Good morning, 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 star then zero on your telephone keypad. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, please press star then two. 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 Dave Borah, Vice President, Capital Markets and Investor Relations. Please go ahead.
Thank you, operator. Good morning, everyone. Thank you for joining today's call to discuss the BT5528 end of phase I results. I'm Dave Borah, and joining me on today's call are Dr. Kevin Lee, Chief Executive Officer, Dr. Dominic Smethurst, Chief Medical Officer, Dr. Nick Keen, Chief Scientific Officer, and Lee Kalowski, Chief Financial Officer. Before we get to the presentation, I wanna 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 morning. I'm excited that we are sharing the top-line results of our BT5528 escalation study with you today. Turning to slide three to review today's agenda. I will give a brief history of EphA2 drug development as well as an overview of BT5528. Then Dom will follow by discussing our clinical progress with BT5528. Initially, the safety and tolerability profile, followed by the efficacy data. We will then open the call up for Q&A, for which we'll all be available. As mentioned, I do want to highlight that this will be mostly a top-line data update. We are reserving a fair bit of PK efficacy and safety data for publication in 2023. Next slide, please. Let me start with the takeaway from today's presentation.
We are very encouraged by what we've seen thus far in the BT5528 phase I dose escalation portion of the trial. We believe the data that we will review today demonstrates further validation of the platform, advancing a high-value cancer target that to date has been intractable to a variety of other antibody-based approaches. We're extremely encouraged by the tolerability, particularly at the recommended phase II dose, which we believe also has the potential to be differentiated from other ovarian and urothelial products in development. BT5528 clearly exhibits tumor penetration ability, especially in ovarian and urothelial cancer patients, and the expansion portion of the trial is currently underway, where we will continue to dose patients at 6.5 mg/m² every other week. Next slide, please.
Now for background, I'll give a brief historical overview of EphA2 drug development, as well as a quick synopsis of our bicycle toxin conjugate, BT5528. Next slide, please. EphA2 is a member of the Ephrin subfamily of receptor tyrosine kinases. Physiologically, this target has roles in the regulation of cell migration, adhesion, proliferation, and differentiation. As the immunohistochemistry figures on the right depict, it is also highly expressed in many solid tumors. All the ones listed on the left are included in both portions of our phase I trial. Next slide, please. As mentioned on the previous slide, several prior attempts by other companies to effectively and safely target EphA2 have failed. In the case of MEDI-547, an antibody-drug conjugate, five severe cases of coagulopathy out of the first six patients immediately derailed the start of this phase I trial.
In Daiichi's case, the EphA2 targeting antibody failed to elicit sufficient responses to justify further development, potentially at least in part, due to failure of the antibody to access the tumor. Finally, in Merrimack's instance, their antibody-directed nanotherapeutics resulted in an unacceptably high number of neuropathy events even after the dosing was lengthened from weekly to monthly. Next slide, please. What's different about BT5528 from all these other drugs? Quite a lot, actually. First, our approach is not an antibody approach. BT5528 is a bicycle toxin conjugate or BTC comprised of an EphA2-targeted bicyclic peptide, a Val-Cit linker, and MMAE. It's at least 40 x smaller than ADCs, and the smaller size bestows a greater ability to penetrate tumors.
We have shown in preclinical models that the toxin is released and retained in tumor cells, leading to tumor cell death and bystander killing. Finally, it has a differentiated PK profile from ADCs with short systemic half-life and elimination via the kidneys, thereby bypassing liver metabolism. This is altogether a novel approach and again, one that appears to be working in ovarian and urothelial cancer patients. Now I'd like to hand over the call to our CMO, Dom Smethurst. Dom.
Thank you, Kevin. Yeah, I'm really proud to share the next section with you today. As Kevin mentioned, I feel it's important to remind you that this is a top-line presentation. We believe this presentation should address many of your questions, and we expect to publish the full data set in a publication next year. Next slide, please. Now onto the dose escalation slide. This was a 3+3 trial design, but you can see from the graphic that we obviously over-enrolled some of the higher dose cohorts with a total of 15 patients at our go-forward dose of 6.5 mg/m² every other week.
With the FDA's Project Optimus front of mind, we dosed as high as 10 mg/m² every other week, but ultimately settled on 6.5 mg/m² every other week, which has been a relatively safe, efficacious dose. It's actually been really helpful and pleasing to see. Next slide, please. Slide 11 is a snapshot of demographic profile of the patients at baseline. When we gave our last update of BT5528 data, we had 24 patients on trial, and today we're presenting 45 in total. Overall, two-thirds of the patients were female, but tilted 60% toward males in the 6.5 mg/m² expanded cohort.
