Good morning. Welcome to the Bicycle Therapeutics call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing star 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 touch tone phone. 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 investor section of Bicycle's website. I would now like to turn the conference over to Dave Borah, Senior Vice President, Capital Markets and Corporate Communications. Please go ahead.
Thank you, operator. Good morning, everyone. Thank you for joining today's call to discuss the BT8009 end of phase I results. I'm David Borah. Joining me on today's call are two GU oncologists as well as members of management. The oncologists are Dr. Capucine Baldini from Gustave Roussy, an investigator of the BT8009-100 trial. The other is Dr. Daniel Petrylak, Professor of Medicine and Urology at Yale School of Medicine. Members of management 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 statements. Now I'd like to turn the call over to Kevin Lee, Chief Executive Officer. Kevin?
Thank you, Dave, and thank you to everyone for joining us this morning. I'm excited to share the results of our BT8009 escalation study with you today. Going to slide 3 to review today's agenda. We have a lot to get through and several important participants. Shortly, I will hand over to Dom, who will cover a couple of slides before introducing Dr. Baldini, one of our lead investigators on the BT8009 phase I trial. After she reviews the phase I clinical data, she will hand the call back to Dom, who will introduce Dr. Petrylak. He will give his thoughts on the data and where BT8009 could fit in the current U.S. treatment landscape. Dom will then discuss the phase II trial design and next steps. Finally, all of us will be available for Q&A. Next slide, please.
Most of the presentation will focus on the phase I design and results. Before we get there, though, Dom will give a brief overview of Nectin-4, the phase I trial design, and an overview of the data before handing the call over to Dr. Baldini. Dom?
Thank you, Kevin. Next slide, please. Before we get to the clinical data, first a bit about the target. Nectin-4 is a cell adhesion molecule and a member of the nectin family. All nectins share a similar structure with three extracellular immunoglobulin domains, single transmembrane helix, and an intracellular domain. It is overexpressed in a number of solid tumors, including urothelial, lung, breast, and ovarian cancers. As many of you know, it is also the target for enfortumab vedotin or Padcev. Next slide, please. Dr. Baldini will go into more detail shortly. This has been a successful study. We've continued to see very convincing efficacy and tolerability results, not just in urothelial, but also in lung and breast cancers. Clearly, the 5 mg cohort exhibits the most promise, producing tumor responses without many of the corresponding adverse events that we typically see with ADCs.
Rash, neuropathy, neutropenia, eye tox, and pneumonitis are really not issues of major consequence for this molecule. At the time of the data cutoff on September 20th of last year, median duration of response had not been reached. As of a more recent data cutoff in January, the median duration of response is estimated to be approximately 14 months, with two of the four responders still on therapy. We are thrilled to receive Fast Track designation and look forward to continuing to engage with the FDA and other key regulatory agencies. Next slide, please. This was a 3 + 3 trial design, and we explored a range of doses and schedules. We started at 2.5 mg, where we saw a partial responder. We then escalated to 5 mg and 7.5 mg weekly.
We explored different dosing schedules, like every other week and two weeks on and one week off. We declared two recommended phase II doses as of our November 8th press release last year. As enrollment has accelerated during the expansion phase, we are focusing our efforts on the 5 mg weekly dose based on the data we have generated to date and to advance the molecule as rapidly as possible. Next slide, please. It is now my great pleasure to introduce Dr. Capucine Baldini, who will review the data from the trial. Dr. Baldini is a GU oncologist working out of the Institut Gustave Roussy in France, Paris. She has been involved in more than 80 phase I trials, has been an author of several peer-reviewed journals, and has been a great advisor and confidante along the way. It is my pleasure to introduce her. Dr. Baldini?
Thank you, Dom. Next slide, please. I am indeed very excited to present the results from the phase I dose escalation part of the trial. I feel this is a molecule with real potential. I really look forward to sharing the data with you. Here are the patient demographics. As you can see, patients were heavily pretreated with a median of three previous lines of treatment, with the maximum being 50. Patients had exhausted all standard therapeutic options. Next slide, please. A total of 49 patients were enrolled in the dose escalation part of the trial. Almost half of the patients had urothelial carcinoma, despite the trial being on commerce. It is also worth noting that these types of cancer all tend to have fairly high Nectin-4 expression. Next slide, please. This waterfall plot shows fairly consistent tumor responses in urothelial patients across different dosage and schedules.
All of the response-evaluable patients in the 5 mg cohort show tumor reductions with an overall response rate of 57%. It is worth mentioning that one of the eight urothelial patients in the 5 mg cohort was previously coded as progressive disease. This patient developed mets after the initial dose, these lesions were not measured. Because of this patient was deemed not response evaluable. At the 7.5 mg, two weeks on, one week off, and 10 mg cohorts, the overall response rates were 50%. What is also notable is the tumor response across all cohorts. Next slide, please. This spider plot shows very consistent tumor response among urothelial patients. To be clear, all of the data presented on this slide is as of the data cut-off date of September 20. Median duration of response in the 5 mg urothelial patients still had not been reached.
