All right. Hello, everyone. Thanks for joining us. My name is Jonathan Chang. I'm part of the Leerink Partners Equity Research team. It's my pleasure to host the management team of Replimune. We have with us today, CEO Sushil Patel and CFO Emily Hill. Thank you guys very much for joining us.
Thanks for having us.
Would you like to first take a few minutes to briefly introduce the company?
Sure, Jonathan. Replimune was founded on developing the next generation potent oncolytic immunotherapy. We have a couple of assets that are based on an HSV platform that has a number of transgenes encoded to sort of further stimulate the immune system. Our lead asset is RP1 that's being developed in skin cancers, and we currently have a PDUFA date with the FDA for advanced melanoma on April 10th. We're gearing up for that and are launch ready, and we can talk more about that later. Our second asset, RP2, also has a CTLA-4 encoded in the transgene to sort of further drive the immune system. That's being looked at for a uveal melanoma. We have a registrational trial ongoing called REVEAL, which is enrolling very well.
We also have a number of trials, including in HCC and BTC that are enrolling well. That's kind of our next generation as we think about taking the platform to a more prevalent tumor types.
Great. maybe just start on the regulatory front with RP1. What has happened in the past, where do things stand today, and what is ahead of us?
Good question. Thank you, Jonathan. RP1 for advanced melanoma, back in mid-2024, we shared the centrally reviewed data from the IGNYTE-2 trial. After that data was disclosed, we received Breakthrough Therapy designation from the FDA. Subsequently, we submitted a BLA application and got a priority review for that application. We went through mid-cycle, late-cycle reviews, and very robust inspections. Got to labeling discussions, had a very productive review, but around that time, there were changes in leadership at the FDA, and we ended up with a very surprising complete response during our July 22nd PDUFA. After the PDUFA, we were able to schedule a Type A meeting with the FDA, where we discussed the data and the application. Subsequent to that, we came to the conclusion to resubmit the BLA.
That resubmission was accepted, and as Sush mentioned, we were given an April 10th PDUFA. During the review process, we've received additional information requests. We've responded to those information requests, and we are working towards our April 10th PDUFA now.
Great. What would you say are the key reasons for confidence in potential approval of RP1 at this point?
Yeah. I think the main thing is this is, you know, the anti-PD-1 failed melanoma space is one of very high unmet disease need. We continue to hear that resounding support from physicians, from patients. We feel very strongly that our data really provides an important treatment advance for those patients, including a range of anti-PD-1 failed melanoma patients with a very attractive safety profile, which is something the market very much needs, given other options that are available today are limited, and the ones that are there have come with significant toxicity. Those are a couple of areas why we feel very confident. We've had a lot of support from the patient advocacy groups.
just recently, we actually had received a letter, well, CBER had sent a letter to the patient advocacy groups in response to a letter they'd sent in from more than 300 patients, again, just identifying the unmet need in this space and recognizing that this is a real unmet need for patients and one where they are actively reviewing treatments for these patients.
Got it. You know, of course, another topic that's been coming up is of course the turnover at the Agency. Has that sort of impacted sort of your engagement and interactions?
At this time, we've had a very, you know, I think collaborative and ongoing discussion with the FDA. We're getting information requests. We're responding to those thoroughly and rapidly. At this point, I think we're right on track from where we would expect to be.
Understood. How should we be thinking about the contribution of components for the RP1 plus PD-1, anti-PD-1 combination?
I think this is an important question as you're thinking about a combination product and a single-arm trial. Contribution components. There's a couple of ways that we address this, Jonathan. Initially, we selected and defined a very selected and stringent criteria for PD-1 failure. These patients that had confirmed progression while coming onto treatment had at least two scans to confirm that progression. These had progressed while on PD-1. For all these reasons, we believe that this is a population where further PD-1 based treatment would really not expect to do very much, a response rate of 5%-7%.
With the IGNYTE data, we saw a 33% response rate when you combine RP1 with nivolumab, which I think further shows the contribution of RP1 to the benefit that's being seen here, as well as I mentioned, a very favorable safety profile. Another way we could look at contribution is things like the scientific rationale and sort of scientific plausibility. One of the things that we've done is look at biopsy samples for patients at day zero and look in the tumor microenvironment. These are patients that really didn't show any sort of immune activation. At day 43, after RP1 treatment was added to the nivolumab after definitive progression, we really see a sort of the immune system really ignited.
We see different immune signatures suggesting that there's activation, and then we see allows the PD-1 to work against. That's one thing. Just as I mentioned, finally, just the efficacy data we've seen in this population further, you know, suggests that we're seeing the contribution of RP1.
Got it. What, what is the status of the IGNYTE-3 confirmatory study, and have there been any changes to the study post the regulatory feedback?
One of the questions and one of the concerns, when we got the CRL was, is the phase III study appropriate for regulatory purposes? During that meeting with the FDA, we did manage to confirm with them that the reason why we chose the dealer's choice combinations that we did was because these are approved options for PD-1, or at NCCN-approved uses in monotherapy, PD-1, chemotherapy. We actually shared with the agency that nearly all the patients had actually received Opdualag, and that this was an appropriate comparator, and they seem comfortable with that. We now believe that the I-3 data is sufficient for regulatory purposes.
