Good morning, everyone. My name is Jeff La Rosa, and I'm an equity research VP on the immuno-oncology team here at Leerink Partners, and I'm thrilled to welcome Context Therapeutics to the final day of our global healthcare conference. Joining me from Context to participate in a fireside chat is Chief Executive Officer Martin Lehr. Welcome, Martin, and thanks for being here.
Thanks for having me.
I think just to start off, to set the stage here, can you just give a brief setup to Context and, you know, to orient investors, and what are your current strategic and pipeline priorities right now?
Yeah. Context Therapeutics is solely focused on developing T-cell engagers for solid tumors. We're a research and development company, so we don't have any in-house research. All three of our programs we acquired externally, two licenses, one acquisition. The focus of positioning our T-cell engagers is to address ADC resistance. Large pharma has made very significant investments in ADCs. They're driving the use case to the frontline setting in almost every solid tumor. The question is, what do you give after that to address that resistance profile? That's where a T-cell engager comes in. The benefit of T-cell engager is that they're incredibly potent. The risk with a T-cell engager is that they can induce cytokine release syndrome. That's the balance one tries to achieve.
What we have found and believe is that clinicians have really figured out how to manage CRS. They do it with step dosing and steroid prophylaxis. You now can dose right through CRS and achieve appropriate therapeutic windows. That's yielded great data in solid tumors. We have three programs targeting claudin 6, mesothelin, and nectin-4. Claudin 6 and mesothelin are in the clinic. We'll have data for the Phase 1a portions of those trials this year, in Q2 for claudin 6, in the middle of this year for mesothelin. Our nectin-4 program is literally on the doorstep of the clinic and will enter the clinic any day.
Excellent. Let's dive into the first program, the claudin 6 TCE. And before we get into, you know, its development, the data coming up, you know, why claudin 6? What attracted you to claudin 6 as sort of the first target for your lead program? And what's really differentiating about, you think, the TCE approach, but also specifically your molecule relative to, you know, other forays at the target?
Yeah, I think so as an oncology drug developer, we're all searching for targets that are exquisitely selective for the tumor. There aren't many of them. Usually when you get your hopes up that one is selective for the tumor, it ends up not being over time. Claudin 6 is oncofetal. It truly is only found in the tumor. That creates a real opportunity to dose the patient pretty hard, because of that selectivity advantage. As a result, multiple players have entered the space with CAR T, ADCs, T-cell engagers. We think the real unmet need, given the expression profile of claudin six being heavily enriched in ovarian, is to treat ADC resistance. We have one approved ADC in ovarian, mirvetuximab, which has an MMAE payload. There are some really exciting TOPO-based ADCs in development. There's about 10 phase IIIs ongoing right now.
All those drugs will have cross resistance. What's exciting about us, about our trial is, you know, we're actively trying to enroll ovarian patients. The vast majority of them will be ADC exposed, and so if we can continue to show promising activity post-ADC, that's a real unmet need in this patient population globally. Then over time, given the safety profile we're seeing, again, 'cause claudin six is only found in the tumor, we think there's a real opportunity to push the use case into the front-line setting, either in maintenance or platinum-sensitive in combination with one of those exciting ADCs. Competitively, we have some great competitors. There's a company, TORL, that's private, has a wonderful ADC. We don't compete with them, actually. They compete with the other ADCs. We would be used after all those drugs.
There's two primary T-cell engagers, one from Xencor and one from a private biotech called Third Arc Bio. They are actually very similar to ours except for one fact. They both detune their CD3. We think for claudin six, given the selectivity profile in the tumor, you really wanna use high-affinity CD3. That's the most potent activator of T-cells. That's how you generate the best efficacy data. I think ultimately, our selectivity profile will enable us to differentiate from those TCEs on a safety standpoint.
Yeah.
Using the high-affinity CD3 differentiate on an efficacy standpoint.
On the high-affinity CD3, what is it about the design of, I guess, the molecule that lets you do that without having too much potency in CRS? Do you have avidity-based binding? Is it about the target just being super selective? What kinda allows you to do that?
