Conference Transcript - CNTX 2026-06-03

Martin Lehr, CEO

Good morning, everyone, and thank you to Jeffries for hosting myself and our CFO, Gemini, to this wonderful conference. It's my pleasure to introduce Context Therapeutics and our pipeline of T-cell-engaging bispecific antibodies for solid tumors. I encourage everyone to review on their own time our forward-looking statements and various disclosures. Context is developing three different T-cell engagers, or TCEs, for solid tumors. Our most advanced program is CTIM-76. This is a bispecific antibody that is targeting Claudin-6 and CD3. The basic concept, which I'll reiterate in a little bit, is to encourage the interaction between immune cell and a cancer cell. Our immune system is very good at avoiding cancers. I should say, actually, the inverse. Cancers are very good at avoiding our immune system. And so what TCs do is force the physical interaction between the two. so that the immune system can find the tumors and then release porphyrins and granzymes to induce the apoptotic machinery to kill the tumors. Our Claudin-6 program is being developed in primarily ovarian cancer. We have disclosed that we'll have a data update in a couple of weeks that will run through our Phase 1A, preliminary efficacy, safety, pharmacokinetics, as well as correlative biomarkers such as T-cell exhaustion. That program went in the clinic in early last year, and we are on the pathway to exploring Q3W dosing and ultimately phase 1b and hopefully product registrational trials in time. Our second program is CT95. This is a mesothelin-targeting TCE. We are very interested in exploring the utility of this drug in pancreatic cancers among others this program also entered the clinic last year and is on track to have data preliminary data in september and then our most recent clinical entrant is our nectin 4 program which we refer to as ct202 nectin 4 is expressed in a very wide range of tumors the ones that people are most familiar with are urothel cancer because the approval of padsev and Nectin-4-ADC. So there's great interest in addressing PAD-sev resistance. We also are interested over time in exploring colorectal cancer, breast cancer, and lung cancer. As you can see them on the slide, all three of our antibodies have slightly different formats. Context is a search and development company, so we don't have any in-house research. We've acquired all three of these programs. And so the reason that they have slightly different protein engineering formats is we look essentially for build-to-suit antibodies. Each target that we're going after, whether it's claudin-6, mesothelononectin-4, has unique opportunities and challenges. And so the various protein engineering choices we've made over time reflect the opportunities and challenges of those programs. So for example, claudin-6 is an uncofetal protein, meaning that it is just found in solid tumors. Therefore you can really hit that target hard with a T-cell engager because of its tumor restriction profile, or that's at least our thesis. We use a high-affinity Clon6 binder as well as a high-affinity CD3, that's a very potent immune activator, and we use a very simple format in an asymmetric antibody, no bells and whistles. A lot of other targets, such as PSMA or EGFR, will require a lot more conditionality and technology, such as masking, avidity enhancement, et cetera, but Clon6 is pretty unique in that And it doesn't require those technologies in our view. Our thesis over time and how we intend to build a company is to initially develop our drugs as monotherapy to address resistance to standard of care, which we believe over time will be predominantly antibody drug conjugates in the solid tumor space. And we're already seeing this play out in real time. What we want to do over time and how we really build strategic value with respect to large pharma companies is to develop our drugs in combination with ADCs and PD-1 VEGFs. ADCs debulk tumors, they release neoantigens, create a very warm permissive immune microenvironment. We've seen really wonderful synergy thus far with T-cell engagers in various chemotherapies and ADCs. And so we think this is an opportunity to help ADCs build a moat around what they're doing. PD-1 VEGFs. The concept here is to deepen and make T cell responses more durable. So PD-1 releases the immune cell break. VEGF is inherently immunosuppressive, and so by blocking it, you create a more permissive immune microenvironment. So we think there's a lot of opportunities to partner with some of the largest pharmaceutical companies in the world to exploit the combinations of these various drugs to drive the utilization of our products into earlier and earlier treatment settings so with that groundwork just to remind everyone a t-cell engager forces the interaction between a t-cell and a cancer cell t-cell engagers are still a very new modality the first approval was about 10 years ago was a drug called blend cyto that's now a blockbuster but you can see here there's about a 10-year delay between the approval of one side on other TCs the reason is people didn't really know what to make of one side oh they didn't know if it'd be a commercial success if doctors would use it they'd be scared of cytokine release syndrome and it turns out people got incredibly comfortable with that particular drug leading to lower barriers for development of TCEs and ultimately we've seen globally 12 TCEs registered the bulk of which are in liquid tumors but we do have two approvals and solid tumors and you can see at the bottom right the launch trajectories for these various