As of January 2023, median duration of response is estimated to be approximately 14 months, with two of the four responders still on therapy. As of September 20, six responders were still on therapy. All of the three responders in the 5 mg cohort cited at the time of AACR were still responding as of the data cut-off. Toxicity was not limiting in terms of treatment duration. Next slide, please. This table of response rate in urothelial cancer patients clearly shows tumor response across most cohorts. This is on an intent to treat basis. There was a response in the first dose cohort at 2.5 mg two weekly. The 5 mg, 7.1.5 mg, two weeks on, one week off, and 10 mg cohorts all had 50% response rates on intent to treat basis. The 5 mg cohort data is not for see.
One complete responder, three partial responder, three stable disease patients. The clinical benefit rate in complete response, partial response, and stable disease for 16 weeks or more was 75% in the 5 mg two-weekly cohort. Next slide, please. Here are the images of the 5 mg complete responder. You can see the tumor at baseline shrink and then disappear over four months of treatment. This response was confirmed, and the patient remains on therapy as of January 2023, after over 18 months of treatment. Next slide, please. One of the qualities that distinguishes this molecule from others is its efficacy across different tumor types. If the company will be presenting the poster at ASCO GI, this presentation is largely focused on urothelial cancer. However, I want to spend a bit of time talking about these two responders, one in lung and one in breast.
Both of these patients expressed Nectin-4. The lung patient came on the study effort after four prior lines of therapy, one of which included pembrolizumab. It is worth noting that none of these prior lines exceeded nine weeks. The chart shows he was able to tolerate BT8009 for more than six months and was still active on therapy at the time of the data cut-off. The breast cancer patient's first scan after start of therapy did show a response, and this response was confirmed in December. This patient had one prior line of therapy, palbociclib and exemestane. She remained on this for 14 months. It initially led to complete response, but eventually she progressed. Next slide, please.
This slide is a quick look at anti-tumor activity in both lung and breast cancer. Among the five response evaluable lung cancer patients, there was one partial responder and three stable disease. The only progressive disease patient did not express Nectin-4 and was in the 2.5 mg cohort. Among the six response evaluable breast cancer patients, there was one partial responder and two stable disease. Both of these cancer types, as well as ovarian, will be explored in the phase II expansion trial. Next slide, please. Now we are going to talk about the BT8009 safety profile. At 5 mg, there are only four treatment-related grade 3 or 4 adverse events. There were no grade 5 events across the entire study.
Of the four related grade 3 and, or 4 events in the 5 mg cohort, none was considered to be a serious adverse event. Next slide, please. This is a slide that shows the most common overall treatment-related adverse events across all patients, both in terms of incidence and severity. As you can see, the most common treatment-related adverse events were GI or fatigue related. There was a low incidence of grade 3 events, especially at the RP2D. Next slide, please. These are adverse events that typically are of concern to physician and patient because they can be dose intensity limited with impact on activities of daily living. They are also concerning with the use of Padcev and have shown to be severe with this compound. Skin rash was not an issue whatsoever across the entire study.
Eye disorder were really only an issue with one patient in the 7.5 mg cohort who entered the trial with a number of eye issues at baseline. There was no apathy, but it was mostly low grade. Finally, there were no cases of pneumonitis whatsoever. Next slide, please. This is the first of several slides that show treatment-related adverse events by cohorts. Rash was very benign across all cohorts. There were three grade 1 and one grade 2 across this cohort that were at or below the RP2D. Across all patients, there were only five grade 1 and 1 grade 2. Many of these were site-specific rashes after ECG leads were removed. You can see in the 5 mg cohort, there were only one grade 1 and one grade 2 events. Next slide, please.
Neuropathy has been a key area of focus for urothelial patients and their physicians. You can see in the upper table that there have been no grade 3 or higher events at or below the 2 RP2Ds. The one grade 3 event was in the 7.5 mg weekly dose cohort. The overall incidence is 27%, whether all patients are considered or only those at or below the RP2D. The smaller table is specific to the 5 mg urothelial cohort. You can see that this is unchanged since the company's update at AACR last year, three grade 1 events and one grade 2. Next slide, please. The focus on this slide showing neutrophil count decrease and neutropenia is grades 2 through 4 and grades 3 through 4.
