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

Great. Thank you. Good morning, everyone. Welcome to Barclays Global Healthcare Conference. I'm Pete Lawson. I'm one of the biotech analysts here at Barclays. And institutional investors, of course, can -- if you have questions, do ping me by e-mail, that's [email protected], and you can always get me on Bloomberg as well. And kind of with that, it gives me great pleasure to introduce Replimune. And with us today, we've got Philip Astley-Sparke, CEO; and Robin Coffin (sic) [ Robert Coffin ], the Founder and President and Chief of Research and Development. And I just wanted to welcome you both.

And just as an opening question, I've been asking all of our companies this, just on the differentiation of the company in the oncology space, kind of what you view as the core competencies of Replimune?

Yes, sure. Well, first of all, thanks for the invite to the conference. I mean, really, Replimune was founded to realize the full potential of our modality, oncolytic immunotherapy, which we believe can become the most practical and effective way to get the immune response in play ahead of checkpoint blockade drugs. I mean, put simply, we only have death counts because of failure of the immune system either to recognize a tumor as foreign, or if it does recognize the tumor as foreign, the ensuing immune responses inappropriately shut down. And obviously, over the last 5 to 10 years, the second part of that equation has been at least partially addressed in checkpoint blockade drugs. I don't think the first part of the equation really has had that many key advances. And as I say, we do think the modality itself is the most practical and effective way to get an immune response in play. In terms of practicality, off-the-shelf product is what we're developing, and therefore, it's relatively cheap to produce. It's also well tolerated. And in terms of efficacy, it's effectively a pan-universal neoantigen vaccine, trying to delineate 1 or 2 neoantigens to go off that -- really, injecting the virus into the tumor, blowing the tumor up, and then tap all the neoantigens within that are exposed to the immune system in an optimal environment of necrotic cell death. If you're using the right viral species like herpes, you're triggering the innate immune pathways, you're bringing in adaptive immunity through the immune danger signals thrown off, and with that, also having the ability to carry multiple immune-stimulating proteins into the tumor microenvironment, and therefore, really, you've got multiple mechanisms of action wrapped up into one product.

Got you. And then maybe it's just kind of more of a technology question than anything else and comparisons. Kind of how have you -- I guess the T-VEC, the recent termination of that clinical trial, just if you can kind of walk through that and compare and contrast between yourselves and T-VEC?

Well, I'll leave Rob to do the comparison with the T-VEC, but I'll just make an opening comment on clinical trial design. And obviously, that study was designed probably some 7 years ago, and last patient in was 3 years ago. And we stopped the futility, i.e., the number of events needed to accrue to unblind the study had not occurred. So that does point to some design flaws within the study, not necessarily to point to deficiencies in terms of T-VEC in adding benefit over and above checkpoint alone. Rob?

Yes. We obviously haven't seen any data in regard to that, and we'll be looking forward to seeing what the actual data is when it may come out later in the year. However, we did deliberately design, at the beginning of the company, our products to be very much move-ons from T-VEC. We were always of the view that T-VEC was the beginning of what could be done with oncolytic immunotherapy and approved the point, but by no means the best all that could be done with oncolytic immunotherapy. And T-VEC does work, and it is effective as a single agent, and it's proven to be effective in a randomized controlled trial in combination with ipilimumab versus ipilimumab alone. So we, obviously, need to see the details of that particular trial to comment further. But really, the key point is that all of Replimune's products are designed to be considerably more potent than T-VEC in multiple regards. And the 2 main regards of that are that they're designed to kill much more tumor directly. The lytic and direct killing ability of the viruses are designed to be much greater by virtue of using a new strain of herpes simplex virus, but also and probably more importantly, encoding within the virus, a gene for a fusogenic protein, which substantially increases the direct killing, which the virus is able to do. However, not only does it increase the direct killing substantially, it also increases the immunogenicity of that killing. It greatly increases the level of immunogenic cell death as compared to non-immunogenic cell death otherwise caused by the virus. So that in combination in the base virus RP1 is intended to result in not only much greater direct killing but also much greater systemic immune activation as well. And our preclinical data really does show that we have a very potent systemic abscopal effect mediated through this additional protein called GALV. So that's RP1, which is currently being tested, particularly in PD-1 failed melanoma and in cutaneous squamous cell carcinoma, both in combination with anti-PD-1 therapy. But then we come on to our products, RP2 and RP3, which have been engineered to be substantially further effective, too, through incorporation of additional genes into the RP1 backbone such that RP2 encoding anti-CTLA-4 antibody in the backbone, for which we think there's very strong logic to deliver anti-CTLA-4 directly into the tumor as the tumor is killed by lytic virus replication, which provides so-called Signal 1 into the system. And then RP3 as well as anti-CTLA-4 expresses 2 immune co-stimulatory pathway activating ligands, which act following antigen presentation, i.e., Signal 1, to provide strong co-stimulatory signals into T cells. And again, we think this particular logic of delivering those into the tumor as the tumor dies and Signal 1 is occurring, and that logic is substantially greater than the use of systemic antibodies to try and do the same thing. So the simple answer is we just think our products should be, evidence suggests they are, and were designed to be just far more potent than T-VEC.

