Good afternoon, and welcome to the Bicycle Therapeutics call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your touchtone phone. To withdraw your question, please press the pound key. Please note this event is being recorded. You may listen to a webcast replay of this call by going to the Investors section of Bicycle's website. I would now like to turn the conference over to David Borah, Vice President, Capital Markets and Investor Relations.
Thank you, operator. Good afternoon, everyone, and thank you for joining today's call to discuss the BT5528 interim phase I data and preliminary findings from the BT8009 program presented at the AACR-NCI EORTC Virtual International Conference today. This meeting is also referred to as the EORTC-NCI-AACR Symposium. I'm David Borah, and joining me on today's call are Dr. Kevin Lee, Chief Executive Officer, Dr. Dominic Smethurst, Chief Medical Officer, Dr. Nicholas 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 three 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 two clinical programs fit within our broader strategy based on our bicyclic peptide platform. Lee will review our upcoming milestones across our programs and provide closing remarks. We will open the call up for Q&A, for which we will all be available. Next slide, please. 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 six 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. I also recognized 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 CRUK to sponsor and fund the phase I and phase II-A components of that molecule's progression. We also advanced BT5528 and BT8009 and expanded beyond our bicycle toxin conjugates into IO programs. We've continued to enter partnerships with the therapeutic leaders to realize value from the platform beyond oncology. 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 BT7480, our first IO molecule, has entered the clinic. That's one clinical start every year for four years in a row. Today, we are thrilled to unveil our initial proof of concept data for our two 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 can see that we can safely target EphrinA2, reach tolerable doses, and see clinical activity in two tumor types.
We've seen no coagulopathies pre-clinically or clinically, demonstrating clear differentiation compared to antibody-based approaches. Dom will also review BT8009 today, and again, we're 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 we'll show. It exceeds that of the approved antibody enfortumab vedotin based on phase I results, even though patients enrolled in 8009 were later-line, 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. As you can see, we have an exciting update for two programs today, and we believe further validation of the program.
We're encouraged by the clinical activity seen in the two programs across the two tumor types. With that, I'd like to turn it over to Dom. Dom?
Thank you, Kevin. I'm just going to go ahead and presume that you didn't see Meredith McKean's presentation this afternoon. 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 one platform really do help view the other asset. Starting with slide six, please. Ephrin-A2 is a well-known target and a member of the ephrin subfamily of receptor tyrosine kinases. It is intimately involved in the pathogenesis of cancer, and critically for our molecule, is also overexpressed in human cancers versus normal tissue. This, of course, is helpful in terms of concentrating 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 one that talks about their antibody-drug conjugate MEDI547, which did cause severe clotting patients in five out of six patients. That was felt to be related to the endovascular expression of the target Ephrin, which led the ADC to attack the endothelium in the blood vessels and thereby setting off a clotting cascade resulting in DIC. Next slide, please. The preclinical signals associated with MEDI547 suggested that this clotting would be a concern and would arise, and indeed, it was a brave thing that MedImmune 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.
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 three plus three standard dose escalation with a segue into a Bayesian logistic regression model-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 BLRM tend to have less excessive exposure to unnecessary or high doses. Indeed, I believe we saw that. We had relatively standard exclusion criteria, having noted that patients were excluded with prior neuropathy unless that had returned to a Grade 1 or better. We did not per se exclude patients with eye conditions, nor did we exclude diabetic patients.
We did, after the first few doses and feeling comfortable about the fact we were not seeing any hints of clotting problems at all, change the 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 a nivolumab combination or indeed any other PD-1 combination that comes to mind. Doing this, having achieved an effective and exemplified an effective therapeutic range. Next slide, please. Quickly onto the results. The trial we've presented today had 24 patients in it, and this data was true as of the cutoff of the 14th of 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 at zero, and 54% status at one. I have to say, though, what is particularly noticeable here is the number of prior therapies, which is seven as a median, ranging from 1-16. I'm sure you're all aware, but the number of prior therapies you have is a feature that predicts your likelihood of responding. For example, if you're an agent that might expect a 50% response rate in first-line setting, when you move to second line, you might see that response rate shrink to 35%-40%.
