Good morning, everyone, and thank you for joining us at the Needham & Company's 24th annual healthcare conference. My name is Ethan Markowski. I'm a member of the biotech research team here at Needham. Joining me today from Werewolf Therapeutics are Randi Isaacs, Chief Medical Officer, and Tim Trost, Chief Financial Officer. We'll provide a presentation on the company, followed by a Q&A session with the remaining time. With that, I'll go ahead and turn it over to Randi.
Thank you, Ethan. Thank you to Needham for this kind invitation to have Werewolf speak. This afternoon, I want to share with you not only the Werewolf mission, but some of the data that we have on our first few programs. We have a platform. It's called the Predator Platform. It allows us to generate tunable tissue-targeted molecules, immunomodulators. We call them INDUKINE for inducible cytokines. These are specifically geared to delivering highly potent payloads with an improved therapeutic index over the recombinant counterparts. We have validated this conditional activation platform in two compounds that are in the clinic, which I'll speak about: WTX-124, an IL-2 prodrug, and WTX-330, an IL-12 prodrug. This is a very robust discovery engine.
We not only have a deep preclinical pipeline, and I don't think I'll have a chance to really talk about those this afternoon, which include an IL-21, an IL-18, and IL-10, which is being developed for inflammatory diseases, specifically inflammatory bowel disease, and an interferon alpha INDUKINE, which is fully licensed to Jazz Pharmaceuticals. I think that everyone knows that the challenge with cytokines, especially the native cytokines, has been off-tumor, on-target, but off-tumor toxicity, which has really limited its therapeutic index. It also has suboptimal pharmaceutical properties because of the short half-life. Our solution was a conditionally activated immunotherapy with an optimized therapeutic index that allows for targeting to the tumor microenvironment and activation within that microenvironment. I'll show you how that's done next. This is an example of a molecule, of an INDUKINE molecule. This happens to be WTX-124, our IL-2 prodrug.
It is a tunable tissue-targeted therapeutic. It has four very important components, all of which are critical to the overall activity of the molecule. The most important thing, I think, is the native cytokines. So we see that in yellow. Many others have used either mutated cytokines or cytokines that are directed to a particular receptor. We use the native wild-type cytokine, and this is because this is the one that has the greatest potency for an anti-tumor immune response. In addition, in blue, we have a half-life extension domain. This is an anti-HSA or Human Serum Albumin. Not only does that increase exposure for delivery of the drug on a less frequent schedule, but it also allows for targeting into the tumor. The purple is a blocking domain. This is for peripheral inactivation.
What this allows for is the therapeutic index that I'm going to show you and the safety profile that goes along with that therapeutic index. The little red pieces that you can see there is the Werewolf secret sauce. Those are protease-cleavable linkers. As you know, proteases in the tumor microenvironment are dysregulated. We have selected particular sequences for these proteases that allow for cleavage across a broad range of tumor types and even within the same tumor type. This is the portfolio that I spoke about previously. What I'm going to really gear my talk to is the WTX-124 and 330 molecules that are in the clinic. The challenge with high-dose IL-2, as I'm sure everybody knows, even though there is an approved Proleukin, is an approved IL-2, it does produce durable responses in patients with melanoma and renal cell carcinoma.
It was approved back in the 1990s. Its use has been severely limited by toxicity. The unique advantages of the 124 molecule, the IL-2 INDUKINE molecule, is it is selectively releasing a fully potent IL-2 in the tumor microenvironment to stimulate anti-tumor immunity. We have key opportunities with our molecule. We can provide IL-2 therapy broadly to patients with advanced or metastatic cutaneous melanoma and renal cell who would otherwise be ineligible to receive high-dose IL-2, which needs to be administered in the intensive care unit due to its adverse events. Interleukin-2 therapy may have potential benefit in any of the checkpoint inhibitor-sensitive solid tumor indications. We have actually demonstrated this. I'll show you that data. We address an unmet medical need for patients who've already seen a checkpoint inhibitor and are now relapsed or refractory.
Because of the safety profile, we can combine the IL-2 therapy with other standard of cares, including checkpoint inhibitors. Our goal is really to take the place of high-dose IL-2 in any of the indications for which it's already been approved, but also to go beyond that. Most patients, as I've already said, don't receive high-dose IL-2 due to toxicity. I'm going to show you a couple of pieces of preclinical data, which I think are important. The most important is on the top because this is basically a preclinical demonstration of our molecules, the way in which it acts. If you look on the left-hand side, that's plasma concentration. This is in an MC38 mouse model. On the right is tumor. The blue is the concentration of the WTX-124 INDUKINE. You see very, very little free IL-2. In the tumor, this is inverted.