drugs over the last couple of years you've seen multiple almost I think five or six drugs now billed to what looks to be either one billion or greater than one billion dollar run rates and so you could be in a situation as early as next year where you have three or four of these T cell engagers that are blockbuster drugs which is just a remarkable change in how TCEs are being utilized in the clinical community. One of the questions we get a lot is will T cell engagers work in solid tumors? I mentioned that we've had two approvals thus far. What we show here is just a representative data set of what we believe to be encouraging T-cell engager data in solid tumors. You'll notice it's a range of companies, some very large, some very small, different targets. We have in this slide broken some orthodoxies in the space such as T-cell engagers will never work in cold tumors. You can see tumors here like prostate and small cell lung which are classical cold tumors where these products are having really exceptional data. And exceptional data, in my view, means that you're not only shrinking tumors, but you're doing it for a prolonged period of time, which we refer to as durability. And that's what you're really seeing emerge here. And then the last part is the primary dose-limiting toxicity that people worry about, cytokine release syndrome. We've seen, as a field, that risk decrease dramatically. We think what's happening is doctors have just gotten much better at using these drugs. They employ step dosing and steroid prophylaxis as a mitigation strategy. It's cheap, easy to do. And the result is that you really don't run into dose-limiting CRS anymore for the vast majority of these products. So you can dose through it, get to therapeutically active dose levels, which increases the probability of success for these products. So with this, I'm going to transition into our Caudin6 program, which will be the focus of our discussion today. Claudin-6 is enriched in a wide range of solid tumors we are most interested in ovarian cancer there's two primary reasons for this the first is the vast majority of platinum versus novarian patients will express Claudin-6 and they express very high levels of Claudin-6 having a lot of target on the tumor cell surface increases the probability of a clinical response the second part is in my career ovarian cancer trials have always been very hard to enroll they've been very competitive we've seen a dramatic shift in the clinical algorithm for ovarian cancer now the primary experimental therapeutic that patients are getting or antibody drug conjugates almost all of which are topoisomerase based drugs and as we saw over the weekend at ASCO as Eli Lilly so eloquently showed with their Nectin-4 ADC, the probability of using sequential ADC therapy and generating clinical response is incredibly low. And so, therefore, what clinicians are looking for is something to administer after an ADC, preferably something that has a different mechanism of action, a different adverse event profile, different resistance pathways. Turns out that's exactly what T-cell engagers bring to the table. So, there's always a catch. if Claudin-6 is such a great idea, why isn't everyone doing it? Well, it's very hard to develop a Claudin-6 antibody. While Claudin-6 is restricted to the tumor, it's part of a broader family of proteins, the Claudins, which are tight junction proteins. So they are very similar to cadherins or integrins. They help cells attach to one another. They're also developmental. Well, in the case of Claudin-6, it's a developmental gene. So while we don't have Claudin-6 in our bodies as cancers grow. One of the classical hallmarks of cancer is the activation of developmental genes. And so when we were kids, our bodies were growing like crazy. Cancers want to become like kids and grow like crazy. And so they'll turn on these genes, one of which is clodin-6. So as you look to develop a clodin-6 antibody, there's only a small portion that's surface exposed that would be amenable to an antibody. The problem is in that binding domain, also referred to as an epitope, there is significant homology of Claudins 3, 4, and 9. Those Claudins are found in normal tissue, including the liver, pancreas, and ear. And various studies, knockdown knockouts, have shown that there can be very significant phenotypes associated with impacting those other Claudins. And so driving selectivity for Claudin 6 is really paramount. To achieve that selectivity, we developed an antibody that is asymmetric in structure. We evaluate a wide range of antibody formats to optimize the interface between a T cell and a cancer cell, which is referred to as a synapse. And ultimately, this asymmetric format, which has been around for 20-plus years, was the format that worked the best. We have some additional protein engineering in this antibody, including silencing the FC function through alala mutation and then assuring proper base pairing through another technology. So we can manufacture a drug at high yield, and we do it with a very well-known multinational partner. The key preclinical data is highlighted here. On the left, all Claudin-6 companies hopefully can show that they're very selective for binding to Claudin-6. That's not particularly physiologically relevant. The middle panel is more relevant. The reason I say that is T cells are unique, and they run through bystander effect. So it's not a pure one-to-one interaction as the binding image shows on the left. What happens is a T cell, once it binds to a cancer cell and forms a synapse, it can call its buddies and recruit