Good morning. Welcome to the Werewolf Therapeutics WTX-124 ASCO 2024 D ata Presentation and Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. Please be advised that today's conference call is being recorded. I would now like to hand over the conference call to Ellen Lubman, Chief Business Officer and Head of Investor Relations at Werewolf. Please go ahead.
Before we begin, I would like to point you to slide two and remind everyone that we will be making certain forward-looking statements today. So please see important risks and cautionary statements here, as well as those in our most recent SEC filings. Now, I would like to introduce Dr. Dan Hicklin, President and CEO of Werewolf Therapeutics. Dan?
Thank you, Ellen. Good morning, everyone, and thank you for joining us today. We're excited to walk through this morning clinical data from the WTX-124 phase 1/1b trial that were presented at the American Society of Clinical Oncology Annual Meeting this past Saturday. Moving to slide three for our agenda, on today's call, I want to start out with a brief introduction to our program and a broad overview of what we've achieved thus far.
I will then pass the call over to Dr. Justin Moser, an investigator in our study, to review in depth the data presented at ASCO. Dr. Moser is a respected melanoma and cutaneous oncology specialist and phase I trialist at HonorHealth Research Institute. We're delighted he could join us for today's call. We will then hand the call over to Dr. Randi Isaacs, our Chief Medical Officer, to put the data in context and outline next steps for our development program before moving to Q&A.
In addition to Ellen and Doctors Moser and Isaacs, we are joined today by Tim Trost, our Chief Financial Officer, who will be available during the Q&A portion of this call. For those less familiar with our story, at Werewolf, we're developing a novel class of conditionally activated cytokine therapies that we refer to as INDUKINE molecules. INDUKINEs are cytokine prodrugs that have been designed to selectively deliver a variety of potent cytokine mechanisms on target to tumor tissue. Through this novel drug design, we aim to overcome the therapeutic index challenges that have limited the utility of a number of potent cytokines and deliver the tremendous potential of these cytokines to activate a patient's immune system against malignant disease.
We currently have 2 clinical programs, WTX-124, our IL-2 INDUKINE molecule, which we are showcasing during today's data presentation, and WTX-330, our IL-12 INDUKINE molecule that is currently in development for the treatment of advanced and metastatic solid tumors and lymphoma, for which we are planning to provide an update later this month. Alongside these 2 programs is a pipeline of partnered and preclinical assets for the treatment of cancer, and as we recently demonstrated, potential opportunities for the INDUKINE design outside of oncology and inflammatory diseases. Moving to slide four, the focus of today's presentation is, of course, clinical data for WTX-124, and we are very encouraged by what we've seen thus far in the phase 1/1b trial for this molecule.
As brief background, approved high-dose IL-2 therapy produces durable responses in patients with both melanoma and renal cell carcinoma, but its use has been severely limited because of toxicities. WTX-124 was designed with the enhanced pharmaceutical properties to selectively deliver fully potent IL-2 in the tumor microenvironment to stimulate antitumor immunity, but limit the off-target IL-2 immune activation in normal tissues, which usually induces toxicities. With WTX-124, we believe we can overcome the challenges of approved high-dose IL-2 therapy to achieve four important objectives for patients. The first objective is to expand availability of IL-2 therapy more broadly to patients with improved safety. Second, we hope to address the urgent unmet medical need for the treatment of checkpoint inhibitor relapse or refractory patients. Third, we believe we can expand the utility of IL-2 therapy to other immunotherapy-sensitive solid tumor indications.
And lastly, we hope to deliver IL-2 safely in combination with other standard-of-care immunotherapy agents. We're pleased to say that the data thus far from the WTX-124 phase I program indicate we are executing against these objectives. Moving to slide five. At SITC last November, we presented initial monotherapy dose escalation data from 16 patients across four dose levels, ranging from 1 -12mg . These first-in-human readouts demonstrated WTX-124 was generally well tolerated to patients that are immunotherapy refractory, and in an outpatient setting. Importantly, many of these patients were ineligible to receive high-dose IL-2 based on age, comorbidities, or the type of cancer. The data also established a wide therapeutic index for 124, and patient tumor biomarker data demonstrated a dose-dependent activation of T effector cells in the tumor microenvironment, establishing proof of concept for the INDUKINE design.
These data translated into early observations of monotherapy clinical activity, with two partial responses at the 12 mg dose level and anti-tumor activity in a third patient. This was the first such observation of monotherapy activity in a next-generation IL-2 molecule, an established proof of mechanism for WTX-124. This weekend at ASCO, we presented a data set across 47 patients at dose levels ranging from 1-28 mg of WTX-124, administered either as a monotherapy or in combination with pembrolizumab. From these updated monotherapy data, WTX-124 continues to exhibit a safety profile consistent with those observed at 50. Anti-tumor activity has been further established, now with a durable, complete response in a patient with cutaneous squamous cell carcinoma, who had earlier been reported as a partial response, as well as two partial responses in patients with gastroesophageal junction cancer and in melanoma.