Got it. I'm sorry, and what is the current latest status of the study?
The trial is enrolling very well. At JP Morgan, we mentioned there was over 65 patients already enrolled. We've enrolled more patients since then, and we're now expanding beyond the U.S. to EU sites, Australia and the U.K.
Got it. I guess throughout the sort of regulatory process, can you discuss your commercial readiness ahead of a potential launch and sort of what has happened in the meantime on the commercial front?
Yeah. We've basically maintained most of the sales and commercial organization, again, based on the unmet need and the physician feedback. People have stayed with the organization. What the commercial team has been doing since the CRL is really doing deep profiling of the customers. We're an intratumoral. One of the things that we really want to enable is the ability to do these deep injections. Patients who have liver and lung metastases do require image-guided injections. Our sales team have been working in our target 150 accounts at launch to make sure that they can really connect the dots and make sure the interventional radiologists, the oncologists are identified in these counts.
We know the different processes and procedures of, you know, enabling RP1 utilization at launch. That's what they've been doing in the meantime. We have commercial stock ready, inventory being built up, again, with the awareness and the patient need and the physician need. Also just the amount of physicians that are aware and now using RP1 in our clinical trials, they're ready to go. They're asking for the drug. They're actually asking our sales teams to come in and help them determine how do we set this up so at launch we're ready to go.
How do you see the positioning of RP1, if approved, in the post-PD-1 cutaneous melanoma space?
Yeah, as I mentioned, one of the nice benefits of the combination is not only the efficacy and, you know, I mentioned this 33% response rate. We also see very durable responses, more than sort two years durable responses. One of the nice things about that is that allows us to really be an option for all patient types regardless of how they came into their PD-1 failed, you know, disease. Whether they came in from the adjuvant setting, we're an option for those patients, whether it's front line or second line patients, whether they used Ipi/nivo or monotherapy PD-1 or Opdualag, all those patients are potential options for RP1. We really should be the next available treatment following failure on a PD-1 containing regimen.
Got it. What's the feedback that you've received from clinicians on RP1 and sort of where are you in the physician education process?
One of the silver linings is the extra time we've had has allowed a number of physicians, including U.S. KOLs, to actually utilize and get hands-on experience with RP1 through both compassionate use. We've had more than 50 compassionate use requests for RP1. They've also been using RP1 in the I-3 trial now and have sort of that, as I mentioned, hands-on experience as well as RP2 in REVEAL. It's been very, very positive, and they continue to advocate very strongly for the drug and availability for patients. Just a couple of weeks ago, they had the Melanoma Research Alliance meeting in D.C. which, again, was an opportunity for some key podium presentations for RP1 from some of the leading melanoma treaters, and they really expressed again the unmet need, the desperate need for new and better treatment options for these patients.
Got it. How do you see the size of the commercial opportunity for RP1 in this post-PD-1 cutaneous melanoma setting?
Yeah. We estimate there's about 10,000 addressable patients in the U.S. 80% of melanoma patients will have something that you can inject, as I mentioned, not just superficial lesions which can be injected, by an oncologist or an NP/PA, but also these image-guided lesions, lymph nodes, liver and lung metastases that require interventional radiology.
How are you thinking about potential adoption in academic centers versus in more community settings?
Yeah. As I mentioned, the commercial team's been out there, and our target focus is this 150 accounts. These are predominantly academic and hospital accounts that have integrated interventional radiology within the site. That's kind of our initial focus area. This is a group of sites that already either are using RP1 in clinical trials or have the capability to use RP1 given the kind of dynamics of the site. That's been our focus, and the reps and the medical teams have been out there to make sure that they're ready day one. As we think about expansion over time, we will be going to another 200 or so accounts over the next year or so. That increasingly includes community practices.
As they get more comfortable, as we have a permanent J code that the community be comfortable getting reimbursed and using the drug, we would expand utilization into a broader range of patients, including community accounts.
Got it. Let me check with the audience, see if there are any questions on RP1 in cutaneous melanoma. All right. Maybe we can chat about how you guys think about RP1 and other opportunities beyond cutaneous melanoma.
As I mentioned, RP1 really has now been investigated in a range of skin cancers. Beyond the checkpoint failed melanoma space, one of the exciting areas that we've seen an IST or an ISS, this is investigator-sponsored study, in a neoadjuvant CSCC. We saw 100% complete response rate for those patients. These are patients, these are low-risk patients, but they've had a lot of surgeries. You have to keep cutting. There's areas where you really can't keep cutting depending on the location of the lesions. This is something that would be predominantly treated by dermatologists, so it's an interesting opportunity.
