Good morning, everyone. Welcome to Barclays Global Healthcare conference. I'm Pete Lawson. I'm one of the biotech analysts here at Barclays. Institutional investors, of course, if they have questions, do ping me by email. That's peter.lawson@barclays.com, and you can always get me on Bloomberg as well. With that, it gives me great pleasure to introduce Replimune. With us today, we've got Philip Astley-Sparke, the CEO, and Rob Coffin, the Founder and President, and Chief of Research and Development. Just wanted to welcome you both. Just as an opening question, I've been asking all our companies this just on the differentiation of the company in the oncology space, what you view as the core competencies of Replimune. Thank you, Philip. Yeah. Well, first of all, thanks for the invite to the conference. Really, Replimune was founded to realize the full potential of our modality, oncolytic immunotherapy, which we believe can become the most practical and effective way to get an immune response in play ahead of checkpoint blockade drugs. Put simply, we only ever get cancer because of a failure of the immune system either to recognize a tumor as foreign, or if it does recognize the tumor as foreign, the ensuing immune response is inappropriately shut down. Obviously, over the last five or 10 years, the second part of that equation has been at least partially addressed through checkpoint blockade drugs. I don't think the first part of the equation really has had that many advances. As I say, we do think the modality itself is the most practical and effective way to get an immune response in play. In terms of practicality, it's an off-the-shelf product. It's what we're developing, and therefore it's relatively cheap to produce. It's also well-tolerated. In terms of efficacy, it's effectively a pan-universal neoantigen vaccine. You're not trying to delineate one or two neoantigens to go after. You're injecting the virus into the tumor, blowing the tumor up, and the entire panoply of neoantigens within is exposed to the immune system in an optimal environment of productive cell death. If you're using the right viral species like herpes, you're triggering innate immune pathways; you're bringing in adaptive immunity through the immune danger signals thrown off. The virus itself can be used as a chassis to carry multiple other immune-stimulating proteins into the tumor microenvironment. Therefore, you've really got multiple mechanisms of action wrapped up into one product. Got you. Thank you. Maybe it's just more of a technology question than anything else and comparisons. I guess the T-VEC, the recent termination of that clinical trial. Just if you walk through that and compare and contrast yourselves and T-VEC. Well, I'll leave Rob to do the comparison with the T-VEC, but I'll just make an opening comment on clinical trial design. Obviously, that study was designed probably some seven years ago, and the last patient was enrolled three years ago and was stopped for futility, i.e., the number of events that needed to accrue to unblind the study had not occurred. That does point to some design flaws within the study and does not necessarily point to deficiencies in terms of T-VEC in adding benefit over and above checkpoint alone. Rob? We obviously haven't seen any data in regard to that, and we'll be looking forward to seeing what the actual data is when it may come out later in the year. We did deliberately design at the beginning of the company our products to be very much move-ons from T-VEC. We were always of the view that T-VEC was the beginning of what could be done with oncolytic immunotherapy and proved the point, but by no means the best or all that could be done with oncolytic immunotherapy. T-VEC does work, and it is effective as a single agent, and it's proven to be effective in a randomized controlled trial in combination with ipilimumab versus ipilimumab alone. We obviously need to see the details of that particular trial to comment further. Really, the key point is that all of Replimune's products are designed to be considerably more potent than T-VEC, in multiple regards. The two main regards of that are that they're designed to kill much more tumor directly. The lytic and direct killing abilities of the viruses are designed to be much greater, by virtue of using a new strain of herpes simplex virus, but also, and probably more importantly, encoding within the virus a gene for a fusogenic protein, which substantially increases the direct killing that the virus is able to do. However, not only does it increase the direct killing substantially, it also increases the immunogenicity of that killing. It greatly increases the level of immunogenic cell death, as compared to non-immunogenic cell death otherwise caused by the virus. That, in combination, in the base virus RP1, is intended to result in not