All right, good afternoon, everyone. Thank you so much for being with us today. For our next conversation, we'll be speaking with Context Therapeutics. We have with us on the stage CEO Martin Lehr. Thank you for being here.
Hi.
I know that you brought some slides with you. Why don't you start walking us through some of the background and what brings you here?
To meet investors. That's the easy question. Hi, everyone. Martin Lehr, CEO of Context Therapeutics. We are a small biotech company. We're essentially a roll-up strategy in the T-cell engaging bispecific antibody space, which is a mouthful. I'll refer to the drugs as TCEs going forward. For those of you who are familiar with the space, you'll know that over the last 20 years, it's been pretty unproductive as far as developing these drugs for solid tumors. Something pretty special has happened over the last year where we're starting to see, on a fairly routine basis, success across the field, and so that got us really excited.
In May, we raised a $100 million pipe led by some great investors, including Avidity, Blue Owl, Blackstone, Deep Track, Great Point, and Nextech, and that really gave us the capital to expand our pipeline to three drugs. All three are focused on solid tumors.
These were two licenses and one outright acquisition. The unifier amongst the portfolio is we're only looking for targets that are clinically validated by ADCs. ADCs are fantastically interesting, but we really view the space from a, where will it be five years from now? And five years from now, our view is that ADCs will be in their life cycle management stage. And so what do you give after an ADC or in combination with an ADC to make them work better? And we think that's where a T-cell engager can play. And so when we looked at potential assets to acquire, there's about 20 clinically validated ADC targets. Our view was there doesn't seem to be a rhyme or reason why other companies are picking targets for T-cell engagers. It doesn't seem to be correlated by ease of the target or market size.
We thought, why don't we focus on targets that are generally restricted to tumors, so essentially low-hanging fruit, less safety risk, and ones that had really big market opportunities? That may sound ridiculous to say that that wouldn't be obvious, but it's not necessarily obvious in the field. A lot of companies and protein engineering companies try to prove how good their technology is by going after the biggest, hardest problem. That's not necessarily correlated to market size. We have three products targeting Claudin 6, mesothelin, and Nectin-4. These are three really interesting emerging targets in the T-cell engager space. We have drugs that are very simple in structure, like our CTIM-76 asset, which is an asymmetric format that's been around for 20 years, and our mesothelin and Nectin-4 programs, which are using a butterfly structure that's avidity-enhanced.
These are newer concepts that are having great success in the clinic. Our two most advanced programs are Claudin 6 and mesothelin. We expect both of them directionally to be in the clinic by the end of the year and early next year, with data potentially as early as early 2026. Maybe to jump forward a couple of slides to get into why T-cell engagers, why now? This is how a T-cell engager works. A T-cell engager binds to both a cancer cell and an immune cell. In our case, we only use high affinity CD3. It's a very potent activator of T-cells, and we do that for a specific reason that I'll get into. I mentioned earlier, over the last year, the field has suddenly had great success in solid tumors.
These have been with a variety of products, targets, and cancers, some cancers that are being very cold that don't have many immune cells actually present. What's unifying across them is the fact that there's very low rates of grade 3 and 4 CRS. So for those of you familiar with the space, CRS is the primary dose-limiting side effect. If you are having grade 3 or 4 CRS, you're probably not getting to the therapeutic dose where you can maximize efficacy. So with these five products presented here, you can see incredibly low rates of CRS. They're giving therapeutic doses. The net result is efficacy data that's looking really good. So is it the technology? Is it the approach? Is it the target? Why are they all having success? In our view, it's driven by the clinicians. Clinicians have figured out how to greatly blunt CRS.
They do it in two really easy ways. The first is they give a step dose, also referred to as a priming dose. You give a low starting dose. It warms up the immune system and prepares it for the full dose. The other thing they do, and this is counterintuitive, is they give prednisone, a very potent anti-inflammatory. It turns out prednisone does a very good job of dampening the immune response without impacting activated T-cells. And so if you can premedicate with prednisone in step dose, you don't see a whole lot of CRS in the clinic these days. And the net result is some really cool data sets. So I always like talking about the Innovent data set. They had a 38% response rate in pancreatic cancer targeting CLDN18.2 with their T-cell engager.
