Study Update

Jun 3, 2021

Good morning, and thank you for joining our midyear data update event. And before we begin, I need to highlight our forward looking statement on Slide 2. I'm Philip Ashby Spark, CEO of Reptimmune, and I have with me today Doctor. Robert Coffin, our President and Chief R and D Officer. We also have Doctor. Mark Middleton, Professor of Experimental Cancer Medicine and Consultant Medical Oncologist at the Oxford Cancer Centre and the Head of the Department of Oncology at the University of Oxford. Slide 3 shows the agenda for the call, which will start with a brief further introduction from me, then a brief summary of the high level updated results by Rob, followed by discussion of the results and number of the individual patients by Doctor. Middleton. Rob will then provide an overview of what will be 1 strand of our future development efforts with RP2-three. Following the presentation, we'll be holding a live Q and A. To ask a question, please type your question and click submit in the Q and A section found at the bottom of your webcast. All questions will be held until the Q and A portion of the event. So moving to Slide 4. We are continuing to make great progress towards our ambition of making our products a cornerstone of immune oncology treatment regimens as the most practical and effective way to initiate a systemic antitumor immune response. The studies that have been ongoing the longest are with RP1 in our Phase II skin cancer cohorts, which support the 2 studies we are running, a cutaneous squamous cell carcinoma, an anti PD-one failed melanoma with registrational intent. We have always said from the get go, our modality and products can result in high rate of complete response. It is these responses that transform lives, give patients the potential for cure and relieve them of disabilities and or the statements caused by disease. 7 out of 9 of our cutaneous squamous cell carcinoma responses are now complete ones, with a further patient to be assessed as a probable 8th complete response pending biopsy. Further, in melanoma, a number of our positive responses have been shown to be metabolic complete responses like PET scan. While this further supports our expectation for a positive outcome in our registration directed studies, we also believe that if our well tolerated products are pushed earlier into disease courses, the rates of complete response could go higher still and result in many patients never developing the type of end stage disease we are currently treating. With RP2, the signal in patients who have failed anti PD-one has really picked up from where RP-one left off and reconfirms the ability of our platform to treat anti PD-one failed disease. We look forward to presenting the updated data in this regard today. We also look forward to explaining our decision to advance RP2 or 3 into later stage development to treat patients with liver metastases with very poor prognosis where we are seeing very encouraging reproducible activity. We have also made solid progress putting in place the building blocks to build an entity capable of transforming the immune oncology landscape. Our own manufacturing facility is fully operational, filling GMP batches, and we agree to pass forward recharacterization release assays with the FDA. In addition, we have hired a Chief Commercial Officer who is starting the planning process to ensure, if approved, our products are widely adopted in the marketplace. Finally, we have a strong balance sheet to execute on our vision. As a reminder of our technology in MOA on Slide 5, oncology immunotherapy is the use of viruses that when injected into tumors partially or completely destroys them through virus replication, firstly, if tumor cells open and exposing all the released cancer antigens to the immune system in an environment and the cause of cell death. This leads to activation of a patient specific systemic immune response and the destruction of uninjected deposits. We believe that herpes simplex virus is an optimal species of virus for onclytic use, it being both highly mesic and inflammatory and having the ability to carry multiple immune stimulating proteins into the tumor microenvironment to further amplify the immune response. Our next generation constructs have been specifically designed to maximize each of immunological signals 1, 23 in harmony to provide full activation of adaptive immunity combined with the potent activation of the innate immune system as well. Our strain of HSV has been deliberately selected for its analytic properties in human tumor cells. And from all our products as our base platform, we express a fusogenic protein that greatly increases direct tumor killing, immunogenicity of cell death and systemic immune activation. These design features ensure maximum presentation of antigen on the MHC of antigen presenting cells or so called SIGNAL-1. We then expressed various proteins from the virus intended to maximize co stimulatory signals at the antigen presenting cell T cell interface or so called signal 2 to ensure optimal T cell priming. Our lead product RP1 additionally expresses GM CSF. RP2 additionally expresses an anti CTLA-four antibody to stop the negative feedback loop of the CD28 CTLA-four axis and RP3 to further immune co stimulatory pathway activating proteins targeting CD40 and 41BB, which also lead to downstream inflammatory cytokine release or so called signal 3. Moving to Slide 6. We believe our products are the most practical and effective way to ensure a tumor is recognized as foreign where there is an absence of an effective preexisting immune response. Fast forward, as all our products are off the shelf that come in a simple vial, manufacturing is relatively straightforward in shape and our products are well tolerated. Effective, while the approach is off the shelf, it is also patient specific and acts as a pan universal neoantigen vaccine as the tumor is lice open and all the cancer antigens within are exposed to the immune system in an environment of necrotic cell death, a major immune danger signal. Our approach has multiple further MOAs packaged into 1 product through the expression of immune stimulating proteins, which carry into the tumor microenvironment to further amplify the immune response as I described on the previous slide. Our development plan is shown on Slide 7. The data we're providing an update on today pertains to the top 2 bars where we fully enrolled the 30 patient melanoma cohort containing both PD-one failed and the non naive patients. We are close to full enrollment in the non melanoma skin cancer cohort as it pertains to the first 30 patients who are anti PD-one naive, of which 15 patients have cutaneous squamous cell carcinoma. However, this cohort has now been expanded to include nonmelanoma skin cancer patients who have failed anti PD-one, where enrollment is now underway. As a reminder, we have 2 registration studies ongoing in cutaneous squamous cell carcinoma and anti PD-one failed melanoma as depicted. We're also providing an update on RP2 as single agent and releasing initial data for the first time with RP2 in combination with OPDIVO. However, it should be borne in mind that this data set is immature and as much as they include many patients who remain on therapy and may therefore further respond or progress. Finally, we intend to expand development with RP2 beyond Phase 1. Be giving our initial thoughts on where we plan to focus our efforts during 2022 during the course of this presentation. I will now hand on to Rob to summarize today's data sets. Thanks, Philip. So I'll just now briefly summarize the data update today, which is for RP1 in skin cancers, as Philip said, and for RP2 before I hand over to Professor Middleton, who'll present the data in much more detail. So first, cutaneous squamous cell carcinoma. As Philippe said, we've now enrolled 15 patients into the IGNITE study with CSCC. And this shows that while we recently enrolled a number of patients with a particularly high tumor burden, who quickly went off study, which Mark will discuss a little bit as well, the theme of achieving a high rate of response and particularly complete responses continues. The complete response rate in this group is now 46.6 percent with 2 additional complete responses since October and 1 further response awaiting biopsy confirmation, which would bring that to 54.4% if that biopsy shows to be negative. The response rate in CSCC is now 60% with continued very good durability of those responses and multiple responses now out over 600 days. So in our fully enrolled melanoma cohort of 30 patients, the registrational directed indication we're also pursuing. The objective response rate in anti PD-one naive patients is now 62.5%. And for anti PD-one failed patients, it remains at 31.25%. Remember that cohort fully enrolled early last year and so is now really quite mature. With