Replimune Group, Inc. (REPL) Earnings Call Transcript & Summary

Good afternoon, everyone. Thank you for joining us here. It is my great pleasure to introduce Sushil Patel, CEO of Replimune. We were thrilled to have here at our 45th Annual Healthcare Conference. Sushil, thank you for joining us. We look forward to walk through the presentation.

Thank you, Ryan. Good afternoon, everyone. Just to remind you about forward looking statements. So Replimune was founded with the goal of really developing more potent and systemically active oncolytic immunotherapy. And right now, we have 2 assets in the clinic, RP1, which is very much focused and has generated compelling activity in the range of skin cancers, including anti-PD1-failed melanoma and I'll be sharing some of that data with you shortly. And we're now well on the way for a BLA filing in the second half of 2024. RP2 is very much focused on looking at rare cancers or hard-to-treat cancers. Again, we've seen activity in the range of those. The plan is to move forward in uveal with a registrational study, which again, I'll be telling you a little bit about more shortly. And just to remind everyone of the mechanism action, there's really a two-fold approach here. There's local who are killing, which releases neoantigens, which then drives a more broader systemic reaction. The platform is based on a herpesvirus, HSV-1, the very lytic virus for cancer. And then there are a number of transgenes encoded into the virus with all our platform, we have one that's a fusogenic protein that drives sort of cell to cell fusion. So it creates quite a potent local immunogenic killing, but it also drives immunogenic cell death, and that really is quite potent and drives a more systemic reaction. And so that GALV protein, which is based on another virus gibbon-ape leukemia virus has a very potent activity in this construct. In addition to GALV for RP 1 and 2, we also have GM-CSF. And with RP2, we also encode a CTLA-4 molecule, which, again, the idea there is to drive even more potent and systemic immune activation, particularly for more immune insensitive tumors. And so as I mentioned, RP1 focus on skin cancers. I'll be sharing some of the data in skin cancers with you shortly. And then RP2 is focused on some of the rarer cancers. You can inject these both superficially and viscerally and I'll talk a little bit about that as well. We've seen systemic and visceral activity with both assets. And now I'm going to move on to the RP1 data and skin cancer starting with our IGNYTE data, and we're very excited about this in anti-PD1-failed melanoma. Let me just remind you of the environment and the landscape. So despite a recent approval in the anti-PD1-failed melanoma space to TIL therapy, the significant unmet need remains. The existing drugs either have modest response rate, limited durability or come with significant toxicity. And so there really is an opportunity to advance the landscape from multiple angles. Always when you look at some of the existing treatments and data in the anti-PD1-failed space, the criteria used for resistance is quite varied. And one of the things that we've done, I think, a very good job of is having a very specific and stringent criteria, so that these patients really would not benefit from additional treatment. These patients had confirmed progression while on a PD-1. They had to have been on PD-1 for at least 8 weeks. And that progression was confirmed by 2 scans. So we can really be quite confident that these patients have truly had -- will not benefit from further treatment. And this is one of the differentiators that you're seeing from many other trials in this space. So this is the data I'm going to share with you, which we just presented at ASCO. It's on 156 patients. It's a 140-patient registration-intended cohort, plus 16 patients from our Phase I experience for 156 patients. All these patients have been followed up for 12 months. And so I think one thing we feel very confident as it represents a truly real-world and broad population of and presentations of anti-PD1-failed melanoma. I would sort of direct to the M1b, C and D, which -- these are patients that had visceral active involvement, about 50%, about 50% had also received prior ipi/nivo. And then we had impressively about 2/3 of the patients had primary resistance to their checkpoint inhibitor. That means they blew through their prior treatment in less than 6 months. These are what they call the bad actors who really do not do very well with further treatment. So it's a real-world population. It's one with a high unmet need where existing subsequent treatments really would not do very well. Here's the efficacy that we presented at ASCO. We had a 32.7% response rate overall, also a 27% response rate in patients who failed both ipi and nivo, again, very tough population. And as I mentioned, that primary resistance population was 2/3 of the population, we saw a 34% response rate. The 1 in 3 respond, and we see very good activity across these different subgroups. One of the important things with intratumor agencies, do you see both systemic as well as local activity and there's always the idea that we're only seeing a local activity here. And so this is an analysis we did on the first 28 patients where we looked at all lesions uninjected and injected the -- red is the injected lesions. The blue is the uninjected lesions. And you can see the response dynamics are really similar whether lesion was uninjected or not injected and 70% of responding