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

All right. Let's get started here. Welcome, everyone, to the 42nd Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Priyanka Grover, LaRhea Hall and Malcolm Kuno. Our next presenting company is Replimune. Presenting on behalf of the company, we have Philip Astley-Sparke. Phil?

Thank you, Anupam. So Replimune, Replimune is an industry leader in oncolytic immunotherapy. We're progressing 2 assets, RP1 and RP2. RP1, we plan to establish a broad skin cancer franchise. In this regard, our foundational study is in PD-1 failed melanoma. We're in a 140-patient registrational cohort. We've shown benefit in approximately 1 in 3 patients by way of durable response and plan to file a BLA by the end of this year. We've also generated data in multiple non-melanoma skin cancers, principally in cutaneous squamous cell carcinoma patients. Late last year, we announced the results of a randomized controlled trial in the first-line setting, comparing RP1 plus Regeneron's anti-PD-1 cemiplimab, which is the standard of care against cemiplimab alone. The study missed significance at P=0.025 for 2 dual endpoints of overall response and complete response tested separately. However, clear clinical benefit for RP1 plus cemiplimab was demonstrated. The complete response rate was improved from 25% in the monotherapy arm to 38% in the RP1 arm of p=0.040. We also showed a better durability of response in the RP1 cemiplimab arm. We've also generated other compelling data sets in non-melanoma skin cancers and not least in patients who develop skin cancers after solid organ transplants. Here we've administered RP1's monotherapy with a 35% response rate. Assuming approval in PD-1 failed melanoma, we are in position to start generating commercial revenues in late 2025, which will hopefully be further supported by either on-label or compendia listing approvals in various non-melanoma skinny cancer settings. Moving to RP2. RP2 targets less immune sensitive tumors than skin cancers. We've shown very compelling and durable monotherapy activity and also shown in combination in homogeneous signal in second-line Uveal melanoma, where we're planning a randomized controlled registration study as a foundational study for a rare cancer disease franchise. We have a strong balance sheet with $466 million as of the 31st of December 2023 and runway into the second half of '26. So what is oncolytic immunotherapies? Use of virus is selectively replicated in and kill tumor cells but leave healthy tissue unharmed. On injection into a tumor deposit, that deposit is invariably either partially or completely destroyed. And in doing so, the virus rips open the tumor cells and the cancer antigens within are exposed to the immune system in an environment of necrotic cell death. This attracts antigen-presenting cells to the injection site. They internalize those escape cancer antigens, drain the lymph nodes and prime T cells to destroy uninjected deposits throughout the body. So it's a 1, 2 mechanism of action, direct viral-mediated tumor cell lysis followed by the engineering of a full systemic immune response. Our platform is based on the herpes virus as our viral species of choice, it being naturally highly lytic, immunogenic and having high carrying capacity to carry in other immune-stimulating proteins into the tumor microenvironment to further amplify the immune response. Our particular species of strain of herpes virus has been selected from testing a variety of strains across a number of different tumor cell lines to deliberately pick out the most aggressively listed among possible. And then as part of our platform in all of our products, we express a glycoprotein, which increases the immunogenetic and lytic potential of the construct 10 to 100 fold. RP1 also expresses GM-CSF, and RP2 an anti-CTLA-4 antibody. As April mentioned, RP1, we're planning to establish a broad skin cancer franchise, where we've shown both efficacy and tolerability, compelling efficacy and tolerability and RP2 ditto we've shown in a variety of very difficult to treat tumors, a compelling efficacy and tolerability. So starting with RP1 and the establishment of a broad skin cancer franchise. As I said, the central plank of which is our registrational study in PD-1 failed melanoma. Patients coming on to study here, PD-1 is shown to be futile for the PD-1 use by the fact that patients have progressed while on anti-PD-1 that confirmed progression more on anti-PD-1 they've had at least 2 months of therapy. There's 140 patient cohort in the study with a 15 patient leading with a total of 156 patients of which we've shown approximately 1 in 3 having benefit by way of durable response. And moreover, we've seen compelling activity in all subsets of the disease, including late-stage visceral patients, Stage IV BCD including patients who failed not just PD-1, but also anti-CTLA-4, which is over half our population a response rate of 26%, and for patients that have just failed mono anti-PD-1, a 36% response rate and for those with late-stage III early stage IV disease, response rate approaching 40%. This waterfall plot shows that over 50% of patients actually had tumor reduction. It also shows the depth of responses in as much as a significant number of these responses are complete in nature, giving patients the potential for cure includes across all stages of disease, including the very late stage M1c/b patients. Duration response has been very compelling indeed. 