Good morning, thank you for joining our investor conference call. We're excited to have this opportunity to share with everyone our first data set from a study being run with the registrational intent. Before we begin, I need to highlight our forward-looking statement. On slide three. I'm Philip Astley-Sparke, CEO of Replimune Group, I have with me today from management, Robert Coffin, our President and Chief R&D Officer, and Sushil Patel, our Chief Commercial Officer. We're also very pleased to have with us today several leading physicians from sites all with considerable experience of using our products. Dr. Mark Middleton, PI on the IGNYTE study for which we are reporting data today. Mark is Professor of Experimental Cancer Medicine and Consultant Medical Oncologist at the Oxford Cancer Center, Head of the Department of Oncology at the University of Oxford. Dr. Mike Wong, Professor in the Department of Melanoma Medical Oncology at MD Anderson, and Dr. Kevin Harrington, Professor in Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant Clinical Oncologist at the Royal Marsden. Slide four shows the agenda for the call, which will start with a brief further introduction from me, followed by three content sections. The first section covers the data from the first 75 patients, of our 125 patient study in anti-PD-1 failed melanoma being run with registrational intent. The data speaks to the emergence of a potential new treatment option in this unmet need setting, with a 36% overall response rate, a 20% complete response rate, strong durability to date, and strong data in all stages of disease, including late stage four. The second section will speak to the commercial opportunity, as we seek to establish a broad skin cancer franchise with RP1 before providing an update in section three on RP2/3. Here we will disclose which of RP two or three we plan to bring forward, in relation to our previously disclosed phase two program in CRC, HCC, and head and neck cancer. We are also excited to announce today a cost-sharing collaboration with Hoffmann-La Roche in the potential faster market indications, of third line CRC and second line HCC. As proxies for success in hard to treat immune-insensitive tumor types, we'll be presenting some additional data in uveal melanoma and sarcomas. Following the presentation, we'll be holding a live Q&A. To ask a question, you'll note there's a question submission bar on your screen that will be open throughout the presentation this morning and during the Q&A session. We will collect those questions throughout the morning, and take as many as time allows. All questions will be held until the Q&A portion of the event. On slide six. As a reminder, we are the leader in tumor-directed oncolytic immunotherapy with three wholly owned programs. As aforementioned, we plan to establish a broad-based RP1 skin cancer franchise, and today have taken a giant step towards realizing that ambition, with strong melanoma data in patients with limited other options. We now look forward to revealing data in our randomized registrational study, in frontline cutaneous squamous cell carcinoma in the first half of 2023, having generated a high rate of complete response in a prior study. With a broad-based mid-stage development plan now in place for RP2/3 beyond skin cancers, the company has the potential to generate substantial revenues beginning in 2025. We have made solid progress putting in place the building blocks, to build an entity capable of transforming the immuno-oncology landscape. Our own manufacturing facility is fully operational. GMP batches have been released to the clinic, having shown comparability to the contract material we've used in our studies to date, and our BLA consistency lock campaign is now in full swing. In addition, our Chief Commercial Officer and his team are continuing the planning process to ensure, if approved, our products are widely adopted in the marketplace. Finally, we have a strong balance sheet to execute on our vision with runway into 2025. Next slide. As a reminder of our technology and MOA, tumor-directed oncolytic immunotherapy is the use of viruses that when injected into tumors, partially or completely destroy them through virus replication, bursting the tumor cells open and exposing all the released cancer antigens to the immune system in an environment of necrotic cell death. This leads to the activation of a patient-specific, systemic immune response and the disruption of uninjected deposits. On slide eight. Our platform is based on the herpes simplex virus, which we believe is an optimal viral species for oncolytic use, it being both highly lytic and inflammatory and having the ability to carry multiple immune-stimulating proteins into the tumor microenvironment to further amplify the immune response generated. Our strain of HSV has been deliberately selected for its lytic properties in human tumor cells, and from all of our products as our base platform, we express a fusogenic protein that greatly increases direct tumor killing, immunogenic cell death, and systemic immune activation. These design features ensure maximum presentation of antigen on the MHC of antigen-presenting cells. We then express various proteins from the virus intended to maximize costimulatory signals at the APC T cell interface to ensure optimal T cell priming. Our lead product, RP1, additionally expresses GM-CSF. RP2 additionally expresses an anti-CTLA-4 antibody to stop the negative feedback loop at the CD28 CTLA-4 axis. RP3, two further immune costimulatory pathway activating proteins targeting CD40 and 4-1BB, which also leads to downstream inflammatory cytokine release. Our confidence in our ability to establish a broad skin cancer franchise with RP1, is underpinned by broad activity across a variety of skin cancers as monotherapy and in combination with checkpoint drugs, including in the checkpoint refractory setting, where clear systemic long-term responses have been generated now in a substantial number of patients. Moving to slide nine. We are continuing, therefore, to make great progress towards our ambition of making our products a cornerstone of immuno-oncology treatment regimens as the most practical and effective way to initiate a systemic anti-tumor, tumor immune response. We are operating in only a small number of significant white spaces left in immuno-oncology, where we have the potential to have transformative benefit. Firstly, checkpoint failed disease and secondly, patients with liver metastases. On slide 10, the benefit now shown in anti-PD-1 failed skin cancers from multiple cohorts is now clear and obvious, and we've also seen anecdotes in multiple other non-skin cancers that we can benefit checkpoint failed patients. The dataset we're presenting today from 75 patients, is consistent with all our previous datasets in anti-PD-1 failed disease, with a 36% overall response rate and a 20% complete response rate, and points to the emergence of a new treatment option in this setting. On slide 11, we also look forward to seeing if we can broadly benefit patients with liver metastases, where IO drugs have hitherto been ineffective and prognoses are poor. We have seen multiple anecdotes of being able to benefit patients with liver tumors across a number of cancer types and look forward to progressing studies in HCC and CRC. Today, we announce we'll be collaborating with Roche in these indications, validating our approach. I will now hand on to Dr. Middleton, the PI on the IGNYTE study, to summarize today's dataset in anti-PD-1 failed melanoma. Thanks very much, Phil. Next slide, please. I'm gonna talk about second-line melanoma, and the landscape at the moment here is that there are no good options for our patients who've progressed on anti-PD-1 therapy. You can have anti-CTLA-4 treatment, either as a single agent or in combination with PD-1, but the toxicity here is quite significant, and the benefit is only seen in somewhere between one in three to one in six patients, depending upon circumstance. Although we're seeing a change in the landscape with the use of anti-LAG-3 agents, this is very much in the first line as a mitigation of toxicity for combination immunotherapy, and there's no meaningful activity that I'm aware of in anti-PD-1 failed melanoma patients. We have the option in about 40% of our patient population of targeting the MAP kinase pathway, but although that's highly successful, it's transient. Responses last in the order of about a year before resistance develops, so it's not a long-term solution for patients in the way that IO promises and has delivered, albeit for a minority. And there are other options available that are experimental, in particular, cellular therapies such as TILs, and the response rates here are about one in three, and showing some promise, but it's logistically enormously complex, not suitable for all of our patients, and comes again at the cost of considerable toxicity. Overall, for the second-line melanoma population, leaving aside MAP kinase inhibition, about- At best, one can get benefit in about one in three of the population, but at considerable expense, both in terms of logistics, toxicity, and finance. Moving on to the next slide. What I'm gonna talk about here are the data from the IGNYTE registration cohort of anti-PD-1 failed melanoma, and then link that with prior reported PD-1 failed melanoma patients from our phase two cohort in the earlier part of the study. Median follow-up's now just short of 10 months, and the data I'm gonna present you includes a variety of patients, including those with moderate and high tumor burden, and the majority of patients had not responded to prior anti-PD-1 therapy, so either had stable disease or were refractory in the first instance. We're gonna show you