And then maybe we can think through some of the data that's coming through this year. So you've got a healthy set of data this year already, an interesting set. So you've got potentially RP3 data, what is that, I guess, around 8 to 10 patients initial Phase I data. What kind of de-risks that -- I mean, I guess, it's RP1 and RP2 what we've seen already, but anything else that we should be thinking about that kind of helps de-risk the initial solid tumor data we get for RP3?

For RP3 -- so you're correct, we deliberately did take a step-wise approach to our product development with RP1 first, RP2 and RP3, to enable us to properly understand the underlying characteristics of each of those products, which all had novel characteristics as compared to anything else, which had previously been tested in humans. So we felt it was sensible and pragmatic to test RP1 initially, particularly as it adds the potent modality of the fusogenic part of the product, then build -- and it did turn out to be well tolerated, is clearly demonstrating a useful clinical activity and led to our pivotal trials or cohorts currently ongoing, which then led to RP2. We have, we think, compelling early data with RP2 expressing anti-CTLA-4, including, we think, strong single-agent data in very hard-to-treat tumors, again, with good safety and no evidence of additional toxicity beyond -- when combined with anti-PD-1 beyond the individual oncolytic virus and anti-PD-1 separately. So that provides a good bedrock to have good confidence that the underlying platform should be both well tolerated and effective upon which we could then bolt-on CD40 ligand and 4-1BB ligand, the 2 immune co-stimulators. Those are very potent molecules preclinically. They provide, encoded in the virus, very potent abscopal immune-mediated effects and agonistic antibodies, and again, those 2 targets have shown evidence of clinical activity in humans. However, systemic administration of those antibodies has had toxicity issues. And we believe, as I said, delivery into the tumor should retain or, in fact, increase activity because they're present when and where exactly needed, but also reduce toxicity caused by systemic administration. So we do think we should have good confidence based on everything we've done to date, which is based on solid underpinnings that we should see safety. And bearing in mind what we've already seen with RP2, we should have good confidence that we're well-founded to expect potent efficacy, too. However, obviously, time will tell. We're still early in development with RP3, and it won't be until later in the year when we begin to also combine RP3 with anti-PD-1.

Got you. Maybe you could talk through the anti-CTLA-4. I'm increasingly finding that intriguing with this kind of safer versions of CTLA-4, just kind of how well it expresses and what the -- what it's looked like in whether it's animal studies?

So we expressed from a virus something which is very similar to ipilimumab. It's accretive. It's not exactly an antibody, but it's a very much antibody-like molecule, which does have a human IgG1. So it has the 2 components of ipilimumab. However, the systemic levels of the antibody, which would be generated following replication in tumors would be expected to be rather low and below any systemic level, which could cause any systemic toxicity. However, the levels present in tumors would be expected to be -- as predicted by our mouse experiments, to be entirely sufficient to provide the necessary block between the CTLA-4 and B7 interaction locally in tumors and draining lymph nodes. So we think there should be an optimal and correct amount where it's needed, but only very low levels systemically where it's not needed, which is likely what would result in toxicity. So to date, as I said, RP2 has been well tolerated, and in combination with nivolumab, as we did say at SITC last year, in the first few patients, there's been no evidence of the type of combinational toxicity you see with ipilimumab and nivolumab. So from -- we expect to have a good safety profile and not that the downsides of combined ipi/nivo.

