All right, let's go ahead and get started. Thanks, everyone, and welcome to the J.P. Morgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at J.P. Morgan. I'm joined by my squad, Priyanka Grover, Malcolm Kuno, and Ratih Phinhai. Our next presenting company is Replimune, and presenting on behalf of the company, we have CEO Sush Patel.
Thank you, Anupam. So it's certainly been a very busy and exciting year for Replimune, and we now have reached a pivotal stage of the company and have a substantial body of evidence to support our oncolytic immunotherapy platform. Now, starting in skin cancer and RP1, we've now demonstrated a very compelling data set in anti-PD-1 failed melanoma, where we've been able to get 30% or almost a third of patients into a durable response and have seen strong systemic activity, including hard-to-treat visceral disease and with a very nice safety profile.
Importantly, we've also been able to progress the pipeline forward with our second asset, RP2, in a registration study in uveal melanoma, and we recently enrolled our first patient. We've also moved forward with our first patient enrolled in HCC, and this is a study that's in Atezobev-failed patients. We are now actively enrolling a number of U.S. sites. Now, based on the strength of the anti-PD-1 + RP1 data, we received breakthrough designation from the FDA, and shortly we should be hearing about our BLA acceptance, most likely in the coming few weeks.
Now, as a result of the breakthrough designation, we're planning for a priority launch in the second half of 2025, and we feel very confident that we'll be able to successfully launch, and that confidence is further bolstered by our strong cash position, where we have more than $500 million available, and we also have a very attractive cost of goods, which comes from Replimune manufacturing its own products, including RP1, at our facility in Framingham, Massachusetts. Our oncolytic immunotherapy platform is really based on a dual mechanism of action, and it's really derived from a herpes simplex backbone with a number of immune-stimulating payloads expressed.
Now, this results in injected local responses as a result of direct tumor killing, but we also see non-injected systemic responses due to the ability of tumor lysis and neoantigens release, which is then further bolstered by the expression of these immune-stimulating virus payloads. Now, these immune-expressing payloads differ across our different constructs. RP1 includes a GM-CSF and also GALV, which causes cell fusion and a potent immunogenic cell death, which enhances direct killing but also drives broader systemic immune activation.
Now, in addition to GM-CSF and GALV, RP2 also includes a CTLA-4-like antibody, and the idea here is that we express CTLA-4 locally so that we don't deal with some of the systemic toxicity typically associated when using this immunotherapy. So the therapeutic objective of both the RPx platform, in combination with our ability to precisely administer the drug locally intratumorally, results in a number of benefits and overcomes various limitations we see with other agents such as checkpoint inhibitors, such as resistance, which invariably results in many patients.
Another advantage is our ability to combine with a number of different modalities, including targeted therapies, and avoiding some of the toxicity burden that typically comes when you use these combination approaches. So now I'm going to talk about RP1 and melanoma and our potential of the pipeline to deliver on the promise of oncolytic immunotherapy and the data we have to support that. Now, I'll just remind you that while we've made significant progress in melanoma, there remains significant unmet need in the refractory setting.
When patients have progressed on a PD-1-containing regimen, there still are really very few treatment options and very few good treatment options. Now, if we retreat patients who are truly resistant with single-agent PD-1, we really wouldn't expect to see a response rate of more than 6% or 7%. Now, if we're going to use combination immunotherapy in these patients, for patients who have failed on frontline Ipilimumab or Opdualag, we typically wouldn't see more than a 12% or 13% response rate, and this comes often with a significant toxicity burden of grade 3 or 4.
And finally, the only approved agent in this setting is TIL therapy, but unfortunately, this really isn't an option for many patients due to the timely, costly logistics associated with the treatment and the significant toxicity that patients experience, with nearly all patients having grade 3 or 4 toxicity. So I think this unmet need and the unique opportunity that RP1 presents to improve outcomes for melanoma patients is quite exciting. Now, in the next few slides, I'm going to be sharing with you our IGNITE data. Now, this was the basis of our recent BLA filing and breakthrough designation from the FDA, and this is looking at the response rates that we've seen for the study.
Now, firstly, if we look at all patients enrolled in the study, we see almost a 34% response rate. I also want to highlight two important subgroups here. The first subgroup is patients who failed CTLA-4 and PD-1 combination treatment or ipilimumab, and we see almost a 28% response rate in this group. This is a particularly tough-to-treat population with very few options afterwards. Importantly, two-thirds of the patient population was primary resistant.
