Medicenna Therapeutics Corp Aktie

Good morning, everyone, and welcome to the Medicenna Company presentation and KOL webinar. [Operator Instructions] As a reminder, this event is being recorded, and a replay will be made available on the Medicenna website following the conclusion of the event.

I would now like to turn the call over to Dr. Fahar Merchant, President and Chief Executive Officer of Medicenna. Please go ahead.

Thank you very much, Tara, and welcome to all of you who are joining us today at this KOL event.

Before I proceed, let me mention that really important for us as a company to thank all the families, the patients, the clinical centers, sites that have participated in the clinical trial and their valuable contributions to the ABILITY-1 clinical data that we will share with you today.

So as part of this presentation, I just want to mention that we will be making forward-looking statements and therefore, encourage you to review our regulatory filings on SEDAR.

Joining us today, and I think really important for us as a company to have the privilege of having the participation of two outstanding investigators, key opinion leaders in the field of cancer immunotherapy. First and foremost, we have Dr. Hussein Tawbi, who is a prominent international physician scientist in the immuno-oncology space. At the moment, he is the Executive Director of Immuno-Oncology Clinical Drug Development Program at the Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas, perhaps the world's best cancer research center. Really privileged to have him. He is a recipient of several awards, has been part of numerous breakthrough therapies that have become now standards of care for different immune therapies.

Also joining us is a young rising star from Portugal, Lisbon, Dr. Andre Mansinho, who is a principal investigator for the ABILITY study and has enrolled several patients in this clinical trial. He is the Director of Clinical Research at START Center for Cancer Care at the University of Lisbon. And then finally, myself, President and CEO of Medicenna.

So today's agenda, I'll provide an introduction and a brief overview about MDNA11 and why we think it is such a differentiated molecule compared to the IL-2s that have been in development for the past 3 decades. And then I'll pass it on to Dr. Hussein Tawbi, who will focus on unmet needs in immunotherapy and the potential role of MDNA11 to address those challenges. After that, Dr. Mansinho will present the Phase I/II ABILITY study data and the clinical design and protocol and of course, the data resulting from this particular study. And going back to Dr. Tawbi, he will provide us his contextualization, understanding of the data and what the potential future direction might be for MDNA11. I will then conclude, and we'll open the floor up for Q&A.

So as a company, Medicenna has really focused on building interleukins, very specifically interleukin-2, interleukin-4 and interleukin-13. These have been engineered using directed evolution, and they come from the lab of Professor Garcia at Stanford University.

These naked Superkines that we have licensed from Stanford have been brought into Medicenna. And since then, we have sort of dressed them up to generate what we call long-acting Superkines, so that they can stay in the bloodstream much longer.

We've also dressed them up by creating bifunctional Superkines and also mask them so that we are able to switch these Superkines right at the tumor site. We won't talk about BiSKITs or the T-MASK platform today, but we'll focus on the long-acting IL-2 super agonist.

So if you look at our platform right now, as you can see, around the IL-2 Superkine, we've got 3 assets. The one that's the most advanced asset is MDNA11. And today, we'll be focused on MDNA11 and particularly the ABILITY-1 study, where it is examining the potential for MDNA11 in a single-agent monotherapy setting and then also in combination with Merck's KEYTRUDA. And here, I would like to acknowledge Merck for their generous contribution and clinical collaboration. And of course, the supply of KEYTRUDA that has been used to dose hundreds of doses to patients in this ABILITY-1 clinical trial.

Separately, we have an MDNA11 super agonist study underway in neoadjuvant melanoma patients. This has been conducted by Dr. Paolo Ascierto and 12 other centers in Italy, and it's funded by the Fondazione Melanoma. And using the IL-2, that is the key component in MDNA11, we have now recently created a bifunctional anti-PD-1 IL-2 using the same IL-2 that's currently in MDNA11, and that program is currently in preclinical studies with the intent of entering clinical trials next year.

And then finally, using the same IL-2 as in MDNA11, we have recreated a IL-2 super antagonist using the IL-2 super agonist as the backbone. So the intent there being to really block IL-2/IL-15 signaling so that we can address patients that need treatment for autoimmune disease.

So today, I think the key message is why are we developing an IL-2, which is not alpha, but beta enhanced. And I think we are all aware of the challenges with IL-2 over the past 3 decades since its first approval in the 1990s. And we believe that the challenges have been addressed to many extent with the design of MDNA11.

So I'm hoping that at the end of today's session, we will be able to restore conviction in the immense potential of a properly designed IL-2 in cancer immunotherapy as was intended by the first developers of IL-2.

So what is different about MDNA11? And as I said, our molecule is beta enhanced and it's not alpha binding. And it is, as you can see from the picture or the cartoon on the left, it comprises an engineered IL-2 where we have inserted mutations to avoid binding to the alpha domain on T cells and therefore, reduce vascular leak, reduce immune suppression, but enhance the safety of this drug, which has been a huge problem in the past.

Second, to compensate for loss in alpha binding, we have enhanced beta binding. And the purpose there is to increase activation of the immune cancer fighting T cells, improve their memory and, of course, prevent exhaustion of natural killer cells.

Finally, we have linked the IL-2 to human albumin. And the purpose there is to not only improve the pharmacokinetics of the drug, but also to accumulate the drug in the tumor and the tumor draining lymph nodes. So overall, what we have done is created novel pharmacology with this engineered IL-2 with MDNA11.

So as you can see on the left-hand side or rather the right-hand side, native IL-2 will bind to the alpha domain, not as tightly to the beta gamma receptor, which is expressed by the cancer-fighting immune cells. And therefore, the challenges that you see is that it will invariably cause safety issues, but also immune suppression.

With MDNA11, we have reversed it, so we don't bind to the alpha domain, but instead bind with exceptionally high affinity to the beta gamma receptor and therefore, are able to secure durable antitumor response, as you will see in today's presentation.

So if you look at IL-2, the one that was originally developed some 30 years ago, on the top left, you can see that the IL-2 will bind with extremely high affinity to the alpha receptor or CD25. On the bottom, what you see is the same IL-2 binding with relatively weak affinity to the beta domain. So in essence, the native IL-2 tends to bind tightly to alpha, but not to beta.

And over the years, what has happened is to in order to generate a safer version of an IL-2, various companies have attempted to reduce binding or block binding to the alpha domain. In the end, what happens is you get the binding of an IL-2, as you see on the top right, but very weak binding to the beta receptor.

What we've done is change that paradigm completely so that we now have enhanced binding to the beta receptor and that, therefore, makes it a beta biased and beta enhanced binding with no alpha binding.

So in addition to changing the binding affinity, what we have been able to do is reduce alpha binding. And therefore, as you can see on the left of this particular slide, that the signaling is dramatically altered when you make that change on native IL-2. So when you remove the alpha binding capacity of native IL-2, which is what a lot of other companies have done, is you can see the curve shifting to the right and in that case, showing that the drug is becoming less active in stimulating cancer-fighting immune cells.

On the right plot, on the other hand, what you see is MDNA109 or H9, it was as published. With removing alpha binding, you are able to maintain the tight signaling, binding and therefore, activity of the drug without sacrificing the activity. So basically, what we are doing is bypassing the need for alpha binding and therefore, stimulating CD25-positive activated CD8 T cells without the need for alpha binding.

So when we look at the very first big failure in the IL-2 space, particularly BEMPEG as a good example here, which contained native IL-2 with PEGylation, so that the PEGs that were 6 of those PEGs would gradually be released. And from the Phase III study that failed, basically showing that the Treg population, as you can see on the left of this plot, substantially increases in population, whereas that of CD8, NK cells, et cetera, remained relatively modest. And not surprisingly, therefore, what you did see with this combination of BEMPEG with nivo was simply that the combination of BEMPEG and nivo was worse than nivo on its own. So then there were attempts to really avoid this linkers or PEGs from coming off. And therefore, there were better designs to really permanently block alpha binding, which was not the case with BEMPEG.

So what you see is, as an example, nemvaleukin essentially did that. They limited alpha binding very efficiently unlike BEMPEG, but did not do anything to enhance beta binding. And therefore, what you see on the plot at the bottom from the human clinical studies is that you do achieve those red boxes or squares on the plot are showing that your Tregs are not expanding, which is perfect. However, you're seeing more of an expansion of your NK cells, but not of your CD8 T cells. And therefore, in the end, 2 phase registration trials for melanoma and ovarian cancer, both of them failed due to poor activity of this particular version of IL-2.

So non-alpha without beta enhancement was not only a failed program with Mural or Alkermes, but similar attempts were made with Xilio, with Synthorx, Cue, et cetera, where similarly, the programs could not progress because of lack of single-agent activity.

We, on the other hand, with a beta enhanced design, as you can see on the figure on the left, the Treg activity is substantially diminished. We do see expansion of NK cells, but what we do see is substantially greater boost of the cancer-fighting effector CD8 T cells than those of NK. And with this flip that you see the switch over, we've been able to demonstrate compelling single-agent activity in a checkpoint refractory setting.

So with this, we've been able to overcome the need for alpha binding. And as you can see, not only did we increase the number of CD8 T cells, but we are substantially expanding the population of high-quality cancer-fighting immune cells, including CD8 CD25-positive activated CD8 T cells.

So what you see on the left is data from 40 patients, and we've seen significant expansion of CD25+ TCF or stem-like CD8 T cells, et cetera, including memory cells, et cetera.

So moving on to essentially what others have shown, not Medicenna, but this is independent labs, clearly showing that beta enhanced IL-2 does provide much better outcomes, including more recently on the top left, work done at BioNTech to show that an IL-2, which has beta enhanced is much better when combining with mRNA cancer vaccines.

So with that, I'll pass it on to Dr. Tawbi and his discussion on how MDNA11 could play a role in cancer immunotherapy. Dr. Tawbi?

Thank you so much, Fahar, and thank you for the very kind introduction you gave about me. But I'll actually take a minute here to share with the group why I'm so excited about this particular IL-2 agent. And as you heard from Fahar, this is showing activity in places that we really hope IL-2 will be able to kind of really make a huge impact.

So I'll share a couple of things. I've been personally in melanoma drug development and IO drug development since 2005. And so have really witnessed the power of interleukin-2 and we'll kind of discuss that in a little more detail. When I started treating melanoma patients, it was the only thing that could cure patients. And so we know that that's an FDA-approved approach and a powerful one.

The second thing I'll say is I've been involved very much in kind of FDA approvals. I've been an FDA reviewer for multiple drugs that got FDA approved and have personally filed FDA kind of applications for drugs that became FDA approved and more importantly, in the last few -- even months have been on the advisory committee for the Replimune RP1 agent that got FDA approved.

So I think in a lot of ways, really thinking about how we can position this agent with the great activity that's showing to be on that path, I think, is what we're here to discuss today. And so we're going to talk briefly about the fact that the unmet need is quite great and the specific places where this has already shown activity are really quite relevant and immediately actionable.

So we think about MSI-high tumors or MSS TMB-high tumors. And a lot of people say, well, single-agent checkpoint inhibitors have activity there. And is this a space that we could really make an impact? And the truth is it's really remarkable that these cancers because of the high tumor mutational burden, because of the presence of so many mutations do end up responding nicely to checkpoint inhibitors. But as I told you, I've been in melanoma for 20 years, that's a disease that has a very high tumor mutational burden and a lot of our patients don't respond. So already, we're very impressed with the fact that checkpoint inhibitors work in ICI-naive settings, but there are actually quite significant caveats.

One is the fact that if those cancers and a lot of them are GI, as you see here, if they have liver metastases, suddenly that activity drops dramatically. So as you see on the left lower corner, that while you report high response rates in these patient populations, as soon as you include liver metastases, we know that's a place that's quite resistant to checkpoint inhibitors, so that response rates drop even in the naive population.

More importantly, we see that patients progress after being -- after responding. This is the secondary resistance to checkpoint inhibitors. And once that happens, the response rates drop also to the 10% to 12% range, which is almost identical to what you get from a random Phase I trial. So really kind of a place that needs improvement.

And so if you kind of contextualize that for metastatic MSI-high GI tumors specifically, there's about 25% that will have primary resistance and then patients that do respond can still progress up to 44%. So you're talking about 3/4 of those patients that will need additional therapy and additional treatment. And as you see on the right side, as soon as you include liver metastases, those numbers become even more daunting.

So as I mentioned, in the presence of liver metastases, the chance of -- or the odds of having a primary resistant disease more than double. And if you've received 1 prior line of therapy, again, the chance of secondary resistance is almost close to double as well. And so this is where this study and this ABILITY-1, that you'll hear from Andre a little later, and specifically MDNA11, not only has included those patients, but actually has shown activity both as a single agent as a combination regimen in those specific diseases.

So on the one hand, I think the unmet need is a very big opportunity, which I'll talk about in a minute. We do need kind of to see the disease control, and you see that monotherapy has 35% to 45% response rate either as a monotherapy or combination. And importantly, that ability to have a response in liver metastases, which almost all of those patients that have liver metastases, a lot of drugs fail exactly at doing that. And I think that really highlights the biological impact of MDNA11.

So the second thing I really wanted to highlight is I really strongly believe in the accelerated approval path and the FDA has kind of persisted in making this available when you actually go for a population that has a high unmet need, you show activity. And you can sometimes with a single-arm trial, really get through to a registration path. And I'm showing here specifically this population we're discussing the MSI-high or TMB-high, where we now know it's a tumor-agnostic approval for several of the checkpoint inhibitors. And this actually offers an opportunity.

The FDA is really very excited about being able to approve things that are tumor-agnostic, especially if biomarker-driven. And I think this idea that you could check the TMB, the MSI and determine that those patients would be appropriate and then you have a drug that has activity both as a single agent combination, I think, really improves the chances of this kind of following that accelerated approval path.

The second thing I want to -- the third thing I want to discuss is melanoma, right? So I've been dealing with melanoma for almost 2 decades. And I can tell you that's a tumor with a high tumor mutational burden, but not every patient responds. And most of it, as you will hear a little bit from the data that Andre will show, it's not about having mutations. It's also very significantly about the tumor suppressive microenvironment and about antigen presentation. And those things, if you could really enhance them with MDNA11, you could utilize the fact that those mutations exist to ignite an immune response.

So in melanoma, we know that half of our patients progress in the first line as a primary resistance and then there's still about half of those that respond that could still progress. And so in that space, there are only 2 currently FDA-approved regimens, AMTAGVI, the TIL therapy and RP1.

So AMTAGVI, TIL therapy is a really, really tough thing to do, highly select population. There's only so many patients you could treat. They have to have stable disease, not very progressive, highly progressive disease. And the response rates are actually somewhat disappointing. So important, FDA approved -- by the way, 130 patients to get the accelerated approval, right? But also a regimen that's not applicable to most of our patients.

RP1, again, I was part of the advisory committee that convinced the FDA to approve this regimen. I think it's going to be helpful to patients, but it's also limited in its activity. It's injectable, so it requires a procedure to be done. And you will see that its activity is helpful but relatively limited. And I think that's what places MDNA11. It's already something we know in melanoma. It was the only thing that cured patients. You can administrate it intravenously and basically will be available to a large proportion of patients, especially as you'll hear the safety profile allows it to be applicable across the board.

When we're comparing some of the data you'll see from Andre to what's been already published from the IGNITE trial, we want you to take a close look at the patient characteristics. And you will see that this ABILITY-1 really went after some of the toughest patients. And all of them Stage IV, liver metastases up to 30% and 77% had already seen prior PD-1 and CTLA-4, PD-1/LAG-3. And that's, I think, very important to contextualize the results.

So when you place what you're going to see in the context of what's approved in melanoma, you will see that AMTAGVI and ipi/nivo, RP1, it's all about 30%, but each of them come with a very select population -- and again, patients that are not progressing very rapidly, 24% for RP1. And we have with monotherapy in a secondary resistance cohort, you could have a 30% response up to 40% with combinations. And remember, this is a population that if you compare across trials, it's a population that's a lot tougher than even what was included in those.