some responses across all subgroups. I think it's interesting to note, that although we see the expected difference in response rates according to the extent of disease, we still see responses across all subgroups of melanoma. The vast majority of those are ongoing, so in terms of the benefit, there's power to add from the snapshot today. We also see responses in uninjected lesions, the so-called abscopal effect, which includes patients with visceral disease. We're going to see examples of responses in solid organs like liver, in patients who've been injected in superficial lesions, for example. The other thing to note is that this combination was pretty well-tolerated, with only grade one and two on target side effects attributable to RP1 and the expected toxicities of the nivolumab. With, you know, the relatively low rate of toxicity that we understand from that agent. Survival data where the progression-free or overall is not yet mature, but we're seeing some interesting trends, and I'll cover that right at the end of my section of the talk. Moving on to the next slide. This summarizes the way in which we're treating the patients in the cohort, with starting with the RP1, increasing the dose and adding in the nivolumab at the second cycle, two weeks later, and continuing with eight injections of RP1, and then the nivolumab going for up to two years with the possibility of reintroducing the RP1 during that time if necessary. I draw your attention bottom right to the criteria for having failed on checkpoint inhibitor treatment. These are quite strict criteria requiring at least eight weeks of prior treatment and confirmed progression, whilst on anti-PD-1 based therapy. Notably, we do include patients who have progressed whilst on adjuvant therapy, requiring confirmation of that progression before they could be enrolled in the study. Next slide. These are the demographics. On the left-hand column, you can see the original 16 patients from the early part of the study. In the middle, the 75 we're reporting on now, and on the right, the combined cohort. I draw your attention to here is that this is a relatively representative population of PD-1 failed at melanoma. There's a significant proportion, about a third of patients, who come having only had PD-1 as prior adjuvant therapy rather than for metastatic disease, and I'll come back to that later. We see a good bunch of the patients, half in total, who've got M1b and M1c disease, so proper metastatic disease. In the current cohort, a slight increase in the proportion of patients who've got an elevated LDH, which as you'll know, is an adverse prognostic indicator in this setting. Next slide. The toxicities, and I refer you to the grade three, four, and five columns in the middle of this table are really, you know, quite mild. Very small numbers in those columns. Some of those, but the minority attributable to the RP1 in the green box there. The majority of the higher grade toxicities, those that we expect to see with nivolumab continued over a two year period. Overall, the message here is that there's very little in the way of additive toxicity compared with nivolumab alone, and it's very well tolerated. Of note, this is all the skin cancer patients being treated with RP1 and nivolumab across the trial program, this is a higher number than the 91 that we're talking about in the PD-1 failed melanoma cohort. We don't expect toxicity to differ between other skin cancer patients and those in that cohort. Next slide. Here's a snapshot of the data looking at the response rate, split on the left-hand side between the original cohort and today's 75 patient snapshot. Of note, within that group, over a third of patients responding, 36% objective response rate, and over half of them showing evidence of disease control. I think the key point to note here is as we scan across to the right on the table, is that responses are seen across all settings, whether that's patients who've had PD-1 in the adjuvant setting as their prior therapy, or those who've had PD-1 as part of treatment for metastatic disease. It's also the case for those patients who've had CTLA-4 in combination with PD-1. We see good responses in patients with late stage three and early stage four disease. Also high response rates for patients with stage four B and four C disease, which often has been refractory to experimental therapies. Next slide. Showing these data in a different way. This is the waterfall plot. I think the key point to take away here is the depth of response that we see with all those bars on the right-hand side going down to -100, indicating complete response in target lesions. Over 50% of patients have had a reduction in their target tumor diameters. As you can see, if you dig down into the detail, I draw your attention to the green and the orange bars, complete responses being observed in those patients with M1b and M1c disease. Next slide. Looking at these data in a slightly different way with a spider plot, the key takeaway from this, is that responses have the potential to deepen over time and are proving extremely durable with many of these curves out beyond the two years of treatment or approaching that. Next slide. Looking at this in one final way, with a swimmer plot. What we're showing here is the durability of those responses. If you look at the very top, 720 days is two years of treatment, give or take 730, and you can see responses going out beyond the end of treatment. A lot of patients continuing on treatment at earlier time points, suggesting that we're seeing very durable responses. On the next slide, we can see that these obtain whether patients have had relatively short, and ineffective prior PD-1 therapy, or can also be obtained in those who've been on PD-1 for quite some time before failing that and moving on to the study. Again, 85% of our responses are ongoing, so the duration of response is likely to increase over time or the median duration of response. The majority of those responders are now already out over a year, despite this being an early snapshot of the data. Next slide. We see responses in uninjected lesions as well as injected lesions. Here we've got the numerical consideration in blue of the lesions that have been injected. Many of the patients, it's only a single lesion, but in some, particularly those with superficial disease, we can get at multiple lesions, with 13 being the highest. That being said, we also see responses in uninjected lesions or stable disease in lesions that haven't been injected, as indicated by the orange and green bars. The majority of responding patients have lesions that we haven't been able to inject, so we can get responses systemically by treating a minority or a proportion of the accessible disease. Next slide. I said earlier on that we would talk a little bit about the survival data, although these aren't mature. I think that what one can take away from this, despite the censoring and the relatively early cut of the data, is strong evidence for plateauing. Those patients who get through the first couple of months of treatment without progression have a high chance of remaining on treatment. That's borne out with impressive PFS interim statistics and also the overall survival that we see there, although this is immature. Next slide. I want to finish by talking a little bit, about some of the cases that we've seen in the trial to demonstrate some of the important points that come from these data. This is a patient from Utah who's been injected in a single lesion on the forehead, as shown here. Throughout the slides that follow, injected lesions will be ringed in red and uninjected lesions will be ringed in yellow. You can see here that over the course of nine months, there's almost complete resolution of the injected lesion. Next slide. More impressively and importantly, when we look at visceral disease that's uninjected, surrounded by the yellow ring, we can see impressive responses on the left in liver and on the far right in mediastinal lymphadenopathy. This patient had been exposed to both pembrolizumab and to nivolumab for their stage M1c disease. We also see responses in lung, as shown here, which are deepening over time. Next slide. In a second patient now, treated in Leeds here in the U.K., a patient who’s had both combination and single agent PD-1 exposure in the past with M1b disease. My colleague Adel Samson in Leeds injected the subcutaneous nodule shown here on the left-hand side at baseline. We were able to obtain responses in both the injected lesions and in uninjected lesions subcutaneously and on the next slide, in the lung too, with a pretty sizable lesion at baseline, showing considerable diminution in size, on a year of treatment, refer you over to the pictures on the far right. Next slide. A further patient who had only had pembrolizumab as prior adjuvant treatment. Again, this is a nodal lesion that's been injected, we see responses both in that lesion and also in uninjected lymph nodes at multiple locations. Next slide. Showing that in considerably more detail and looking at the responses going out to over a year, in the evidence that we can present today. Next slide. Finally, one of my own patients. A patient who'd progressed on anti-PD-1, treatment for their stage M1c disease and had also had prior BRAF and MEK inhibition. He had spinal metastatic disease, which you can see bottom right, as well as a subcutaneous lesion in the groin, which we injected, which is there on the top left. Although that was the only lesion that we injected, and ultimately we got a complete response in that, which evolved relatively slowly over the course of a year. We saw resolution of his lung disease, shown bottom left, improvement in his spinal disease. It's perhaps best appreciated on the