This means that they blew through their prior treatment in less than six months and really had very poor outcomes, and in that group, we see almost a 36% response rate. Now, importantly, these responses are durable, and we see a median duration response from response initiation of 21.6 months. Now, undoubtedly, these durable responses are contributing to the promising overall survival benefit we're seeing, and if you look at the three-year landmark survival, almost 55% of patients are still alive at three years, and currently, the median survival from this study has not been reached at the time of this analysis.
Now, what we hear as the most notable aspect of the data and most compelling is the systemic benefit we see, particularly in visceral uninjected responses, where we see deep and durable responses. Now, if you look at the left-hand side, this is a waterfall plot of all responders, and you can see the pattern of response and depth of response is similar whether you inject the lesions, which are in the blue lines, or the non-injected lesions, which are the red lines. Now, turning to the right-hand side, most of these non-injected lesions were actually visceral lesions, almost 50% of them, and if we look at the visceral lesion responses uninjected, we see almost two-thirds achieved at least a 30% or more response.
Now, specifically looking at the liver and lung lesions within that, which comprise most of those visceral lesions, we see almost a 70% response was achieved of 30% or more, and again, these are particularly hard-to-manage manifestations in this setting. We also hear that this data is particularly compelling for the KOLs, who tell us that while they've seen some systemic benefit intratumoral agents, they've not seen this extent of benefit, and this is something that's highly differentiating. Importantly, safety is another consideration when we're thinking about treating these patients.
RP1 plus nivolumab was extremely well tolerated with predominantly grade one constitutional-like symptoms: fevers, chills, indicative of immune activation. However, we didn't see any grade five toxicities. Now, in line with our objective to move forward rapidly with accelerated approval, we've also initiated our confirmatory phase III trial, IGNITE-3, and this is a study with a primary overall survival endpoint, but we also have a planned interim overall survival. This is rapidly enrolling.
We enrolled the first patient in August, and are working very diligently to make sure that we enroll this trial in a timely fashion and expect that to be about two or three years. We've been discussing with the agency the enrollment updates in line with recent guidance and feel confident that we're meeting those. We're also expanding beyond the U.S. sites that we currently have to the rest of the world and particularly Europe, as this study is going to form the basis of our global pricing and reimbursement. Recently, we just started our expanded access program.
Now, this is complementary to the IGNITE-3 study, and it's going to allow utilization outside of the traditional clinical trial sites, including trial sites in the community. So, in summary, we have a differentiated data set across patient subgroups, including strong systemic benefit, which really should allow us to address the significant commercial opportunity. We've got a lot of commercial work underway, and in the next few slides, I want to share with you how we consider the commercial opportunity and what we're doing to capitalize on it.
Now, we have 13,000 patients and a significant opportunity here, and when we break down that patients, these are patients who are progressed on a PD-1-containing regimen. About 2,000 of those are progressed in the adjuvant setting. We estimate around 80% of these will be injectable by RP1, and importantly, these will be injectable in the outpatient setting, so these will not require inpatient treatment. And as you think about the lesion location, four out of 10 patients will have a superficial lesion, and eight out of 10 patients will have a deep lesion.
Now, lesion location is mutually exclusive, but what's really important is when you have these deep lesions that will require the involvement of image guidance and interventional radiology, and we're very confident that our commercial model will allow all eligible patients to be able to be treated. We've also done extensive analysis on understanding where these patients are treated, and we see that it's quite a concentrated patient population, with 80% of patients treated either in academic or hospital-based systems or in large community networks such as those shown on this slide.
Now, as I mentioned, to capitalize on the patient opportunity, it is important that we have image-guided injections and work with interventional radiology, and importantly, 50% of these patients are in academic centers or hospital-based systems where interventional radiology is on-site, in-network, and has access to electronic medical records and can easily manage patients.
Now, another 30% of these patients are in these large community networks, and these have established relationships with interventional radiology, and one of the jobs of our commercial team is really to ensure that we support patient co-management and also ensure that RP1 can be efficiently administered by interventional radiologists. Now, one of the most exciting aspects of the modality, and I think it's very different in the treatment of melanoma and really provides a new tool for oncologists, is the idea of working together with interventional radiology in this space.
