39th Annual JPMorgan Virtual Healthcare Conference

Jan 12, 2021

Welcome everyone to the 39th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm 1 of the senior biotech analysts here at JPMorgan. I'm joined by Chesler Romero and Matt Bennett from the team. The next presenting company is Replimmune and speaking on behalf of the company, we have CEO, Philip Ashley Spark. Before turning it over to Philip, I just wanted to remind everybody on the webcast, if you'd like to submit a question, please use the Ask a Question feature in the portal, and I'd be happy to ask a question on your behalf. With that, I can pass it over to Philip. Thank you, Adam. Safe Harbor on Slide 2 and starting on Slide 3 with the Retimmune overview. Retimmune was founded to realize the full potential of oncolytic immunotherapy. Our products are designed to maximally activate a systemic immune response against a patient's cancer. We believe that our programs will become the 2nd cornerstone of immuno oncology. RP1, our lead asset, principally targets immune responsive tumor types and having generated strong data sets in PD-one naive cutaneous squamous cell carcinoma and anti PD-one failed melanoma. We have 2 registration studies ongoing in those settings. We're also pleased to announce that we hope to this quarter have a further study with RP1 initiate in lung cancer. RP2, RP3 are intended to treat less immunoresponsive tumor types And following the generation of strong RP2 single agent data in heavily pretreated patients with immune insensitive tumor types, The combination phase, the Phase I study with Opdivo is now enrolling. We also announced last week, very pleased to announce that RP3 is also now in the clinic, and dosing has commenced in a single agent portion of the Phase I study. We have bought manufacturing in house. Our commercial scale manufacturing facility is now fully constructed and operational, and GMP production is under obliged to deliver with $493, 000, 000 estimate on the balance sheet as of the 31st December, funding us into the second half of 20 24. So what is a reminder of oncolytic immunotherapy is the use of viruses that replicate in tumor cells and destroy them, but do not replicate in healthy tissue. On injection into a tumor mass, the tumor mass is invariably either completely or partially destroyed. And as the virus rips through the tumor, the neoantigens within are exposed to the immune system in an optimal environment of necrotic cell death. This is a major immune danger signal, attracts antigen presenting cells to the site, but internalize those escaped neoantigens, drain to the lymph nodes where they're prime T cells to destroy uninjected deposits throughout the body. So it's a dual mechanism of action, direct viral mediated tumor cell lysis followed by the engendering of a full systemic immune response. There are many different viral species being used as oncolytics. We use the herpes virus. We believe the herpes virus to be an optimal species for oncolytic use, it being highlylytic and inflammatory and having high carrying capacity to be able to carry in multiple immune stimulating proteins into the tumor microenvironment to further amplify the immune response. Within the herpes field, not all constructs are created equal. Our construct is a new clinical isolate that's been deliberately selected after a comprehensive screen of 30 or so isolates and picked for its lytic ability. And then from all of our products and part of our platform, we express a fusogenic glycoprotein from a given a leukemia virus, which essentially increases the lytic and immunogenic potential of the construct 10 to 100 fold. And these aspects are designed to maximize antigen presentation or so called SIGNAL1. We then further express immune stimulating proteins from this backbone designed to maximize T cell co stimulation of the antigen presenting cell T cell interface, so called SIGNAL2. And with RP1, we express GM CSF, RP-two, an anti Cetyl A 4 antibody and RP-three, in addition to anti Cetyl A 4, the ligand CD40 and four-1BB, which have pleiotropic effects and also induce inflammatory cytokines. We do believe this is the most practical and comprehensive way activate a systemic immune response against a patient's cancer. In terms of practical, it's an off the shelf product, simple to produce and relatively cheap to produce. It is also a relatively well tolerated legality. On the efficacy side, it is effectively a pan universal neoantigen vaccine, not confined to 1 or 2 neoantigens. If you're using the right viral species like herpes, you're triggering innate immune system pathways. And through the necrotic cell death created through the virus, you're quickly bringing in the adaptive side of the immunity. And then further, through expressing these various immune stimulating proteins, you can layer in multiple additional mechanisms of action. So a quick recap of our pipeline. As I said right at the beginning, we have 2 potential registration studies