100% of patients are in response at 6 months after baseline and nearly 80% of patients did in response of 2 years after coming on with aggressive disease from baseline. And we're also seeing an impressive survival plateau starting to form. On the right there, you can see that red line, those patients that have failed both CTLA-4 and anti-PD-1. And as I say, you can see a clear survival plateau forming. Couple of patient examples, which also illustrate the mechanism of action. This patient was a Stage IV M1c patient, patient had failed KEYTRUDA as well as BRAF and MEK and had injections into this large growing lesion in the red circle, which you can see resolving away and you can also see uninjected disease in the lung and very difficult disease to treat in the bone also resolving away. This patient is in complete response at around about 2 years. This patient actually failed OPDIVO was adjuvant on anti-PD-1 and then failed KEYTRUDA in the first line for metastatic disease after progressing on adjuvant and nonetheless progressed as well. Here, the injection site was on the forehead on the red circle, which resolved away. And here, you can see after the T cells primed to destroy the uninjected deposits, resolution of disease in the liver, as you go from top to bottom in the first 3 panels, and then the highly malignant of the lung as you look from top to bottom in that final panel on the right. So where do we go from here? We have met with the FDA who have acknowledged that the IGNYTE population in the study is one of unmet need. We have agreed should we file for accelerated approval, a confirmatory study, which will be in the second and third line setting against physicians' choice as the comparator arm. And as I said at the beginning, we do plan to file a BLA in the second half of this year pending central review by RECIST 1.1 and following all patients for at least 12 months after last patient in, the data that I just presented was 6 months after the last patient in as well as following all responding patients for at least 6 months. So that is melanoma. As I said, we're also generating multiple data sets in non-melanoma skin cancers, principally in cutaneous squamous cell carcinoma. It's not as well known as melanoma, but it's the second most common skin cancer and actually kills as many people every year in the United States as melanoma does. Where it is different from melanoma, whereas melanoma typically spreads and causes mortality through metastases to the lung, the liver, the brain and bones, about 80% of patients with CSCC actually die from local regional progression, it tends to be disease of the head, the neck and the scalp and invades critical structures. The standard of care is Regeneron's cemiplimab and anti-PD-1 is around about a 50% response rate and a 15% to 25% complete response rate. This is our CERPASS study which compared RP1 plus cemiplimab as standard of care against cemiplimab alone, a 211 patient study randomized 2:1 with 2 dual independent primary endpoints of complete response and overall response with each one tested separately, the threshold for success being P=0.025. Whereas we do not see an improvement in the overall response rate of any magnitude, we did see an improvement in the complete response rate from 25% in cemiplimab arm to 38% in the RP1 arm at P=0.04. So below P=0.05, but as I just explained the actual threshold for success in this study with each endpoint tested separately, given there was 2, was 0.025. The typical stratification in this disease is locally advanced given the fact that locally advanced has a real impact on mortality and morbidity and then metastatic in a locally advanced setting had a very striking increase in the complete response rate over doubling from 22% to almost 50%. And these complete responses really do set the patients up for the potential for cure. Here are some of the most visually impactful CRs. You do not typically see responses of this magnitude complete responses to cemiplimab alone and you can see a very distressing disease in terms of morbidity and actually leads to mortality here with 5 patients resulting in complete remission and potentially setting these patients up for cure. In terms of duration of response, as would be expected with a better mix of complete response to partial response in the RP1 arm, we have seen a better durability of response. 72% of responses in the RP1 plus cemiplimab arm were complete in nature as compared to 48% in the cemiplimab arm, and that has translated to a 45% reduction in the risk of coming out of response, we look forward to continue to follow this time-based endpoint. So what are the next steps for CERPASS. CERPASS did miss its primary endpoints while demonstrating clear clinical benefit in terms of complete response rate and duration of response. The time-based endpoint of dual response, PFS and OS are immature and will be followed to maturity. And the totality of the data will then be analyzed to determine whether any filing or compendia listing strategy is warranted. A couple of other studies in non-melanoma skin cancer I want to highlight, our ARTACUS study. This is a study in patients with organ graft transplants who have been immunosuppressed. The immunosuppression leads to -- if these patients last 10 or 20 years to 70% of patients developing skin cancers and it's a very difficult problem to treat. PD-1 can be used but leads to a high risk of loss of graft that typically is not. So here, we give an RP1's monotherapy with a 35% response rate. And then in PD-1 failed non-melanoma skin cancers, where there are no FDA approved options much like for melanoma, also shown with RP1 nivo, a 30% response rate. So in terms of the commercial opportunity for RP1, this starts with PD-1 failed melanoma. There are about 13,000 patients in the U.S. failing PD-1 each year. There is no standard of