumor space, multiple myeloma, BCMA-based T-cell engagers, where that carries actually a pretty significant infection risk. Once patients have an infection, they get pulled off treatment, they get their antibiotics or antivirals as needed. For that period that they're off drug, which can often be a month or two, the vast majority of those patients stay in relapse, and so it's the activated T-cells that are circulating that drive that. We think T-cell engagers can really be the best of both worlds, right?
Robust efficacy and durability, through step dosing and steroid prophylaxis, a very, very clean safety profile. Getting into our specifics for programs, we're really excited about Claudin 6. It's a fascinating target. It is only expressed in cancer cells, which should mean that it has a very, very low risk for cytokine release syndrome. It is expressed in a wide range of tumors. We think ovarian right now is a very clean, very exciting use case, particularly post-ADC, ultimately the ability to push the utilization of this drug into earlier treatment lines, such as the maintenance setting or platinum-sensitive. Different than published literature, at least in our hands, we find that almost 80% of platinum-resistant ovarian patients are Claudin 6 positive.
The surprise to us was, all the patients basically have very high levels of Claudin 6, typically H-scores in that sort of 200-250 range. That is a great place to be for a T-cell engager. You have a lot of target very cleanly expressed across the target cells, and that usually leads to good things for patients and their cancer. Here we just show what Claudin 6 looks like. It's a tetraspan protein. It is very stable, expressed in the membrane, does not internalize all that well. What you do need to keep an eye on, which is highlighted here on the right side, is that, while Claudin 6 is only found in the tumor, it's part of a broader family of proteins. The claudins are tight junction proteins. They help cells attach to one another.
Claudin 6 looks very similar to Claudin 3 and Claudin 4, which are found in the liver. What you want to do is minimize binding to Claudin 3 and Claudin-4. None of these antibodies are perfect. No one can perfectly bind Claudin 6, but we do think we have a potentially best-in-class Claudin 6 binder relative to our Claudin 6 TCE competitors. Why should you believe that our drugs could potentially work in ovarian cancer? Well, because peer companies, BioNTech with their CAR T, which is a wonderful comp for a T-cell engager, and TORL, a private company with their ADC, have exceptional data in ovarian cancer. BioNTech had seven of 12 ovarian patients have a response. There are challenges with CAR T. It's a one and done. Their durability is quite poor.
TORL with an ADC, there's, as you may know, 10 ADCs in phase III development for ovarian cancer right now. They're just competing with those particular companies. We have no dog in that fight. We want to treat ADC resistance, we think we're well-positioned to potentially have CAR T-like efficacy with better durability and to be used after ADCs. This is our antibody. It's an asymmetric format. People have been using this format for 25 years. It is very well-validated, easy to manufacture, and a lot of clinical precedent for it. Our data pre-clinically, what we want to show here is that our drug is highly selective for Claudin 6. The middle pane shows a physiologically relevant assay, which is a cell death assay in the presence of activated T-cells.
T- cells can recruit other T- cells. You want to look at assays that replicate the human condition. Here we show 500-fold selectivity for Claudin 3 and 4. That's how one should think about our therapeutic window from an in vitro standpoint. On the far right, dose-responsive regressions and actually resolution of cancer in mice. Where we are in the trial, as of our last update, we're in cohort five, wrapping up the phase I-A as we look to data disclosure in Q2. We would have durability data for all of these cohorts, increasing as we try to expand and backfill additional ovarian data points, we'll have hopefully at least response data and glimmers of durability data for those particular patients.
Think about it as a classical oncology update with waterfall plots, spider plots, swimmer plots, but with a TCE twist looking at PK, IL-6 to underwrite CRS, and markers of T-cell exhaustion and activation. We did provide a little glimmer of what early data looked like as of Halloween, where we had enrolled 12 patients at that point. We had safety through cohort four and efficacy through cohort three. Moving from top to bottom, the PK at this time point was exceptional, dose proportional, linear, no evidence of ADAs. The PK from an exposure standpoint was actually better than we had anticipated. We're seeing PK supporting absolutely dosing out to every two or three weeks. You might be wondering, you're dosing your trial weekly, how does that happen?