ongoing in PD-one failed melanoma and cutaneous squamous cell carcinoma, and we've generated strong data sets in those settings. We do also have a study ongoing cohort in the MSA high cancers, colorectal cancers predominantly and as I mentioned, about to start a cohort in lung cancer. Switching to RP2, RP3. We've seen very compelling single agent activity with RP2, and RP3 is now in the clinic. We're giving considerable thought to indication prioritization where to place our bets in terms of later stage development in immune insensitive tumor types. Our lead indication at the moment is cutaneous squamous cell carcinoma. We have several studies ongoing in this setting, not as well known as melanoma, but the minimum addressable population is equivalent in terms of a number of deaths. Up until 2 years ago, it was largely an unmet need, but PD-1s, anti PD-1s are now approved. Libtayo and Keytrudo giving response rates ranging from the mid-30s to 50%, but still very low complete response rates on label single digit. Our study, our potential registration study, the SURPASS study is in 2 40 patients where we're comparing RP1 plus Regeneron's Libtayo against Libtayo alone. This is a cross sharing collaboration with Regeneron, and the primary endpoint is overall response rate. We empowered the study to show a 15% delta improvement, such for example, if the Libtayo arm got 40%, we would win in the mid-50s. But moreover, from what we've seen to date and what we know about the modality, we expect to show a 2 to 3x improvement in the overall complete response rate, which more closely correlates with survival. To date, the data we reported at CSCC is generally a lot of wax and wane slightly basically delivered a 80% response rate and a 50% complete response rate in CSCC. And those responses have been very durable in nature and obviously, a very high rate of actual complete response, very deep responses. And we've seen responses both in systemic disease and in advanced locoregional disease, which is actually a highlight in this indication is actually the primary driver of mortality, it being Prince Maria disease of the head, neck and the scalp and invades vital structures. But this is an example of a full systemic immune response whereby a patient presented with a large lesions in the neck retroperitoneal node and extensive METs in the bone in the spine. And we injected the 1 area of the neck with a priming dose of RP-1 as mono, and the tumor flattened and started to resolve as an uninjected 1 on the other side of the neck. We then led in anti PD-one by 16, 24 weeks, the extensive disease as shown by the CT scan in the neck had resolved as had the retroperitoneal node and the bone METs looked to be static, and they were confirmed to metabolically inactive a year later, and the patient was declared as a complete responder. These were the most recent patients that we had gave an update on in October over and beyond what we had disclosed last June, the top patient there presented with a very nasty ulcerative mass on the foot and tumor burn in the groin area, which was injected. Those lesions resolve, the uninjected lesions on the foot side to resolve, and then additional injections were made around the periphery, and this patient continues to improve. So pictogram tells a 1, 000 words. Overall, our responses are very durable in nature. Now out to around 600 days. We've only ever had 1 patient progress, and that patient was in response for quite some time. And the responses are, as I said before, very deep and durable in nature and give us high confidence that we will meet with success in our potential registration study underway. Switching to anti PD-one failed melanoma, which is still a real unmet need. Majority of patients, despite the advance of anti PD-one, will become primary or have acquired resistance to that therapy. And when they do, treatment options are limited. The response rate to second line of anti PD-one for patients that have truly progressed confirmed through 2 scans is very low, mid single digit at best. So we have dosed 16 patients in cutaneous melanoma that have failed anti PD-one in a very late stage population of 87.5% stage 4m1bm1c advanced fishable disease. As of last October, when we last had a data cut, 9 of these patients have shown some evidence of clinical benefit as defined by at least stable disease with evidence of antitumor activity, of which 5 were formal responders, 1 CR and 4 PRs, 4 out of these 5 having failed both anti PD-one and anti CTLA-four, given a current response rate around about 31%. A further patient is an ongoing surgical CR up to 12 months of disease having not returned, and a further patient remains on study with stable disease. To give some examples in this setting, this first patient at the top, ipinivo failed melanoma, extensive fishable disease, fairly progressing when coming on to treatment. And we injected a liver lesion shown in the red circle, which has almost resolved away at the last