sagittal views on the bottom where you can see it disappear, although the kink in the spine didn't recover. I saw him actually only last week where he remains disease-free. Next slide. In summary, the combination of RP1 with nivolumab continues to be pretty well-tolerated with transient grade one, two side effects attributable to the RP1, and in no way adding to the side effect profile that we expect with nivolumab. Over a third of patients in our cohort have shown objective responses to treatment and one in five of the patients in the cohort, and that's in the whole cohort, not in the responders, so a pretty impressive statistic, have shown complete responses to treatment. Five out of six responses are ongoing and durable to date, and most of these responses have come in patients who did not respond to prior anti-PD-1 therapy, as opposed to those who did respond and then lost that response. The combination of RP1 and nivolumab has pretty meaningful clinical activity across a range of situations in which patients who have failed prior anti-PD-1 therapy, whether that's in the adjuvant setting, whether that's as multiple lines of treatment for metastatic disease by the single agent or in combination with CTLA-4 and includes patients with M1b and M1c disease. We've seen responses in patients in both injected and uninjected lesions, including, as I showed in the, in the last few cases, in visceral disease. Overall, the progression free and overall survival look promising, although currently relatively immature. Next slide. That concludes my portion of the talk. We're saving questions to the end, so I'm gonna hand over to my colleague, Sush, who's gonna talk about the commercial opportunity. Thank you, Dr. Middleton, for that comprehensive overview of the IGNYTE data. It's, it's certainly exciting to see the snapshot data is very much in line with the target product profile we've tested with customers and consistent with our ambition to provide transformative benefit for skin cancer patients. Over the next few minutes, I'm gonna share the market opportunity for RP1 in skin cancer, and importantly, explain why we believe we are able to realize that opportunity for a large proportion of patients. Let me just start by putting the data Mark just reviewed into a commercial perspective. Firstly, the data demonstrates we are able to help a range of anti-PD-1 failed patients that occur in routine clinical practice. I think importantly, one involving area and growing area and usage of anti-PD-1s is in the neoadjuvant/adjuvant setting. Despite this approach curing many patients, unfortunately, about a third of patients will relapse within a year. There are a portion of those patients that really blow through treatment quite quickly, often viewed as sort of those patients who progress in less than six months. There really is a need for better options for those poor prognostic patients. As seen by the data today, we believe RP1 in combination with nivolumab provides a compelling option there as well. I think another important aspect as we think about broad utilization of a treatment regimen is not only whether it works in a broad range of patients, but one that's well-tolerated. Many currently used treatments, including combination regimens and emerging approaches such as TILs, have a significant patient toxicity burden. That's clearly an area of opportunity for us. Given the RP1 tolerability profile, we believe this is an area where we can grow the treatment market as many patients unfortunately forgo treatment due to toxicity today. Next slide, please. Starting in the middle of this graphic, given the anti-PD-1 failed melanoma data generated today, we believe we can help a significant portion of the patient population, including those patients who have failed prior adjuvant treatment and second line plus patients, regardless of their BRAF mutation status. Said another way, we have the opportunity to help patients no matter what part of the treatment journey they are on. As mentioned, given our tolerability profile, we can help grow that treated market to approximately 13,000 patients. The IGNYTE data also builds on the strong signal we have seen in cutaneous squamous cell carcinoma, where RP1 has the opportunity to help many more patients, including those where existing checkpoint inhibitors are not indicated, such as immunocompromised patients or those who have failed checkpoint inhibitors. Given this high complete response rates we've seen for RP1 in CSCC, we have the potential to change the treatment mindset, and expand the treated population of advanced CSCC, in terms of those who are currently deemed ineligible for curative surgery or radiation. Again, this could amount to another 10,000 additional patients. Finally, the high ORR, and particularly the high CRs we've seen in both cutaneous squamous cell carcinoma and checkpoint failed melanoma, means that RP1 presents a logical partner for new and existing treatments used in the earlier disease setting. There's a lot of drug development going on in this space, and there's also a lot of patients. Next slide, please. Skin cancers represent the ideal setting for tumor-directed treatment with RP1, as a high proportion of patients have a superficial lesion that can be easily injected without image guidance. In CSCC, this is around 90% of patients as the disease typically presents local regionally. We also believe the unmet need and activity seen in visceral disease with RP1 in the IGNYTE data, as shown by some of the patient cases that Dr. Middleton shared with you, can really help us achieve strong penetration in these melanoma patients with simple and widely available ultrasound guidance. Where we can then tackle approximately 70% of the patients, and provide that opportunity and benefit to a much broader range of patients. Next slide, please. Our mission is to ensure as many patients as possible can benefit from RP1-based treatment. To realize that ambition, we aim to launch broadly in the community across practice settings. We have done a significant amount of market research to understand what it will take to achieve this goal, and believe strong data will result in strong adoption, and are working actively to ensure that there is customer confidence in RP1, and that the administration can be done routinely and result in a positive experience. There are three key areas as we think about facilitating broad adoption. Firstly, we are planning for product that can be stored at refrigeration for an extended period, rather than as opposed to minus 70 or minus 80 degrees in cold storage. We also want to ensure that we identify and train injectors at all our key target accounts. Finally, we want to make sure that we're educating on how to safely and efficiently handle RP1, to make things as easy as possible for patients and the whole care team. Next slide, please. As discussed, our critical success factors are about ensuring customers have confidence and a positive experience with RP1. Our goal is broad community launch and adoption. There are many reasons we believe we are set up for success with this objective. It starts with transformative data, in particularly the high PRs and CRs that are durable, which is clinically meaningful for both our initial skin cancer indications. We also have strong U.S. clinical sites and patient enrollment in our skin studies, and there is existing customer and key opinion leader experience to build on and leverage as we start our launch activities. As we consider the important aspect of practice economics, especially for community MDs in the U.S., it's important to remember that we are adding RP1 onto existing checkpoint inhibitors versus replacing them. This aligns with the current buy and bill reimbursement model. Next slide, please. Finally what's necessary for broad adoption is the availability of sufficient and reliable supply of RP1. Here we're making really good progress on manufacturing of commercial product, including tech transfer, comparability analyses, and initiating BLA consistency batches. Our state-of-the-art facility will produce sufficient RP1 to meet global demand. It should be noted that RP1 comes with very attractive cost of goods. We will now move to the next part of the presentation, which will focus on updates to RP2 and RP3. With that, it's my great pleasure to introduce Professor Kevin Harrington, who as a reminder, is at The Institute of Cancer Research in the UK and a renowned expert in head and neck cancers, skin cancers and novel therapeutics. I think he is coming to us live from ESMO IO. Over to you, Kevin. Sush, thanks very much indeed. Thank you for this opportunity, to share some thoughts around the development of the RP2 and RP3 platforms. Indeed, you're correct, I am joining you from ESMO IO. I hope if any extraneous noises occur, you'll understand that they aren't entirely under my control here at this meeting. If I could have the next slide, please. I'm gonna talk to you first of all around the area of RP2 in the treatment of patients with uveal melanoma. I'm gonna give you some context to that, if I may. You may be aware that ocular or uveal melanoma is a rare cancer occurring in about 1,000 individuals per year in the United States. It arises within melanocytes that exist within, the normal eye structures in a number of places, including in the iris, the ciliary body, and also in the choroid, as sites that can occur for this condition. The nature of this disease is it's a poor prognosis tumor with a median overall survival of about 12 months. Again, many of you will be aware that uveal melanoma behaves entirely differently from cutaneous melanomas. It is a highly metastatic disease with a dominant metastatic burden occurring in the liver in up to 90% of cases. Once this