If you use the same agent in third line, you might actually see it shrink to kind of 25%, 30%, 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 in existence. Seven therapies is a lot. Of course, cancer therapies are evolving all the time. Every time a new one gets approved, which is great for the patients, it gets added to the queue. 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. As physicians always comment, any kind of response is truly impressive. Next slide, please.
This slide represents an overview of the key adverse events, notably the patients, specifically those adverse events that are Grade 3 or greater and which were related to product. You can see, there's not anything particularly standing out other than the two observations. We obviously had a reasonable degree of neutropenia that's recognized as a classic VEC and should probably be attributed to the payload. Zero bleeding disorders. Zero conjunctival disorders. I haven't even seen a Grade 2 with that particular issue. Zero cutaneous adverse events of Grade 3 or higher. We did have one patient who had a rash. Turned out it was a kind of Grade 1 on their ankle. Got better with some moisturizer after a couple of weeks. Zero neuropathy as well. We had a patient who came on with a Grade 1 neuropathy.
That was a legacy of their 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 with these kind of similar, but obviously not the same, agents. We also saw tumor lysis syndrome. That's a rare event, extremely rare, an eye-opening event, of course. In terms of efficacy and safety, it's worthwhile noting that in solid tumors, because we see it all the time with hematological malignancies, but in solid tumors particularly, this is a very severe and grave thing to have happen. That patient did unfortunately pass away as a result of the sequelae of that challenging situation.
We had one 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 six days. The actual dose escalation we got through is here, and it does require some cautious explanation on my behalf, because there are a couple of notable points. The 8.5 mg/m² every week stage early on in the escalation, the physicians got together after a group of patients had been dosed. Although none of those patients had a formal dose-limiting toxicity as described and as typical for a first-in-human phase I, the physicians did say, "Well, look, the number of patients here have had either a Grade 3 or Grade 4 neutropenia. It's not lasted long enough to hit the DLT, but there has been an additional degree of gastrointestinal discomfort, some electrolyte abnormalities.
Nothing in itself to write home about. You know what? I don't think it'd be wise to go any higher. We should explore around what's going on here. They kind of avoided the next scheduled dose escalation, and I think when we look back on what we saw at the 10 mg level with the Grade 3 fatigue and pneumonitis, I'm very glad to say that we didn't carry on what would've otherwise been quite unhelpful dosing levels. I think what I'm saying is they got it right. In between, we also then started exploring 8.5 mg every other week and 6.5 mg every week. Broadly speaking, I can tell you I actually just came out of the Safety Review Committee last week, we're very much looking forward to and excited about the next dose we've chosen to explore, which is 6.5 mg every other week.
There may still be room to 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. More of that to come in future conversations and calls. Next slide, please. Onto efficacy. These plots are divided up to highlight them. On the top right, you have the spider plot showing cycle by cycle, the RECIST measurements. They're all normalized at baseline, and what you see is shrinkage if it's going down and growth if it's going up to sort of +20%. Within that, you can see we had one formal partial response sitting at 30% threshold or indeed greater than 30%. That was amongst eight patients who were dosed with ovarian cancer, who had ovarian cancer.
Indeed, four out of five patients with EphA2 staining, that's what I'm hoping you're seeing with the dark purple or turquoise line, all had some degree of shrinkage. It was one of those that was the partial response. Even more striking, though, perhaps, and to some extent not surprising, was the two urothelial cancer patients, both of whom had responses after a couple of months after the first couple of cycles, and who have had continuing deepening of those responses, one of them beyond the 60% shrinkage level. Next slide, please. This slide shows H-score, which is a composite score for the degree and intensity of an individual cell staining, and then added up amongst that, the percentage of tumor cells when you look down a histology slide that are positive.
What we have going along the horizontal axis is increasing intensity for the staining of our target on urothelial and cancer patients. This is kind of breaking news here, because it also shows that correlated with the % change according to RECIST. As Dr. McKean commented earlier, there really does appear to be a sort of intriguing correlation between the intensity of target staining and the degree of shrinkage. I would ask you to consider carrying forward that observation whilst thinking about the intensity and depth of staining you get with, say, example Nectin. The next slide, please. 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.