again very good durability being seen and multiple patients now having converted from originally stable disease or partial response to now complete response. We now have 11 patients with other non melanoma skin cancers enrolled and clinical activity continues to be demonstrated across the breadth of these different cancers. And we've also found interestingly that giving a second course of RP-one, the initial first course is only 8 doses over a couple of months. So a small number of patients may benefit from additional doses of RP-one, those being patients who achieved an incomplete response or progressed after initial response And where in a very small handful of patients we've now done that, this has been seen to be well tolerated. And also each of the patients has shown evidence of clinical activity, which is something which we think is quite unique in oncology drug development. Overall, the data with RP-one in skin cancers continues to show that the combination with Opdivo is well tolerated and that the combination drives deep and durable responses, which we do believe strongly supports our registrational directed activities in both cutaneous squamous cell carcinoma and in anti PD-one failed melanoma. So if we now move to RP2, a brief summary there. So with regard to the single agent part of that study, that was fully enrolled last year and we presented initial data in October. And there were 3 out of the 9 patients enrolled who had responded. These patients with further follow-up have continued to show good durability with the patient with mucoepidermoid carcinoma. There was a complete response in October, maintaining that out now to 15 months. The patient with the esophageal cancer has maintained very good partial response now out at 18 months. And the uveal melanoma patient progressed at 15 months, although obviously showing quite impressive durability before that. So relevant to our liver metastasis strategy, which and all and all 3 of those patients showed evidence of activity following those injections. If we move on to RP2 in combination with Opdivo, the new data which will be presented today, there are 27 patients who've been enrolled into that combination portion of the study so far with a range of different tumor types typical for a Phase I trial. And we now actually currently intend to expand the number of patients in that study with liver metastases to be treated with RP2 also to provide further support to the LIVEMET strategy, which we'll come to later. So while this data is still rather early and immature, so far out of the 27 patients, many of which still ongoing treatment, 6 have achieved an ongoing response in patients with uveal melanoma, cutaneous melanoma and head and neck cancer. All of those patients having had prior anti PD-one and which at this early and immature stage of the study, we think is very promising And also has reinforced the signal we've previously seen in some of those tumor types with RP1 in the past, and which is supporting our registrational development at the moment. So with that very brief summary, I'll now hand over to Professor Middleton, who will go through the data in somewhat more detail. So Professor Middleton, as Philip said, is our lead investigator in Oxford, who's been extremely important in our enrollment to date and really has recruited the most patients of any investigator at any site globally. So has by far the greatest experience with both RP1 and RP2 of anybody. So he really is the perfect person to describe the data in detail. So over to Mark. Thanks, Rob. So to start with RP1 and the IGNITE study where it's given in combination with nivolumab, just to review that for melanoma, we're now concentrating on patients who failed PD-one directed therapy and also enrolling non melanoma skin cancer cohort. The nivolumab is given in the standard way up to for up to 2 years, but the RP-one is given every fortnight as a neutral tubal injection for 8 doses additionally. So that completes treatment well within 3 months of starting. And although we can inject the RP-one directly into superficial or powerful nodal tumors, we also use image guided injection quite a lot, so we can access deep tumors including a visceral organ such as the liver. And since the start of this year, we've had the option to give up to 8 further doses of RP-one according to fair criteria specifying the protocol. So for single progressing lesions or where we think the response is stalled, we would benefit from further treatment. And we've got some very early data of this, which is a pretty unusual approach for an oncology drug because generally the principle has been that once you've tried it, if it's not working, then you move that off and try something different. So moving on to talk about safety. Broadly speaking, the safety information is unchanged from the previous presentation with treatment pretty well tolerated and with the toxicity that you might expect for patients who are receiving nivolumab. There has been 1 significant toxicity in March of this year of patients who had already completed their RP-one course, she was on the nivolumab maintenance phase of treatment. The latter myocarditis will be associated this year and succumbed to that. The investigator assessment of this is clearly related to nivolumab rather than to the RP-one. Otherwise, as the table shows, it's a very well tolerated regimen. Moving on now to talk about efficacy in this situation and focus initially on nonmelanoma skin cancer. This table summarizes the response data. And you'll see in the red columns focuses on the changes that have been since October. As Rob touched upon briefly, we've enrolled 4 more patients with continuous squamous cell cancer. I think it's probably fair to say that I and my fellow investigators gave up what a pretty hard challenge in enrolling some very advanced patients who've not benefited from treatment. In fact, all of them progressed really very, very quickly. And perhaps patients that in retrospect didn't precisely meet the bill with their rapidly progressive disease. Having said that, as Rob already touched upon, we've seen some of the responses that we've previously reported deepens, so that now 7 of the responding patients have got complete responses and there's the potential for 1 more to join them in the near future. We've also seen additional responses in other tumor types, basal cell cancer, Burkle cell cancer and angiosarcomas, all of which are listed in the subsequent columns. So a broad spectrum of activity across an important set of patients. Let's go into a little bit more detail. We apologize for the slightly gruesome slide, but it does speak to the issue of the severity of the disease of patients that we've enrolled since the last briefing, both pictorially here and also looking at scans with very, very extensive tumors that defied treatments led to rapid progression and then leaving the study within a couple of months to move on to palliative care. We look at the waterfall plots describing the extent of response than what you can see here color coded according to histology. It is how deep these responses are with a very significant proportion of patients experiencing complete response both radiologically and with the potential for more to join with a number of patients still on treatment. And looking at that in swine of block terms sorry, swine of block terms to show the duration of that, Again, Rob gave the headlines earlier. We're now starting to see patient depression 2 year mark in complete response and some with deep partial responses. And the durability of response has been very impressive across this COVID and indeed with other patients who've been treated with RP-one and 2. And to look at this another way, individual by individual on the spider block, what you can see here is the depth of that response, the speed over which it develops, which is often quite quick in this patient population. But there's merit in persevering the treatment because there are some examples of patients who have a modest response initially, which then deepens significantly over time. I draw your attention also to the right hand part of this spot where you see a patient who has reinitiated. There's a small uptick in the line and then you see it going down again as a result of reinitiation therapy. And we'll talk a little bit more about that in a few more slides' time. So updates on individual patients now for patients since what we talked about back in October. If we look at this patient here, who's a new complete response, it's suckled, but what you can see in the baseline scan in June is deformity of the maxilla. You can see how it's pushed back where the tumor is. And with ongoing treatment at 6 months at the end of last year and now early this year where we've got a complete response, what you can see is normalization of the architecture around that. And that