Importantly, 100% target lesion reduction was observed in responding patients. Altogether, these data have enabled us to declare our recommended monotherapy dose for expansion and open expansion arms for this study. With our first look at data in combination with pembrolizumab, we've established the combination regimen has been generally well-tolerated, including at 12 mg dose level with WTX-124, which has demonstrated clinical activity as a monotherapy and strong biomarker signals that are supportive of enhanced combination immune activation. As we continue to recruit patient data in both the dose escalation cohorts and expansion arms, we anticipate that these results will enable us to progress the WTX-124 clinical program and continue to reinforce our conviction of its best-in-class potential. Moving to slide six, I'd now like to hand off the call to Dr. Justin Moser to provide an overview of the WTX-124 clinical data in detail.
Thank you for being here, Dr. Moser.
Thank you again for the introduction. So like he mentioned, I'm Dr. Moser, one of the medical oncologists at HonorHealth Research Institute and investigator on this study. You know, there's been a lot of promise for cytokine therapy in regards to the treatment of cancer for many years and decades, but we've yet to make it work kind of clinically in a meaningful way without significant toxicity. And it became clear to me a couple of years ago that we really needed a new approach to how we deliver these cytokines to really make them more effective for patients. So when Werewolf reached out to me a couple of years ago about potentially participating in this trial, I was really excited because I think that this is the new mechanism that we need to make cytokine therapy, you know, benefit more patients.
I was really excited to be selected as an investigator and be able to offer this to my patients. Let's move to slide seven. WTX-124 is a first-in-human study of monotherapy and combination dose escalation and expansion. So far, 47 patients have been treated with at least one dose of WTX-124, 35 in the monotherapy escalation and 12 in escalation with pembrolizumab. When we look at the monotherapy dose escalation, we can see that we've completed escalation up to 18 mg and are currently enrolling at 23 and 28mg . For combination, we've cleared up to 12 mg and are currently enrolling in 18mg cohorts. For the monotherapy and combination dose expansions, we're going to expand in a couple of different cohorts, including renal cell carcinoma, metastatic cutaneous melanoma, advanced or metastatic cutaneous squamous cell carcinoma, and other advanced or metastatic immune-sensitive tumors to be determined.
We see that the cohort of metastatic cutaneous squamous cell carcinoma is bolded, and that's because this was not necessarily a patient population or cohort we were going to expand in prior to starting this study, but we chose to do this based on the activity and some of the clinical data, which we'll review further in this discussion. On slide eight, we will look at the patients who've been treated for. So the mean age of patients who were treated is 65, and we see that just over half of these patients were male. In regards to the tumor types of these patients, over half were Melanoma, but we do see a significant group and diversity of other immune-sensitive tumor types, as including non-small cell lung cancer, renal cell carcinoma , and other sites.
When we look at the prior treatments, this was a very refractory and heavily pretreated patient population. We see that just about 24% of patients had four or more prior line therapy, and over half the patients had at least three prior lines of therapy. The protocol does dictate that patients must have been treated with an FDA-approved checkpoint inhibitor prior to becoming on study, and we see that all the patients have had prior immune therapy because of this. However, when we look at the new lines of immune therapy, we see that over half of the patients have had at least two prior lines of immune therapy, showing that this is a very refractory immune therapy-treated population as well. Moving to slide nine. On slide nine, we'll start to take a look at some of the safety signals and side effects.
As you see, overall, WTX-124 has been very well tolerated as monotherapy in the outpatient setting. The most frequent treatment-emergent adverse events are arthralgia, fatigue, pruritus, and eosinophilia. All of these are side effects consistent with IL-2 that we saw previously with high-dose IL-2 back when that was commonly used. The majority of the treatment-emergent adverse events were Grade 1 and Grade 2, and we did start to see some Grade 3 side effects at the 18mg cohort and higher doses. However, these, in general, were manageable and reversible. There were no Grade 4 or 5 treatment-emergent adverse events, and most importantly, we saw no evidence of vascular leak syndrome or Grade 2 or higher cytokine release syndrome, which are known life-threatening complications of high-dose IL-2.
Also importantly, we saw that treatment with WTX-124 did not cause the recurrence of any prior immune-related adverse event that a patient may have had with prior checkpoint inhibitors. Moving to slide 10, we're going to look at the side effects of the monotherapy versus the combination cohort. In doing so, you see that in general, the distribution and types of treatment-emergent adverse events that we see in the combination arm with pembrolizumab are very similar to that monotherapy. Additionally, with similar frequencies, we do not see a signal of increased toxicity with the combination of pembrolizumab. In general, the side effects with the combination are mild or continue to be mild as well, with most of the side effects being Grade 1 and Grade 2, and only a couple of the side effects having Grade 3 toxicity.
Moving to slide 11, let's start to look at the clinical activity of WTX-124. So looking at this swimmer plot, we see that at doses of 12 mg and higher, we do see clinical activity with partial and complete responses in a variety of different cancer types. On the top line, we see a patient with cutaneous squamous cell carcinoma who has had a complete response that is ongoing for over 8 months. We see that we had a patient with melanoma, also treated at the 12mg cohort, who had a partial response as well. And at the 18mg cohort, we had a patient with gastroesophageal junction cancer who also had a partial response. On slide 12, we'll look at the change in the target lesions of these patients.