care for those failing ipi/nivo, anti-CTLA-4 and anti-PD-1, and there was really nothing for those failing PD-1 mono. Of course, they could then get ipi/nivo, but the RP1 nivo data appears stronger in terms of the efficacy tolerability profile. So we would expect really widespread adoption. We are planning to launch into the community at the same time as academic centers, no reason not to do that. And our research tells us about up to 80% of patients have a lesion or a tumor that can be injected with about 3/4 of those being a simple superficial injection or simple ultrasound guidance techniques. So hopefully, following an approval in PD-1 failed melanoma, we have other opportunities to bring RP1 to patients. We have generated, as I described compelling data sets in non-melanoma skin cancers, not least in cutaneous squamous cell carcinoma, where we would hope for, if not a label, then potential for companion listing. There's a further 11,000 patients. And then given our high rate complete response and our well-tolerated products, we hope to then push earlier into skin cancers in terms of the cause of the disease with the further buckets of opportunity. In terms of manufacturing, we have our own in-house manufacturing facility near Boston. The materials used in our clinical studies were from a contractor. We have done all the comparability analysis to show comparability between the contract material used in our clinical trials to date with the facility that we plan to launch from in Framingham, Massachusetts. Product has been released to clinic, and we have now actually completed the 3 BLA validation runs successfully and are building inventory for commercial launch. So that's RP1. An update on RP2, RP2 is RP1 that expresses an anti-CTLA-4 antibody, to stop the negative feedback loop at the antigen-presenting cell T cell interface. RP2 is really compelling durable monotherapy activity in very difficult to treat tumor types. And we've also seen a homogeneous signal in very difficult to treat second-line newbuild melanoma, where we're planning a randomized controlled trial, the foundational plank for a rare disease strategy in some of these other tumors where we've also seen activity not least in sarcomas. This is a patient that we've actually featured in prior JPMorgan, which was featured in the BBC news during the course of last year, as one of the highlighted durability, this patient is now moving on to 3 years in complete remission after being told to put their affairs in order. It's a true miracle. There's no other words to describe it. I've been able to work as a builder again and spend time with my family. There's nothing I can't do. Second esophageal patient also remains in complete remission. This is a new patient originally with RP2 monotherapy, which is a 9-patient cohort and we reported out 3 responses 2 of which are ongoing, complete responses. We have now recruited more patients for RP2 into monotherapy. We have a further 5 of valuable, and this is an example of a further response in very difficult to treat chordoma, which comes out of the embryonic cells in the bone. You can see a very large mass here that's grown out into the gluteal muscle where we've injected that. And as you look from left to right, you can see resolution of that disease. And then in the priming of the T cells, you saw the resolution of about 50 small deposits in the lung as well as deposit in the liver. So as I mentioned, we've also seen a homogeneous signal in second-line Uveal melanoma. Uveal melanoma is a cancer melanocytes in the eye, often patients are nucleated having their eye removed. And 70%, 90% of patients metastasize to the liver. And if that occurs, your survival odds of 12 months thereafter are only about 10%. So a very difficult disease to treat in the first-line setting, KIMMTRAK is used for patients with 50% of patients with the right HLA haplotype. But for those failing KIMMTRAK or those with the wrong HLA haplotype is a real unmet need. So here, as I say, in a heavily pretreated population, all of which have failed ipi/nivo, not that, that does much. We have around about a 30% response rate. This is a patient, which we haven't presented in the past. You can see as is typical metastasizing to the liver with the red circled lesions being injected resolving away. And then you can see the uninjected lesions in yellow. This patient has also been highlighted on new channels. I was also told to put their affairs in order. She says she no longer thinks about dying anymore and is preparing to run a marathon moving out beyond 18 months from coming on to study with progressive liver disease. So as I said, we are planning a registrational study now in the second-line Uveal melanoma. So in summary, in skin cancers, we believe that RP1 plus nivo has transformative potential and plan to file a BLA by the end of this year. While CERPASS and cutaneous squamous cell carcinoma missed its primary endpoints of P=0.025 clinically meaning benefit was shown with an improvement in the complete response rate of P=0.04, an improvement in the durability of response and we've generated other compelling non-melanoma skin cancer data sets, not least in very difficult to treat solid organ transplant patients. As I mentioned, with RP2, we continue to see a compelling monotherapy activity, and we're now planning a registrational study in Uveal melanoma as a foundational study to establishing a rare cancer franchise and we have a strong cash position, $466 million on the balance sheet as of 31st December 2023, with cash runway into the second half of '26, which does not include any draws from the debt facility we also have in place. Thank you.