obviously has very, very profound consequences for the patient in terms of how they feel, how they look as well as being impressive on the radiology. Then a second patient who we reported previously as a partial responder on the basis of the picture you see in May October of last year has had further treatment, which is now converting this to a complete response. And what's really important is that, as you might expect, looking at these pictures of the patient's foot, she's regained full mobility, having previously been unable to walk on that foot. And so it's not just pictures of the scan, but a very important and practical difference to the patient's life as well. We've got in this slide set now describes a partial response to a patient with basal cell cancer. And we think that this may impact the complete response because as you follow the scans from October through to February, You can see that they are approximating normality and it's far from clear whether this tumor, which incidentally is a patient who failed, was not again the standard of care in this situation. We're increasingly optimistic that this represents scar tissue. And so the patient will have a biopsy to see whether this is the case and may end up being a complete responder. And then finally, if you look at a patient with Merkel cell cancer, what we see here is a very impressive response in the injected lesion in the top panels with a very significant mass, 5 centimeters in diameter, but also an abscopal response in the non injected lesion, which again is tending towards modality, but we'll need to get biopsies to prove whether this is a complete response. So I'm now going to turn to the data for melanoma in the combination of RP-one and nivolumab. What you see here is a summary of the disposition of the patients treated so far in the initial cohort. Were principally patients with contagious disease, although we do have some with mucosal and uveal melanoma. I think it's important to note that this is a relatively advanced population with the majority of patients having prior exposure to PD-one agents and being of a relatively high end stage with over 3 quarters of the patients having M1B or C disease. So this by no means a highly selective population. So again, same format as with the non melanoma skin cancer. In the red columns, we've got the update in favor of what was presented in October of last year. And this is a relatively mature cohort because enrollment completed early last year. And what you can see here again is a similar story with increasing responses across the piece. And we're seeing deep responses with the anti PD-one naive cohort, now 3 complete responders and overall response rate of roughly 2 in 3. And then a response rate of about 1 in 3 in the PD-one failed cohort with a complete responder as well as 4 partial responders, 1 of whom we have assessed as a metabolic CR. And then looking across at the mucosal data for complete mucosal responder. That was a patient who we previously reported as having a partial response and stable diseases that still have the potential to respond, albeit in the late stage in the New Deal COVID. And we'll talk a little bit more about New Deal when we discuss after 2. Looking at the waterfall plots, again, what you can see is a high proportion of patients with complete responses, which I think is significant and marks out this approach to treatment from some of the other IO drugs in development. And then the sugar crops, again, a similar story to what we presented already in the nonmelanomastine cancer with ROCA patients still on treatment starting to approach that 2 year mark and we're enduring responses whether partial or complete. And then with the spider plot, perhaps a slightly slower trajectory towards the best response that you see with the non melanoma skin cancer. But again, I draw your attention to a patient with stable disease who then progressed and then responded to reinitiation of PD-one, which in fact is 1 of my patients who had failed anti PD-one before joining the study and a prolonged period of study of disease and then re responded in his firstly choosing a PR based upon reinitiative treatment. So just to talk a little bit more about reinitiation, as I said before, this is a relatively unusual approach, but it speaks to the ability based upon the mechanism of action to get a subtly different response from injecting a new lesion or a lesion that's progressing in the face of prior successful or reasonably successful treatment. And it's an opportunity to deepen responses that we've already achieved or to achieve a response once more where it's been lost often locally in an isolated lesion tube. So we've got evidence of activity in all 4 of the patients that we've treated so far. So we're still at a very early stage. And there's an example here of a patient not treated at my center, but in Liverpool by Doctor. Joe Sacco. So what you can see here is the baseline scan on the left, the initial response to therapy through until March of last year, Local regrowth of the tumor at the beginning of the year And it was at this time that we gained the approachable amendment the ability to re initiate treatment. And that was done with the resulting complete response evidence on the far right picture at the middle of last month. So to talk a bit in a bit more detail, there are 2 now. Next slide please, Rob. Then the key eligibility criteria here, again, a broad set of tumors eligible RP2 given, again, every couple of weeks for 8 doses with the nivolumab started with the 2nd largest dose and being able to continue for up to 2 years. And again, in exactly the same way as being with RP-one, We didn't specify that we had to go for superficial or nervous tumors with new, particularly in Oxford, we were enthusiastic using the image guided injection to broaden the scope of patients that we control. And slightly earlier to the RP-one, we had the opportunity to reinitiate the RP-two in the fall of last year. So this table summarizes the patient disposition. As Rob highlighted at the beginning, we had 9 patients in the RP2 only dose that previously been reported. And we've got 27 of the 30 patients enrolled in combination. It's a broad spectrum of tumors, but you'll see that we have melanoma very well represented, including uveal melanoma, some squamous cell cancer that had a neck in the range of sarcomas as well. Safety has been very tolerable. The majority of patients experience only GRADE 1 and 2 toxicities, and this is very similar to the story that we've seen with ARP1 in a larger patient set. And in surprise, we have seen higher grade side effects that are very consistent with either injection and therefore not the disease, but the disease of the INP, but deliver it all within the body of methods within the DRP2. And then just to summarize briefly, the monotherapy Suezmax, we talked about these responding patients. The uveal melanoma patients have been treated in Oxford. Sadly, we lost control of that excellent response after 15 months. And patient progression died very rapidly. And I suspect that COVID was a factor in being able to seek medical attention as it came from some way away and have that dealt with promptly. But I'd also draw your attention to the top patients, whom again, Rob had mentioned previously, another patient with migraine with esophageal cancer and liver metastatic disease, who's had an excellent partial response. And incidentally, this patient had been treated in a clinical trial and therefore had been exposed to an anti PD L1 agent as well as to chemotherapy before joining the study. And we were able to confirm with a PET scan last month that there was no metabolically active disease remaining, although we can't claim a complete response because there are still visible lesions on cross sectional imaging. But I think this points to the exciting potential for Rp2 to create deep and durable response. We move on now to the patients who received RP2 in combination with nivolumab. We've got across the whole cohort a response rate of just over 20%. But there are still a significant number of patients in whom it's too early really to determine their ultimate disposition as far as treatment is concerned because these data really aren't very mature. I would draw your attention though to the patients with continuous and new glioma, where we've got ongoing responses in patients who've had significant prior exposure to immunotherapy. And then looking at the Schwinniprop, you'll be familiar with this story now. Obviously, we're a little bit earlier in the piece. Therefore, we don't quite go out to the 700 days that we're able to look at with RP-one. But what you can see here is a number of patients ongoing with treatment now getting on to the 6 month mark with good responses. Interestingly, as for RP-one, a number of patients who showed initial progression including new lesion have