Study Result

Oct 7, 2021

Good afternoon and welcome to the Bicycle Therapeutics Call. All participants will be in listen only mode. Questions. Please note, this event is being recorded. You may listen to a webcast replay of this call by going to the Investors section of Bicycles' website. I would now like to turn the conference over to Dave Bora, Vice President, Capital Markets and Investor Relations. Thank you, operator. Good afternoon, everyone, and thank you for joining today's call to discuss the BT-five thousand 528 interim Phase 1 data and preliminary findings from the BT-eight thousand and 9 program presented at the AACR NCI EORTC Virtual International Conference today. This meeting is also referred to as the triple meeting. I'm Dave Borra, and joining me on today's call are Doctor. Kevin Lee, Chief Executive Officer Doctor. Dominic Smetters, Chief Medical Officer Doctor. Nick Keen, Chief Scientific Officer and Lee Kalowski, President and Chief Financial Officer. Before we get to the presentation, I want to make you aware of our forward looking statement. Now I'd like to turn the call over to Kevin Lee, Chief Executive Officer. Thank you, Dave, and thank you to everyone for joining us this afternoon. Turning to Slide 3 to review today's agenda. Dom will begin by discussing our clinical progress in BT5528 and BT8009, and Nick will provide context on how the recent data from these 2 clinical programs fit within our broader strategy based on our biccyclic peptide platform. Lee will then review our upcoming milestones across our programs and provide closing remarks. We will then open the call up for Q and A for which we will all be available. Next slide, please. Now before we jump into the data presented today, I wanted to provide a brief overview of our strategy and pipeline. When I joined the company just over 6 years ago, I saw an absolutely revolutionary technology with seemingly limitless potential to deliver a new class of molecules that could change the way we approach the treatment of disease. But I also recognize the critical importance of a strategic plan that ensured we were advancing our programs in a way that maximized the value of such a broad platform while remaining focused and disciplined. To that end, we created a collaboration on BT1718 with CR U. K. To sponsor and fund the Phase I and Phase IIa components of that molecule's progression. We also advanced BT5528 and BT8009 and expanded beyond our bicycle toxin conjugates into IO programs. And we continue to enter partnerships with the therapeutic leaders to realize value from the platform beyond oncology. And we've worked tirelessly to deliver on all of our milestones. As many of you know from following us, prior to, through and after our IPO, we've delivered on all of our milestones with BT1718 entering the clinic in 2018, BT5528 in 2019, BT8009 in 2020. Later this year, we hope to announce that BT-seven thousand 480, our first IO molecule, has entered the clinic. That's 1 clinical start every year for 4 years in a row. Today, we are thrilled to unveil our initial proof of concept data for our 2 wholly owned company sponsored BTCs, BT5528 and BT8009, which Dom will review in detail in a moment. With BT5528, we've advanced this molecule, showcasing the platform's ability to reach a target that to date has been unachievable using antibody based approaches. We're very excited to say that we see that we can safely target fRNA2, reach tolerable doses and see clinical activity in 2 tumor types. We've seen no coagulopathies preclinically or clinically, demonstrating clear differentiation compared to antibody based approaches. Dom will also review BT-eight thousand and 9 today. And again, we are thrilled to provide an early update as the escalation continues. As we know, there is significant interest in this program. While still early days, we are encouraged with the efficacy seen to date as will show. It exceeds that of the approved antibody enfortumab vedotin based on Phase I results, even though patients enrolled in 8, 009 will later lie and even though the escalation is not yet complete. Perhaps more importantly, we are also encouraged by early but clear signs of tolerability differentiation, another validation of the bicycle platform compared to antibody based approaches. So as you can see, we have an exciting update for 2 programs today, and we believe further validation of the program. And we're encouraged by the clinical activity seen in the 2 programs across the 2 tumor types. With that, I'd like to turn it over to Dom. Dom? Thank you, Kevin. And I'm just going to go ahead and presume that you didn't see Doctor. McKim's presentation this afternoon. And we'll talk extensively about what we're seeing in the clinic with both programs. And specifically, I'll try and share with you my view on how insights from 1 platform really do help view the other sorry, 1 asset really do help view the other asset. So starting with Slide 6, please. Efrain A2 is a well known target and a member of the efren subfamily receptor tyrosine kinases. It is intimately involved in the pathogenesis of cancer and critically for our molecule is also over expressed in human cancers versus normal tissue. This, of course, is helpful in terms of concentrating on our toxin in the cancer and not in the normal tissue. The target itself has a more checkered history as MedImmune published a few years ago. The paper referenced at the bottom of this slide is actually 1 that talks about their antibody trichamjiCA, MEDI-five 47, which could really cause did cause severe clotting patients in 5 out of 6 patients. And that was felt to be related to the endovascular expression of the target efferent, which led the ABC to attack the endothelium and the blood vessels and thereby setting off a cotton cascade resulting in DIC. Next slide, please. So the preclinical signals associated with MEDIT-five 47 suggested that this clotting would be a concern and would arise. And indeed, it was a great thing that Mediapine did, both taking it into the clinic. And we're very grateful for them having published and discussed the data extensively since. We, of course, were deeply aware of those concerns when we started this trial. And though we do have to say our molecule preclinically did not show any of these clotting problems. Our trial, as by intention, was intentionally a 3 plus 3 standard dose escalation with a segue into a Bayesian logistic regression method based escalation towards the second half of the dose escalation as we entered into what we had predicted would be efficacious ranges. The idea there being, of course, that DLRMs tend to have less excessive exposure to unnecessary or high doses. And indeed, we believe we saw that. We had relatively standard excluding criteria, having noted that patients were excluded with prior neuropathy unless that had returned to a Grade 1 or better. We did not just say exclude patients with eye conditions nor did we exclude diabetic patients. We did, after the first few doses and feeling comfortable about the fact that we are not seeing any hints of crossing problems at all, changed inclusion criteria to enrich for higher amounts of the efficacy target. We had a very standard set of objectives, first being safety and tolerability and quite right, too secondly, pharmacokinetics and thirdly, pharmacodynamics. The view is that we will go into cohort expansion and of course consider nivolumab combination or indeed any other PD-one combination that comes to mind and doing this, having achieved an effective and exemplified an effective therapeutic range. Next slide, please. So quickly on to the results. The trial we presented today had 24 patients in it. And this data was true as of the cutoff of the 14th July. The data is not fully source verified to date, and it is emerging data. However, we believe it to be a true account of what I've been hearing from the investigators. We have here the standard sort of spread of good performance status patients. 