What you see is the tumor is bathed in prodrug, but you see a constant amount of free IL-2 that's in the tumor microenvironment. That amount goes across the entire dosing period and beyond. In addition, you can see on the upper left-hand side of this slide that there's an improved therapeutic window compared to recombinant IL-2 with a minimal efficacious dose versus a maximum tolerated dose. In the mouse model, this therapeutic window was greater than 20. This is a schematic of our first in-human trial, which is currently still enrolling. We have completed dose escalation with 65 patients, and we have monotherapy and combination therapy dose expansion ongoing. 18 mg IV delivered every two weeks systemically has been selected as both the monotherapy and combination therapy recommended dose for expansion. We have a clinical trial service agreement for provision of pembrolizumab for this trial.
Dose expansion is open for both monotherapy and combination in renal cell carcinoma, cutaneous melanoma. We have cutaneous squamous cell carcinoma in monotherapy only and PD-L1 positive non-small cell lung cancer in combination therapy. This is our safety findings from the first in-human trial. It is preliminary clinical data as of last May when we presented at ASCO of 2024. The most frequent related treatment emergent adverse events were arthralgia, fatigue, and pruritus. The majority of the events were grade one and two. We had no evidence of vascular leak syndrome or cytokine release syndrome or infusion reactions. This is critical because vascular leak syndrome is the sine qua non of adverse events for high-dose IL-2.
Of importance, we had no new safety signals seen in combination with pembrolizumab and no recurrence to date of the immune-related adverse events that had occurred in these patients on prior immune checkpoint inhibitor therapy. All of the patients on this trial did receive prior immune checkpoint inhibitor therapy and were all indications for which checkpoint inhibitor therapy is approved. This is some early data, again, from May of last year. What you can see is that three patients had objective responses and an additional seven had stable target lesions at the potential recommended doses for expansion with activity at 12 mg and 18 mg. Of note, when we see responses, they occur very quickly within the first two cycles of drug. This is an example of a patient.
This is a 72-year-old man with metastatic cutaneous squamous cell carcinoma who had progressed on standard of care therapy, was initiated treatment with 12 mg of 124 every three months after discontinuing standard of care cemiplimab. What you can see is not only a baseline CAT scan showing a premaxillary target lesion that's denoted by the T and a non-target lesion NT, which extended into the pterygopalatine fossa. At three weeks, when we do on-treatment biopsy in all of our patients, a target lesion showed no tumor. At eight weeks, the restaging CAT scan showed a partial response with a 62% decrease of the target lesion and no increase of the non-target lesion. That's represented in panel C. At 12 weeks, a PET scan was performed, which showed a complete metabolic response of both target and non-target lesions consistent with a complete response.
The patient tolerated the therapy well, and this response is now ongoing at over a year off therapy. In combination with pembrolizumab, we saw at the 12 mg combination dose level two patients with melanoma, both of which had anti-tumor activity. One, an ongoing partial response, and a second one, a complete response. Both of these patients are ongoing at over eight months. Here is the PK profile for WTX-124. This is the reason for the safety profile that you see and the increased therapeutic index. At 18 mg IV every two weeks, which is our recommended dose for expansion, WTX-124 has a 1.5-fold higher Cmax than high-dose IL-2. Remember, we are higher than high-dose IL-2, and we do not see the adverse events that are consistent with high-dose IL-2.
Peak free IL-2 exposure, which is on the bottom of this panel at 18 mg, is 136-fold lower than high-dose IL-2. That accounts for the safety profile that we're seeing. From a biomarker standpoint, and we do biomarkers on all patients, we do pre and on-treatment biopsies in order to look both at immunofluorescence, immunohistochemistry, as well as NanoString. The largest changes that we see are at 18 mg in monotherapy and 12 mg in combination. We see upregulation of genes that are associated with enhanced effector T cell function, including granzyme B and IL-2 receptor A. The Treg genes, including FOXP3 and TNFRSF4, do not increase with dose, as you can see on the bottom. The data indicate preferential expansion of effector T cells over Tregs and no carryover effect from prior checkpoint inhibitors.
The key takeaways for this study are that monotherapy activity and an improved tolerability profile has been demonstrated in heavily pretreated patients refractory to standard of care therapies, including ICIs. We can combine ICIs and standard of care, including in earlier lines of therapy, and this is supported by that tolerable safety profile that I showed you. We have a patient with cutaneous squamous cell carcinoma who remains in complete response for greater than 12 months off therapy and other patients with anti-tumor activity. So 124, 18 mg has been selected as both the monotherapy and combination therapy RDE based on clinical activity safety profile, as well as biomarkers, and all expansion arms are now open for enrollment.