had responses thereafter and raises the question whether these are inflammatory reactions to the therapy and consistent with the Beckman interaction. And I think 1 of the learnings that we've taken from the whole program is that once started, it pays to persist with viral injection and the nivolumab out until at least the completion of the vial injection part of the treatment before making taking a view as to whether this patient benefit. And just to talk through this with some examples. So this is a patient of Professor Harrington with the Royal Marsden Hospital with uveal melanoma. What you can see here is a local tumor recurrence. The patient also had bone metastases, which are not shown here. So this patient had a nucleation. And this is a tumor in the socket that you can see in the picture as well, dated October of last year. And then as the scans and the picture show, there's very good resolution of tumor. And again, this has a significant impact upon quality of life as well as longevity. And there's a further example from Doctor. Sacco again. This is a patient with cutaneous melanoma who had prior exposure to nivolumab, have bulking disease in the neck as well as small lung lesions. And there's been substantial initial progression. If you look here at the baseline scan and focus on this lesion in the upper neck circled in red. You can see that over the course of the 1st 3 months, the distinctive progressive disease, but we've learned to grit our teeth to carry on with treatment. And you can see here that another 3 months down the line, that this is achieved with partial response as the impact of treatment starts to take hold. This was associated with stability in the more of the 788 smaller visions and significant functional improvement that's allowed the patient to return to work after a considerable amount of time unable to do so. And then finally, a patient with a prior exposure to the anti PD-one and the tumor devolumab as well as standard fluoropyrimidine and platinum chemotherapy as well as radiotherapy. And what you can see here is an injected and uninjected lesion, both of them are responding to treatments in perhaps a more conventional way within a couple of months of initiation treatment. So in summary, RP-one combined with nivolumab continues to provide deep and durable responses in the range of skin cancers and remains pretty well tolerated. What's new compared with previous presentations is that we've got some experience in our reinitiation of RPWAN, which remains very well tolerated and for which we've got early indications of clinical activity for the patients treated so far. You recall that biomarker data, the data that OCR continues to support the mechanism of action of the agent and broadly speaking, turning cold tumors hot. As far as RP2 is concerned, it's very well tolerated, whether given alone or in combination with ebolumab. And we continue to see exciting initial activity in patients who failed anti PD-one and also in the range of patients with cancers that perhaps haven't hitherto been considered to be particularly immunotherapy. So I'm going to hand back to Rob now, who's going to talk about some of the development plans that we have. Great. Thank you very much indeed, Mark. That was wonderful. So we're now going to move to a bit of a discussion as how we're intending to move beyond skin cancers, particularly with RP2 and RP3. And in particular, our plan to initiate a relatively broad development program in patients with liver metastases specifically. So as everyone will be aware, the liver is 1 of the most common sites of metastatic disease, including for many of the larger tumor types like lung cancer, breast cancer, colorectal cancer, etcetera. The prognosis for these patients is particularly poor, and they also respond particularly badly to immune checkpoint blockade. This may be due to the fact that liver metastases appear to selectively remove tumor reactive T cells from the circulation, which I'll come back to in a minute. But as oncolytic immunotherapy aims we'll be able to reverse that, which our initial data suggests may indeed be the case, some of which Mark alluded to and showed. So this slide shows the numbers of patients with liver metastases in some of the larger indications showing on the left that the potential commercial opportunity in just these 3 highlighted indications is around 80, 000 patients per year in the U. S. Alone. And on the right, the proportion of patients with liver metastases from a broader range of tumor types is shown, which altogether, as you can see, adds up to a very large number indeed, such as the potential market is clearly very substantial indeed, if 1 had a therapy, which was able to provide activity in patients with liver metastases. Sorry, I'm experiencing a bit of a delay. So on Slide 48, this shows on the left, the patients with liver metastases treated with immunotherapy tend to fail at distant sites rather than only in the liver. So if they only had liver mets in the 1st place, they don't actually tend to fail locally, they tend to fail systemically, which really does indicate a systemic deficiency in immune activation. And that on the right, patients with liver metastases across tumor types also achieve less benefit following immunotherapy than patients who don't have liver metastases. Whereas interestingly, this difference isn't seen with things like chemotherapy or targeted agents. The difference between liver and non liver meds is actually specific to immunotherapy, it being immunotherapy, which is particularly impacted negatively by the presence of liver metastases. And if 1 then looks specifically at response rate and survival across tumor types to immunotherapy, these are both reduced in patients with liver mets, as you can see, where survival is considerably impaired in patients with livermets as is the response rates achieved across these tumor types mentioned in the slide. So recent publication on Slide 50 looked into the mechanism by which liver met patients do particularly poorly on immunotherapy. This is still somewhat hypothetical at the moment, but the data does seem to back it up. So this indicated that macrophages, which accumulate in liver metastases present antigens derived from tumor, which can then bind antigen reactive T cells, which are then killed by apoptosis induced by the macrophage by the FAS pathway. And therefore, T cells which react to the tumor are selectively depleted in the systemic circulation, resulting in poor systemic efficacy of immunotherapy. If, however, we're able to kill off the tumors in the liver, for example, with RP2 or RP3, that would reduce not only the tumor in the liver, but also the number of macrophages at the same time as at the same time as inducing an army of new tumor reactive T cells to increase overall systemic efficacy. With RP3 in particular, the expression of CD40 ligand and 41BB ligand should also reduce the degree of T cell apoptosis and also increase T cell activation, further enhancing the therapeutic effect. All of which suggests to us that there really is a particular opportunity for us in patients with liver mets, which we're hoping to exploit. So this next slide, which may be a little lag. This next slide does show a number of patients so far we've treated with Liberumex, which really we do think is pretty impressive, bearing in mind the nature of the disease these patients had. There are 6 patients here, all of which with had substantial tumors in the liver, some of which were injected in the liver and a couple of which were injected at other sites and some of which were treated with RP-one plus nivolumab and others with RP-two. But what in aggregate it shows are the patients with liver metastases can not only respond, but respond systemically and also have very good durability of effect as well, with 1 of these patients out now to nearly 2 years following initiating therapy. So this body of data, we really do think supports that we really can potentially do useful things in patients with liver metastases, which has inspired us to begin this development pathway for those patients. So our development strategy in patients with liver metastases described in outline here is still early and work in progress. But the plan at the moment is to initially expand enrollment into the RP2 study to include patients with specific tumor types with Libermets, including GI cancers, lung cancer and breast cancer, together with a few additional patients in uveal melanoma to further confirm the signal we're already seeing in uveal melanoma with RP2. And then in parallel, we'll be continuing to assess the safety and clinical metastases. We're currently in the Phase 1 dose escalation single agent part of that trial and we'll move to combination therapy later in the year. Then depending on the data we see with each of those RP2 and RP3, we'll then initiate a multi cohort