What's really noticeable, this is of course always the case with phase I, but I don't think it can be understated, is how heavily pre-treated this patient population was. Median number of prior therapies was seven and six for the overall and 6.5 mg/m² cohorts respectively. We had seven for the overall and six for the 6.5 mg/m² dose. The median lines of therapy were four for both. Any way you look at this was a salvage population that truly had exhausted all other avenues. One last thing to point out here that is the data cutoff is fairly recent, August 1st. Next slide, please. Here's an overview of the 45 patients from trial by tumor type.
Just a reminder, this was an all-comers trial, and we definitely have discovered that our investigators were making an effort to recruit ovarian and urothelial patients. Many of those other tumor types still continue to inform us about both the efficacy and safety, and clearly there is more to be understood here. Next slide, please. In Slide 13, this table presents treatment-related adverse events or TRAEs. All TRAEs with 15% or higher incidence across the entire 45 patients on study. This is a slide full of amazing statistics, especially when you consider some of the safety issues that have plagued attempts by other companies targeting EphA2. While our patients experienced mostly low-grade events, there were very few numbers of grade III and higher treatment-related adverse events. This is especially true of the 6.5 mg/m² cohort given every 14 days.
Please let me discuss the neutropenia for a minute because this is an area of interest for some of you and indeed for us. While there was 22% incidence of grade III neutrophil count decreased overall, there were none in the go-forward dose. Neuropathy is also an adverse event worth pointing out. Only seven cases overall, and they were all low-grade. 6.5 mg/m², there were two low-grade cases and none grade III or higher. Next slide, please. Slide 14 continues the theme from the last slide. This slide displays three other treatment-related adverse events of interest. The two cases of skin rash were all low-grade maculopapular. To be clear, we cast a wide net when we scoured the clinical data here for more skin rash treatment-related adverse events. Our definition of skin rash followed clinical norms.
We just didn't find anything outside of the two cases mentioned. Similarly, we looked far and wide for hemorrhage cases because of the history. This is a relevant area given MEDI-547's disseminated intravascular coagulation. We found no cases of treatment-related hemorrhage. Of course, there were no cases of coagulopathy. Lastly, eye disorders followed a similar pattern as the other two treatment-related adverse events. We searched broadly for all events, but only found two patients who collectively shared three low-grade adverse events. I really hope you agree that this adverse event profile for the go-forward dose is very compelling, particularly when you put it in the context of the previous failures of targeted EphA2 and the broader toxicity profile of toxin conjugates in general.
It's a testament to the increasingly differentiated properties of BT5528, but also to the growing understanding of our physicians and how they've gained abilities in using this new class of molecules in the optimal way. It is a novel therapy after all. Next slide, please. On slide 15, we're going to shift gears and discuss efficacy in the EphA2-expressing patients. This colorful waterfall plot has bars for each of our 35 responsive evaluable patients, and the asterisks denote EphA2-expressing patients. You can see first that there are many stable disease patients. In such a sick patient population, this is, as my investigators reassure me as well, very encouraging. You'll also notice that many of the EphA2 expressers on the left are pancreatic patients. This is sadly a very challenging patient population for efficacy, and so far our trial is no different.
We will focus on ovarian and urothelial expressers on the next slides. Next slide, please. On slide 16, I'm just reminding myself, back in October, we showed a graphic that depicted early signs of a relationship between EphA2 expression and tumor shrinkage. This waterfall plot of urothelial and ovarian patients is further evidence of what is seemingly quite a high correlation. As you can see in this exhibit, every single patient with meaningful tumor shrinkage was EphA2 -positive. I'd also like to draw your attention to the definition of EphA2 -positive. Here, any patient who had 1% or greater of cells showing any degree of positivity for EphA2 among all valid and viable tumor cells is marked with an asterisk. We will continue to explore and elucidate the relationship between EphA2 expression and response in the expansion cohorts.