All right. Thanks, Philip. Just wanted to highlight 3 things -- Rob, do you want to come on. I want to highlight 3 things. There are 3 ways to ask the question, right? Old school, raise your hand, I'll call on you. New school, use the portal, and it will come up on this fancy iPad. Or there's like an intermediate route where you can e-mail me the question, and I will ask on your behalf. So we have our first question.

I'm stunned by those -- I'm Jake Kushner from McNair Interests. I'm stunned by those complete responses. That's spectacular. You guys are doing amazing work. So let me just ask the question about nonoperatable squamous cell carcinoma of the mouth. So lots of surgeons will try to cut this out and they leave patients profoundly disabled. Would RP1 potentially be used for those kinds of patients? And could you send people with these massive mouth lesions into complete remission?

Yes, I believe we -- I'm Robert Coffin, I'm in charge of R&D at Replimune. And yes, I believe we certainly could. As you've seen that we have got really amazing response in patients with very bulky nasty impactful disease, which is clearly hugely impacting their life. And the only alternative to that is very, very disfiguring surgery. And we have achieved amazing complete and durable responses. So while we haven't specifically targeted patients with mouth disease, there's no reason why similar results couldn't be achieved.

Especially first line because, again, some of these surgeries are profoundly disabling and disfiguring, it's a huge potential market. And does your product -- is it going to work both for HPV-positive squamous cell carcinoma as well as HPV-negative.

So this is cutaneous squamous cell carcinoma and not squamous cell carcinoma of head and neck. So these aren't patients with HPV positive. However, we do have less data in squamous cell carcinoma of head and neck, where we have seen activity also. We don't have a specific program in that tumor type at the moment, but I would expect it to see good results, yes.

The therapy for HPV positive squamous cell oropharyngeal carcinoma is said to be easily tolerated, it's not, I have several friends who have undergone it. And you can easily imagine the market expanding to those patients as well with the radiation.

Exactly. We're keen on the idea of combining with standard of care chemo radiation for those sorts of patients, although currently, we don't have a study ongoing for that.

There's a lot of market opportunity.

Exactly.

Great. What are the gating factors to starting the confirmatory study in anti-PD-1 failed melanoma.

So Anupam, we have agreed in concept, the trial design for the confirmatory study and really its final sign-off of the protocol with the FDA and operationalization of the study. We have agreed with the FDA that, that study needs to be started, but not more than started at the time of BLA filing. And obviously, therefore, our intent is to have that study going in the second half to align with the BLA filing time lines.

And I guess, Philip, you talked about the market a little bit here. What would you say to those on the street who say that the anti-PD-1 failed melanoma market is more niche in opportunity. I guess, what are the -- what's the Street underappreciating in terms of levers to making this a bigger product than say, niche?

Yes. This is Sushil Patel, Chief Strategy Officer. So as Philip mentioned, there's about 13,000 treatable patients and as he also mentioned, we believe RP1 can be injected in about 80% of those patients, 3/4 of those should be pretty straightforward to inject without involving interventional radiology. I think the other factor that maybe is underappreciated is based on the IGNYTE data, we really can treat every type of anti-PD-1 presentation, whether these are adjuvant failed patients, second or third-line BRAF regardless of their mutation status. And so I think -- and also ipi/nivo failed patients where I think is very high unmet need. So we really are an option for all patients. I think the other thing that's really underappreciated a little bit is the toxicity patients have to go through in this rare disease treatment of these patients. Given our favorable toxicity profile, I think we can actually increase the treated population and importantly, as Philip mentioned, we don't just see this as a modality for academic sites. We're planning a launch in the community and the academic so that we can help as many patients as possible, a lot of melanoma patients are treated in the community.

And one pushback on that has been the intratumoral approach as well as the need for sterile environment and cold storage. Has that been a pushback in your market research?

Yes. Thanks, Anupam. We've done a lot of research on this. And really, we're not seeing any major barriers to the treatment of these patients. We, in most cases, the steps used to treat patients the same as any are IV oncolytic, you go through many of the same protocols and steps. There are some unique aspects around intratumoral that we're working on, but really haven't seen any major issues. You will need a room to do the injection in, obviously, and most community practices have that. We'll also be able to need to train people when staff within the community practices do that. But again, we know that NPs, PAs can be trained to do this. We're not -- we haven't seen any major issues around that. And again, we'll just make sure that we're providing training around the logistics to overcome any misperceptions around some of the safety concerns.