other T cells. It can also proliferate and split into multiple T cells over time. And that's referred to as a scaffolding function. And so you can have multiple T cells per synapse. So what we do is a potency assay in the middle. So this is just a standard cell death assay. you overexpress, either Claudins 3, 4, 6, or 9, and you introduce immune cells, either PBMCs or activated T cells, and you do a concentration gradient. And so here, from an in vitro standpoint, we think about the therapeutic window for our drug is about 500 fold. And so that's the window with which we use to determine our first in human dosing and then ultimately the math for how we want to get to therapeutic activity. And then on the right, we have great in vivo data, as you would expect. So this is our trial design. We have learned a lot over the course of the trial, and as I like to say, hindsight is always 20-20 with your first T-cell engager. When we started the trial, all of our peers were doing basket trials, ovarian endometrial and testicular. As I mentioned earlier, ovarian trials were historically very hard to enroll, and so we all wanted to hedge and include endometrial and testicular patients. What we learned is that actually ovarian, given the circumstances of the clinical landscape and the very high target prevalence, is very easy to enroll. There was no facile way with how we constructed this protocol to say one day we want to enroll more ovarian patients than just them. So we had to do some maneuvering, which was the two middle cohorts of 210 and 280 to ultimately get to where we want to be with the Q3W. But to unpack that a little bit, we started with what's referred to as a Mabel dose, which is your EC20 and your most sensitive assay. We then went to a second dose level. Both of these doses were projected to be subtherapeutic, which they were. And then we would get very quickly into active dose levels, starting at 140 micrograms. We projected activity as being the dose at which our drug would be above the EC50 for the duration of treatment. that weekly interval. The EC50 is the dose required to kill 50% of the cells in that cytotoxic acid I mentioned on the previous slide. And then we continued to escalate, ultimately getting to a dose range that we felt comfortable with. Because it was a 3 plus 3 trial design, there was no efficient way if we did not run into toxicity to expand the number of patients. So we added the two additional cohorts, the 210, the 280, to increase the number of ovarian patients that we would have in our June dataset. So where we are right now, we've enrolled quite a few patients, about 15 of whom are at target dose levels, and about 10 of those 15 are platinum-resistant ovarian patients. And we've previously guided that the vast majority of those patients, almost all, are ADC experienced. So we think it's a highly relevant clinical dataset that we'll be presenting in the coming weeks. And then ultimately, we were pleasantly surprised the pharmacokinetic profile of our drug after a week there's still a lot of drug present and so ultimately for patients we think we think that every three-week dosing referred to as q3w dosing is really what those patients are looking for from a patient convenience standpoint q3w dosing also aligns with the administration schedules for ADCs and PD-1 VEGFs which strategically is very important. And then lastly, some of you may have seen, this is getting very geeky and technical, but at ESMO this year, there was a wonderful data set from J&J featuring their drug, Pesrydomic. So this is a KLK2 TCE. And what they showed very elegantly was to optimize T cell activity, you don't want the T cell engager fully active for the dosing interval. That constant, what's referred to as tonic signaling through CD3, will lead to exhaustion and a loss of response. And so J&J took their weekly dose, went every three weeks, and ultimately every six weeks, and found that if you let the drug be active for a period of time and then wash out and then let the T cells recover and re-energize, two remarkable things would happen. One, the efficacy got substantially better, deeper responses, more durable responses. But then also there was no reintroduction of CRS. And so even though you're letting the T cells recover, you would not stimulate cytokine release syndrome. And so we think the profile that we're seeing right now could create a scenario where if we're dosing in 21-day intervals, the drug may be on board for 10 to 14 days, wash out, let the T cells recover for a week. And so ultimately, you know, what we think could happen is better, more durable responses over time. That's not to say we're We're not happy with what we're potentially seeing right now, but I do think the field's going in a direction that is very positive for patients and sponsors alike with less frequent dosing. The most recent deep update we provided was right around Halloween, where we provide an update on the first four cohorts. So this was dosing through the 280 microgram dose from a safety standpoint, and then efficacy for the first three cohorts, which was up to 140. And as I mentioned earlier, the first two cohorts were subtherapeutic, and we were just getting into therapeutic target ranges at 140 micrograms. Of those 12 patients, about half of them were ovarian, and then the rest were a mix of endometrial and testicular. They were heavily treatment experienced that continues to be the case. And as we look, moving around this slide, from a pharmacokinetic standpoint at this point, We were seeing linear and dose proportional PK, which is great, it's a very