These events were transient in nature, manageable and reversible, and similar or better to other agents with a cytotoxin component. It is worth mentioning that none of the patients were treated with G-CSF and given this profile, prophylactic use would not be warranted. Next slide, please. For such a heavily pretreated population, it is impressive that no patient at or below the RP2D discontinued treatment. That there were only nine interruptions compares favorably to other drugs. Some of these interruptions were patients going on vacation as well, so not all of the interruptions were due to tolerability issues. Finally, only six patients had to reduce dose. Next slide, please. This slide shows a similar picture of a very tolerable molecule. Relative dose intensity is the ratio of how much drug a person is taking versus how much a person is pre-prescribed.
Dose modification, as seen on the previous slide, would reduce this number below 100%. The fact that the overall relative dose intensity was 99% is fairly unprecedented for a phase I oncology trial like this and really contrasts the experience with antibody-drug conjugates. Next slide, please. This is my final slide, then I turn it back to Dom. To conclude, this is a very promising molecule for several different reasons. It is very efficacious, especially in urothelial but also in other Nectin-4-expressing cancers. The duration of response we've seen is a result of this efficacy as well as the tolerability profile that is unmatched. It's been a pleasure being part of this trial, I look forward to answering questions during the Q&A. Now let me hand the call back over to Dom. Dom?
Thank you very much, Dr. Baldini. We very much appreciate all the hard work and dedication from you and all of our other trial sites. Next slide, please. As we near the completion of the presentation, we will cover a few topics that are relevant as we look forward and assess where an agent like BT8009 would fit in today's treatment landscape, as well as next steps in clinical development. Next slide, please. To cover the topic of providing context for the BT8009 trial results and where it could fit into the treatment of urothelial cancer, it is my great pleasure to introduce Dr. Daniel Petrylak. Dr. Daniel Petrylak is a Professor of Medicine and Urology at Yale School of Medicine.
He is Co-director of the Cancer Signaling Networks research program, and he has authored over 200 peer-reviewed articles on prostate and bladder cancer research. I'm also pleased to say that he will be an investigator for our phase II trial. Dr. Daniel Petrylak.
Thank you, Dom. The treatment paradigm for urothelial carcinoma has changed significantly over the last 10 years. 2012, 2013, in that time era, we only had standard treatment with gemcitabine cisplatin and MVAC as first-line therapy for those patients who are eligible to receive cisplatin. For those patients who are ineligible, carboplatin with gemcitabine. Once patients progressed, we had little to offer these patients. The median survival was six months, and the response rates were less than 20%. With the discovery that checkpoint inhibitors have significant activity and improve survival, as well as the newer targeted therapies such as enfortumab vedotin, sacituzumab govitecan, and erdafitinib, we're now seeing second and third-line treatments being routinely administered to our patients.
The significant activity of these drugs in the third-line setting, particularly in those patients with visceral disease, the justification for moving these treatments up earlier in the course of treatment. In fact, there are studies that are now looking at enfortumab combined with pembrolizumab in the frontline setting for metastatic disease as well as in the neoadjuvant setting as well. I think what's going to be important is clearly the efficacy of these agents. Also if we're moving these agents up the long-term toxicities, neuropathy, skin changes, these will be very important not only towards the overall quality of life and survival of these patients, but also in terms of whether the patients can receive local therapy. I think that the field is shifting. We're seeing the movement of these novel agents up earlier.
Of course, as patients are living longer, we want to be sure that they're living well. That I think is an important paradigm for this disease. I think that's one of the things that we want to see our patients do. As patients are living longer with disease and also living into their seventies and their eighties, we want to see them be able to work, to spend time to see their grandchildren graduate from college, do other activities that they've always wanted to do their entire lives. Their retirement should be time for them to enjoy themselves, enjoy their families, and clearly not having the burden of disease would be important to that.
In some respects, we can be the victim of our own success by having an active drug that leads to toxicities which would lead to either dose reduction or breaks in treatment or even discontinuation of the drug. Neuropathy is one particular side effect that can be debilitating if it, in its worst form, can be annoying in its minor forms, but can have a significant impact upon quality of life. Clearly what we need are agents that have less neuropathy over the long-term period of time. Also, we need to understand exactly how we can prevent this. This would of course lead to better outcomes. What are some of the other supportive care measures that we can use to prevent neuropathy in our patients? This is in general true of any drug.
We want to limit the long-term side effects. We want to have good ways of treating these side effects if they occur because this clearly impacts upon the ability to deliver full doses of drugs. Well, skin rash is an important side effect for not only MMAE-targeted therapy, but as well as immune therapy. The early recognition of skin rash can prevent the progression of this to a more toxic form, such as Stevens-Johnson syndrome. The early recognition, treatment with topical steroids, systemic steroids, is crucial to making sure that the patient is able to receive a long-term dose of these drugs. There is, I think, promising activity not only in urothelial carcinoma, but in other tumor types.