Our next steps for this program is to enroll fully the cutaneous melanoma dose expansion arm as monotherapy by the end of the first half of this year and the combination with pembrolizumab by the end of the year. We are planning on engaging the regulators to discuss potential registration paths both in monotherapy and in combination, including potential accelerated approval in the second half of 2025. The interim data from this, the completed dose escalation, as well as the expansions, we hope to present and release in the fourth quarter of this year. The development strategy is as follows, with a fast market and priority indications, indication expansion in other immunotherapy-sensitive tumor types, and then moving upstream into standard of care combinations. Now I'll move into our second program in the clinic, WTX-330, our IL-12 INDUKINE. IL-12 has been a difficult target for many, many years.
It does not have approved drug targeting that mechanism. It is a pleiotropic cytokine that could address a substantial unmet medical need for patients who are resistant to standard of care immunotherapies. It has demonstrated activity in less immunogenic tumor types. In the past, systemic administration of recombinant human IL-12 has been associated with severe unmanageable toxicities, including death. The opportunities here enable patients to benefit from this mechanism for the first time through improved tolerability. Also, to address a significant unmet medical need for patients with poorly immunogenic tumors, and then to investigate complementary combination strategies not only with standard of care, but within our portfolio. This is just to show you some of the early preclinical data that we had. Most importantly, you can see the activity in the MC38 tumor model and the therapeutic window that this affords over recombinant chimeric IL-12.
In addition, if you look at the differential gene signatures in the lower right-hand corner, you can see that specifically IL-12 activates multiple antigen presentation mechanisms versus IL-2, which is quite specific for T cell activation. These are data from our—this is our design of our first in-human WTX-330 phase I clinical trial. The data from this particular trial is now being used in this next trial with the design here, which is a dose and regimen determining trial. There is a fixed dose finding as well as step-up dose finding in order to then move into selected indications, not only in melanoma, in MSS colorectal cancer, but also in combinations, and also in advanced non-Hodgkin's lymphoma. The results of the fixed dose finding will inform the step-up dose to be explored.
Criteria for advancement of a specific regimen include not only the exposure of WTX-330 delivered to patients, but the adverse events and the extent and frequency of IL-2 pharmacodynamic activity, as well as anti-tumor activity. If we look at the first in-human trial, these are the key safety findings. The most frequent related treatment emergent adverse events were cytokine release syndrome, pyrexia, chills, fatigue, and elevated liver function test abnormalities. These are toxicities that are typical for systemic IL-12 therapy, less severe compared to recombinant human IL-12 and improved with continued dosing. One patient had a confirmed partial response, and I will show you pictures of that, and other activity in colorectal cancer, specifically MSS or microsatellite stable. Here's a picture worth a thousand words of a 76-year-old woman with a BRAF wild-type metastatic in transit melanoma who had progressed while receiving adjuvant pembrolizumab.
The patient had diffuse right lower extremity cutaneous metastases, a non-healing melanomatous ulcer, and an enlarged inguinal lymph node. Patient initiated treatment with WTX-330 more than two months after discontinuing pembrolizumab. At three weeks, an on-treatment excisional biopsy of a right lower extremity skin nodule showed no tumor. What you're seeing from March of 2024 until May of 2024 is that these now have become tattoos. At seven to eight weeks, there was a 47% decrease of the target lesions, which is a cluster of right lower extremity skin nodules, with no increase in non-target lesions. At 10 weeks, and this I refer you to the bottom, the PET CT showed reduced tumor metabolic activity. This goes from the left where you see that active white area to the right where that has disappeared.
At 16 weeks, the RECIST PR was confirmed with an ongoing target lesion response and complete resolution of one non-target lesion. At 28 weeks, which was approximately 12 weeks after discontinuing WTX-330, the patient was noted to have an ongoing response at a subset of lesions, but also complete clearance of that melanomatous ulcer. Changes in deep gene expression by NanoString was caused by WTX-330 demonstrated IL-12 activity. You can see that by not only the interferon response and the cytolytic response, but also by the antigen presentation response. Additionally, in MSS-CRC, which notably is a non-immunosensitive tumor type, one can see that with treatment of WTX-330, an increase in both granzyme B and CD8 positive cells.
Again, looking at the PK curves, you can see that at doses of 0.024 mg per kilogram IV every two weeks, WTX-330 had a 22-fold higher Cmax than recombinant human IL-12 at its maximally tolerated dose. That is on the left-hand upper panel. The peak free IL-12 exposure after that same dose is approximately five-fold lower than the recombinant human IL-12 at its maximally tolerated dose. You can see that also on the bottom of the left-hand side. Across all dose levels, the free IL-12 levels were quite low. PK exposure was generally preserved upon repeat dosing.