That's not to say it's a cure or it's perfect data, but if you asked me a year ago, would anyone have success in pancreatic cancer with a T-cell engager? I would have said no, because no one has success in pancreatic cancer. And so that gives me hope that we're within shooting distance of having a T-cell engager work in any particular solid tumor. The other thing that's really notable about the space over the last year is, from a success standpoint, you had Harpoon being acquired by Merck for $680 million, Janux with great data in February and a potential data update with their PSMA program later this year, and then the accelerated approval of tarlatamab, now known as Imdelltra by Amgen. What's not talked a whole lot about is the fact that all three of these drugs use high affinity CD3. They use a very potent payload.
We think the reason that they're having success is the payload. The analogy I always give is ADCs. If you can manage the side effects of an ADC, you will almost always have a better outcome having a DAR of eight than a DAR of two. The same idea with T-cell engagers. The more aggressive the payload, assuming you can manage the toxicity profile, the better the outcome for patients. Why are we different? Why has the space evolved? T-cell engagers I mentioned over the last 20 years have not been successful. It turns out, if you look back at the targets people started with, they were, in retrospect, crazy. Of course, you were going to run into CRS.
If you pick targets that are broadly expressed in your body, CEACAM, EpCAM, HER2, you're giving a lot of substrate for these drugs to bind to and to activate an immune response, and so by being more thoughtful in one's approach to target selection, premedicating with a steroid and doing step dosing, you can mitigate the risk of CRS. You can get to efficacious doses and start having really good data, and then ultimately, we see the use case here being further expanded beyond monotherapy use to combinations, potentially with checkpoint inhibitors to improve T-cell persistence so that you have a more durable response, or with ADCs, so why ADCs, well, ADCs are sort of the yin to the yang for T-cell engagers. Different mechanism of action, different side effect profile, different resistance profile. You think about an ADC, it requires very high target expression to get sufficient internalization.
It also, for the chemotherapy to work, requires a rapidly dividing cell. Well, not all cancers look like that. For a T-cell engager, a T-cell engager is very, very potent. It's typically 50-100x more potent than an ADC. And so that means it usually can work in low and medium and high-expressing cells, the full continuum. And generally speaking, it prefers a less rapidly dividing cell. And so combining both approaches, tumor debulking with an ADC and then hitting the rest of the tumor targets with a TCE combined with a new antigen release and the warming of the immune synapse, you can have a winning strategy. And I think we have a slide. Yep, we do, so this was a thesis, the ADC combination thesis, that we thought would emerge over the next couple of years.
We were taken a little bit aback in August when the first deal was announced. And so it turns out, most likely, Merck bought Harpoon not for the platform, but for the specific use case of combining a DLL3 T-cell engager with a B7-H3 ADC. On the heels of that, Marengo, which is a fascinating private biotech company, announced a partnership with Gilead and TRODELVY to expand the use case potentially for TRODELVY. And then Amgen, which is also developing a DLL3, Imdelltra, they announced a partnership with MediLink to combine with a B7-H3. And so we really do think this is where the market is going. If you think about our own portfolio, there are some really interesting combination potentials with ADCs. So I mentioned earlier on we have a Claudin 6 program. Claudin 6 is co-expressed with Cadherin-6.
As some of you may know, Merck just advanced their Cadherin-6 program into phase III. They acquired that program a year ago from Daiichi for $1.5 billion after 50 patients were treated in a phase I trial, and then for mesothelin, it's not why we talked about, but it's co-expressed with folate receptor alpha, which is a really interesting ADC target, but really is underexploited. It's only being developed in ovarian cancer. It's found in over a dozen different tumor types. Ovarian is just where they had initial success, and so we think there's real potential to expand the pipeline from a clinical development standpoint, so we're at a really exciting time for the company. We just reported earnings last week. We are well funded with cash into 2027 and looking forward to questions.