occurs, historically, this has been associated with a very short prognosis, with only 10% of patients surviving a year or more with that occurrence. Historically, even in the era of the checkpoint inhibitors, this has proven to be a very difficult to treat disease, with limited activity of checkpoint inhibitors in a number of studies. You may be aware that there has been a first approved agent in patients with uveal melanoma, which is Tebentafusp or Kimmtrak. That agent is specific for those with HLA-A*02 disease, which is about 50% of the total population, especially in a Caucasian population. There exists a continuing unmet need in uveal melanoma patients. There is a requirement for improved efficacy and tolerability. The treatments that I've just discussed very briefly are associated with significant toxicity. We have the unmet need for those patients who are HLA-A*02 negative. We also have to consider the treatment of patients who have had Kimmtrak or anti-PD-1 therapy and have either responded and then progressed or have failed to respond primarily. Next slide, please. Here I show you the initial experience that we have, of patients treated with RP2 with uveal melanomas. I show you here in this rather busy slide, and I'd like you to focus in the first instance, if you will, on those patients highlighted with the green color. This is the first 14 patients for whom the outcome is known in terms of their response to RP2 therapy. All of these patients are in that anti-PD-1 failed subgroup of patients. four of the 14 patients have developed responses. Many of those responses, and I'll show you data from these, are deep responses and highly durable responses, including clinical Complete Responses. You will see highlighted at the bottom of the slide details of three other patients who are ongoing, all of whom have liver, one with liver and lung disease, for whom we do not yet have the full characterization of their response. One with stable disease, two patients in whom the response is not yet evaluable. Again, notice all of these patients have received an anti-PD-1 therapy, and many of these patients have also received an anti-CTLA-4 drug. This is a group of patients for whom there is a significant unmet need. Next slide, please. Here I show you some data of a patient who had previously been treated with both nivolumab and ipilimumab. Patient receiving RP2 as a monotherapy agent, not in combination with an immune checkpoint agent. You can see, again adopting the schema that Professor Middleton showed you, injected lesions highlighted in red, uninjected lesions highlighted in yellow. You can see that this patient with very heavy burden of liver disease. On these slices from the scan, I show you some of the lesions, by no means all of the disease that this patient experienced. As you can see, over time, from screening through three, then six, and then nine months, the evolution of a very solid partial remission. Regrettably, the patient progressing at 15 months, but nonetheless, evidence of response both in injected and in uninjected, so-called abscopal or anesthetic lesions. Next slide, please. This is a patient who I treated within my own practice. This is a patient who had received prior nivolumab therapy. You can see that this patient had undergone enucleation of her left eye. The patient regrettably had developed recurrence in the orbit, an extremely difficult to treat area that had been attempted to be addressed with surgery. We'd also in the past had seen this lady for radiation therapy. She came to us really with a very difficult to treat problem. She was enrolled in the study where she was treated with RP2 plus nivolumab. Again, you can see from the screening scan at the top, the injected lesion through to the scans that evolve over time to nearly two years, a clinical and radiological complete remission. Now, this patient had disease in the neck, which was uninjected and showed a response, and also had bone metastatic disease, uninjected. You can see that over that nearly two-year period, resolution of soft tissue, but really remarkably also healing of the bone with recalcification of the bone. This patient had a dramatic symptomatic benefit and on a PET-CT scan, has an ongoing metabolic complete remission at nearly two years. Next slide, please. Here I show you another patient, again from a colleague, and this is from the team in Liverpool. Here is a patient again with liver metastatic disease, prior treatment both with anti-CTLA-4 and anti-PD-1 therapy. You can see on this MRI scan, initially at screening in December of 2021, so a year ago. Sorry, could we go to the next slide, please? Thank you. You can see the initial screening scan from about a year ago and then the follow-up scans about nine months later. You can see in the various sites across the liver the evolution of an impressive partial remission of this disease, including responses within uninjected lesions. Next slide, please. I'd now like to switch gear and give you a flavor of some of the emerging data that we're seeing in patients with soft tissue sarcoma disease. Now, this is an area of considerable unmet need. Over 13,000 cases per year in the United States this year. The standard of care following surgery includes radiation, often followed by chemotherapy. anti-PD-1 therapies are used in some sub-types of sarcoma, but not many, and these are in the relatively responsive subtypes. You may be aware that in this area of higher net need, the FDA has approved a drug, trabectedin, Yondelis, for unresectable or metastatic leiomyosarcoma and liposarcoma having progressed on anthracycline-based chemotherapy. That approval was based upon an overall response rate of 7% versus 6% and a progression-free survival of 4.2 versus 1.5 months. I think you may conclude that that's a relatively low bar. We also consider that for many or most subtypes of sarcomas, overall response rates in the range of 25% or indeed often lower, would be considered as promising, especially in the second-line setting or later. There are several subtypes of this disease for which there is no FDA approval of drugs. The NCCN lists a number of agents, not necessarily on evidence base, but that can be used. Many of the subtypes are documented as being resistant to anti-PD-1 therapies, and indeed, anti-PD-1 therapy in single agent or combination remain unapproved for many of these diseases. A significant unmet need. We could conclude that there are tumor types here where single-arm data based on this unmet need with a strong overall response rate and durability of response might yet be suitable for approval. Indeed, that is an opportunistic data-driven development of RP3 that we would consider. Next slide, please. Here I'm going to show you data from the first five patients who have been treated with RP3 in combination with nivolumab. You will see they represent a range of these histotypes that we see epithelioid sarcoma, leiomyosarcoma, myxofibrosarcoma, osteo and chondrosarcomas. All of these patients had failed prior therapies, standard of care, surgery, chemotherapy and other therapies. And so far, for the first three evaluable patients, all of them have shown a response to treatment. On the right-hand side of this slide, I showed you briefly the appearances of those lesions, but now I go on to a case, patient treated under my care. A patient with metastatic epithelioid sarcoma, originally arising in the perineum. The patient relapsed with pleural disease and chest wall disease. This is a view from the lateral side of this man's right chest wall, and you can see horrible disease. Patient with significant pain, recurrent pleural effusions. Received treatment with RP3 in addition to immune checkpoint inhibition with nivolumab, and you can see for yourselves a dramatic response. The patient did not require analgesia and did not require further pleural effusion drainage, revolutionizing this man's life. I draw your attention to the fact that in an ESMO publication, 80 patients treated with rare types of sarcoma, there was only a 15% partial response rate. No CRs in that study with single-agent pembrolizumab. Next slide, please. Here I show you another patient. This is a man with multiply recurrent leiomyosarcoma who had undergone at least 12 surgical procedures. You can see the battle scars for that. This is a view of this man's back of his leg at the level of the thigh. This man was approaching needing an above-knee amputation for this disease when the surgeons referred him to our care. He received RP3 therapy in combination with immune checkpoint blockade. You can see for yourselves, over a relatively rapid period of time, a dramatic response of his disease such that this man now has no evaluable disease. Next slide, please. Here I show you the final case, which is a patient with a myxofibrosarcoma. You can see this glows very brightly on the MRI scan. Again, you can see in multiply injected lesions and on the right-hand side you see the clinical evolution of a dramatic clinical response. This patient with disease in the forearm, in his dominant arm, he's a right-handed man with a right arm sarcoma, was facing an above-elbow amputation, a catastrophic surgical procedure. He has enjoyed an extremely good clinical response, is left asymptomatic with excellent healing of these lesions and is on the way, we hope, to a solid indeed complete remission. Next slide, please. With this, I turn the presentation back over to Dr. Rob Coffin, and I thank you for your attention. Thank you very much indeed, Kevin. I'm now going to summarize our current plans for the phase two development with RP2 and RP3 that's intended to initiate next year. This doesn't currently include any further expansion in uveal melanoma or in sarcoma, as Kevin's just described, despite