The emergent data begins to support the notion that possibly a large number of patients that had previously been considered may benefit from this therapy based on the cutoff that I've just described. Some of the responders elicited quite robust responses that impressed our investigators. Obviously, the one on the far right is a complete responder, not just in their target lesions, everywhere. More on this patient in a second. Next slide, please. On slide 17, we see a table. This shows best overall response in EphA2 positive response evaluable ovarian and urothelial patients. Just pointing out some of the statistics here, the ovarian EphA2 response rate is two out of nine or 22%, and the ovarian disease control rate is six out of nine or 67%. These are all actually very respectable numbers, especially when you consider that this is a late-line setting.
Our ovarian patients had six prior lines of therapy as a median. They were more heavily pretreated than the overall population in the trial. In urothelial, the n= 3 is obviously modest, but our overall response rate of two out of three, or 67% if you will, is no doubt encouraging for the platform as well as for the individual patients. To answer a question that will surely be asked, our overall response rate amongst EphA2 responsive evaluable ovarian patients at the go-forward dose, 6.5 mg/m² every other week, was one out of two or 50%. What's worth mentioning perhaps is what's depicted in the footnotes.
Three of the other four responders started at a higher dose and were reduced to the 6.5 mg/m² every other week, where many of their responses either developed first time or deepened. Next slide, please. Slide 18 shows before and after images of our ovarian cancer complete responder. This patient had previously been on carboplatin, Taxol and Avastin for 17 weeks, followed by maintenance therapy of letrozole for 92 weeks. When she entered our study, the investigator said they would be pleased if they had simply seen a few months of stable disease in this relatively young patient who is still in the workplace. Patient started our trial in Cohort 5 at 8.5 mg/m² every other week, where she showed tumor shrinkage on her very first scans.
Our investigator was really impressed, not only by the fact that she wasn't expecting anything out of this patient, but also the relative immediacy of the response. This joy turned into frank shock, and they said to me that it nearly fell out of their chair, and the partial response was dialed up by the radiologist as a complete response. This coincided with a decision to lower the dose to 6.5 mg/m² after several grade I-II adverse events, mostly GI-related and fatigue. These were increasingly taking a toll in the workplace. This patient is still responding after nearly a year and a half on BT5528. Next slide, please. On slide 19, we have an example of another responder, this time a urothelial patient. This woman came onto our trial after several prior lines.
One of the prior lines was enfortumab vedotin or PADCEV, which she did initially respond to, but ultimately could not tolerate and withdrew following a case of pancreatitis. She entered our study in Cohort 5 at the 8.5 mg/m² every other week dose level. After first dose, she had a manageable decrease in neutrophils, which led our investigator to dose reduce to 6.5 mg/m² every other week. Thereafter, the patient successfully tolerated every single dose, so they only had one dose at the 8.5 mg level. This example, and others like it, reinforced our decision to use 6.5 mg/m² as a recommended phase II dose.
Her response only deepened at this dose, and she remained on study through to the end of cycle six and into cycle seven, where she unfortunately had to withdraw due to CNS progression. That was brain metastases. Though the ongoing lesions otherwise outside of the CNS were still decreasing. One important item I'd like to mention is an analysis we did with the consistency and levels of dosing at each cohort. 6.5 mg/m² every other week cohort exhibited remarkable consistency of dosing. Of the 15 patients in that cohort, only one had a dose interruption, leading to a collective relative dose intensity of 99% for that cohort. Next slide, please. This is a trial designed for the expansion portion of our phase I/II trial.
We are enrolling 14 patients in each basket of ovarian and urothelial, and then seven apiece in non-small cell lung cancer, head and neck, gastroesophageal, and triple-negative breast cancer. We are pleased with the pace of recruitment, and we intend to give an update next year. Next slide, please. Slide 21 is the final slide, and then we'll be happy to take questions. Just to recap and emphasize some of the things that have been said earlier on in this call, we are really encouraged by not only the signs of anti-tumor activity in ovarian and urothelial cancer, but also the really quite remarkable safety profile of a drug of this kind of nature with the toxin attached. Dosing is underway in the phase II expansion, and we are very pleased with the progress therein.
I will add that it has been very moving to witness, and I indeed want to pay tribute to the Bicycle team, the sites, the patients and the investigators with regards and thanks for their enthusiasm and ongoing belief in this project. Finally, we expect to provide, as I said, additional data on this program next year, and I think that's gonna be very exciting. Operator, I'd like to hand it over to you to begin the Q&A portion of the call. Thank you very much.
Thank you. We will now begin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question comes from Jonathan Chang with SVB Securities. Please go ahead.