Now, interventional radiologists are certainly not new to oncology procedures. They do a lot of things such as ablation, TACE, and TARE, and also things like Y90, and when we shared the IGNITE data with them, they're very impressed with the data and excited to be part of the new treatment dynamic. Now, what they consistently tell us in our market research is they're very impressed with the systemic benefit, particularly in uninjected visceral lesions, and I think this is nicely demonstrated by the quote in the middle from Dr. Sheth from MD Anderson, who has an extreme amount of experience using intratumoral agents.
The other thing we hear from interventional radiologists who, when we walk them through the procedure, is this is quite simple and way more simple than most of the procedures they do, which take a lot more time and are a lot more complicated, and the analogy they may most often refer to is this is like a biopsy or actually more accurately a reverse biopsy because we're injecting something versus taking something out. And then the other important aspect of RP1 injections is we use a very thin-gauge needle, so the risk of bleeding events is quite low relative to repeat biopsies, for example.
So, beyond the RP1 data itself, there are a number of product attributes that should enable broad and rapid uptake. This includes off-the-shelf therapy that can be ordered and used immediately, as opposed to a number of cell-based treatments which may require some time for the treatment to be made. Importantly,
RP1 is administered in the outpatient setting, and this allows utilization in the community, and then finally, there are very favorable economics, and RP1 will be billed by standard buy-and-bill and importantly is used in combination with nivolumab, so we believe we'll be well-positioned to be the first choice after PD1 progression for most patients, and this is based on a combination of, I think, compelling safety and efficacy data, a comprehensive understanding of the patient population and prescriber base, and the launch model that's really going to enable us to do intratumoral injections and work closely with interventional radiology to do this efficiently.
Now, importantly, we'll also be able to meet demand because we have commercial in-house manufacturing established. So, now I'm going to move on to RPx expansion opportunities in the next few slides and where we see the pipeline going. So, starting with RP1, beyond anti-PD-1 failed melanoma, we also see a very compelling data set in anti-PD-1 failed non-melanoma skin cancers, including Merkel cell carcinoma, basal cell carcinoma, and cutaneous squamous cell carcinoma, where we see about a 30% response rate, and there's an attractive patient opportunity here.
Another highly underserved area is solid organ transplant patients, and many of these develop non-melanoma skin cancers, and we see almost a 35% response rate with a high rate of complete responses in these patients. Now, this is a setting where there's no approved treatments, and single-agent checkpoint is typically not used because of the risk of organ transplant, and RP1 is used as monotherapy here in a little different way because these patients have underlying immune suppression, so we're really treating them chronically, and the dosing we use is a bit different.
The course of treatment here is 26 doses versus the typical eight doses we use in other settings. Now, moving on to RP2, we see encouraging activity here in uveal melanoma, and this is really not so much a skin cancer but cancer of the eye, and nearly all these patients have progression in the liver, and when that happens, the prognosis is extremely poor. Now, if I draw your attention to the patient case, what we see, which we've also seen with RP1, is that we see the ability to shrink both injected lesions, which are shown in red, and non-injected liver lesions shown in yellow, and these responses are very durable.
So, I think this is a very compelling data set, and when we look at 19 patients that we treated here, we see almost a 30% response rate and a 60% disease control rate, which is very meaningful for these patients. Importantly, there's a favorable safety profile and that we've demonstrated that we can actually do repeated liver injections without a significant risk of additional bleeding risk, which is important. Now, this has resulted in us rapidly moving into a registrational study in checkpoint-naive metastatic uveal melanoma, where we recently enrolled our first patient.
This study has a co-primary endpoint of PFS and overall survival, and at the final PFS analysis, we should be able to file for accelerated approval with conversion on overall survival at the final analysis. Just starting at the bottom of this graph, we're looking forward to bringing RPx to skin cancers and now have a substantial body of evidence where if we are able to treat all the patients and skin cancers that we've seen activity in, we would almost have 15,000 treatable patients. However, I think what we're most excited about is really the ability to build on the systemic and visceral activity we've seen with RP1 and also RP2 and then take that into more prevalent tumor types such as primary liver cancer.
Here we've, as I mentioned, started our first trial in hepatocellular carcinoma in Atezobev-failed patients. Now, the ability to inject these lesions also and inject many other more prevalent tumor types is only increasing with improvements in image guidance, injection technology, robotics, and when we consider that lung and liver lesions and metastases, excuse me, are very common in these cancers, I think this opens up a lot of possibilities because those are very problematic to manage and are a cause of significant mortality.