So I'll end with the fact that I really do believe that this beta binding has really kind of highlighted the specific role of IL-2. And I think the impact on the tumor microenvironment is going to be relevant for both secondary resistance populations and primary resistance populations, specifically in the fact that it's not enough to have the tumor antigens or neoantigens from mutations, but also to be able to impact the immune microenvironment, to be able to allow more antigen presentation and kind of to reverse exhaustion that already exists.

So you see from kind of these preclinical trials, the impact of interleukin-2 and the fact that it's so much more decreased in patients that have already been progressing. And then if you add MDNA11, and this is kind of a couple of some of the data that you're going to see, you increase exactly that effector cell population and you exert immune control.

So from my perspective, as you are going to see shortly, the -- both the biological impact, the clinical context, and now the clinical activity from ABILITY-1 really positions this agent to be the success we've been really waiting for in the IL-2 space.

So with that, I'm going to turn it over to Dr. Mansinho, so that he can share with you the data from ABILITY-1.

Thank you, Hussein. Thank you, Fahar, for the also kind introduction. Good morning, good afternoon to everyone. So building on the biological rationale Fahar just shared and this post-ICI clinical gap Hussein just highlighted and being that we're a Phase I unit, I'm delighted to walk you through the clinical data of the ABILITY-1 study of MDNA11 and try to show you why we're so excited with these results.

So this slide shows our study design. ABILITY-1 evaluated MDNA11 across 2 parallel arms, so monotherapy on the left and combination with pembro 400 mgs every 6 weeks on the right. And in dose escalation, we reached 120 mgs -- micrograms per kg. This was done every 2 to 3 weeks without hitting a maximum tolerated dose. And this defined our biologically effective dose range at 60 to 120 micrograms per kg. And ultimately, we selected 90 micrograms per kg every 2 weeks as our recommended expansion dose for both arms. And this is due that we didn't see an increase in the expansion of the T cell population or the target population that we were assessing on that particular dose increase.

Additionally, I can tell you that my personal experience and by having treated some patients here, 120 micrograms tends to be not as tolerable as the 90 micrograms. So this seems like a rational approach.

And notice our expansion cohort. So monotherapy focuses on secondary ICI-resistant melanoma and MSI-high dMMR or TMB-H tumors, while the combination tackles primary ICI-resistant melanoma, MSI-high or tumor mutational burden high tumors as well and secondary ICI-resistant MSS endometrial cancer.

So out of the 152 enrolled patients -- and this data cutoff was done on October 28 -- we have 118 patients that are efficacy evaluable within the biological effective dose range, 53 on monotherapy, 65 on combination. And within this population, our core efficacy cohorts comprise approximately 36 patients with MSI-high or TMB-high tumors, 26 with cutaneous melanoma and 9 with microsatellite stable endometrial cancer.

Note that the TMB-high is strictly defined here as per the last FDA definition, so microsatellite stable tumors with TMB over 13 mutations per megabase. So the MSI-high and TMB-high groups are mutually exclusive, and this is an important note.

So this slide summarizes safety across these monotherapy and combination patients. Unlike first and second-generation IL-2s, as Fahar mentioned, MDNA11 has a remarkably clean, I would say predictable as well, outpatient profile. This is important. We saw 0 DLTs, so no dose-limiting toxicities through the 120 micrograms per kg, 0 Grade 5 events and over 90% of treatment-related adverse events are either Grade 1 or Grade 2, mostly transient infusion reactions, pyrexia, chills, nausea that resolve, and within my clinical experience, I would say, after the first 48 hours.

Grade 3 or Grade 4 events, and this is important to notice, are predominantly asymptomatic, so essentially reversible liver enzyme elevations. No hair loss, which is important with only a single transient Grade 4 CRS in a patient, which already had baseline hypotension. I think that's notable. That resolved also quick in 4 days. And I would say that adding pembrolizumab introduces no relevant safety signals.

Now let's look first at the MSI-high and MSS TMB-high gastrointestinal cancers. And this slide, I think, is particularly important because it highlights just how heavily pretreated our 20 evaluable GI patients are. First, this is a true third-line, fourth-line salvage population. So we see that we had a median of 3 prior systemic lines, up to 10. 45% having received 4 or more prior regimens and 65% having progressed on prior checkpoint blockade. And this includes 82% on the monotherapy cohorts. So this is very important to establish the baseline characteristics. Second, as you can see here as well, baseline tumor burden is relatively high with a median sum of diameters of 75.5%, 85% on the monotherapy. And third, as Hussein highlighted, 35% of our patients entered with active liver metastases. So we know that this is a major driver of immunotherapy resistance, and we'll see further on ahead why this is important for these patients.

So across all 36 evaluable MSI-high, TMB-high solid tumors, we can observe a 28% of overall response rate, so almost 1/3. Most importantly, 78% disease control rates across 6 tumor types. But if you focus and look at the coral bars here, which represent GI tumors versus the blue non-GI bars, we see that responses are heavily enriched in the GI subset, where we achieved a 40% overall response rate, so 8 out of 20 patients and an 80% disease control rate.

So if we zoom in into those 20 GI patients that we presented on the last slide, and if we take into account what just Hussein just presented, historical post-ICI rechallenge or salvage chemotherapy yields an average of 11% to 13%. So let's focus on the 10% number here. And we see that MDNA11 monotherapy achieves a 36% overall response rate with a very good disease control rate as well, while MDNA11 plus pembro achieves a 44% overall response rate.

So if you look at the waterfall plot as well, 55% of the patients achieved tumor regression. And as you can see here, as shown by the gray boxes along the bottom, these responses are occurring directly in ICI refractory patients, which are pancreatic, biliary, colorectal cancers, alongside -- and this is very important on the palliative setting -- durable, stable disease that exceeds almost 50 weeks. So this is really important when we look at the palliative setting.

Now I think slide -- this slide here captures what matters most in second or third line plus GI oncology patients, which I think is duration of response. I know in late-line disease, if we tend to compare this with chemotherapy, for instance, we know that brief chemotherapy shrinkage rarely alters survival.

So what patients need in this setting is durable immune memory, vaccine-like memory. As you can see here, median duration of response is not yet reached. So this is greater than 32 weeks with responses ongoing.

And if you look at the top 2 bars, our first MSI-high pancreatic cancer patients on monotherapy stopped treatment after 91 weeks, which remains in complete remission. So treatment-free remission for 138 weeks. This is actually a very long time mark for a pancreatic cancer patient. And right below that, we see a TMB-high CRC patient in combination that continues to experience response deepening of treatment with a duration of response that exceeds 78 weeks right now.

So let's see the scans for that top swimmer plot patients. So Stage IV MSI-high pancreatic cancer, liver mets, very important, who failed 3 prior lines. So every treating oncologists know that this is a very bad prognostic patient. And we had a very rapid primary progression on pembrolizumab. So 6 weeks after failing pembrolizumab, single-agent MDNA11 drove 100% complete progression of both liver target lesions, as we can see here, leading to that ongoing treatment-free remission that we saw in the swimmer plot. So really remarkable patient and a very good case, of course.

And this slide shows a second monotherapy hepatic responder. So as we can see here, Stage IV MSI-high as well, cholangiocarcinoma, nearly 12 centimeters of baseline tumor burden, primary progressor as well, first-line gem, cis and durvalumab. And on third-line MDNA11 monotherapy, this large liver lesion shrank significantly. So this is a confirmed PR with an approximately 47% target lesion reduction that remains ongoing last 24 weeks.

The third case, and this is an MSS CRC, we can see here TMB-high patient, Stage IV colorectal cancer, importantly, MSS patients treated in the sixth-line setting after failing 5 prior regimens, including -- this is important -- primary resistant to pembrolizumab without a single prior objective response. So if we see at the tumor growth index and previous line responses, this is very remarkable. And with MDNA11 plus pembrolizumab, it achieved a confirmed PR, 84% target lesion reduction and complete reduction of nontarget lesions. So this duration of response already exceeds 32 weeks, and this is really remarkable on this clinical setting of MSS colorectal cancer.

Now just to note why it is important to take into account that RECIST might not always apply to these patients. I think this is important because some patients might derive clinical benefit even after classical immunotherapy progression.

So this slide illustrates what we call the classic immunotherapy pseudoprogression. This was on MDNA11 monotherapy. And in a chemotherapy-resistant MSI-high pancreatic cancer, what we see here is that at week 8, initial immune infiltration caused a significant, I would say, almost 1/3 -- 35% enlargement in a new liver lesion. And -- but because the patient was clinically well, he had no, of course, options beside this clinical trial, treatment continued. And by week 16, we can see the new liver lesion vanished and the target liver lesions shrank by 35%. So this is what we call an immune PR, and this is really notable. But most importantly, and in line with what Hussein said, we should pause on a moment to see this. I think this is one of the most remarkable charts in our data set.

We know that liver metastases are notoriously immunologically cold, nearly double the risk of primary ICI resistance in GI cancers, yet across all 4 out of 4 evaluable patients here, MSI-high GI patients treated with MDNA11, 8 out of 8 hepatic target lesions. So in these 4 patients, they all regressed. And we have 100% clearance of 4 liver lesions across 2 patients. So I think this level of single-agent hepatic activity is truly differentiated. And so a very important information to highlight.

Now briefly on this slide and outside of GI tumors, that's showing a very aggressive, I would say, PD-L1-negative TMB-high small cell neuroendocrine bladder cancer with a massive tumor burden, 16.2 centimeters of tumor burden after 3 prior chemo lines, so heavily pretreated. And rolling over from monotherapy to MDNA11 plus pembro, we can see that this pelvic mass shrank by 89% to 1.8 centimeters. And I would say this is a complete metabolic response in a PET scan, duration of response also very large. And again, it's very unlikely that the mass like this achieved CR on a CT scan because there is residual fibrosis. So this is something that we see metabolically in the PET more concretely.

Now turning to checkpoint resistant Stage IV cutaneous melanoma. I would say -- and remember how advanced this cohort is, I presented this data previously, 100% Stage IV disease, 92% M1b-D and 77% prior PD-1. So this is patients that failed ipi/nivo. And even here, MDNA11 monotherapy achieved a 30% overall response rate, a very high disease control rate as well, which I would highlight again, it's the more important endpoint when we look at the palliative second, third-line setting, while MDNA11 plus pembro achieved an almost 40% overall response rate in the primary ICI resistance. So after a 90-week -- 98-week complete response on monotherapy, 32 weeks of therapy, we see the patients.

So let's see our swimmer plot in similar way to what we showed in the GI tumors. This underscores that durability is also a theme here. So across all 26 melanoma patients, the median duration of response is an impressive 68 weeks. The range is quite large, but we have 3 responses ongoing. And beyond our top patient, who responded upon monotherapy retreatment, notice the second patient also achieved a very deep response after an initial radiographic progression. So this is truly remarkable. And we'll show some cases as well with some liver lesions to highlight the activity of this drug.

So we can see here that our hepatic activity extends directly to visceral melanoma as well. The Stage IV M1c melanoma patient with primary progression after just 1 month of ipi/nivo on second-line MDNA11 plus pembro achieved a complete PR, 55% overall with their liver metastases also shrinking.

On the next slide, we see another primary ipi/nivo-resistant melanoma patient also with massive lymphatic involvement, a very large 16 centimeter liver mass surging transaminitis. So LDH around 600 units per liter. We know -- and Hussein has a lot of experience treating melanoma patients -- this is a very bad prognostic patients. And within 8 weeks of treatment, we see that this mass shrank dramatically to 13 centimeters. And remarkably, I think the patient clinically improved, and we see that all the biologically laboratory values, AST, ALT, LDH, PCR normalized to the upper limit of normal within 50 to 70 days. So this rapidly rescued liver function in a patient that otherwise was very compromised.

Now let's just focus here on the MSS microsatellite stable endometrial cancer. And we see that among 11 enrolled patients treated with MDNA11 plus pembro, the median prior therapy was 3 lines. We see that 100% that progressed on prior ICI and 82% at secondary ICI resistance. So we did not exclude also aggressive histologies. So we have aggressive serous carcinosarcoma subtypes. And crucially, we saw deep regressions, including a complete target lesion clearance in a patient who already had failed len/pembro.

And focusing, I know this is, of course, less patients at the other cohorts, but the other plots show that across all 9 evaluable patients, the confirmed overall response rate is 22%. And even in the secondary ICI resistant disease, MDNA11 plus pembro achieved an almost 1/3 of confirmed overall response rates with a very high disease control rate of 71%.

So as Hussein will highlight next, I'm sure, I think 29% confirmed overall response rate in the post-ICI setting in these patients matches the 30% benchmark of len/pembro with vastly better tolerability. I would highlight that doing len/pembro is quite challenging. So I would say that given the toxicity profile that I know for this patient is remarkably tolerable.

So this Slide 54 confirms that these responses and disease stabilization are durable across high-risk histologies like uterine carcinosarcoma and serous carcinoma extending from 24 to nearly 60 weeks on the study.

And I would end my part of the presentation by saying that we have a manageable safety and selective pharmacodynamics. The MDNA11 is well-tolerated even through the 100 micrograms per kg with no DLTs and robust expansion of memory and stem-like TCF-1+ CD8+ T cells.

On MSI-high dMMR or TMB-high GI cancers, we have a 40% combined overall response rate, more than tripling the 11% to 13% post-ICI benchmark with a very -- and this is very important, median duration of response that was not reached. So multiyear treatment-free remissions. And I believe this is also something to highlight, we have unprecedented hepatic activity. So 8 out of 8 measurable liver target lesions regressed across 4 monotherapy patients with deep hepatic regressions.

And I would say that in the ICI refractory melanoma setting, 30% monotherapy overall response rate and almost 40% in combination in primary resistance with a 68-week median duration of response is quite remarkable. As well, as I just showed in the last cohort, a 30% confirmed overall response rate with a 70% disease control rate in secondary ICI-resistant disease is also remarkable.

Now I will hand the floor back to Dr. Hussein to put this data into the registrational context. Thank you.

Thank you so much, Andre. We do want to give you some time for questions. So I'll be very, very brief. I think I made the case before that this is -- I mean what you're seeing really is a validated target in the context of IL-2 itself for several decades, we know that this can cure patients. The beta specificity is allowing this activity in the hardest cohorts and you see patients with -- you've seen the liver metastases specifically for both MSI-high refractory patients and TMB-high refractory patients. If you place this in the context of currently available therapies, they're all in the 10% range or so, and we see both single-agent activity and combination activity to the tune of 40%.

I placed this in the context of melanoma, 30% in secondary resistance and 40 -- or close to 40% in primary resistance in a population that is even significantly harder to treat than the RP1 cohort that showed a 24% response and got FDA approved. And maybe what's really shocking to me in a way being an IL-2 person as well is the fact that the tolerability of this beta specificity is allowing every 2-week intravenous dosing at a high enough dose that we know biologically active.

We didn't have time to show you some of the translational work. And it is actually better tolerated than things like pembro/lenvatinib. I treat patients with pembro/lenvatinib for some of our brain metastases studies. And it's a very tough regimen, FDA approved in endometrial. And this comparison where you're actually showing a combination of an IL-2 with a PD-1 is, in fact, more tolerable than this combination that's FDA approved.

So with that, I'll just turn it back to Fahar and happy to help answer any of your questions as well. But I think really the opportunity is really quite remarkable at this moment.

Fahar, you're on mute, I believe.

I'm on mute. Well, thank you very much, Hussein and Andre, for your thoughtful comments and really detailed presentation. I will not go through the key takeaways. I think you've all done a really good job in sort of messaging that story. But I think going forward, as far as the company is concerned, with the next steps, clearly, we have all the patients being followed. We have another 15 or 14 patients without a scan.