We're putting in place this adaptive trial design that will enroll these patients. We're also keen to explore further signals in non-small cell lung cancer, head and neck, gastroesophageal cancer, and triple negative breast cancer as well. 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. In conclusion, we've communicated this afternoon Bicycle's first-ever clinical data of a Toxin Conjugate, the BT5528. There clearly is no evidence of clotting abnormalities. I think that's something very interesting regarding this platform's ability to attack targets that are not otherwise addressable by other technologies. The doses were generally well-tolerated, with the obvious caveats that I've shared with you. I actually just spoke with the investigators this afternoon, and they said, "Yeah, no, this is good.
It is tolerable," and we're still learning, of course. To have all of this in the context of anti-tumor activity in more than one tumor type is, well, it's genuinely arresting. The additional points I've noticed, we really haven't seen any neuropathy. There haven't been any eye problems. No skin toxicity other than that Grade 1 ankle rash. I think, again, I make no apologies for pointing this out, and I would ask you to hold on to those observations whilst we look at BT8009. I think these, yeah, these general platform observations, and that's been part of the fun and the fascination, has been bootstrapping together this BT5528 data, and what's going on with these two molecules and coming out of the same platform. They both have thiolate linkers. They have the same MMAE payload.
We can look at other programs with thiolate linkers and MMAE payloads. Finally, this sort of fascinating correlation with the EphA2 expression. We're getting ready to expand, and the investigators are really very excited and keen to do that. 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. 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 with the intent of talking about BT5528. Again, it is preliminary emerging data, but we've kind of looked at this data, which you can see is very recent.
We said, "Look, the question is really not if we should share this data," but really it was important for us, and I would argue the patients and the investigator community as well, to get this data shared as soon as possible, as there really are some very exciting insights here building on what I've just shared with you about 5528. Before I dive into the data, slide 16, please. I would just share with you some important insights about the target. Nectin-4 is a cell adhesion molecule, also known as PVRL4, polio virus-like receptor 4. It shares a consistent structure with the other 3 Nectins in the family, 3 extracellular immune globulin domains, a 1 transmembrane helix, and an intracellular domain. Like EphA2, it is overexpressed in cancers, and that overexpression is correlated with tumor progression.
Finally, as most of you know, it is the target of the FDA-approved PADCEV and enfortumab vedotin. Next slide, please. Again, similar trial design as per the previous one, 2.5 mg 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 model. We've also recently started the 7.5 mg dose as well. I think it's important to emphasize we are still escalating. Of course, that's one 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. 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. 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 recruitment has been really excellent and has caught up, if not surpassed, what has been going on in the BT5528. We've got 26 patients, as you can see here, a similar mix of male and female, slightly more female than average. Yeah, I think the next slide, we'll look at urothelial cancer perhaps in a bit more detail. Yeah, this is a quick breakdown of the number of patients who are on BT8009 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. I think it's worth commenting that the first half of the trial was really in the U.S.A., 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. Onto slide 20, please. This is more specifically those 11 patients who had urothelial cancer. Again, nothing too striking here, other than that half of our patients, as it says, that the median number of therapies there is 2, but actually all of them had 2 or more therapies. There were no patients that had 1 therapy.
I think that's important, because whether we like it or not, the main comparator that we're put up against at a similar stage presentation at ASCO in 2016, they had 40% of their patients who'd had one prior therapy. Next slide, please. This is a quick overview of the adverse events for all these patients with all genotypes, because, of course, the adverse events are not totally related to the tumor type, but they do inform us what's going on with the drug overall. Again, I make no apologies for emphasizing this is an ongoing phase I trial, and at this stage, we're not preemptively treating any issue like some of these events. 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 BT5528, we see this with BT5528 in our preclinical models. There's essentially idiosyncratic presentation of hypertension, and some electrolyte abnormalities, and of course, some fatigue. I don't really think there's anything too standoutish here. They all deserve to be considered. I think it's important to say, and I think you can see now the similarities and overlapping of BT5528 and BT8009. I kind of view both of these in three dimension, and you sort of view it stereoscopically with one eye on BT5528 and one eye on BT8009, and I think that brings the platform into a much more useful focus.
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. This is a summary of what is really quite mind-bending efficacy. We've seen in 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. As you can see here, they mainly go down. I think, yeah, 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.