So, we look forward to providing more information on how we want to move forward with RPx in an R&D day that we have coming up shortly. So, in summary, it's been a very productive six months, and we've now achieved a number of the regulatory gates for RP1 in anti-PD-1 failed melanoma. We've also rapidly moved RP2 into a pivotal study in uveal melanoma and liver cancer, and now I want to draw your attention to some important upcoming milestones for the company.
So, as I mentioned, we're eagerly anticipating our BLA acceptance in the coming weeks, and as I just mentioned, we're planning an R&D day to provide more guidance and information on the expansion possibilities in the first half of 2025. Now, given Breakthrough Designation, we're planning for a priority U.S. launch in the second half of 2025 and are now actively working on our commercial plans, and I look forward to sharing more of those with you in the coming weeks and months, and we're very excited about the possibility to treat as many patients as possible with RP1. Thanks for your attention. Could you want to invite the team up?
Yeah.
Sure. So, we just want to introduce a few of the Replimune team here. So, we have Emily Hill, our CFO, Costa Xenos, our Chief Medical Officer, and Chris Sarchi, our Chief Commercial Officer.
I just want to remind everybody that there's three ways to ask a question, right? So, you can raise your hand the old school way. You can send an email to me, or there's a question portal thing here that maybe you could hand to me. It looks like there's some questions. But I will start out here with a quick question on, you know, with the BLA filing now complete for RP1, you know, you got Breakthrough Designation granted as well. What are the key regulatory milestones and timelines we should be considering?
Emily, take that.
Yeah, sure, I'll take that one. As Sush mentioned, we submitted our BLA to the FDA in late November. Based on the anticipated regulatory timelines, that would leave us to expect the FDA to file or approve our BLA in the coming weeks, late January or early February. At that point, they'll officially give us our PDUFA date, which, based on Breakthrough designation, we expect to be a priority review. In the interim between that and the expected approval at the end of the summer, we would have manufacturing inspections, and we're preparing for those as we speak.
And so, I guess, I mean, you mentioned in the slides many of your kind of pre-commercial activities. If you could dig in a little bit about how you're educating the market, how you're mapping patients besides what you talked about in your presentation.
I'll let Chris take that.
Yeah, so we're going to, over the next couple of months, we're going to continue to generate in-depth understanding of the market while we complete our commercial build-out, as Sush said. Now, we also mentioned that this is a highly concentrated market with roughly half the melanoma patients being treated across 200 accounts in the U.S. We expect, by the time of approval, to have completed in-person profiling of all 200 accounts, again, at the time of approval.
From there, we're also going to be continuing to gather very valuable insights in terms of ways of working between medical oncologists and interventional radiologists while we also uncover some of the unmet needs that still exist that we believe our commercial model is going to help successfully address. You know, the additional, probably, key milestones that are coming in the next few months are going to be the completion of our distribution model as well as our patient support hub, which, while we've already begun pressure testing those, we have several different pressure tests coming in the months ahead to ensure we have a seamless execution upon approval.
We have a question on who at the company is leading the regulatory process with the FDA.
That would be Carrie Yaski, our regulatory lead. Yeah.
Yeah, so the regulatory lead, basically, the regulatory lead is what kind of experience do they bring to the table?
She has a very extensive experience from a regulatory perspective. Has also been at the company for quite a few years now, and I think came in from a very extensive career in regulatory in Big Pharma.
Questions from the audience? What is going to be the size and scope of the field force that you're ultimately going to have out there?
So, you know, one of the beauties of having such a concentrated market is our ability to be pretty targeted with our approach. So, when we, actually, by mid-April, we'll have a trained team of about 30 sales representatives ready to support the product. We'll also have some surround sound for teams to help support patient pull-through. We'll have a team of oncology nurse educators. We'll have a team of market access and reimbursement specialists. And we'll have a dedicated team of interventional radiology oncology coordinators, or IROCs.
And this is a team that's going to be challenged with helping to coordinate the efforts between medical oncology and interventional radiology. And so, that's going to help ensure a positive first patient experience upon approval. We won't be having company cars that are Corvettes for the IROC team, so we can have the Camaros. That's right.
The medical educators and the IROCs, they're going to be separate from your 30 persons here.
Exactly, yeah. Total footprint, I'm probably about 65 for the field-facing teams that I just described.
We've also had a number of the medical affairs team out there several years now under Costa's guidance, really educating the market as well.
Correct. We have 10 of ourselves that are out in the field now already.
Questions from the audience? We've got another portal question here: Would you expect that all RP1 administrations by interventional radiologists would be only for deep lesions? Is that how T-VEC was formerly used?