46% of patients had good performance status of 0 and 54% status of 1. I have to say though, what is particularly notable here is that the number of prior therapies, which is 7 as a medium ranging from 1 to 16. I'm sure you're all aware, but the number of cryo therapies you have is a feature that predicts your likelihood of responding. So for example, if you're an agent that might expect a 50% response rate in first line setting and you move to second line, you might see that response rate shrink to 35% to 40%. Then if you use the same agent in 3rd line, you might actually see it shrink to kind of 25%, 30 percent, so on and so forth. That's the way it's discounted. And it represents the evolution of cancer as it learns to meet certain challenges and existences. 7 therapies is a lot. It's, of course, cancer therapies are evolving all the time. Every time the new 1 gets approved, which is great for the patients, it gets added to the queue. And when you're a first in human trial, you go to the back end of that queue, and that's quite right and proper. I do think it is worthwhile reflecting that the efficacy and results we've seen here are in terribly sick patients who've had lots of prior therapies. And as physicians always comment, any kind of responses is truly impressive. Next slide, please. So this slide represents an overview of the key adverse events, notably patients, specifically those adverse events that are Grade 3 or greater and which were related to product. As you can see, there's not anything particularly standing out other than the 2 observations. We obviously had a reasonable degree of neutropenia. That's recognized as a class effect and would probably could should probably be attributed to the payload. 0 bleeding disorders, also 0 conjunctival disorders. And I haven't even seen grade 2 with that particular issue. 0 cutaneous adverse events in grade 3 or higher. We did have 1 patient who had a rash. Turns out it was kind of grade 1 on their ankle, got better with some moisturizer after a couple of weeks. And 0 neuropathy as well. Again, we had a patient who came on with a Grade 1 neuropathy. That was the legacy of the prior ovarian cancer therapies. That patient was on trial for a year and the neuropathy impressively got better. I think that observation is truly remarkable when thinking about the platform and the history of neuropathy that is kind of similar but obviously not the same agent. We also saw tumor lysis syndrome. It's a rare event, extremely rare and eye opening event, of course, both in terms of efficacy and safety. It's worthwhile noting that in solid tumors, because we see it all the time, the hematological malignancies, but in solid tumors, particularly, this is a very severe and grave thing to have happened. And that patient did unfortunately pass away as a result of sequelae of that challenging situation. We had 1 other, Grade 5 event, which was a patient who went into acute renal failure, having gone home and become severely dehydrated and not contacted their physician for 6 days. So the actual dose escalation we've gone through is here, and it does require some cautious explanation on my behalf because there are a couple of notable points. The 8.5 milligram per meter squared every week stage early on in the escalation, the physician got together after a group of patients had been dosed. And although none of those patients had a formal dose limiting toxicity as described and is typical for 1st in human Phase I, the physicians did say, well, look, the number of patients here have had either a grade 3 or grade 4 It's not lasted long enough to hit the DLT, but there has been an additional degree of gastrointestinal discomfort and electrolyte abnormalities. Nothing in itself to write home about. But you know what? I don't think it'd be wise to go any higher. And we should explore around what's going on here. So they kind of avoided the next scheduled dose escalation. And I think when we look back on what we saw at the 10 milligram level with the grade 3 fatigue in pneumonitis. I'm very glad to say that we didn't carry on what would otherwise have been quite unhelpful dosing levels. I think what I'm saying is they got it right. In between, so we also then started exploring 8.5 milligrams every other week and 6.5 milligrams every week. Broadly speaking, I can tell you, I actually just came out of the Safe Review Committee last week, and we're very much looking forward to and excited about the next dose we've chosen to explore, which is 6.5 milligrams every other week. And the domestic yields go up there, but what we've got right now is good. And it's going to be in that region, as I'm sure you can deduce for our recommended realistic Phase II dose. But more of that to come in future conversations and calls. Next slide, please. So on to efficacy. These plots are divided up to highlight them. On the top right, you have the spider plot showing cycle by cycle the resist measurements. They're all normalized at a baseline. And what you see is shrinkage if it's going down and growth if it's going up to sort of plus 20% or and then within that, you can see we have 1 formal partial response, setting the 30% threshold or indeed greater than 30%. That was amongst 8 patients dosed with ovarian cancer who had ovarian cancer. And indeed, 4 out of 5 patients with efferent staining, which is that's what I'm hoping you're seeing with the dark purple or turquoise line, all had some degree of shrinkage. And it was 1 of those that was the partial response. Even more striking, though, perhaps, and to some extent not surprising, was the 2 urothelial cancer patients, both of whom had responses after a couple of months after the first cycle the first couple of cycles and who have continuing deepening adverse responses, 1 of them beyond the 60% shrinkage level. Next slide, please. So this slide shows the Page Score, which is a composite score of both the degree and intensity of an individual