Good morning, everyone. Thanks for being here this morning. I am Mike King, Director of Research and Senior Biotech Analyst at Rodman & Renshaw. I am here with Dr. Jim Bianco as our guest. Jim is the President and CEO of TuHURA, and he is with us this morning to share some very interesting preliminary findings from the company's open label phase I-A/II-B study of IFx-2.0 in patients with metastatic Merkel Cell Carcinoma, also known as MCC. It is our pleasure to welcome Jim this morning. The update is timely given some avelumab data that was presented this weekend at ESMO. The title of that presentation is "Real-World Effectiveness and Safety of First-Line Avelumab in Patients with Stage III Merkel Cell Carcinoma: Results from a Prospective German Registry" known as MCC-TRIM.
This is in 98 patients with Stage III MCC that were treated in the frontline setting with the PD-L1 antagonist avelumab, which is also known as BAVENCIO, the Pfizer-Serono PD-L1 antagonist. Avelumab demonstrated a response rate of between 38% and 42%, depending on the subgroup that was analyzed. Recognizing that patients with Stage III MCC will have better response rates to checkpoint inhibitors like avelumab compared to patients with Stage IV metastatic disease, it underscores the relevance of the preliminary data that you are seeing with IFx-2.0 in bulky metastatic disease. Turning now to what this means for TuHURA, and just as a disclaimer, we do follow the shares of TuHURA and rate them buy.
The preliminary data from three patients that was just announced this morning may be a little unusual to report preliminary data on such a small number of patients, but because the data are extremely compelling and directly relevant to the company's ongoing phase III trial in the frontline advanced setting or metastatic Stage III/IV MCC, I thought it was important to have the company share the data with you, especially given the early responses that are being observed. Jim, let me turn the call over to you to walk through the background, the rationale, the study design, and this early data of the 2023 trial, if you will, sir.
Will do. Thank you, Mike, and thanks for hosting this fireside chat today. Before I get started, as is typical with presentations of this type, we will be making forward-looking statements and remind you to look at our SEC filings for more information on the company's development programs and the associated risks. Before I jump into the results, why don't we go ahead two slides, Jack. There you go. All right. Before we talk about the results, I think it is helpful to provide a little background on the different Merkel cell patient subsets. We will talk about the trial design. We will touch on how it relates to our ongoing phase III study. MCC is a very aggressive form of skin cancer. It is unlike melanoma or other forms of skin cancer. About 3,800 new cases diagnosed in the U.S. each year.
About 15% of those 3,800 patients, they will present with local regional disease, and they undergo potentially curative surgical excisions, and then they get adjuvant Keytruda to try to prevent possible recurrence. Then there is about 55% of patients who have advanced cutaneous and superficial nodal disease, Stage III, or metastatic disease, Stage IV, and they receive Keytruda in the frontline standard of care. That is the patient population that we are studying in our ongoing phase III study. This is the group that we are going to talk about today. 30% of patients, however, have metastatic Stage IV disease when they first see a physician. They have these so-called deep-seated metastatic lesions.
It is this subset of patients that we are enrolling in our phase I-B, from which we will present kind of a first look at how is IFx working now in the frontline treatment setting of metastatic disease, especially large bulky tumors. You may recall our phase III randomized placebo-controlled trial of IFx plus Keytruda or Keytruda plus placebo requires patients to have tumors that can be injected with a relatively small needle that is being used in the phase III study. 30% of the patients that do not present with cutaneous and superficial nodes essentially are not eligible for that phase III study. To address the potential of how IFx could work in the frontline treatment of these patients, we designed the current phase I-B, what we call our 2023 trial. We used to call it the Basket trial, but we refer to it internally as our 2023 trial.
We go to the next slide, and we will show you the design of the study. There we go. All right. This trial focuses on patients administering IFx via a weekly times three schedule. These patients that are on this study will often have large bulky tumors that are deep in muscle or the abdomen or organs like the liver or lungs, and they require ultrasound or CT-guided methods to administer drugs like IFx-2.0. The design of the study, this is a frontline treatment study like we are doing in the ongoing phase III study. IFx is given weekly times three injections along with Keytruda every three weeks per the product label. As I mentioned, this is the first time that we are looking at IFx outside of the existing placebo-controlled trial in the frontline setting. The endpoints are pretty straightforward of a phase I-B study.
We are looking at both the feasibility of administering IFx this way through ultrasound or CT-guided techniques. Of course, we need to evaluate the safety of administering IFx. We are also going to look at efficacy, and here we are determining the objective tumor response to therapy and duration of response, and we use what is called the RECIST criteria, and this is the universally accepted method for determining tumor responses. This trial provides us, as I mentioned, clinical response data for the first time in a frontline treatment setting, and really can serve as kind of a proxy for potential response rates that we may see in our placebo-controlled phase III trial, which as I mentioned, is also in a frontline setting.