only much greater direct killing but also much greater systemic immune activation as well. Our preclinical data really does show that we have a very potent systemic abscopal effect mediated through this additional protein, called GALV. That's RP1, which is currently being tested, particularly in PD-1 failed melanoma and in cutaneous squamous cell carcinoma, both in combination with anti-PD-1 therapy. We come onto our products, RP2 and RP3, which have been engineered to be substantially more effective too, through the incorporation of additional genes into the RP1 backbone, such that RP2 encodes an anti-CTLA4 antibody in the backbone, for which we think there's very strong logic to deliver anti-CTLA4 directly into the tumor as the tumor is killed by lytic virus replication, which provides so-called signal one into the system. RP3, as well as anti-CTLA4, expresses two immune co-stimulatory pathway-activating ligands, which act following antigen presentation, i.e., signal one, to provide strong co-stimulatory signals into T- cells. We think there's particular logic to delivering those into the tumor as the tumor dies and signal one is occurring, and that logic is substantially greater than the use of systemic antibodies to try and do the same thing. The simple answer is we just think our products should be; evidence suggests they are and were designed to be just far more potent than T-VEC. Thank you. Maybe we could think through some of the data that's coming through this year. You've got a healthy set of data this year, really, an interesting set. You've got potentially RP3 data. What is that? I guess around eight to 10 patients, initial phase I data. What kind of de-risking is that? I guess it's RP1 and RP2, what we've seen already. Is there anything else that we should be thinking about that kind of helps de-risk the initial solid tumor data we get for RP3? For RP3, you're correct; we deliberately did take a stepwise approach to our product development with RP1 first, RP2, and RP3, to enable us to properly understand the underlying characteristics of each of those products, which all had novel characteristics as compared to anything else that had previously been tested in humans. We felt it was sensible and pragmatic to test RP1 initially, particularly as it adds a potent modality of the fusogenic part of the product, and it did turn out to be well-tolerated. It's clearly demonstrating a useful clinical activity and led to our pivotal trials or cohorts currently ongoing, which then led to RP2. We have, we think, compelling early data with RP2 expressing anti-CTLA-4, including, we think, strong single-agent data in very hard-to-treat tumors. Again, with good safety and no evidence of additional toxicity when combined with anti-PD-1 beyond the individual oncolytic virus and anti-PD-1 separately. That provided a good bedrock to have good confidence that the underlying platform should be both well-tolerated and effective, upon which we could then bolt on CD40 ligand and 4-1BB ligand, the two immune co-stimulators. Those are very potent molecules. Preclinically, they provide, encoded in the virus, very potent abscopal immune-mediated effects, and agonistic antibodies against those two targets have shown evidence of clinical activity in humans. However, systemic administration of those antibodies has had toxicity issues. We believe, as I said, delivery into the tumor should retain or, in fact, increase activity because they're present when and where exactly needed but also reduce toxicity caused by systemic administration. We do think we should have good confidence based on everything we've done to date, which is based on solid underpinnings, that we should see safety. Bearing in mind what we've already seen with RP2, we should have good confidence that we're well-founded to expect potent efficacy too. However, obviously, time will tell. We're still early in development with RP3, and it won't be until later in the year when we begin to also combine RP3 with anti-PD-1. Got you. Good. Maybe you could talk through the anti-CTLA-4. I'm increasingly finding that intriguing, this kind of safer version of CTLA4. How well it expresses and what it's looked like in, whether it's animal studies? We express from our virus something that is very similar to ipilimumab. It's secreted. It's not exactly an antibody, but it's a very much antibody-like molecule, which does have a human IgG1. It has the two components of ipilimumab. However, the systemic levels of the antibody, which would be generated following replication in tumors, would be expected to be rather low and below any systemic level, which could cause any systemic toxicity. However, the levels present in tumors would be expected to be, as predicted by our mouse experiments, to be entirely sufficient to provide the necessary block between the CTLA4 and B7 