cell staining and then added up amongst that is the percentage of tumor cells when you look down the histology slide that are positive. What we have going along the horizontal axis is increasing intensity for the staying of our targets on urothelial in cancer patients. And this is kind of breaking news here because it also shows that correlated with the percentage change according to RECIST. And as Doctor. McKeen commented earlier, there really does appear to be a sort of intriguing correlation between the intensity of target staining and the degree of shrinkage. And I would ask you to consider carrying forward that observation whilst thinking about the intensity and depth of stain you get with, say, example, Nektar. Next slide, please. So I don't want to trouble you too much with the details on this slide. It's just to show that we obviously have a number of questions, exciting positive questions to answer around urothelial cancer and ovarian cancer. And we're putting in place this adaptive trial design that will enroll these patients. And we're also keen to explore further signals in non small cell lung cancer, head and neck, gastrosophageal cancers and triple moditive breast cancer as well. And there'll be a couple of small interesting cohorts there, not wanting to leave extra potential efficacy on the table, of course. Next slide, please. So in conclusion, we've communicated this afternoon Bicycl's first ever clinical data of a toxin conjugate, the BC-five thousand 528. There clearly is no evidence of clotting abnormalities. And I think that's something very interesting regarding this platform's ability to attack targets as are not otherwise addressable by other technologies. The doses were generally well tolerated with the obvious caveats that I've shared with you. And I actually just spoke with the investigators this afternoon, and they said, yes, no, this is good. It is tolerable, and we're still learning, of course. And to have all of this in the context of anti tumor activity in more than 1 tumor type is, well, it's genuinely arresting. The initial points I've noticed is we really haven't seen any neuropathy. There haven't been any eye problems and no no skin toxic still in that grade 1 ankle rash. And I think, again, I've made no apologies for pointing this out. I would ask you to hold on to those observations once we look at 8, 009. I think these, yes, general platform observations, and that's been probably the fun and the fascination has been bootstrapping together this 5, 528 data and what's going on with these 2 molecules and coming out of the same platform. They both have Valset linkers. They have the same MME payload. And we can look at other programs with Valset linkers and early payloads. And then finally, there's some fascinating correlation with the FA2 expression. We're getting ready to expand, and investigators are really very excited and keen to do that. So really solid, robust evidence of efficacy with repeat patients in a context where some patients can tolerate therapy for up to a year. And indeed, it's the clinical disease that progressed and not the absence of tolerance. And it's yes, it's really exciting when we consider, next slide, please, the 8009 data. Now that wasn't particularly talked about at the conference this afternoon because the paper was accepted, we intend to talk about SHYSTRA-twenty 8. And again, it is preliminary emerging data, but we kind of looked at this data, which you can see is very recent. And we said, look, the question is really not if we should share this data. But really it was important for us, and I'd argue the patients and the investigator community as well, to get this data shared as soon as possible. There really are some very exciting insights here building on what I've just shared with you about 5528. So before I slide dive into the data, Slide 16, please. I would just share with you some important insights about target nectin for the cell adhesion molecule, also known as PBRL4, cholio biosnake septor 4. It shares a consistent structure with the other 3 lectins in their family, 3 extracellular immunocrobulin domains, a single transmembrane helix and an intracellular domain. Like FA2, it is overexpressed in cancers, and it is that overexpression is correlated with tumor progression. And finally, as most of you know, it is the target of the FDA approved padsef and fortamab for doting. Next slide, please. So again, similar to our design as per the previous 1, 2.5 mgs and 5 mg doses are the main doses that we'll be talking through today. Again, 3 +3 escalation followed by the Bayesian logistic regression method. But we have also recently started the 7.5 milligram dose as well. I think it's important to emphasize we are still escalating. And of course, that's 1 of the things that keeps me warm at night. This is just what we've got so far. We are looking to do further cohort expansions. And there's a consideration in the protocol around combinations, which I suspect will be an increasing talking point. And we're looking at standard first in human criteria. Again, we allow patients with bladder cancer onto the trial without imposing any requirements around nectin levels, but we are selecting other tumor types on the basis of their nectin expression. Of course, we're still looking at safety and tolerability, our primary objective, and we've been gathering PK and efficacy data along the way. Next slide, please, Dave. As we've commented to a number of you over the past year, the returns has been really excellent. And this quarter, if not surpassed, what has been going on with the BT5528. We've got 26 patients, as you can see here, similar mix of male and female, slightly more female than average. And yes, I think the next slide will look at urothelial cancer perhaps in a bit more detail. So yes, this is a quick breakdown of the number of patients who are on BT8-nine by cancer type. You can see that unsurprisingly urothelial cancer is the most common amongst them, but there are a lot of other patients worth of experience there as well. And I think it's worth commenting that the first half of the trial was really in the USA, and that meant we had non urothelial patients. And the urothelial cancer patients are very much the most recent set of patients that we've been dosing. So on to Slide 20, please. So this is more specifically those 11 patients who had the Osteo accounts. Again, nothing too striking here other than that half of our patients, as it says, the median number of therapies there is 2, but actually all of them had 2 or more therapies. So no patients have 1 therapy. I think that's important because whether we like it or not, the main comparator that we're put up again at a similar stage presentation at ASCO in 2016, they had 40% of their patients who had 1 prior therapy. Next slide, please. So this is a quick overview of the adverse events for all these patients with all genotypes because, of course, the adverse events are not