So if we take a step back, you may recall our experience with IFx in advanced or metastatic Merkel cell was not in the frontline setting, but rather these were patients who had progressed while receiving the standard of care in frontline with a checkpoint inhibitor like Keytruda or avelumab. You may recall 50% of patients who receive frontline therapy with the standard of care Keytruda will progress. They will fail, and when they fail, they have no subsequent approved or effective therapies. We recognize that as really representing a significant unmet medical need, and that was the patient population we initially studied in our prior IFx-2.0 trial. In that study, patients who failed Keytruda or a similar class of drug were enrolled on IFx. They received IFx weekly times three, like we are doing here.
Following IFx, they were rechallenged with Keytruda or again, a drug within the same class, which is called avelumab. IFx in that study was able to salvage 67% or five of eight patients who achieved a major durable anti-tumor response. We saw both complete responses, where there was no evidence of tumor, or partial responses that were lasting on average 23 months, some even as long as 33 months. So that was the data that we took to the FDA to determine what kind of trial design would provide the fastest possible route to potential approval given the unmet medical need in this patient population.
The FDA, specifically the so-called Oncology Center of Excellence, encouraged us to consider their Project FrontRunner initiative given the encouraging results that we were seeing in the phase I study amongst patients who were failing frontline therapy and being salvaged by IFx when they are rechallenged with drugs like Keytruda. Give you a little background on Project FrontRunner. It is really a significant move for the oncology community. As you know, clinical development of most new cancer therapies are conducted in relapsed or refractory patient populations, just like we did. The clinical investigation of new therapies in the earlier treatment settings may give more patients the opportunity to receive an investigational agent when their disease-related factors do not prevent them from participating, and when the treatment has the potential to alter the course of their disease more effectively.
I mean, essentially, the comment that was made, if you can prevent patients from progressing, would not that be better than trying to salvage them after they failed a therapy? That was the rationale for the design of the currently enrolled rolling phase III frontline study. With that background for the rationale for the 2023 trial, I want to share some preliminary results of IFx-2.0 for the first time in the frontline treatment of patients with large, bulky, deep-seated stage four metastatic disease. All right, so this is the first patient who was treated at Moffitt Cancer Center. As shown, it was a 78-year-old male. As you will see, had stage four metastatic Merkel cell carcinoma, and the patient's disease was involving the right gluteal intramuscular lesion. You will see he had a lot of lesions deep in the muscle.
Also had disease in the pelvic lymph nodes, in the lung as well. This patient received CT-guided IFx-2.0 in the intramuscular administration weekly times three, and then received a standard dose and schedule of pembro, which is Keytruda, every three weeks. pembro is typically given per the label every three weeks until either you see the patient progress, until the patient may have a pembro-related toxicity, or they reach two years. Importantly, not only was it feasible to administer IFx to this patient, but it was safe. Safe meaning that we didn't see any serious adverse events, so-called SAEs. The encouraging part was that this patient had a confirmed partial response at the week 12 evaluation as well as the week 24 evaluation. The gluteal lesion that was injected with IFx was one of the lesions that was included in the so-called response assessment.
I think it's fair to say that a 60% reduction in tumor size, along with minimal toxicity, is a very good benefit-risk profile. Importantly, it's encouraging, right? This is the first time that we have data in the frontline tumor setting. I'm going to show you what that looked like for this patient with some CAT scans. If you look in the upper left-hand panel where that green arrow is, you see what looks like all those white dots. Those are metastatic deposits deep in that patient's muscle. So those were the lesions that were injected. You can also see on the panel below, if you want to look at a different perspective from the CAT scan, you can see all that whiteness in that Dark area, those are tumors. Those are metastatic deposits.
Now, if you go to the right upper panel, this is after week 24, and you can see that essentially 60%, 70% of those are gone. That's also confirmed if you look at the next bottom panel again. So this patient had a pretty dramatic response, 60% reduction for deep-seated lesions. It is very encouraging. It not only was seen at week 12, but now it's considered durable. If you're familiar, according to RECIST, you do a CAT scan at week 12 or other forms of radiographic imaging. You look for reduction in tumor volume in the so-called target lesions, and then you confirm that essentially a month later, and then if the response is still there at six months, that is considered a durable response by both the oncology community and importantly, the regulatory community, and that's what the FDA typically needs to see for an endpoint.
That is one of the endpoints, matter of fact, the approval endpoint in our ongoing phase III study. Let's go to the next patient. This one is really dramatic, and I think this has made all of us feel very good about what we do for a company, and certainly encouraged for the ongoing study. So this is a 79-year-old female, again, stage four metastatic disease. This disease involves both her liver and her cervical lymph nodes. You'll see why this patient required ultrasound-guided IFx into those cervical lymph nodes weekly, times three, and again, got the standard pembro every three weeks alongside following IFx. Again, no serious adverse events were seen, no grade three or greater toxicities. Grade one and two, grade one is considered mild, doesn't require any intervention. You can see what those are listed here, whether those are IFx related or not.