Yes. I mean it's a fantastically clever approach to get that CTLA-4 in. Is that the most complex construct you've inserted into the virus?

Well, it's just a single-coating region. It's a single gene. It's a single chain approach to generating the antibody. So from the virus' perspective, it's just another gene. So in RP1, we have 2 genes expressed, GM-CSF and the GALV protein; in RP2, 3 genes, GM-CSF, GALV and anti-CTLA-4; and RP3, 4 genes, GALV, anti-CTLA-4, CD40 ligand, 4-1BB ligand. And from the virus' perspective, it doesn't make any difference what all the coding and sequences are.

Okay. And then just with RP3, what are the best tumor attacks you think? Do you get any sense from preclinical data or hints from other people's data where it'd potentially work better?

We anticipate a very broad utility. And in a way, it's actually a sort of nice problem to have. We are actually in the process of doing a very thorough landscape analysis of where we think we should proceed into later-stage development with RP2 and RP3 based on all considerations, including likelihood of success, development pathway, unmet need, et cetera, et cetera. And the nice problem to have, I mentioned, is the fact that, really, these approaches are potentially applicable to literally all solid tumors. There are -- HSV will infect essentially -- and replicating essentially any human tumor type, which you sort of feed to it. And we do believe we already have evidence that we can have clinical activity in not only traditionally immune responsive tumor types but also completely immune nonresponsive tumor types, which really means the problem as to where we develop our products, more relates to where the opportunities are rather than necessarily where we think the product has a greater or lesser likelihood of success. So we really do believe that RP3 particularly should have potentially very broad future utility across oncology. But for us, at the moment, it's the decisions as to what exactly to do next to best showcase that potential.

Yes. Yes. Follow that biology. What should we see -- what should we look for in that kind of biology? When we see the data, I guess, like probably maybe at SITC, what should we be looking for? Other than kind of deep durable responses, but what are the things before that we should be thinking about?

So the RP3 Phase I trial is very, very similar to the RP2 Phase I trial. And therefore, the cadence of data generation would be expected to be similar. So last year at SITC, we presented initial single-agent data, which was in 9 patients at that point, which demonstrated good durable responses in a number of those patients. And what we saw was that responses did take a little time to fully kick in. At the first scan, the full response had not been achieved. And it wasn't until the second or third scan actually that the full maximal response was achieved, even though the actual treatments have been terminated a long time before. So in immune-based therapies, things can take a bit of time to mature. And we don't necessarily expect it to be different with regard to those kinetics with RP3. It's also the case that when we present first data is intended to be in the fall, as you said. The data will be still early and relatively immature, but we do expect to be able to show signals that RP3 is indeed able to not only be safe but also provide early evidence of activity and where that activity is being demonstrated that we would expect and hope that it will be demonstrated to be durable. But it is a Phase I trial in a mixture of mixed bag of Phase I type patients. And therefore, as with RP2 and other things we've done before, it will be very important to look at each individual patient on its own to really getting underneath what we and observers believe it shows.

Got you. Maybe switching gears slightly just around RP2. We get updated data for that kind of midyear, so potentially, hopefully, ASCO. And how should we think about that update? How many more patients you think can follow up?