Phase 2 program in Liberumet patients with specific tumor types, which will provide us with further signal confirmation and tell us which tumor types we have the strongest signal in and where, therefore, to enter registrational development. So it's a stepwise approach, which should be able to be relatively rapidly executed and will be very much stated about dependent. And the exact details will depend on that data as it will whether it's RP1 or RP2 sorry, RP2 or RP3, which is used in a particular circumstance. But all of that will kick off later in the year with the expansion of RP2 into further patients with liver mets. So Slide 54 sums up the prior comments I've just been making and reiterates that based on the theoretical considerations, the huge unmet need in patients with livermets and on our emerging data that we believe livermets to be a very real opportunity for us, which is worthy of aggressive development as we so far mainly apply to patients with skin cancers. So we're now aiming to take a similarly aggressive approach and proceed hopefully rapidly through development in patients with liver mets as well, particularly with RP2 and RP3, which was specifically designed to try and treat patients with less immune responsive tumor types I'll hand back to Philip, who's going to do some summing up. Sure, Robin. Thanks, Mark. So looking ahead over the next 6 to 12 months, we look forward to being able to share further data across our programs to support our ability to treat patients who have failed anti PD-one across a broader swathe of tumor types, including initial data in anti PD-one failed cutaneous squamous cell carcinoma and anti PD-one failed non small cell lung cancer. We also look forward to presenting around the year end single agent data with RP3 and providing more details on the Phase II program we plan to run with RP2, III in patients with liver metastases from prevalent tumor types. The responses we have highlighted today in the liver are profound. They include single agent responses. They include PD-one failed responses. They are deep, durable and provide a very large value opportunity beyond our skin cancer franchise. In skin cancer, we're maintaining guidance. We expect to release top line data from our 2 ongoing studies with registration intent in CFCC and MCPD-one failed melanoma in 2022, and we'll provide further details on timing expectations later in the year. We'll now turn over to Q and A. The patients recently enrolled with high tumor burden CSCC, would these patients have been eligible for SURPASS based on inclusion, exclusion criteria? We would have to look at the patients in detail to determine that. It's quite likely based on other inclusion criteria not relating to tumor burden, relating to to comorbidities and performance status that they wouldn't have been eligible, but I can't formally answer the question. We do have to remember in SURPASS, it's a randomized controlled trial, and therefore, there would be expected to be a balance of such advanced patients between the arms if they were to be enrolled, which would mean that the trial would not be negatively impacted 1 way or another by enrolling such patients. Thank you. We've got a question for Doctor. Middleton. Doctor. Middleton, how confident are you that you are seeing abscopal effects that is not onfluidivirus spreading by, for example, leaky vasculature? I think very complex indeed. The majority of patients who retreats have had prior exposure to herpes simplex virus carry antibodies that neutralize any virus that escapes into the systemic circulation. And if we look across the range of data that we presented previously and today, what you can see is clearly distinct tumors which are responding. So it's not possible to put that down to viral leakage in a direct form effect. This is immune mediated effects by tutoring the immune system to act systemically on the basis of local self care. And the fact that you can then see that again, that reinitiation further supports that potential. Great. And we've got another 1 you, Doctor. Middleton. What are the disadvantages of using oncolytic virus versus antibody or small molecule based therapies? Oncolytic virus limit the potential uptake in academic centers? The obvious disadvantage is that current systems of care are very well set up for intravenous or oral drug administration. And you have to learn a new way of doing things in order to administer things intratumoral. And you have to have the intervention to access intervention to access visceral tumors. But 1 of the reasons we've been able to contribute so significantly to this program is because we have those capabilities in place in Oxford. And they're by no means special to Oxford. Interventional radiology is available in almost all major hospitals in the Western hemispheres. It's used well beyond cancer as well. And where we have effective treatment, radiologists are extremely enthusiastic, having had to be persuaded that this was a program we wanted to pursue. They can see the fruits of their labor from scan to scan, from cycle to cycle and they're very vested in the program. So although it undoubtedly adds a layer of complexity and you have to be prepared to manage the small number of side effects that go with deep injections into viscera, it's by no means insurmountable. If you compare it with the complexities associated with intravenous adoptive cell therapies or bone marrow transplantation, they're trivial. This is something that can be sorted out if we've got the efficacy. Great. We have a question on dosing, Philip. Are you planning to extend RP-one to dosing beyond 8 doses for all patients? Do you think you could do you think this could extend the durability or response? Rob? No, we're not. We do think that the 8 doses, we got it about right. The vast majority of patients have up to 8 doses. Cases, there's quite a few cases, nothing left to inject well before that full 8 doses and then achieve good durable responses, which in nearly all cases has remained ongoing to date. It's only been a very small handful of patients who it has been thought could benefit from a further course of up to 8 doses. So we are now comfortable that having the initial dosing regimen of the Q1 of up to 8 and then the allowance for the small number of patients who may benefit from the 2nd course of a further course of up to 8 really is right, and we now have no plans to amend that further. If I could just add from a clinician's perspective, the ability to retreat or reinitiate RP-one makes a massive difference. With all immunotherapies, whether it's nivo, ipi, when we first started using that and so forth, there's always been a discussion of how long we go on for. And we all strongly suspect that we over treat patients. So we were very pleased with the initial AIDS injections only approach because it draws a line. And we saw patients who continue to respond and have deeper responses after the end of injection, which gave us a lot of confidence that we had triggered an enduring change in the immune system. The fact that you can say to a patient, look, we go with 8, we know we can get good results with that. But if it happens not to be right for you, we know we can come back and give more is, I think, a hugely better approach than we're going to sign you up to having an injection in your liver every 2 weeks for all the time. I think if we go back to this slide, it is worth pointing out here in relation to these patients with who got single agent RP2. The treatment course for single agent RP2 in the Phase I part was actually just 5 doses to really just sort of get the Phase I part done more quickly. So highlights in the green. But as you can see, the patients didn't actually fully respond the responding patients until after the period of treatment. And then that those responses continue to deepen. And none of these patients had any other therapy with anything else since these first 5 doses of RP2. So we really are achieving deep durable effects following a short initial course and just having the opportunity to give a second course in the relatively rare cases where that might be needed, we really do think is quite noble and also about right as Mark was highlighting. Maybe moving on to livermets. When treating liver metastases, would the clinical approach be to inject only tumors in the liver or also inject the primary tumor organ? So I'll answer the question and Mark can further comment. So the rules for dosing are of patients are really the dose the largest easily injectable tumors and you have up to 10 ml of injectate to use on each injection day. So the largest easily injectable tumor is in the liver. You'd inject the appropriate volume into that tumor. And then if there's any leftover of the 10 ml, you would inject into other injectable tumors, which may or may not be in the So in many cases and in most cases, so far, where