Again, grade one is typically not concerning for any investigational product. There was a confirmed response, again, at week 12, and that response continues like the other at week 24. I am going to show you really a dramatic example of how this therapy may provide clinical benefit to a patient. In the left upper hand panel, that large lesion, that large ball that is hanging down below the patient's jaw is her tumor. This is her baseline. You can see it both on the side profile and the panel below looks at that extensive mass on the left-hand panel below, large tumor. If you go to the middle panel on the CAT scan, you can see that large ball. That is the tumor. If you go and you see that little white spot above it, that is her jaw.
The upper jaw is white, and then between the jaw bones is the base of her tongue. If you go to the right on that panel, you see the spinal cord, nope, same in the center, Jack, right there. What you do not see where the tongue is, you do not see her esophagus, and that shows in the right upper hand panel. Large tumor mass, that white hole is her trachea, and you do not see her esophagus. This patient had difficulty, obviously, with eating and swallowing. Go to the next slide. This is her week 12 assessment. Dramatic change, left upper hand panel, that tumor is regressed significantly. You can look at it on the forward profile. Importantly, for the first time, if you go to the center panel, that lesion has shrunk dramatically.
That thing above is where her jaw bone is, her base of her tongue. Importantly, to the right of the base of her tongue, you start to see this dark area, that is her esophagus. Now this patient is having marked reduction in her symptoms with regards to swallowing. If we go to the week 24 assessment, the next slide, you can see that it looks like it is gone. I am going to show the center panel. So base of her tongue and that long dark tube. Now her esophagus is visible, is open, and her swallowing is near normal. Clearly clinically beneficial for this patient. If you go back to the first set of graphs, again, look at the middle panel. Now go back to the last slide and look at the middle panel. So that is true clinical benefit if you are this patient.
As the physician said, this patient had a dramatic reduction in her symptoms, and it is ongoing at 24 weeks. I am going to talk about third patient. Some of this data was one particular site, Stanford Health, wanted to participate in the study, IRB reviewing it. They had a patient that came in that had metastatic disease, a younger woman, 61 years old. I will say young because I am older than 61. A young woman at 61 years of age. Right lower extremity, large soft tissue lesion, also had paraspinal disease, so clearly stage four metastatic Merkel cell. This patient had a clinically palpated guided IFx administration with a larger needle than what we use in the phase III study into that right lower extremity soft tissue lesion. She received a combination checkpoint inhibitor of ipi/nivo, got that every three weeks for four cycles.
Interestingly, again, no serious adverse events, no treatment-emergent adverse events. This patient had a confirmed response of PR at 12 weeks, which is ongoing at 24 weeks. We are in the process of trying to get a hold of those scans. This is a community site, so requires a little bit more lead time than what we see, for example, from some of the academic sites. The last patient I am going to talk about is very early in the process, but another Moffitt Cancer patient, 88-year-old gentleman, stage four metastatic disease involving the liver. This patient received CT guided IFx weekly times three to the liver lesions, so-called intrahepatic. Received Pembro every three weeks. Had their third dose on the 21st of October. Again, no serious adverse events reported. The RECIST criteria assessment occurs at 12 weeks, at some time in the next couple of weeks.
Again, this patient shows even with deep-seated liver administration, it is feasible to give IFx, and it appears safe to give IFx this manner. We are encouraged that this patient is likely going to be another responder in this study. At that point, I think we are done with the presentation and happy to turn it back to you, Mike, see if you have any follow-on questions for us, et cetera.
Yeah, sure. Thank you, Jim. Definitely looks interesting. Those images are quite compelling. One of the concerns that we have had from investors was that all the data you have got in Merkel cell is in the second line setting, yet you chose to move, again, at the behest of FDA, but you chose to move it into the frontline setting based on their encouragement under Project FrontRunner. Is that why you are conducting the 2023 trial to address the concern of whether IFx will achieve similar response rates that are observed in the phase 1b in the frontline, that can carry over?
Great question. We designed this trial to address several questions, including the one that you just raised. First, we have to show whether or not IFx can be administered, the feasibility of administering it through radiologic-guided injections to deep-seated lesions with CT or ultrasound. Then we need to determine when you put IFx into very large, bulky lesions that are visceral in nature, et cetera, whether or not the safety profile looks similar to what we saw when we were administering it to large skin lesions or superficial nodal lesions.