So we'll be looking to solidify the durability of MDNA11 in each of the 3 expansion cohorts. And with those data, we plan to have an end of Phase I meeting with the FDA and see if there is a path forward for MSI-high or biomarker-driven GI tumors and even advanced cutaneous melanoma and perhaps even the endometrial cancer population that the data seems to mature. But clearly, we think there is opportunity here to pursue accelerated approval.

We are currently conducting a neoadjuvant study in cutaneous melanoma. We'll have more data on that. And we think the potential is here not only to see if MDNA11 can be used in combination with checkpoints, but perhaps other treatment modalities and also see if there is potential for us to partner with pharma to further advance this program.

So in the end, I hope that today's presentation provided us with a sort of a restore conviction with respect to the potential or immense potential of a properly designed IL-2 in cancer immunotherapy.

With that, I will pass the floor on to -- for Q&A to the audience. Thank you.

[Operator Instructions] So our first question comes from David Martin at Bloom Burton.

The first one is for the KOLs. As the analyses focused on specific tumor types and mono and combo therapies, and was relatively small for each group. In your view, are there enough patients in some of these groups to have strong conviction that ORRs will hold up in larger trials and that MDNA11 is competitively active?

I'll handle that. Yes. Thank you, David. I mean, I think the points we were making are kind of the fact that there are several shots on target. One is that you could go tumor-agnostic biomarker based with the TMB-high secondary resistance and also in combination with the primary resistance. So that in itself is one path. And then you could actually differentiate into tumor-specific paths with melanoma, for instance, widely open for a registrational approach, again, showing kind of the context of RP1 as it stands. And I think the MSS endometrial as well is quite impressive.

And I will say that from an FDA perspective, in my opinion, the tumor-agnostic biomarker-driven path is something that is probably going to be the most palatable because it has also that monotherapy activity. So you prove single-agent activity, you have combination activity and you can be tumor-agnostic and biomarker-driven. So those are kind of all the check boxes that the FDA needs generally.

So that would be my perspective. Remember, some of the accelerated approvals happened with 130, 140 patients. So we're not that far if we make a specific push in those spaces.

Okay. I do have one for the company, and then I'll get back in the queue. Last week, Merck abandoned Sutro partnered IL-2 drug. Has there been any changes or anticipated changes to your supply agreement with Merck?

Thank you, David. No, there has been no changes with respect to our collaboration with Merck. Their support continues, and we recently acquired additional supply from them as well. So that's certainly not affected our program.

Our next question comes from Andre Uddin at Research Capital.

I just have a simple question. The data for the 20 heavily pretreated patients with gastrointestinal cancers look very promising. And based on that data, do you think it would be worthy to explore the combination of MDNA11 and KEYTRUDA in the first- and second-line treatment setting?

Andre?

Okay. I can take that question. I would say that the benchmark is rather high in first-line MSI-high tumors. If you look at the colorectal cancer data, we see the high response rates and duration of treatment. So I don't know if MDNA11 in the first-line setting would have that meaningful responses.

Now in the ICI refractory setting, I'm very positive that it will -- I mean, we tripled the overall response rate. But even more importantly, the duration of response is quite remarkable. And we need to take into account this is heavily pretreated, highly refractory and the majority of the patients did not have the ICI previously.

So if you look at that data, we can reverse secondary resistance. And even in PDAC, for instance, we saw remarkable responses. So on GI cancers and moving forward to an agnostic approach, I would favor the refractory setting rather than the primary first-line setting.

Our next question comes from Dev Prasad at Lucid Capital Markets.

Congrats on the progress. I have a couple of questions. One is, so the presentation showed 40% ORR in GI cancer versus 12.5% in non-GI. Do you believe there is a biological rationale for greater sensitivity in GI versus other? Or is it too early to conclude?

And then in general, like -- to Dr. Tawbi, maybe. Given the landscape in post-ICI, including TIL and RPI, how do you view MDNA11 efficacy and safety profile? And what level of ORR and durability would make a competitive treatment option?

Yes. Thank you, Dev. I mean, I think the couple of things you have to take into account is really the biology that we're targeting. And so to answer the first kind of question you were specifically highlighting, I do think it's about being able to decrease the -- to improve the CD8+ T cell infiltration.

I think we need to improve antigen presentation because those are tumors that already have a lot of neoantigens, but they may not be able to do as much antigen presentation. So the impact on NK cells is going to be very important. And so in that context, I see the responses in GI malignancies that are TMB-high or MSI-high are going to be very clinically relevant. So that's the first question.

The second question around melanoma. I actually think there's a tremendous opportunity in the second-line melanoma. Cellular therapies are, by definition, only appropriate for a select population. I can tell you, at MD Anderson, we see over 1,000 new melanoma patients a year, and we are a high-volume center, and we end up treating about 100 patients with TIL therapy a year. We're trying to expand, maybe we'll be able to get to 200, but a small tiny proportion that ends up getting the cellular therapy.

The newer therapies like TCR-T may be a little more available, but look at, for instance, IMA203, which is the cell therapy from Immatics, it's also HLA-A*2:01 restricted. So I think MDNA11 sits in a space where it will be available for more patients with this activity, both as a single agent as a combination. It will be available to every patient that's ICI refractory.

And also remember one last point that Fahar made that I think is really critical for everyone to keep in mind. If this moves forward, it can be combined with other things, not pembro alone, it may actually be relevant for TIL therapy. Every TIL patient we treat with 6 doses of high-dose IL-2 inpatient right now, and that's hard. That's what limits the availability of this therapy. It could be that MDNA11 may actually be a better partner for TIL. So there's a lot of opportunity to expand on its indications.

Our next question comes from Daina Graybosch at Leerink.

Maybe three for me. One, just practically on TMB, I'm wondering if this is tissue or liquid biopsy based given particularly in CRC, I think that the liquid has been showing better correlation with checkpoint sensitivity.

The second question is if you could discuss why you think this particular IL-2 is giving effective responses in patients with liver mets. And for here, I'd be really interested in albumin and how albumin helps traffic to the liver and if you think that this particular construct over other, let's say, bispecific IL-2s biologically has better rationale for the liver activity.

And then finally, for the KOLs, we also saw some data with Werewolf's IL-2 at SITC and they've taken almost an opposite approach with a masking in a wild-type alpha and also had some single-agent responses. And I wonder if you could just talk about the 2 data sets taking two different approaches and how we should think more broadly about IL-2 targeting.

So maybe I'll address the albumin specificity and the relevance to liver, and I'll turn it to Andre for the rest. But I actually think those are exactly my thoughts that the albumin may be allowing for more of the reticuloendothelial system to take this up. And so you're almost targeting the myeloid compartment, you're almost targeting exactly the things that lead to the most immune suppression in the liver. So the Kupffer cells are part of the reticuloendothelial system. It is possible that they're taking up this agent at a kind of more significantly than other cells in the tumor microenvironment.

So I'm really intrigued about this liver activity, and we've been talking to Fahar about maybe even biopsying like normal liver in these patients to try to understand that component of the science. But I do think there is a definite component of that, that's helping to see this activity we see.

I'll turn it to Andre to address the rest of your question.

Yes. I mean, looking at the WTX candidate 124 that was presented at SITC and not focusing on the non-small cell lung cancer data, focusing exclusively on melanoma. And I have a difficult time always comparing different trials, different populations. So this needs to be taken into account with a grain of salt. But if you look at the overall response rate on the primary resistant or ICI resistant melanoma patients, it's half of what MDNA11 showed. So I would say that the biological approach of MDNA11 from a rationale or a biological rationale standpoint is better designed. But of course, it is limited data, limited data sets. It's pretty hard to draw a conclusion from here, but this is my first impression.

Andre, could you sort of talk about the blood biopsy approach for TMB-high selection? Because obviously, in the study, we did not use blood-based TMB. So...

I mean, it's -- when we talk about the liquid biopsies, we have a more accurate figure of what the current picture is. And we know that on these patients which have high chromosomal instability mutations tend to evolve as Stage IV disease progresses. So they tend to accumulate more mutations that ultimately, that's what drives progression. Of course, liquid biopsy, and we know that the majority of the tissue that is enrolled on these trials are either from the primary or from a diagnostic biopsy. So of course, liquid biopsy might reflect the actual panorama, but we have some limitations. I mean, heading is an issue. So not all patients have accurate liquid biopsy displays.

I think the ones that do with a good cellularity and if we identify very high percentage of allelic fractions that are really a picture of what the disease reflects right now, yes, I think we can select and enrich the patients in a liquid biopsy. But given all the limitations, I wouldn't say it's a straight pathway forward still, but I think yes, as sensitivity increases, it's probably the way to go.

Our next question comes from Chad Messer at Lake Street.

Great presentation. I know we're over time here. So maybe just one for me. I'm interested in the sort of dose finding work and whether the KOLs think we're kind of covered here if we wanted to go into the targeted population. I know Dr. Mansinho, you commented that 120 was less tolerated in some of the melanoma patients, but we didn't have any -- if we are actually going after the targeted patients, we didn't have any there. So do you think we've got Optimus covered with the data? Or would a little bit more dose-finding work be necessary if you're going into the GI group first?

Well, if I may tackle that question, I would say looking at the preclinical data that we did not show here or the pharmacodynamic data, what we see is that when we increase the dose from 90 to 120, we don't have any biological or at least significant biological effect.

So in terms of cell expansion, at least at the peripheric level, we do not see an increase on the target population. Of course, biopsy work could be, I mean, useful to see if the infiltration increases. But I would say that from my experience, and this is not reflected on the cohorts, but renal cell cancer that I included in this trial was on the 120 every 3 weeks.

And what I see is that the tolerability is quite -- or it's significantly different. So the patient has the side effects for more time, fatigue, essentially some kind of chill and pyrexia that with the 90 tend to last 48, 72 hours in the first cycles at most. But with the 120, the patient reported those complaints for about a week.

So what we saw with the dose decrease was that this kind of side effect profile vanished. So the tolerability improved quite remarkably. And I think I might comment on that. But we saw during the course of the trial, some patients decreased from 120 to 90, but none from 90 below that. So I would pretty much be convinced that given the efficacy that we are seeing and the tolerability of the 120, 90 is the way to go.

And I would just add to that, just I completely agree with Andre. And I think from an Optimus perspective, we're covered because of the dosing of IL-2. You actually need to consider two things. The fact that you want to do repeated dosing and for people to tolerate it a little bit longer-term, you don't really want to be at the DLT or close to it. So I like the idea of being able to be manageable Grade 1, 2 toxicities.

And second is kind of with IL-2, we've been burnt with the high doses. I mean, we know that this is betas specific, but it's not the better answer to give a higher dose. Sometimes that's actually what resulted in previously negative outcomes. But I think the translational data from ABILITY-1 is very comforting to me as a translational scientist in seeing that we're seeing the impact that we want to see at those doses. And there is a dose response, if you look at the translational data as well.

Our next question comes from Mayank Mamtani at B. Riley.

Mike on for Mayank here. For Dr. Fahar, so most of the data here is in KEYTRUDA, but we also know that the NEO-CYT data, the NEO-CYT is going on and with where that's also tested with Opdivo. Do you think MDNA11's benefit is tied to a specific PD-1? Or do you expect it to combine with any PD-1, including the newer PD-1 VEGF bispecifics that we're seeing? Do you have any preclinical or clinical data for that?

And also for Dr. Tawbi, I think you may have hinted at this, but for patients who've progressed on PD-1 plus CTLA-4, know the TIL therapy is now an option, but it's also kind of complex and limited to specialist centers. Where would you place a ready-to-use IV therapy like MDNA11? And what response rate and durability would change your practice or other physicians practice?

Thank you for your call, Mayank. Just with respect to the first part of the question regarding the NEO-CYT study specifically, obviously, it's very early, but we've tried different versions of checkpoints, and we haven't seen much difference. Even when we create bispecific versions of checkpoints with pembro or nivo, we've basically seen very similar profiles with respect to safety, PK/PD, et cetera.

So with respect to the human data, we obviously don't have much experience with nivo. That study has just started. The intent here in the combination study between -- with MDNA11 and nivo is to really compare pathological responses in sort of two different cohorts, namely MDNA11 plus nivo versus the sort of the current gold standard, which is MDNA -- sorry, nivo plus ipi.

So we will get more data on that towards the sort of the second half of next year, and we'll obviously get a chance, particularly with the fact that we have better access to tumor, et cetera, to really analyze the sort of the combination in a much better way. But I don't think, at least my thinking is that the checkpoint inhibitor selection should probably have a similar effect irrespective of which brand you use, but I'll pass it on to Hussein, if he's got some other thoughts.

Yes. I mean, my position on the second-line setting in melanoma has been kind of publicly stated at the advisory committee. I think a 30% response of a tolerable regimen that could be widely available to patients would very quickly enter clinical practice.

I mean, if you look at nivo, well, I'm kind of the person that led to its FDA approval in the first-line setting. I almost never use it in the second-line setting because it has a 10%, 12% response rate. So if I have checkpoint plus MDNA11 that gives me a reliable 30% that is tolerable, I'll go for that. So I think the presence of other things like TIL therapy and RP1 would be immediately relegated if MDNA11 makes it through.

So Fahar, this concludes our verbal portion from the analysts. I'll turn it back to you.

Well, thank you very much for all of you being part of the conversation today. We've obviously received several other written questions. We certainly do not have the time to go through them.

I really appreciate Dr. Tawbi and Dr. Mansinho for making themselves available despite the busy schedules for another extra 15, 20 minutes. So thank you very much. Really appreciate your thoughts, your feedback. And those that we could not answer those questions, we'll certainly reconnect with you guys by e-mail or phone. So feel free to contact us separately. Thank you all, and a good day to all of you.

Thank you so much. Take care.

Thank you.

Yes. Bye-bye.

Welcome to Medicenna Therapeutics KOL Webinar. [Operator Instructions] As a reminder, this conference call is being recorded. If you have any objections, please disconnect at this time. I'd now like to turn the call over to Dr. Fahar Merchant, President and CEO.

Good morning, good afternoon, everyone, and thank you for joining us today. My name is Dr. Fahar Merchant, President and CEO of Medicenna Therapeutics. We are thrilled to welcome you to this exclusive webinar as we discuss exciting new clinical data from our ABILITY-1 study evaluating MDNA11. Before we begin, I'd like to remind everyone that this webinar contains forward-looking statements within the meaning of applicable securities laws. Forward-looking statements may be identified by the use of words such as believe, may, will, continue, anticipate, intend, expect, should, would, could, plan, potential, promise and similar expressions. These forward-looking statements are subject to risks and uncertainties, including, but not limited to the risks inherent in clinical drug development, regulatory approval processes, competitive factors and other risks described in Medicenna's filings with the Securities and Exchange Commission and Applicable Canadian Securities regulators.

Actual results may differ materially from those expressed or implied by forward-looking statements Medicenna disclaims any obligation to update these forward-looking statements, except as required by law. For those not familiar with Medicenna, we are a clinical-stage immunotherapy company focused on developing next-generation Superkines. These are engineered cytokines that are designed to harness the power of the immune system to treat patients with serious cancers.

Today marks an important milestone for our company, and we believe for cancer patients worldwide. The data we are about to share with you demonstrate the compelling clinical activity and potential of MDNA11, our lead program, as both a monotherapy and in combination with checkpoint inhibitors, particularly pembrolizumab or KEYTRUDA.

Before we dive into the clinical data, I'd like to quickly introduce the outstanding members of our management and clinical team who are on the call with us today. Dr. Arash Yavari is our Director of Clinical Strategy, who is also a clinician -- clinical scientist at Oxford University. Arash will walk us through the detailed clinical data from the ABILITY-1 trial and discuss what these results mean from a mechanistic and efficacy perspective.