When we look at the change in the dimension of the lesions that followed, we see that we can see complete regression of target lesions in our responders. On the right side, we see the patient with melanoma, whose target lesion was a liver lesion that completely regressed and had 100% reduction, as noted in the waterfall plot. Just to the left of that, we see our patient with cutaneous squamous cell carcinoma, who had a complete response and complete reduction of all of his lesions. Just to the left of that, we see our patient with GEJ cancer, who had a 56% reduction. This patient is unique, and so there's a red caveat next to it, and that is this patient's measurable disease was a lymph node, and lymph nodes are normally present and do not disappear.
And so if you have cancer in a lymph node and it completely goes away, you never see the dimension of the lesion go to zero because the lymph node will always be there. And so the way we define having a complete response in a lymph node is or does the lymph node go back to normal size? And in this case, you know, we define the lymph node normal size as having less than one centimeter in the smallest dimension, and that was the case for this patient. So all these three of these patients had a complete regression of their target lesions. On slide 13, looking at the Spider Plot, we can see that the kinetics of response are quick.
Most or all 3 of our patients who had a response had a sign of a tumor regression and a response at the 8-week scan, and we see that the responses are durable, with all patients having their target lesions continuing to respond, the longest of which was our cutaneous squamous cell patient, who again, is about 8 months into therapy. Moving to Slide 14, we'll start to take an individual look at the patients who've had a response. This is our first patient, a 72-year-old male with metastatic cutaneous squamous cell carcinoma. He initially was treated with radiation and cetuximab, but developed progression of disease.
He was then treated with 12 weeks or 4 doses of nivolumab, an FDA-approved PD-1 therapy, and upon treatment, after 3 weeks, his PET scan showed progression, and we can see that in Panel A with the PET scan labeled June 2023. The patient then was started on clinical trial with WTX-124, 12 mg every 2 weeks, and you can see in Panel B his screening CT scan from September of 2023. The important thing to note when we compare this CT from September and June is that his premaxillary lesion, which is just to the left of his nose on the images, grew in that timeframe. Anytime a patient is treated with an immune therapy, we always ask ourselves, "Could this be pseudoprogression? Could it be a delayed response?"
The way we determine that is by repeating scans at least a month later and proving that the lesion is not shrinking. In this case, we had a CT scan in September, just about three months after the initial scan in June, and it showed that his tumor was growing at that time, which rules out that this could be pseudo-progression from his treatment. The patient was started on treatment and did well. He went in for his 3-week on-treatment biopsy, and his biopsy was technically challenging because the lesion had shrunk so much. Interventional radiology was struggling to get a biopsy. On his 8-week scan in Panel C, you can see that the mass had disappeared in his premaxillary area, but there was still some kind of white haziness uptake that did not have clear borders.
Unclear if this was tumor or residual scar from radiation in that area. Because of this, we got a PET scan, and the PET scan showed complete resolution of the uptake in that area, and it also showed resolution of the prior uptake in the pterygoid muscles as well, consistent with a complete response. Around the same time that we got the PET scan in Panel B, we also got the pathology review from his biopsy, and it was determined that there was no active cancer on the biopsy that was done three weeks after initiating therapy. This patient has stopped therapy, given his complete response, and has an ongoing complete response of over eight months. Moving to Slide 15, we'll review our patient with malignant melanoma. So this is a 78-year-old male with a history of BRAF wild-type cutaneous melanoma.
He was treated with adjuvant nivolumab after surgery, but unfortunately, this was discontinued due to toxicity. He then developed progression of disease and was treated with nivolumab and relatlimab, initially having a response, but again, developing progression of disease. Upon progression with upadacitinib, we see that he did have a 1.4 cm liver lesion that's noted on the PET scan and CT from July 2023 in panels A and B. The patient also had a lesion in his right humerus as well. He was started on treatment and went in for his on-treatment biopsy five weeks later, at which time the biopsy could not be performed because interventional radiology could not find the lesion. His eight-week scan showed that the lesion in the liver, which was the biopsied lesion, completely regressed and was no longer present, which we can see in Panel C.
The patient continued on study, but his 16-week scan showed that some of his other non-target lesions, some bony lesions in T11 and some other areas may have been worsening. Because of that, a PET scan was performed. Unfortunately, this did show progression in the bones, but of note, the right humerus lesion that was noted at baseline in July 2023 did resolve and was not there in November 2023, which you can see in Panel D. On Slide 16, we'll review a patient with gastroesophageal junction cancer. So this is a 63-year-old male with metastatic GEJ adenocarcinoma. He was initially treated with FOLFOX and nivolumab, and then nivolumab in a clinical trial of an anti-interleukin-8. His best response for both of these was stable disease.
He was then treated on the 18mg cohort of WTX-124, and his initial biopsy site was a left axillary lymph node. His target lesion was a 1.6 cm mesenteric lymph node, which you can see in the top image on the right. After starting treatment, he went in for his on-treatment biopsy three weeks later, at which time they could no longer identify his left axillary lymph node, which was previously biopsied. His 8-week scan showed that he had a 56% reduction in his target lesions with normalization of the lymph node and no increase of his non-target lesions. His 16-week scan showed that his target lesion continued to be responding. However, per the radiology report, there was growth in 1 of 4 of the non-target lymph nodes.