As I mentioned, 30% of patients with Merkel cell will require that type of administration, meaning deep-seated lesions, so they would have to use a radiologic-guided mechanism. But the second reason we did this is, you are spot on. We've been asked, like you said, why do we think it would work in the frontline setting when all the data you have is in the second-line setting progression. As we know in oncology, in the treatment of cancer, when you intervene early, that's always provided the best results. As you mentioned, this was certainly an encouragement from the FDA.
We were interested in demonstrating that IFx, when you give it to patients in the frontline setting alongside of Keytruda, that in fact it will produce encouraging anti-tumor responses in a percentage of patients similar or even potentially superior to what we observed in our phase I experience. You can think of this as kind of like a proxy for what we might see in the phase III trial. Obviously, we still have to wait to see results in more patients, but this is certainly very encouraging, seeing these types of responses in the first three patients. These are major tumor regressions. It's encouraging for us having, again, the first three patients in a frontline trial.
Yeah. No doubt. I guess the related question and something, again, that we hear from skeptics is, these are small numbers. How should we consider evaluating whether these can be extrapolated into the phase III setting. Also, one of the questions that often occurs with checkpoint inhibitors is when you do a combination study, do you really know that your effect is a therapeutic benefit driven by your drug rather than some kind of latent awakening or some other effect that you're having on the checkpoint rather than from IFx?
Good questions, Mike. Let me take the last one first and then I'll move in. How do we know that this is an IFx contributed effect versus the checkpoint inhibitor alone? I think if you go back to the phase I-b study in patients who failed a checkpoint inhibitor, when we gave them IFx, it allowed them to respond for the first time to a checkpoint inhibitor. We're pretty confident that IFx is the reason that checkpoint inhibitors will work in patients where otherwise they would fail, and that there's likely going to be that additive benefit of activating the immune response and then amplifying it with a checkpoint inhibitor. I think that gives us some comfort to that concern. Most importantly, as you mentioned, you never want to overread results in such a small sample size.
But there's a few aspects that makes this encouraging, right? As I mentioned, we're seeing similar responses being reported across three different centers, and that really does address some of the concerns of potential bias when you see response data generated from a single institution. The other thing is the depth of responses in such bulky tumors, again, including, as the investigator mentioned in one of the call-outs, that one tumor started regressing just after the IFx-2.0 dose. And that also is encouraging, right? Then lastly, any patient that experiences such a dramatic response for what was a debilitating bulky tumor in their neck really underscores the potential meaningfulness of the clinical benefit that was seen with this drug. If you look at the ESMO meeting yesterday, Iovance reported data on eight patients, right? And so it had a response rate of about 50%.
The reason that's meaningful is because TIL therapy was now shown to have responses in two very difficult-to-treat diseases in terms of desmoid sarcomas, et cetera. So I think much like that, showing only three or four patients of data that is impactful in metastatic Merkel cell, which as you mentioned from the beginning of this presentation, avelumab, which is just like Keytruda in terms of how it works, and it's shown to work almost as good as Keytruda, had a 39%-41% response rate in good risk Merkel cell. Meaning Merkel cell patients that didn't have metastatic disease. And metastatic disease is much more difficult-
Sure
to treat. So seeing three out of three responses, it certainly encourages us.
Yeah. We got a bunch of questions in the chat, Jim. Let me just ask one quick follow-up, and then I'll address the questions that are coming into the chat. But I guess it's a two-part question, if I may. First is, why do you think the fourth patient who isn't scheduled to have their response scans completed for another three weeks is responding? And second, one of the questions that always comes up, and this is related to this fourth patient, is how do we know that they are truly refractory to the checkpoint? There's a lot of debate amongst investors, obviously, because if the interval or that gap or the prior lack of response or response is not predictive of what they may respond going forward, how do we truly know this is an IFx effect and not a continued effect of checkpoints?
Good questions. First question about patient four. The tumor kinetics, as I mentioned, for Merkel cell is totally different than melanoma. If you are going to respond to a checkpoint inhibitor, you are going to respond within the first three doses. If you do not, 90% of patients will not respond. The majority of people who are going to respond do so early. The fact that this patient got their dose, is scheduled for their week 12 evaluation is encouraging. Again, just given the prior experience that we and the community has with using checkpoint inhibitors in Merkel cell. To your other point, how do we know that IFx in this is not just kind of a checkpoint inhibitor effect? You do not see 100% or 50% or 60% or 70% of patients with metastatic disease responding to a checkpoint inhibitor. That was the argument for Project FrontRunner initiative.
If you put it in front line, normally half of these patients respond to Keytruda. That is a mix of advanced and metastatic, where advanced, as we said, typically have a better response rate than patients who have metastatic disease. If you look at that benchmark, 50% are not responding. The FDA's argument, and it meets the biology of how this drug works, if I can give it to everybody coming in with their disease, now you have the potential to have their tumors look foreign to their immune systems before getting a checkpoint inhibitor. For those patients who would not have responded may now respond. If you start seeing response rates of 65%, 75%, 80%, that is not Keytruda, right? This is just in metastatic. When you look at the data in metastatic, it is below 30%. This is only stage four deep-seated lesions. You would not
Yeah
see 60% or 70%. That is why this is encouraging to us that in fact, we may have hit the mark in the ongoing phase III study, and we will know.