terribly related to the tumor type, but do inform us what's going on with the drug overall. And again, I make no apologies for emphasizing this is an ongoing Phase I trial. And at this stage, we're not preemptively treating any issues like some of these events. And then although they have been extremely well managed, they are likely to be better managed with the use of foresight and prospective interventions. Clearly, we once again noted a slight excess of bone marrow suppression. We see this in our preclinical models. We see this in 5, 528, we see this 5, 528 in our preclinical models. There's essentially idiosyncratic presentation of hypertension and some electrolyte abnormalities and of course some fatigue. But nothing I don't really think there's anything to stand out this year. They all deserve to be considered. But I think it's important to say, and I think you can see now the similarities and overlapping 5528 and 8, 009. I kind of view both of these in 3 dimension. And we sort of view it steri scopically with 1 eye on 5, 528 and 1 eye on 8, 009. And I think that brings the platform into a much more useful focus. And again, you can then look beyond that, these 2 observations, and start to see some emerging similarities and some even more striking dissimilarities with the antibody drug conjugates in the same way. Next slide, please, Dave. So this is a summary of what is really quite mind bending efficacy. We've seen the first 2 doses of this trial. Again, you've got the spider plots. They're normalized. As you move along from left to right, that's time, and then the deviations either go up or down. And as you can see here, they mainly go down. I think, yes, it's there's 1 patient there who's got the 2 month scan results. But again, it just underlines just how early this data is. It's very much my expectation. These results will continue to develop and mature over time in these patients. And I'd be very surprised if these reductions don't further deepen, like we saw with the urothelial cancer patients on 5, 528. So we've got 1 response of the 2.5 milligram dose out of 4 patients. That was a 37% reduction. And then stepping up to the 5 milligram dose, which again has now been passed and deemed to be very well tolerated by the safety committee, we're seeing 3 out of 7 patients. And as you can see, that's not just 3 responses. They are really deep, and they are fast acting. Even the 1 patient there that isn't part of those 3 responses, it doesn't quite breach the 30% threshold, showed an initial 26% reduction and then a subsequent 20% reduction. So even the stable diseases are arguably less stable and more response like than many stable diseases we typically see in our 1st in human trial. Finally, I would just remark that it's evident for these patients that have not progressed by first count, even the patients that are not showing shrinkage are contributing to a 75% disease control rate of a 2.5 mg dose and a 71% disease control rate of a 5 mg dose. Next slide, please. So it's very much, Bicycle's intention to develop these special, highly effective peptides in their own right, in their own way. And the differentiation that we've been talking about here kind of demands that in a way. I think if we only ever try to be as good as inflotimab, we would only ever become almost as good as inflotimab. But actually, we don't want to do something different. We deserve to do something different. And our investigators are very much relishing the prospect of doing something different. It's discovering new medicines, discovering a new platform of medicines, a new way forward. Medicines and discovering a new platform of medicines and new way forward that really excites them. Just copying and pasting what other people do is not what we're around. However, at the same time, we have to reflect on the fact that if we're not as good at inflotimab, there's probably an extent to which we're not going to get very far in developing these new medicines. But we are as good and possibly safer. I need to acknowledge that this is a side by side comparison. It's not a direct head to head, a separate trial. And there's an extent to which that is not purely scientifically perfect, but it goes on all the time. And I've got a lot of experience of doing this. And they're done in the same centers. They're done using or rather similar centers, experienced phasorologists. And yes, I think it's striking what's going on here. So what we've done is we've taken the original 2016 publication from Rosenberg, which was essentially in the emerging part of their dose escalation, and we compared that. And we are comparing at the 2.5 milligram level on the left there with our drug, we shared in the last slide, the 25 percent response rate and the 5 milligram level just to the right of that with 8, 009, we're seeing a 43% response rate. And then combining them together, looking at all cohorts we have, and we're still in escalation. There's still more data to come. We have an overall response rate of 36%. And in comparing those 2 doses, if you take the low dose, of course, 25% response to 2.5%. And then fortamumab for the 1 mg and below, we think that's going to be comparable there to 23% response rate. And then at the all cohorts analysis, looking at 33 patients, kind of got a 30% response rate, and we've got an all cohorts analysis of 36%. We believe those things compare very favorably, except, of course, for the absence of high toxicity, which is deeply reassuring, both for us and patients, the absence of skin toxicity and the inability to demonstrate any real peripheral neuropathy. There was a signal turned up early in Phase 1, I, a grade II peripheral neuropathy. Patients still have to be on trial for a long time, but we've got a lot of patients who've been on trial, including 1 patient who's been on for 2 68 days, a patient who is on for almost a year, 5528. And it just feels to me like whilst we might see some kind of regression to the mean or more peripheral neuropathy probably will turn up because it's kind of a side effect of the efficacy. It just feels to me like I don't think we're going to be seeing the degree of neuropathy that other agents have seen in this context. So next slide, please. I think just to bottom line it, it's probably easily the best solid tumor data response I've ever seen in a trial I've been associated with. There are CAR T therapies out there and solid tumor indications that will be proud of this degree of efficacy. I've worked on CAR T in the past, and I would have gained my left arm actually to be looking at these results. These are not just responses that tick the already quite robust 30% level where we have, say, patients B and D, both in the 5 milligram cohort to have 89% 52% shrinkage. Patient C is almost an outlier in that respect in the cohort because the tumor shrinkage is still fantastic at 48%, but it appears like the weakling in the litter amongst the 5 milligram patients. But I just want to say