patients had non-injected lesions. So again, hinting to the systemic activity and that we're really seeing not just the local activity, but that systemic activity that I talked about. Importantly, when you're treating these patients, you want responses, but you also want very durable responses, and that's the case here. We've seen 100% of patients last at least 6 months from time of baseline, and we see a median duration response of more than 36 months. One of the nice benefits of the modality is the really nice safety profile. But if you look at the combination of RP1 plus nivolumab, we see generally mild to moderate side effects, constitutional side effects, mostly grade 1 and grade 2. We do see a smattering of grade 3 and 4 side effects, but we have not seen any grade 5 reactions. Again, this is very different to many of the other treatments that patients have in this setting today. So in conclusion, RP1 with nivolumab shows in patients who had confirmed progression by strict criteria shows deep and durable systemic responses, a very favorable safety profile. As I mentioned, about 1 in 3 patients respond across the different subgroups enrolled and that these are very durable. Now I'm going to transition from that was the investigator-assessed data of 156 patients. This is the primary analysis that we just presented in Investor event last week on the 140 patients, which is our registration intended cohort. And so I'll start on the left. The -- if you remember, I just shared with you modified RECIST data from the 156 patients. That was 32.7%. In this -- of the 140 patients, you see 32.1%, so consistent. Now moving to the right-hand side, the 2 investigator-assessed central review -- sorry, independent reviewed data. This is the primary analysis of the study. The middle number is 33.6%, which has increased over what we saw in the investigator modified RECIST, which was encouraging. The other number you see there is RECIST 1.1. This was an analysis the FDA requested just so they can really cross-compare our data because we used the modified RECIST criteria to other treatments in the landscape. And again, you see a very consistent 32.9% even in RECIST criteria as well. So just to give you an example of a patient, this is a highly treated patient had multiple previous lines, including experimental treatments. Just to orient you, the red circles are where RP1 has been injected in those, you can see there is some decline in the lesion size, then you have the yellow or the uninjected lesions. And here, we see activity in bone. We also see abdominal reductions in lesions and importantly, visceral lesions in lung on the bottom right. So again, we -- when we summarize the central review data relative to the investigator data I shared with you very similar consistent patterns in terms of 1/3 of patient respond. As I mentioned, the ORR actually increased marginally to almost 34%. Responses remain durable, whether they were by investigators assessed or the independent review and the safety continues to be very well tolerated in terms of grade 1 and grade 2 relative to grade 3 and 4 side effects. This full data with additional subgroup analysis will be presented at upcoming congress. Now I'm going to move on to the next steps in terms of regulatory. At central review data, the top line data has already been shared with the FDA, will be requesting a pre-BLA meeting. But just to sort of orient to previous conversations we've had and why we feel that we're meeting the criteria we had based on those discussions with the agency. We had a Type B meeting and a Type C meeting more recently. The FDA gave us a lot of direction of what they wanted to see. And as I mentioned, one of the key things is to make sure that we had a real-world population that we saw clinically meaningful activity across subgroups, which I shared with you. We believe we've met that bar. As I also mentioned, the FDA want to see RECIST 1.1 data from central review. Again, that data is held out relative to the investigator-assessed data. And one of the important things that the FDA did say is we're a combination treatment. So how are we going to look at the individual contribution. It's a tough setting to actually identify that given the heterogeneity of the population. And they did say that we can use individual contribution of components by literature. And as I mentioned, if you use the criteria we use, we would not really expect to see any more than 10% response rate for single-agent anti-PD-1. So again, we believe we've met that criteria as well. And again, we're going to now start enrolling in our confirmatory Phase III study. The FDA was very clear that they wanted this underway. We're hoping to have the first patient enrolled in that study, our IGNYTE-3 trial in Q3. This is the study. It's in advanced melanoma patients, who have progressed on ipi and nivo or ineligible for CTLA-4. They can also get a dealer's choice in the control arm of Opdualag chemotherapy or further rechallenge with monotherapy anti-PD-1. The primary endpoint of this trial will be overall survival. And as I mentioned, the idea is to get as many of these patients enrolled, there was a lot of excitement on this trial coming out of ASCO, so we want to get as many patients enrolled prior to BLA. So now I'm going to move on to monotherapy data. Previously, I presented combination data with RP1 plus nivolumab. Now let's look at monotherapy data. This is in the setting of organ transplant. These patients sadly will eventually get a skin