these clearly being very exciting opportunities, where we have seen in a relatively small number of patients, admittedly clear and meaningful clinical activity. That's for the future. For today, I'm gonna focus on the phase two development plans we previously announced and provide more details of those. I'll also detail where each of RP2 and RP3 are going to be used for the program, including in the clinical trials where we're collaborating with Roche, as we also announced earlier today. As previously indicated, we're intending to start three phase two clinical trials around mid-next year with the first of these in head and neck cancer. Where here we'll use RP3 nivolumab under our collaboration with BMS. We do think that head and neck cancer may be particularly low-hanging fruit indication for RP3. That strays a little bit from our liver-centric approach, but we think there's a key opportunity in head and neck cancer for us beyond CSCC, which is often predominantly a head and neck disease as well. This head and neck cancer trial has two cohorts. The first of these will be in patients with locally advanced disease, where we'll combine RP3 with standard of care chemoradiation, and we'll then follow that with adjuvant nivolumab. This cohort is going to be randomized from the outset, it's a relatively large, sorry, signal finding phase II trial, which will recruit 100 patients randomized one-to-one to the standard of care, compared to the standard of care, combined with RP3. We'll have an initial output of metabolic response rate to the initial therapy by PET scan, and then comparative one-year relapse-free survival as the key endpoint from that trial. The intent of this trial is that it will evolve into a full registrational trial, based on the initial data which we hope to see. The second cohort in that clinical trial is going to be a 30-patient signal finding group of patients with recurrent or metastatic disease who have low PD-L1 levels. It's those patients who do particularly poorly, to standard of care chemotherapy or combination with anti-PD-1 therapy. We'll focus on those low PD-L1 patients for signal finding purposes. Here we'll treat patients with nivolumab combined with chemotherapy and RP3, so essentially adding RP3 to the standard of care, where we aim to see a good rate of response and duration of response. Depending on that, we would intend to enter into registration development. The next two trials towards the bottom of the slide, are under our newly announced collaboration with Roche. Here we will combine RP3 in both cases with atezolizumab and bevacizumab in both hepatocellular carcinoma and colorectal cancer, with one additional cohort in colorectal cancer, using RP2 as compared to RP3. Each of these trials does have a faster market potential, as there's no current standard of care, particularly in second line hepatocellular carcinoma and third line colorectal cancer. As I said, there really isn't a good standard of care, so one could imagine that single arm registration development could be possible if we see a sufficient signal in the initial signal finding cohorts. These specific trials, as I said, will be in first line and second line hepatocellular carcinoma, with RP3 combined with atezolizumab and bevacizumab, in two 30-patient signal finding cohorts. In third line CRC, where two 30-patient cohorts will also be enrolled. Here, one with RP2 combined with atezo-bev, and one with RP3 also combined with atezo-bev. For CRC, which is a particularly immunologically cold tumor type, and particularly challenging to treat with immunotherapy, we do think this may be a particularly good setting to assess any differences between RP2 and RP3. Although as you can see, most of the activity in this phase two program will be conducted with RP3, which is our most advanced and intended and expected to be the most potent of our three RP viruses to date. As you can see, these last two trials do fall right in line with our liver-centric strategy, where most of the patients would be expected to have liver-focused disease. The next slide highlights both the challenges and the opportunity in patients with liver metastases. This includes that while the liver is the most common site of metastatic disease across really all tumor types, those patients also have a particularly poor prognosis. Liver metastases appear to specifically eliminate T-cells from the circulation through the action of liver-resident macrophages. This reduces the efficacy of anti-PD-1-based immunotherapy, which does rely on pre-existing T-cells for its activity. This is demonstrated on the right-hand side of the slide, where a bispecific anti-CTLA-4 and anti-PD-1 antibody demonstrated promising data with a 24% overall response rate in colorectal cancer. Notably, there were no responses at all in patients with liver metastases, really highlighting the unmet need there. RP viruses across our portfolio are designed to directly kill tumors, which remove the resident macrophage sink. As you kill the tumor, you also remove the macrophages, and also should stimulate a systemic anti-tumor immune response, which should provide abundant new tumor-specific T-cells to provide both systemic and durable effects. We do think our new data with RP1 today, in actual fact, further highlights that the possibility of being able to do this today in PD-1 failed melanoma, including in the liver, which we again, does think, provides us confidence that in these phase two settings, we have a good chance of providing benefit. In the next slide, we have. This is a slide describing the experience we have so far in injecting patients in the liver, in particular in relation to safety. We have already, as you can see here, demonstrated that injections into the liver are both feasible and appear to be safe in patients with liver mets, with the demonstration of clinical activity in a smallish number of patients so far, in each of anti-PD-1 failed cutaneous melanoma, uveal melanoma, as Professor Harrington showed you earlier, and also some patients with esophageal cancer, and also MSI-high colorectal cancer. You can see from the table that patients have received up to eight doses, which is a full course of RP viruses injected into the liver, with the medium number of injections being either five or six, depending on whether that was RP2 or RP3, in this data presentation, which was presented at a conference earlier in the year. The side effect profile has been very similar to patients receiving injections at other sites, i.e., not in the liver, although there was a somewhat increased level of the same Grade one and two side effects, largely constitutional, as Professor Middleton showed you earlier. Really the same Grade one and two profile, but possibly a little bit more frequent in patients following injections into the liver. We think we've shown that injection of our viruses into the liver is both feasible and appears to be safe. We've generated a strong initial demonstration of clinical activity in hard to treat tumor types, which we do think sets us up well for the phase two program planned with particularly RP3, but to a lesser extent, RP2. If we now move back to melanoma. In summary, we believe that RP1 is positioned from the data today combined with our prior data, to really be a go-to treatment option for melanoma patients who progress on or indeed after anti-PD-1 therapy. With the data today confirming the same signal we saw in our prior data, with, as you saw, a 36% overall response rate and a very impressive 20% complete response rate, with while the data is relatively early, good durability to date. Importantly, clinically meaningful activity has been seen across each of the settings in which patients need additional therapy following progression on anti-PD-1, both alone or indeed in combination with other agents, including anti-CTLA-4. This includes in all stages of disease, including in patients with the most advanced stage for M1b and M1c disease, and includes a very striking 30% complete response rate and 50% overall response rate in the growing and rather challenging to treat segments of patients who progressed often rapidly while on adjuvant anti-PD-1 therapy. We also believe that bearing in mind the attractive safety profile we've seen so far and continue to show, and the level of activity seen across a range of different anti-PD-1 failed melanoma settings, that RP1 may actually be optimally positioned directly after a patient's first exposure to anti-PD-1, including before they might receive, for example, an anti-CTLA-4 or other potentially toxic therapy where they haven't already had those as their first line therapy option. With that, summary of the further summary of the melanoma data, I'll hand back to Philip, to wrap up. Thanks, Rob. Before I wrap up, I actually wanna speak to Rob's final remarks and remind everyone, we've always said from the get-go, our modality and products can result in high rates of complete response. We're seeing this play out in patients with end-stage disease, in cutaneous squamous cell carcinoma and melanoma. It is these responses that transform lives, give patients the potential for cure, and relieve them of disabilities and/or disfigurements caused by disease. We continue to believe that if our well-tolerated products are pushed earlier into disease courses, the rate of complete response can go higher still and result in many patients never developing the type of end-stage disease we're currently treating. On the ultimate side, in summary, with RP1, we are on course to establish a major skin cancer franchise. In addition to today's melanoma update, we've completed accrual in our registration-directed randomized controlled CERPASS study in cutaneous squamous cell carcinoma, and plan to release top-line