Therefore, this patient was taken off study, but of note, this patient has not progressed in regards to his cancer or needed any additional anticancer therapy for 3 months, suggesting that there is ongoing benefit from his treatment with WTX-124, despite growth in one lymph node. Moving to Slide 17, we'll review the pharmacokinetic data. So we see at the highest doses of WTX-124, that 18- and 28-mg doses, that the level of the drug in the blood exceeds that of IL-2 when given as high-dose IL-2, like we used to do for prior treatment of cancer. This really is proof of concept that this INDUKINE strategy of an inert prodrug without activity is effective. You know, when we give high-dose IL-2 in the hospital, after that dose of high-dose IL-2, these people get incredibly sick.
They have high fevers, despite being pretreated with Tylenol, ibuprofen, or other NSAIDs. They get uncontrollable rigors or shakes, they get low blood pressure, and patients will tell you their days of getting high-dose IL-2 are the worst days of their life. That is not the case with WTX-124. Despite getting the same level of drug, these people are doing well as an outpatient, which again, just confirms this INDUKINE strategy that the prodrug is not active. When we look at the level of IL-2, we see that there is a 136-fold difference between the WTX-124 prodrug and active IL-2, which explains the difference in tolerability between WTX-124 and classic high-dose IL-2. Also of note, but not shown here, we do not see pembrolizumab on the PK in the combination cohorts, and repeat dosing does not seem to cause any accumulation of WTX-124 or free IL-2.
Moving to slide 18, we're going to start to look at some of the pharmacodynamic data. This slide looks at the gene expression changes of T cell-associated activation and regulatory genes as compared to the on-treatment biopsy and pretreatment biopsy. We see that there is a dependent change in T cell-related genes that really comes on at the highest dose levels of 18 or 12 mg and higher. On the top part of the graph, you can see genes associated with T cell, T cell activation that are increased in a dose-dependent manner. This includes granzyme B, which is a marker of T cell activation, and interleukin-2 receptor alpha, which again is a marker of T cell activation. On the bottom part of the graph, you see that there is no dose-dependent change of T regulatory genes.
You know, it was previously thought that free IL-2 or naked IL-2 can increase T regulatory cells and actually suppress the immune system at lower doses. We're not seeing that with WTX-124. In general, you know, the field is kind of questioning if that is—if that's actually a true thing. There was a lot of discussion of that this year at the scientific conferences. When we look at the averages of the changes of the important genes on the right, you see for IL-2 receptor alpha that there is, on average, a dose-dependent increase, suggesting we are increasing the amount of activated T cells, but we do not see a dose-dependent increase in the amount of FoxP3, so we're not increasing the amount of T regulatory cells.
And you can see that on the bottom when we look at the ratio of activation of interleukin, of the activated T cell marker versus the T regulatory cell marker. The other thing to note on this slide is that we do see a distinct difference in the gene profile changes of the monotherapy versus the combination cohort. All of the patients in the monotherapy cohort did have to be pretreated with or receive prior treatment with a PD-1 antibody or other immune checkpoint inhibitor. There's always a question of: Is the immune therapy still on board? And is there a carryover effect, and is that explaining the activity that we see with monotherapy? And this data suggests that that's not the case. If we still had an effect from the PD-1 therapy, we should see similar gene profiles between the monotherapy and combination cohorts, but we clearly do not.
Moving to slide 19, we're going to start looking at things that can predict response on a pretreatment biopsy. These are biopsies from three patients who benefited from WTX-124, and specifically their pretreatment biopsy. One of the commonalities we've seen between these patients is that at baseline, the patients who seem to benefit from WTX-124 typically have markers of T-cell inflammation and activation prior to treatment. If we look at the picture on the left, this is a biopsy from a patient with cutaneous squamous cell carcinoma who was treated at the 12mg cohort and has an ongoing complete response. This patient had a significant number of red dots, which are T cells, and as well as a scattering of yellow dots, which are markers of activated T cells.
When we look at the middle picture, our patient with melanoma, the liver biopsy that also completely regressed, we see that there is again a high number of red dot T cells and yellow dot activated T cells. On the right, we're looking at a biopsy of a patient we have not discussed so far. This is a patient with renal cell carcinoma who was treated at the 18-mg cohort and has stable disease. And again, we see that there is a high number of T cells and activated T cells in the biopsy at baseline. Moving to the right, we see on average for patients who had a partial response, complete response, or stable disease, they have a higher number of CD8 cells and CD8 positive Granzyme B positive, the activated T cells at baseline as compared to people who had progression of disease.
Looking on the bottom, we're looking at the bottom right corner. We're looking at the gene expression rather than the cells. And in the gene expression, we see that at baseline, patients who have a partial response or complete response have a unique signature prior to starting treatment. And we see that the signature, again, reflects the markers of T-cell activation, with Granzyme B being elevated, interferon gamma and other genes associated with T-cell activation. So moving to slide 20, we'll summarize what we've just discussed. So in general, WTX-124 has been well tolerated in the outpatient setting. We see no evidence of vascular leak or Grade 2 or higher cytokine release syndrome, the serious side effects of historic high-dose IL-2. The majority of treatment-emergent adverse events were Grade 1 and 2 and reversible, as well manageable.