interaction locally in tumors and draining lymph nodes. We think there should be an optimal and correct amount where it's needed, but only very low levels systemically where it's not needed, which is likely what would result in toxicity. To date, as I said, RP2 has been well-tolerated. In combination with nivolumab, as we did say at SITC last year in the first few patients, there's been no evidence of the type of combinational toxicity you'd see with ipilimumab and nivolumab. We expect it to have a good safety profile and none of the downsides of combined Ipi/Nivo. Yeah. It's a fantastically clever approach to get that CTLA4 in. Is that the most complex construct you've inserted into the virus? It's just a single coding region. It's a single gene. It's a single-chain approach to generating the antibody. From the virus's perspective, it's just another gene. In RP1, we have two genes expressed, GM-CSF, and the GALV protein. In RP2, three genes: GM-CSF, GALV, and anti-CTLA-4. In RP3, four genes: GALV, anti-CTLA-4, CD40 ligand, and 4-1BB ligand. From the virus's perspective, it doesn't make any difference what those coding sequences are. Okay. Thank you. Just with RP3, what are the best tumor types, do you think? Do you get any sense from preclinical data or hints from other people's data where it potentially works better? We anticipate a very broad utility. In a way, it's actually a sort of nice problem to have. We are actually in the process of doing a very thorough landscape analysis of where we think we should proceed into later -stage development, with RP2 and RP3, based on all considerations, including likelihood of success, development pathway, unmet need, et cetera. The nice problem to have, I mentioned, is the fact that, really, these approaches are potentially applicable to literally all solid tumors. HSV will infect, essentially, and replicate in essentially any human tumor type that you sort of feed to it. We do believe we already have evidence that we can have clinical activity in not only traditionally immune-responsive tumor types but also completely immune non-responsive tumor types, which really means the problem as to where we develop our products more relates to where the opportunities are, rather than necessarily where we think the product has a greater or lesser likelihood of success. We really do believe that RP3 particularly should have potentially very broad future utility across oncology. For us at the moment, it's the decisions as to what exactly to do next to best showcase that potential. Yeah. Follow the biology. What should we look for in that kind of biology? When we see the data, I guess at, like, probably maybe at SITC, what should we be looking for other than deep durable responses, but what are the things before that we should be thinking about? The RP3 phase I trial is very similar to the RP2 phase I trial. Therefore, the cadence of data generation would be expected to be similar. At last year's SITC, we presented initial single-agent data, which was from nine patients at that point, which demonstrated good durable responses in a number of those patients. What we saw was that responses did take a little time to fully kick in. At the first scan, the full response had not been achieved, and it wasn't until the second or third scan, actually, that a full maximal response was achieved, even though the actual treatment had been terminated a long time before. In immune-based therapies, things can take a bit of time to mature, and we don't necessarily expect it to be different with regard to those kinetics with RP3. It's also the case that when we present the first data intended to be in the fall, as you said, the data will still be early and relatively immature. We do expect to be able to show signals that RP3 is indeed able to not only be safe but also provide early evidence of activity. Where that activity is being demonstrated, we would expect and hope that it will be demonstrated to be durable. It is a phase I trial in a mixture of a mixed bag of phase I type patients. Therefore, as with RP2 and other things we've done before, it will be very important to look at each individual patient on its own to really get underneath what we and observers believe it shows. Got you. Thank you. Maybe switching gears slightly just around RP2. We get updated data for that mid-year, so potentially, hopefully, ASCO. How should we think about that update? How many more patients— So- Length of follow-up. As I described, the phase I trial with RP2, which is still ongoing, had an initial single-agent dose -rising part of that upon which the RP2D was determined. That dose -rising part consisted of nine patients. We reported the initial data from those nine patients last SITC. At this upcoming ASCO, we would present longer -term follow-up from those first nine single-agent patients. Subsequent to