Is there a known difference between the superficially in terms of response rates, if it's for the superficial lesions versus the deep-seated?
Yes. If you look in the literature, stage three disease responds much better than stage four disease. The outcome for stage four disease is much worse than for just stage three, even 3B, where you have some lymphatic involvement in the skin. Those patients typically have a good response to checkpoint inhibitors that are durable. Whereas if you look at stage four, the responses can be anywhere from 20%-30% at best, and they relapse very quickly.
Okay, great. I have some follow-ups on this phase I-B/II-A, but we've got some questions in the queue as well, and we've got a couple from Kumar at Brookline. Let me start at the top. The study successfully demonstrated the safety of using CT or ultrasound guidance to inject IFx-2.0 into deep-seated tumors. What are your thoughts on whether this method will continue to prove manageable and safe as more patients undergo the procedure?
Good question. Thanks, Kumar. Well, I think four out of four have shown a really good safety profile. You have to recall, you're injecting deep-seated lesions with essentially an innate immune agonist. So you're activating an immune response in a very large, bulky tumor, and you're not seeing serious adverse events associated with that. The other thing we're not seeing, quite frankly, if you think of 24 weeks, every three, that's eight cycles of pembro, and you're not seeing serious IR-related toxicities. So we think that profile will continue. We saw this in 13 Merkel cell in patients who had already failed in the phase I-B. So, we're encouraged that both feasibility and safety are going to be demonstrated in a larger sample size. Importantly, quite frankly, I think we're going to continue to see these types of results.
It is obviously CT-guided, correct?
Correct. They do ultrasound as well. For example, in a large lesion in the neck, it was easier to use an ultrasound to make sure they were not going to hit any vascular structures, et cetera.
Yeah. Okay. Kumar, second question is: if these preliminary results continue, what would be the regulatory strategy in these patients given the ongoing phase III?
Yeah, great question. One of the rationales for doing the trial is that since 30% of these patients would not be in the so-called label that we are pursuing with the ongoing phase III study, we would have a discussion, obviously, if this data continued in 10 or 12 patients, if you see 89% of these patients having meaningful response. The question would be to the agency, to the FDA, how many patients would we need to see safety, feasibility, and efficacy in for the potential to include it if the phase III study meets its primary endpoint for that BLA? Could we supplement the BLA at the time of filing to include this patient population in the label? If we were successful doing that would increase the market size by 30%.
Nice. Okay, great. Fingers crossed for that. How might this compare? I think you talked about it in the answer to my previous question, but I think we know the historic response rates to Keytruda. But how would these results you are seeing compare? It is probably pretty tough given the small numbers, but I will let you answer the question.
To Keytruda?
Yeah. It says, "How might this compare to the use of Keytruda alone?" That is the question.
Right. In the study, that Keytruda was approved in the frontline setting for Stage III-IV advanced metastatic, the response rate was 56%. For avelumab, it was 46%, and for the Incyte product that was recently approved, which is also a PD-L1 antagonist, about 50%. The consensus would be about 50% in a clinical trial setting. I think what the German registry group showed us in the community setting, in a much better population, now you are stage three, they showed 40%, where quite frankly, it should have been 60% or better in just the stage three group.
I think given that hurdle, the same way we looked at powering the phase III trial, could we take it to 70%? In this study, if we're really seeing 70% or 80% or even higher, then obviously that is why I made that comment about maybe it is a proxy that we would beat Keytruda by itself in the ongoing phase III study.
Got it. Okay. Lots of questions coming in. I hope you can stay till the bottom of the hour, Jim. The final question from Kumar is, what do you think the factors are driving the high response rate? How could it be maintained as more patients. That's a great question, because as more patients are enrolled in the trial, and that was going to be my question about how many more patients do you expect to enroll in the trial and by when? We can compound those two.
Yeah. Good question. The study was initially we kind of broke it into two stages. First stage was going to be the safety and feasibility in 9 - 12 patients. We have two other centers that are coming online this quarter. We believe we would have at least eight patients in the first quarter to look at. We want to get at least eight of the 10- 12, so to speak, for an ASCO submission, because, obviously, the submission's before the presentation in June. I think by mid-year, we would have all 12 patients at least out 12 weeks or longer. We would be able to look at durability of these early patients who have responded, as well as the overall response rate in those 10- 12 patients.
