Day of Bank of America's 2025 Healthcare Conference in Las Vegas. My name is Jason Zemansky. I'm one of the mid-cap biotech analysts here at B of A, and I'm very pleased to have joined me on stage here for this session. Dan Hicklin, Founder and Chief Executive Officer, and Randi Isaacs, Chief Medical Officer of Werewolf Therapeutics. Thank you both for being here.
Thank you, Jason.
Thank you.
Maybe just let's start with some quick background just to help frame our discussion as we provide some context for those newer to the story. Can you provide a brief overview of Werewolf and its platform?
Sure. Werewolf is a clinical stage biopharmaceutical company. We are developing a novel class of conditionally activated biologics for the treatment of cancer and other serious diseases. The company has developed an engineering approach around biologics to really address therapeutic index challenges with a number of very potent biologics. In doing this, we have developed a quite extensive pipeline of cytokine prodrugs. We refer to these molecules as INDUKINEs. Our lead INDUKINE program is WTX-124, which is an IL-2 INDUKINE, and WTX-330, which is an IL-12 INDUKINE. Also, with this technology, we have recently come out with another set of molecules that are T-cell engagers that we call Inducers that are also along the same lines as INDUKINE, engineered to, again, address the therapeutic index challenges of T-cell engagers.
Thank you for the great introduction. I think it's a wonderful place to start because when we think about IL-2, a number of other competing programs have tried to sort of change the molecules' binding. Why has that failed? What's special about Werewolf's WTX-124?
Yeah, it's been an effort that's been ongoing, frankly, for decades. I guess I would start off with answering that question in that we learned a lot from all of the different approaches that have been out there and have come before us. I guess the short answer is we really have a very different design than some of the other modalities and approaches that have been out there in terms of having a potent cytokine engineered into the molecule in the first place, a novel way of masking that activity while it's in circulation in normal tissue environments, a novel linker technology that allows the molecule to stay turned off, but also be activated preferentially in the tumor microenvironment, and then also dialing in pharmaceutical properties into the molecule that allow it to reach exposures in the tumor microenvironment.
It's really kind of the whole package in terms of the design features that are quite different from what else has been out there.
Great. Maybe Randi, could you give us a sense of the clinical data to date for 124 with an eye towards both the monotherapy and combination studies?
Sure. The last time we presented the data publicly was last year at ASCO. We have completed dose escalation for both monotherapy and combination therapy with pembrolizumab and have decided on a dose of 18 mg. It is a flat dose delivered systemically IV every two weeks, and that is the dose that will be used for both combo and mono. All of our expansion arms are now open. We have expansion arms in a more homogeneous population, less heavily pretreated than in dose escalation, still all immunotherapy pretreated patients. Everyone has seen a checkpoint inhibitor. We are looking at, for monotherapy, cutaneous melanoma, renal cell carcinoma. Those are two indications for which high-dose IL-2 is approved.
A third indication, cutaneous squamous cell carcinoma, where we've seen some remarkable data that we've presented on one patient who had failed primary failure of cemiplimab, which is the standard of care for advanced cutaneous squamous cell carcinoma. That patient went on very quickly to have a complete response to our drug as a monotherapy. The patient was discontinued from the drug at 21 weeks because without a tumor microenvironment, there is really no reason to continue our drug. There's no place for it to be unmasked. The patient is now in a CR over a year. This was something we were very excited about. In second line, there is really nothing for these patients and high unmet medical need. We added an arm in monotherapy for that.
In combination, we have melanoma, kidney cancer, and also PD-L1 positive non-small cell lung cancer.
Great. This is going to be a pivotal year for the company. You're targeting fourth quarter to present updated interim data from both studies here. What do you expect to have at this point, and what would be a win on both efficacy and safety?
I think we've already demonstrated from a safety standpoint. We have no evidence of any of the hallmark toxicities of high-dose IL-2. This is delivered as an outpatient and can be delivered to any patient. We've had 90-year-old patients on this trial. Anyone walking into a clinic, a doctor's office can receive the drug. There's no limitations to that. The expectation, I think, from a safety standpoint, I think we've already met that. From an activity standpoint, I would say that we've already met that too. We see monotherapy activity, which is critical for immunotherapies. You have to have monotherapy activity before you expect to see anything in combination. Anything for monotherapy north of 20% or so in terms of overall response rate, durability, 4+ months for combination would be something higher than that. Those are the bars that we are looking towards.
Enrollment is going extremely well. We have guided to having full enrollment in the monotherapy melanoma arm by the end of this half and then combination by the end of the year. In addition, we have robust enrollment in all of the arms of the study.
Yeah. One of the aspects of having this data around the fourth quarter is to go to FDA about a path forward here. I think you hit the nail on the head twofold. One, you've demonstrated the safety profile. Obviously, this is a high-dose IL-2. On the other hand, you've demonstrated some efficacy consistent with what that molecule does. At what point, what is the agency looking for? I mean, what do they need to feel comfortable with on both kind of sides of that argument there?