I'd be very surprised if these reductions don't further deepen, like we saw with the urothelial cancer patients on 5528. We've got 1 response at the 2.5-milligram dose out of 4 patients. That was a 37% reduction. 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. 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, that doesn't quite breach the 30% threshold, showed an initial 26% reduction and then a subsequent 20% reduction. Even the stable diseases are arguably less stable and more response-like than many stable diseases that we typically see in a first-in-human trial.
I would just remark that it's evident for these patients that have not progressed by first scan, even the patients that are not showing shrinkage, are contributing to a 75% disease control rate at the 2.5 mg dose and a 71% disease control rate at the 5 mg dose. Next slide, please. It's very much Bicycle's intention to develop these special, highly effective peptides in their own right, in their own way. 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 enfortumab, we would only ever become almost as good as enfortumab. Actually, we'd 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 and discovering a new platform of medicines, a new way forward that really excites them. Just copying and pasting what other people do is not what we're about. At the same time, we have to reflect on the fact that if we're not as good as enfortumab, there's probably an extent to which we're not going to get very far in developing these new medicines. We are as good, and possibly even 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. They're done in the same centers.
They're done using or rather, similar centers, experienced phase I-ologists. Yeah, I think it's striking what's going on here. 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. We are comparing at the 2.5 milligram level on the left there with our drug, we shared in the last slide, the 25% response rate and the 5 mg level just to the right of that with 8009, we're seeing a 43% response rate. 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%.
In comparing those two doses, if you take the low dose, of course, 25% response at 2.5 and enfortumab for the 1 mg below, we think that's broadly speaking, comparable there at a 23% response rate. At the all cohorts analysis and looking at 33 patients, they 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 eye 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 I, it was a Grade 2 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 one patient who's been on for 268 days. A patient who was on for almost a year, 5528. It just feels to me like while we might see some kind of regression to the mean or more peripheral neuropathies probably will turn up because it's kind of a side effect of the efficacy. Just feel 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. Next slide, please. I think just to bottom line 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. I would have given 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, who have 89% and 52% shrinkage. Patient C is almost an outlier in that respect in the cohort because their tumor shrinkage is still fantastic at 48%. It appears like the weakling in the litter amongst the 5-milligram patients. I just want to say that patient was scanned three and a half weeks in, and after only having had one dose. They were scanned whilst looking for an infection. They happened to come across a disappearing tumor.
They actually couldn't find an infection. 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 the tumor. If the patient had gone on to have full two cycles of therapy two months in, I suspect that shrinkage would have been even greater, perhaps somewhere between the shrinkage we see with patient B and patient D. Of course, still early, but nevertheless, quite robust and undeniable data points that we're looking at here. 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% - 43%.
It's the depth, the degree of response as well, going up from the 2.5 to the five, which really gives me pause to reflect. Less shrinkage with the smaller dose. Huge, awesome shrinkage with the 5 mg dose and now we've actually started to dose patients on the 7.5 mg level, and it's going well. Slide 25, please, Dave. I was discussing this with investigators a few days ago. This patient had a 89% shrinkage. These are two not inconsiderable lesions that are actually requiring morphine. The patient's off morphine now. This is an 89% response, initially reported as a complete response, but you can see there it's not actually a complete response. There's a residual, some sort of degree of echo. There's a ghost-like image of scarring, residual tissue, who knows? And again, the other one's almost completely disappeared.
It's more obliterated by the radiologist's calipers there, the little red line. It's just so rapid, and it's genuinely amazing. Again, this is the first scan. We're looking forward to next month to getting the next scan, but this is just how fresh this data is. I'm sure you can begin to appreciate why Liz was so excited and keen to share it with you. Maybe it will be a complete response. It doesn't matter to some extent, it's still a resounding response. I think if it isn't this one, it will be some patient in the future. Slide 26, please. Before I go through the summary, the only thing I'd say is I was talking with one of our lead investigators the other day, and he quite rightly said, "Look, Dom, 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.
Yes.