If you're running a trial, we started this trial in January of 2025. Some patients have been on drug for quite some time. They miss drugs, you know, treatment for any number of reasons. You know, a month ago, we had snowstorms in the Midwest. Some of the patients, when they miss a dose, you can get glimmers of data dosing out to two weeks or every three weeks. There we still see very nice exposure out to two weeks, in some cases out to even three weeks. If we can get to dosing every three weeks in later portions of this trial and subsequent trials, that's much more convenient for patients. Certainly if you can get to dosing every three weeks, that would align with ADC and PD-1/VEGF dosing schedules.
From an efficacy standpoint, again, cohort three was evaluable. Cohort three was the edge of our active range. In that cohort, we actually had one ovarian patient who had a very deep and durable confirmed response. This was about a 50% reduction that deepened to 85%. Then importantly and clinically relevant is this patient was ADC experienced. They had received prior mirvetuximab, which is a folate receptor alpha ADC, and still had a robust response. Ultimately, again, in PROC, we want to show that our drugs can work in the post-ADC setting. Competitively, we do view Xencor and Third Rock as our primary competitors. Where we differentiate from those two companies is in our fundamental belief that one needs to use high-affinity CD3.
If you detune CD3, the challenge is you're trying to avoid CRS. I don't think CRS is a major issue for T-cell engagers anymore. You have to absolutely keep an eye on it, but you ultimately are optimizing the therapeutic window for on-target, off-tumor tox. If you weaken the immune activator, you're gonna have to give a higher dose of your drug, and that increases the potential risk of on-target, off-tumor toxicities. We think, you know, ultimately over time, we will significantly differentiate from Xencor and Third Rock in our ability to have a clean safety profile. That's super important for all drugs, but particularly for our drug in that we want to push it to earlier treatment lines through the use of combinations, safety is paramount in that regard.
Given the time left, spend a minute on mesothelin, which again, our CT-95 program will have data, and we've guided to middle of 2026, so about a quarter behind our Claudin 6 dataset. Mesothelin is a larger market opportunity than Claudin 6. It's expressed in a very wide range of tumor types. For phase I-A, we are most interested in pancreatic, ovarian, and mesothelioma, for the reason that almost 100% of these patients will be mesothelin positive, you don't actually have to screen for expression in those patients. The challenge with mesothelin is that it's a cleaved protein. It's also a protein that's found in the lungs. First, you need to bind to the portion of mesothelin that's only attached to the membrane.
Second, 3% of our lung cells express mesothelin in the full-length form, and so you need to avoid binding there. The way we avoid mesothelin binding in the lungs is we took a page out of the Arcellx and Autolus playbooks. These are two CAR T companies targeting BCMA and CD19 respectively. They truly have best-in-class safety for those targets. The way they achieve that is, compared to their peers, they have the lowest affinity binders, and that has to do with tonic stimulation of the target. We did the same thing. We are 40-fold lower affinity for mesothelin than all of our competitors. At least clinically thus far, we are currently in cohort four and have publicly noted we are seeing really exciting safety. Safety has been an issue for mesothelin.
Because of the lung expression, you would expect hypoxia in these patients. Many of our TCE peers have never gotten active doses in their trial, we were seeing activity in cohorts three and four. This is something we're really excited about. Again, I think it was from protein engineering choices that we made early on in the molecule's development. The way that's exemplified is here with this in vitro data. Shed mesothelin is something that you can test pre-clinically. You do a cell death assay. You incubate cancer cells in the presence of activated T cells or PBMCs, you introduce shed mesothelin. Mesothelin, shed mesothelin at physiologically relevant concentrations, which for a high expressing cancer like ovarian or pancreatic, you'd expect about 25 nanomolar of shed mesothelin.
We actually do increasing doses of 10 and then 30 nanomolar here. On the left, you can see a historical comparator, Harpoon Therapeutics, which never had any efficacy clinically, never had any safety issues. The reason was they were binding quite efficiently to shed mesothelin. Here you can see a rifled right shift, which is a loss of potency, and it's dose responsive. By the time you give 30 nanomolar of shed mesothelin, they had a 110-fold lower level of efficacy with their drug. As we look to our competitors, I think at this point we're basically the last man standing, there's pros and cons to that. You always want a little competition. I think that's important.
The pro is this is a very large market opportunity as it relates to number of treatment-eligible patients. What we have believed and heard anecdotally, Amgen's drug is a very atypical format that looks to be highly immunogenic, and it appears clinically they ran into ADAs neutralizing antibodies rather quickly. That program hasn't been formally discontinued but has, the trial has been stopped and decreased from over 200 patients down to about 35. This past fall, J&J and Zymeworks, shut down their programs, in both cases due to hypoxia. While J&J bound to the portion of mesothelin that was attached to the membrane, they had no other protein engineering, approaches, conditionality such as masking, avidity enhancement, detuning their mesothelin binder, and so they hit mesothelin in the lungs.