Yeah. I think there's some confusion now in the investor world about CRS. We don't view CRS as the primary dose-limiting toxicity for TCEs anymore. I think clinicians truly have figured out how to use these drugs. What they do is they give a low starting dose that allows the immune system to warm up before the full dose. You typically give a steroid before the first two doses. Then if things get out of whack, you can use an anti-IL-6, like tocilizumab, to rescue the patient. Almost every company in the solid tumor space doses right through CRS. What we all tend to focus on much more now is traditional drug development risk, so on target, off tumor liabilities. That is how we really think about therapeutic window.
Within that therapeutic window challenge for the on-target, off-tumor, that's when these conditional technologies really come in at this point. What can you do to localize the activity to the tumor? There's masking, there's pH-dependent, there's avidity enhancement. We don't have a platform, so we have a little bit of each.
Yeah
In each one of ours. We like following, you know, what smart companies do. Our Mesothelin asset's a great example. I loved what Arcellx and Autolus did with their CAR T programs using a lower affinity binder than their peers with the idea of differentiating on safety. We did the same thing with Mesothelin. We're 40-fold lower affinity for Mesothelin than any of our competitors. That really has yielded fruit thus far clinically with a really nice therapeutic window thus far. To sum it up, I think people thinking about those conditional technologies for CRS, I think that matters less, and it's better to use those technologies in minimizing on-target off-tumor, just direct binding effects.
Yeah. One thing I get asked a lot with the when something's potent, whether it's the CD3 or what have you, that it could drive T cell exhaustion or-
Yeah
You know, or I guess activation-induced cell death or what have you. Do you see that as a risk? Is that something you're seeing in your programs right now?
Yeah. If you have a drug that's active, you will absolutely see that. You'll see dose proportional T-cell exhaustion. What, as an industry, we had hoped would happen, and fortunately it did, was this idea that if you could extend out the dosing interval, you would allow T cells to re-energize, and that would generate better data. Everyone knew that that would intuitively work. The question was, if you let the T cells re-energize, are you gonna have CRS at every single dose? The FDA and global regulatory authorities were very reluctant for sponsors, particularly in the Phase 1a, to explore anything but once-weekly dosing. If you dose weekly and you have good PK, you're gonna rapidly exhaust the T cells. The first data set that really excited people was this fall.
J&J has a KLK2 T-cell engager called pasritamig. They showed very convincingly that dosing every three weeks was vastly superior to dosing every week, and that dosing every six weeks was not inferior to every three weeks. Well, if you're developing a prostate drug and you wanna take it into the community setting, having a very low incidence of CRS, they had 8% of patients with CRS, you can give it every six weeks. Like, it doesn't get more convenient than that. But the coolest part was they didn't have any incremental CRS with each subsequent dose. What we've learned as an industry is there's a small pool of hyperreactive T cells. Those are cells that typically drive the TCE immediate side effects in the first dose or two . They typically burn out very quickly, either through exhaustion or by killing each other through fratricide.
Once that pool's gone, it's gone. What you've seen is this cadence of data. It was first J&J, then it was Janux and Vir and Amgen showing that if you increase the interval, the PFS data and the response data gets better without an increased risk of CRS. I think you're gonna see almost every company start exploring longer dosing intervals. We've even heard some companies in the heme space dosing every three months, and that's just tremendous for patients.
That includes your programs, I imagine. Yeah.
I don't know if we'll get to every three months, but.
Yeah, right.
Yeah, we're gonna definitely explore dosing less frequently.
How have you implemented that so far? Is that something you've been able to pretty quickly extend the dosing intervals? Where are you at with your programs on that?
It's one of those, you know, hindsight's 2020. Two years ago when we designed the protocol, there was never, you know, the idea like, oh my God, one day every three-week dosing would be a possibility and the FDA would be cool with it.
Yeah.
We didn't write that clause into the protocol, so you have to think creatively about a protocol amendment to do that. It's absolutely on our strategic priority list for this year. We'll disclose more about that shortly, so that we can explore every three weeks, and we wanna do it with all of our programs. Again, it's not something until very recently we all thought was a possibility, and so we're most companies are scrambling how to actually effectuate that clinically, quickly.