data cut. But you can see the uninjected lesions in the liver and the spleen have completely resolved away, and you can see resolution of a lower mass there in the lung and reduction of a very large mass in the top back of the box at the CT scan. The bottom patient had a very large groin lesion, was essentially homebound and wheelchair bound and also had extensive METs in the groin nodes, the lung and suspicious bone lesions. We again only injected 1 mass in the groin area, which resolved away as did uninjected disease in the lung and other nodal disease. And the bone mets look static. So it's not actually clear this patient has any disease at this point in time, not an official CR, but a what we would call a clinical CR. And very interesting biomarker data from this patient, On the right there, in the immunohistochemistry, you can see a classic mechanism for primary resistance to anti PD-one, which T cell exclusion from the tumor microenvironment. After layering in our regimen, that immune tolerance is broken and the profound clinical benefit is evident. Again, these plots tell a 1, 000 words, very durable responses in melanoma, generally, not just an anti PD-one fail, but the other melanoma types we tested in and gone into responses, including mucosal and also in PD-one naive disease. Again, all but 1 patient has ever gone into response remains into response beyond 4 50 days. So the responses that we are engendering are uniformly very durable in nature. And the spider plot there, I think, is of interest that the red lines are PD-one failed patients and the green lines are PD-one naive, and they pretty much overlap, which I think really shows the potential of RP-one in the PD-one failed setting. And again, we have high expectations that we will meet with success in our potential registration expansion cohort of 125 patients, and we'll be discussing that study design with the FDA towards the end of the quarter. Switching to RP2, which is RP1 that, in addition, expresses an anti CLLA-four antibody. This isn't just to limit systemic toxicity of anti CTLA-four. There is a strong efficacy rationale to marry up maximizing signal 1 answering presentation on the MHC through the basic action of our virus with ensuring there's no negative feedback loop to the CTLA-four pathway. So the single agent data with RP2 showed that similar side effects to RP1, really mainly erythema at the injection site and febrile reactions. This modality is generally very well tolerated. Patients can often go back to work following treatment the next day. But we also saw compelling single agent responses in immune insensitive tumor types, including carcinoma, uveal melanoma and esophageal cancer. We saw a further interesting patient who won't be an official responder because it did progress. But after progression, non target lesions started to resolve. This is a patient with a microsatellite stable colon cancer, another immune sensitive tumor, major unmet need. This patient initially presented with a high disease burden in the lung, spleen, liver and 1 other site. Again, these are the data cutoff of October. These responses are all deep and durable and ongoing. And in terms of the actual patient examples, weak epidermoid carcinoma is a salivary gland cancer, untraceable checkpoint, upgrade drug, does nothing. This patient would have had a very bad prognosis leading to death. And at the moment, it's an ongoing durable complete response. Over 4 months, the nodal disease and superficial disease have resolved away. It was confirmed as a CR 8 months through PET showing the tumor, no metabolic activity. This is a response in uveal melanoma, ocular eye cancer, melanocytes in the eye, where the eye is often surgically removed, but often and typically metastasizes to the liver, which is often actually the only site of metastases. Once metastasized to the liver, 1 year survival is 10% to 15%. It's generally a fairly immune insensitive tumor, single percentage response rates to single agent checkpoint blockade, a little bit better maybe in the teens in combination. But regardless, this patient failed Ipinivo when coming onto our study with extensive liver beds. So we injected the devolution in the red circle, you see that's nearly resolved away. And you see uninjected ones in the yellow circles having either completely resolved away or also resolved in the way this patient continues to improve at each subsequent scan. This is an esophageal cancer patient treated with simulation RP2, came on the study having failed anti PD L1, a kinase inhibitor and 4 rounds of chemo, actually had more than 1 liver lesion. It's not a particularly good scan, but you can see that lesion resolving the way that was injected and scopal effect in the abdominal lymph node. So that's the summary of our clinical data. I do also want to highlight, as I said at the beginning, that we have completed the construction of our manufacturing facility. We only broke ground at the time of the IPO 2.5 years