Announcer here at the firm, and it's my pleasure to introduce Werewolf Therapeutics. Today, we have Dr. Randi Isaacs, Chief Medical Officer of Werewolf Therapeutics, and we're also joined by CFO Tim Troost. Randi, welcome.
Thank you for having me.
Werewolf has positioned itself as a leader in conditional activation immunotherapies, both with your INDUKINE and INDUCER platforms. For people that are less familiar with the platform, could you maybe explain some of the nuts and bolts for the PREDATOR platform and what differentiates your masking technologies from other traditional approaches that we've seen with cytokines?
Great question. We view ourselves as a company that takes molecules that have traditionally been very toxic to deliver. Think of cytokines. You can also now think of T-cell engagers for us and use a modular approach to both mask and also to activate in the tumor microenvironment in a conditional fashion. What differentiates us is several things, and I'll start with the cytokines because that's where the company started. Number one, we use native cytokines. No mutants, no shifting to any particular receptor subclass. For IL-2, it is the native IL-2. The masking technology actually was adapted because you have to think about blocking in the periphery so that you don't have systemic toxicity.
The blocking needs to occur in such a way that when that piece of the molecule comes off, and I'll talk about our protease-cleavable linkers, when that piece of the molecule comes off, it doesn't rebind. This has been a differentiating feature for some of the other molecules where if you use a piece of the receptor, obviously that receptor could rebind. That has been adapted. We also have a half-life extension in order to make sure that the molecule is in circulation for a certain period of time and you can dose infrequently. Finally, the secret sauce for Werewolf Therapeutics are the agnostically chosen sequences that are protease-cleavable linkers. These were chosen very, very carefully. A diligent effort was made preclinically to look at a number of different sequences. It's not specific for any one protease class.
You'll note that other conditionally activated molecules choose a particular sequence that is specific for a protease class like MMP. We don't. We chose the linkers. We allowed patient tumor samples, dissociated samples, to actually choose a sequence that was cleaved across the majority of tumor types that were looked at. These were 100 or more patient samples, and now it's been even more. Not activated, not cleaved in normal healthy tissue. Our linker sequence, I couldn't tell you in any particular patient which protease class is cleaving that linker. We know that it's cleaved across a number of different tumor types. We actually have taken that assay and converted it into an assay that we use in the clinic where we take a piece of the patient's tumor at baseline, we dissociate it, and we look to see if there's linker cleavage.
In the majority of patients, in fact, more than the majority, you know, 19 out of 20 that we've shown, there's been cleavage of the molecule. That differentiates us both on the linker, on the native cytokine being used, and on the blocking.
Great, very helpful. WTX-124 has been engineered to deliver fully potent IL-2 directly to the tumor microenvironment. I guess if you could walk us through some of the compelling preclinical as well as clinical data that you've generated so far, that gives you the confidence that it's the best in class amongst the IL-2 therapies.
I'm not going to spend much time preclinically because we have clinical data now. All I can say is that the data that we accumulated preclinically on how much of the prodrug gets into the tumor microenvironment, how much free IL-2 is released, the cells that we see, all of the things that we've seen preclinically have now translated to the clinic. What's so compelling, we actually have proof of concept. We validated the INDUKINE design. We see not only a tremendous therapeutic index, we see a safety profile that's very, very different than high-dose IL-2. High-dose IL-2, as I'm sure many of you know, was the first immunotherapy to actually be approved in the 1990s. It's really fallen off in terms of use because of its toxicity, because patients have to be admitted to the intensive care unit for monitoring.
It has a short half-life, so it has to be delivered very frequently. What we've done is we've now shown in the clinic that not only do we have a safety profile that's differentiated from high-dose IL-2, we don't see vascular leak syndrome. We also have a PK profile that's consistent with our preclinical work, but shows this massive therapeutic index that's actually responsible for the safety profile. We've seen anti-tumor activity as well as biomarker activity.
Great, very helpful. We're expecting some further interim data in the fourth quarter this year. Can you walk us through what metrics we should be really focused on and what's shaping the program for your FDA discussions, specifically maybe in your path for melanoma?