that patient was scanned 3.5 weeks in. And after only having had 1 dose, they were scanned whilst looking for an infection. And they happened to come across a disappearing tumor. They actually couldn't find an infection. So a couple of days later, they did a full RECIST criteria workup, and this is what came out. The investigator was deeply pleased, A, because the patient's infection got better and B, almost with equal rapidity, so did their tumor. If the patient had gone on to have full 2 cycles of therapy 2 months in, I suspect that shrinkage would have been even greater, perhaps somewhere between the shrinkage we see with patient B and patient D. But of course, still early, but nevertheless, quite robust and undeniable data points that we're looking at here. And then finally for patient A, I think for us to develop a thesis, it's not only the prevalence of response in each cohort, which shows a dose related effect going up from 25% to 43%. It's the depth, the degree of response as well going up from the 2.5% to the 5%, which really gives me pause to reflect less shrinkage with a smaller dose, huge, awesome shrinkage with the 5 milligram dose. And now we've actually started to dose patients on the 7.5 mg level, and it's going well. So Slide 25, please, Dave. So I was discussing this with investigators a few days ago. This patient had 8% to 9% shrinkage. These are 2 not inconsiderable lesions that are actually requiring morphine on patients off morphine now. And this is an 89% response initially reported as a complete response, But you can see that it's not actually a complete response. There's a residual there's some sort of degree of echo. There's a ghost like image and scarring residual tissue. Who knows? But and again, the other one's almost completely disappeared. It's more obliterated by the radiologists' calipers there, the little red line. But it's just so rapid, and it's genuinely amazing. And again, this is the first scan. I'd love we're looking forward to next month getting the next scan, But this is just how kind of fresh this data is, and I'm sure you can begin to appreciate why it is. We're so excited and keen to share it with you. But maybe it will be a good response. It doesn't matter to some extent. It's still a resounding response. And I think if it isn't this 1, it will be some patient in the future. So Slide 26, please. So before I go through the summary, the only thing I'd say is I was talking with 1 of our lead investigators the other day, and he quite rightly said, look, Tom, great efficacy, really exciting. We're keen to get patients on, but you need to make sure, as you are doing, that you concentrate on the side effects. I think through improving those, and when we were both in agreements on this, and finessing those, giving them the supportive care, taking time to delve into these and having the investigators just grow their experience base and mature and percolate their understanding of how to manage them, that will bring you the efficacy to an even greater level. So this, in conclusion, is why we're really hopeful. And yes, we haven't even talked about the doses that the urothelial patients got on the 5, 528. But I just want to say they got 6.5 and 8.5 milligrams. And so yes, we can jokingly say it's a 100% response rate. The patients are not joking. They're very grateful. It's 2 out of 2. It's a different molecule, but it is in the same platform. And I think given we're seeing similar tolerability levels dose by dose overall, accepting the odd pharmacokinetic idiosyncrasy here and there, I think it suggests that we've got further to go here and that additional dose won't be saturated. It will be a meaningfully additional dose. These all the dose ranges we've talked about today have been very comfortably tolerated. And most of the side effects of GI, grade 1, grade 2, we're very much looking forward to sharing more data on this in 2022. It has genuinely been a moving thing to share this data with you today. A real pleasure and privilege and looking forward to what comes next in the story. So Slide 27. This still is clearly just the beginning for 809-5528. And the engineering and architect of those molecules that I've been sharing with you today have been still working hard at it. And it's my pleasure to hand over to Nick, our Chief Scientific Officer, to talk about what is going to be the next act of the bicycle in this respect. Thank you, Dom. Building on the incredibly exciting clinical data that Dom has just shared, it's very clear to us now that bicycles are highly effective vectors for the delivery of toxin payloads to solid tumors. But we're a platform company and a big idea company. So I'll take you through some future facing components of our portfolio. Building on the work that you've already seen, we're building a broad portfolio and building depth in tumor antigen binders. We're actively screening against multiple high value tumor antigen targets, both those of current antibody drug conjugates but also those that have failed as antibody drug conjugates and those that would likely not work with antibody drug conjugates. Additionally, we're expanding the depth of the platform by evaluating 3rd generation molecules where we're looking at alternate payload with alternate mechanisms of action. And those include, for example, DNA damaging payloads. Very excitingly, given the clinical data that you've just seen, it's apparent that bicycles can direct very effectively to tumors, and we believe that they will direct other bicycles to tumors. And we're building on that in our new IO area. Our first tumor antigen targeted CD137 engaging molecule BT-seven thousand 480 is heading into patients later this year with BT-seven thousand 455 following on behind that. We're also looking further beyond that in immuno oncology. We're generating binding vesicles to many receptors in the immune system. Our second foray in this space are multiple receptors expressed on NK cells. And what's probably not so obvious from the earlier part of the presentation is it's very straightforward for us to click bicycles together and to generate multifunctional molecules, and it will be our pleasure to talk extensively about that in the future. Finally, it's not escaped our attention that these are likely excellent molecules for combination. In contrast to antibody drug conjugates, which have an extended plasma half life, these molecules intrinsically have a short plasma half life. And that will likely enable, for example, sequencing in a more facile way than for longer lived molecules. So we're actively investigating combinations both inside and outside of our portfolio. So turning to Slide 28. I'll now pass on the call to Lee for a review of upcoming milestones and closing remarks. Thank you, Nick. Today, we have provided an update on our clinical progress for BT-five thousand 528 and BT-eight thousand and 9. We are encouraged by the clinical activity we've seen so far and are excited to be advancing these programs. And as Nick just outlined, we see significant opportunities beyond just BT-five thousand 528 and BT-eight thousand and 9. Before we conclude today's call and open the line for questions, we wanted to briefly review our upcoming milestones. First, we look forward to initiating the BT-five thousand 528 expansion cohorts in urothelial and ovarian cancers, as well as a basket cohort that may include non small cell lung, head and neck, esophageal and gastric and triple negative breast cancers. We expect to dose the 1st patient in the expansion cohorts in 2022. 