Jason, I think we're going to find out. The plan is to take our data and bring it to the agency at some time in the next couple of quarters and to get an idea of what they think about both the monotherapy data and the combination and our ideas around registration. We believe that in patients who have failed a checkpoint inhibitor or can't get a checkpoint inhibitor again due to toxicity, that there's a role for monotherapy. We'd like to see an extension of our current arm, our single-arm study. It's not in combination with a checkpoint inhibitor. It's just the drug alone in this patient population and perhaps get an accelerated approval pathway for that.
We also have ideas around randomized controlled trials, and we have ideas around combination with pembrolizumab, what that would look like in terms of a randomized controlled trial in an earlier line of therapy.
You know, if you think about IL-2, native IL-2, you have somewhat lower response rates, but the durability is staggeringly long here. Can you beat efficacy while also recapitulating some of that durability?
I think we've done that with the cutaneous squamous cell patient. I mean, when patients have a complete response, it's basically a cure with high-dose IL-2. But remember, that's single digits. And the response rate, overall response rate for high-dose IL-2 is in the teens. If we can be north of there with durability, I think we have a positive outcome here.
Got it. Maybe to switch gears somewhat because you do have a fairly broad pipeline. If we could talk about WTX-330, this is the IL-12 INDUKINE. It's been challenging to dose IL-12 given its toxicities. What evidence suggests that like IL-2, it may have therapeutic properties?
We did see we had a first-in-human trial, which is now complete. In that trial, we reported at SITC this past year that not only do we have a safety profile, which allows for delivery of this drug as an outpatient, the tolerability profile was good. The adverse event profile was typical of IL-12. There were no surprises. We also showed very nice biomarker activity, and we actually had anti-tumor activity. This package of data has led to a study, which we've just opened, where we are going to dose and regimen optimize in order to then move forward into specific indications or specific combinations.
Makes sense. Maybe this is a sort of a broader question, but given that the INDUKINE platform has demonstrated, kind of alluded to this earlier, the ability for the first time to combine with a cytokine, the problem, and it's a good one to have, is how do you prioritize what to combine it with?
I think it's pretty obvious. The checkpoint inhibitors are the mainstay of immunotherapy. There's approval in pembrolizumab, 18 different indications. It makes most sense to start there and to see the increase in activity that might come from that combination. In all honesty, you can combine within the portfolio, and you can combine with any standard of care with the cytokines, with our INDUKINEs.
Makes sense. Maybe again, switching gears, recently you discussed your new additional platform here, the conditionally activated T-cell engagers called inducers. What can you tell us about the inducers, and how are these different from the other T-cell engagers in the field?
Yeah, early, the catalyst for that effort and those programs was to take the engineering approaches and some of the learnings that we had from the platform and our INDUKINE approaches and applying those to T-cell engagers. T-cell engagers, extremely powerful molecules, but they suffer from therapeutic index challenges, specifically cytokine release syndrome in early dosing, often leads to dose-limiting toxicity. This obviously leads to suboptimal effects in patients because you're not giving enough of the drug in some cases to get that clinical benefit. We challenged the scientists at Werewolf to come up with an engineering approach that, first and foremost, masks the immune cell engaging component of the molecules in a much more robust way to try to get rid of that cytokine release that you see in early dosing of the molecules.
That was the engineering novel approach that led us to the inducers and the inducer platform itself. We feel that robust CD3 masking and silencing, along with our linker technology, which, frankly, we've already shown some proof of concept in patients with the INDUKINEs in that respect, will lead to a much larger window in terms of therapeutic index. Applying some of those approaches also to different targets and whether to dual mask or single mask is also an important concept that we're introducing into the platform.
Great. Maybe in the time we have left, exciting six to 12 months here, what are the pace of readouts here? I mean, again, WTX-124, we'll see fourth quarter. When will you give us updates on terms of what the regulators have said? When do we see 330 updates and when do we see inducer updates?
I'll start from the last and work back. For the inducers, we mentioned in our release last week that we will have a development candidate nomination this quarter. Imminently, we do plan to come out with more information around our molecules and the technology this year. I can't tell you exactly when, but sometime this year we'll be doing that. In terms of 330, we're not really guiding yet because it's so early on in the study in terms of when we might have data. That's to be determined sometime later this year as we start accumulating data around that program. The cadence for 124 is pretty clear.
We would like to have a very robust package of data, monotherapy combination data, and a significant number of patients with enough data in different indications to really give a good read on the molecule on the platform.
The feedback from the health authorities, which will guide us to basically tell everyone, this is where we're going.
Wonderful. Exciting times. Dan, Randi, thank you so much for joining me.
Thank you.
Thank you, Jason.