Hi, guys. This is for Jonathan. First question I wanted to ask, could you provide some more insight on the cases of peripheral neuropathy, specifically, were observations different between bladder and ovarian cancer and did peripheral neuropathy correlate with time on study? Thank you.
Thanks for the question. I'll hand that one over to Dominic. Dom?
Yeah. I think, again, thanks. The general answer did correlate with time on study. There were, for example, extra detail. There were two low-grade peripheral neuropathies, as we said in the call, that were treatment-related adverse events in the 6.5 in Q2W Cohort. There was a patient who got peripheral neuropathy on day two and has remained grade one throughout the rest of their therapy, but they withdrew after a couple of doses. They had a gastric sarcoma. They were anticoagulated from a prior history coming onto the trial, because of embolus and this anticoagulation led to bleeding in and around the tumor. It was cauterized, but basically the patient withdrew. Not really much on that.
It happened at day two. The other patient was also at the go-forward dose. They had intermittent pins and needles in their lower leg, and this was a grade I from day 21 on cycle. There was one episode of it rising to a grade II, cycle three, day 16. This resolved within 24 hours. It basically had an interruption in their treatment. This patient was heavily pre-treated. They had peripheral neuropathy from the study entry, then had a previous platinum therapy. I hope that gives you further color. The other three patients were in the 8.5 mg cohort every other week. There was a grade I, and another grade I, and then a grade II.
Again, the grade II, and I think this is interesting from a platform viewpoint, that grade II occurred on day 36. I think the urothelial patients are not so early. They are very aware 'cause of the multiple rounds of platinum therapy. That dropped from grade II to grade I, day 43. Kind of, you know, a week of grade II after a dose reduction. When we are seeing that, this very pleasant ability to stay away from the neuropathy with dose reductions, not obviating the dose entirely, just staying away.
Got it. I guess you started to answer this a little bit already, but we just have one more question. If you could provide any more insight on why you chose 6.5 every other week instead of 8.5, where it also looked like you had a good number of patients.
On balance, when we looked across the cohorts, the fact that we see good activity at 6.5, we have response at 6.5. Every patient who's had a response has considerable time on 6.5. We think it's a really good dose to move forward. Very pleased with the consistency of dosing and looking forward to seeing how that dose does in the expansion.
Thank you for taking our questions.
The next question comes from Li Watsek with Cantor Fitzgerald. Please go ahead.
Hi, guys. Thanks for the update. I guess first one, on the three patients with bladder cancer who are also EphA2- positive, can you share, I guess, the data on the EphA2 expression level for the one patient that progressed versus relative to the two responders?
That data we're gonna hold back for publication, Li. Obviously it's hard to draw any conclusions on an n=3. I think the bigger message here is that we're seeing activity which is based on EpCAM expression, and that's where we'd like to leave it for now.
Okay. I guess just follow up on, I guess, the cutoff, I think you mentioned is sort of the 1% that you sort of used in this study. Is that a cutoff that we should be thinking about, going forward, maybe for expansion cohorts and in later development stage?
You know, I think it's a really good question. It's very exciting to see that we can, you know, reduce the cutoff and still see activity. Again, N is low. I think it's hard to draw conclusions at this stage. One thing to mention, we have a CDX that we're now working up, and the cutoff we ultimately will land on will depend on the progress we make there as well. The take-home here is we're seeing activity in EphA2-positive patients. I think it's also important to take a step back. No one has ever got this far with EphA2. No one, multiple attempts, no one's got a therapeutic safely into man.
I think you'll agree our safety profile is actually quite astounding, given the background to this target. Not only are we seeing a great safety profile, we're seeing activity. We're really excited by what we've got. Lots more to do, and we'll continue to investigate the relationship between EphA2 expression and activity.
Perfect, got it. I guess just last question on the durability. I guess can you just comment briefly, I guess what duration of response that you believe is good in, these population?
I mean, I'll give you my view, and then Dom, I'm sure, will have a comment. I think, again, important to remember these are very sick patients we're dealing with. We've talked about the ovarian patient with a complete response still on therapy after 18 months. In our triple meeting update, we had a patient who didn't quite get to a partial response, but was on therapy for a year. We think we get nice durable responses with the therapy. In terms of what the ultimate duration of response will be, again, I think that's something we have to wait and see. Dom, any comments?
Yeah. I mean, thanks for the question. I really like it, 'cause it's a critical factor. To sort of predict a question I might get asked about what do we do with urothelial et cetera, I think it really does depend on us taking a long, hard look at those patients, some of whom are on. We had duration of response with another stable disease as well. We should at least see some of the fruits of what's happening with Bicycle Toxin Conjugates with respect to this, the interplay between duration of response and efficacy, which is working out very nicely.