Awesome. Well, thanks for the great setup. And I'd love to dive into some of your lead programs. So let's start with CTIM-76. Now, this is the selective Claudin 6 bispecific that you were talking about. So you were talking about this being an interesting target. Can you elaborate on that and specifically on the multitude of opportunities in all the different tumor types that Claudin 6 is expressed in?
Yeah, so for most biologics companies in the cancer space, they're looking for targets that are selectively expressed in cancers. There aren't a lot of them, and the ones that most often come up are the oncofetal proteins. These are proteins required for the development of a child and then most often epigenetically suppressed post-birth, and so those would be MAGE, NY-ESO-1, ROR1, and others. Claudin 6 is an oncofetal protein, so it's not found anywhere in our bodies. It is expressed in a wide range of solid tumors. No one knows exactly what it does. It probably actually does a bunch of nothing, actually, in cancer cells, but it's there, and cancer cells need it to attach to one another, so it's a [tetraspanin] protein. If you have four domains going through the membrane, that's probably really stable, so it's enriched in cancers. It's very stable.
It's expressed at a pretty high level. It's pretty ideally suited for a CAR-T or a T-cell engager. We obviously like TCEs because it's a more modular technology, and so this is a target that's increasingly on people's radars. It's being developed primarily at the moment in gynecologic cancers. We announced that we're targeting first patients shortly for our trial, and what we really bring to the table with this asset is a selective CLOT6 asset, and so CLOT6, while only being found in tumors, our bodies have two dozen different types of CLOT6. There are sister proteins, CLOT3, 4, and 9. They're in critical organs in our body, and so discriminating between six and those other CLOT6 is paramount, and that's really the special sauce here. Otherwise, it's a very vanilla antibody, which is probably reflective of how straightforward the target is.
Super. And so I know that you mentioned that you're moving into the phase I. You're going to be treating the first patient shortly. So as we think about moving into the phase I, remind us what are the key learnings from your preclinical studies of CTIM-76 and gives you the confidence moving forward into phase I?
Yeah, that it worked. So you never know with biologics development. It's kind of a white-knuckle experience given the capital intensity of the space. We actually just presented over the weekend at SITC our first dose selection process for that asset and really delved into how we translated the in vitro to in vivo work first for mice, then monkeys, and then ultimately selecting a human dose. Claudin 6 isn't in our bodies. And so the risk was putting it in monkeys and just having it circulating around for a bunch of days would it hit something else. And it was remarkably clean. As I always like to tell people, if you have overt toxin animals, you'll probably have overt toxin humans. But if you have nothing, that doesn't really tell you a whole lot.
So we have a drug that appears to be very clean, very well tolerated in animals, very potent, and so assuming there is linearity between the various species in humans, what we guided to at Context is starting around cohorts probably four and five, you would expect to start seeing therapeutic activity that ultimately you would have saturation of effect by cohort seven, eight, nine.
Super. Talk to us about the indications that you've selected for your phase I trial and how that relates to the market opportunity?
Yeah. So the market opportunity is broad. We are a growing company, but still a small company. In my view, going back to my venture capital days, which is my background, is that basket trials are really hard for small companies. And really, it just does not give investors what they're looking for, which is speed to data and data that they can understand. Equity analysts too, because you all have to underwrite future success. And so what we did is really streamline the focus of the trial to gynecologic cancers. Ovarian and endometrial have a very high prevalence of claudin 6. The relative expression is quite high within those tumors as far as target density. And you would only need to work with gynecologic oncologists. And so it was a very tight focus group.
The other thing that's really helpful, given the advanced development of assets in the ovarian space, I think there's pretty good appreciation what good data looks like. Even though these are single-arm dose escalation and expansion trials, something over 35% response rate in ovarian seems to grab people's attention right now. And then in endometrial, with Pembro being moved into the front line, second line is totally open. You're probably looking at a 20%-25% response rate is getting people excited.