I think that based upon what we see here, this certainly merits further investigation, expansion to larger cohorts of patients, into a phase II trial than, of course, to a phase III study. I think it's important this is an important trial. The combinations of checkpoint therapy with enfortumab vedotin has shown significant activity in patients with metastatic urothelial carcinoma. I think that the trial combining BT8009 with pembrolizumab is important because of this observation that's been made with the combination of ADCs plus immune checkpoint therapy. This may be the next direction for this drug. Certainly I think it's an important trial to prove this concept. Back to you, Dom.
Thank you, Dr. Petrylak. Next slide, please. We are currently enrolling five cohorts in the expansion phase, EV exposed, EV naive, and then three outside of urothelial cancer, ovarian, triple-negative breast, and non-small cell lung cancer. Our path of combination relies on potentially deescalating from the 5 mg weekly dose. We have enrolled patients in this de-escalation phase, and we felt comfortable starting at the 5 mg dose rather than having to work our way up to it, as the main worry in this context would normally be skin rash, but our molecule appears to be considerably de-risked on this front. We've also enrolled patients in a renal cohort. That's three baskets of six patients each. Findings from the de-escalation and the renal cohort should allow us to begin the combination cohort later this year. Next slide, please.
We have 21 sites up and running now and expect to more than double that number by the end of the year. We have been floored by the amount of interest in this trial from the clinical community, internationally as well as in the U.S. Fast Track designation was an early and positive sign of our working relationship with the FDA. Discussions remain ongoing with the agency, we look forward to providing initial details at the appropriate time as we continue to advance BT8009. Next slide, please. We're really very pleased with the trial so far. The molecule is active not only in urothelial but in other cancers, which we are exploring in the expansion phase. The duration of response is a number that we pay a great deal of attention to because it is where efficacy and tolerability meet.
Not to mention, it's something that the patient appreciates as well. We continue to be very encouraged by what we see here. The enrollments and expansion has been tracking well. We hope to have more data to share with you by year-end. We should have more information regarding the regulatory path later this year as well. One thing to point out before we open up the questions, we made a real effort in this presentation to put our data in proper context. To that end, we have included some relevant slides from enfortumab vedotin's clinical trials in the appendix. We believe that our data compares rather favorably to theirs across a number of metrics, accepting of course that this is a cross-study comparison. On that note, without further delay, let me now hand the call back to the operator to begin the Q&A. Thank you.
We will now begin the question-and-answer session. To ask a question, you may press star then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the key. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. In the interest of time, please limit yourself to one question and one follow-up. At this time, we will pause momentarily to assemble our roster. Our first question today comes from Li Watsek with Cantor Fitzgerald. Please go ahead.
Hey, good morning. Congrats on the data, thank you for taking my questions. I was just wondering if you can comment on the duration of response that you observe in this trial versus Padcev since that the median DOR is a bit longer for 8009. Maybe just to clarify how many of these eight patients are platinum ineligible and could that impact the DOR? Thank you.
Hi, Lee. It's Kevin. Thanks for the question. I'm gonna hand it over to Dom.
Yeah. All of our patients had prior platinum and, despite the small numbers, it really is a very pleasing occurrence to see the duration of response that we've got. Just listening on a weekly call, it really becomes apparent that that's tolerability and efficacy. Yeah, we're really pleased.
Next question.
The next question comes from Ted Tenthoff with Piper Sandler. Please go ahead.
Great. Thank you. Good morning. Can you hear me okay?
We can hear you well, Ted.
Great. Congrats on the data. Very impressed by the efficacy. Question just with respect to the safety profile and maybe for the doctors on the call. I was really kind of intrigued by the minimal neuropathy or lack of neuropathy signal. I just wanted to kind of get a sense for how this maybe compares to your experience with Padcev, and maybe you can just refresh on maybe what that mechanism might be of why we're seeing lower neuropathy. Thanks.
Thanks, Ted. I'll ask Dr. Baldini to ask the first question and Nick to address the second. First of all, Dr. Baldini.
Thank you.
Yes, sure. Thank you very much for that question because indeed, peripheral sensory neuropathy has been a limiting factor with the use of using Padcev. As it is usually dose limiting, and the related dose intensity is really an issue with this ADC. The mechanism of action is actually related mainly, is mainly due to the MMAE component, the cytotoxic component that is actually the cause, the origin of the neuropathy because this cytotoxic usually has this toxicity profile. That was very interesting to see that with the BT8009, we didn't have the same number of peripheral neuropathy. That it's very easy to manage in clinical practice.
I think this is something very strong with this molecule, and that allows us to actually treat the patient longer and that may explain also the median duration of response.
Thanks, Dr. Baldini. Nick, anything to add? Nick?