ago. And I think it's testament to really experience of the team that this facility is already operational and having completed tech transfer from the contract manufacturing organization. GMP Manufacturing is underway, and we have had a positive meeting with the FDA in terms of comparability to this contract material. The suite of tests that we will have to run-in order to use this as launch material. And so my final slide is really a summary of news flow over the next 2 years. In 2021, we expect to present in some entirely new data sets over and above what we have presented in the past, which is predominantly focused on Phase II data sets in melanoma and cutaneous squamous cell carcinoma as well as Phase I all come as data sets. So over the next year, we'll have new defined data sets in PD-one failed lung cancer, very much an unmet need. And we've never dosed a lung cancer patient, but the reason why we decided to proceed with this is we have seen that we can inject lung mets from other tumor histologies and see effects both in the injected lung lesion and in uninjected lung lesions. So we are intrigued to see how this cohort does over the course of this year. We also announced at the end of last year that we plan to go into the PD-one failed set in cutaneous squamous cell carcinoma, which is kind of intuitive given the responses we've seen in anti PD-one failed melanoma and an anti PD-one naive CSCC. So we have high expectations that we will also our products will also be a benefit in this setting. We have talked about in the past about CSCC transplant patients. These are patients that develop the disease after being immunosuppressed for organ graft transplants and anti PD-one is contraindicated due to the risk of loss of graft. This actually gives us an opportunity to generate in an ethical way more single agent data with RP-one. RP-two plus Opdivo, part of the Phase I study is enrolling and enrolling well. So expect towards the middle of the year to be able to report out data in that cohort. And we're excited to have got RP3 into the clinic and should be in a position to report out single agent data in the second half of the year. And of course, during 2021, we'll also have additional updates on all the studies we've talked about during 2019. And then in 2022, which isn't too far away now, we expect to have the primary readout from our 2 potential registration studies in PD-one naive CSCC and anti PD-one failed melanoma as well as the combination phase of the RP3 Phase 1 all comer study and could also have, obviously, other readouts from studies we plan to initiate in the interim. We have a full indication prioritization analysis underway as we map out where we will take RP2 and potentially RP3 in terms of later stage development and development with registrational intent. And we're in a strong position in terms of capital, having cash 2 years beyond reaching or hopefully reaching all these milestones with runway into the second half of 20 24. Okay. Thanks for that, Philip. And maybe if you want to introduce the broader team on the line, we can come in with the Q and A. And just a reminder to those on the webcast, if you want me to ask a question on your behalf, just send it through the portal. Yes. Thanks, Anapan. So I'll introduce Rob Coffin, our President of R and D and Founder Gene Fantry, our Chief Financial Officer and Pamela Esposito, our Chief Business Officer. Great. So maybe we'll start out with RP-one and the Phase 2 SURPASS study in CSCC. Maybe you can give us an update on how the enrollment curve is shaping up? And I know the data is expected to be in 2022, but how we should think about the enrollment curve here? Sure. Rob? Well, we're not providing granularity on exactly where we are in enrollment. We are guiding that we're on track for the primary output in 2022, which means that we need to complete enrollment of the trial around the end of the year, if a bit after. However, it would be expected, as with all clinical trials of any size, that the enrollment curve would be relatively hockey stick shaped, including as over time, we bring on additional sites in countries which aren't immediately open at the beginning of the trial. And it is the case we have seen some effects of COVID on enrollment in this trial, which means that we have taken the mitigating steps of increasing the number of countries and sites to complete the trial, which will exaggerate that hockey stick shape. But we're confident we'll meet the timeline as previously indicated. Got it. And then in SURPASS, I guess, what's your assumption for how the control arm performs LABYTO? I mean, there's a wide range of single agent activity there, I think in the mid-30s to low-50s. And is a 15% delta in improvement in ORR clinically meaningful in the eyes of physicians and how are you thinking about CR rate differentiations? So obviously, as you say, there's a range of expectations for anti PD-one therapy. There's various different data sets out there. But