In conclusion, it's why we're really hopeful and, yeah, we haven't even talked about the doses that the urothelial patients got on the BT5528 yet. I just wanted to say they got 6.5 mg and 8.5 mg. Yeah, we can jokingly say it's 100% response rate. The patients are not joking, they're very grateful. It's two out of two. It's a different molecule, but it is in the same platform. I think given we're seeing similar tolerability levels dose by dose overall, excepting the odd pharmacokinetic idiosyncrasy here and there, I think it suggests that we've got further to go here, and that that additional dose won't be saturated. It will be a meaningfully additional dose. The dose ranges we've talked about today have been very comfortably tolerated, and most of the side effects are 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, looking forward to what comes next on the Bicycle story. Slide 27. This still is clearly just the beginning for BT8009 and BT5528, the engineering and architects of those molecules that I've been sharing with you today. I've been still working hard at it's my pleasure to hand over to Nicholas Keen, our Chief Scientific Officer, to talk about what is going to be the next act for 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. 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 third-generation molecules, where we're looking at alternate payloads with alternate mechanisms of action. 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, BT7480, is heading into patients later this year, with BT7455 following on behind that. We're also looking further beyond that in immune oncology. We're generating binding Bicycles to many receptors in the immune system. Our second foray in this space are multiple receptors expressed on NK cells. 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, that will likely enable, for example, sequencing in a more facile way than for longer-lived molecules. We're actively investigating combinations both inside and outside of our portfolio. 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've provided an update on our clinical progress for BT5528 and BT8009. We are encouraged by the clinical activity we've seen so far and are excited to be advancing these programs. As Nick just outlined, we see significant opportunities beyond just BT5528 and BT8009. 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 BT5528 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 first patient in the expansion cohorts in 2022. Second, the dose escalation for BT8009 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. Third, BT7480, which is our Nectin-4/CD137 Bicycle TICA, 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 third-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 you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. We ask that you please limit yourself to one question and one follow-up. Please stand by while we compile the Q&A roster. 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 interesting on both programs. Maybe two from me, so I'll be respectful. Just can you clarify what not fully QC'd means? Does it mean that the patients have RECIST response and have had these scans or not? Is my first question. My second question is just, I guess more around when you look at the TLS, do you think there's ways to mitigate that? I know venetoclax and other drugs have it, but did you use a prophylactic regimen or anything like that? I figured you wouldn't since you probably didn't know. Thanks.
Thanks, Alethia.
Yeah.
Dom, do you want to take that?
Yeah. Thanks, Kevin. Thank you, Alethia. Firstly, RECIST, QC'd. It's version 1.1, they don't have to be confirmed. Actually, a couple of the urothelials in 5528 were, it's just so early that we've not had a chance to rescan yet. A lot of these are in the last month. The other question was I forget what the other question was, please repeat it.
It was just around the TLS. Did you use any prophylactic-based regimen, or do you have any plans to do that going forward?
Oh, right. Yeah. No, the TLS is fascinating. As Meredith McKean intimated earlier on, it doesn't fit the usual pattern. These are not usual drugs. The patient did have a large amount of tumor volume. It happened within the first week of dosing, which is typical. The patient had the full clinical syndrome. I think with respect to prophylaxis, we're warning physicians, the solid tumor physicians. They're not used to seeing it. It probably just requires an extra degree of vigilance, and I think that's it. That's in the BT5528 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. It may be less apparent in this program.
Can you say what dose you saw the TLS at in that study?
I can. It was a first dose, and it was 6.5. Meredith said she thought 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 impressed. I'm wondering, and I appreciate what you were showing with respect to the expansion cohort and, again, the comments too on combination. What should we be anticipating as potential combinations here, both for 5528 and 8009? When do you think you might actually start evaluating different combinations? Thanks so much.
Yeah. I'll assume that with regard to the combinations, we think that the platform's intrinsically lends itself to 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-1 combo. I think that's going to be very interesting. I think PD-1s also cause peripheral neuropathy, they can, we're aware, the neutropenia, I think PD-1 is the natural one that lends itself. We have had some patients with this kind of weird pyrexia of unknown origin. They've extensively investigated microbiology, they don't seem to have signs of infection. Nothing grows on cultures. We're beginning to wonder if it's actually a feature of the response itself, a kind of pyrexia or tumor lysis syndrome without any of the other systemic anomalies.
I think that really does speak to a potential immune effect. I think it speaks to the exciting prospect of combining with PD-1. I really want to establish what the monotherapy signal is first. I think with 7.5 milligrams, that's just going to be way too intriguing. I think the essence of your question is, do we want to get a move on with PD-1 combo? I think absolutely we do. I think there'll be many people who will be keen to join us on that journey.