Okay, wonderful. We've got some questions from John Vandermosten from Zacks. Two questions. They're related. How might this compare to the use of Keytruda alone? He says, "I imagine that you are reviewing KEYNOTE-017 as a proxy for Keytruda performance alone for MCC." I think you commented about the response rates already. Is it a good resource to isolate the performance of IFx-2.0 from Keytruda?
I'll start with the last question first. John, thanks for the question. That was the FDA. If you look at the Project FrontRunner initiative, one of the benefits to the patient population is you're treating them earlier. But to the clinical community and to the FDA, you have to have a control arm. Keytruda's approved in a frontline standard of care for advanced or metastatic Merkel cell, where they had that 56% response rate.
I would say that the actual response rate outside of the first time a checkpoint inhibitor is used in that disease is probably around 50%, being conservative. Our current study is asking the question directly. It's the gold standard, as they say in the FrontRunner Initiative. A placebo-controlled trial of Keytruda and placebo versus Keytruda IFx will absolutely tell you the contribution of IFx to the response rate of Keytruda.
Yeah
With no equivocation. Again, we think that this is a good proxy because nobody's seen. Three out of three, four out of four coming from different institutions, there's a signal there. I've been doing this for 35 years in clinical oncology practice as well before. That's why it's encouraging. It's why we wanted to take kind of this first look and share it with the community in general.
Yeah. John has one more question that I was going to ask, which is an excellent question, which is: Is there any pharmacodynamic evidence in these patients of IFx-2.0's mechanism being engaged?
Those biomarker studies, translational studies are all done retrospectively because they get pooled. It is easier to do them as a group than to try to do them individually, both from time and expense bases. I think the published data in melanoma is absolutely correlative, as well as in the animal models, that you are in fact developing antibodies to a strep protein on the surface of a tumor cell, that you are in fact using TLR2 as the mechanism on your antigen-presenting cells to recognize that protein.
Then importantly, these patients make antibodies to hundreds of tumor antigens, so-called neoepitopes, that were not present previously in the patient before getting IFx. You are activating a tumor-specific immune response, an adaptive response from the innate activation of those T cells and B cells, and that it is durable and it is lasting because we see those antibodies persist at three weeks, et cetera, including against so-called viral oncoproteins, which was what was shown in the Merkel cell cohort.
I think mechanistically, the translation of what you would see, for example, in the melanoma mouse study, translated very well into the translational biomarkers, as well as the responses that were in that published manuscript, showing that you can overcome resistance in advanced treatment-refractory melanoma. Yes, I think we will see that in this study. I think the degree of anti-tumor response with bulky lesions, this is just metastatic disease. There is no better risk patients in this population. Seeing responses of this character that are durable in this many of the patients who have been treated, I think again, bodes well for what we are trying to do in the phase III trial.
Great. The last set of questions comes from Josh Werman, who is sitting in for Sylvan Turcan at Citizens. Do most patients have well-defined deep-seated lesions, and generally do they present with single large lesions, or do they generally present with multitude of lesions? Adjacent to that question is, do you see any abscopal effect or impact on lesions non-injected?
Yep. The first question is for these patients, they do not know they have Merkel cell. The doctor does not know it either. They will present maybe with jaundice because they have a big tumor in their liver, shortness of breath, or some other abnormality that brings them to a physician that takes a scan or gets an X-ray, and they see a large lesion. They biopsy it, and lo and behold, it is Merkel cell. This is typically called Merkel cell of unknown primary because you do not know where it started, but you know that it is everywhere, right? They all present with metastatic disease by definition, and typically in multiple sites. Just like you looked at the patients in the first four patients here, they all had multiple lesions, liver, lymph nodes, pelvic nodes, muscle, et cetera. That is the first aspect for presentation.
I think it was mentioned on the one slide that this patient's tumor started regressing outside of IFx in other lesions before they even got pembro. I think the fact that it is a little confounding in terms of abscopal because you are giving essentially a checkpoint inhibitor. I think if you looked at the phase I-B study that we did, if I inject your skin lesion and you start to see regression in large lesions in the abdomen and development of antibodies, right? You are having a systemic immune response. As I mentioned a while back, we think that you need a checkpoint inhibitor to amplify that response so that, in fact, you now have a much more robust anti-tumor effect.
Great. We appreciate everybody's questions. I have a couple more before we wrap it up. Jim, if the results continue to be encouraging, when would you plan meeting with the FDA, and what would the objective be for that meeting?
Right. I think if you have 10, having had the experience where we had an 85% molecular remission rate in high-risk patients with a type of leukemia called APL, the FDA did not need to see 100 patients in a randomized trial, right? Because from that type of response rate-
You would know about APL.
Acute promyelocytic leukemia. Yes, I would.
You would know a few things about that.