There were no Grade 4, Grade 5 treatment-emergent adverse events, and we see no new safety signals in combination with pembrolizumab. In regards to the clinical activity, we have seen multiple objective responses at doses of 12mg or higher in the monotherapy escalation. This includes a confirmed durable, complete response in a patient with cutaneous squamous cell carcinoma, two partial responses in a patient with melanoma and gastroesophageal junction tumor. For our patients who had responses, we did see 100% regression in the target lesions, and we do see a dose-dependent expansion and activation of effector T-cells in the tumor microenvironment that is further enhanced with combination therapy. Altogether, this establishes a safety and efficacy profile that supports monotherapy phase 1B expansion and continues dose optimization in combination with pembrolizumab.
Because of this, we have determined 18 mg is our recommended dose for expansion, and the expansion cohorts are now open and enrolling. With that, we'll move to slide 21. So I would like to thank the Werewolf team for allowing me to speak and review this exciting data, and I'll hand over the call to Dr. Randi Isaacs.
Thank you so much, Dr. Moser, for walking us through the exciting update to our monotherapy data and the initial combination data for WTX-124, which really does reinforce its potential as a best-in-class IL-2 therapy. I would like to now put these results in context of our program objectives and the next steps for the program. Please go to slide 22. As you saw, WTX-124, administered as a monotherapy every two weeks in an outpatient setting, was generally well tolerated at doses that produced objective, rapid and durable clinical responses in heavily pretreated patients with immunotherapy-sensitive indications. These findings indicate that WTX-124 may extend the therapeutic opportunity to patients with renal cell cancer and cutaneous melanoma who would not be able to tolerate high-dose IL-2, and further, to indications where high-dose IL-2 therapy is not approved.
We believe this supports single-agent development in immune checkpoint inhibitor relapsed-refractory indications, where there is a high unmet medical need. We observed no new safety signals in combination with pembrolizumab, as well as enhanced immune activation by NanoString. Although the data are preliminary, we did observe in the interval between the May 1 data cutoff and today, clinical activity in two melanoma patients at the WTX-124 12 mg combination dose level, recalling that this is the same dose level at which we saw monotherapy activity. We saw one partial response and one near partial response, with a 29% reduction in target lesions. We believe that these data support continued exploration of immune checkpoint inhibitor combination therapy in both dose escalation and expansion, including in other immunotherapy-sensitive indications, as well as in earlier lines of therapy. Please move to slide 23.
We have selected a dose of 18 mg IV every 2 weeks of WTX-124 as our recommended monotherapy dose for expansion and are now enrolling both monotherapy expansion arms in advanced or metastatic renal cell carcinoma, cutaneous melanoma, and a new expansion arm in cutaneous squamous cell carcinoma. We expect preliminary data from these expansion arms in late 2024 or early 2025, which should provide evidence of monotherapy clinical activity in a more homogeneous, less heavily pretreated population, still following immune checkpoint inhibitor therapy and provide greater clarity into a development path in each of these indications. We will continue dose escalating for WTX-124 in combination with pembrolizumab and anticipate selecting our recommended dose for expansion and opening of those combination expansion arms in the third quarter of this year.
Additionally, we hope to meet with the FDA to discuss potential registration pathways, including strategies for monotherapy accelerated approval in immune checkpoint inhibitor relapsed-refractory indication. As we first saw with our data presented at SITC last year, and what we have now seen here at ASCO, these data are indicative of a potential best-in-class interleukin-2 therapy. We believe that there is much to be excited about with our data set, especially as we extend therapy beyond the patients and indications eligible to receive high-dose IL-2. Before closing, I would like to remind everyone of our earlier guidance regarding a program update for WTX-330, our IL-12 cytokine molecule, and note that we will be providing initial phase I dose escalation data for this program later in June. And with that, I'll hand the call over for closing remarks to Dan Hicklin. Dan, please flip to slide 24.
Thank you, Randi, and special thanks to Dr. Moser for joining us today. Today's update marks a significant step forward for WTX-124 and for Werewolf. The phase I data continues to demonstrate WTX-124's potential as the next generation IL-2 therapy. With these data in hand, we are moving forward with a recommended monotherapy dose and expansion arms and continue to dose escalate in the combination arm. I want to express my appreciation to the patients and our investigators in this study and to our Werewolf employees for their hard work and dedication to this program. And with that, we'll open up the queue for Q&A. Operator?
We are now opening the floor for question-and-answer session. If you'd like to ask a question, please press star, followed by number one on your telephone keypad. Our first question comes from Daina Graybosch from Leerink Partners. Your line is now open.
Hi, congratulations on the data, guys, and thank you for the question. Let me ask two. The first one is, let's say you go to FDA and it's on your development path, and along with their, you know, recent encouragement and guidance for sponsors to consider randomized accelerated approval paths and earlier lines. If you get that kind of feedback, is there an alternative approach beyond the single-agent relapsed refractory single- arm you might consider developing WTX-124? And then my second question is more of a platform one. Now that you have the data on efficacy, safety, and biomarkers, what learnings have you taken for your INDUKINE platform and anything you might do differently in your earlier INDUKINE program? Thank you.