I think we shouldn't have any kind of acceptance for any duration of response that doesn't look respectable when put alongside other therapies, and I remain very hopeful about that. I hope that helps answer your question.
Perfect. Thank you, guys.
The next question comes from Tara Bancroft with Cowen. Please go ahead.
Hi. Good morning, and thanks for the question. I just wanna clarify first, how many responses you said were attributed to the 6.5 mg every other week dose level, and was the ovarian complete response maintained when the patient dose reduced, after cycle 12? And then I have a follow-up on safety.
The response was maintained after the dose reduction. In the EphA2-positive ovarian cohort, we have one positive at 6.5, one out of two to date, complete response.
Okay. That's great. Thanks. Can you describe the nature of the high-grade anemia that was seen in the two patients at the 6.5 dose level and how that's managed?
Yeah. It was grade III. It was never grade IV. Because this patient's still in kind of escalation, it was treated with infusions. Indeed one of those patients we actually inherited with a low hemoglobin at the beginning of trial. It went from a grade I to a grade III rather than a de novo grade III.
Okay, thanks.
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Oh, hey, congrats on the results, and thank you for the update. Can you talk about what percent of ovarian and urothelial cancer patients are EphA2 -positive based on your TPS greater than one cutoff? Do EphA2 expression levels correlate with number of prior lines of therapies? I had one follow-up.
Thanks, Jay. Great question. That's something that we are continuing to investigate and obviously we're working on a new diagnostic. I think we have to do a bit more investigation before we can clarify exactly the number of patients that'll respond to our cutoff.
It's well established that the EphA2 expression increases with disease progression. I think it's as patients go through the lines, there will be an increase in EphA2 expression. I think it'd be exciting to go and look if there's any kind of double dissociation, any patients with a short duration of disease that have had multiple lines, and likewise, any patients with long duration disease and a few lines to see if there is any actual correlation. We're very pleased. I mean, there's massive confidence intervals on this, but we've got a working figure of around half of our patients being EphA2 -positive, and we'll obviously get more and more refined on that as we go on.
Great. That's super helpful. Thank you for that. Would it make any sense to initiate BT5528 therapy at a higher intensity loading dose followed by a lower dose for maintenance treatment?
It's a great question and one that we will, you know, continue to consider as we progress the study. Right now, we feel very comfortable with the 6.5 every other week. You know, we're doing science here. This is real-time investigation, and we'll continue to be guided by the data.
Great. Thanks for taking the questions.
The next question comes from Kelly Shi with Jefferies. Please go ahead.
Thank you for taking my questions. For ovarian cancer, for that nine patients screened with EphA2 -positive status, what is the median follow-up time? Have you observed the response deepening over time? I remember the CR, I mean, for the complete response you have achieved, it's conversion from PR, and I wonder when did that happen. I also have follow-up. Thank you.
There's quite a lot of questions in there. Let me see if I can remember them. The responses deepen with time. I think that's the case for all of our patients. Could you repeat the questions, Kelly, please?
Immediate follow-up of nine patients, EphA2-positive patients with ovarian cancer.
Yeah. I don't think we've actually calculated that on a disease-specific level. It's been short 'cause of the glut of patients we got in in February, March. With respect to the PR converting to a CR, that was after 12 cycles. It was very interesting. We were just on a call, site call, and the nurse said, "Can we dose reduce?" We're like, "Well, they kind of got a partial response," and they figured they'd like to hold on to that. She said, "Oh, no. No, no, they've got a complete response," and they've had that now for a while, and they were wondering why they need to take the drug. The physician is just saying, "Well, actually, we'd like to carry on," but the compromise we came to was a dose reduction.
Like I say, it wasn't typical phase I dose reduction because the patient wasn't, it wasn't interfering with activities of daily living per se. It was just they had a relatively high commitment in their workplace and were wondering if they could do with a little bit less fatigue. It's kind of nuanced, but I hope that answers your questions. We'll look into all of the duration of response data as it matures.
Yes, very helpful. I also have follow-up. Regarding the two responders with ovarian cancer, could you elaborate a little bit more on the patient baseline? For example, have they been previously treated with Avastin and a PARP inhibitor? Also, are other, like, ADCs therapies in clinical trial? Importantly, do we have the information that whether EphA2 expression overlap with FRα in ovarian cancer? Thank you.