Yep. Great. Even beyond PD-1, too. That'll be really exciting. I was super intrigued by what you were saying about the NK cell engager. Excited to hear more about that in the future. Thanks so much, guys.
Thank you. Our next question comes from Kelly Shi of Jefferies.
Thank you for taking my questions. Congrats on very impressive progress. I have a question for BT8009. I wonder, all the PRs and all the partial response and the stable disease actually achieved the urothelia. I wonder for other tumor types, could you actually disclose the H-score? Are they actually showing a low expression level, Nectin-4? Also, do you notice there's a different homogenous expression of the Nectin-4 across different tumor types? Thank you.
Yeah, we've not looked at the heterogeneity from a clinical point of view yet. We are screening for the Nectin 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. When you look at the enfortumab comparison, when they did their dose escalation, they actually had a cutoff. They were enriching for efficacy during their escalation, and we weren't, which I find really reassuring. Yeah, 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 a strategy you see in the future? Is it reasonable to propose that AZ009 move to earlier line, and 5528 could be used following Nectin-4 refractory patients?
I think it's a bit too early to address that, Kelly. I think we've got a lot more work to do before we could get to the point where we can be clear on that. Of course, there is the possibility of using the two in combination, as well as other therapies, and we also have our TICA molecules coming through. I think it's very exciting what we can do in bladder. I 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.
Oh, hey. Thanks for this update and for taking the questions. For 8009, were any of the urothelial cancer patients previously treated with PADCEV? Have you seen any efficacy signals in other tumor types? I had a follow-up, if I could.
Yeah.
Do you want to take that one?
Yeah. Thank you, Kevin. No, in the BT5528 program, there was that one patient who previously had the pancreatitis on PADCEV, currently, the BT8009 program excludes prior PADCEV, we're making a protocol amendment because I'm really keen to see what happens in the face of patients who've failed PADCEV. I think it will help us establish a better case with the regulatory authorities for going ahead of PADCEV or not having the patient to have had PADCEV to come on our trials. I think the data today is the beginning of that foundation for that kind of discussion. Yeah, I think that's where we go forward. 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. Thank you. As we look across these BT5528 and BT8009 data, it seems like the efficacy signals support the BTC mechanism. Also, it seems like the tumor target is also important. We're 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. 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. I think the totality of the data is really exciting from my perspective. I don't know, Nick, did you have anything to add?
As I mentioned briefly earlier on, 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. There are really two axes we can take here. One is, as we've already mentioned, to identify multiple other bicycles to other high-value tumor engines, including those that don't work for ADCs, and we're actively doing that. The second is to evaluate different payload classes with different mechanisms of action. Again, we're actively evaluating those.
Great. Congrats on the results. Thanks for taking the question.
Thank you. Our next question comes from Graig Suvannavejh of Goldman Sachs. Your line is open.
Great. Good afternoon. Thanks for taking my questions and very nice data that you presented. Questions just around comments around potential regression. 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? 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. I guess this is related to the fact that you've got disclaimers that these are not fully QC'd data. That's my first question. My second question, also, is related to some of the data cutoffs are in July, I think, one urothelial 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 patients are still in response? Thanks.
Thanks, Graig. I'll let Dom chip in a second. I think the July cutoff was related to the Triple Meeting. I think we'll give further updates in due course. What was the first question? Sorry.
The first was the-
Oh, the-
Confirmation.
Yeah.
Yeah, regression.
As we indicated in the presentation, we'll give further updates in 2022 as the phase I trials progress. Dom, anything you wanted to add to that?
I wouldn't have presented any patient today as a response if they'd subsequently progressed without telling you about it. Those are all still in genesis and looking good. Eventually, as with all the enfortumab and glembatumumab data, these patients do show progression in this later stage. I don't think this will be anti-gravitational forever, and I 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. What really keeps me warm at night in bed is the idea that that patient with the urothelial cancer carried on for a very long time.
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 8009. Anything to suggest that they are 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 again.
Thank you. Our next question comes from Swayampakula Ramakanth of HCW. Your line is open.