Dr. Andre Mansinho, the presenting principal investigator of the ABILITY-1 trial, who is based in Portugal at the University of Lisbon and the Faculty of Medicine there. Andre will provide critical clinical context around these results and discuss how these data fit into the broader landscape of IL-2-based immunotherapy and checkpoint inhibitor combinations.

Mr. David Hyman, our Chief Financial Officer, who has been instrumental in guiding Medicenna's strategic and financial planning as we advance our clinical programs. We also have members of our clinical and corporate teams available to support the Q&A session, specifically Dr. Min To, who is VP of R&D, and we will be available at the end of the webinar and during the Q&A session.

So let me briefly set the stage for why we are so excited about MDNA11 and the data that we're going to share with all of you today. So what are the challenges? The challenges with conventional IL-2 therapy has long been limited by significant toxicity, particularly vascular leak syndrome and immune-related adverse events, which has restricted its use in clinical practice and limited its potential to help more patients. What we have at Medicenna is a solution where MDNA11 has been designed as a next-generation IL-2 super agonist with superior affinity for the CD122 receptor or the beta receptor and importantly, no CD25 binding or rather no alpha binding.

This selective engineering allows us to preferentially activate cancer-fighting CD8 T cells and NK cells while minimizing the toxic immune overreactions associated with unselective IL-2 stimulation. The hope is that the data that we are about to discuss today demonstrates that MDNA11 can deliver on the design and the hypothesis and this hope. The hope to show durable single-agent activity, potent immune effector responses and a better tolerability profile that differentiates it from conventional IL-2 approaches as well as other next-generation IL-2 therapies being developed.

So we are incredibly grateful for the dedication of our clinical trial sites, patients and their families who made this clinical data available and possible.

We also want to recognize the investigators, particularly Dr. Mansinho and his colleagues at the University of Lisbon and the clinical site in Lisbon for the thoughtful and meticulous execution of the ABILITY 1 trial.

So now let me turn the call over to Dr. Arash Yavari who will walk us through the clinical data in detail. Arash.

Thank you very much, Fahar, and hello, everyone. It's an absolute pleasure to be with you today. So what I would like to do over the next few minutes is to walk you collectively through the ABILITY 1 data. Starting with the trial design, then the patient characteristics, moving on to safety and tolerability, efficacy in the monotherapy and combination arms together with some of the mechanistic insights we are starting to see with this molecule.

And finally, how we start to think about this data in the context of current standard of care as well as some of our next steps.

So let's start with the design of the ABILITY 1 trial. ABILITY 1 is a first-in-human international, multicenter, open-label Phase I/II study of MDNA11 in patients with advanced refractory solid tumors. The trial is evaluating MDNA11, both as monotherapy and in combination with the anti-PD-1 inhibitor, pembrolizumab. In patients with advanced or metastatic disease who have exhausted standard of care options and this includes prior immune checkpoint blockade inhibitors in many cases.

So as you see from the schematic, the study comprises several sections, including monotherapy dose escalation, where patients received MDNA11 intravenously every 2 weeks and in some cases, 3 weekly at doses ranging from 3 to 120 micrograms per kilogram. We also have combination dose escalation where MDNA11 was given on a similar schedule in terms of frequency together with pembrolizumab.

You'll also see that we have dose expansion cohorts and these are particularly enriched for tumor types and biomarker-defined subsets that we believed [ pylori ] would be more sensitive to MDNA11 specific mechanism of action and these include cutaneous melanoma progressed after immune checkpoint blockade in addition to MSI High or dMMR tumors as well as TMB-High tumors.

And as a point of reference going forward in the presentation, when we refer to Phase II eligible patients today, what we're discussing is patients with tumors selected for these expansion cohorts who were treated within the biologically effective dose range.

In other words, at or above 60 micrograms per kilogram. So from these dose escalation phases, we did define that as being the biological effective dose range.

Let's turn now to patient demographics and baseline characteristics. Patients enrolled in ABILITY 1, a very typical of late line advanced solid tumor populations in an early phase study. Patients had substantial disease burden, including a significant proportion of patients with impaired ECOG status, hepatic metastasis and multiple prior therapies.

The majority of patients in both arms had progressed on prior immune checkpoint inhibitor therapy. So when we come to talk about the efficacy data in a couple of minutes, it's worth keeping in mind that these are really largely patients for whom, unfortunately, standard immunotherapy has ultimately failed and for whom there is no clear standard of care. In other words, patients with a very high level of medical unmet need.

So you'll see that the trial has enrolled a broad range of tumor types, among them cutaneous melanoma, MSI-High, dMMR cancers, but also colorectal and pancreatic tumors, patients with endometrial cancer, both proficient MMR and deficient triple-negative breast cancer, non-small cell and small cell lung cancer and a variety of others.

So moving on to safety and tolerability. We observed that across the monotherapy in combination cohorts, MDNA11 has shown a manageable and predictable safety profile. And clearly, this is of paramount importance, particularly for next-generation IL-2 therapy. Over 90% of treatment-related adverse events were grade 1 or 2 and transient, typically resolving within 48 hours or less.

Now specifically, we have observed no formal dose-limiting toxicities in either monotherapy or combination arms up to and including a dose of 120 micrograms per kilogram of MDNA11. There were very few grade 3 or 4 events and the great majority of these were actually transient laboratory abnormalities, not associated with any direct clinical sequelae.

So really, from a comparative standpoint, for the time being, we are seeing a very different profile from conventional high-dose IL-2, which is associated with substantial grade 3 for toxicity and in many cases, a requirement for inpatient ICU-level care, despite selecting for otherwise very fit patients who are robust enough to tolerate high-dose IL-2 therapy. Now that said, of course, these are early phase data with relatively limited numbers, and so we need to continue as we will, to follow up patients carefully. But at this point, the safety profile looks very encouraging.

So let's turn now to efficacy, and let's start with MDNA monotherapy. So in other words, evidence of single-agent activity, which again is of critical importance for development here. So you'll see depicted here on the swimmers plots that among Phase II eligible patients treated within that biologically effective dose range, in other words, between 60 to 120 micrograms per kilogram with single agent MDNA11, we observed clear evidence of single-agent activity across a range of tumor types in patients who had exhausted all standard of care options.

These include, for example, a patient with MSI High pancreatic ductal adenocarcinoma, who progressed on pembrolizumab and who has, in fact, remained in remission for over 21 months of all systemic anticancer therapy. In addition, a patient with cutaneous melanoma would again exhausted standard of care options with over 7 months of remission of therapy to date.

So importantly, both of these patients had progressed on immune checkpoint blockade. So obviously, whilst these are individual cases, they do show that MDNA11 can induce deep durable and clinically meaningful responses in settings where we would typically not expect durable control after failure of immune checkpoint inhibition. So what you see depicted here now is some of the objective response rates and disease control rates to date based on RECIST version 1.1 for specific tumor types that we are enriching for an expansion. And these include close to 38% objective response rate in patients with secondary ICI resistant cutaneous melanoma.

If we turn now and focus specifically on the subset of patients that we think may be really quite informative for future positioning of MDNA11, we observed that patients who received MDNA11 as the next line of therapy immediately after progression on a checkpoint inhibitor. Within that group, the objective response rate, albeit with limited numbers is 42% with a disease control rate of 83%. So we feel this may be important because it suggests that when MDNA11 is introduced as the early sequence following immune checkpoint failure we may be able to reinvigorate a meaningful antitumor immune response in a substantial proportion of patients who have exhausted standard of care options.

So what you see here now depicted are the details of some of these patients with objective responses. And these include, as you will see, patients who progressed on doublet of immune checkpoint blockade, so specifically including patients who progressed on a combination of anti-PD-1 and anti-CTLA-4. So specifically, that was ipilimumab, nivolumab and in addition, we observed objective responses in patients with liver metastases, and we know that those can be particularly challenging clinically in the context of the hepatic parenchyma effectively representing an immuno-tolerant immune contexture.

Let's turn now to some of the initial combination data. So here you see the swimmer plots depicting the response data again, for Phase II eligible patients treated at that biologically effective dose range with MDNA11 now with the addition of pembrolizumab.

Again, MDNA11 is given here between 60 to 120 micrograms per kilogram on largely 2 weekly basis and in some cases, a 3 weekly basis. Again, we observed objective responses across a range of tumor types. And these include tumor types that are not economically thought of us being immunosensitive or particularly sensitive to interleukin 2. And they include, for example, microsatellite stable endometrial carcinoma that has progressed on immune checkpoint blockade, cutaneous melanoma patients with MSI-High or deficient MMR tumors as well as a range of tumor potential burden high tumors.

So among these within the microsatellite stable endometrial cancer patient population with secondary immune checkpoint inhibitor resistance, this really is a population with very limited treatment options at this stage. Amongst 4 patients enrolled, we observed an objective response rate of 50% and a disease control rate of 75%. Indeed, one patient achieved 100% shrinkage of target lesions. And again, just to underline, this patient had progressed on prior immune checkpoint blockade plus a TKI.

So this is some of the individual cases depicted here that, again, underscore the clinical potential of the combination based on the early data that we're seeing here. So exemplifying this is K6 and this was a 43-year-old patient with advanced metastatic cutaneous melanoma. Unfortunately, you had primary resistance to really the best immunotherapy that we can give these patients at the moment in first line, which is a combination of nivolumab plus ipilimumab. This patient also had hepatic metastatic involvement and this patient has achieved a partial response to MDNA11 plus pembrolizumab at the first on-study scan.

We also observe additional deep responses, as I mentioned, in tumor types that are not typically regarded as particularly responsive to immunotherapy, you could characterize these as relatively cold tumor types, for example, anal squamous cell carcinoma.

So again, whilst these are obviously, as a Phase I trial, non-randomized cohorts and the numbers are still relatively limited. Taken together, we do observe consistent signals of activity across multiple tumor types and multiple mechanisms of immune checkpoint blockade resistance, both with MDNA11 alone, together with the combination with pembrolizumab.

So if we move beyond response rates, another important question for any immunotherapy is whether disease control potentially could translate into meaningful survival benefit. And there's obviously a way of assessing this in an exploratory fashion, which is what you see depicted here. So when we pull all patients treated within this biologically effective dose range for monotherapy or combination and then look at survival as a function of disease control we see a clear association.

So if you focus on the left-hand side, what you see is that in the monotherapy cohorts, patients with disease control and by that, we mean patients who have a complete response or partial response or stable disease on imaging, had a median overall survival of approximately 120 weeks. This compares with approximately 29 weeks in patients who unfortunately did not achieve disease control, yielding a hazard ratio of approximately 0.29 with a nominal p-value of 0.0023.

On the right-hand side, we observed a relatively similar pattern with this early data in the combination cohorts. So patients with disease control had a median overall survival that has not yet been reached. This compares with a median overall survival of 26 weeks in patients without disease control. And again, we observed a very similar hazard ratio of 0.28 with a p-value of 0.014.

So whilst these findings are exploratory and the data clearly need to mature further and be replicated with more substantial cohorts and are derived from a nonrandomized study without being adjusted for potential prognostic factors. With those caveats and due caution, they do nevertheless provide an important early signal suggesting that potentially the disease control that we are inducing with MDNA11 in these patients who have exhausted standard of care options whether it be an objective response or indeed prolonged stable disease has the potential to be quite clinically meaningful.

So let's turn now briefly to some of the pharmacodynamic data. And obviously, this is a rich data set, but we exemplify some of it here for you. So within the pharmacodynamic analysis, we do observe a robust expansion of effective CD8 T cells in addition to stem like CD8 T cells in peripheral blood. This is consistent with the molecular engineering. In other words, design consistent with proof of mechanism. And both the monotherapy and combination cohorts, these changes are highly statistically significant with statistically highly persuasive P values for the effector cells as well as stem like CD8 T cell population.

So why are these potentially important? Well, as I mentioned, these data do validate and support the intended mechanism of action. In other words, they support the MDNA11 is preferentially activating the CD8 T cell effector and stem like compartments that are thought to drive durable tumor control in the response to immunotherapy. And they potentially provide, if you like, a pharmacodynamic bridge that may help explain what we are starting to observe clinically with MDNA11 in terms of durable responses and disease control in heavily pretreated immune checkpoint blockade-resistant patients.

So where from here, well, in the near term, our priorities are very much to continue enrollment and follow-up carefully in the Phase II eligible expansion cohorts within ABILITY 1 and to obviously expand the sample size where we've seen very attractive signals of clinical efficacy in key tumor types and to mature out both the response as well as survival data.

In parallel, I may take the opportunity to just mentioned that based on some of this encouraging single-agent activity and safety profile, we are supporting a collaboration for a study called the Neo-CYT study, and this is in patients with high-risk resectable melanoma, where MDNA11 is being evaluated in the neoadjuvant therapy context, in other words, specifically before surgical, definitive surgical resection and this trial will obviously provide an important opportunity to really evaluate and understand MDNA11 effects earlier in the disease course.

In other words, in patients with a more intact immune system, in addition to providing access to tumor tissue, both pre- and post-treatment, which will clearly be invaluable for deepening our mechanistic understanding of MDNA11.

So with that said, I will stop here. Thank you all for listening and hand over to our expert investigator here to whom we are extremely grateful. My colleague, Dr. Andre Mansinho, to kindly provide his perspective as a treating investigator on how these data fit both into current oncological practice and where potentially he might see MDNA11 adding value for our patients in the future.

Thank you so much, Dr. Arash. Just to start, I think to fully appreciate the rationale behind MDNA11, I think we must first address what were the historical limitations of the previous IL-2 landscape. So for the ones that have used it before, native IL-2 has been a therapeutic paradox. So we established long ago it was a potent cytokine capable of deriving profound immune activation. However, its clinical activity and utility has been severely hampered by its promiscuous binding profile.

So Native IL-2 binds with high affinity to the alpha receptor, CD25, and this interaction is very problematic for 2 reasons. So primarily, it drives severe toxicity, specifically the capillary leak syndrome. And biologically, it also preferentially stimulates the Treg cells, which will dampen the very immune response we are trying to induce. So through this engineering, MDNA11 has been modified to exhibit 0 binding to the sulfur receptor, mitigating the Treg stimulation and VLS risk and simultaneously possesses a 30-fold increased affinity for CD122.

So in terms of PD, this solves a fundamental biological hurdle. We are effectively removing the immunosuppressive break, and we are amplifying the activation signal to the CD8 effector T cells. So in this study, ABILITY-1, we try to design and test this hypothesis in populations which are significantly unmet needs. So we are not looking at frontline easy-to-treat cases. We are focusing on 2 distinct refractory cohorts and particularly 3 populations that are very hard to treat. So if you look at secondary resistant melanoma, MSI-High patients, endometrial cancers, the secondary therapeutic that we need to offer to these patients are very limited.

So we are looking at the secondary resistant population. And these patients typically present with T cell exhaustion, MHC Class I complex exhaustion as well. So standard salvage therapies are after offer limited benefit. And also the cold tumor population in which these tumors are historically unresponsive by this immunotherapy strategy due to the lack of T cell infiltration. I think from a safety profile and from a patient experiencing by having treated over 10 patients in this trial, I think the most distinct differentiation of MDNA11 is from the historical IL-2 is the safety profile.

So if we look at the historical IL-2, these patients would require inpatient ICU monitoring due to the risk of hemodynamic collapse and systemic complications. And in stark contrast, this data demonstrates a very clean safety profile with no capillary leak syndrome and no DLTs up to a dose of 100 micrograms per kg. So I think this tolerability allows for an outpatient administration with side effects, which are primarily limited to transient, low-grade flu-like symptoms that resolved within 48 hours. And I think this tolerability is very critical because it ensures high patient compliance and it allows subjects to remain on therapy long enough to derive clinical benefit.