Just, I just wanted to add to that. I think, you know, it's pretty clear that what we're seeing is quite different. I think, you know, the molecules are fundamentally different at their core. An ADC like Padcev, of course, will bind to receptors like Fc receptors as well as the Nectin-4 expressing cells and therefore has a sort of a double mechanism, if you like, for delivery of payload into potentially into normal tissue like skin that expresses Nectin-4, but also into normal tissue that's rich in Fc receptors. That could certainly include not just skin, but also components of the peripheral nervous system as well.
We feel there's a fundamental difference in mechanism that's giving rise to a fundamental difference in the performance of the molecule clinically. Thank you.
Next question.
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Hey. Congrats on the data. Thank you for providing this update. Can you talk about whether or not any of the patients treated so far with BT8009 had brain mets and whether or not you've observed any CNS activity? Maybe as a follow-on question, since your Bicycle platform is a modular platform, can you talk about what the success of BT8009 so far teaches us about the strength of your platform and how it can inform your other programs?
Great question. Thanks, Jay. I'll ask Dom to answer the first one, Nick, the second. Dom.
Yeah, thanks. We have had patients with central nervous system metastases. We've seen stable disease and disease control, but we can't comfortably say we've seen activity in those mets other than that we've got the usual level of patients with CNS disease and that is not an explanation as to why our duration of response is longer. Those patients are in there.
Nick.
Yeah. Thank you for the second question. I think these data are actually quite important in informing us about the platform itself. If you'll forgive me, if we go back a little bit in time and think about target selection, we chose a tumor antigen called EphA2 for a sister molecule called BT5528. That was a target where ADCs have trialed and failed repeatedly, largely due to coagulopathy. No coagulopathy and very good overall tolerability for 5528, especially in a heavily pre-treated phase I population. For our sister molecule, we're clearly seeing difference to a comparator or to comparator antibody drug conjugates. We chose Nectin-4, where there is an FDA-approved drug, but one with significant side effect issues.
Of course, as you've seen today, we're not seeing it anywhere near the level of issues that were reported for Padcev. Certainly, the difference in skin toxicity seems to be quite remarkable. Finally, I just wanna say that, you know, we're now looking at novel tumor antigens for Bicycle binders, novel linkers and payloads to improve upon the current generation of molecules. It'll be exciting to talk to you about what those molecules look like in the future. Thank you.
Next question, please.
The next question comes from Tara Bancroft of Cowen. Please go ahead.
Hi, good morning, guys. My first question is for Dr. Baldini. I'm just curious, you know, based on your experience, where you think the 14-month DOR could ultimately end up and, you know, describe your confidence in this MDOR that's in now in small patient numbers, holding up, you know, in more patients in later stage trials. A follow-up would be, could you explain a little bit more what led to patients in the 5 mg RP2D cohort being non-evaluable? Thanks.
Perhaps, Dom should answer the first question and give a view on the DOR as well, and then we'll hand to Dr. Baldini for the first question on the response rates.
Yeah. The rate of 50% refers to the fact that eight patients went on that 5 mg cohort. And very specifically, when we look at the waterfall plot, our statistician, who's very experienced at these things, was keen to point out that there was no scans post-dose available for 1 patient. That's why you've got seven patients on that floor. It kind of technically gives you a 57% response rate. Wanting to be cautious and fully disclosed, we felt that the intention to treat or essentially the full analysis group of four out of eight responses at a 50% response rate, which is still pretty good, especially when you look at the duration responses, is where it fell out. We wanted to give both those statistics.
Yeah, but I'd love to hear what Dr. Baldini has to say about duration of response. I think I would call the question was what, where one might see it ending up.
Dr. Baldini.
Yeah, thank you, Dom. Obviously is something that is very clear is that this trial is a phase I dose-escalation trial. At the beginning, you know, the patient population is patients that are heavily pretreated and that receive previously, sometimes, for most of the time, platinum therapy and also immune checkpoint inhibitors and sometimes other type of chemotherapy. Even when, even if it's possible that they receive also targeted therapy. It's by definition, an heavily pretreated population that might be resistant to prior lines of therapy. Seeing this level of response after all of those treatment is quite reassuring.
This is also phase I, so patients are obviously highly selected, as you know, and they have obviously a good we call it performance status. They are in good shape physically, physical good shape. We really need to see what would be the results in even in the expansion part of the study would be very important. In the end, the phase II. For the for a dose escalation path, because obviously all the patients are not at the RP2Ds, and we are seeing response also at 2.5 mg, it's already very very enthusiastic results.
Thanks, Dr. Baldini. Next question, please.
The next question comes from Jonathan Chang with SVB Securities. Please go ahead.
Hi, guys. This is [Faisal] for Jonathan. wanted to ask, can you discuss the timelines to data for the combo study in frontline cisplat ineligible, and also how you sort of consider that timing relative to the potential for a full approval for Padcev frontline? I have a follow-up as well.