patients have been given injections into the liver, they just get the full dose into liver, But there may be some occasions where they get injections into both liver and elsewhere. Yes. So we've been slightly changing our approach in Oxford based upon the results that you've seen today. So I consented a patient to this program yesterday who has relatively small subcutaneous lesion in their back and has liver disease. And perhaps 2 or 3 years ago, we said we'll go for the low hanging fruit, we'll inject a small amount of virus into the surface lesion and see what that does. But based upon what we've been seeing today, we're keen actually to inject the full 10 ml. So we'll be injecting a right sided liver lesion in this patient as well as the subcutaneous disease. And that's not driven so much by the Nature Medicine paper that Rob referenced, but by the observation and the 2 patients that Rob called out in the RP2 only slide are good examples of that. So we've seen some really impressive results in patients with predominantly liver disease by injecting 1 lesion there. And in a way that is out of line with what we've come to expect with IO, where it's often a site that does less well. So we're interested, obviously, when we discuss with the patients what's involved in participation, we're frank about the slightly increased risk by introducing the needle into a vascular organ like the liver. But I'm happy to say that I think that the risk benefit, the undecided benefit to this because of what we've seen acknowledging that the data are always open. We can also look at these examples just to further illustrate that if we go through these patients. So this patient just had injections into the liver. This patient likewise just had injection into the largest liver tumor. They did have disease outside of the liver, a much smaller disease. This patient only had disease in the liver, but quite a number of tumors in the liver, as you can see, and just the largest 1 was injected. Likewise, this patient, I believe, is 1 of Mark's only had disease in the liver and was injected in the liver. This was an MSI high patient, again, disease in the liver injected the largest tumor in the liver. This patient was interesting. This patient had quite extensive disease in the liver, but actually it wasn't the liver, which was injected. The tumor, which was injected was in the thigh, but both the thigh and the liver responded to achieve a complete response, which is ongoing. And then this final patient had quite a lot of disease in the liver, where just 1 lesion, the largest was injected in the liver. But the patient also had quite a lot of disease outside of the liver, none of which was injected and all of which responded. And this patient has ongoing partial response now. And in actual fact, a PET scan was done a day or 2 ago, and none of the sites of disease are avid any longer including large tumors in the lung. Doctor. Middleton, this question is for you. Does the LAG-three plus PD-one data from Bristol change the way or delay the use of potential oncolytic virus therapy? No. I would add that we at Replimmune are very keen to combine with things which aren't anti PD-one, including additional promising immune modalities. So that includes things like anti LAG-three, anti TIGIT, also molecules which impact the macrophages in the tumor microenvironment as well or regulatory T cells. And we're also interested in combining with things which aren't immunotherapy at all, combining with standard chemotherapy agents and targeted therapies, where we think there could be a lot of potential value there, particularly to combine with standard of care in tumor types, which are not currently treated with immunotherapy. Yes. And to expand on my answer, I think where we start to see the potential for changes in standard of care in earlier lines of treatment, that might certainly change the patient population, for example, in melanoma that comes to us as a PD-one progressor. But I think the bottom line is that if you look at the therapeutic landscape at the moment, I don't foresee any significant changes, which mean that we end up with a fundamentally different patient population that might have a different response to this approach. If we look beyond melanoma, I'm a big fan of combining immunotherapy with chemotherapy. I think the data from non small cell lung cancer, the early data from esophageal cancer, which is my other tumor area of interest away from drug development, point to the potential there. And this program is in its early stages. It's asking a very particular question. I think it's asking the right questions to its next stage of development. But with infinite time and resources, then 1 could see adding it in much earlier in the patient pathway and in combination with chemoimmunotherapy, for example, as being a reasonable way to go. But as you'll know, these are significantly more expensive than there for potential risky studies. And I leave it to the company to discern when they have the runway and the data to support that program. Yes. I mean, we haven't gone into that level of detail yet, but the RP32 LIVEMETZ program isn't intended to be limited to only combining with anti PD-one, but also potentially combined with actual standard of care in tumor types where anti PD-one isn't active or approved. Next question. It seems that persistence pays where continued treatment often results in PRs after PD-one therapy. How is this built into the study protocols? And what is the plan to treat patients through pseudo progression in future clinical trials? So I'll comment first and Mark further comment. So our protocols already allow for pseudo progression to the extent that progression needs to be confirmed on 2 scans for the patient to go off therapy. If they see progression on a first scan and it's felt to be clinically warranted to continue. The patient gets then consented to continue therapy, pass progression and carry on treatment. And as you have seen, a number of patients where that has occurred, patients have then achieved response. And our response criteria require that for progression to count as progression, it has to be confirmed. But if it isn't confirmed, then they achieve a response, then their best response is still that response. The protocol also allows for treatment for up to 2 years with the anti PD-one. So they get the short course of RP-one or RP-two or RP-three, then they carry on with the anti PD-one for up to a standard 2 years and are monitored throughout that process or that period for response and can have a best response documented anytime during that period. So we already account for pseudo progression in a way which we believe the FDA is fully happy with. Yes. I think that the principal difference is the rules that we have for pseudo progression, treatment beyond progression are pretty much the industry standard rules that we see across a large number of trials that we run here at Oxford. So I think the big difference is that it is 1 of experience. We've treated a large number of patients in this program. And if you compare it to true progression versus tumor progression for, say, combination of in vivo and melanoma, we talk about it a lot. We see it rather less often. And for most patients whose rumps get bigger on ipilimumel, the reason they're getting bigger is they're not responding to the therapy. And it's the occasional patient who is a late responder and it's a true COD progression. What's been striking throughout this program has been right from the get go, the number of patients who've had their best response after completing viral therapy and also the proportion of patients with an initial flare who then go on to get clinical benefit, which does mean that we are able to be much more aggressive than perhaps I would choose to be with ipinivo because I think the chances of this turns out to be a sugar progression are really very much higher. I can't put a quantity on that, and I apologize for that, but it's not something that we tracked formally within the data. But it's our fellows on the unit rotate every 9 months. They start slightly cynical about this notion of tumor progression and they leave us with believing. And I think that's compelling. This is also why it's sort of important why investors get experience with our approach, because an investigator who, for example, only treated this was their first patient, if it was. So this sort of increase may not be motivated to continue, whereas an experienced investigator who's treated a number of patients and has seen good responses in them knows that it's worthwhile to persevere. And then this lady has ended up in a very good place. So experience is sort of very important to learn about what to really expect for your patients with this type of therapy. We've got another question for Doctor. Middleton. For the rapidly progressing non melanoma skin