Not only that, they are treated in an ambulatory setting, which contrasts very starkly with the old IL-2. Clinically, we are also observing compelling evidence of durability, which we believe serves as a surrogate for immunological memory. This is -- I mean, we've seen -- I mean, Dr. Arash present notable examples, and I would highlight the pancreatic cancer patient who remained in remission for over 21 months of treatment, which is an exceptional outcome in this indication, very, very hard microenvironment to treat.

And also the translational analysis that links its durability to the expansion of TCF1 positive CD8 T cells. I mean these stem cell-like T cells are essential for sustaining the immune response and also to prevent exhaustion validating this mechanism of action.

Now benchmarking against the standard of care, the signal is very strong. I mean, in the post-TCI melanoma setting, MDNA11 demonstrated an overall response rate of 37.5% and also a DCR of 75%, which is considerably superior to the historical expected patients for the carbazine or rechallenge with ECI as well as MSI-High patients who don't typically have any options and are refractory to standard of care treatment and also focusing on endometrial cancer, in which the combination achieved a 50% ORR. I mean, despite small numbers, this contracts very, very highly with the single-digit responses typically seen with PD-1 monotherapy in this setting.

So I think this data clearly supports a clear path forward. I mean we also found a statistically significant correlation between disease control and overall survival with patients achieving even stable disease for a prolonged period of time. And I think from a clinical development perspective, if we focus on this ECI refractory space in the melanoma MSI-High patient, we have really the potential for giving those patients a very good solution for this unmet need. So thank you.

Thank you very much. Dr. Mansinho, really appreciate your comments. Of course, we'll have a Q&A session shortly. But before we do that, let me share with listeners today, some additional opinion from key opinion leaders who have had the generosity of talking to us during a conference last week and their thoughts on MDNA11 and the data we have so far. So we'll run a short video clip, and I'll ask the moderator to play the video clip, please.

[Presentation]

My name is Hussein Tawbi. I'm a Professor of Melanoma Medical Oncology and Investigational Cancer Therapeutics at MD Anderson Cancer Center, and I'm the Executive Director of the Immuno-Oncology Clinical Drug Development Program at MD Anderson, considering the question of where does this stand compared to other IL-2 targeted therapy, so to speak. I think it is really a molecule that's very smartly designed and has the potential to be the best-in-class.

The results in a clinical setting where we have responses in patients that are PD-1 refractory is really impressive, seeing responses and diseases that are usually not responsive to immunotherapy has particularly caught my attention. So I do think it is a candidate, if not the best in class at this time.

In terms of optimal positioning of MDNA11 and the treatment landscape for melanoma, I really do think that this activity that we see both with monotherapy and with combination and the second line is really impressive. I would prefer to focus on that in the short term because this is the unmet clinical need and the faster route to registration in this disease. If we get to a place where the clinical activity is validated in the second-line setting and you have FDA approval, one can consider using this in the first-line setting.

I am quite excited to hear about the potential use of this in an adjuvant setting. In terms of treatment combinations that I would consider prioritizing, I think checkpoint inhibitor combination makes sense. I personally think that nivolumab and relatlimab or PD-1 LAG-3 based combinations because of their low toxicity profile or good safety profile would make probably great candidates for combinations. With MDNA11, I'd be interested in seeing what the ipi/nivo combination would look like. Of course, and at this point, that would be my primary focus.

In the future, if MDNA11 does have consistent validated results in the second-line setting and maybe neoadjuvant, I could imagine how it could replace IL-2 in everything we do, including cellular therapies and the way that currently IL-2 is used to support cellular therapies.

I really do think the field has been waiting for a good IL-2 molecule. It's the one drug that we had from the AV that was improving survival for melanoma. It is a validated therapeutic approach. So I think having designed and interleukin-2 molecule that looks this impressive both from a PK, PD, this has all of the determinants to be a potential winner. Thank you.

Hello. I'm the Professor Igor Puzanov. I work at Roswell Park Comprehensive Cancer Center in Buffalo, United States. And my specialty is drug development in Phase I as well as melanoma and skin cancer treatment for patients.

Professor Puzanov, based on the clinical data you've seen so far with MDNA11, what do you think stands out the most compared to other IL2 variants in development?

Yes. So I would say that MDNA11 stands out by its unique profile of engaging the beta with the chain of the IL-2 receptor and in enhanced fashion and avoid alpha and at the same time, it also binds to gamma. It's a unique profile compared to the other efforts. And the clinical data sent out by its single-agent activity. And what I also like about that is the clean cytotoxic profile, very little problems with just mild cytokine release syndrome, no issues with large skin toxicity or arthralgia. The first data coming out from these clinical trials are promising, sufficiently promising to take it forward to the next step.

Where do you see as the optimal positioning of MDNA11 in the emerging treatment landscape for solid tumors and perhaps particularly with reference to cutaneous melanoma.

I think in melanoma, these days, one is almost bound or like clever to go to refractory post PD-1 type of patients. In the U.S., it's probably post PD-1, CTLA-4 or the combinations really are the new normal in the United States for sure. It's becoming a new normal around the world. But refractory space because the activity of checkpoint inhibitors in melanoma is almost the highest and with 50% of patients surviving more than 5 years now or 6 years it's so clear that one has to address the issue of the other 50%.

So based on the clinical data you've seen to date and what you know about IL-2 biology, what other indications would you prioritize developing MDNA11 outside of melanoma.

Outside of melanoma, I would actually prefer a basket approach, histology agnostic because I think there is an opportunity to actually look at the biology of the tumor, for example, with the information you can glean from neoadjuvant melanoma trial and see, for example, if patients who are refractory to PD-1 but they still have the tumor-infiltrated lymphocytes in those tumors, maybe the ones who actually would be served, not just in melanoma, but in other tumor types as well.

Do you think there's sufficient data to consider testing MDNA11 in earlier less refractory lines of therapy?

I would start probably the old school with refractory and then move to the earlier lines.

What are the treatment combinations would you prioritize testing with MDNA11? At the moment, the combination partner is an anti-PD-1, is pembrolizumab or potentially others?

Yes, I think that's a correct one. I like pembrolizumab as well. I will stick to the combinations, which are already in use and standard like a combination of a PD-1 with CTLA-4 that would be nivolumab/ipilimumab or a combination of a PD-1 with 3 that would be an nivolumab for the overlap.

In your estimation, how clinically meaningful is MDNA11 therapeutic potential if it were to continue along the same path?

More valuable than high dose interleukin 2, which we know actually cure people with melanoma and kidney cancer, I think that could be it. And it could probably serve the population of about 20%, 30% of these refractory patients and perhaps with multiple histologies. But we don't know that yet.

I think we touched on it briefly earlier, but about this new trial that has been recently highlighted the Neo-CYT trial of MDNA11 in combination with ipi/nivo and cutaneous melanoma. How excited do you think you are obviously and should the community be about that with MDNA11?

I am excited because the ipi/nivo is a new standard. We know that not everybody responds. The complete response is 57% or so. And then we have 25% patients who are nonresponders. If we see some of those no responders convert into responders, there you go. And even for responders, potentially a very unique and valuable drug.

Dr. Puzanov, thank you very much for your time and your insights today.

Toni Choueiri, Dana-Farber Cancer Institute, Boston.

So the first is, obviously, renal carcinoma is regarded as a tumor type that is sensitive to immunotherapy. How attractive do you think an IL-2-based superagonist is for improving efficacy and objective responses in renal cell carcinoma compared to current regimens?

An IL-2 super agonist, IL-2 is an established regimen in renal cell cancer, not used much now because of the toxicity and the low response rate, but anything that shows responses initially in the ICI refractory setting, could be quite interesting in renal cell.

I believe you've seen some of the data with MDNA11. So if this were to continue to show single-agent activity that were deep and durable, so clinically meaningful in the post checkpoint blockade patient population. Would you regard that as potentially meaningful to test in a renal cell carcinoma patient population, given the historical precedent of IL-2?

Absolutely. I think a 20% response rate will be extremely meaningful, especially if these responses are durable and the toxicity are manageable to take it to the post PD-1 setting, which remains an unmet medical need for immunotherapy. We don't have immunotherapy that are approved in the post PD-1 setting. So that will be quite enticing, especially if they are durable.

At what point do you think we could start testing MDNA11 in earlier, so perhaps even first-line settings.

I think taking it and building on the IO-IO or IO VEGF is very reasonable. I love the tail of the curve like what happened when CTLA-4 was added to PD-1, ipi was added to nivo with the IL-2 that will be a big win. We in metastatic RCC are still now curing some patients, but certainly a minority. And hopefully, IL-2 will make a comeback.

My name is Paolo Ascierto, Medical Oncologist and Food Professor of Oncology at the University of Naples Federico II and also Director department of skin cancer, cancer immunotherapy and development therapeutics, the National Cancer Institute of Naples, Fondazione Pascale.

Immunotherapy changed the story of several diseases, melanoma is one of these. The idea to design the NEO-CYT study was to add MDNA11 to check inhibitor, we believe in nivolumab. The goal is to demonstrate that the addition of MDNA11 to the checkpoint inhibitor. It's something that can increase the benefit. There is a lot of expectation for this study. It will be an Italian study with possibility to centers outside of Italy.

Looking to the MDNA11, the genetically modified IL-2, I look into the Phase I study, one of the important characteristics of this kind of IL-2 is that we have seen a response in some cancers, like pancreatic cancer, that, in general, historically, are resistant to motor. So this is an important signal. We had also other interesting response. And all these aspects make MDNA11 very intriguing for possible combination with the classical approach with ipilimumab and nivolumab.

The major pathological response rate is about 60%. And with the addition of the MDNA11, we wanted to get at least 10% more. So 70% could be an important milestone for us, probably one of the best place for MDNA11 could be the second line, the patients who progress after checkpoint inhibitor, after checkpoint inhibitors and target therapy, there is nothing. And I believe that in both settings, so the new adjuvant in the second line MDNA11 in combination can have an important role.

Thank you for still being online with us. At this moment, can I ask the moderator to open up the Q&A session. Operator?

[Operator Instructions]

Our first question comes from David Martin.

Congratulations on the data. First question, do you see either the mono or combo arms is heading towards successfully meeting the criteria for tumor-agnostic activity in MSI-High and TMBH tumors per the ESMO ETAC-S. And if not, are there specific MSI-High and TMBH tumor types that are worth pursuing?

Thank you, David, for that really important question. I'll sort of pass it along to Arash first and perhaps get some feedback from Andre as well. So Arash, any thoughts on that?

David, thanks so much for the great question. I think we're still at the relatively early stage in terms of taking the ETAC-S criteria box, as you say. So I think from our perspective, the key thing is really to demonstrate evidence of clinical activity beyond the pancreatic tumors that we've demonstrated so far. So we do believe, to some extent, this is kind of a matter of numbers as well. So we do need to expand the numbers.

In terms of your thoughtful point around, we expect this to be kind of single agent play or a combination play with anti-PD-1. I think, again, our starting point is actually that single agent could potentially be sufficient, right? We've got the clear evidence of single-agent activity. We presented the case that you'll remember quite well of an individual who's 21 months, close to 2 years out, actually post ICI anti-systemic therapy with a MSI-H PDAC in complete remission.

So I do believe that single agent would be the strategy, but the formal way to do that is obviously to accrue more numbers in the combination and to perform a comparison of the 2 arms.

Okay. Great. So what are the next steps overall? Are you going to continue to expand all of the cohorts that you have been expanding or are you narrowing it down to the ones that you reported the data for today?

Thank you, David. Yes, I mean the plan is certainly for us to continue to add more patients. We already have some more patients in these cohorts, Unfortunately, as of today, we don't have their first scans. So we're expecting additional scans in the coming weeks as well. So we will be able to have more patients. But of course, we continue to recruit additional patients. The idea is to get above a dozen patients at least for each of the tumor types and get some better signal we think this will add to the generating additional uncertainty.

But Arash, any thoughts here?

Yes. I think, David, the point I would make here is we really want, I think, double down on the signals we've already identified, right, which we would still regard as preliminary. So specifically, I think high on the list, as you've heard, supported by the KOLs, is cutaneous melanoma that's progressed post ICI, both primary and secondary. Another important one in a very pleasing way, it's really the microsatellite stable endometrial cancer patient population. So again, we see a very, very clear signals there, which are obviously very pleasing.

But I think, again, we need to double down further, really add more numbers and get more of a sense, for example, of a potential molecular profile that may be more amenable or less amenable TP53 abnormal, for example, or a nonspecific molecular pattern. So those will be larger numbers.

But the other thing actually you heard Dr. Igor Puzanov just in that discussion we had with him in the KOL interview, actually to highlight something that, again, we've been considering in detail here, which is really a cohort, which is histology agnostic, but is CPI refractory with MDNA11 basically being the therapy in the following sequence of the next line of therapy.

So the utility of that is, obviously, it will be -- provide us kind of further ability to really identify more signals of activity. I think the totality of the day-to-day do support the potential of this molecule even beyond those canonical immunosensitive indications I've mentioned.

Our next question comes from Dev Prasad from Lucid Capital.

Congratulations for the data. Just one for me. Can you walk us through your development strategy for MDNA11 as a monotherapy versus combination with KEYTRUDA, particularly in melanoma? And a follow-up would be how many patient data would you need to make next step here, whether you want to go with monotherapy or combination? And what would be the expectation in terms of efficacy and durability.

Thank you, Dave. Thanks for joining the call and your question. Certainly, the data for cutaneous melanoma look very compelling. And of course, there are many options here as to how we can proceed next, and we got some guidance from the KOLs, but I'll ask Arash and Andre to perhaps provide some additional context here in terms of the best approach.

Yes. Thanks, Fahar. So Dev, thanks for your question. I think really the first thing really to address here, Dev, is really a clear understanding on our side as to where the maximum potential of clinical benefit is with MDNA11 monotherapy in the post-ICI selling for cutaneous melanoma. So specifically, you recall, the majority of our responses are really in the secondary resistant setting. We have had responses, obviously, outside of melanoma in the primary ICI resistant setting. So I think that's something that we need to explore more with additional numbers.

With respect to combination, this is obviously from a theoretical immunological perspective are very, very obvious, at least additive, if not synergistic effect that we would expect from a combination with KEYTRUDA. But the numbers at the moment that we have in combination for the melanoma indication in particular, really very modest. So we would look to expand those.

If you were to push us and say, look, guys, what sort of numbers would be reasonable. I think really the feedback that we've had from a variety of external parties, including major strategics would be something of the order of 20 per cohort. And obviously, that could also be done potentially in a randomized type fashion to avoid bias of baseline characteristics.

I'll offer it over now to André to see whether he wants to add additional color.

Thank you, Arash. And I agree fully. I mean I think cutaneous melanoma is a very interesting space to proceed further development. I mean, in the ECI refractory setting, we have a very unmet need for these patients. I mean they desperately look for options. And we have seen, despite small numbers, I mean, we have less than 20 patients and overall response rate that's around 40%. And this contrasts very, very, very historically with the options that we have available.

So -- and taking into account, I mean, the project Optimus FDA guidance, I would expand these numbers for beyond 20 between 20 and 30 patients to see if the signal maintains. And I think the secondary resistance or primary resistance to IO in the melanoma space is really no way to go here.

MSI-High patients and also taking the first question into account. I think it's a little bit early to go and to see if this is really an agnostic. We have a very, very good signal on the PDAC patients. Some other patients also responding and controlling disease quite remarkably. And we know this is a very aggressive disease. They rarely respond to standard of care options.

So this is encouraging, but I also need to -- I mean to highlight that expanding those numbers is really needed to pursue this option in current endometrial space, I think Arash already covered this.

Our next question comes from Kambiz Yazdi from BTIG.