We had a great deal of data that came out of our dose escalation. We did dose escalations as monotherapy and also in combination with pembrolizumab via a clinical trial service agreement with Merck. What we saw was not only this safety profile that emerged, we had anti-tumor activity, we had biomarker activity, and that has shaped what we've thought about in terms of moving into expansion arms. We have a recommended dose that we've disclosed publicly of 18 milligrams for both monotherapy and combination. Our expansion arms are in renal cell and melanoma, both as monotherapy and combination. Not surprisingly, those are benchmark indications for which high-dose IL-2 is approved. We also have an expansion in monotherapy for cutaneous squamous cell carcinoma, and that's because of a very, very profound effect that we saw in a patient with cutaneous squamous cell carcinoma, primary resistant to cimaplamab.
Within several weeks of receiving, three weeks to be exact, of receiving WTX-124, started to have a profound response and went on to have a complete response. That complete response has been maintained now for over a year off study drug. We added an arm of cutaneous squamous cell in second line after checkpoint inhibitor therapy. There's absolutely nothing for these patients. Our fourth arm is in non-small cell lung cancer, PD-L1 positive as a combination with PD-1. The expectation for the data reveal later this year, along with the discussion with the FDA, is really around the majority of the data from the escalation as well as the expansion arms, preliminary, mind you, and looking not only at continuing to develop that safety profile, PK, biomarkers, but also to start to hone in on anti-tumor activity.
We saw some very nice anti-tumor activity in melanoma during escalation and early expansion. We will be going to talk to the FDA about a path forward in advanced metastatic cutaneous melanoma.
Very helpful. Touching upon a comment you just said about the combination appears to be very well tolerated with pembrolizumab. How should we be thinking about its positioning as a combination in earlier lines in either melanoma or RCC treatment, particularly in the context of the already well-established PD-1?
That's a great question. I'm sure you know that not everyone succeeds with early lines of therapy, so there's always room for moving forward. We certainly see a development path for the combination, and not only in earlier lines, but in retreatment. Second, third line, obviously a randomized controlled trial is required for that. We can see WTX-124 moving into earlier lines of therapy, into any immunotherapy-sensitive tumor type. There's no reason that IL-2 shouldn't be effective for indications that are immunotherapy-sensitive. What I mean by that is checkpoint inhibitor-sensitive.
Very helpful. Maybe an add-on quick question would be, you know, how do you envision the regulatory pathway, maybe scenarios playing out in terms of, you know, are you set that there will be a clear path for a registrational trial in melanoma or, as you just touched, maybe a randomized phase two study more likely? Help us parse your expectations for the pathway forward.
I don't know if anyone in the room was in the FDA panel this morning. I think, you know, the issue around, and we do contemplate meeting with the FDA before the end of the year and discussing the development path. Our first step forward is really to go for a monotherapy, single monotherapy, single arm trial and expansion, looking at a second, third line advanced metastatic melanoma population where there really isn't a lot of other therapies available to patients, remembering that there's already a molecule that's on the market that isn't used. We come in with something that can be given to everyone that's safer, has a wonderful profile, and you actually know whether you have activity fairly soon, which is great for patients, you know, and great for physicians. They take it off the shelf. You can give it to everyone. You know if there's activity.
That's how we think about this moving forward. Now, I can't predict what the FDA will, how they'll come back and see this, but that is our initial approach.
Very helpful. In the interest of time, I want to highlight that the engineering that the team has done is not just relegated to IL-2. The company is also developing WTX-330, which is an IL-12 INDUKINE. I guess, in the viewpoint that IL-12 has been viewed as almost undruggable, unusable because of its toxicity, can you bring us up to speed of what you've accomplished there and what we could look forward to in the future?