cancer at some point in their lifetime, most likely. And this is a high unmet need, because for those patients who really can't give further checkpoint inhibitors because of the chance of organ rejection, particularly for liver, lung and heart transplants where you really don't have a fall back. Obviously, you have a kidney transplant, you go back to dialysis. That's still not optimal for the patients. So this is a single agent RP1. It's a bit of a different dose and schedule to what we use in combination where we use up to 8 doses. Here, we use up to 26 doses, and you can redose the patients. These patients usually develop of the different types of skin cancer, it's almost always cutaneous squamous cell that develops about 90% of them, which is consistent to the real world actually developed cSCC and this what we saw in this study. We saw a very impressive response rate of 35% and a 22% complete response rate. Now what's so meaningful is, as I mentioned, for many of these patients, you really can't get further checkpoint inhibitors or if they do risk choosing a checkpoint, because you've got the choice of either dying from your cancer or rejecting your organ, you can also have -- you may have to deal -- change their steroid regimen and immunosuppression, one of the benefits in our trial as we did not have to change their underlying immunosuppressive drugs, so they could maintain those, and we saw no organ rejection, early data, but quite encouraging. We're looking to enroll more patients, including heart, liver and lung. But just to give you a little bit of background on what's the sort of opportunity size and patient population, it's about 1,500 patients. We are seeing a real explosion in the number of organ transplant patients that occur in the U.S. There's been more than a doubling over the last 8 years. As I mentioned, these patients have a significantly increased risk of developing cancers and loss of organ rejection. And as I mentioned, I shared the data there in the dosing and schedule and our safety profile. So we're excited about this opportunity. This is an area where we may be able to take this data, given the unmet need for a potential registrational path. Now I'm going to move on to another trial that we did, CERPASS. This was a locally advanced or metastatic cSCC. This is a randomized trial of RP1 plus cemiplimab versus cemiplimab. Unfortunately, this trial narrowly missed its primary endpoint of CR or dual one of its dual primary endpoints of CR. However, what we did see is a really compelling activity in locally advanced cSCC, where we saw a doubling of the complete response rate seen in right on the bottom there, 48% complete response rate in the control in the experimental arm versus 22% in the cemiplimab lone arm. We're going to continue to follow this trial. And the reason it is because we do see significant benefit for patients. These patients on this trial, some of them had very, very significant tumor burden, very large outward growing tumors that we could get into complete response. This is really meaningful. So if you can bring some patients like this into complete response, it means a lot to the patients and their treating physicians. Now I'm going to just move on to the commercial opportunity with RP1. And I talked about a lot of the different skin cancers starting on the left side, about 13,000 anti-PD1 failed melanoma patients. I'll just break that down for you a little bit. There's about 2,000 patients who come from prior adjuvant treatment who fail is sort of misunderstood sometimes that those patients can actually if they've got primary resistant disease, can blow through treatment quite quickly and then just in need of treatment as other patients in melanoma. About 8,000 patients have second-line failed melanoma from frontline ipi/nivo, Opdualag or a BRAF inhibitor, and then there's a 2,000 or 3,000 third-line class patients. So significant opportunity there. We also, as I mentioned and showed you some of the data we have in non-melanoma skin cancers, there remains a significant opportunity there. I mentioned in the locally advanced cSCC, the solid organ transplant. We also see activity just like we saw in melanoma for anti-PD1 and for non-melanoma skin cancers as well. Some of these may be compendia listings if we're able to get RP1 approved, others will be potential registrational path will pursue. What's really excited about the modality really lends itself is to moving into the earlier stage neoadjuvant setting and there are a significant number of patients there, a lot of drug development going on there, and we do think we can further raise that already high bar in some cases. So as we think about how would we use and position RP1, we do think it can be broadly adopted in the U.S. across different settings. As I mentioned, we believe that we are a great first option for melanoma patients who have progressed on either their first adjuvant treatment or the first-line setting, given the deep and durable responses, the safety profile and the administration relative to some other options like TIL therapy. We also believe it provides a compelling option for a range of PD-1 failed presentations. And we've done some analysis around [indiscernible] melanoma, we'll have something that you can inject, it will either be a superficial lesion or something that can be image-guided deeper lesions that will involve interventional radiology. So we do think not only we will be able to help a range of anti-PD-1 failed melanoma, but we can also