Good morning, Daina, and thank you for those questions. I'll hand it over to Randi to address those.
Thank you, Dan. Good morning, Dana. So the first question was related to the pathway, the FDA pathway, correct? Or was that the second question?
Correct. If they ask for a randomized accelerated approval path, what ones you might consider?
Yeah. So we have thought about that, and we do have some ideas on what a randomized controlled trial could look like, even in the relapsed- refractory setting, where we run WTX-124 in an indication against physician's choice. And that, you know, we know that that has satisfied them for a randomized controlled trial for other programs. So that's under consideration. And then, obviously, in thinking about a combination or in an earlier line of therapy, which we would have to also have as a confirmatory trial at the same time that we have an accelerated approval pathway identified. And then your second question was regarding?
What you learned about the INDUKINE platform that you applied.
Yeah. That's actually a great question. And, you know, I feel that we've had such success with the WTX-124 program. You know, I try not to be formulaic in how I think about doing the early phase trial. You know, I think it's important to focus and to look at the biology and then get your proof of concept in an indication or a selected patient population and then move from there. And so, you know, at this point, it's proven successful with 124. We will demonstrate the 330 data at the end of this, you know, towards the end of this month. And so, you know, we continue to learn about biomarkers.
I think that's the biggest piece is, you know, how do you—what are the best ways to demonstrate the biology? And that's, you know, something that we're learning as we evolve in the trial.
Yeah, maybe I'll just add to that, Daina, that, you know, one of the big question marks for us in the beginning, putting the technology together was the conditional activation piece of the platform. And the question always was, you know, was our novel approach to developing a protease cleavable substrate for these molecules going to translate to the clinic? We felt very strongly that, you know, the protease heterogeneity amongst different cancers and patients was something that we needed to address. And we attempted to de-risk that as much as possible by using this novel protease approach. And I think we're at least now encouraged by the early data showing that these molecules are, in fact, activated as we had hoped they would be in patients.
We have a lot more data, of course, to generate there, but at least thus far, it looks like that's translating to the clinic.
Great. Thank you.
Thank you.
Our next question comes from Kambiz Yazdi from Jefferies. Your line is now open.
Morning, team. Nice to hear you all this morning. About three questions for me. For the dose expansion cohorts, are you going to enroll, less heavily pretreated patients, and how are you gonna go about that? Second question, was the overall adverse event incidence, dose dependent? And, if we happen to still have Dr. Moser on the line, as a third question, what type of patients do you typically administer high-dose IL-2? And given the tolerability experience of WTX-124, in the clinical trial, could you imagine more expanded utilization? Thank you.
Good morning, Kambiz, and, thanks for, for those questions. I guess, Randi, do you want to start off and then, hand it over to Dr. Moser?
Sure. So, you know, I think that Justin can give his personal experience with administering high-dose IL-2 and the patient population. But, you know, Kambiz, if you look at the age and the comorbidities of the patients that we're treating, you can see that we can, excuse me, easily extend the therapy to a much wider group of patients. Not only within the approved indication for high-dose IL-2, but obviously beyond those. The expansion arms that you asked about, they are less heavily pretreated melanoma, renal cell, cutaneous squamous. And we've certain definitions and eligibility criteria that we've built into the protocol. So for example, in dose escalation, we allow, you know, four lines of prior therapy. But those lines of therapy are restricted in the expansion arms.
And there's only, you know, several things that patients must receive and in a certain order. So for example, in melanoma, patients who are BRAF wild type can have received only one prior line of therapy, which would be an immunotherapy line. And that's true, you know, for the other lines. Obviously, in renal cell, you also give a TKI. So, you know, I think that will help us to create a more homogeneous patient population of less heavily pretreated patients in expansion. I think I may have missed one of your questions.
Yeah, sorry. The middle question is, was just overall adverse event incidence, dose dependent?
Yeah, we showed that actually, initially at SITC, where we see dose dependency in the adverse event profile. And that continues to be true. And so, for example, we saw no Grade 3 events at any of the dose levels up to 12 mg, including 12. We had several Grade 3 events starting at 18. So yes, there is certainly dose dependency in the adverse event profile, but there aren't any adverse events that aren't reversible and manageable, and it's a very, very small number.
Thank you.
Justin, do you want to go into the, patient population eligible to receive?
Yeah, happy to. So, you know, when we give high-dose IL-2, there is a black box warning on the FDA packaging insert. So all of these patients, prior to getting high-dose IL-2, have to get cardiopulmonary testing with PFTs and an echo. And really, you know, when you look at what patients are eligible, it very few people will give people or give patients who are over 70, high-dose IL-2, just because it is so rough. And, you know, really, we really look for the youngest and fittest patients. You know, I think high-dose IL-2 kind of fell out of favor when the PD-1 came along in melanoma, but they did still use it in renal cell up until probably 5-10 years ago.
Really, when you look at the GU doctors who were selecting patients for high-dose IL-2, it was really the youngest and fittest patients. It was a very select patient population. The vast majority of patients with renal cell were not getting high-dose IL-2 because of the toxicity. I think that's completely different, you know, with this drug. I mean, one of my first patients, I think, we put on this trial, she was 80-something, and my nurse at the time, who's a very seasoned phase I nurse, who's been doing this for 30 years, grabbed me and said, "Justin, this is IL-2, are you crazy?" I said, "Well, look at the data. It's been very safe." You know, she went on and did very well, tolerability-wise. So this is very different and definitely is more applicable to far more patients than classic high-dose IL-2.