Yeah, it was a perfect molecule for the INDUKINE approach. You know, we presented last year in November at SITC our first-in-human trial, 25 patients that we had treated across three dose levels. A couple of key takeaways from that presentation were not only that we were able to deliver the molecule as an outpatient every two weeks, but that we were giving more IL-12 systemically than had ever been given before. That's a testimony to the blocking and then the conditional activation. We saw some activity in melanoma. We saw a confirmed partial response. We had some very interesting biomarker activity in microsatellite stable colorectal cancer, which is interesting because if you think about IL-12, it doesn't need to have an inflamed microenvironment unlike IL-2 to be active. It actually can create its own immune activity de novo. We are following on that.
We have another trial that's ongoing, looking at regimen and dose, trying to explore that a little bit more, and maybe moving into some combination settings and some specific indications.
Great. We've been focusing primarily on the INDUKINE platform, but Werewolf Therapeutics has a secondary INDUKINE franchise that's coming about. Maybe you can split this question with Tim. Can you talk about how should investors, how are you thinking about capital resource allocation? Obviously, the focus is on developing WTX-124, but for some of the earlier stage programs, what was the order of operations of bringing them to the clinic? One add-on question for you, Tim, is with the cash runway that you have, can we expect some new entrants or where does that leave us in terms of stages of development? You best can split that.
I'll start maybe, and Randi, you can take it. The answer was somewhat embedded in your question. The far and away lion's share of our resources is being devoted towards the clinical stage WTX-124 asset because that's our lead clinical asset and it's clinical stage, which obviously consumes more resources. Having said that, we are advancing the T-cell engager portfolio in addition to the already identified T-cell engager. We've guided to expect a second nomination by the end of this year. It's not like there's nothing going there. There's something going there, but just kind of from a rough allocation standpoint, that's kind of how we think about it.
If you could walk us through.
Certainly. It's interesting because we've been able to directly take the lessons from WTX-124 and apply them to the T-cell engager program. As you know, T-cell engagers are very hot right now, but they still suffer from, I want to say, a smaller therapeutic index. You still see CRS. They could benefit not only from a better masking technology, but also from a better linker technology across various tumor types. We think we have a best-in-class IL-2 at this point, and we think we'll show the same with our T-cell engager platform. There's a great deal of business development activity going on in the company around the T-cell engager program and also around our lead asset.
Maybe one question to really combine the ethos of our talk today is, you know, you've been at the forefront of cytokine development for quite some time now. Could you maybe help investors kind of understand what are the most common misconceptions that still persist in the reflexatory sentiment towards cytokines and how directly the platform, the technology addresses them?
That's a great question. I think the issue with the cytokines, you know, it's sort of, there was a wave of great excitement. A number of the IL-2 molecules have now fallen by the wayside and have failed. They had a hypothesis that if you don't bind to the high affinity receptor, that you'll lower the toxicity, the immunosuppression. In point of fact, what happened is you actually modulated the efficacy too. I think cytokines are meant to be delivered locally. We think our approach, it's a difficult thing to do clinically, and it's also difficult commercially for intratumoral or whatever. We think our approach is probably the best one to deliver something systemically that can then be directed to act locally. I think there's still a lot that can be done with cytokines.
I know that there's some bispecifics now looking at combinations of checkpoint inhibitor and cytokine that look more like the checkpoint inhibitor and less like the cytokine. It'd be very difficult to parse what piece the cytokine has. There are patients who have had, let's say, immune-related adverse events from a checkpoint inhibitor, and those patients can't get a checkpoint inhibitor again. Here's another option where you can give them something that can affect a profound immune response. What we've seen is we do not reactivate IRAEs. That's a high-end medical need population.
Great. Maybe one last housekeeping question. Can you remind investors what to expect before the end of the year? We spoke about the catalyst for WTX-124. Anything else we could be expecting?
I think the main catalysts for the rest of the year are really around WTX-124, meeting with the FDA, and then data release, obviously ongoing business development activities. We're planning on a second INDUKINE development candidate by the end of the year. The first one, which no one mentioned, is actually STEP1, which we mentioned recently.
Great. I'd like to take the time to thank Randi and Tim for joining us. We look forward to future updates and congratulations on all the progress thus far.
A lot of progress. Thank you.
Thank you.