The key takeaways for WTX-330, and this is the second INDUKINE to validate the proof of concept for this molecule, the first systemically administered IL-12 therapy with monotherapy clinical activity and a generally tolerable safety profile, an increased therapeutic window as expected for the INDUKINE design, the second clinical program validating that design, anti-tumor activity demonstrated by a confirmed RECIST partial response and target lesion shrinkage in two melanoma patients. We are on track to initiate a phase I two dose and regimen finding trial, as I showed the study design at the beginning of the talk, to optimize 330 exposure in the tumor microenvironment. We are then exploring anti-tumor activity and anticipate opening expansion arms in a number of selected indications as well as combinations. I thank you very, very much for your attention.
Yeah, I will pick it over from here.
As a reminder, any viewers who are watching through our conference portal are able to submit questions via the ask the question feature below the video feed. I'll be keeping an eye out on the feed, but maybe to kick things off, I'll go ahead and start with WTX-124. You touched on it in the presentation, but can you just provide a little more color on what led you to select the 18 mg dose over some of the higher ones that were studied?
Sure. It was a combination of things and keeping in mind Project Optimus, which is not, you know, the highest dose is not always the optimal dose, right? We started seeing clinical activity at 12 mg, and that included biomarker activity. The 18 mg dose was chosen.
We also did enrichment at the 12 mg and 18 mg dose level while we were continuing to do dose escalation at the higher dose levels. It was a combination of not only anti-tumor activity, safety, you know, even grade one, grade two events, you want to try to, you know, minimize those if you can, as well as the biomarker data that I showed, which showed the greatest activity at 18 mg, at least as of that time. Those three things predominantly, we knew we were getting enough exposure in the tumor microenvironment was the choice, you know, dictated the choice of 18 mg.
Great. That's helpful.
Maybe with the upcoming readout in 4Q, I know investors are always asking what the bar is and maybe what you're seeing in terms of response rates or I guess what's a success look like for you in the upcoming readout in 4Q?
Sure. The data that, you know, there's a little bit of extra data there, but the data that you have here is almost a year old, you know, and goes back to ASCO of last year. What we're really looking for, and we've already shown it. We already have proof of concept here, and we've already shown monotherapy activity, which I think is critical. I think everyone knows now for immunotherapy agents, you must demonstrate monotherapy activity if you believe there's going to be any sort of additive effect with a checkpoint inhibitor.
You know, thinking about development in both monotherapy and combination, you know, the bar, if you think about high-dose IL-2, complete response rates were single digits and overall response rates were in the teens to 20%. I think we're looking at something over 20% with durability, you know, four to six months, and certainly something even more in combination.
Great. That's very helpful. This one's more of a broader question, but is there any thoughts or would there be a way to potentially apply your masking technology to other modalities like T cell engagers, for example, which have become really popular of late?
I didn't get to that, but we certainly can use our technology for other therapeutic modalities. You know, not only T cell engagers, but, you know, bi specifics, ADCs.
I mean, there's lots of ways to use that conditional activation, that masking approach for those modalities, and certainly something that we're thinking about.
Great. And then maybe one for Tim while we have him as well. Obviously, it's hard to ignore the current market conditions and everything going on externally. One kind of obligatory question we're asking a lot of our companies is if there's any potential impact of tariffs that you guys foresee. Although I will say that it seems like the clinical stage, maybe earlier stage companies are faring a little better in that regard, but curious your thoughts there.
That is something that we're studying very closely, as you would imagine. At this moment in time, it seems to be a bit of a moving target. I don't know how that's going to settle out.
I think I'd probably better leave it at that at this moment.
Yeah. That's very fair. I think a lot of companies are in the same boat where they're actively studying it, but still a moving target, like you said. We'll check the feed, see if we've got any questions. If not, maybe one more from me. I know for sake of time, we didn't go into it very much, but I wonder if you guys could talk a little bit more about your program in IBD. It's a pretty competitive space, at least in terms of biologics, TL1As, et cetera. Maybe what differentiates or potentially differentiates your program there and next steps and what timing looks like there?
I mean, what I can say is we're very excited about the target. You know, we have presented at last year's AAI meeting.
You know, it's a novel mechanism. From a preclinical standpoint, it's shown tremendous ability to ameliorate findings associated with ulcerative colitis in a mouse model. I would say, you know, that we're actively, and Tim, you can corroborate this, actively, you know, looking for partnering opportunities for our pipeline, which would include, you know, we're an oncology company. Even though the masking technology works extremely well for this particular target in IBD, you know, this would be a perfect opportunity for a partnership.
Great. Great. Yeah. No, I think that makes sense. There's definitely still a very large unmet need in that indication. I think you could see that by the development in the space.
People need options, you know, and the options without toxicity. I think, you know, that's the biggest piece.
Yeah, definitely.
I am looking, I'm not seeing any more questions in the chat at this time. I just want to take the opportunity, thank both of you for coming on, talking a little bit about Werewolf, and excited to see where things play out the rest of the year.
Thank you, Ethan. We're delighted to have been here this afternoon.
Thanks. Thanks very much, Ethan. Have a good.