So as I described, the Phase I trial with RP2, which is still ongoing, had an initial single-agent dose rising part of that, upon which the RP2D was determined, and that dose rising part consisted of 9 patients. We reported the initial data from those 9 patients at our last SITC. So at this upcoming ASCO, we would present longer-term follow-up from those first 9 single-agent patients. Subsequent to determining the RP2D towards the end of last year, we opened a 30-patient cohort of RP2 in combination with nivolumab, which is still recruiting at the moment. We're recruiting pretty well. And the data at ASCO will include the initial data from the patients, those to date with RP2 plus nivolumab as well as longer-term follow-up with single agent. So those patients, by definition, because it's relatively recent, will still be very much work in progress, still often being treated. Some patients will have had 6 to 9 months maximum follow-up and others will have had it much shorter. So again, it will be an early output of work-in-progress data, which we hope will be directionally informative, but by no means by that early point, in any way, definitive.

Okay. I just -- I had a question from a client. And it was just -- could you walk through the abscopal effects of the systemic effect you kind of see? What you've seen so far? What's kind of helped de-risk that sense that you are getting a kind of more systemic effect after a local injection?

Actually -- go ahead, Philip.

I think what's particularly pleased us over the last 6 to 9 months is we've seen abscopal effects not just from injecting superficial lesions but also from injecting visceral lesions. And we're always very confident when we dose a single patient that we'd have a product, at least a niche product, but that's not our ambition. Our ambition is to become a foundational cornerstone of immuno-oncology. And over the course of the last 12 months, we generated consistent data that we can inject the likes of the liver and see abscopal effects in uninjected lesions in the liver, beyond the liver, like the spleen and even as far away as the lung. We've also seen effects through injecting lung lesions and uninjected local regional impacts as well. So those are really documented on our website where we've got fairly extensive data having red circles with the injected and yellow circles with the uninjected, which really completely proves the point.

Yes. And just to kind of flip back to RP2. What do you want to see in that update to kind of move it forwards? And how should we think about the strategy there for potential registrational studies and which tumor types you pick?

Yes. I mean we have a full indication of prioritization now, which is ongoing at the moment. We plan to say -- start saying more about the output from that around the middle of the year. Obviously, we're looking at everything from commercial potential to type of study to have to run, how large it would be, what the endpoints would be, how long it'd take to read out. Obviously, with RP2, RP3, we are focused on the less immune responsive tumor types to become this foundational cornerstone of immuno-oncology. And I sort of already kind of referenced one bucket of ideas here, which is to tackle very problematic liver mets. Obviously, a lot of large indications with test size of the liver. It's a real unmet need. Even in immune responsive tumor types, when you metastasize to the liver, your response rate to checkpoint blockade drugs plummets, and the accumulating evidence of our products is that we can have real benefit through clearing out liver mets.

And that's with direct injection into the liver or guts?

Well, we've seen both. We've directly injected the liver and seen the injected lesion, the uninjected lesions in the liver, and we've also seen good responses when we've injected outside the liver.

Got you. And then just -- sorry, we're backwards on this, but RP1, when is the next update we get from CSCC?

Rob?

So we aim to be -- we have submitted an abstract basically to ASCO, which will update on, one, the melanoma cohort from RP1 combined with nivolumab, which is a 30-patient cohort, which completed enrollment last year -- earlier to begin -- towards the beginning of last year, but also the non-melanoma skin cancer cohort of RP1 combined with nivolumab, which was not fully recruited and is still recruiting, which is a predominance of CSCC patients. So the data which we have -- find extraordinarily supportive of our strategy of RP1 combined with cemiplimab versus cemiplimab alone, our pivotal trial, why we think that's very strongly founded is because of that prior data with RP1 combined with nivo in a smallish number of CSCC patients so far. So at ASCO, the aim would be to present, obviously, longer-term follow-up from those patients already treated, where back at SITC last year, we were showing a 70% to 80% response rate and a roughly 40% to 50% complete response rate with very good durability. At ASCO, we would expect to show a longer-term follow-up of those patients plus additional patients, which have been recruited more recently.

Got you. Okay. That's perfect. Sorry, so we have to stop the conversation now. We're at that kind of 25-minute mark. It's been a pleasure speaking to you both. Thanks so much for joining us at Barclays Global Healthcare Conference. And look forward to seeing you guys.

Thanks, Peter. Speak to you soon.

Thank you.

Yes. Bye.