A way to think about it is, like, a maintenance kind of like a downshift in sort of the exposure, like, but just an extended step up. 'Cause, like, Janux, for instance, you know, they do the step up and then they do two cycles of the once weekly, and then they're moving into less frequent. Is that sort of the way to think of, like, an induction to maintenance type of strategy?
Yeah. I mean, I think every company is gonna play with it a little bit. It depends on your CD3. It depends on the PK of your drug, and then the PK obviously can change between doses and as exposure goes up. I think you'll see everyone with, like, slight tweaks. It might be weekly, then you give a dose, and then two weeks later you give another dose. Everyone's gonna play with it, but the same goals will be there, right? Step dose to reduce CRS risk and then get to a full dose that you can give less frequently. I think the thing that people always forget about T-cell engagers, even with those priming doses, there's often this thought that the priming doses aren't active. For most of us, the priming doses are quite active.
They may not, at that dose level, be able to induce responses, but if you look at biomarkers, so, you know, like CA-125 levels in ovarian, you can have a very profound impact on the PD markers as you roll into the full dose.
What's been your lessons and experience so far with CRS management and prophylaxis and really the relationship with balancing, you know, not having limiting CRS of course?
Mm-hmm
also not compromising efficacy, for instance?
Yeah. I think there's some concern within circles that if you prophylax with steroids, this narrative was created that you would impact your therapeutic activity. We really like steroids, so it mitigates the risk of CRS, it washes out within 24 hours, and the other net benefit is the day after you give the steroid, the patient feels really good. You know, they have energy, they eat, they report less adverse events. That's why steroids are given kind of ubiquitously with oncology products. Almost every chemotherapy patient will get a steroid because they eat the next day. I'm not sure how this narrative started.
Mm.
Our view is, because a T-cell engager really works through proliferation and bystander effect, you don't wanna use an IL-6 on the front end. You wanna save that on the back end, where the IL-6 could impact that proliferative effect. People confuse T-cell engagers with CAR T. CAR T, you're shooting in a modest amount of cells, and if you're lucky, they engraft and expand a little bit. You're not worried about proliferation there, so you can give an IL-6, which is a really potent modality to mitigate CRS. The T-cell engager, you wanna make sure that you form the synapse, the T-cells replicate, they recruit other T-cells and so that's why I think a steroid's probably better on the front end, and then if you really have breakthrough CRS, you can save it with an IL-6.
Okay. We're coming up to data, you know, an updated that you said Q2 of 2026.
Mm-hmm
I believe. Can you just sort of set up how your dose escalation experience has progressed and what you expect to show and what those levels, et cetera, and indications at this in Q2, and are you targeting a medical meeting for that?
Yeah. Q2 will almost certainly be a company webinar. It's just very hard for a small company.
Yeah
To get their act together at a medical meeting, so early on in the company's life. I think certainly over time, we wanna present increasingly at large medical meetings. For that data, I describe it to people, no good deed goes unpunished, so you learn a lot in your clinical development. This is the first time in my career ovarian's been really easy to enroll.
Mm.
We didn't expect that. Had I known that, we would have only enrolled ovarian patients out of the gate. The protocol was designed to enroll ovarian, endometrial, and testicular. What we're trying to do within the confines of the protocol is enrich for ovarian.
Yeah.
Not so easy to do. The other thing is that 80% of our ovarian patients ended up being claudin-6 positive, which was about 2x what we projected.
Okay.
The hit rate's higher, and then the last part is, because once a patient progresses on ADC in ovarian, there's not much else for them. You know, it's just a very clean, interesting patient population. We've had to get a little creative.