Yeah, we did 40 patients for approval. The question
Yeah
here is if you have a high response rate, what maybe the FDA would, of course, we'd ask the question, is there an accelerated approval path for a single arm study? How many more patients would we have to put in the 2023 trial to potentially address the sample size and duration and response rates that they'd want to see? I previously mentioned ideally getting it into the label, either initially if the phase III is positive or filing a supplement afterwards with regards to, those would be the discussions with the FDA.
It would likely happen in the second half of this year. We'd certainly want to have at least 24-week follow-up data on the patients that would, the first 10 or 12 patients, because that's the big hurdle that the FDA sets for what's considered a real response when you look at ORR definitions for approval, overall response rate definitions for approval.
I would imagine durability as well.
Correct. That six-month hurdle-
Yeah
is standardized in all FDA approval trials.
Speaking of that, it is a nice segue into the next question I was going to ask, which is about durability. What have you seen so far, and what kind of average duration do you think you are going to need? I guess the six months landmark is critical. Is that for accelerated approval or full approval?
For both. Well, full approval, you need to have a durable response, which by the FDA's definition, and by RECIST definition. So at 12 weeks, you have to show tumor shrinkage of 30% or greater in your so-called target lesions. They have to be there at 28 days later. That is the confirmed response.
Yeah.
The durability of the response is six months. If it is still, again, shrinking or still below the threshold that you need, that is considered a successful drug endpoint, if you will, for the patient. Accelerated approval will let you use ORR by itself. Full approval or regular approval typically would require a clinically meaningful endpoint, beneficial endpoint, such as PFS or OS. In our ongoing phase III study, if we hit ORR at six months, that we have a higher response rate than the control arm, that is submitted for accelerated approval. When PFS matures, that is submitted for full approval. If it is successful, that is how you flip. That is-
With the same data set, just to be clear, that's the same data set, correct?
Correct.
Yeah.
Right. That's the beauty of the Project FrontRunner initiative,
Yeah
because you have a randomized control study, you can do secondary endpoints without having to do another trial.
Do you take a statistical hit?
The way the study's designed, no, because in advance, you're predicting that you should have, and you can power it and show in the study. They call it a key secondary endpoint, and it is what's termed the hierarchical step-down, stepwise design, so that you preserve the alpha. If you hit the primary, then the 0.05 is then carried down to your secondary, so you don't have to split your alpha between the two endpoints.
Right. Very cool. Okay, and then you also mentioned about 30% of patients with metastatic MCC present with the deep-seated tumors are not accessible to standard methods for administering IFx. Maybe you can discuss the addressable market size for IFx, including if you were successful in having CT or ultrasound-guided administration included in the product label.
Sure. We said there were 3,800 patients annually that's supposed to grow to 5,400 by 2034, given all the published research on Merkel cell. That's just a U.S. number. 15%, and let's take 3,800, 15% of those patients were potentially curable. That wouldn't flow into an IFx label in terms of an indication. The initial label is about 2,000 patients, 55% of the 3,800 would be approximately the number of patients in an addressable market size. If we included the additional 30%, it would take your market from about 2,000 to about 3,140, right? So you're essentially capturing 85% on label of the patients that are eligible to be treated in an IFx therapeutic regimen with Pembro. It is a significant contributor. Importantly, shouldn't forget, it's frontline, and so this would be essentially the frontline standard of care.
Right.
It's not like you're in second line or third line. It's not like there's four other drugs approved in the same indication.
Right.
I think that is also important when one looks at adoption rates in oncology, and more importantly, uptake over time in terms of how much of that addressable market share you capture. And likely, it is much shorter in terms of early adopters and the ability to get 60% or 70% adoption relatively quickly.
Great. Okay. Just a couple of wrap-up questions before we go. Can you talk about I think people should understand what IFx-2.0 is. Talk about Emm55 and why this makes sense and why you think it works in this setting, and could it potentially work in others beyond Merkel cell?
Yeah. Good question. Thanks for bringing that up, Mike, because I did not touch on it. The primary-
That is what I am here for, Jim.
You always do a great job at it, too.
Oh, stop.
The primary reason that a patient doesn't respond right out of the gate to a checkpoint inhibitor is that their tumor doesn't look foreign. To have checkpoint inhibitors work, you have to have an activated T cell, i.e., an immune response against the tumor, so that you can checkpoint release the T cells to go amplify and seek out and destroy the tumor. The holy grail of trying to overcome that primary resistance is how do you make an immune response against a tumor when there isn't one present at the beginning? If you can do that, you can then amplify a checkpoint inhibitor's work. That aspect is agnostic to what type of tumor. If you don't respond with a checkpoint inhibitor in lung cancer or breast cancer or colorectal or Merkel cell, it's basically 80% of the time for the same biologic reason.
The goal in overcoming primary resistance is making the tumor look foreign to your immune system. What IFx does, it does it in a very exquisite way, in a way that your body has no choice. We're pre-wired, right? We're born with what's called an innate immune system, and our innate immune system protects us from viruses, any type of pathogen, and every pathogen has what's called a pathogen-associated molecular pattern or fingerprint.