Thank you so much, team.
Our next question comes from Jason, Jason Zemansky from Bank of America. Your line is now open.
Good morning. Thank you so much for taking our questions, and congratulations on the update and progress. Two for me, if I may. Given the early consistencies you're seeing in the baseline biopsies and biomarker analyses in the responders, how is that, if at all, influencing your combination strategy and approaches? Is there an ideal partner here that could potentially, you know, increase the CD8 positive T cell density and, you know, potentially prime more patients for activity?
And then secondly, I know what we're seeing on the PK/PD as far as the, you know, serum levels of WTX-124, but I was curious, do you have similar evidence that, you know, you're reaching kind of that saturation point as far as, you know, tumor markers and IHC, that the 12 and 18 mg doses are giving kind of maximizing out? I mean, in other words, at greater concentrations, would you have seen more responders, you know, within the tumors themselves? Thanks.
Thanks, Jason. Good morning. Thanks for those questions. Maybe I'll maybe start off with the answer to your first question and hand over to Randi to follow up. Your question's a good one, and I think, you know, based upon the data that we've shown in terms of the biomarker data and the combinations and showing that there's a baseline of immune activation that's quite low in these patients, and that can be enhanced with monotherapy activity and then further enhanced with the combination with pembrolizumab. I think that speaks well to our aspirations for a potential combination effect down the road. As you heard earlier today from Randi, we're already seeing some now some indication of activity with the combination at the dose level of 12 mg of WTX-124.
So, for us, I think that's, you know, been the big question about whether we're going to actually see that combination effect, and so far the data is suggesting that there is potential there. Randi, you want to further follow up with that question or the second question?
Sure. So, Jason, can you rephrase? Can you repeat your second question, please?
Sure. I was just curious. You know, again, I know that what we're seeing on sort of the PK/PD as far as the, you know, getting circulating, WTX-124 levels kind of at their maximal levels. But you know, if you increase the dose here, I s the tumor response greater, at least in terms of the biopsy and IHC analysis? In other words, you know, if you start pushing that dose a little bit higher, w ould you see more reactions from the individual tumors?
W e are not done, even though we've chosen 18 mg as the recommended dose and are opening expansions. For us, you know, that dose sort of checks all the boxes. It's safe. There's anti-tumor activity. For the biomarkers, it shows right now the highest degree of T effector cell activation. But we are still dose escalating in order to understand the full range of activity, to understand, you know, the full range, let's say, above all, safety, to look at anti-tumor activity, and to continue to understand the biomarkers. So we're not done there, and, you know, we will continue to explore that. We have flexibility. Let's say, you know, a higher dose appears to demonstrate greater anti-tumor activity. We certainly have the flexibility to look at that.
It's a good question and not one that we have, you know, decided we're going no further to look at some of those aspects.
Awesome. Thank you so much for the color.
No problem.
Our next question comes from Andres Maldonado from H.C. Wainwright. Your line is now open.
Great. Thank you very much. Congrats on progress, and thanks for taking my questions. Two from me. First one is, when we're looking at the particular diversity of responses, let's say, across the melanoma, you know, how are you guys thinking of what is the crux of the diversity of the response there? Is it genetically based? Are there any kind of other patient characteristics that, you know, are leading to a more robust response there? And then second, as a follow-up to the last couple of questions on the biomarkers, you know, just wanted to be clear, what exactly do you need to see in terms of some of the biomarker trends before you're comfortable in fully leveraging some of those findings in future clinical studies? Thank you very much.
Morning, Andres. Thanks for joining us, and thanks for those questions. Randi?
Sure. So let me take the biomarker question first. The biomarkers, you use them in order to understand they're necessary but not sufficient . So you use them to make sure that you are engaging your target and that you have downstream activity. For us, the biomarkers were also critical for us to understand that we had active conditional activation, that we had cleavage. W e are doing a cleavage assay that we have developed to try to understand if there are degrees or variables around cleavage. Patient's baseline tumor sample is dissociated, and then in vitro, we look at cleavage of the INDUKINE. And with a larger dataset, we can start to assess any correlation with response.
So that will be ongoing, even in future trials, because obviously we want to understand the conditional activation of our molecule. The last slide, which starts to look at patient selection criteria. We've had high-dose IL-2 on the market for 40 years, and for many reasons there's still no selection strategy for patients for high-dose IL-2. T echnology evolves, and then we're able to actually use that to understand things that were not available to us previously. Can you repeat your first question again for me?
Sure. So just diving into some of the diversity responses that we've seen, I know these are in the context that they're early days, but particularly, t here may be, let's take melanoma, for example. Curious on just some high-level thoughts of where some of those mechanistic differences are coming from, whether it's maybe a MAPK alteration in the case of melanoma or other kind of patient characteristics that can bifurcate the the intensity response rate.