Yeah
in the protocol. Ultimately, the goal for Q2 is we wanna get to directionally 10 patients with platinum-resistant ovarian who are ADC exposed at target dose levels. If we can have a 30% response rate there, that would be tremendous. That benchmarks against standard of care, which is paclitaxel and doxorubicin, which is a 5%-10% response rate and about a three-month PFS for those drugs. If we can show strong response rates in effectively sixth-line ovarian with hints at durability, and I say hints because it's a limited data set, so you know, you're gonna see some patients who've been on drug for a while, others have been on drug for a short period of time with an arrow to the right.
What we're trying to just paint is a picture of, you know, through the first half of this year, that we have a very clear therapeutic window, excellent safety that could hopefully support not just every three weeks from a patient convenience standpoint, but outpatient dosing ultimately, given how clean the target is, and then a line of sight with the PK data that will show, that will give people confidence we can easily dose every three weeks.
Yes. This post-ADC setting is obviously going to become more and more of a defined treatment segment as, you know, there are probably 12 phase III ADC trials going early, front line maintenance, second line maintenance, sensitive, platinum resistant, what have you. For this at this junction of time right now, are these mostly post-ELAHERE patients, or is it a little bit of, you know, clinical trial? Now, I kinda say that from a perspective of-
Yeah
You know, these different payloads, for instance. You know, the microtubule inhibiting for ELAHERE seems to be maybe a little more IO sensitive than topo one inhibitors by sort of my read to the data. Is that potentially an opportunity to sort of show some synergy in this from a sequencing perspective? I guess thoughts on that, and then just the thoughts of like what these patients and tumors look like in this setting.
Yeah. We've learned a lot. I think we need more data points. As we're preparing for the phase 1b, we are prospectively screening patients who are last line standard of care for claudin 6. We've got a data set of about 100 of these patients. I'd say about. We are, to be fair, focused on U.S. large academic centers, so it does bias the data set a little bit. About 80%-85% of the patients are ADC experienced.
Mm.
The vast majority are mirvetuximab experienced. What we're seeing more recently, particularly at one or two academic centers, is some of the Trop-2 being trialed, and then some of those actually in combination with an HER2, which I'm not quite sure how the patients tolerate that, but.
Oh
It is being trialed. I think you're right. It's gonna be ubiquitous. Whether a T-cell engager versus a checkpoint inhibitor is better suited post one or the other, we'll find out. I honestly don't know the answer to that, and we would need to be data-driven. I think, you know, this data set, we're not gonna have that answer. I think you probably need to get 50 or more data points to start feeling like you can suss one or the other, because I think probably over time, even in our phase 1b, 80% of the ADC patients are still gonna be MMAE, and so it's gonna be a very small smattering of topo-based payloads that are either, you know, claudin 6, NaPi2b, or folate receptor alpha.
I guess part of that, are more patients, I guess, folate receptor positive than maybe-
The label would indicate?
Yeah. The label might indicate.
Yeah. I think that was a learning experience for me.
Yeah.
When we did the math, right, you know, so the label says 75%.
Yeah
Of patients have to be 2 plus, and we're seeing like every patient being CRS experienced.
Yeah. Right.
The math wasn't adding up. What was explained to us from clinicians is very different than five years ago. The amount of assets in development besides the ADCs for ovarian is very limited right now. Their feeling is, as long as you're 1% positive for folate receptor, you should get mirvetuximab.
Okay.
They're getting prior authorization, at least in the U.S. That, you know, represents, I don't know, 80%-85% of ovarian patients who would be 1%, and they all Fully overlap with claudin six. The use is much broader than you would think.
On claudin six, you know, coming in twice your estimates. Is this a situation where claudin maybe in really heavily pretreated patients, is that coming up more than maybe you might get in primary samples?
We have some really neat examples of patients who were platinum-sensitive, and they would have an H-score of 100, for example. Then they would come into our trial three or four years later, platinum-resistant, and have H-scores of 300.
Mm.
Claudin 6 is prognostic. It has always been known that it correlates with disease progression. We didn't really necessarily expect that clear linearity, and when we looked back at our prevalent screen when we were making our diagnostic for screening, that was a commercial biopsy set. Usually those are primary tumors, and we don't know for sure, but I would assume almost all of them were platinum-sensitive. That was about a 45% prevalence and a much more heterogeneous mix of claudin 6 expression. What we see now in late line is 80% of them are positive, and it's typically screaming high. It's a pretty homogenous population. It's rare that you see an H-score below 100, and it's not atypical that you see H-scores of 300.