Super. And so you alluded to dosing the first patient by the end of the year. And this is being a dose escalation study. You expect to see efficacy around dose levels four and five. So talk to me about when we can expect to see kind of a clinical update, when we could see some data, and kind of what metrics we would be expecting at that time?
Yeah. So we usually give pretty conservative guidelines. So the guideline right now to initial data is first half of 2026. We'll see once the first couple of cohorts are enrolled as far as updating guidance and timing, hopefully moving that in a little bit. And then as far as data, our view is we want to give real data that people can understand. And so bleeding out a handful of patients' worth of data, if it's exceptional, that's one thing. But otherwise, I think it makes sense to wait until you have somewhere in the order of 12-24 patients' worth of data that you don't just have response rates, but you can do real swimmer pods and spider pods and things where, again, you can provide data so someone can underwrite their future investment in the company.
Super. And so assuming all goes well with that data, what is your kind of longer-term strategy for CTIM-76 in terms of next steps?
So we own our assets. We want to develop them as far as we can and for as long as we can. And so we want to build an independent biotech company. We're capitalized right now to do so. We have really supportive investors. And so that would be the goal. It may be pie in the sky. I know a lot of companies say that. And ultimately, we'll have to figure out if some of these assets we have to partner, etc . But the goal is build an independent biotech and own the assets for the future.
Super. Let's move on to the next asset, CT-95. Now, this is a mesothelin bispecific antibody. So can you walk us through a little bit of the rationale for this agent, why this is an interesting target?
Yeah, yeah. So the first time I saw this asset, I said, "Oh, dear God, no. We're not doing mesothelin." Because for those of you who were around 2015 to 2020 and made an investment in a mesothelin asset, you lost money. Whether it was Aduro, Atara, Harpoon, TCR2, it was not a successful target. Never really toxic. It just never worked. And it turns out a 2020 paper came out and found out that mesothelin sees six different proteolytic enzymes. And the cleavage sites are through the continuum of the protein. And so those former assets were binding to places that were rapidly cleaved within the protein. And so you needed to bind as close to the cell surface as possible to avoid the cleavage. And when we looked back at the space, we didn't realize that.
Over the last year, there's been a lot of movement between pharma and investors. Pfizer bought from Harbor BioMed a phase I ready mesothelin ADC for $53 million upfront. You had RemeGen on June 3rd, had really remarkable data in mesothelin high ovarian, non-small cell lung, and cervical cancer, really strong response rates that were quite durable. Then in August, Outpace with their mesothelin CAR-T raised $144 million. So it seemed like a lot of people were looking at mesothelin with a fresh eye. And J&J just disclosed the mesothelin T-cell engager program. So when we looked back at the space, we said, "Okay, actually, this is really interesting." What a lot of the companies do now is they develop these assets and they run an assay where you look at the potency of your drug in increasing concentrations of fragmented mesothelin.
And our drug was very good at retaining activity versus some of those historical assets did not. And so it was a very good way to adjudicate the risk profile and opportunity for the asset. It just so happens it was also IND cleared. They had drug supply for the first 1,000 patients ready. And they were a highly motivated counterparty. So it was really an ideal asset to acquire. And mesothelin is found in 30% of all tumors. It's a massive market opportunity and one that we're really, really excited about.
Yeah. So towards that end, you guided to initiating this trial, I think, in the first quarter of next year.
Yeah.
And so given that this target is expressed across many tumors, talk to us about your indication selection for that trial?
We’re going to start initially in ovarian because ovarian. You don’t need a diagnostic to screen for patients. That will be really easy. Frankly, the company we bought the asset from didn’t develop a diagnostic. We’ve been doing that in the background. It’s almost ready. Once the diagnostic’s ready and at the right time, we would do a protocol amendment and start weaving in some of the additional tumor types, things like pancreatic cancer and mesothelioma, just to name a few.