Congratulations. Fahar, can you contextualize how important is that MDNA11 can be given in an ambulatory setting driven by its pretty strong safety here. And then maybe for Dr. Yavari -- all up for Dr. Yavari and Dr. Mansinho, can you contrast how you may utilize MDNA11 at the monotherapy versus how you may utilize it as a combination therapy?

Thank you for the question. Yes, indeed, of course, the opportunity here clearly is from a safety perspective, the intent is MDNA11 provides an opportunity for outpatient administration of this therapy. That's the ITO scenario. I think we are basically getting there. The key question though is -- the conventional IL-2, of course, has shown itself to be incredibly toxic and we are sort of way past that.

I think the other thing that's really important that sort of contextualize from our perspective and something that's not been mentioned in today's conversation is around the fact that it's not the IL-2 component that's been engineered but the given component, that's really not been discussed. And I think this is crucial because we know that the given tends to accumulate in the tumor.

But more importantly, in the tumor-draining lymph nodes. And I think this is really important because that's where the T cells get to be trained. This is where they proliferate. That's -- this is where you build a memory population and stem back population, et cetera. And I think that's a really distinct phenomenon that we have engineered into this molecule. And I think that's something that we will be able to demonstrate in the NEO-CYT where we have access to the patient's tumor pre and post treatment, and we'll be able to see how this drug has affected tumor microenvironment.

With respect to the second question, I'll pass it on to Dr. Yavari and Dr. Mansinho.

Thanks so much, Fahar. Thanks for the great question. So I think, look, when we set out to design this trial with MDNA11, one of our key objectives was demonstrating a superior therapeutic index of the molecule compared to recombinant high dose IL-2. I do believe we've achieved that actually from the safety profile. So that really does lend itself to a paradigm shift in terms of where IL-2 is administered here, right?

So absolutely, ambulatory is highly desirable really for kind of obvious reasons, right? Ultimately, what we want to do here and the reason we get out of bed in the morning and work till 2 or 3 in the morning, each night is really to maximize the ability to improve these patients' lives. So the more barriers we put there, obviously, in terms of requirement, hospitalization, requirement for intensive monitoring. This is undesirable for the patient adds a lot more burden to the science of our investigators, et cetera, and potentially limits the geographic reach.

The other thing I would say is the fact that we have initiated nearside with world-class set of investigators, you heard Dr. Paolo Ascierto, there, given an account of MDNA11. This is a very important signal for you because these are obviously patients who are potentially curable with surgery alone. So admittedly, they are getting near adjuvant, ipilimumab/nivolumab. But the idea potentially of going and adding in a third immunotherapeutic agent and potentially risking delaying that surgery, potentially risking that tumor getting bigger, for example, one has to work the risk benefit there carefully.

So really, what I'm signaling is we are comfortable as a team, as was Dr. Ascierto and his team, for example, to say, oh, the profile looks so good that we are willing to test it in this earlier patient population who've got more intact immune systems, for example. So one would expect potentially tolerability profile could look different there. So I think those are the two key elements.

With respect to mono versus combination, our prior hypothesis, I think, is still playing out here, which is that in the right immunosensitive call it, kind of hot tumor context, that is lost antitumor immunity, if I put it that way, to checkpoint blockade, whether it's mono or it's a doublet. We believe MDNA11 on its own as a single agent could achieve durable outcomes in those patients.

Conversely, for colder tumors, tumors that are immune restricted where there's extensive immune editing and you've got escape of that tumor, we believe potentially the combination may be the best way to go there to deliver durable lasting antitumor benefit and antitumor immunity.

And just heading on top of Arash's opinion. I think that from a tolerability point of view and having treated more than 10 patients, I think this is very different from our standard IL-2. Currently, all of my patients are treated in an ambulatory setting. So the safety profile is very, very mild, typically some chills, flu-like syndromes and fever, patients get a little bit fatigued on the first 48 hours, maybe 72 on the majority of them. And the laboratory abnormalities are very transient and nonclinically significant, mainly AST, ALT elevation.

So the molecule is very feasible to using ambulatory setting. And I think that's the major key coupled with the efficacy, which is also higher compared with historical IL-2 cohorts. So I think...

Do you have any time for any more questions?

We have a question from RK from H.C. Wainwright, if you'd like to take it.

Okay.

A couple of quick questions. Just kind of follow-up to the previous question. If you look at the Slide 19 of your presentation, there is -- you allowed for a rollover of monotherapy patients to the combination therapy there. So it's a 2-part question. What was the rationale behind doing that?

And number two, with the data that you have at hand, does it suggest that combination therapy is the best way to go for these patients? Or is it you have another piece in the armamentarium. So to start off with monotherapy and then the disease progress as roll them over to the combination therapy. That's one big question.

And the other question I was thinking was on the even though you show 120 weeks as the median overall survival, but that's within the disease controlled patients, right? So within that group, what was the contribution from this stable disease cohort? And is this stable disease cohort having decent shrinkage of the tumor, but not meeting the PR threshold. And if they are continuing to be as, what's the duration of that?

Thank you, RK. Really good questions here. Certainly, we haven't gone deeply to further analyze the different subgroups within stable disease, meaning stable disease with shrinkage versus without shrinkage. I think that would be some additional analysis that we could conduct. So I don't think I can sort of unequivocally say what kind of stable disease patients did better. So I would expect that patients had tumor shrinkage would probably do better. But I think I would leave that until we've done some additional analysis there.

With respect to the other questions, probably I just ask Arash to respond to that.

Yes, thanks so much, Fahar. Again, thanks for the really, really thoughtful questions. So look, just on the rollover, I mean this is something we often employ in early drug development. So specifically, your question related, I believe, to monotherapy rollover patients. So this was a kind of a highly heterogenous cohort, the patients we have here. So a variety of different tumors. The great majority of them, almost all of them had prior immune checkpoint blockade and had progressed on that.

So again, in terms of responses, we had a patient who had a partial response, for example, to MDNA11, we had patients who also had stable disease in addition to patients who had progressed. And really then there was a discussion between us a sponsor, Medicine in other words, with investigator and their team to get a sense of whether they felt the patient was experiencing a clinical benefit and was otherwise well enough potentially to proceed to the rollover. And what the rollover demonstrates really is the ability to potentially deepen the response.

So partial response, for example, to become further deepen with the addition of pembrolizumab, similarly in a patient with stable disease, again, to further reduce the tumor dimension. So I do think your point what it does suggest is in some patients, yes, the combination would be desirable.

And then the other thing, obviously, to be aware of that really we often discuss very infrequently is the potential for sequencing is concurrent anti-PD-1 and MDNA11, the optimal strategy or, for example, a leading with MDNA11 or the converse, you could imagine, they're leading with anti-PD-1. Again, there are a variety of immunological considerations that would argue in favor of either of those, and these are additional data that I think speak to that, so which we're pouring over very carefully at the moment.

Is there a possibility for me to do a quick follow-up?

Yes, we'll arrange that separately. So we'll talk to you later on. But I think we're pretty much run off time unless the moderator feels there is some additional room.

We have reached the end of the time we have available for the question and answer session. I'll turn it back to you for closing remarks.

Thank you. So thank you all for the excellent questions that you have presented today. As you've all heard, the ABILITY-1 data demonstrates that MDNA11 has the potential to establish a new standard in IL-2-based immunotherapy, including generally immunotherapy, one that combines potent antitumor activity with tolerability profile that could expand treatment options for patients with advanced solid tumors. We remain committed to advancing this program as rapidly and responsibly as possible, and we look forward to sharing additional updates with the investment and medical communities as our trial progress.

For those interested in learning more, please visit our website at www.medicenna.com or reach our IR team with any follow-up questions. Thank you again for joining us, and we look forward to discussing this exciting progress with you all. This concludes today's call, and you may now disconnect.

Medicenna is a clinical-stage immunotherapy company focused on developing novel, highly selective versions of IL-2, IL-4 and IL-13 superkines as well as first-in-class empowered superkine. CEO Fahar Merchant is here to tell us about the company and the large portfolio of drugs in the pipeline and imminent release of clinical data.

I'm Martin Gagel with Market Radius Research. Please remember, this is neither a recommendation nor investment advice. We're here to learn about the company.

Fahar, thank you for joining us. I've been looking forward to this for a long time. How are you?

Yes. I'm doing very well. Thank you. Great to catching up again. And I think we met about a month ago or so. But good to see you again. Thank you.

All right. You have got a lot going on in your company, a very science company. So I look forward to you doing a relatively brief overview on the story to give us the key highlights. We're not going to try to get too science-y on this, but understand what the implications of the science are. So I'm really looking forward to this. And why don't you take it away? Thank you.

Thank you. Okay. So as always, just to make sure that I put up this disclaimer here for the benefit of our listeners that encourage them to look at our risk profile, et cetera, on our website.

But let's start with the company itself. So Medicenna, as you said, we are a clinical-stage immunotherapy company. The focus is really to transform how we treat patients using approaches that are unique, but at the same time, very compelling based on the data we've generated so far. And just to give you a bit of background in terms of the company, we started the company about 9 years ago, essentially bringing in some assets. The first one that is the most advanced program is called MDNA55 or bizaxofusp or for some may want to call it, biza for recurrent glioblastoma. This is a program that's Phase II ready. We'll talk about it briefly towards the end of this conversation today.

And to complement that particular program, we licensed some really exciting intellectual property from a lab at Stanford University. These are based on what we call superkines and really develop these superkines using technology that became a part of the Nobel prize in 2018. So a really exciting platform that we've got within Medicenna.

And as we went public, thereafter, we sort of advanced the company into clinical trials with our second program, which is MDNA11, we'll talk about it today because we have new data coming up in the coming weeks. And this is a program where we've been able to secure a clinical collaboration with Merck. And we did provide some early data of this clinical trial last year at a conference.

And then we had an inbound interest from one of the largest institutional investors in the biotech sector, RA Capital that conducted a $20 million non-brokered financing, which was -- providing us with really a very strong third-party validation of our programs and our platform, particularly around our superkines assets that we have. And today, RA Capital is the largest institutional shareholders at Medicenna and we'll talk about MDNA11 and our next generation program on the bi-specific space.

Just for the benefit of patients or the listeners here, we are a clinical stage company. By that, I mean we have data now in about 250 patients with half of them with glioblastoma, the other half with really end-stage solid tumors. So I'll share that with you today, and that is really crucial.

So moving on to our pipeline. The top -- the program that we are looking to partner is the brain tumor program. This is recurrent glioblastoma, very aggressive end-stage cancer patients. And we are looking to further provide and present some updated clinical data from this trial in a publication, but at the same time, are working aggressively on partnering this asset.

Today, though, I will talk about MDNA11. This is our IL-2 super agonist and this particular program is -- just to give you a bit of background what is MDNA11? What is an IL-2 super agonist? I think what is really important is to demonstrate or to basically leverage our immune system to fight cancer. And what IL-2 does essentially is boost the cancer, our immune system to really fight cancer very effectively. So if you go back to the slide deck, one of the things what we have is really data that we will share on MDNA11 that's been used on its own, but also in combination with Merck's KEYTRUDA, this is sort of a multibillion-dollar blockbuster that I'll talk about later on.

And then more recently, we just announced the use of MDNA11 in a neoadjuvant setting. So what does that mean? Well, neoadjuvant is very early stage before the patient even gets surgery, we want to treat patients when they have their immune system, which is much more healthier and therefore, more likely to benefit the patient and hopefully, the tumor never comes back. And that's a challenge that we have to deal with. So when we are treating patients right now in the MDNA11 clinical trial, we're really treating patients who are end-stage patients, who have a poor immune system to begin with. And therefore, the approach here is to leverage that information to see can we get and treat patients much, much earlier so that the tumor hopefully never comes back after surgery because we have, in essence, somehow vaccinated the patient by using MDNA11. So that's the third program that we've got going.

And then back to the pipeline, I'll sort of focus on the fact that we have MDNA113. This is our bi-specific program. There's a lot of excitement around this particular space, and I'll share with you on that as well. So really, we'll talk about MDNA11, MDNA113, et cetera, and briefly about bizaxo.

So let's talk about MDNA11. So MDNA11, we have conducted a clinical trial. But just going to basics around MDNA11. MDNA11 is really based on a molecule called IL-2. So IL-2 has been approved actually nearly 3 decades ago for the treatment of patients with skin cancer and kidney cancer. The challenge with IL-2 is that, first and foremost, it doesn't stay in your bloodstream for very long. So patients have to be administered the drug every 8 hours, and therefore, not ideal, particularly when patients have to then stay on and get this drug for 5 days in a row. So really, it's 15 infusions for the patients not convenient.

Second thing, which is really the challenge here is that IL-2 on its own is incredibly toxic. Actually, patients when they come to the hospital to get treatment with Proleukin, they have to go straight into an intensive care unit because the challenge is that the drug might actually kill the patient. So it's a really tough drug to administer and therefore, not surprisingly, it's not a popular drug that's not been used.

So to -- one of the things that is important is that IL-2, although it helped a few patients, it did in some patients, cause what we call long-term cures. And that is important because what is out there that actually cures patients of cancer. So IL-2 certainly has an exciting opportunity, the problem is, it's not the best molecule.

So with MDNA11, as have others, what you see is there's been multiple efforts by Roche, with Bristol-Myers, by Sanofi, multiple transactions, multibillion-dollar transactions have taken place, where they've taken the Proleukin and creating a version that stays in the bloodstream longer. But that alone, as you can see, has not helped. All those trials have failed. And we felt that you have to do something very different. And this is where the superkine platform from Stanford comes into play, because not only are we changing the molecules to make it safer, but we are changing the molecule to make it much more powerful and potent.

And third is that we are modifying the molecule, so it stays in the bloodstream for much, much longer. So you're treating patients once every two weeks instead of three times a day for five days. So these are the key things we've done with Medicenna's drug. As you can see on the extreme right, all the changes we've done are designed to make the drug safer, more effective, et cetera. So we're combining the art of using albumin to extend the half-life of the drug, as you can see on this particular structure is we've inserted albumin.

And what albumin does, it sort of localizes the drug at the tumor site, and also localizes our IL-2 superkine in the lymph nodes. And these lymph nodes is where your immune cells get trained. It's like going to a school to be educated. And that's where the immune cells get educated to attack the tumor. And therefore, really crucial that we are able to do that. And nobody else uses this approach other than Medicenna. So we are doing two things, using the best potential IL-2 molecule, but at the same time using albumin to localize the drug.

So just to give you a -- yes, go ahead.

Sorry. And just to clarify, the IL-2 and the cytokines, they don't actually attack the cancer itself. They're -- it's more about the communication system within the body. The, a, cancer sort of, they're like -- they disrupt the internal communication system and say, "Hey, we're not nothing bad for you. So the immune system, you can ignore me." And then your drugs actually say, "Hey, go attack those things. They are the bad guys." And it's more of a communications mechanism. You're not actually targeting the cancer itself. You're telling the body to target them.

Exactly. So we are using our existing immune system and leveraging that immune system and using IL-2 to use and sort of deploy the immune system, sort of creating, let's call it this way, we've got the immune system, think of them as solders, and we're sort of recruiting those soldiers, we are training those sorters, and we are training the solders to recognize who your enemy is. I think that's the important thing. You want to make sure the immune system is able to recognize who the enemy is. And build a really strong army to attack the tumor. So that's the really important thing, okay?

Excellent. Thank you.

So one of the approaches has been in recent decade or so, the immune system has been leveraged by pharma companies like Merck and Bristol-Myers. You can see the world's second best-selling drug, I mean the Ozempic just is now ahead, but the second best-selling drug in the world is KEYTRUDA. And KEYTRUDA is being used. The current revenues are just under $30 billion a year for this particular drug. And in end-stage patients, it shrinks tumors in about 15% of the patients sometimes much, much lower. And this drug when patients are newly diagnosed, it only helps about 30% of the patients. The remaining 70% of the patients do not benefit from this drug.