determining the RP2D towards the end of last year, we opened a 30-patient cohort of RP2 in combination with nivolumab, which is still recruiting at the moment but recruiting pretty well. The data at ASCO will include the initial data from the patients doses to date with RP2 plus nivolumab, as well as longer -term follow-up with a single agent. Those patients, by definition, because it's relatively recent, will still be very much a work in progress, still often being treated. Some patients will have had six to nine months maximum follow-up, and others will have had much shorter. Again, it will be an early output of work-in-progress data, which we hope will be directionally informative but by no means, by that early point, in any way definitive. I had a question from a client, and could you walk through the abscopal effects or the systemic effect you see? What you've seen so far, what helps de-risk that sense that you are getting a more systemic effect after a local injection? Actually- Sorry. I think what's particularly pleased us over the last six to nine months is we've seen abscopal effects not just from injecting superficial lesions but also from injecting visceral lesions. We're always very confident before we dose a single patient that we'd have a product, at least a niche product. That's not our ambition. Our ambition is to become a foundational cornerstone of immuno-oncology. Over the course of the last 12 months, we've generated consistent data that we can inject the likes of the liver and see abscopal effects in uninjected lesions in the liver, beyond the liver, like the spleen, and even as far away as the lung. We've also seen effects through injecting lung lesions and uninjected local regional impacts as well. Those are really documented on our website, where we've got fairly extensive data with red circles with the injected and yellow circles with the uninjected, which really completely prove the point. Got you. Yeah. Thank you. Just to flip back to RP2, what do you want to see in that update to move it forwards? How should we think about the strategy there for potential registrations? That is, which tumor types you'd pick. Yeah. We have a full indication prioritization analysis ongoing at the moment. We plan to start saying more about the output from that around the middle of the year. Obviously, we're looking at everything from commercial potential to what type of studies you'd have to run, how large it would be, what the endpoints would be, and how long it'd take to read out. Obviously, with RP2, RP3, we are focused on the less immune -responsive tumor types to become this foundational cornerstone of immuno-oncology. I sort of already referenced one bucket of ideas here, which is to tackle the very problematic liver mets. Obviously, a lot of large indications metastasize to the liver. It's a real unmet need. Even in immune -responsive tumor types, when you metastasize to the liver, your response rate to checkpoint blockade drugs plummets. The accumulating evidence of our products is that we can have real benefit through clearing out liver mets. That's with direct injection into the liver. Well, we've seen both. We've directly injected the liver and seen the injected lesion and uninjected lesions in the liver resolve, and we've also seen liver responses when we've injected outside the liver. Got you. Thank you. Just, sorry, we went backwards on this bit. RP1, when's the next update we get from CSCC? We have submitted an abstract basically to ASCO, which will update on one, the melanoma cohort from RP1 combined with nivolumab, which is a 30-patient cohort that completed enrollment last year, towards the beginning of last year. Also, the non-melanoma skin cancer cohort of RP1 combined with nivolumab, which was not fully recruited and is still recruiting, has a predominance of CSCC patients. The data which we find extraordinarily supportive of our strategy of RP1 combined with cemiplimab versus cemiplimab alone, are our pivotal trial. Why we think that's very strongly founded is because of that prior data, with RP1 combined with nivo, in a smallish number of CSCC patients so far. At ASCO, the aim would be to present obviously longer-term follow-up from those patients already treated, whereas back at SITC last year, we were showing a 70%-80% response rate and a roughly 40%-50% complete response rate with very good durability. ASCO, we would expect to show a longer-term follow-up of those patients plus additional patients who have been recruited more recently. Got you. Okay. That's perfect. I'm sorry that we have to stop the conversation now. We're at that 25-minute mark. Been a pleasure speaking to you both. Thanks so much for joining us at Barclays Global Healthcare conference, and look forward to seeing you guys next year as well. Yeah. Thank you. Bye. Thanks, Peter. Speak soon. Take care.