data in the first half of 2023. Large-scale manufacturing has been established, and commercial planning for launch in the U.S. is advancing. With RP23, we have an exciting mid-stage program to pursue in GI cancers and head and neck cancer, where expedited approvals in some settings could be feasible. We are pleased to announce a cost-sharing collaboration in GI cancers today with Hoffmann and Roche. Finally, we have a strong cash position to drive value through multiple meaningful data, near-term data catalysts. We will now turn over to Q&A. As a reminder, if you wish to ask a question, please type your question within the Q&A bar located at the bottom of the webcast and click Submit. We will get to as many questions as we can. Thanks again for everyone's time this morning, and we now look forward to answering your questions. Could please the management team and physicians turn their cameras on? Yes. Thanks, Philip. Just to go to our first question. Were there any notable baseline differences between responders and non-responders of RP1 plus Opdivo? For example, timing of anti-PD-1 therapy or size of tumor lesions? Take that in the first instance, Rob? Sure. I don't think there's any notable differences. We can't really home in on who might respond and who won't respond from the data. It really probably relates to the pace of progression. You can see that a significant proportion of patients really do progress rapidly, as shown by the PFS curve. If they get through that first period out to two or three months, then they have a good chance of ultimate benefit. I think it probably relates to the pace of progression on the prior anti-PD-1 therapy before they came into our trial. More than that, I don't think we can really say. Thanks. Our next question. Congratulations on the progress. Can you provide insight into what durability looks like in M1b and M1c patients? Again, if you look at the swimmer's plot, that tells you the durability. We don't see any lesser durability in M1b or M1c patients than we see in the other stages of disease. As indicated, only four patients so far have progressed out of the 27 responding patients, that is across the range of different rolled population, not specifically M1bc or any other stage. Next question. Can you put the portion of adjuvant patient population enrolled in the study into the context of the real-world setting and put the response rate into context? I think I might hand over to Dr. Mike Wong to address that, who has a large melanoma practice at MD Anderson. Thank you, Dr. Coffin. Appreciate the opportunity to participate in this exciting data release. Patients who progress on adjuvant therapy in melanoma, especially during the adjuvant phase, are thought to be primarily refractory to immunotherapy. They have been traditionally a very difficult subset to treat, and oftentimes, you know, you know, we revert to combination checkpoint inhibition therapy, recognizing this fact. I'm impressed by the fact that this particular population has a significant response rate, I believe it's 50%, and a number of complete responders. To put things in perspective, this is a particularly difficult patient population, and to see a response in this setting, is a signal that tells us that this is an active therapy. With regard to the proportion of patients in our group, do you see that as sort of representative of what you might see in your practice of patients needing further therapy after anti-PD-1? Yes. This is about how what we see in our patient population. Of course, it depends on, you know, whether you're a, you know, tertiary referral center or a primary center. Here at MD Anderson, because of our surgical practice, we see a number of these patients. Because of that, we have a large cohort of stage three patients that are undergoing adjuvant therapy. What we see here is representative of what we see in our patient population. Thanks. Thank you, Dr. Wang. The next question is how will RP1 fit into the treatment landscaping, including TILs, and how will clinicians view the competing modalities? I think on that question, it'd be good to hear from all of the physicians. We'll start with Dr. Wang and then go to Dr. Middleton and then Dr. Harrington. I mean, it's a true fact that the PD-1 refractory patients are a difficult subset. I see two things that are exciting to me. First, I talked about the primary refractory disease patients, which are those that fail adjuvant therapy. Also, I'm impressed by the fact that there are a significant proportion of patients on this cohort that we describe who have failed ipilimumab plus nivolumab. These are patients who have received the top line, most aggressive immunotherapy that we have currently that's FDA-approved. You're seeing significant activity in this subset. Again, it tells you there's a signal of activity that is significant here because that is a very difficult patient subject to treat because of its refractory nature to checkpoints. There are no real good standard of care. Those are flags of activity for me. When you see activity in this situation, in a refractory situation, what that brings into the discussion, is what role this particular strategy can play in a frontline setting. This has been mentioned before on this broadcast. Because of a safety profile, I can envision a situation where we can even think of neoadjuvant therapy, which is with the hot area in skin cancers and melanoma presently. I think, this, you know, what I see here data-wise, really has legs. I'll defer to my colleagues on the call, but I was formerly head of solid tumors and had a large sarcoma practice prior to coming to MD Anderson, and I'm very impressed by the sarcoma data, which is traditionally known as a cold tumor. I'll stop here and let my colleagues weigh in. Mark. In the U.K., I think there's a significant concern about cellular therapies and their scalability. We operate in a more cost-constrained model than the U.S. When I look at, you know, what cell therapy is doing in other tumor types, it's likely that PD-1 failed melanoma is going to get squeezed out, or we'll have severe limitations on what we can offer. Leaving aside the reimbursement issue, we also have to recognize that a significant proportion of our patients are relatively old, relatively comorbid, and therefore an option such as this with a similar response rate, with a toxicity profile that's analogous to having nivolumab or pembrolizumab as a single agent is gonna be much more attractive. Just by way of example, the rates of primary single agent PD-1 in the metastatic setting in melanoma are somewhat higher in Europe and in the U.K. than they are in the U.S., where, you know, that balance of toxicity and response perhaps puts more weight on the toxicity than is the case in the U.S. Maybe I could just add a comment as well, Rob, on this. I think the questioner was asking really about, I think, attitudes maybe to sequencing treatments, because of course, for patients with this sort of problem, it's likely that they may need more than one therapeutic approach to this. For me, one of the interesting things around intertumoral oncolytic immunotherapy is that it can potentially recondition that tumor microenvironment. One could envisage a situation where, of course, in order to generate something like TIL, you have to resect a tumor, making it therefore unavailable for injection. One might envisage in a way that Professor Middleton and Professor Wong have said, you might actually see that injecting the tumor and giving rechallenge with anti-PD-1 therapy might be a very good first option. If you then come to TIL therapy, you might actually be harvesting from a tumor deposit, where you may actually have reconditioned some of the microenvironmental factors. Who knows? It would be very interesting to see the quality of the TILs that come out of a lesion that has received oncolytic immunotherapy versus one that hasn't. I can see lots of further opportunities there, which is, I guess, a little speculative, but I think I would sequence this probably the viro therapy first and then the TIL therapy possibly as the backup, especially for those patients with more comorbid conditions. Can we loop back actually to Dr. Wang? Because it was sort of postulated that maybe in the U.S., we're prepared to see a slightly higher toxicity profile. Can I put that one back to you, Dr. Wong, in terms of positioning our approach versus potential other approaches, including TILs, as far as toxicity is concerned? Sure. I mean, first of all, the data speaks for itself. The paucity of grade four toxicities and extremely low rate of grade three toxicities opens the door for a population, you know, that extends into geriatric range. That's important. Dr. Harrington actually has mentioned one of my favorite, sort of, postulates, which is, you know, if you have a educated, conditioned immune system that allows checkpoints to work better. I remind folks that theoretically, checkpoints, all you do is take the foot off the brake, and if you don't have a nascent antitumor immune response, then you don't get any response whatsoever. This is one of the mechanisms of why checkpoints do not work. I agree with Dr. Harrington that, using oncolytics is a methodology to induce a primary novel immune response. It's a vaccination, after all. Everything that happens immunologically downstream of that is affected by that, including using combination checkpoints, including anti-LAG-3, which are all checkpoints. Mechanistically, it is a completely different approach, and the only one which allows us to generate a novel immune response. I'm totally aligned with that strategy. In fact, it's one of my teaching points when I give my immunotherapy lectures. Having said that, TIL is something we do at my institution. It's