Super. And so with that phase I trial, can you remind us what is the design of that trial and what would be kind of our timeline to seeing some clinical readout from that?
So that is very similar to our CLOT6, except our CLOT6, the first two cohorts are single patient, and then you move into a three by three. The mesothelin trial is a Bayesian design. And so that will be an adaptive trial. So it makes it a little bit harder giving firm timelines, given the flexibility. But the asset for the mesothelin is very potent. And so they're actually the company we bought from was very good at convincing the FDA to start a pretty reasonable dose, which is atypical for a T-cell engager. And so that's one where we really do have high hopes pretty early on to see some activity for it.
Super. Well, we're looking forward to seeing that as well.
Yeah.
Can you, before we move on to the next program, just remind us what your longer-term strategy is for the development of CT-95?
Step one is always show that it works in phase I. What investors are looking for is a lack of grade three and four CRS and then the ability to shrink tumors. I always kind of frame this like the goal of cancer drugs is to shrink the tumor. How you optimize the durability effect, particularly the T-cell engager, can happen over time. You first have to show it works in an overt manner. For us, we want to show that we have a profound impact on tumors and then optimize the dosing, the sequencing over time. For this asset, we very much want to explore it as a monotherapy, particularly in mesothelioma where there's no approved drugs, but then potentially as a combo with a Pembro or a folate receptor alpha ADC over time.
Awesome. With the time that we have remaining, let's talk about your other program, CT-202, which you recently announced the licensing of this Nectin-4 bispecific antibody. Talk to us about what's unique about this program and why Nectin-4 would be well suited for a T-cell engager.
Yeah. I mean, I love Nectin-4. I always have to remind people we're not developing this to compete with PADCEV. We want as many Nectin-4 ADCs developed as possible and ending up in the hands of large pharma. And we build radioligands. Theirs too because radioligands, ADCs, they're all DNA damaging products. And so a T-cell engager is ideally suited to be used after an ADC. And so what I think is fascinating about Nectin-4 is it's a huge market. You're looking at colon cancer and triple negative breast, and particularly within colon microsatellite stable. These are large underserved markets that if you compare it to something like a PSMA as a target, you're looking at a market opportunity that's three or four X the size. And so that was the initial draw.
The fact that PADCEV is approved with a really gnarly safety profile makes us feel like there's a pretty low bar from an underwriting standpoint of safety. However, this asset's really cool. So from a protein engineering standpoint, both our Nectin-4 mesothelin programs are avidity enhanced. So they have really sort of moderate binders to their target. When they see the monomer of their tumor-associated antigen, which may be expressed in normal tissue, so for Nectin-4, you have it in keratinocytes, hair follicles, sweat glands. It has a very high on-off rate. When you get bivalent binding at the tumor cell surface, that is where the avidity kicks in. It's a very thermodynamically stable bond with a very high on-rate. So it stays stuck to the tumor. You have a lot more target in the tumor than you do in normal cells. So you get preferential uptake.
Over time, you'll get a concentration gradient. The other thing that's interesting is that butterfly format that we have, the FC domain provides steric hindrance for the CD3. So even though we have two CD3s present, only one can bind at a time. And so to activate a T-cell, you need directionally at least a half a dozen of these antibodies present to potently activate it. So you need a lot of concentration of drug in the tumor for this to work, which also helps lowering the ability to have an impact on normal tissue. The last thing that's very neat about this is people talk in our space a lot about logic gating. So you have targets that are broadly expressed. You need technology, masking, pH dependence, avidity enhancement to overcome that. This drug is pH dependent.
So for cancer cells that are dependent on a glycolytic-based metabolism, they produce a lot of lactic acid. It's a highly protonated tumor microenvironment. So the pH is a little bit lower. So our drug is designed to have better affinity in a protonated environment. And so that selectivity drives increased activity within the tumor microenvironment. So it's really a three-pronged approach: avidity enhancement, steric hindrance, and then pH dependence to drive that activity. So it's a really, really neat program. That'll be in the.