2nd, the dose escalation for BT-eight thousand and 9 remains ongoing with patients currently being enrolled in the 7.5 milligram per meter squared weekly and every other week cohorts. Patients are being enrolled in these cohorts. This remains ongoing and we expect to present updated results in 2022. 3rd, CT-seven thousand 480, which is our next in 4 CD137 bicycle pica, our novel tumor targeted immune cell agonist, this remains on track to be in the clinic this year and expect to provide a further update this quarter. Finally, our 3rd generation bicycle toxin conjugates and NK cell engagers are in development and we continue to explore additional opportunities to expand our pipeline in oncology and beyond. At this time, I'd like to thank you for your time and interest. And with that, we'll turn the call back over to the operator to open the line for questions. Operator? Thank Our first question comes from the line of Alethia Young of Cantor. Your line is open. Hey, guys. Thanks for taking my questions and congrats on the data. It looks very, very interesting on both programs. So maybe 2 for me, so I'll be respectful. Just can you clarify like what not fully QC means? Does it mean that the patients have RECIST response and have had 2 scans or not? Is my first question. My second question is just, I guess, more around when you look at the TLS, like do you think there is ways to kind of mitigate that? I know venetoclax and other drugs have it. But is there did you use a prophylactic regimen or anything like that? I figured you wouldn't since you probably didn't know. Thanks. Thanks, Elythia. Dom, do you want to take that? Yes. Thanks, Kevin, and thank you, Elythia. So firstly, Resist QC'd. The it's Version 1.1, so they don't have to be confirmed. Naturally, a couple of the urothelial's in 5, 528 were. And it's just so early that we've not had to rescan yet. A lot of these are in the last month. And then the other question was I forget what the other question was. Sorry, please repeat it. It was just around the TLS. Did you use any prophylactic based regimen? Or do you have any plans to kind of do that going forward? Right. Yes. The TLS is fascinating. And as Doctor. McKean intimated earlier on, it doesn't fit the usual pattern, but then these are not usual drugs. The patient did have a large amount of tumor volume. It happened within the 1st week of dosing, which is typical. The patient had the full clinical syndrome. I think with respect to prophylaxis, we're warning physicians that the solid tumor physicians, so they're not used to seeing it. And it probably just requires an extra degree of vigilance. And I think that's in the 5, 528 program. Although bladder cancer patients can get quite significant amounts of disease, we've not seen the same bulky volume of disease yet so far. So it may be less apparent in this program. And can you say what dose you saw the TRS at in that study? I can. It was a first dose and it was 6.5. Meredith said that it was 8.5, but it was 6.5. Great. Thank you. Congrats again. Thank you. Our next question comes from Ted Tenthoff of Piper Sandler. Your question please. Great. Thank you very much and my congratulations too. Really, really impressed. I'm wondering and I appreciate what you were showing with respect to expansion cohort and again the comments too on combination, but what should we be anticipating as potential combinations here both for 5528 and 8, 009? And when do you think you might actually start evaluating different combinations? Thanks so much. Yes. I'll assume that with regard to the combinations. I mean, we think that the platforms intrinsically lend itself combination with some of the side effects. I don't think if I had a rash or a skin disease, I'd want to take a PD-one combo. And I think that's going to be very interesting. I think PD-1s also cause peripheral neuropathy and they can we're aware of neutropenia, but I think PD-one is the natural 1 that lends itself. We have had some patients with this kind of weird pyrexia of unknown margin that extensively investigated microbiology and they don't seem to have signs of infection. Nothing grows on cultures. And we're beginning to wonder if it's actually a feature of the response itself, kind of pyrexial tumor lysis syndrome without any of the other systemic anomalies. So I think that really does speak to a potential immune effect. And I think it speaks to the exciting prospect of combining with PD-one. I really want to establish what the monotherapy signal is first. And I think with 7.5 milligrams, that's just going to be way too intriguing. But I think the essence of your question is, do we want to get a move on with PD-one combo? I think absolutely we do. And I think there'll be many people who will begin to join us on that journey. And even beyond PD-one, too. So that'll be really exciting. And I was super intrigued by what you're seeing about the NK cell engagers. So excited to hear more about that in the future. Thanks so much, guys. Thank you. Our next question comes from Kelly Hsieh of Jefferies. Your line is open. Thank you for taking my questions. Congrats on very impressive progress. I have a question for 809. So I wonder all the PRs and all the partial response and the stable disease actually achieved the urea failure. So I wonder for other tumor types, could you actually disclose the h score? Are they actually showing low expression level 19 4? And also, do you notice there is a different homogeneous expression of the 19 4 across different tumor types? Thank you. Yes. We've not looked at the heterogeneity from a clinical point of view yet. We are screening for the Denectin target amongst those patients with the non bladder types. I think it's interesting that a couple of the bladder patients were below what the threshold was. And when you look at the emfortumab comparison, when they did their dose escalation, they actually had a cutoff. So they were enriching for efficacy during their escalation. We weren't, which I find really reassuring. But yes, I think we've not really reported on the other tumor types yet, but there's certainly interesting insights to be had in there for sure. Thank you. I also have a follow-up. Since you have shown response for both programs in urothelial cancer, I wonder with this data, how do you think about the strategy in UC in the future? Is it reasonable to propose that A009 to earlier