For a T cell engager where, just like an ADC, activity is typically correlated with target density.
Yeah
If you have large tumors with a lot of target, to be fair, it does increase CRS risk, but it also increases the risk that your patients will respond to drugs. That's been really favorable for us. Any claudin 6 company.
Yeah.
We all have the same population.
Is this post ADC setting one where there's potentially an accelerated approval type single arm path?
Yeah.
I, you know, if the standard of care, I mean, the sort of 5%-10% respond with chemo that you might get after all that sounds like it could be a setting that FDA could be amenable to. How are you thinking about next steps after?
I generally find CEOs who opine about accelerated approval get in trouble later. Look, I think our base case is full approval for all of our drugs. If an opportunity affords itself and the regulatory agencies are supportive, I think that would be interesting. We'll see where it goes. I think if you were to honestly look at data points, so mirvetuximab did get accelerated approval, but now the new ADCs that all had 50% response rates.
Yeah
Went into full phase III trials. I think that's a pretty good data point for us. The thing about ovarian is, you know, the phase IIIs aren't huge. You know, you're looking at 400-450 patients randomizing against chemo. That's a manageable trial even for a small sponsor to execute.
As you go or think earlier line, I mean, what are your thoughts on ADC combinations instead of after that? I mean, there's some data emerging that, you know, CRS risk can go down without really compromising efficacy and, I guess what are your thoughts on sort of exploring that? Yeah.
It's a huge goal. I think what we need to do this year, first half of the year, establish therapeutic window, second half of the year, get to dosing every three weeks. If that looks good, that aligns with the ADC dosing schedule. For background, what got people, including myself, super excited about that concept is you had the Boehringer Ingelheim DLL3 T-cell engager obrixtamig, which on its own in small cell lung had a 17% response rate. When you put topo on top, it jumped to 70% and people were like, "Whoa," like, "This is crazy." That got all of us really excited about combinations with topo-based payloads of which there's a zillion right now. For us, T-cell engagers typically are tox in the TCE industry is the first two doses and then it goes down.
The tox for an ADC accumulates over time. There's a really nice synergy, or I should say lack of synergy from an AE profile.
Mm-hmm
that makes the combination really exciting. The ADC, right? It's the same thing as chemo. Debulks the tumor, releases neoantigens, creates a warm environment for our drug to work in synergy with it.
Moving to the second program, Mesothelin. Also one that's very you know, strongly expressed in ovarian cancer.
Mm-hmm.
Can you just sort of talk about what's like the how you think about the benefit risk profile or product profile with the second program versus claudin 6 and how you're sort of thinking about that positioning?
Yeah. It's a big swing. We, the good news, bad news is the good news, we're the only T-cell engager for Mesothelin right now. The bad news is we're the only remaining T-cell engager. Both Zymeworks and J&J shut down their programs this fall. You have Mesothelin on your lungs. Both of those programs ran into hypoxia, and they shut it down. Amgen has not formally shut down their program, but the molecule is kind of atypical looking, and you would say, "That's probably gonna be immunogenic and have neutralizing antibodies." Our understanding was it did.
Right.
What do we need to do to unlock Mesothelin? We need to show that we can have activity without hypoxia that's dose limiting. If we can do that, we'll be well positioned. I really like our construct. We talked a little bit about lower affinity Mesothelin binder. We also bind to the portion of Mesothelin that's attached to the surface. That's worked clinically thus far. I will say, lesson learned from the claudin six program, we have a much more flexible protocol if we want to explore where we wanna take the drug. The idea of a claudin six Mesothelin combination of ovarian over time is pretty cool, but I think where we wanna go, and frankly it's an area that scared me years ago, is pancreatic cancer.
Okay.