As we think about where the skin cancer landscape is going in general, they're moving to earlier and earlier disease. We're excited about the opportunity for an intratumoral such as RP1 to help earlier stage patients and ultimately get to cure. Another area that we've seen really exciting data with RP1 is in solid organ transplant patients. A number of these organ transplant patients will develop non-melanoma skin cancers over time, unfortunately. We see that again, RP1 as a monotherapy can really help these patients. We see about a 30% response rate with a very durable benefit in locally advanced CSCC patients. Again, these patients don't have great options today because typically you can't use PD-1-based treatments, especially if you've got patients who have such a thing as a liver or a lung or a heart transplants.
It's not very easy to give them a backup strategy. If you have a renal transplant, you can go onto dialysis, so they'll sometimes use PD-1s there. For those other patients with other types of transplant, there aren't great options. RP1 provides a really nice option for these patients. The other nice benefit of using RP1 is you don't really need to sort of moderate their steroid regimen, which again, is something if they have to use a PD-1, they often have to mess with the steroid regimen, which can create problems for those patients. Many of the skin cancer physicians are really excited about the opportunity for RP1 to also benefit those patients.
I guess just remind us, what is the latest status of the efforts of RP1, advancing RP1 in those other tumor types and settings?
Yeah.
Is it all pending, sort of, y ou know, sort of elephant in the room.
S ince the CRL, we've put a number of things on hold. We have a good number of ARTACUS patients that we believe could certainly be submitted for if we get an approval of RP1 in melanoma. This is a significant dataset that we could submit for a publication at NCCN and given the unmet need. The neoadjuvant CSCC is early, but that would be something that we would then discuss should the funding situation arise, working potentially with a partner to think about a study in that population. There is a lot of patients as you go up the sort of funnel in CSCC. Those are things that we're discussing right now, and at the right time, we certainly may want to advance those.
Understood. How are you thinking about opportunities for your second gen program, RP2, versus RP1?
RP2, as I mentioned, was designed to sort of go up that potency scale. As we think about more immunologically inactive tumors, such as uveal melanoma, that was really how we were positioning RP2. That trial, the registrational trial, is going very, very well. We mentioned there was more than 50 patients. JP Morgan, again, that trial continues to enroll very well. We're also expanding those sites beyond the U.S., and that's going well. As we think about the whole idea of that, it's really mostly uveal melanoma patients have liver metastases. It's a very poor prognosis, and we are seeing that we're able to inject these liver metastases.
The physicians are very excited about this option because not only is this really tough to treat, that they actually feel like the safety allows them to do these repeat liver injections. That trial was initially designed predominantly as a second, third-line trial with the REVEAL study, actually we're seeing quite a lot of front-line patients treated both in HLA positive, where tebentafusp is typically used today, as well as the HLA negative subgroup. It really is an option for a broad range of uveal melanoma patients and has a very different profile than the other treatments that are being studied in that setting.
Got it.
As we think about where that then goes to, you know, the fact that we've been able to do these liver injections, we're also looking at primary liver, so HCC and biliary tract. We have a signal-seeking study that's enrolling, and we would hope to have some of that data towards the end of this year, early next year.
Got it. How should we be thinking about the timelines for these additional RP2 efforts?
REVEAL, one of the next pieces or milestones for that trial will be looking at 90 patients of data which, we should expect early next year. That will really kind of a futility, safety, early efficacy look from a phase II to phase III transition. Hopefully, we would see that it replicates the phase I data we have in that population. In the, as I mentioned, the HCC/BTC, we should have sufficient follow-up for about 15-20 patients by the end of this year to really give us a signal of are we seeing that activity in primary liver, and biliary tract.
Got it. I asked you, I guess in the positive scenario, what will happens if RP1 gets approved? You know, what happens if it doesn't get approved? How does this impact some of the development plans that you mentioned for these other programs?
I'll let Emily take that one.
Yeah. I mean, I think that, in the case of a further delay for the approval of RP1, we would obviously have to take some cost-cutting measures, but certainly preserving the value in those programs would be a priority. As Sush mentioned, there's a lot of interest in, the REVEAL study. I think we would really wanna continue to create value for those, for shareholders through the further development of those studies.
Got it. What is your cash position and runway currently?
We ended the year with about $269 million. We did take an additional $35 million in debt subsequent to that, which puts our cash position into early 2027.
Got it. maybe just, to finish it off, remind us what the catalyst and milestones are for this year?
Obviously, we're eagerly awaiting the PDUFA date. That's the first one. Our real focus is if we get that approval is to really make sure we sort of execute a strong launch with this modality, and as I mentioned, enabling that interventional radiologist oncology utilization, particularly for these patients with these deep liver and lung metastases, which I think unlocks a lot of opportunity for the platform, and also improvement for patients. The other one is some of the milestones that I mentioned, the HCC/BTC data that we would have, depending on how the REVEAL data goes with that 90 patients. Right now, we're expecting early, next year, but given that the enrollment's going so quickly, it could be possible that we see some of that data before the end of the year as well.
Understood. Let me just do a final check for questions from the audience. All right. Thank you guys very much.
Thank you.
Thank you so much.