Do you wanna take that, Dom?
Well, yeah. I mean, we aim to kick that off by the end of the year. As we said in the call, we're very pleased with our renal cohorts and our ongoing experiences with the patients who so far dosed in combination. I think that's the easier part of the question. I think with respect to what happens with the first line, I think that there is an extent to which Padcev is pioneering. It's leading the way there. There's also an extent to which it is creating a potential hazard for the. When you look at the
Both the neuropathy and the rash, and that in itself may open up an opportunity regarding an unmet need inside of that, which does not exist until such time as they have got approval. Which one would predict will exist once it is approved. Particularly, nobody can really say what the post-marketing experience is gonna be like there, but it's something that will be keenly observed. And we still see this very much a way forward there. In the first line, patients are treated for longer. As Dr. Petrylak said, quality of life is an issue and side effects are particularly pertinent. We're very keen and we're very optimistic in that context.
Yeah. Just to add to that, I mean, the bottom line is we're incredibly excited by what we're seeing with this molecule. It doesn't have anywhere near the apparent tolerability issues of Padcev as a monotherapy, let alone as a combination. We started our, as Dom said, our combination de-escalation, and we're really looking forward to creating the data package that, as in the case of the monotherapy, should speak for itself. Next question, please.
The next question comes from Kelly Shi with Jefferies. Please go ahead.
Congrats on the progress. I have a question on safety signals. The grade three fatigue and asthenia were reported occurred on the trial. This is the question for doctors. What could it be the underlying causes for these two types of toxicities? Are they more related to like a neutropenia or like a neuronal tox or it's overall impact from everything? Thank you.
Kelly, could you just repeat that? You were a little bit quiet at the start, and I want to make sure we get the get it right. It was concerning the... You are happy to repeat it.
The grade 3 fatigue and asthenia were reported on the trial. I'm curious about the underlying cause of these two types of toxicities. Are they more related to other type of toxicities or it's like overall impact from everything?
That's a question for Dr. Baldini. Yeah, I think you wanted Dr. Baldini to answer that. Dr. Baldini?
Yeah, sure. Obviously it's a difficult thing to capture because usually when we report treatment related adverse events, we report the fatigue as an adverse event and also the concomitant adverse event that can be, for example, neutropenia. I know that neutropenia can also participate to a fatigue. Clearly the asthenia/fatigue is the same and it's an event by itself. Yeah, it's related to the molecule and we have seen some asthenia that is very manageable again.
Yeah. It's worthwhile remembering.
I'm sorry.
Kelly, it's worthwhile remembering that those were seen at very high doses compared to our go forward dose. You know, part of, you know, the objective of the phase I is to go to non-tolerable doses to find, you know, what high tox, what high doses do. Part of the normal course of drug development, we're not concerned with it in the slightest, and as I say, they're higher doses. Did you have another question? I think you were trying to jump in.
No, I'm all good. Thank you so much.
Okay. Thank you. Next question, please.
The next question comes from Peter Lawson with Barclays. Please go ahead.
Hi, this is [Shay Fenneon] for Peter Lawson. Thank you for taking the question. Just firstly, how many of these phase I patients were cisplatin ineligible for the bladder patients? Secondly, how many were post Padcev, specifically at the recommended phase II doses? Then maybe for Dr. Baldini or Dr. Petrylak, how would you expect this to potentially influence the duration of response that we've seen depending on that prior exposure? Thank you.
Okay. First question to Dom and then to Dr. Baldini.
Yeah. All of the patients had been platinum exposed. 100% of them had prior platinum. Of course, I can't speak to whether they were platinum ineligible by the time they came on our trial, but they were at least one time platinum eligible. The next question is for Dr. Baldini. Dr. Baldini.
Yeah, sure. That's a very important question because, obviously you need to know what you expect, seeing that the mechanism of action and also the bioengineering of the drug is to be more effective and, to have a better penetration into the tumor. To increase the level of efficacy and maybe to have also, you know, an efficacy in patients that were pre-exposed to Padcev. In France, at the time we did the dose escalation part of the study, there was an issue because we were not able to prescribe Padcev, because there were three toxic deaths related to Stevens-Johnson syndrome that were actually reported by the pharmacovigilance.
At the time of the dose escalation in France, at least, we were not able to use Padcev for more than six months, so we did not treat patient pre-exposed. In the expansion phase of this trial, we actually have a cohort of patients either pre-exposed and either naive. I think that will really answer the question to that. This cohort would be very interested to look at and to see the results. We have to wait a little bit to make a clear response to the efficacy pre with the pre or Padcev exposure.
Thanks, Dr. Baldini. Next question, please.
The next question comes from Bill Maughan with Canaccord Genuity. Please go ahead.