Questions from the audience. When -- how should we think about the timing of the primary analysis for IGNYTE and PD-1 failed melanoma. What are we going to learn beyond kind of what we know is the next update going to be kind of like what you file like centrally reviewed, you'll have the 12 months of follow-up in patients.

So the data cut for the primary analysis of that study is 12 months following the last patient enrolled. The last patient was enrolled middle of last March. So the trigger for the primary analysis is the middle of this March. After that, there will be the final data collection, obviously, in relation to scans, et cetera, for the last visits for the patients. And then there will be the center review process, which we already started prior to the trigger for the data cut and the intention is obviously to have the data ready to support a BLA filing in the second half of the year. And that would be preceded by a pre-BLA meeting with the FDA. And while we can't depend on the exact timing, whether we would be presenting at a scientific conference or not in one form or another, the data would be made publicly prior to that point.

Just another question on expanding indications. Have you thought about things for these rare tumors like leiomyosarcoma for RP2 because there's lots of unmet need, lots and lots of unmet need. And in some cases, you'll see large tumors and proximal mets. And so you could easily imagine getting in and catheterizing these things and whacking them, and you can make an enormous difference. They're typically very young people, people in their 20s and 30s. These are people with young families. That can make a profound difference to society.

Thank you. So Philip didn't have time to go into our RP2 data in any more detail. We have got a consistent signal across a range of different sarcomas. Obviously, each individual sarcoma type is pretty rare. And if one is enrolling sarcoma patients, one tends to get a mixture of different types of sarcoma. However, including beyond chordoma, which is the type of sarcoma, we have activity in a range of other sarcomas on an individual patient basis, the reason it's an individual patient basis is the reason I said that we only tend to get one of each, but we've definitely got activity consistently across sarcomas, which we do intend to capitalize on as we go forward.

Additional questions from the audience? What is the size and scope of like what an initial field force might need to be for PD-1 failed melanoma?

Yes. I think it's a little early to talk about the exact size of the sales force. As I mentioned, we are planning to have a team that can launch both in academic and community practices and we'll be appropriately sort of sizing that and having a fit-for-purpose team that really addressed some of the issues I mentioned around intra tumor injection and associated logistics.

We have an e-mail question that came in related to some of your commentary. You said that RP1 should be able to be injected in 80% of patients and of those 80%, 75% were not requiring imaging for...

They may require imaging. They won't require interventional radiology. So you can have portable ultrasound for a large portion of those patients which may or may not involve -- probably wouldn't involve interventional radiology.

Okay. If I can just slightly add to that. So for lymph nodes, for example, which may not be palpable, just a handheld ultrasound scanner is frequently used for that purpose.

Got it. Questions from the audience? In terms of sharing the CERPASS data from -- in CSCC with regulators, what are the time lines for that? And kind of like what are you hoping to learn from them?

So I'll address that. So we have already shared the current data with the FDA, as you'd expect us to do once we have new relevant data, the intention of that data is to use that in support of the melanoma filing at the moment. The data we have currently in CSCC is not in itself likely sufficient to achieve an approval. However, it clearly did show treatment benefit to patients and did demonstrate contribution of components between RP1 and anti-PD-1. And in that regard, we believe is highly supportive of our overall data package with RP1 in skin cancer, specifically melanoma, which is what the BLA will be filed upon. We will, as Philip said, the time-based endpoints from the study, which are particularly important, duration of response, PFS and OS are very much immature at the moment, and we will be doing further data cuts of that as time goes on. But that would likely be beyond the time frame of the initial BLA filing. And once we have that further data, we will determine following -- obviously, analyzing it, how it exactly can be used either in support of a potential CSCC indication or to support a different commercialization pathway. But it's by no means the end of the story on the CERPASS study. We do think it has generated compelling evidence already. And as time goes on, we expect that to strengthen but the key purpose of it at the moment is in support of the melanoma filing rather than seeking an approval in CSCC itself at this time.

Questions from the audience? In the update this morning, you talked about your cash -- and in your presentation, Philip, you talked about your cash position into the second half of 2026, which is a bit of a change from early 2026. What are the levers to drive the extra couple of quarters of cash?

Yes, sure. Thank you for the question. This is Emily Hill, CFO. We have, since the CERPASS data done further program prioritization to be able to extend our cash runway into second half of 2026. And obviously, our priorities remain filing the BLA in melanoma and the Uveal study.

Questions from the audience. Any final questions? Alright. Thanks, everyone.

Thank you.