Sure . Okay. So, we've been looking at all sorts of factors in patients who do not respond or have partial responses or stable disease, and those that respond, obviously have complete responses to understand what kind of factors might exist. The data set is still small. And I think there's many reasons why patients are resistant to therapeutics . Certainly, with IO agents, if there isn't the antigen presentation or the recognition of an antigen, then you're going to not have an immune response. The T-cells are not going to be able to recognize the tumor. Among that. And then there are many, many other reasons for resistance.
You know, with time, perhaps we will be able to come up with a data set that allows us, again, this goes a little bit towards the patient selection, as to why certain patients respond and, and certain patients don't. But that's true for IO in general.
Great. Thank you very much.
You're welcome.
Before we move on to our next question, if you'd like to ask a question to our presenters, please press star followed by number one on your telephone keypad. That's star followed by number one on your telephone keypad. Our next question comes from Reni Benjamin from Citizens JMP. Your line is now open.
Hey, good morning, guys. Thanks for taking the questions and for setting up this call. A couple from me. Maybe the first, can you talk through a little bit more, provide some color regarding the non-target lesion progression, kind of how you're viewing that, and any thoughts on treating patients through progression for maybe at least one or two cycles to see if the therapy might be able to bring that under control? Or are there any other strategies that you might be able to invoke to get through a second scan to confirm the responses? And I'll have a couple of follow-ups.
Morning, Ren. Thanks, thanks for that question. That's a great question. I'll hand it over to Randi to address that.
Sure. So , from a standpoint of RECIST criteria, there are very specific guidelines around non-target lesions. And if one is read as progression, that is considered progressive disease. I think you're talking specifically about our third responder, the one with the GEJ, where one of the non-target lesions was read by radiology as increased. You know, I think every patient is an individual. Obviously, if we could have biopsied that lesion, that lymph node, we would be able to determine whether that was T-cell infiltration, or true progression of disease.
But the fact that the patient has now been off therapy, for three months and has neither progressed nor needed any further therapy, whereas when they started, they were definitely progressing prior to coming on trial. I think that gives you some hints. And we can only go with the criteria, that we have unfortunately. We do have the ability to treat beyond progression at the discretion of the investigator. So we have done so, and I'm trying. I don't have at my fingertips how many patients we've had that happen to. I'm gonna ask, Justin, have you treated any of your patients beyond progression?
I don't know if Justin's fallen off or not, but in any case, we do have the ability to do that for the patients who have had progressive disease and have continued therapy. We have not seen as of at this time anyone who's then gone on to have a response.
Got it. Okay, thanks for that clarification. And then just if Dr. Moser comes back on, otherwise, Randy, maybe you can answer this for me. The Grade 3 toxicities that you're starting to see how do you treat these patients? And presumably, since you're going higher in doses, we, we might see more of these. Is there any way to, to mitigate prophylactically any of these, or are there some pretty established treatment regimens that can, that can take care of, take care of these patients?
So the one thing is they're all different. So if they were all of the same ilk there might be something I can tell you for the arthralgias, which are our most frequent adverse event overall and are IL-2-related adverse event, is an IL-2-related adverse event. We've instituted a management guideline, with the input of our investigators. And at this at this junction, the institution of either prophylactic or at the first signs of arthralgia, NSAIDs, Tylenol, and if necessary, low- dose prednisone. And that has really helped to manage the arthralgias. The other two specific events, the Grade 3 events. One was, if I recall, exactly, an esophageal spasm. It was not cardiac chest pain, it turned out.
It was probably esophageal spasm, and it was dealt with with an H2 blocker. So, and then the third one was increase in potassium, hyperkalemia. So these don't fit into a neat package. And t hese are the kinds of things you see within phase I trials. So they're all manageable, they're all reversible, and we move on.
Gotcha.
Operator please.
Moser is not muted. Thank you.
Oh. I guess my final question has to do with the combination data that you mentioned. Can you just remind me, did I hear it right, that you have one partial response, one near partial response in combination in the 1 2 mg? So I'm assuming it's out of three patients or so. Can you just confirm that, and are these responses confirmed?
Well, since they just came in, between May first and today and the presentation, these were on initial scans. They are. We had four patients in the cohort at 12mg combination, and these are our two melanoma patients, and both melanoma patients have anti-tumor activity. So the first one, it's a patient who's very heavily pretreated, had 3 prior lines of biotherapy, and established a partial response. The second patient had a near-partial response at -29%. You know that 30% is the cutoff. Confirmation will occur in 4-6 weeks on both of those patients. The other patient that we have on that cohort is a non-small cell lung cancer, who has stable disease, and the fourth is a cholangiocarcinoma, who had progression.
So 2 out of 2 on the melanoma at the 12 mg. You know, this also goes back if you look at the biomarkers and the enhanced activity we see at 12 mg in combination. This is very nice affirmation of that.
Excellent. Thank you very much for taking the questions, and congrats on that, on that new data.
Thank you.
Thank you so much. As of right now, we don't have any pending questions or raised hands, so I'd now like to hand back over to Dan Hicklin for final remarks.
Thank you. I'd like to thank everyone for joining us today for this WTX-124 clinical update, and we look forward to speaking with you all later this year with further updates for the program.
Thank you for attending today's call. You may now disconnect. Have a wonderful day.