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

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Okay. So welcome to the Tuesday afternoon session of the 2020 JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Tessa Romero and Matt Bannon from the team. Our next presenting company is Replimune, and presenting on behalf of the company is CEO, Philip Astley-Sparke.

Thanks, Anupam. Safe harbor. So Replimune. Replimune was founded in 2015 to realize the full potential of oncolytic immunotherapy. We believe that our products become the second cornerstone of immuno-oncology. Our lead asset, RP1, primarily focuses on immuno-responsive tumors. And following strong preliminary Phase I/II data announced at SITC at the end of last year, we planned during the course of this year to have 3 potential registrational studies ongoing. The first of which is already underway is a 240-patient randomized study in our lead indication of cutaneous squamous cell carcinoma. Our follow-on products, RP2 and RP3, target less immunoresponsive tumors. RP2 is currently in a Phase I all-comers study and RP3 will enter the clinic in the middle of the year. We're based in Boston, MA, where we recently completed the construction of a commercial-scale manufacturing facility which is state-of-the-art, and we are well capitalized to deliver, having $183 million on the balance sheet as of December 31. We are led by the most experienced team in the oncolytics space. This is the team that, while at buybacks, developed the only FDA-approved oncolytic T-VEC. The inventor of T-VEC is our Founder and President and R&D Chief, Rob Coffin, who is the intellectual driving force behind the company. Colin Love, our Chief Operating Officer, has 20 years of CMC HSV oncolytic experience, presented at ODAC when T-VEC was recommended for approval. And our SVP, Regulatory, oversaw the regulatory package for that BLA filing. Our Chief Business Officer, Pamela Esposito, was instrumental in the sale of BioVex, the company that developed T-VEC to Amgen for up to $1 billion, the majority of which is paid out. And we've recently expanded the team beyond the core BioVex members, welcoming Jean Franchi as Chief Financial Officer, who, for many years, ran Genzyme's finances and more recently, as CFO at Merrimack and Dimension. So what is oncolytic immunotherapy? It is the use of viruses that selectively replicate in and kill tumor cells but do not replicate in healthy tissue and leave them unharmed. On injection into a tumor mass, that tumor mass will invariably be either completely or partially destroyed. And as the tumor cells are lysed opened by the virus, the neoantigens within are exposed to the immune system in an optimal environment and necrotic cell death. That attracts immune-pleasing cells to the site, which internalize those neoantigens that have escaped, drawing back to the lymph nodes where they present them to T cells to prime them to destroy uninjected deposits throughout the body. So the lytic action of the virus is a means for full-systemic vaccination. And the modality has clear single-agent activity. This is the T-VEC data upon which the product was approved. And what is actually a little known fact is in the late-stage 3, early-stage 4 setting, 1 in 4 patients in the final analysis were effectively cured. And the survival curves are pretty impressive in the first-line setting and the late-stage 3, early-stage 4 setting as depicted. T-VEC as a monotherapy do not work in late-stage 4 melanoma, which basically made the overall survival curves more modest. And that is perhaps because the checkpoints are shutting down the ensuing immune response. So in order to broaden and deepen the response rates of this modality, it is intuitive to combine with checkpoint blockade. Oncolytic immunotherapy could be one of the most robust ways to get a powerful immune response in play against an array of neoantigens. At its best, the right viral species many mechanisms of action through innate immunity and adaptive immunity are triggered, and then you layer in the checkpoint to make sure the ensuing immune response is not inappropriately shut down. And this isn't just a hypothesis. The only data that we're aware of from any vaccination approach followed by checkpoint blockade in a randomized setting is T-VEC plus ipilimumab against ipilimumab alone, showing the doubling of the response rate and, moreover, a doubling of the uninjected response rate in visceral lesions playing to the immune mechanism of action. So let's move on to exactly what Replimune is doing. So Replimune, like T-VEC, is a starting viral species for our oncolytic -- is the herpes virus. The herpes virus is highly lytic, highly inflammatory and has high-carrying capacity to bring other exogenous genes, immune-stimulating proteins into the local tumor microenvironment. But unlike T-VEC, where Rob extracted the clinical isolate from his PhD students lip. This time around, we systematically tested 30 clinical isolates to more deliberately choose the most lytic strain possible. Over and above that, in all our products, which is our core platform, the expression of a virus, a glycoprotein from the gibbon ape leukemia virus, which basically increases the lytic inflammatory and immunogenic protection of the virus 10- to 100-fold. And that is our base platform on our RP1 which is our lead asset. And then in our follow-up products, RP2 and RP3, we additionally expressed anti-CTLA-4, and with RP3 additionally to anti-CTLA-4, 4-1BB ligand and CD40 ligand. So in terms of the development plan. For RP1, as I said, we're primarily targeting immuno-responsive tumors. So these are the 4 cohorts here: melanoma, non-melanoma skin cancers, bladder cancer and MSA (sic) [ MSI ] high cancers. As I said that we reported our Phase I data at SITC in the late part of last year, but we also announced just the initial patients in those top 2 Phase II skin cancer cohorts. And with the bladder cancer and MSI-high cancer cohorts, those have initiated accrual, but will take a little bit longer to readout. But based on the strength of the data already in our skin cancer cohorts, as I said at the beginning, we do plan, during the course of this year, to have 3 potential registrational studies ongoing, 2 in cutaneous squamous cell carcinoma and 1 in PD-1 refractory melanoma. RP2 and RP3 are following on closely behind, targeting less immunoresponsive tumor types. So our lead indication is cutaneous square cell carcinoma, not as well known about as melanoma. But there are now almost approximately the same amount of death. So it is a sizable market opportunity. The only PD-1 approved in this indication is Regeneron's cemiplimab, which gave a decent 40%, 45% response rate when it was approved, but actually a fairly low complete response rate at the time of approval. The complete response rate was single digit. So as I said at the beginning, we have a registration-directed, randomized, controlled Phase II study ongoing in a cost-sharing collaboration with Regeneron in 240 patients comparing RP1 asset with cemiplimab against cemiplimab alone with the primary endpoint being overall response rate. Over and above this study, we also plan in spring time frame to start an additional study in a subset of cutaneous squamous cell carcinoma patients that develop their disease after being immunosuppressed for graft transplants. Anti-PD-1 in this setting is contraindicated at least in 40% of patients to graft rejections, which can obviously also lead to death. So here, given we have seen monotherapy activity, we plan to just use RP1 as a single agent, and we should be able to report some data out from this study towards the end of the year. And then we also have further plans to push early in disease course and into the neoadjuvant setting. Our second lead indications, anti-PD-1 refractory melanoma. 70% of patients still either get primary or acquired resistance to anti-PD-1. So still a real unmet need. There is some confusion about whether patients respond to a second or third line of anti-PD-1 having failed a first line. The reality is, is that if patients have clearly clinically progressed that does not see a progression, and especially if they didn't respond to anti-PD-1 in the first instance, the response rate to a second line of anti-PD-1 is expect it to be very low indeed. So let's give a snapshot of the data that we did divulge at SITC a couple of months ago particularly as it relates to our lead indications. We show clear single-agent activity with clear abscopal effects. In terms of our lead indications, we, at the time, announced that 4 or 5 CSCC patients were responding. We can update that now that 2 of these are complete-response patients. And I'll remind you complete responses are relatively rare in this indication. 2 are ongoing partial responses and still doing well. And a fifth patient died at 6 weeks. In terms of the anti-PD-1 refractory melanoma, we reported at SITC that the 3 out of 4 patients were responding to treatment with 2 being official responses. And what was nice about the data is this were married up to a strong biomarker data, which I will present in just a moment. So here's an example of patient 1 of an ongoing complete response. So this is a patient that had extensive disease over the scalp area all over the scalp, came on to study around a year ago, became a complete response after 6 or so months of treatment, but remains an ongoing complete response to date. And that patient had failed all standard of care in the U.K. This patient came on to study with rapidly progressing disease in the cheek, which was invading through the bone, through the maxillary region, very difficult to treat. And after 3 months worth of injections has now been declared a complete response. Cutaneous squamous cell carcinoma is principally a loco-regional disease, the head, neck and the scalp. And 80% of patients' mortality is actually driven by that loco-regional progression, invading either the brain, blood vessels or hemorrhaging. So this is very likely to be a life-saving intervention. Some patients do present with disease beyond the loco-regional area. This is one such patient, which is an ongoing partial response, close to a CR. The patient that we injected with RP1, we actually give a prime dose of RP1 alone and layer in the anti-PD-1 2 weeks later. So it's just RP1 alone. This lesion that was injected was responding as was a bilateral lesion uninjected on the other side of the neck, playing to the immune response mechanism of action. You see just how large that tumor actually is that is now completely resolved. This patient also had a retroperitoneal node, which also completely resolved and also had disease, fairly extensive bone disease along the spine, which was causing considerable pain. That pain has now resolved, and the lesions are looking -- around the bones are looking increasingly sclerotic. There's a fourth patient as well. And if you look back at the SITC deck, the scans that are available is now also a partial responder. That extensive disease in the neck area and lung mets, both of which are resolving. So example, patient 3 here, in terms of marrying out the biomarker data, you'll see at baseline, no CD8 T cell infiltration. And then after therapy, you see the CD8 T cells ubiquitous within, and you