Thank you. Thank you. This is R.K. from H.C. Wainwright, right. Couple of quick questions from me. 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 experienced these events? Also, in terms of their Nectin expression, any commentary at all on that? The third piece within that information I'm seeking for is what sort of therapies were they at, or how severe of a patient they were when they experienced these events? For the second question, certainly, we don't have as deep of a safety profile for 8009 as we have for 5528 at this point. Should we think that some of the safety profile could read through to 8009? They both are independent?
Obviously, they're two different drugs, and so the event profile could be different.
Yes. The tumor lysis syndrome, that's kind of fatal in more than half of occasions, and it was in this one. 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. 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. This patient went home for several days, came back in after the weekend, was suffering a week of nausea and vomiting and was extremely dehydrated. The physician felt she'd already crossed the Rubicon pathologically, and they couldn't get her back. It was very unfortunate. Again, of course, that's still relevant to our platform. I think those are both 5528.
They were both ovarian cancer patients. One was the 6.5, the other was the 8.5, as we said before. In fact, I think we will be very careful if we come to dose any high volume tumors with 8009. I think it's just a sign of very striking rapid efficacy. I think there's more to evolve. With respect to the previous questions as well, the hypokalemia, the hyponatremia, they are littered throughout the history of all of the MMAE 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. I think if you look into the data around the other MMAE bearing conjugates, you see exactly the same profile.
I'm not saying perfect, but it's not something that troubles our physicians too much.
Perfect. Thanks, Dom. I think we got three 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 question. I was curious on the EphA2 ovarian patient. Has that patient been confirmed as a response? On renal safety, can you clarify if there's been any creatinine elevations or any indications otherwise of renal issues? Thank you.
Dom.
Yes, it was confirmed. That patient was confirmed. Every patient that has more than one 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. You still do it if you're in a registrational study, but we naturally get the confirmation when they come in two months after their first post-baseline scanning. That patient was confirmed, yeah. 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. 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 a signal that led us to wander into this. No creatinine problems across the program with either of them. Accepting, of course, that some of the patients have 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 two patients.
Thanks, Arlinda. Operator, next question, please.
Our next question comes from Tony Butler of Roth Capital. Your line is open.
Yes, thanks very much. Two very brief questions. Number one is on 5528. The ovarian cancer patients that responded, one responded out to month two and then regressed. I'm curious, could you argue that there was something unique about that patient that suggested they did not have longer duration? That's question one. Question two is really around, I guess, an observation. I'm sorry. I recognize that these are early days for 8009 in dosing, it's interesting to note that it seems that more patients responded for 5.0 than 2.5. You would expect that, I assume, if you have some sort of dose response. Is there another reason why a patient might not respond, ala they did not have or had very little Nectin-4?
Can you make any judgments, especially in a 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.
I'll take that first one with the ovarian patient. I think if you look, there's monotherapy data published for all of the vedotins, and you do see this occasional idiosyncratic. It goes the other way as well. Sometimes they grow. We've got one 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%. 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 with low scores and negative scores that don't respond. I think that's just 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 with Nectin in bladder, particularly where it is typically quite heterogeneous. 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 one point it was equal to, the number of non-responders. We have looked. There's nothing intrinsically to suggest why that might be yet. We are looking hard.
I'm great. Thank you.
Thanks, Tony. I think we have one more question, operator.
Our last question comes from Kalpit Patel of B. Riley. Your line is open.
Yes, hi. Congrats on the results and thanks for taking the question. Just a couple quick ones from me. First for BT8009, can you comment how many patients remain on therapy to date for the urothelial cancer patients? Second for BT5528, how are you thinking about the H-score criteria for the expansion cohorts, and will this score vary by the indication for ovarian and bladder?
Yes. All of the patients that we presented today responding are ongoing. 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 BT5528 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 deserves to be viewed in context. It is a platform. We look at them all together. I think absolutely the essence of your question around BT5528 and IHC, we're still exploring that. I would really have loved to have set it one 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 that we have to keep on doing that. Again, I see that as a nice burden to carry.
Thanks, Dom. I think that concludes today's call. On behalf of myself and my colleagues at Bicycle, 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 good afternoon. Thank you. Bye-bye.
This concludes today's conference call. Thank you for participating. You may now disconnect.