help a broad range of patients within that group. And this can be done in most health care settings, including in the community, allows community physicians to keep and treat their patients versus having to refer them to academic centers for certain treatments. As I mentioned, we've also seen compelling monotherapy activity in hard to treat non-melanoma skin cancers, which have failed other options and solid organ trials. So just talking a little bit about manufacturing. I shared with you some of our prior FDA interactions and feedback. We also had a recent Type C meeting on our CMC specifications where the FDA provides more clarity on what they need in terms of assay and validation. That was a very productive meeting. So we now know what's required from that perspective. We have a state-of-the-art manufacturing facility in framing in Massachusetts, where we're making all our own drug, and we'll have enough supply for global production of RP1 and RP2 and that our commercial inventory is also underway. One of the other nice aspects of this modality is a very attractive cost of goods and off-the-shelf practicality relative to other things like cell therapies, which can be significant costs. So just now moving on to RP2. So that was RP1. RP2 as a reminder, as all the components of RP1 in addition to the CTLA-4 encoded, we know that CTLA-4 is a potent immunostimulator. And it can be given locally without the systemic activity and toxicity that CTLA-4 often causes that can be very beneficial for patients. On the bottom there, you see 2 examples of uveal melanoma, which are hard to treat, where we are on the first, we see an expansion of the T cell clones, not only existing clones, but new T cell clones, suggesting there's underlying immune activation happening. And on the right, we see another uveal patient who actually has an upregulation of the CD8 or the infiltration of T cells posttreatment and expression of PD-L1. So just talking about uveal melanoma a little bit. It's called melanoma, but really, it's cancer of the eye. And one of the sad and tragic things about it is most of those patients will have liver metastases, 70% to 90% of those patients will get liver metastases with a very bad prognosis. Of course, there's been a recent approval with KIMMTRAK in the frontline setting. However, that's predominantly for HLA positive patients. There's still an unmet need in HLA negative and not everyone can tolerate or can get a KIMMTRAK. And so there is certainly a need for better and newer options for patients. So we also shared our uveal data at this ASCO. And again, we saw some very encouraging activity. We saw almost 30% response rate in these patients were very hard to treat, almost a 60% disease control rate. And they certainly got some of the uveal melanoma treats exciting, and that's why we're moving forward with a potential registrational study. A couple of important aspects. We saw activity whether the patient had HLA positive or negative disease and that 70% of these patients had failed ipi/nivo. Just like I showed you with RP1, the toxicity profile for RP2 is very good and very tolerable. We do see a slightly higher incidence of grade 1 and 2 constitutional reactions, as you might expect, with the CTLA encoded, and we also see some more grade 3. Importantly, we did not see any bleeding, because a lot of these patients, I mentioned, had liver metastases and injection of the liver metastases in a repeated fashion. And so this can be done repeatedly. These are thin needle that you use. It's not like a core biopsy. This is just a patient example. This was a patient who was highlighted on TV in the U.K. In red, you see these very large liver lesions that were injected and that went away. We also see uninjected liver lesions and other lesions disappear in this patient is a continuing response for 19 months. So just to sort of summarize the RP2 approach. We've seen active RP2 in a number of rare tumors. I shared with you some of the uveal data, we've also seen activity in chordoma and spinal cord tumors, which are difficult to treat and sometimes surgery can't be done. And we've also seen activity in other sarcomas, mucoepidermoid sarcoma, et cetera. We see mono and combination activity with RP2. And importantly, rare cancers do represent about 27% of all cancers and now 25% of all cancer deaths. So certainly a significant opportunity there. We look at sort of uveal with our foundational trial, but an opportunity to build on -- beyond that, as I mentioned, in the areas there, but also soft tissue sarcomas, rare head and neck cancers, et cetera. So just to summarize, we were excited about the central reviewed data from IGNYTE. We're going to be submitting and we have submitted the top line data of the FDA and requesting a BLA meeting, looking forward to getting our first patients enrolled in that confirmatory trial, doing the submission before the end of the year, starting the uveal trial with RP2 and then really, we're very much ramping up our commercial activity and readiness in preparation for RP1. Just as a reminder, all our programs are wholly owned, and we have a potential to deliver significant revenue starting in late '25. We have a very strong financial position. We have $420 million in cash as of April -- sorry, 31st of March and a runway into the second half of 2026. So that was a summary of what we've got going on at Replimune, and we're very excited to be talking to the agency and hopefully bringing our first asset to patients in need soon. Thank you.