Zymeworks bound to shed mesothelin, so they had to give a higher dose of their drug, and again, no conditionality to their program, ran into tox. You know, we're gonna obviously have to prove this out clinically and certainly with the data update later this year. I think we made some really great protein engineering choices. Again, lower affinity mesothelin binder, very similar to the Arcellx or Autolus strategy that worked out quite well for them. Binding to the portion of mesothelin that's attached to the cell surface. Lastly, our Nectin-4 program. This is something that we will increasingly emphasize because now we're on the doorstep of the clinic for this program. Nectin-4 is the largest opportunity that we are going after. It's expressed in a very wide range of tumors.
There's one FDA-approved Nectin-4 ADC that is PADCEV. It's approved for metastatic bladder cancer. There are many other cancers here to go after. We are very interested in colorectal, particularly microsatellite stable, bladder, breast, and non-small cell lung. Nectin-4 is highly enriched in the skin. About a third of patients receiving that PADCEV in the real world discontinue treatment due to skin toxicities. What we did here was made both the Nectin-4 and the CD3 pH-dependent. Cancer cells differ from normal cells. Normal cells depend on oxygen for their metabolic needs to create ATP. Cancer cells depend on sugar. As a result, they create a lot of lactic acid, a lot of protons in the tumor microenvironment, and a low pH. What we did was affinity mature our Nectin-4 and CD3 binders in a low pH environment.
What that means from a strategic standpoint, we have a lot of surface area with skin, and so you're never gonna fully prevent Nectin-4 binding. Think about pH-dependence at Nectin-4 as reducing binding to the skin by about 25%. For those antibodies that do bind to the skin, there's another 25% reduction in the ability to bind to CD3 on T- cells and activate those T- cells. The net result is, to our knowledge, we're the only company that has ever successfully completed GLP tox with a CD3 binder going after Nectin-4. The tox profile for this drug, preclinically at least, is exceptional. There is something really special about this pH-dependent technology when you put it not just on the tumor antigen but also on the CD3 binder. That data is just highlighted here.
We did a benchmarking exercise comparing our antibody CT-202 to the parental antibody that we affinity matured in a low pH environment. We call that Nectin-4 mAb, which is PADCEV TCE. You can see here on the left, which is in vivo efficacy data where we implanted human tumors in mice, both drugs perform equally well. Where things get really interesting is immune activation. Part of the worry of dermal toxicity is the activation of IL-6, which is a precursor to cytokine release syndrome. You can see at the top right in blue, we barely get any IL-6 induction even at 5 mg per kg, which is a super therapeutic dose.
In the bottom, even at doses that would be therapeutically active, such as 0.1 and 1 mg/kg, you see rather robust induction of IL-6. What that does is underscore or punctuate the clinical safety profile that we think we can have with. Competition is very limited. To avoid the dermal tox, our competitors are not using CD3, they're actually using Signal 2, which requires activated T cells to be somehow present in the body to maximize their effect. Bicycle Therapeutics use 4-1BB. They enrolled, I think, almost 40 patients in their phase I trial, and they had two responses. That's probably attributed to the weak immune activator. Rondo Therapeutics is using CD28 and a detuned version of that.
Again, there's no clinical precedence for having any robust solid tumor data without using CD3 that has affinity of four to 28 nanometer. We feel really good about where we are. Again, there aren't many cancer targets that can treat as many patients as Nectin-4. You're probably talking about a top three target as far as number of treatment-eligible patients in the world. This is something that, you know, I appreciate. Third program, just entering the clinic now, something that I think over time will be a very, very significant value driver for the company. To round it out, literally one minute, I'm joined here by our CFO, Gemini, who's the best. We also have a great team supporting us in Philadelphia as well.
Just to orient people, we're well-financed. We raised $115 million in 2025. We have cash through all of our material inflection points this year and beyond. Q2 data for Claudin 6, mid-2026 data for mesothelin, Nectin-4 in the clinic Q2 and then there'll be a number of data updates later on as well. I wanna thank everyone, specifically our existing investors, some of whom are present here. Please reach out if you have any questions, and thank you very much.