And same with Bristol-Myers' drug, it's called OPDIVO. And it has the same mechanism anti-PD-1. And as you can see, sales of about $10 billion here. So these are big blockbuster drugs that are able to help about 1/3 the patients and remaining 2/3 not benefiting. And it is these 2/3 patients that we've been trying to treat in our clinical trial. That have failed the checkpoint inhibitor, that are not responding or simply too advanced for KEYTRUDA or OPDIVO to work in these patients.

So this is sort of the early data that we have shared. The key thing here is can we in these patients, mind you, these are late-stage patients of failed multiple therapies, including the blockbuster drugs, can we improve their survival outcomes or even shrink these tumors? And we're already seeing that. About 30% of the patients in the study so far with multiple different tumor types are -- we are seeing tumor shrinkage in some cases, complete regression of the tumor and in tumor types such as pancreatic cancer, which you know and most of us know, is one of the most aggressive tumor types out there.

So it's not only shrinking the tumor, but it is sort of keeping the tumor out of being able to progress for an extended duration of time. So the key thing here is, is it durable? Shrinking the tumor and then the tumor coming back after 4 weeks, doesn't really provide much benefit to the patient. But if we're able to shrink the tumor and keep it that way for several months or years or potentially cure these patients, it's fantastic. It's just unheard of. And this is where we are beginning to see those kind of data.

So let me pick up this one particular patient, this pancreatic cancer patient. This pancreatic cancer patient received surgery, the tumor had metastasized to the liver, and then received multiple chemotherapies, and that patient continued to have the tumor progress, advance, and those chemotherapies were toxic. And then eventually, the patient got the big $30 billion blockbuster drug, KEYTRUDA. And when the patient got KEYTRUDA, the patient's tumor continue to spread and expanded, and this is in the liver, which is really tough to treat when you have metastases occurring in the liver, it's a tough one.

The patient entered the clinical trial and the patient -- when we did the first scan, we saw the tumor shrank by about 25%. And as we did more scans on this patient, we saw that the tumor continued to shrink to a point where 8, 9 months later, the patient decided to take a 7-week vacation. Patient went away on vacation, came back and the tumor that was in the liver had disappeared. But the patient had a new tumor that had showed up. So what they did was, did a single cycle of radiation and started the patient back on MDNA11. And what happened was within 3 months, the liver lesions have gone, the new tumor that had showed up had disappeared. And December 2023, this patient stopped receiving treatment with MDNA11 and has not received treatment with MDNA11 or any drug at all since then. And that pancreatic cancer still remains in what we call remission, and there's no sign of the tumor. So that's pretty impressive.

Same thing with a melanoma patient. We had this melanoma patients who had failed multiple checkpoint inhibitor therapies. The tumor in this patient started to shrink as soon as we started to treat with MDNA11, completely disappeared. And then for at least 10 months now, the patient has no sign of the tumor. So this is showing that we are beginning to see the sort of long-term potential cures with MDNA11 on its own in patients that are end stage.

So the thing is where do we go from here? So if you go to the next slide, what you are able to also see is that in addition to pancreatic cancer and melanoma patients, for instance, we are seeing that in endometrial cancer patients. So this is a tumor type. The patients that we treated now with obesity on the rise, there's a higher incidence of endometrial cancer. Patients typically will get surgery after that they'll get chemotherapy, and after chemotherapy, there is a treatment that's been approved recently is using KEYTRUDA, which is that multibillion-dollar blockbuster drug plus another chemotherapy. The two together have been approved for use.

And basically, what happens is that even those patients do not respond. And this is where we treated endometrial cancer patients that fail surgery, chemo and KEYTRUDA in combination with a chemotherapy drug. And these patients today when they fail the therapy, they have no standard of care, that is there are no approved treatment options for these patients. And we've already found that these patients that were in the study, received a combination of MDNA11 with pembro, two out of four patients had tumor shrinkage. And this is very exciting because otherwise, these patients would not typically have any other options. So we're seeing in end-stage patients, there's an opportunity with MDNA11.

Just to give you an example of a drug, for instance, that being used for melanoma. Just to give you an idea, even if MDNA11 was being pursued for just melanoma, you can see the market cap of the companies that have melanoma drugs approved and you can see that in these patients with a 30% response rate, market cap is about $800 million, nearly $1 billion prior to some recent changes that have occurred. But with Medicenna, you can see our market cap is substantially lower.

The opportunity for MDNA11 is not restricted to just melanoma. As I've seen in pancreatic cancer, in other tumor types, including endometrial cancer, and you can see the current clinical trial is enrolling patients with these other tumor types that are biomarker driven, where the number of patients is much, much larger than melanoma, which is just 7,000 to 10,000 patients.

So in summary, what we are saying is really that if you look at patients who fail these multibillion mega blockbuster drugs and are responding to MDNA11 either on its own or in combination, there is a huge market opportunity for MDNA11 with these different tumor types. And we think that if you take this drug earlier stage in patients who have just been diagnosed with cancer, where the patient has a much better immune system, we think that this will be really a groundbreaking paradigm-shifting treatment option for the patients.

And this is where the NEO-CYT trial. This is a slide that you can see, this is funded by the Melanoma Foundation in Italy, Medicenna requirement is to help with the regulatory filings, but also provide the drug for the clinical trial. But other than that, they conduct a clinical trial in 12 hospitals across Italy and potentially in Europe in patients that have melanoma and these patients are going to receive surgery.

But what we do is ask the patients to delay the surgery by about 8 weeks. We treat them with MDNA11 in combination with the standard of care, which is Bristol-Myers' drug called OPDIVO or nivo. And 8 weeks later, we surgically removed the tumor and we get a chance to see if the tumor shrank with MDNA11 plus the checkpoint inhibitor. And if it did, then the question is why even bother conducting surgery in these patients?

Now in melanoma, it's relatively easy to surgically remove the tumor. But in certain cancers, when you surgically remove it, for instance, if you have a stomach tumor. To remove the stomach has really bad consequences on the patient's quality of life for the rest of their life. If you have anal cancer, if you have rectal cancer or colon cancer or bladder cancer, if you have to remove those organs, the quality of life deteriorates substantially. But if you are able to treat the patient and save the patient from receiving surgery, that would be a fantastic not only in terms of having cured the patient, but also having the patient maintain a good quality of life.

So melanoma is our first venture into this early-stage disease with the potential of pursuing other earlier-stage tumor types that we think could have a huge impact on patient survival and potentially long-term cures where the patient's tumor doesn't come back within weeks or months, which is typically the case with other therapies.

So basically, that's where we are. Moving on to sort of the next slide is our second program. This has really been very exciting. There's been a lot of transactions that have taken place. If you look at what we call anti-PD-1 bi-specifics. And the reason there is this excitement is that data is showing that when you combine or create a molecule that has two functions, namely the checkpoint inhibitor together with another mechanism, you have a better outcome for these patients.

So the top table basically shows that Merck's drug, KEYTRUDA, and Bristol-Myers' drug, OPDIVO, combined annual sales of $42 billion, will be going off patent in about 2.5 years. And we feel there is a fantastic opportunity for us now to leverage that information and create much better molecules.

So on the extreme right, as we go back to the previous slide, just to let you know, over the past 12 to 18 months, the transactions in the bi-specific space has totaled about $35 billion. The most recent one and one of the largest ones was the $11.4 billion deal between Takeda and Innovent. And this is a drug which is an anti-PD-1 fused to IL-2. So let us look at this particular program, the anti-PD-1 and IL-2 approach, and that's what we are using at Medicenna with our 113 drug.

So going to the next slide, this is what we have is -- so what's Medicenna's 113 drug? How is it different from the recent Innovent-Takeda transaction, okay? First and foremost is if you look at that Y-shaped structure, the gray structure on the left on the slide, that's the structure of an anti-PD-1 drug. That's your OPDIVO, that's your KEYTRUDA drug, okay? That's what it is. And as I said, that's going off patent. So the good thing here is what Medicenna is doing is taking one of the world's biggest blockbuster drugs and using that to create this bi-specific molecule.

Second is that green circle that you see there is our IL-2. It's the same IL-2 that you find in MDNA11. MDNA11 has shown single-agent activity, it's able to treat patients who failed checkpoint inhibitors. So we are linking the best IL-2 with the best anti-PD-1, okay?

And the third thing we are doing is we're saying we want to have the drug so that it's safe and it localizes at the tumor site. And for that, you can see those pink squares, those are the -- that's a molecule called IL-13 superkine. And the reason we've put that in is because it localizes the drug, it sort of delivers, it navigates through our bloodstream and takes the drug right to the tumor site and essentially, the drug, while it is traveling through our bloodstream, it essentially is inactive. So it's not going to cause toxicity. The moment it gets to the tumor, the pink boxes are removed and the drug is switched on and that's where the drug will stimulate your cancer-fighting immune cells.

It does two things, it will bind to the anti-PD-1 receptor on the T cell, which is your cancer-fighting immune cell. And the IL-2 will also bind to the same T cell. So now you've got this super strong, call it, the Navy SEALS of your immune system, where you have the best possible immune cells to fight the cancer. And this is where there's a big deal here.

And one other thing to let you know is that the IL-13 is actually targeting tumors and these tumors that have what we call the IL-13 receptor are by far one of the most aggressive tumors. Patients that have the IL-13 receptor have very poor survival outcomes patients with pancreatic cancer, colon cancer, brain cancer, et cetera, breast cancer or lung cancer. They have high amounts of this particular target known as IL-13 receptor. And every year, 2 million patients are diagnosed with this kind of tumor. And therefore, the market opportunity is massive for 113 where you can deliver this drug right at the tumor site, particularly in cold tumors that don't respond to checkpoints, et cetera. This is where MDNA113 will play a big role. And I think we've got a much better version of MDNA11 or MDNA113 than Innovent.

Innovent's IL-2, as you can see here, has got safety issues. You can see that there is a risk of patients dying because of the IL-2 because it's not been engineered the way MDNA11 or our IL-2 has been engineered. So that is the one and first and foremost thing. The second thing is also when we look at just the efficacy data, Innovent's drug in patients who failed checkpoint inhibitors, you have response rates of only 30%, which is great in patients who have failed checkpoint inhibitors and which is what we get with MDNA11 alone. So MDNA11 alone is just as good as Innovent's anti-PD-1 IL-2 molecule.

So this is the big deal that we have is that, first and foremost, the IL-2 we are using has proven to show single-agent monotherapy activity in failed patients, in sort of end-stage patients. That's one thing. Innovent's IL-2 has not shown, in fact, has never been tested in the clinic. So we don't know how good their IL-2 is, except for the fact that we see there is a high risk of death in these patients.

Second, the PD-1 or the anti-PD-1 they use is their own version that's been only approved in China. It's not been approved. It's not like your blockbuster KEYTRUDA or OPDIVO. Medicenna's 113 contains the blockbuster OPDIVO or KEYTRUDA. So that's the big advantage. So we've got the best of both worlds. We've got the best anti-PD-1, we've got the best IL-2, and we have masked the molecule, say, targets and accumulates at the tumor site. So we are basically anchoring our drug right at the tumor site until it does its job, and that's what is unique about our drug plus the safety.

So this is where we are with 113. We are now conducting studies in non-human primates, namely monkeys. We have that data in early January. We hope to share that. And if it shows, the key thing here is for us to demonstrate which of the anti-PD-1s we'll use, is it going to be KEYTRUDA or OPDIVO, we'll select that based on our monkey study. And essentially, what we'll be able to share is the fact that we'll be starting the clinical trial with this drug in the second half of next year. And we think that the way the drug is designed provides us so many more advantages than the other competitors out there, okay?

Fahar?

Yes.

Sorry, just connecting 11 with 113, they're both using the same IL-2 superkine, correct? They're just attached to different other molecules and being targeted in different systems in the body, if that's...

Correct. So MDNA11 is basically linked to albumin. So it accumulates in the tumor draining lymph nodes, et cetera. This IL-2 in MDNA113 it's linked to the checkpoint inhibitor, anti-PD-1, okay? So that's the difference. And to localize the drug and make it accumulate at the tumor site, we're using an IL-13 superkine. So that is very, very specific. It will only bind to tumor cells that have this particular target.

So what I guess I'm getting at, when you get data that the -- your IL-2 superkine works using the MDNA11, that also provides evidence, well, you know what works here and then combined with -- it can hopefully then work out. So the data from one supports in some -- to some extent, data in the other program. Is that correct?

Absolutely. And that's we've demonstrated that our IL-2 on its own works. And there's plenty of evidence. Obviously, we all know the anti-PD-1s are for KEYTRUDA or pembro, those are blockbuster drugs. So we know those work as well. So basically, we've taken the best of both worlds and link them together.

So finally, I think we don't have too much time. So I won't spend much time here on bizaxofusp simply that we want to give you an opportunity for Q&A. So if there are any questions, we can address it. But suffice it to say, this is a program where we are looking to partner this asset. This is a drug to treat patients with recurrent glioblastoma. And just for a bit of background, GBM is by far, like pancreatic cancer, one of the most aggressive cancers out there. Patients typically get -- when they are diagnosed, about 80% of the patients will get surgery. They will then get radiation with a drug called, temodar, a chemotherapy drug, and this would be like a 6 weeks of treatment. And then patients get this high dose of this chemotherapy until the tumor comes back, which unfortunately happens in the majority of patients.

So GBM is the tumor type. I think from a Canadian perspective, we know Gord Downie. He passed away because of GBM. In the U.S., we had Beau Biden, son of former President succumb to GBM. We had also one of the Kennedys as well as Senator John McCain, all succumbing to GBM. And there's really been nothing out there for the past 30 years, particularly when the tumor comes back. And when the tumor is recurrent, that means the tumor has relapsed, those patients have much more deeper, more aggressive tumors and majority of these patients will pass away in about 6 to 9 months.

So the key thing here, just to give you a message here is the drug that was approved 30 years ago was temodar, and this is still the standard of care, in newly diagnosed patients who are first diagnosed with brain cancer. Temodar has improved survival by 10 weeks and became a $1 billion blockbuster for Merck. We, on the other hand, are looking at patients who have failed temodar, have failed surgery, have failed radiation. The tumor has come back, it's now deeper in the brain. And our data, if we show the next slide, will show that we've been able to demonstrate that not only have we increased survival with bizaxofusp, we are improving survival not by 10 weeks, but we are improving survival by several months. It's about 7 months nearly doubling the survival in these patients.

So really encouraging data, we'll be publishing some updated results from the clinical trial. We are partnering this asset, I know we've been trying to partner this asset, but they've been really bad data from previous attempts by other companies trying to develop a drug for GBM. So we think now there's been a bit of interest in this GBM space. We're seeing a lot of inbound interest. We're hoping that we'll partner this program sometime next year. And not only for GBM or recurrent GBM, we feel there's an opportunity for tumors in the brain that's spread from the breast, from the colon, from the kidney because there's a much bigger market opportunity. So potentially a huge opportunity for GBM.

And our current focus and the spend of the company's current cash resources is on MDNA11 and 113. We have enough cash to take us into Q3 next year. And we have, as I mentioned, RA Capital as the largest institutional shareholder, insiders own 22% of its outstanding shares. So there is really skin in the game. And we have analyst coverage by various banks out there, the most recent one based off New York by Lucid capital.

So key highlights, I would say, in the coming weeks. We'll be presenting data on tenth of December on MDNA11, the monotherapy and combination data. We are planning to complete enrollment in this clinical trial as soon as you possibly can, it's sort of heading nicely. As I said, we've enrolled about 120 patients so far. So these are the key data readouts coming up in the next few weeks. We also will have data by early January on our non-human primate study with the bi-specific MDNA113. And we continue to advance bizaxo in terms of trying to partner that asset.

So with that, I'll stop and take questions.