one of the leading institutions that does TIL, and we've been doing TIL for decades. I take no credit for it. Many of my predecessors have really set the program on track. We were also one of the clinical trial sites for some of the TIL products which are in front of the FDA presently. It is an elaborate procedure. You have to have a proper patient that can undergo surgery or resection of the tumor. You have to have a lab component which grows and makes legally. In that interim time, the patient may or may not be on therapy. There's the delay getting patients on. When you come into the hospital for TIL therapy, you have to undergo at least five days of top-line chemotherapy to drive your immune system to zero, followed by infusion of these cells, followed by high-dose Interleukin-2. Of course, there are different strategies going on, that's sort of the backbone. Just by saying that, you can imagine that's not every patient, especially those who are in a geriatric range who have any comorbidities. Despite our higher tolerance for IO toxicity, we are highly selective about this resource intensive, both on the patient side and on institution side, therapy. Having something that with a low morbidity can come in front of that makes a lot of sense, especially, like, to circle back to the statement made before, which especially if you can condition an environment which ensures even a higher rate of success. Thank you, Dr. Wang. Our next question, for the IGNYTE cohort, can you clarify timing expectations for enrollment completion and how many months of follow-up you'd need for the full analysis? Rob, that's a question for me. Yeah. The cohort is a 125 patient cohort in total. The data today was from the first 75 patients who've been followed for at least six months. It was at least six months ago when we enrolled the 75th patient. We expect to complete the 125 patient enrollment around the end of the year, very close to the end of the year. There will probably be a little bit of over-enrollment up to probably 130 something, which is similar to the CERPASS trial, which ultimately enrolled 211 patients, which is a little bit beyond our target enrollment. In the first early part of next year, first couple of weeks to months, we should fully complete enrollment of this particular cohort. The primary analysis is triggered one year after the final patient has been enrolled. On the basis of this good data, we will be obviously discussing with the FDA next steps, including the design of a confirmatory study, which we will need, at which point we will also be sharing the data with the FDA to see exactly what the path forward with agreement of the FDA is going to be. Thanks, Rob. Next question. Can you put into context the toxicity profile in light of the efficacy shown today? I think the physicians have already obviously talked in relation to TILs, but maybe we could then also explore our toxicity profile, maybe any other options patient may have. I mean, clearly we have many patients who have failed both CTLA-4 and anti-PD-1 and have very limited options, but maybe we could pose that question in terms of maybe if patients have only just had anti-PD-1, would then ipi/nivo be the treatment of choice in terms of potential safety efficacy profile as compared to RP1 on the basis of today's data? Maybe the physicians could answer that question again with the same order, starting with Dr. Wong. Of course, our frontline ipilimumab plus nivolumab carries with it a significant response rate, also a very significant toxicity rate. You know, the original papers and what we've seen as well show that your high-grade toxicity rate, grade three, grade fours are in the range of 50+, up to 57% in trials. In the original clinical trial, over half the patients could not complete all four cycles that were planned. The type of toxicities that we see can be significant, including colitis, pneumonitis, myocarditis, you know. These are significant, life-altering and oftentimes permanent issues. You see things like hypophysitis. When it occurred, I had to go and look it up at a book, internal medicine book. That's where you basically inflame your pituitary gland. You lose all your thyroid, adrenal, and sex hormone axis. It's a significant issue. It impacts quality of life and also fertility. I'll stop here because it's just from these few seconds, you can understand this is a, you know, a very sort of powerful but particularly morbid situation. There is a flip dose which a phase two study have shown that you can actually use a different dose by altering the doses of ipilimumab and nivolumab, still you may drop that to high-grade toxicity rate into the 30% range, the type of toxicity does not change. And then, of course, I already mentioned what we have seen already on this presentation, the paucity of grade three toxicities and extremely low single digit, if at all, you know, grade three toxicities. I think the data speaks for itself. Mark. Yeah. Rather than comment on standard care options, where I think we've got well understood and inferior toxicity profiles for response rates that are certainly no better than our early data presented here today show, that my practice is almost totally experimental in melanoma and almost exclusively PD-1 failed patients. I've had nothing on the books in the last few years or indeed presently, that has the same response rate and the same lack of toxicity. If you're looking at a risk-benefit consideration, this is the, I can't say market leader 'cause it's not on the market, but you know what I mean in the vernacular. Yeah. Thank you. Any further comments, Kevin? Yeah. Maybe I could again just echo some of the comments of Mark Middleton. Our focus has been quite strongly on intratumoral therapies. I would look at the potential comparative toxicities with maybe other oncolytic agents that we've worked at or worked with, and also the STING agonists, because we have worked now with three STING agonist agents, all of which have thus far been delivered by intertumoral injections. And the toxicity profile of those agents is has been really quite impressive compared with very modest toxicity from RP1, modest but possibly slightly more exaggerated toxicity with RP2. I think it's probably fair to say, albeit with relatively limited data, RP3 with its greater cargo carriage is associated with potentially a perhaps a greater cytokine release profile than maybe some of the other agents. When we compare them, and I compare them with my experience of using cyclic dinucleotide STING agonism, it is a milder toxicity burden. Most importantly, as the others have said, it's associated with responses which actually we haven't particularly been able to see in a strong way for the STING agonist. I think you get the benefits of a modest toxicity profile for significant efficacy with this platform. That, for me, is what makes it, again, avoiding Mark's term of market leader, but certainly in terms of the profile of things we've been looking at, I haven't seen anything with this level of activity and tolerability in the last three to five years. Thanks. Our next question. Were there any patients that have received RP1 again at a later time point on disease recurrence where you saw rescue of response? Rob? We certainly saw that in our prior group of 16 patients, which we've reported on before, who've obviously got a longer follow-up than this group. A small minority did indeed have a reinitiation of RP1, both in the setting of patients who had extended stable disease but didn't quite get into response. Patients who had extended stable disease and then began to progress, and patients who had actual response and then a new lesion appeared. In each of those settings, we've seen reinitiation of RP1 to be valuable. The experience of reinitiation in this new group is less at the moment 'cause we have less follow-up, but there are a number of patients, well less than 10%, who've had a reinitiated course of RP1, where there has been evidence of benefit, including allowing patients who hadn't actually got into response to get to a response following a few extra doses of RP1. We do think it's sort of a unique attribute of this type of therapy, that you can reinitiate without expecting resistance to have kicked in. You can imagine that actually patients could continue until futility had kicked in to inject new lesions if they appear down the line. That's very much in a minority of patients. Most patients who have a response, their responses tend to be durable. Mark and Kevin have both reinitiated patients with RP1, so they may have further comments. Yeah. One of the patients in the 16 rather than the 75 cohort that I reinitiated led to a reinduction, essentially of a complete response after reinitiation with RP1. She's now completed all treatment and is just on follow-up and remains disease-free. I think this falls into line with what we've learnt around IO in general, which is that when we see a lesion responding differently, such as a new lesion responding on a background of overall success, then treating that aggressively, you know, has benefits. Whether that's by ablation, excision, irradiation or, you know, handily, the ability to reinitiate treatment with an oncolytic virus, you know, it has the potential for dividends. Clearly, in the background setting of overall success for the combination treatment, it's very attractive to be able to come again with what has worked before. Thanks. Our next question is, how are you thinking about the commercialization of RP1, and the opportunity? Are there any worries, resistant points from physicians, training, et cetera? Sush? Yeah. No, I think I sort of shared with the audience the fact that we're looking to launch broadly in the community, and we've been doing a lot of