Hi, good morning, and thanks. We see that as of the September cutoff, there were six responses ongoing across urothelial. Can you tell us how many remained ongoing as of the most recent follow-up? As a follow-up question, have you been able to draw any conclusions, either from your own data or from the field at this point, about how much loss of response is due to antigen loss versus some other mechanism? Thank you.
Thanks, Bill. Dom, to you.
We don't really wanna talk about anything in the expansion phase. A lot of those patients are ongoing, and we're still waiting to see the extent to which those patients manifest a good duration of response and the extent to which they manifest things like neuropathy is critical in our ongoing decisions around kind of the beauty contest we have around picking the dose.
The responders.
Yeah.
Yeah. We're certainly not in a position to discuss how many of the responders are still ongoing, but they seem to have good long responses the last time I looked. Next one. Next question.
The next question comes from Rajan Sharma with Goldman Sachs. Please go ahead.
Hi, thanks for the question. Just on kind of tumors outside of urothelial, just what do you think is the Nectin-4 expression rate in both breast cancer and also in lung? Just related to that, for both of those two settings, what do you see as kind of the bar for efficacy? Thanks.
Yeah. I mean, I'll take the first one, and then Nick can answer the second one. You know, I've said this on a number of occasions, it's, you know, ORR is important, but duration of response is as, if not more important. You know, if we can keep patients on therapy for beyond 18 months, which we already are doing, I think that's really a step forward, for certainly for the drug conjugate field. I think we have to look at that in that lens as well. Nick, in terms of numbers of patients with Nectin expression in, I think it was lung and breast.
Yeah. You can go and find those figures in. We have a number of posters on our website that break down Nectin-4 positivity across multiple tumor types. For each of the indications that you've asked about, these are both in the high double-digit %.
Next question, please.
The next question comes from Jeff Hung with Morgan Stanley. Please go ahead.
Hi, this is Mike Riad on for Jeff Hung. Thank you for taking our question. You noted that for the 7.5 mg and the 10 mg dosing schedules explored in the phase I dose escalation, that they delivered approximately the same payload as the 5 mg per meter squared over the six-week period. Given that, can you talk about why you saw different rates of neuropathy and neutrophil count decrease across the doses? Was this due to short-term dose intensity? Thanks so much.
Yeah, I mean, This is, and again, I've said this before, you know, we are the first company to be exploring this modality, so we're learning as we go along as well, and we're trying to understand is it, you know, is it Cmax, is it AUC, what's driving the efficacy and the tolerability? One can surmise from the data, and you have all the data now, that actually, more than likely it's a lower Cmax is better from a tolerability perspective. Importantly, however we dose it at in that range, we're not losing efficacy, which is really quite exciting for us. Next question, please.
The next question comes from Tony Butler with EF Hutton. Please go ahead.
Yes, thanks very much. I suspect this is for Dr. Baldini. It strikes me that given the 37 patients in the Recommended phase II dose, zero discontinuations are quite important, but there were dose interruptions and reductions, and I just wondered if in fact there was a pattern to the interruption. Was that just missing a single weekly dose or was a dose reduction perhaps at... Was there a pattern to that? For example, down to 2.5 mg or some other number. Perhaps most importantly, did either of those activities lead to a reduction in the duration of the response the patient was seeing? Thanks very much.
Dr. Baldini.
Yes. Regarding the dose interruption, following the weekly schedule, some patients were not able to come sometimes for personal reasons. It's very frequent actually in the real life, and sometimes it also has an impact on the patient's venues in the at the hospital, when during the clinical trial. It was mostly the reasons, and sometimes you have also interruptions, you know, for, so it can be for personal reasons. I think that would be interesting to look more into the data, and to see what precisely are the reasons for interruption. In my experience in our patients, we didn't... I mean, it was really manageable and sometimes we have to dose reduce afterwards.
Dom, I don't know if you wanna jump in as well.
Yeah, it's very difficult to say if a reduction did impact efficacy, but the efficacy we've got is really good. The reductions are fairly few, and as you identified, the discontinuations are zero out of 49 patients. We'll continue to observe that. I think it's just a fascinating metric.
Next question, please.
And if I-
Oh, sorry, Dr. Baldini.
Yeah. If I tend to tag that, you know, at the, I'm not really sure that the. You know, at 2.5 mg, we also had, we also saw responses. There is, probably, the question on the biomarker was really relevant, and it would be also interesting at the end to have the results regarding some potential biomarker to help us also guide the treatment at the end. It's interesting to see that we have responses at lower dose also.
Thank you. Next question, please.
The next question comes from Reni Benjamin with JMP Securities. Please go ahead.
