Medicenna Therapeutics Corp. (MDNAF) Earnings Call Transcript & Summary

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.