Dom, do you wanna take that one? Yeah. The EphA2, FRα and others, we've not looked into that yet. I think it's a very relevant question. Let me just take you through some of the narratives I've got. We had an ovarian partial response with a 65-year-old female, diagnosed with T3N1, so a large tumor with muscle invasion and nodes, one positive node. Of course they went to operation on that. They had neoadjuvant carboplatin paclitaxel for six weeks. They had adjuvant after the carboplatin paclitaxel. They went through a whole gamut of therapies, so Doxil Avastin, carboplatin Doxil rucaparib, then rucaparib plus Avastin, and then rucaparib again, each time with various elements of progression. Olaparib, everolimus. Carboplatin gemcitabine Avastin, niraparib, olaparib. I think we mentioned that the lines of therapy that the other patient had had with the doublet chemo and the letrozole.
Thank you for sharing the details.
The next question comes from Reni Benjamin with JMP Securities. Please go ahead.
Hey. Good morning, guys. Thanks for taking the questions. You know, Dom, maybe just starting off, I know we've talked about durability of response and it seems like the two ovarian patients continue to respond, whereas the two urothelial responders, you know, one stopped around six months, one stopped around three months. Can you talk a little bit about those urothelial responses? Did they progress, or was there a tox that took them off the study? What kinda led to that?
The one that was on went into their seventh month of therapy. That's five months duration of response. They had 15 weeks on EV before. I don't know if you wanna. It's probably not fair to say you can add together that duration of response, but they're certainly already, the tumor's somewhat familiar with the MMAE payload. The other patient, they didn't come off due to adverse events. They came off because the physician felt that their tumor was progressing.
Got it. As we think about, you know, outside of the responders, obviously you have several patients that are obtaining some sort of a clinical benefit, right? SDs. Can you maybe talk about those patients? How long is the CBR, you know, kinda lasting? Is there anything in particular about these SDs that we should be paying attention to?
Yeah. It's a great question. I think of course, it's nice to get stable disease in more than half the patients, 'cause you're sort of thinking that's when your PFS, your median's gonna arise. It will be incumbent upon that median if you ever go to a control group. You know, some of the patients were on for more than a year. You know, we were saying to these patients with stable disease, "Do you want to knock up the dose to the higher doses that we tried in this trial?" We got a very firm answer back, "No. We would, we don't.
We really are very happy with the dose that we've chosen. Yeah, I mean, our initial patient at 4.4 every week, they were on for over a year. Again, they weren't coming off because of symptoms. In fact, that patient came to us fresh from chemotherapy, had neuropathy, and that neuropathy got better. That's happened with two patients. Ovarian patients now. They've had neuropathy coming onto the trial, and it's got better on trial and disappeared. Yeah, really not coming off due to things. Then, yeah, we've had a couple of other stable diseases for more than six months, which is partly why we're holding fire on being fully definitive around the EphA2 diagnostic and things.
We've got a whole set of guidelines in there for the investigators in the expansion phase about how to deal with that. Of course, as we progress and mature the companion diagnostic, the CDX, we also want to look very specifically and in great detail at those things.
Got it. Just switching real quick to safety. You know, you write neutrophil count decrease, which includes neutropenia, which seems like a much more stricter definition of neutropenia. Am I thinking about that correctly, or why the kinda change in definition, if you will?
Yeah. No, thanks for that question. That's really helpful. We wanted to get every neutrophil count that decreased, and we didn't want to ignore something just because an investigator had called it, you know, low neutrophils or, you know, neutrophil count decrease, neutropenia. These are all different terms, and we gathered them all up into a senior term. So there is not a single patient that had neutrophils on this trial that has not been reported to. So really, thank you for asking that. It was more, we didn't go specific. We went generic on it.
Got it. Okay. Thanks for the clarification. One final one for me. On the overall trial design for the expansion study, is there kinda like a go, no-go decision that's made, you know, once these 14 patients are enrolled in both ovarian urothelial before expanding to the 40? And if so, what, you know, what triggers that?
Yeah. We'll make that decision on the totality of the data, Reni. You know, I think it's complex, right? If we've got patients who are doing extremely well, it's well-tolerated. I think we have to look at the totality of the data, the commercial opportunity we think is there, and make appropriate calls. Watch this space.
Great. Well, thanks for taking the questions, and congrats on the data.