Fahar, thank you. That was -- I feel a lot smarter now. I feel like I know a bunch more. So I appreciate that.

I'm just curious, since you have it on the screen here, you're releasing the data on December 10. Is that in conjunction, is that the ASH conference? Or is that -- are you presenting data at a conference where you sort of booked the time in that? Or can you -- what's the rationale for December 10?

So December 10 is consistent with the conference called the European Society of Medical Oncologist, there's ESMO meeting taking place. It's focused on immuno-oncology taking place in London, in U.K., and that's when we'll be presenting our data at that conference. So we'll share that pretty much on the same day.

On the MDNA11, you've been doing end-stage cancers. You focused on that. And then with the melanoma that is you're focusing on earlier stage. Is there a reason you started at the end-stage. Is it easier to get regulatory approvals since they don't have many options? Or what was the rationale for that end-stage strategy?

Really good question here. And I think I appreciate that because I failed to mention this. But one of the reasons that you would look at end-stage patients is there is a good possibility, particularly in the tumor types that we are looking at, that the FDA will allow you to conduct a Phase II trial and that would be enough to get you approval based on data from about 50 to 100 patients. So that is one of the reasons, and that's one of the approaches that we are pursuing with MDNA11 in end-stage patients.

Although we have conducted the Phase I/II trial, we have demonstrated that the drug works on its own or in combination, and in patients who failed standard of care. So these patients generally do not have any other treatment options. And the only thing they can do is enter a clinical trial. So the FDA and other regulators, including the Europeans will allow you to get the drug approved based on a Phase II trial. So that's the way to get into the market quicker and faster and less expensive.

The data we're expecting on December 10, is that powered enough that, that could trigger the accelerated approval? Or would you need an additional study to...

Yes. We would need to do a small Phase II study, yes. So we need more patients. So anywhere typically from 50 to 100 patients, it could be as many as just 70 patients to get the data readout, to get approval. So it's relatively small compared to, let's say, melanoma in newly diagnosed patients that might be hundreds of patients. So that's much faster, quicker. And then quickly, if you could transition into first-line therapy after that.

And given the data that comes out, if it's positive enough, do you then take that to the FDA and they say, "Hey, this looks potential that we could do a smaller pivotal trial for end stage." And then you're going to get pre-approval for them, then yes, this structure like this. And if you get past certain thresholds, this could trigger the accelerated approval?

Correct. Exactly. So basically, once we have this data, early next year, the plan needs to meet with the FDA, provide our data and get their feedback with respect to a potential pathway for accelerated approval. And then based on that, we would then design the study to meet the FDA guidelines and pursue a small Phase II clinical trial, either our own or in partnership with a bigger pharma.

All right. And I guess I just want to go back to broader on the MDNA11. Because it triggers the immune system, it just dawn on me that -- because you're targeting a lot of drug companies I talk to, they have one drug targeting, one very specific indication. You're like all sorts of tumors, melanoma, pancreatic. Is that because it is like an immuno-therapy where it just gets the body like the soldiers trained and so forth? And then I guess there was one chart you showed that like as once you knock down each of these targets, it just potentially creates a much bigger market for you or many markets for you to go after? Is that a good way to think of it?

Very good way of thinking of it. It's very much like KEYTRUDA. For instance, KEYTRUDA today is used to treat a couple of dozen tumor types. So you can imagine there's sort of a huge opportunity, although the first approval was for melanoma. It's now essentially being used for 20, 30 different tumor types. So that's the same approach here by KEYTRUDA or OPDIVO, those don't attack the tumor. They basically are -- basically what they do is they remove the brakes from the immune system, so that immune system can now function because the tumor is clever. It sort of puts a break on the immune system so that the immune system does not recognize the tumor. The immune system is neutralized. But by using pembro, they basically restored to sort of remove the brakes on the immune system, so it can attack.

What MDNA11 does is basically takes the immune system and trains the immune system to fight the cancer. And I think that's where the big difference is in terms of being able to use the drug for many more tumor types rather than just one particular tumor type.

Okay. We've got a bunch of questions from the audience. Fahar, can you talk about the interest in partnering activities with Medicenna and all the recent conferences Medicenna has attended?

Yes, of course. I mean the thing is, particularly with MDNA55, there's renewed interest with the GBM or the glioblastoma program. But more interestingly is the recent transaction of Takeda with Innovent. As you know, in the past, the IL-2 space, had multiple multibillion-dollar transactions that took place. Unfortunately, the IL-2 programs that they were developing were not showing activity and therefore, the interest in the IL-2 space diminished. But now again, with the recent deal with Innovent, the interest in the IL-2 space is reinvigorated. The data readouts that we will share in the coming weeks and months will be based on MDNA11, but also MDNA113. We think, and we've seen that a lot of interest, a lot of inbound interest coming into Medicenna without us soliciting any meetings, we've been getting some encouraging feedback on the data. So really excited about what sort of the upcoming milestones are, but also the interest that we are generating with our platform.

I'm going to stick to the sort of the corporate side of things here. You mentioned recently big pharma in M&A buying spree likely driven by patent cliff dynamics. What stage does Medicenna need to be, I guess, for the various programs to be an M&A target? And I just want to break that out a little further, with the different programs, there's M&A potential, but there's also licensing, like obviously, the GBM indication that's ready and packaged up for it, I guess you're getting a little more data. But for each of the MDNA11 and the 113, like is MDNA11 have enough data? Or obviously, they're going to wait for this upcoming one here? I've said a lot and sort of please respond to that general theme.

Yes. So no, certainly. I mean, the key thing here is, as you mentioned, there could be partnership transactions, it could be licensing, very much like what Innovent did was $11.4 billion deal with about $1.2 billion upfront. So in a sense, it could very well be a meaningful partnership transaction and not necessarily an M&A transaction. It could be both. I mean it could be M&A for the program, but MDNA55 or bizaxo could be partnered. So there's sort of different ways of structuring that.

The key thing here is data wise, the data that we are generating with MDNA11 so far, the feedback generally is from a pharma company perspective, typically, data in different tumor types would be ideal to have data from about 20 patients for each tumor type, which we are approaching in some tumor types. So we are continuing to build that database from MDNA11.

With MDNA113, it could be -- I mean, the recent transaction was -- with Innovent's drug already in the clinic, although their clinical trial has been conducted all in China. They are sort of starting next year, a clinical trial that will be global, so they will be enrolling patients in U.S. and so on. But I think as we've done in the past, we'll be studying the clinical trial right away with MDNA113 globally, starting in the territories that we've used with MDNA11 in the past. The question is, will they wait for clinical data to transact with Medicenna on 113? Or is data from non-human primates going to be sufficient enough together with our preclinical data for them to get comfort around the fact that the drug is safe, it has the right profile with respect to its pharmacokinetics, pharmacodynamics, et cetera? Because the big negative about Innovent's drug is that it is toxic.

And just to let you know, it wasn't Takeda only bidding, there were other companies bidding as well. So there was a competitive process going on. We don't know who the others were, but we know they were. So there is certainly interest in other big pharmas to acquire anti-PD-1 IL-2 program. But I think the key thing here is the differentiation will be the fact that we have an active IL-2 and best-in-class checkpoint inhibitor and a safe molecule. So that's the key thing.

All right. Is the enrollment completed in both mono and combo or is it still ongoing?

Still ongoing. We are continuing to enroll until the end of this year. We'll be looking at some of the things that as we are contemplating a Phase II registration trial, the FDA generally likes to have something called Project Optimus. they want to be sure of what those will implement in a Phase II registration trial. So we may extend that to add another dozen or so patients, but that's basically been already incorporated in our sort of runway calculations.

With that potential or that expected potential small Phase II study for the FDA for an accelerated pathway, just ballpark, like roughly would that be a 1 year or 2 year? Can you give us some indication of how long that process would take?

Yes, it depends on the tumor type. So for instance, melanoma, endometrial cancer, those are much faster to recruit than patients with, let's say, MSI-high tumors, TMB-high tumors, again much faster to recruit. So it depends on the tumor type. It could be as short as a year or as long as two years, depending on the tumor type. So that's -- it sort of ranges. Yes.

All right. What objective response rate or ORR percentage is considered very good for the upcoming MDNA11 drug? What would be good results there?

Yes. So really, the threshold or the benchmarks that we want to sort of achieve. I think with endometrial cancer, for instance, the response rates there are very poor in this patient population. It's as low as 5% to 8%. So if we get response rates well above that in the sort of 15%, 20% range, that would be fantastic. MSI-high, TMB-high. Again, these are patients who failed checkpoint inhibitors. The benchmarks we've been told is going to be about in the 20% range. With melanoma, 30% would be fantastic as well. So those are the sort of the range anywhere, depending on endometrial cancer being the lowest bar to melanoma being the highest bar.

On December 10, when you present, will you be presenting a poster or will you be making a presentation?

This will be a poster presentation by investigators. So it's the -- one of the hospitals that's treating patients will be doing the poster presentation.

What has Merck, your partners' feedback been on MDNA11 combination data so far? Can you comment on that?

Yes, they obviously are encouraged with the data so far. We continue to interact with them every quarter. We certainly cannot disclose publicly what discussions we're having with them, but suffice it to say that they are encouraged with both monotherapy and combination data of MDNA11.

Is there a benefit or potential significance that Bristol-Myers is supplying the checkpoints for the Italian study versus Merck who's supplying the KEYTRUDA for your current MDNA studies. The fact that you're working with two large pharmas here, should we read anything into that? Obviously, they know who you are.

Yes. I mean the thing is that it's obviously -- we want to use the drug that is currently standard of care. For neoadjuvant purposes in melanoma, the standard of care is the Bristol-Myers drug, which is ipi and nivo. So this is sort of OPDIVO is the standard of care in neoadjuvant setting, pembro is not. So that's why we are working with Bristol-Myers on that.

With the other tumor types that we're talking about are like MSI-high, the endometrial cancer, the TMB-high, et cetera, multiple -- and melanoma, there are multiple checkpoints have been approved, including pembro. So basically hedging our bets, I would say, having both -- trying the drug with both different drugs, both checkpoint inhibitors, including 113. We have a version of 113 that contains Bristol-Myers' OPDIVO. We have a version of anti-PD-1, which is a KEYTRUDA, Merck's drug. We'll be testing both of them in non-human primates, and we'll pick the best one of those two.

You said you have cash runway right now until Q3 of 2026, there's a question here on when will you raise cash. I guess that's a little bit based on -- and just discussed these different -- there's so many different paths that could happen, how good the data is and then does that create a partnering or a licensing deal and so forth or you may just raise equity on the back of good data. Can you just talk about the different potential funding paths you have ahead of you?

Yes, it could be any one of them. So all options are open in terms of -- there could be inbound interest. Just to let you know, we had, for instance, RA Capital on the back of good data last year. This basically came in with a commitment to a reasonably sized $20 million check. So the key thing here is we could do that. If that occurred, the potential of a partnership, potential for collaboration, et cetera, those could be, again, discussions that would be in the open in terms of open to that kind of deal structure as well and/or do an equity raise on the back of more data, more data from the MDNA113 program as well.

So it's sort of no particular timetable per se, but certainly, if we are aggressively going to pursue a Phase II registration trial, yes, we will need additional capital. And the question is, where does that come from? And that sort of could be inbound interest, could be something we pursue on our own with the banks or it could be a partnership deal, which could bring non-dilutive capital in the company.

And you can weigh them all against each other, depending on how strong the share price is. You could do equity that would maybe be better than a partnership or the partnership could be very advantageous or do a combination thereof?

Correct. Agreed, agreed. Yes, the more clinical data we have, the better deal structure we can have in a partnership setting.

Do you envision MDNA11 and MDNA113 working together over time? Is the idea that MDNA11 restores immune architecture and 113 amplifies the response?

Yes, really good question, and that's something exactly what we are also studying right now is certainly sequencing, the treatment approach. MDNA11, as I mentioned to you, is generating on its own, boosting the population of immune cells very substantially. MDNA11 is generating your sort of, call it, high-quality cancer-fighting immune cells, call them the Navy SEALS. And as you do that, the question is, how can you further push the immune system. And this is where MDNA113 comes in play. So once you built up your army, let's put it this way, you've got enough soldiers now. And now you want those sources to be very targeted, very specific, precise and execute their mission, that's where 113 comes in. So it sort of makes obvious choice instead of combining MDNA11 with a checkpoint, why not combine MDNA11 with 113.

What's the difference between the current combination trial, MDNA11 plus KEYTRUDA versus MDNA113?

Well, that's a good question. Again, I think the key thing here is the MDNA11 purpose is different. It's basically to build up the immune cell population. And the second thing is the KEYTRUDA is there to simply release the brakes on the immune system. So the immune system can go working at it.

Now with that approach, when you're injecting two drugs separately, the IL-2 is going to stimulate your immune cells and the anti-PD-1 is going to release the brakes on immune cells. Does it do it on the same cells? Probably not. So what happens is when you administer MDNA11 on its own and KEYTRUDA on its own, two separate injections, the probability that both MDNA11 and KEYTRUDA will attach to the same immune cell is low.

Whereas if you have 113, the way it's designed, the two molecules work are connected together. Once it binds to the IL-2 and binds to the anti-PD-1, that effect is occurring on the same T cell, the same immune cell. So now you're creating a different kind of immune cell, this is your sort of call it Navy SEALS of your immune cells. And that's what it is. So that's basically when I said you would probably treat patients with MDNA11 first to really build up the T cell population, and then you treat patients with 113. So now all those T cells or your soldiers, instead of only some being your Navy SEALS, all of them are your Navy SEALS, right? So you're -- that's basically the difference.

All right. And then one final question here, and then we really will wrap it up. Are you planning any orphan or breakthrough therapy designation for any of this from FDA?

Yes. So certain indications, I think if you look at patients who have failed, let's say, checkpoint inhibitors, that being the case with melanoma, for instance, that being the case for endometrial cancer, for instance. So those are potential areas where you could seek out orphan drug, fast track, et cetera, designations with the data that we have on hand. So yes, certainly, we'll be looking at that as well.

All right, Fahar, we should wrap it up now. Thank you very much. Any final thoughts or ideas to leave viewers with as we wrap it up here?

Yes. I think it's really important to say one thing is that the IL-2 that we have is really the core of a lot of ability that it has to really boost the immune system. I think it's highly differentiated with so many other IL-2s being pursued, the way we've engineered the molecule addresses so many key issues that are not being addressed by other IL-2s, or other cytokines for that matter.

And the fact that we are sort of leveraging our drug in terms of using the sort of the argument to localize it at the lymph nodes, that is really important because you need a versatile lymph node in and around the tumor. And albumin allows us to build that and repair that lymph node, so that you have a productive lymph node producing high-quality immune cells, and that is, again, something that's not being done by others.

And the third thing is that it's a really strong prerequisite in the sense that I believe that MDNA11 will become a prerequisite for other immunotherapies. It could be checkpoint inhibitors. It could be oncolytic viruses. It could be cell-based therapies. It could be antibody drug conjugates, we think that all of those treatment modalities, if helped by MDNA11, will do much better because you'll be able to generate what we call memory immune cells. And these memory immune cells then behave like -- almost like your own personalized vaccine that prevents the tumor from coming back as you've seen in a couple of patients already, despite the fact these were end-stage patients to see the tumors disappear and not show up for several months or now, a couple of years with the pancreatic cancer patient.

So that's, I think, the long-term goal is to destroy the tumor, but hope that the tumor doesn't come back. And that's basically the aspiration is essentially to do those two things, okay?

Fahar, thank you. That's leaving it with a big ambition there, big opportunities. So thank you very much. I really appreciate your time, very informative, very exciting. We've got lots of potential catalysts here coming up over the next few months. So that's very exciting and good to see. Thank you.

Thanks a lot. Okay. Take care.

You, too.

Okay. Bye-bye.