work around that, obviously learning some of the lessons from other products such as T-VEC. One big thing is how can we just make this easy and routine for customers? And one aspect of that is how do we avoid some of the cold storage challenges as we think about communities. Some of those practices don't have, you know, minus 70, 80 fridges. So if we can do extended storage up to two to eight degrees, which is regular refrigeration temperature, that's one thing. We also have a very good safety profile, and in reality, you know, oncolytic viruses are very safe to administer, but there can be institutional guidelines around certain things that add certain hurdles, and we're working actively to generate data, working with institutional boards and other groups who can help us really think about what data do we need to generate to sort of overcome some of those hurdles. There's nothing there that we don't think we can overcome with data and education. As we think about community practices, we really are feeling quite confident that this can be done. What we've heard drives adoption is having an option that addresses a high unmet need. I think, you know, we've seen the day-to-day, they clearly are having an unmet need for these patients. Often, community practices will refer refractory patients for clinical trials or to academic centers because they don't want to deal with some of the toxicities, whether that's ipi, nivo, and they certainly won't be able to handle TILs therapy. We haven't heard anything. It's gonna be a lot of education. Whenever you introduce a new modality, that's part of the deal. We've done a lot of work, and we feel that it starts with strong data and working on some of those things that just make things more simple and routine to incorporate into existing clinical guidelines and SOPs. Thanks, Suj. Next question. Were all of the PRs and CRs confirmed? Yeah. Do you have any clue on how many intratumoral injections may be needed to drive a clinical outcome? Yes, all of the, all the responses pre-presented today are confirmed responses. As you can see, nearly all of them, all but four, are durable to date. With regard to the number of injections, the standard first treatment course with RP1 is up to eight injections. The median number of injections is either seven or eight in the patients who have responded. Most patients do get their full course of injections who are responding patients. Across the whole group of patients, the median number was seven. Thanks. Next question is, how are you thinking about the potential to expand the development plan for RP1 in melanoma settings? You want to take that, Rob? Yeah. We're in the relatively early stages of our thinking process there, and it is related to what we finally do as a confirmatory trial in melanoma. Obviously, we know that this is a single arm dataset and is expected, and the FDA has informed us that a confirmatory trial would ultimately be required. However, optimally, we would conduct a confirmatory trial which adds to the label if we can, rather than just confirms a pre-existing label. Exactly what we do in melanoma will be influenced by what we agree with the FDA to be a confirmatory trial, which we aim to discuss with the FDA in the early part of next year. Obviously, a particular relevance could be development in the neoadjuvant setting. I think our data very much speaks to development in the neoadjuvant setting. While we don't have any firm plans currently to do so, it's certainly an area of great interest for us as it also is in cutaneous squamous cell carcinoma, where our thoughts are a little bit more advanced than they are in melanoma. I think the conversations with the FDA in the first part of next year will really help us there. There are also other opportunities in melanoma as well, including things like mucosal melanoma, which are underserved currently, and where there's nothing specifically approved. Again, while we don't have any formal plans at the moment, it's certainly also something on our radar for the future. Thanks, Rob. This is a bit of a follow-up to that question. The data in uveal melanoma and sarcoma are also compelling. Obviously not the focus, but assume the phase I, II studies will remain ongoing and provide a basis for potential discussions with the FDA about a path forward. With regard to the uveal melanoma group with RP2, we have finished enrolling that, so we're not gonna have more patients with uveal melanoma from that trial. We do think already that that data is very strong. As I said, while again, we don't have any formal plans at the moment to proceed with further development in uveal melanoma, it's certainly something very solidly on our radar, and which we're thinking about. There will be some patients with RP3 also treated with uveal melanoma. We'll get a feel for RP3 in uveal melanoma too before formally deciding what to do. In sarcoma, really, the situation is very similar. We think we have a good, strong initial signal worthy of further development. As a company, we're sort of huddling together to think about exactly how we should take that forward in the context of everything else we're already doing, including preparing for the phase 2 trials in head and neck HCC and CRC. I would say watch this space would be the real answer to that. Thank you. The next question. Did you observe differences in clinical data or biomarkers that led you to choose RP3 over RP2, or just on the expectations that RP3 should be more potent and RP3 safety was comparable to RP2? To some extent, the latter in reality. Obviously, we've only treated a relatively small number of patients with both RP2 and RP3, and trying to definitively determine which may be better in inverted commas, is challenging where both of the products are clearly clinically active. The reason for proceeding with RP3 in head and neck, and mainly in HCC and CRC, included that we have seen good safety, although a little bit elevated side effects which are on target. We think that's good, but no less tolerable. Combined with we have seen clear evidence that RP3 is clinically active, and theoretically and preclinically should be and is more active. For that reason, we have, with our partners, determined that we'll largely proceed with RP3 while still conducting an experiment comparing RP2 and RP3 in the particularly challenging situation of colorectal cancer. We expect that RP3 will pan out to be at least as active and potentially more active. Thanks. This may be a bit of an add-on to that, Rob, but can you provide any additional color on your decision to move forward with RP3 in head and neck and HCC and to access RP2 for CRC? Well, I think I refer you to my prior comment. Professor Harrington will be or one of the co-PIs on the head and neck cancer study. Maybe Kevin may want to comment on the head and neck study in RP3, using RP3 for it. Yeah. Thanks, Rob. I think we could probably make a good case. I apologize for a bit of background noise. I'm just on the periphery of the poster session here that's just starting. You could make a case perhaps for the RP2 agent. For me, I think the RP3 agent in head and neck cancer brings a great deal to the party. I think from my perspective, the role of the CD40 ligand and the 4-1BB ligand agonism, both of which, as agents, have shown some anecdotal evidence of impressive responses in cohorts of patients with head and neck cancer without necessarily themselves justifying registrational path type studies. The expression from of those agents from the virus is particularly attractive. The potential role also of CTLA-4 blockade in head and neck cancer, albeit with the negative phase three studies CheckMate 651 that we were involved in, 714 also, and also the study with KESTREL that's about to be presented. Although those were headline negative for CTLA-4, there is potentially evidence of really impressive responses for some patients. I just draw your attention, for instance, to the CheckMate 651, showing that the median overall survival in the first line setting with combination of ipilimumab and nivolumab was 18 months, which is unprecedented in patients with relapsed head and neck cancer in the first line setting. For me, the package that's in RP3 looks particularly attractive, for patients with head and neck cancer. Again, I think you could probably make a case for RP2, but you can only do so many studies, and for me, RP3 is more attractive. Again, I apologize for background noise. As a reminder, we will be doing both RP2 and RP3 in colorectal cancer. Thanks. We have time for one last question, so perhaps we'll turn it back to the IGNYTE data. Philip, do you expect the final 125 patient data to be similar to the first, the data you've seen in the first 75? We can't say for sure exactly. What I can say, if you look at the overall response rate table, that we see very strong rates of activity in all subtypes, including late-stage 4 M1c disease with a 28% response rate, including a non-adjuvant with a 30% response rate. It's hard to see whatever the final mix is. The overall picture is gonna change in terms of the fact that we, with the side effect profile, efficacy profile that we presented today, we will not have a potentially here a product for all melanoma presentations. Thanks. That concludes question and answer. If we did not get to your question, we will do our best to get back to you. We did have a lot, so apologize for that. I'll turn it back to Philip for closing remarks. Yes. Now, I'd just like to thank those for listening in. Particularly like to thank the physicians for joining us on our panel, Doctors Wong, Middleton, and Harrington. I'd also actually like to thank our staff, both here in Woburn, Framingham, and the U.K. for their dedication to the cause. Thank you very much.