I can start that, and then we can go on to Chris. Now, T-VEC was predominantly used in superficial lesions and did not have a label for deep injections, which really comes from the fact that they really haven't demonstrated the uninjected systemic benefit that we've seen, including visceral organs with RP1. So, I think that was just a consequence of the data they had. And I don't know, Chris, if you want to talk about the second part of the question.
Yeah, yeah, so superficial lesions will primarily be injected in the medical oncology office. In all the interactions we've had with interventional radiologists, there's absolutely an appetite to inject both superficial and deep lesions when patients are there, and it'll be dependent upon more practice-specific needs, whether it's contained within the institution or if it's a community-based hospital or a community-based account that's having the IR work done in a local hospital.
And then another portal question is: You said you don't need to be substantially enrolled in IGNITE-3. Is that because you've reached an agreement with the FDA, or is that because your approval would be in a different population than IGNITE-3?
Sure, no, I'm happy to take that. There have been a lot of questions recently about FDA draft guidance that suggests a study should have a confirmatory trial fully enrolled before accelerated approval. Because we've had Breakthrough Designation, we've had several interactions with the FDA, starting with a pre-BLA meeting in September where we outlined the expectation for our accelerated approval confirmatory trial, IGNITE-3. That trial will take two to three years to enroll. The FDA is well aware of that timeline and subsequently granted us Breakthrough Designation.
So, we feel that not only have we had clear communication with the agency around the expected enrollment timeline, but that we are doing diligent and thorough efforts to ensure it is rapidly enrolled in the U.S. and then pivots to continue to enroll ex-U.S., as it'll ultimately be the foundation for our global pricing and reimbursement strategy.
Questions from the audience? There is a little bit of back and forth on the street on the commercial opportunity for RP1. What do you think? You did a good job outlining all of the levers to think about here in the presentation, but what do you think the street is really missing on this opportunity?
Yeah, if I can. So, we know that 80% of these lesions can be injected with RP1. We also now know that the vast majority of these patients can receive access to interventional radiology either through in-house, in-network, or with relationships that exist. I think for us, over the last six to 12 months, with all the market research, the medical interactions we've had, the key findings for us, I think, have really been at the level of excitement, not that they're excited, but the level of excitement across the interventional radiology community with the data, what that data means for patients and their ability to take part in the injection process.
And so, for us, a key objective here is going to be to, where those relationships don't currently exist, to establish those. Where they do exist, to strengthen those, to ensure that when a patient presents who's a candidate for RP1, that RP1's presented in the most valuable way. And this is going to be a key functional role of that IROCs team I noted a minute ago.
Yeah, and I would say that, I mean, there really is no other option in the marketplace that I think provides the combination of the efficacy we've seen and, in particular, the systemic visceral activity as well as the safety profile that we bring to patients, which I think really does allow us to treat a lot of patients and hopefully expand the treated patient population.
We have another portal question: Is your R&D day in the first half going to focus largely on commercial, or will it focus also mostly on the broader pipeline strategy?
I mean, we haven't fully determined the content, but it'll be mostly on the R&D strategy.
Questions from the audience? You said that from right now, the IGNITE-3 would take two to three years to enroll?
Yeah.
Is that right?
A few years for enrollment, and the FDA is aware of that.
Yeah, we have about 50 sites selected for IGNITE-3, and half of them are already activated and recruiting. So, we expect about two to three years.
Those are U.S. sites.
U.S. sites, yes.
They're all U.S. sites?
Correct, and our global strategy is well underway, so we're implementing the strategy.
We would expect to have more than 100 sites globally once we're up and running.
Yep. And then you've kind of disclosed that you've started the studies for RP2, Uveal Melanoma, HCC already. How do you think about the enrollment curves of those two studies?
So, both studies had their first patient last week. We have several sites that are open, and we have a few sites that are coming up in the next few weeks. For HCC, we're looking to expand the study ex-US, and we're looking at countries that have a high prevalence of disease. So, both of our studies are ongoing at the moment.
Questions from the audience? And maybe a final question from me: Just find us some of your cash runway and what milestones are assumed within that runway?
Yeah, so our cash position unaudited at the end of 2024 was about $536 million. That takes us to the second half of 2026, at which point we would expect to have generated several quarters or a few quarters of revenue. So, that puts us in a position not only to fully fund our launch, but also to invest in expanding our pipeline, which we have started, as well as to fund the IGNITE-3 study.
All right. Thanks.