well-behaved antibody. As far as chloratives, we were seeing very nice T-cell extravasation, meaning that when you give the drug, the T-cell moves out of the bloodstream towards your target and then recovers back, and then dose proportional cytokine elevations. On the efficacy side, we had reported that at that point, we had one patient in the 140 microgram dose level who had a deep and durable response. This is a patient who at week eight had about a 50% decrease in their target lesions. That deepened the 85% at week 16 and they continued on treatment. That patient I think is very clinically representative of the ovarian patients that we've been rolling to date. This patient basically got the greatest hits of ovarian cancer treatments. Mervituximab, which is a folate receptor alpha ADC, olaparib, which is a PARP inhibitor. They got bevacizumab. All of our patients get MEGF, sometimes multiple times across their treatment journey. And then they got an experimental therapy as well. So I think that just punctuates the stage of disease that the patient was at. And so that was really encouraging to us. You always want to see good data early and, you know, a jumping off point, so to speak, that you can build off of. As far as safety, the drug at this point has has been exceptional so we noted in October that one patient had had grade one CRS at that point there were no DLTs and no MTDs we think what's happening is a combination of Claudin-6 being oncofetal so purely restricted to the tumor which lowers the probability of CRS and then the fact that we're doing steroid prophylaxis on cycle one day one and cycle one day eight as well as step dosing and so you take the combination of that we're seeing you know potentially very low rates of CRS and that opens up a wide range of really interesting development opportunities particularly as you think about pushing the drug into earlier lines of therapy and the utilization in the clinical community obviously a trial like this we're running it in large academic centers but to bring the drug to the masses it has to be able to be administer in the community and so what we think is if this safety profile continues to hold that is a real probability with this drug which is incredibly exciting competitively we really see ourselves and Zencore is breaking from the pack Zencore is about based on our read of their public disclosures about six months ahead of us I think the truth is it's hard to say how we're dramatically different than them at the moment we need to compare clinical data there are some nuances between our antibody approaches they have detuned their CD3 and they are a two-by-one binder typically one detunes their CD3 to mitigate the risk of CRS I mentioned earlier I don't think there's a lot of inherent risk of CRS with Claudin-6 so if you detune the CD3 the probability that you're gonna have really strong efficacy actually decreases because to be equipotent R-drug, you have to significantly increase the dose administered. The second thing is they're a two-by-one. And to be fair, we have two avidity-enhanced antibodies, our mesothelin and nectin-4 program, so we like that approach. We just think it may be a challenged approach with Claudin-6. The reason being that if you have two arms that can bind to a tumor antigen, yes, they could both bind to Claudin-6, but they can also bind to Claudin-3, 4, and 9. And, again, direct binding to those off-targets can lead to clinical phenotypes. And so now you, from a stoichiometric standpoint, have increased the probability of one of those inadvertent binding events. So I think these things either may be really important over time, maybe just on the margin, but we'll have to find out. Again, we're reporting our initial data this month. Zencore has guided to preliminary disclosure later this year. and so we should be able to know more definitively at that time. The other products are more emerging with, in our view, some significant liabilities in their protein engineering choices and approaches that may limit their utility. So, you know, we think it's, again, a two-horse race as you look at commercial opportunities for Zencore and ourselves. Right now, there are six different topo-based ADCs in phase three development for ovarian cancer as well as an approved folate receptor alpha ADC with a different payload. All seven of those programs are being developed by large pharmaceutical companies. And so, you know, I think there's a lot of opportunity for two entrants to partner with those companies. So I don't think a second group is limiting in any fashion. I do very much hope over time that we substantially differentiate from Zencore and take a dominant position. But I'm not sure how much in the short term that particularly matters. So given the amount of time, I really just wanted to focus on Claudin-6 today. We do, in summary, have two other wonderful programs, our mesothelial and T-cell engager, which will have preliminary phase one data in September, and our Nectin-4 program, which will have first patient dose shortly. We learned a lot about TCE development, particularly around clinical protocol design for that program. And so we think that should be in a position to have clinical data in 2027, so right around the corner. From a financing standpoint, we last raised substantial capital in 24, and we still have cash into the middle of next year, so about a year's worth of runway or so. So with that, just want to thank my team and Jeffries for hosting us today, and I think we have about five minutes for questions if people want. Perfect. And we're good. Thanks so much.