Yeah.
We are pre-wired to see bacteria, right? So strep has a very specific fingerprint. It is called a motif. Our antigen-presenting cells that we are born with say, "Hey, I recognize that. That is a bacterium." These antigen-presenting cells essentially chew up what they think is the bacterium, and they process any of the proteins, any of the so-called foreign tumor antigens that are in that tumor cell, and present it to newly formed T cells and B cells. Now you have educated your adaptive immune system to what the tumor looks like, and your B cells will make antibodies against it, and your T cells will go out, seek it, and destroy it. Now you have an activated T cell with an activated checkpoint that you can release, i.e. now checkpoint inhibitors work. It is a very efficient way of doing it.
It is a way that your body, your immune system, your innate immune system cannot ignore, because that is your first line of defense against a pathogen like a bacterium. We are not doing anything manipulative except making your tumor look like a bacterium. So that strep protein gets expressed on the surface of the tumor cell, and that is what activates the response. We know that from the translational data, these patients will make antibodies against the strep protein, and they will make antibodies against all of these foreign tumor proteins that it did not see before. As we saw from the phase I-B, you can overcome that resistance. So I think mechanistically, this is a much more efficient way than doing it, and quite frankly, a natural way of doing it, if you will, in terms of leveraging the science and biology, than some of the other approaches.
Right. So is this effect, compound question again, is this effect more generalizable to other solid tumors? Maybe talk a little bit about why would you start with Merkel cell when you could get melanomas, that are much more easily accessible, instead of these deep-seated Merkel cell tumors.
Right. Good question. I think let us talk about melanoma. It is an immunologic disease, number one, and much more immune-sensitive than we will talk about Merkel cell in a minute. There are a lot of good therapies in frontline melanoma, in second-line melanoma, in third-line melanoma. From that perspective, there are many choices that physicians have in the frontline, second-line treatment of melanoma that work very well. They have changed the landscape. Melanoma was a death sentence.
Now, some patients are cured with curative intent and adjuvant checkpoint inhibitor therapy. So when we looked at the patient population, because we did do work in melanoma, and it looked, we had three out of four overcome primary resistance. In the third-line setting, you have BRAF/MEK inhibitors, you have checkpoint inhibitors, you have LAG-3, PD-L1, CTLA-4, and others that are coming in. We didn't see that same unmet medical need as the Merkel cell study, right?
Okay.
These patients, it's a polyoma viral-driven disease. It's increasing in incidence. If you fail frontline, there is nothing else. To be able to show that effect in that population, we thought that that clearly would address an unmet need, faster time to market, quite frankly, a larger addressable market size if we're successful. Lastly, if you think of the best place to have antigen presentation, it's always going to be in a cutaneous or superficial nodal setting, because you have the most rich macrophage dendritic cells environment.
So it was a good kind of test of principle. I think what we're seeing, quite frankly, in the IFx trial here is that you may not need to have that degree of so-called antigen presentation in a very large bulky tumor. You may, in fact, have many more cells that are being transfected, and you're expressing much more of the protein.
Right. Okay. In the interest of time, last question. Give us an update, if you would, on the phase III. You got an SPA in place when we launched in April. You're moving along nicely in the enrollment. I think our projection was late this year or early next year for complete enrollment. Are you still on track for that? Maybe just give us a quick update on when we can hear more about that.
Right. We changed that forecast based on the number of sites, the rate at which we were able to bring sites up. We initially were focusing on 25 sites. We have 22 of those up. We have another 21 that are in the process of coming online. The program currently is, and what we have provided guidance for, is that we will complete enrollment in the second half of next year, likely end of third quarter, early fourth quarter.
That is our current schedule. We have included Australia, so we are going to bring them online. If you look at essentially the patient contributions, Australia put about 15 patients on the development trial in a relatively short period of time. So, we are feeling much better about our ability to meet the timeline for next year. That is our current guidance, likely late third or early fourth quarter to complete enrollment.
Great. Yeah, no, that tracks. Absolutely tracks. Unfortunately, I was blabbering so much on my own agenda that I neglected to see that Sylvan Turcan had some follow-up questions, but we are limited on time, and I need to get back to the ESMO presentation. So I am going to wrap it up, but I would suggest that maybe Sylvan wants to follow up with Jim outside this call. Apologies for that. Or to, I guess it was Sylvan's junior. Anyway, we appreciate your time, Jim. Exciting story. People should stay tuned for upcoming events for TuHURA. It is going to be an exciting end of the year. If you have any questions, feel free to reach out to me, mking@rodm.com, and I would be happy to engage. Thanks so much, everybody. Have a good day.
Thanks, Michael. Appreciate it.
All right, take care. Thanks for having me.