cancer patients, is RP-one still the most promising approach you have? And would you consider adding some form of chemo to slow the tumor down and give IO a chance to get going? I think that's a very sensible suggestion. Say Professor Harrington is not here, because he's really the expert in non melanoma skin cancer skin and has treated the majority of patients. I think to answer the first part of the question, promising approach we have. What the last 4 patients have taught us is it's not a panacea. There are limits to what could be achieved, and we will need to think more creatively about how we create how we set the circumstances in which RP-one can do its best work. And I think chemotherapy is certainly an option, although it's not terrific with immunosensitancy. So I mean, those patients were patients, at least a number have already failed prior chemotherapy. They're not patients who haven't already had everything thrown at them. So obviously, we did talk about earlier combining RPX with chemotherapy as well, which we think is a potentially promising approach. But those patients already had chemotherapy and not benefited from it. At least 2 of them now. Just to stay in the obvious, then obviously what really ought to happen is that those patients are treated early in their disease course with a type of regimen that involves an oncolytic and a checkpoint blockade drug. Probably, we wouldn't expect a fair number of those patients would never get to that stage. Yes. I mean, obviously, as Philip was saying, it takes quite some time for tumors to get to be this sort of size. And if there were a known to be effective therapy available for those patients, they should not really have waited to get to tumors of this size before they were treated. So 1 would hope in a real world population post approval that the patients wouldn't have patient tumors of this size, but would be treated far earlier and hopefully cure them much earlier and never mean they never get to this rather nasty spot in their life. On RP2, for RP2 plus Opdivo, were you surprised to see a lack of PRs with the PD-one naive patients? Can I just quickly answer that? I mean, so for any patient who has who'd be eligible for anti PD-one in the combination with RP-two, there weren't they have to have had anti PD-one first. It's a Phase I population who failed all available standard of care. So the only patients who wouldn't have had anti PD-one are tumor types where anti PD-one is not approved. We didn't enroll, for example, any melanoma patients who haven't had prior anti PD-one or any other tumor types where anti PD-one is approved and they haven't had it. Another RP2 question. How do you view the response dynamic from RP2 and EVO combo, for example, post outright response, post stable disease or progression? I think it's too early to say, but based on the data that we presented today, if you look at spider plot, the shrimp plot, which outlines the individual patient experience, which is all that we can really talk about at the moment, the dynamics do not look significantly different to MASP-one where we have more mature data. And the key issue there is, I don't know of anything else out there at the moment. If you look at RP-one, where a third of patients who progress with PD-one, you can get a response, an objective response. Again, that's better than Tevi and some of the other agents that I've been involved in developing in this space over the last 5, 6, 7 years. But to come back to the ILP2 question, the early indications are not of anything that's substantially different. It's not what I expect it to be. If you think about what's different between RP-one and RP-two, it's essentially the CTLA-four inhibition. And we know that the kinetics of that are relatively slow and more compared with chemotherapy or cell therapy. And therefore, it would be something of a surprise if it's bringing things up. So this slide here just reminds you of the tumor types, which were involved in the RP2 plus nivo combination part. And as you can see, they're a mixture of quite rare tumor types. Generally, they really are a Phase 1 population. They failed everything, which they could have under standard of care. So it is a salvage population. And those with melanoma, uveal melanoma, head and neck have already had anti PD-one before coming on to the trial. And obviously, the other tumor types anti PD-one is not approved because it's either not being tested or known to not be effective. We have a question. What are the considerations for deciding whether you will be advancing RP2 or RP3 in any setting? So we definitely think that the RP2 data, both as a monotherapy and in combination, is extremely promising. And if we didn't have RP3 following along rapidly behind, I think we'd be very motivated to enter broad development with RP2. However, as we do have RP3 following quite rapidly behind, we think it is sensible to gather additional data with RP2 and the initial data with RP3 before deciding which to push the button on for broad future development. There is a sort of interim potential approach, which is progressing RP2 in 1 indication, for example, uveal melanoma, where we clearly got a signal and then reserving everything else for RP3. But exactly what we do will depend on the data as it accumulates over the rest of this year and early next, which will tell us whether we should do everything with RP3 or do most things with RP3 and just a smaller number of things with RP2, for example, or in any combination thereof. So it's all going to be data driven and we'll follow the data. But if RP3 really has properties we really like, the intention would be to do most things going forward with RP3. Another question here. Can you elaborate on how you're thinking about a registrational development path for patients with liver metastases? That really is too early at the moment to further comment on. We do have some internal things we've been thinking about, but it's too early to comment on publicly at the moment. Question, it appears like persisting through pseudo progression is providing good outcomes. How consistent are the protocols in allowing for this persistence when there seems to be initial progressive disease? All of our protocols have exactly the same wording, so it's entirely standard across all of our everything we're doing. Yes. Just to reiterate the point made earlier, what you write in the approach, Paul, is very different than what you train the investigator and the value of experience there. So all approach goals carry roughly the same language in answering their progression these days. So it's very much about the experience with the agents. And I think the power of anecdotes, either somebody else's or when an investigator first sees for themselves what happens by the system that drives this. And I don't think there's a way around that. It's about choosing investment in sites carefully. It's about picking people with the relevant experience. And I think also the right patients and patient population will be greatly helped because the nature of this early part of the program is that patients don't have huge numbers of options when they come off the program. And therefore, it's not that they're going to come off because they're attracted to some other effect. They are therefore willing to persist. I think it's also about communication. When I say communication, I mean with regard to running the trial such that we do have investigator meetings, such that the investigators are hopefully properly collaborating together and are all as a group aware of the group experience. So even if they themselves have only recruited 1 or 2 patients and haven't necessarily seen this sort of thing occurring as yet or indeed haven't recruited a patient at all, the group experience is communicated such that the group motivation is there. Another question coming in. Given the desirable investigator experience with RP, what are the company's plans to get U. S. Physicians and KOLs involved in trials? The protocols are active. So the RP-one protocols are active globally in the UK, in Australia, in Europe and in the U. S. We have a substantial number of U. S. Sites participating in the SURPASS study and participating in the IGNITE RP-one trial, including the melanoma 125 patient cohort. And they are delivering substantial numbers of patients into those trials. With RP2 and RP3, we've always taken the approach at Replimmune due to our relationships with investigators and history that we've conducted the initial Phase I part of trials in the U. K. In collaboration with particularly Mark, the Institute of Cancer Research, Royal Mailson in London and now Joe Sacco in Liverpool and then moved out more globally, in particular in the U. S. As we get past Phase 1, and the same would be intended to be the case with RP2 and RP3. So the LIVEMET program we've been describing or in early outline would