line and the 5, 528 could be used following get to the point where we can be clear on that. Of course, we can't there is the possibility of using the 2 in combination as well as other therapies, and we also have our cheka molecules coming through. So I think it's very exciting what we can do in bladder. Think we've got lots of optionality and we look forward to providing an update in due course. Okay, great. Thank you. Thank you. Our next question comes from Jay Olson of Oppenheimer. Your line is open. Hey, thanks for this update and for taking the questions. For 8, 009, were any of the urothelial cancer patients previously treated with TADCEV? And have you seen any efficacy signals in other tumor types? And then I had a follow-up, if I could. Yes. Thank you, Kevin. The no, in the 5, 528 program, there was that 1 patient who previously had the pancreatitis on PADCEF. But currently, we the 8, 009 program excludes prior PADCEF, and we're making a protocol amendment because I'm really keen to see what happens in the face of patients who failed PADCEF. I think it will help us establish a better case with the regulatory authorities for going ahead of PADCEF or not having the patient to have had PADCEF come on our trials. And I think the data today is the beginning of that foundation for that kind of discussion. And yes, I think that's where we go forward. And no, we've not commented on what efficacy we're seeing in the other tumor types yet. That would be for another update. Okay, great. And then as we look across these 5, 528 and 8009 data, it seems like the efficacy signals support the BTC mechanism. But also it seems like the tumor target is also important. So we are wondering, if you have any plans to design new BTCs that would target more well established tumor antigens? I think that's a great question, Jay, and Nick partially addressed that. Of course, I think what we've shown today is that we can open up the full range of targets that are both addressable with ADC targets and also the many targets which are not addressable with ADC targets. So I think the totality of the data is really exciting from my this, to this to us indicates that the concept is valid. Clearly, we can get enough and a lot of payloads into tumors and get them to respond. And so there are really 2 axes we can take here. 1 is, as we've already mentioned, to identify multiple other bicycles to other high value tumor antigens, including those that don't work for ADCs, and we're actively doing that. And the second is to evaluate different payload classes with different mechanisms of action. And again, we're actively evaluating those. Great. Congrats on the results. Thanks for taking the questions. Thank you. Our next question comes from Gregg Svanovich of Goldman Sachs. Your line is open. Good afternoon. Thanks for taking my questions and very nice data that you presented. Questions just around comments around potential regression. And so just given the data that we've seen thus far with granted very early stage, when do you think that you'll perhaps be in a position to actually confirm that these responses are actually real and that there may not be progression? So I'm just trying to get a sense of, even though very encouraging, how to think about it as we see these responses evolve over time? And I guess this is, I guess, related to the fact that you've got disclaimers that these are not fully QC data. So that's kind of my first question. And then my second question also is related to some of the data cutoffs are in July. I think 1 neurothelial cancer patient was in response and that was as of a July cutoff. I'm just wondering if as of today, since we're in October, if you can say that these are still patients are still in response? Thanks. Thanks, Greg. I'll let Don chip in a second. The July cutoff was related to the triple meeting. And I think we'll give further updates into due course. What was the first question, sorry? The first question, yes. Yes, as we indicated in the presentation, we'll continue to we'll give further updates in 2022 as we as the Phase I trials progress. Dom, anything you wanted to add to that? Yes. I wouldn't have presented any patient today as a response if they'd subsequently progressed without telling you about it. So those are all still in Genesis and looking good. I mean, eventually, as with all the enfortumab and glenvetumorab data, these patients do show progression in this later stage. And so I don't think this will be anti gravitational forever. And think it's great to embrace the idea that the next question we have to ask about this platform is not if we have comparable response rates, but if we have comparable durability. But what really keeps me warm at night in bed is the idea that, that patient and the urothelial cancer carried on for a very long time. And if I could just have a quick follow-up just on some of the Grade 3, perhaps more idiosyncratic AEs that were noted hypertension, hypokalemia and asthenia for 8, 009. Anything to suggest that they're anything but idiosyncratic relative to any preclinical data that you might have seen? We have no preclinical data that suggests any of those. Okay. All right. Thank you and congrats, Yan. Thank you. Our next question comes from Swayampakula Ram of HCW. Your line is open. Thank you. Thank you. This is RK from H. C. Wainwright. A couple of quick questions from me. I'm just trying to understand a little bit more about the patients that did have Grade 5 events. The background information I'm looking for is what sort of dose levels were these patients at when they experience these events? And also in terms of their efferent expression, any commentary at all on that? And the 3rd piece within that information I'm seeking for is what sort of therapies were they at or like how severe of a patient they were when they experienced these events? And for the second question, what sort of certainly, we don't have as deep of a safety profile for 8009 as we have for 5, 528 at this point. Is there should we think that some of the safety profile could read through to 8009 or they both are independent? Obviously, they are 2 different drugs and so the event profile could be different. Yes. So the tumor lysis syndrome, that's kind of fatal in more than half of the occasions, and it was in this 1. It's very unfortunate. It is what it is, and we're not going to get much more data on that. The other patient was very unfortunate. They went home and they did not want to trouble their doctor. And you get this in a small percentage of patients. They kind of suffer in silence. They're kind of an older generation. That's what they do. And this patient went home for several days, came back in after the weekend, suffering a week of nausea and vomiting and was extremely dehydrated. And the physician felt she'd already gone to cross the Rubicon pathologically and they couldn't get her back. It was very unfortunate. And again, of course, that's still relevant to our platform. And I think those are both 5, 528. They were both ovarian cancer patients. 