Right now we're seeing fifth line pancreatic. Drug's actually looking pretty interesting there. Ultimately, the idea is, hats off to Arrakis and Revolution Medicines and what they're doing.
Yeah.
I think third line post KRAS and PRMT5 would be tremendously exciting. Also from a clinical execution standpoint, you can just follow where their phase 3 trials are and enroll patients as they progress off.
Sure.
For us, almost every pancreatic patient will have pretty high levels of mesothelin. It's a large population. There's about, you know, 60,000 patients in the U.S. who have third-line pancreatic. The bar. I always think it's odd when people from there say, "Oh, it's a low bar." Well, it's a low bar because it's a really hard cancer to treat. You know, about a 5% response rate and two-month PFS for chemo in that setting. If we can do something there, I think that would be tremendously exciting. High risk, high reward, very different than our-
Yeah
claudin-6 program, which is more of an execution play. We're pretty excited about that. That data will be about a quarter behind the claudin-6 data.
We should expect, I guess, pancreatic patients in that data set?
Yes. As I joke, you know, and our CMO Karen's in the front row, the claudin-6 protocol has no lever to say Marty and Karen want to enroll more ovarian patients. The mesothelin does. We've been able to enroll a bunch more pancreatic to really underwrite the potential there.
Okay. Do you wanna get to Nectin-4? 'Cause this is the one that I'm excited about perhaps the most 'cause-
Yeah
It's very, has a lot of validation, very attractive target, but it's, you know, it is expressed on the skin and other places, and maybe that's why you went with a masking approach. If you could just sort of talk about, you know, that product and.
Yeah
You know, what you think, why pH-sensitive masking, all that.
You framed it in a very nice way. I think I just recall we had a meeting at JPMorgan with a pharma company, and they thought we were crazy for going after Nectin-4. They said, "We removed it from the target list. It's too hard." I said, "That's true." You know, you have Nectin-4 in your skin, and skin's a lot of surface area. But I think, you know, kudos to Verve showing data two weeks ago. There's something special about dual masking, right? The pH dependence that we have in Nectin-4 is very similar.
Our antibody is pH-dependent, Nectin-4, you know, about 30-fold lower affinity for Nectin-4 in the skin, which has a physiologically normal pH, and then you know, an equally lowered affinity for binding to CD3 and activating a T-cell in the skin. You take those two together, we believe we're the only company using CD3 to ever successfully complete GLP tox with a Nectin-4 targeting drug. We went up to 200 times our intended therapeutic level. We would have kept going, but at that concentration, the drug started aggregating. It was incredibly clean. We licensed the drug from BioAtla, so hats off to them for coming up with the technology. There's something really special about that dual abrogation of activity that seems to drive the safety benefit.
For Nectin-4, there's, you know, only a handful of targets that truly have, without squinting, $5 billion+ peak sales potential. This is one. It's an exciting and scary target for that because if it's good, you know, that's
Yeah
That's a lot. We're excited.
That's gonna enter the clinic this year? Yeah.
Super soon.
Super soon, okay. I realize I do wanna ask one more, back to claudin-6, that data's coming up. There's been some CAR T from like BioNTech that showed some really strong responses, but not a lot of durability. People hope for durability in these T-cell type of mechanisms. I guess when we look at the data coming up, like what are your expectations from a like duration of response type of profile? Is that, was that a target thing with BioNTech and CAR T and just sort of how you're thinking about that?
The BioNTech data you referenced was 12 patients, 7 of the 12 had a response, and the response was very brief. I think that's just more of a challenge of a CAR-T, which is a one and done. The whole benefit of a T-cell engager is the ability to titrate and redose and maintain that effect. I think there's a dialogue created by one or two T-cell engager companies, that T-cell engagers don't have good durability, even though those same companies present data that shows good durability. T-cell engagers have the opportunity to have really prolonged responses in patients. What we hope to show, obviously with a limited data set, is line of sight to that.
That's okay.
in very challenging patients.
All right, I'm looking forward to it. A lot of exciting things from Context this year. I think we're out of time, so thank you all for being here, and thanks for coming.
Thank you.