Hey. Good morning, guys. Thanks for squeezing me in. Maybe just the first question for Dr. Petrylak. You know, from a, from a regulatory perspective, you know, what advice would you give the company, and how might you design, you know, a study going forward for approval, especially given, you know, that the front line setting is likely to change, you know, with a Padcev/pembro combo? Maybe as a follow-up, I think, Dr. Baldini, you mentioned that, you know, there was really no reason to give prophylactic GCSF, and I'm kind of wondering why. Like, why not? You know, it seems like, you know, you'd be able to reduce the number of potential dose reductions and improve upon the side effect profile. Is there something I'm missing there? Thanks.
Thanks, Reni. First question was to Dr. Petrylak. Dr. Petrylak?
Good morning. I think that there are two ways to approach this. One would be from an efficacy standpoint. This is a different mechanism, and we don't know whether this mechanism is better or the same or, you know, than what we see with Padcev. One would be to look at a large trial to see if that shows. The other one, of course, would be to, this is the first line setting, to look at toxicity and to power the study to detect differences in toxicity with skin and as well as neurologic, your, as well as peripheral neuropathy. Again, we don't know how, if there's cross resistance between these drugs or not, so another potential could be in Padcev failures. There are multiple ways I think this could be approached.
Thank you. Dr. Baldini for the second question.
Yeah. Regarding neutropenia, we have guidelines actually on the use of prophylactic GCSF. When looking at the number of high-grade neutropenia, we don't need to prescribe it in front line for all patients. Obviously we need to follow the guidelines. This level of, you know, of grade three neutropenia is very low and doesn't require that we use a GCSF prophylactically.
Thank you. Next question, please.
The next question comes from Swayampakula Ramakanth with H.C. Wainwright. Please go ahead.
Thank you. Good morning, folks. Most of my questions have been answered. I have a clarification to ask. In your next phase of dose escalation studies, you state that Nectin-4 prescreening for Nectin-4 expression is not needed. Just trying to understand, you know, the reasoning behind it.
Hey. Hi, RK. First of all, just to be clear, we're now in the expansion phase, so we're moving forward with our recommended phase II dose. At this point, we don't feel that using a diagnostic is necessary. We want to try and understand more about the potential of this molecule. Trying to get patients with a full range of expression is gonna be important. We will obviously retrospectively look at expression. For us, it's trying to understand the relationship between nectin expression and activity. To do that in the best way possible, you need the fullest range of nectin expression. Next question, please. I think this is the last question, if I'm not. Then I might add a few remarks at the end. Last question, please.
The last question today comes from Ami Fadia with Needham. Please go ahead.
Great. Thanks for squeezing me in. Maybe a question for, you know, Dr. Petrylak. You know, if you do fast-forward, how do you see BT8009 fitting into the treatment regimen with, you know, in the context of ADCs becoming available in first line? A question for the Bicycle team. What read-through does this data provide for your platform, particularly the BT5528? In terms of, you know, to what extent does it de-risk that? Thanks.
Thanks for that. Dr. Petrylak, the first question.
If you have EV in the first line and this drug is available, our question for further analysis would be, can you salvage patients who've been on EV with BT? We know that the mechanism attachment to nectin is different. That could be one of the reasons for resistance to enfortumab over time. I think we just need data to further look at that particular question. Same thing with the toxicity issues. Would this be a better drug to use in this particular situation based upon toxicities or efficacy? The phase II and the phase III trials will sort that out.
Thanks, Dr. Petrylak. The last question was regarding the read-through for the platform. I think that's a good way to end. From our perspective, we're extremely encouraged by what we're seeing with this phase I escalation study. BT8009 does appear to have a differentiated safety profile. This compares with its, I think, very promising antitumor activities is combining to present an extended duration of response, which is just worth well remembering it's almost 2 x that of some drugs which are used to treat this condition. We're very excited by that. We're very pleased with the collaboration we're forming with the FDA, who have recognized the potential of the molecule through the award of the Fast Track designation in late line.
That is a really exciting time for 8009. We're equally excited by 5528. As Nick said, you know, EphA2 is a target which everybody has failed. Everybody has failed. Most companies have not even got into man with their development molecules. We're now experiencing over 100 patients, certainly not seeing the catastrophic toxicity that others have reported, and very excited by this novel molecule. Beyond that, we are, as you, many of you know, working in the IO arena with our Nectin-4 CD137 molecule. That molecule we're again very excited by. Very exciting time for the company.
We think we have a deep portfolio, a highly differentiated portfolio, and we're really excited to be where we are today and looking forward to sharing more data in due course with you all. All that remains now is me to thank the participants, in particular Dr. Baldini and Dr. Petrylak. Really appreciate the support and the collaboration that we have and we're forming. Again, many thanks to everyone who's joined today's call, and we look forward to speaking with you all in due course. Thank you. I'll end the session now. Thank you. Bye-bye.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.