Thank you.
The next question comes from Bill Maughan with Canaccord Genuity. Please go ahead.
Hey, good morning, and thanks for taking the questions. Can you share how many patients in your dose expansion cohorts are EphA2 -positive? When you publish the data next year, can we expect the same August 1st cutoff, or will we see longer follow-up? Thank you.
Second one first, rather. The update will be determined by the speed of recruitment and other factors. We're not gonna specify when we'll update the markets on the progress of the trial, other than we will give an update in 2023. In terms of the EphA2 expression, we're doing it retrospectively, but I think it's important, you know, I've had discussions with many of you who, you know, wanted to institute a cutoff from day one. I think that's the wrong approach for the reasons that we're now seeing.
We have to do the experiment correctly, understand the relationship between ephrin expression and response with the go forward diagnostic, and then make the appropriate calls. That's what we are doing, we continue to do, and that way we'll get the best possible outcome for the molecule and for the patients. Retrospective, and there will be other patients on trial, coming onto trial who are ephrin negative, which will help us continue to build the hypothesis that we are building.
Okay, thanks. Can you share development plans for the tumor types other than ovarian and urothelial?
Yeah. It's more modest with going into TNBC, head and neck, lung, esophageal. We'll have a quick look at seven. I think this is where both, you know, investors, as is often the case, investors and regulators and ethics committees are aligned. There's a desire to look at these patients for a small number of patients, and see if there's anything there, and we're actually really excited about that. There's also a desire to make sure you just don't keep on, like some unfortunate gambler at the table losing and spending patients on an ineffective therapy. We'll start off at seven and then potentially expand to 14, and then potentially even expand to 40 if we get things there. It's not like those tumor types have not responded to other MMAE-based dosing strategies as well, so.
Thank you.
Thank you. The next question comes from Ami Fadia with Needham. Please go ahead.
Hi, this is Isa Leon Ferrami. Thanks for taking our question. Maybe the first one just on slide 16, can you kinda characterize the level of, you know, EphA2 expression, you know, patient of the slide? Like, were we seeing, you know, directionally the, you know, the greatest response in seeing in patients with the greatest, EphA2, expression?
We're gonna, I think, as I mentioned, leave that for publication for a number of reasons. One, these are low numbers. I think it's hard to pull any correlations until we get a few more numbers. I also think that it's too early to draw a lot of conclusions from the data. We gave a preliminary update on the relationship between EphA2 expression and activity at the Triple Meeting, and I think broadly it's still valid. We wanna do the analysis with the right diagnostic. Up till now, we've been using a polyclonal. We're now switching to our own proprietary monoclonal and therefore we'll have a much more valid and important data to share when that's complete.
Got it. Maybe just a quick second question from me. Can you comment kind of on the number of cycles of treatments for the patients that you saw responded to? Thank you.
The responders. I think we've already highlighted two on the call, the ovarian patient, which I think is cycle 17. I mean, mostly they were. It was a 28-day cycle and apart from the first cycle with some of the 8.5s, they got most of it throughout. Certainly the long-term CR patient, they were getting it every week with the occasional exception of going away on vacation for a week, et cetera. Broadly speaking, you can divide the amount of time on the trial by the number of months, and that's the number of cycles and there wasn't many hiccups or missed doses once we'd got our dosing right.
Got it. Thank you.
Thank you, due to time constraints, we ask that you please now limit yourself to one question. The next question comes from Peter Lawson with Barclays. Please go ahead.
Great. Thanks. Thanks for taking the question. Just really trying to triangulate average duration on therapy and in ovarian and bladder, and also whether there's kind of patients where you saw responses at a higher than recommended phase II dose, if that had an effect, and kind of how you kind of triangulate that and how that could contribute to the response rate. Thank you.
Yeah. I think this comes back to an earlier question about kind of sort of boosting them at the beginning and where I have the kind of equipoise there is that actually a lot of the patients with particularly the neutropenia which is prevalent in the 8.5 mg dose that those patients there's kind of 60% rate of grade three or higher in the 8.5 mg dose. So the neutropenia got better, so it's almost as though you might consider kind of settling them in at a 6.5, and then particular patients who are untouched, and some of them really were untouched, you might consider going up later. Of course we've got
The PK is broadly speaking, as we've shown before, there's no real differences. It's linear. It goes with dose. There's short half-life of parent and then same half-life for MMAE as we've seen with both compounds. That comes with a coefficient of variation of around 30%-40%, which provides a natural degree of variability in exposures as you go throughout, and you can then use that looking at sort of broader scale-PK efficacy correlations to properly map out whether a higher dose would truly be effective. But the dose interruptions and the withdrawals in the 8.5 meant we just weren't getting enough drug into the patient. Of course, early on, we had the experiences with the severe dehydration at the 8.5, so it wasn't trivial.