see a marked-up regulation of PD-L1. So let's give some examples now from the anti-PD-1 refractory melanoma setting. This is an ipi, pembro failure. This is a patient who has clearly progressed -- clinically progressed across 2 scans and not responded to a prior line of anti-PD-1, would not be expected to respond to a second line of anti-PD-1. Here, we injected a lesion behind the ear, and you can see clear abscopal effects in the lung area and the mediastinum. This patient also had disease around the spleen and other areas, is an ongoing partial response. This is a second example patient in the anti-PD-1 refractory setting that has failed, ipi/nivo. On ipi/nivo, the best response was stable disease, clear clinical progression coming on to study with infections in the thigh area. You can see the extent of the disease on these scans here. The patient also had lung metastases, which are resolving. You can see on the scan here the lesion in the thigh area responding. And in terms of marrying up the biomarker data, here, you can see when the patient comes on study, having failed anti-PD-1, you can see the clear primary resistance. The CD8 T cells are kept out of the tumor microenvironment and around the edge. And after giving out our regimen, the T cells become ubiquitous within. And the clinical benefit of that is evident in the prior scans as I just showed. We've also seen activity in other tumor types beyond skin cancers. This is an esophageal cancer patient who have failed 8 lines of prior therapy coming on the study. We injected the lung lesion, which is resolving as an ongoing PR. I think one very comforting aspect of the Phase I data set as a whole, is we were shown that it's feasible and efficacious to directly inject [ visceral ] lesions, most notably in the lung and the liver. So that's RP1. Coming on to our follow-on products. As I said, they target less immunoresponsive tumors. So here, we will be having in RP2 anti-CTLA-4 over above the GALV protein. And in RP3, the co-stimulatory ligand, CD40 and 4-1BB. There is a issue with these co-stim antibodies is the therapeutic window between toxicity and efficacy is very small. So the idea here is to express these antibodies and proteins instead in high concentrations, in the local tumor microenvironment where they're needed and avoid systemic toxicity. So just one piece of our preclinical data show that the potentially the RP2 and RP3 are potentially more efficacious than RP1. This is mouse data. This is the sort of classic contralateral tumor model, where you have a right-hand flank tumor and a left-hand flank tumor, and you inject the right-flank tumor only to see whether or not the immune system takes out the uninjected tumor. Each one of these lines is one individual animal. And we've gone down to a subtherapeutic dose of RP1 here. We get too many complete responses to see the incremental benefit of adding the anti-CTLA-4 for RP2. So the subtherapeutic dose, you can see we've got some complete responses in the uninjected tumor. But once you layer in RP2, then 9 out of 10 of these animals were complete responders. So RP2 is in an all-comers Phase I study and RP3 plan to enter the clinic during the course of the year. I think we're fairly unique within our space of owning our own in-house manufacturing facility. The team is highly experienced in this regard and has constructed both the BioVex facility, which is commercial-grade T-VEC. And some of the team also did uniQure's manufacturing facility in Lexington, outside Boston. So this is a real area of expertise. We have now completed the construction of our facility, got an occupancy certificate, and tech transfer activities are underway, and we should be producing clinical-grade material for our studies under GMP come the third quarter. So my final slide is a summary of our milestones as we look forward to this year. We plan to initiate and release some data from the subset cutaneous squamous cell carcinoma study in transplant patients by the end of the year. We're also, around the middle of the year, have additional data out from our CSCC indication in the 30-patient study we're running in the collaboration with nivo. And obviously, that will then -- should have reached through to people being able to get comfortable whether or not we're likely to be successful in the major 240-patient registration-directed study, which is underway. We plan to initiate shortly a potential registrational clinical study in the anti-PD-1 refractory melanoma setting. And again, we'll be releasing more Phase II data around the middle of the year in melanoma, generally in both the anti-PD-1 refractory setting and the PD-1-naive setting. The MSI-high bladder cancer cohorts that we're running in Phase II are running slightly behind. So that data will be available more towards the end of the year or initial data to determine go, no-go about whether to run further registrational-directed studies. RP2 should have Phase I data from -- towards the end of the year, and RP3 will enter the clinic around the middle of the year. And beyond all this, we really believe that, looking at all the data this modality has generated that if we can move earlier in disease causes, we can have the most profound effect, including potentially increasing the cure rate. So over the course of this year, we'll obviously be looking at potentially further indications where we can do just that. And we are well capitalized to deliver with $183 million on the balance sheet, which funds all of the above and is sufficient to run our operating expenses into the second half of 2022. Thank you for listening. I think it's Sussex is the breakout room?

Yes.