I do think whatever the control arm shows within that range or even slightly above that range, bearing in mind what we're already seeing in CSCC in combination with Opdivo that we should have good confidence that assuming in combination with suniplimab is similar that we have the headroom to show the needed benefit from a statistical perspective. Discussion with both investigators and in fact the FDA in relation to the design of the trial indicated that the statistical objectives of the trial, which are a minimum delta, as Philip said, of around 15% would be deemed to be clinically meaningful. However, as with all data packages, it's dependent on the totality of the data, in particular, durability as well as response rate per se. And obviously, increasing the CR rate would also be thought to be particularly clinically meaningful because CR is what most likely to contribute to greatly extended survival. And there again, from the data we have already with nivo, we are expecting to move from the low single to roughly 10% maybe range of CR at the time of the data cut, which would be expected for single agent Libtayo to 2 or 3 fold that based on our current data with nivo. So we think we have good confidence that we have a well designed study, which should easily enable us to show clinical benefit. And we got a portal email portal question here on RP-1. Maybe could you comment if SURPASS and the PD-one refractory melanoma studies ongoing are going to be used for registration? Certainly, that's the intention. The SURPASS trial was designed with registration and intent in the first instance and was discussed with the FDA on that basis, who have indicated support to the design assuming successful and based on the totality of the data. The melanoma single agent trial was set up to sorry, single arm trial was set up with the intent of registration. And while all our advisers indicate that single arm of a trial of that size with the expected efficacy hurdle or objective should be appropriate. As Philip indicated, we don't yet have FDA formal buy into that, but we are having a Type B meeting within pretty short order to get formal buy into that design. Got it. Philip, in your presentation related to RP2, you mentioned multiple times that you guys are taking the process right now for indication selection. Maybe you could walk us through kind of like what the push pull levers are and how you think about what could emerge as 1 or a few of the indications that get prioritized here? Sure. I mean, obviously, we'll be predominantly data driven as part of the reason why we expanded the RP2 plus Opdivo part of the Phase I study from 12 patients to 30. But at the same time, we are in conjunction with a consultant doing a full analysis, looking at everything from market potential to the size of study we have to run, what the endpoints might be, how long they might take to read out, what line we might be in, a real comprehensive analysis. So that's the sort of framework answer to the question. And a little bit of meat on the bones. We don't quite yet know what's going to bubble up to the top, but we do think it is of real interest that we have seen that in multiple tumor types, we can inject liver lesions and see the injected and non injected ones in the liver and beyond respond. And obviously, there are many tumor types that metastasize to the liver, large tumor types, and treating those liver mets is particularly problematic. Got it. I am going to pass it over to Tess to ask some questions on the heartbeat Yes. Hey, guys. This is Tess. Yes. So I know the RP3 program recently initiated. You got that off the ground. It sounds like we're going to see some data this year from that program. I guess, do you think you guys will follow kind of a similar playbook as you followed for RP1 and RP2? Just remind us of kind of what you're thinking in terms of size and scope of data for that initial data set later this year? So the RP3 Phase 1 trial is really very similar, if not identical to the RP2 Phase I trial, which has a dose rising phase, which is relatively modest in size, which goes through 2 dose rising level cohorts, which obviously would expand to larger cohorts if any DLTs were observed. And then that after determining the RP2D based on that single agent data, injecting RP3 into both superficial and deep tumors through imaging guidance. We will then enroll a 30 patient cohort in combination with anti PD-one therapy. So it has standard Phase I inclusion criteria of all comers who failed standard of care. And if there were no DLTs and no cohort expansion, the numbers of patients would be similar to what we showed with RP2 in October, but obviously may be larger if there were any reason to expand the cohort. I think we're about at the time here. So just wanted to thank you guys for this productive session. And I hope you guys have a good rest of the conference. Great. Well, thank you for the invitation to the conference. Thanks, Jonathan. Thanks. Thank you.