1 was the 6.5, the other was the 8.5, as we said before. And in fact, I think we will be very careful if we come to dose any high volume tumors with 8, 009. I think it's just a sign of very striking and rapid efficacy, but I think there's more to evolve. And with respect to the previous questions as well, the hypokalemia, the hyponatremia, they are littered throughout the history of all of the M and A payloads and they're kind of Grade 1, 2 events. I wouldn't want people to concentrate too much on those. I guess you do when you don't have the skin rash and the ocular events to go elsewhere. But I think if you look into the data around the other MMAE bearing costs, you see exactly the same profile. It really is and I'm not saying perfect, but it's not something that triples our physicians too much. Perfect. Thanks, Tom. I think we've got 3 more questions. Operator? Yes, sir. Our next question comes from Arlinda Lee of Canaccord. Your line is open. Hi, guys. Thanks for the update and thanks for taking my questions. I was curious on the FA2 ovarian patient. Has that patient been confirmed as a response? And then on renal safety, can you clarify if there's been any creatinine elevations or any indications otherwise of renal issues? Thank you. Tom? Yes. So the it was confirmed. That patient was confirmed. I mean every patient that has more than 1 cycle, the second cycle acts as an automatic confirmation. We don't automatically come in and confirm after a month because that's not RECIST 1.1, that's the old RECIST. And I mean, you still do it if you're in a registrational study, but we naturally get the confirmation when they come in 2 months after the first post baseline scanning that patient was confirmed, yes? And then I'm sorry, what was the other question? On the renal safety issues, can you confirm if there's any serum creatinine? And maybe can you talk about if the TLS patient went into renal failure? Thank you. The TLS patient did. That was part of the final sort of set of events. There was the patient who went home and got severely dehydrated. Of course, their creatinine was up. But across the rest of the program, we have not seen a pervasive or consistent signal. I think we would have caught it earlier if we had, but it was the absence of the signal that led us to wander into this. But no creatinine problems across the program with either thing. Accepting, of course, that some of the patients who got bladder cancer and their creatinines are not the best as it starts, but certainly no incremental changes in their creatinine levels across the program apart from those 2 patients. Thanks, Erlinda. Operator, next question please. Our next question comes from Tony Butler of ROTH Capital. Your line is open. Yes, thanks very much. 2 very brief questions. Number 1 is on 5, 528. The ovarian cancer patients that responded, 1 responded out to month 2 and then regressed. And I'm curious was could you argue that there was something unique about that patient that suggested they did not have longer duration? That's question 1. And then question 2 is really around, I guess, an observation. And I'm sorry, I recognize that these are early days for 8, 009 in dosing. But it's interesting to note that the patients that it seems that more patients responded for 5.0 than 2.5. We would expect that. I assume if you have some sort of dose response. But is there another reason why a patient might not respond, all of they did not have or had very little Nekton-four? Can you make any judgments, especially in the 5 milligram dose that in fact there was something unique about those patients that did not respond other than the simple dose? Thanks very much. So I'll say that the first 1 is the ovarian patient. I think if you look, there is monotherapy data published for all of the vedotin and you do see this occasional idiosyncratic. It goes the other way as well. Sometimes they grow. We've got 1 of these as well. They grow and then they shrink back later. Then there's the patient with stable disease that was 26% and then 20%. So I'm not too worried about that. With respect to the patients who have an early response and trying to divine those who may not have responded, there was nothing intrinsically that recommended to us that they might not respond. I think we will see patients natural. In fact, it's inherent in part of the design. We go for a bystander effect. Everyone says if you don't internalize, you're not going to get responses. Now we've got responses we don't internalize. We should expect to see a broader outreach of response that is not quite as tethered to the level of target in the next in the bladder particularly. It is typically quite heterogeneous. So I'm not worried about that. It is a nice position to be in a place where the number of responders is almost equal to and at 1 point it was equal to the number of non responders. And we have looked, but there's nothing intrinsically to suggest what why that might be yet. But we are looking hard. I'm great. Thank you, Antonio. I think we have 1 more question, operator. Our last question comes from Kalpip Patel of B. Riley. Your line is open. Yes. Hi. Congrats on the results and thanks for taking the question. Just a couple of quick ones from me. First for 8, 009. Can you comment how many patients remain on therapy to date for the urothelial cancer patients? And then second for 5, 528, how are you thinking about the age score criteria for the expansion cohorts? And will this score vary by the indication for ovarian in bladder? Yes. So all of the patients that we presented today responding are ongoing. I mean literally some of these were just like a couple of weeks ago. The burgeoning level of efficacy we had when we had a conversation said we can't just sit on this whilst we talk about the 5, 528 results. We have to share it. It's just too meaningful. I think the events that will be reviewed in retrospect around today, where it clearly was a meaningful set of data and it all deserve to be viewed in context. It is a platform. We look at them all together. I think absolutely the essence of your question around 55, 228, and IHC, we're still exploring that. I would really have loved to set it 1 side and said no, there is no correlation. But there's something very scientific about this platform. There's something intrinsically related to target expression and the efficacy of our molecules. That means we have to keep on doing that. And again, I see that as a nice burden to carry. Thanks, Dom. I think that concludes today's call. So on behalf of myself and colleagues at Bicycl, I'd like to thank you all for joining the call and for the interest and for the great questions. And we look forward to following up individually in due course. Many thanks again and have a good afternoon. Thank you. Bye bye. This concludes today's conference call. Thank you for participating. You may now disconnect.