be conducted globally, particularly including the U. S. Rob, can you talk about the advantages of using CD40 and four-1BB over other co stimulatory agents? Yes. I mean, I think the greatest advantage of four-1BB and CD40 over the other co stims, which include things like OX40, Gitter, IQOS, all that while those other pathways are clearly very active in mice, the human experience with those other pathways has been really rather disappointing. CD40 and 41BB are also active in mice, but not any particularly more than OX40. But there is human data, which suggests that targeting CD40 or 4 1BB in humans really is a worthwhile thing to do in humans. So the reason we chose them was based on not only the fact that we could get very good outcomes in mice, but also in contrast to the other things we also tested, which worked well in mice, antibodies agonistic antibodies developed by others have shown promising early activity, although in some cases compromised by toxicity caused by the systemic administration approach of the antibody. So we obviously aim to retain the activity, but get rid of the toxicity by delivering the activating ligand directly into the tumor where it's really needing needed and limiting the systemic exposure to a very low amount. What is the likelihood of generating CRs for visceral tumors by RPX, the ASCO effect? So we have demonstrated CRs in visceral tumors following administration of RP-one into superficial tumors. So we do see that. Those 6 patient examples, as Rob previously presented, include examples where the liver has been injected and you've seen a scope of effects in nodes in the abdomen, you've seen a scope of effects in the spleen after injection in the liver with complete resolution of disease in the spleen. And as Rob also referred to, resolution of disease as far away as the lung, where a metabolic complete response has recently been declared in patient 6. Yes. So this patient number 5 is specifically a patient who had a lesion in the thigh, which was injected and also these lesions in the liver, which completely resolved. So these are systemic responses? We have a question here. What data do you need to be able to move into earlier lines of treatment in larger cohorts? And when you anticipate having this? Well, within CSCC, we're already conducting a registrational study in the first line setting or at least in the patients who are eligible who haven't had any prior therapy. They just need to be not eligible for radiation or surgery. So we're already in the first line setting there. But for us to get earlier in disease courses in general, it will be starting to combine with whatever the standard of care is in the first line setting, whether or not that first line standard of care happens to be an anti PD-one agent. 1 can also think further down the line to particularly neoadjuvant approaches in various diseases, which is something we're also extremely interested in. So a combination of the 2 really. What are your thoughts on evaluating RP2 for second line PD failed head and neck squamous cell carcinoma? We certainly think that that's a potentially attractive indication for us. However, also upfront combination with chemoradiation in the neoadjuvant approach is also potentially attractive indication in head and neck cancer. We've certainly got interest from investigators to test RP2, particularly in head and neck cancer, and we'll see where that interest leads. Next question. Do the co stims built into RP2 and 3 play a role in the abscopal effect or do they only play a role in the injected tumor? The aim of expressing those is to increase the systemic immune activation and therefore the ASCO effect. We would expect we'd have more limited impact on the injected tumor. The idea is they're expressed in the tumor and provide the co stimulatory signals to maximally activate T cells to provide a systemic army of T cells to systemically treat disease. So the aim is to increase systemic effect, not local effect. In actual fact, if you look at our mouse data, you see that adding in the CD40 ligand, 4, 1BB Ligand or indeed anti CTLA-four has a much greater impact on uninjected tumors than it does on the increased activity in injected tumors. We have another question on RP2. With RP2, are you seeing deepening of responses over time in either the monotherapy or in the early PD-one combination data? Mark can also further comment, but if 1 looks back at this slide again, absolutely, we are. As I've said earlier, they get the short cohort they got the short cohort of 5 doses with single agent RP2. At the first scan, this patient was a stable disease, which then deepened to a partial response, which has been maintained down to the present day. And as Mark said, has recently had a PET scan indicating no metabolic evidence of active disease. Similarly, this patient at their first scan after completing the course of RP2, the patient had a stable disease, which then deepened to a good partial response. Unfortunately, as Mark indicated, he's succumbed to his disease at roughly 15 months. And then this 3rd patient had a PR at their first scan, which deepened to a complete response, which is still ongoing in a very stunning fashion. I was talking to Kevin Harrington yesterday, who's the investigator, and this patient really is a true miracle as compared to what would be expected face prognosis otherwise. So in all these 3 patients, response has deepened over time and after completing the course of RP2 treatment. Okay. Maybe time for a couple more. 1 coming on RP1. Does RP1 reinitiation always involve a new lesion? When it worked, was the lesion a deeper lesion than the original? And how many lesions are generally injected? So we only have a very small number of patients the Q1 of the Q1 of 'eight is about right. I believe it's 4 patients who've been reinitiated with RP-one. And as I think about it, I haven't got it off the top of my head, but they have so far been 1 patient who had a that local recurrence. The second was the local recurrence in the thigh, the example we showed, which is the site of the originally injected tumor. The patient additionally had tumors in the groin and in the lung, which responded in the 1st place and not further progressed. So the only site of relapse actually was the initial tumor in the thigh, which was reinjected and responded. So that's 2 of them. The 3rd patient is Mark's patient who had disease in the shoulder, as far as I remember, who initially achieved a very durable stable disease. And then that began to progress and reinitiation occurred, and now they're now down to a nearly a partial response better than their first response. So it's again at the local site of the initial disease. And then the last patient is a patient who had lots of lesions in their leg who achieved a very good and durable partial response for whom reinitiation was pursued not because of any sort of relapse, but to try and convert that patient into a CR. And that patient is does seem to have further benefit from that second course. So there hasn't been a case where there's been a distant relapse, which has been reinitiated. It's actually only been very small local relapses, which so far have been kept under control by the reinitiation. But it's a mix of new lesions or lesions of the reasons that are previously going to run gone and then come back. And then a couple of patients where there's always been something to speak to the original question. Yes. So we have I was talking about RP. So with RP2, we've had a number of patients who've had some new lesions appearing after the initially injected lesion had gone away, actually before the Folate had been used and then those new lesions were injected and response had occurred. And final question, when do you expect to provide more specific timelines for SURPASS and Ignite pivotal readouts? Philip can answer that. Yes. My current guidance is quite broad with the primary readout within the 2022 time frame. So obviously, if you move into second half, it's appropriate given more granularity on that. And we will do so within the next 3 months or so in terms of giving guidance on when we expect full enrollment and when we expect the primary readout probably at the next quarter's release. So just before turning it back to you, Philip, if we didn't answer any questions, we will try to get to those in the future on future calls. But we'll turn it back over to Deepak. Yes. I just want to thank everyone again for their time this morning. We look forward to towards the end of the year giving more granularity on this, particularly the Phase II program in liver. This will involve prevalent tumor types like colon, breast and lung. And obviously, look forward to a future base as well on the data side around the year end. And just like to thank Mark for his participation and again everyone for their time and time to close out the meeting. So thank you.