We dealt with that well. We've put in an amendment to the protocol. We've asked physicians to give them prophylactic prochlorperazine. We are comfortable with the 6.5 dose, but it's not necessarily a walk in the park. It's achieved with a level of oncological supervision that is great. I mean, there may be a 7.5 somewhere along the way, but for me it feels like this is where it's at. The next question we need to ask now is an expansion question around efficacy, and I think that's gonna be really cool.
Thank you. The next question. The other question in there was just around the average duration of therapy for ovarian, and I assume it's kinda too early to tell for bladder.
Yeah, it is. I mean, the phase I trials, the duration of therapy, other than the ones we've said PR, there's a few stable diseases. A lot of patients come on, just gave us a month, got through DLT and left, especially early on. I'm afraid we can't really give you a figure for that now. It's something we'll be looking keenly at for the expansion phase, and it will very much contribute to our view, not just for reasons of drug usage and commercial desires, but actually duration of therapy is a subtle correlator with just how much the patient's getting benefit.
Yeah, it's very fair, and I'm afraid we can't give you that data right now, just 'cause we don't really have it, except for in those patients who've left early, and that would give you a sort of disproportionate view of what it actually is in the end.
The next question comes from Swayampakula Ramakanth with H.C. Wainwright. Please go ahead.
Thank you, and thanks for taking my questions. Though most of them have been answered. One quick one. Kevin, do you think there was any impact of prior therapy on some of these adverse events that you had noticed in some of the patients?
Hi, R.K. I think you only have to look at the number of prior lines. These patients are very beat up. I think all of the ovarian patients have had platinum. It's remarkable that we see, I think, such low neuropathy given multiple rounds of platinum. You know, once bladder patients get to the end of existing lines of therapy, we know they're very sick. So for me, and I think for the team, we just don't think it's remarkable the side effect profile we're seeing and real testament to the technology and the potential of the therapy. I also. It's not just about the molecule, it's also the target. I've said it once on the call, I'll just say it again.
This is a target that is just intractable to other approaches. No one has ever successfully taken an EphA2 targeted molecule into the clinic and got past dose escalation. We're really excited about what we're seeing and really looking forward to continuing to explore the potential of this molecule.
The last question from me. On the diagnostic assay itself, do you have any idea when it could be ready? Or could it be ready for your next set of investigation, say like the phase II/III studies with either ovarian or bladder?
Yeah. It's lab now. Obviously we're scaling up and building the dataset. You know, we're already in a position where we're beginning to utilize it. I think that's coming together very nicely as we're progressing the molecule.
Perfect. Good luck.
Thank you.
The next question comes from Tony Butler with ROTH Capital. Please go ahead.
Thanks very much. Kevin, you've made some comments around EphA2 expression and obviously response. Question really is, EphA2 is also cleaved via protease. So the question might be, if EphA2 expression increases with progression of disease or even if it doesn't, is there a correlation between protease cleavage and progression of disease? In other words, trying to hit that biology really at the right time. Part B would be, BT5528, do you know if the Bicycle binds above or below that cut site? Thank you.
Hey, Tony. Great question. The literature says that the EphA2 expression increases with progression. I would argue the patient population that we've been treating up to now are probably the most progressed you can get. The fact that we're seeing activity, you know, in that population, you know, if you follow that kind of thinking through, you know, you can only get better. In terms of above or below, our molecule binds above the cleavage site, which again, I think is interesting in terms of the relevance of the cleavage in terms of an activity. We're also minded that you know, the Daiichi molecule, which failed in phase I, actually bound below. I don't know the significance of the cleavage at all. Obviously it's something that we'll continue to explore.
Thanks, Kevin.
This concludes our question and answer session. I would like to turn the conference back over to Kevin Lee, CEO, for any closing remarks.
Thank you, operator. Just a big thank you to everyone for participating in the call. Great questions. Really enjoyed the dialogue. Look forward to following up with you all individually, and hopefully you're as excited by the data as we are, and look forward to giving a further update in 2023. Thank you, and goodbye.
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.