Innate Pharma S.A. (IPH) Earnings Call Transcript & Summary

Welcome, everyone. At this time, I would like to welcome you to Innate Pharma Investors and Analyst Meeting. Today's conference is being recorded. [Operator Instructions]. At this time, I would like to turn the conference over to Jonathan Dickinson, Chief Executive Officer of Innate Pharma. Please go ahead.

Good morning, everybody, from here in New York City. We're delighted to be here on behalf of Innate Pharma this morning to basically share with you the latest and greatest from a Nectin-4 ADC perspective. Before we do that, I would like to -- if we can go to the next slide, just to take you through a couple of things. So first of all, we have our standard disclosure statement. So we can go to the next slide. So this is the agenda we have for you today. So I'm going to give a quick introduction. I'm then going to hand over to Yohann Loriot, who is joining us today from the Gustave Roussy Institute in Paris. He's an expert in the Nectin-4 space, and he's going to take us through some of the latest from a Nectin-4 perspective, where then I will hand over -- we'll go on to Yannis Morel, who is our Chief Operating Officer and Yannis will take us through all of the latest preclinical data from an IPH4502 perspective. And then we'll hand over to Sonia Quaratino. Sonia's our CMO. Sonia will take us through the clinical development plan for IPH4502 and the latest in terms of where we are to date. So if we can go to the next slide. Just to remind you, before we get into Nectin-4, we have 3 pillars to our strategy at Innate Pharma, we announced this at the beginning of the year in terms of refocusing our strategy. And those 3 pillars are based around our ANKETs. They're based around ADCs, which is what we'll be focusing on today, and then our current late-stage assets. So if we move to the next slide. You can see where we are overall in terms of takeaways from an Innate pharma perspective. So today, we have actually 8 products in the clinic, a mixture of partnered and proprietary assets, a mixture of late-stage and earlier-phase assets. We're driving forward our ANKET platform, our NK-cell engagers. And recently, we've initiated the collaboration with IFLI which we see as a validation of what we're doing in the lymphoma space with IPH6501. Also, our ANKETs are moving forward with our partners with Sanofi. We are in Phase Is and Phase IIs with the lead asset IPH6101. We'll talk about ADCs later, so I'm not going to go into any more detail. And then in terms of late-stage assets, we have lacutamab, which went through a recent FDA interaction. We have an accelerated path to approval potential. We're working on the confirmatory study, which is advancing very nicely and we're looking to establish a partnership to take that particular asset forward. And then finally, we have monalizumab which is in partnership with AstraZeneca. We have a big milestone coming up in 2026, which is the primary endpoint, big clinical milestone in 2026, and we're looking forward to that. Cash position of the company. We've communicated audited finances to the end of this year, and we're working on basically extending that runway well into mid-2026, and that will be announced after we have year-end results and the audited accounts. So on that point, I'd like to hand over to Yohann Loriot and he can share some of the latest from an Nectin-4 perspective.

Good morning or good afternoon, everyone. So I'm Yohann Loriot, so I'm a Medical Oncologist, Professor of Medicine here in Paris at Paris-Saclay University and the Deputy Chair of the Department of Early Drug Development at Gustave Roussy. And one of my interest, I would say, is the oncology. So I was involved very early in the development of many ADC and including enfortumab vedotin which is relevant for today. So as you know, ADC's new technology to administrate chemotherapy, but also any other adjuvants and there is -- there are basically 3 different pillars, 3 different components of ADC, the antibody, the linker and the payload. And historically, most ADC were construct based on tubulin inhibitors, but there is now new trends since 2022, the numbers of topoisomerase inhibitor based ADC is going up and now is even super to tubulin inhibitors. And especially now there is a growing number of exatecan based ADC, so one component of the topoisomerase inhibitors class. So Nectin-4 is a validated target and why because as you know, enfortumab vedotin, an ADC developed by initially Seattle Genetics and now Pfizer and Astellas was approved worldwide in one specific disease in urothelial carcinoma and metastatic urothelial carcinoma based on 2 Phase III trials that I will show you in a second. So the first and the only one ADC targeting Nectin-4 approved across solid tumors. So it provides some huge interest in targeting Nectin-4. And as you can see on this slide, there is a lot of new ADCs currently under investigation. So basically, there are 2 class of ADC targeting Nectin-4 on the antibody that include tubulin inhibitors as a payload and the other class, as I mentioned earlier, the topoisomerase I based ADC. So at the bottom of this figure, you can see here the numbers of ADC with tubulin inhibitors as a payload. So some of them are currently in Phase II, Phase III trial, like one from China MW2821 and one from Bicycle Therapeutics called BT8009 or Zelenectide Pevedotin. Other ADC with tubulin inhibitors payload are currently in Phase I and Phase II. But now we have more and more, as I said before, ADC with topo-1 inhibitors, and ADC in clinical trial. So in a Phase I trial from Eli Lilly, from Merck, that is of course from Innate and there is only Phase-III trial ongoing with the ADC and topo-1 payload in a Phase III trial. So why there is some excitement and commitment now to develop more and more ADC target in Nectin-4. As mentioned earlier, we have positive Phase-III trial with ADC targeting in Q4. So the first in this class of ADC is enfortumab vedotin, which is approved in metastatic urothelial carcinoma as single agent in patients previously treated with chemotherapy and then PD-1 inhibitors in cell line but also in first line, so upfront in combination with immunotherapy. So at the top here, you can see the Phase III EV-301 trial. So in cell line patients were treated with EV monotherapy versus old chemotherapy, would say, like [indiscernible] docetaxel, paclitaxel so the -- of course, these trial met the primary endpoints and the median of survival was around 30 months versus around 9 months with chemotherapy, and importantly enough response rate 40% for patients treated with enfortumab vedotin versus only around 18% for the patient treated with standard chemotherapy. There was a rationale to combine enfortumab vedotin and Immune Checkpoint Inhibitors. It seems that ADC can induce some immune activations and a Phase I trial was conducted 5 years ago and reported at ESMO 2019 showing that in around 60 patients, the response rate in first line, so in naive patients, response rate could be as high as 70%. So based on this data, Phase-III trial was conducted, EV-302. So again, we are here in first-line metastatic setting for patients with urothelial carcinoma. Patients were treated with either the combination of enfortumab vedotin and pembrolizumab or the standard of care, so the chemotherapy followed by maintenance treatment with immunotherapy. And here, you can see here, the dramatic improvement in overall survival, hazard ratio was 0.47. So now it's a new standard of care in many countries in North America, in Europe and worldwide. But you can see that there is still some problem. The first problem is the primary resistance, around 20%, 25% of the patients do not benefit from this combination upfront. And number two, the acquired resistance, secondary resistance, as you can see here, the shape of the curve, so meaning that some patients will develop resistance to this drug even it's very active initially. So as the drug is in daily practice in the first line and second line, so we are now very experienced with the use of this drug. And so it's a drug that is tolerable, but there is some problem in terms of safety profile. The first problem is a skin action and why? Because around 15% of the patient will develop serious skin reaction. So Grade 3 and 4. So it is a main problem initially when we gave this drug to the patient. And the second problem and maybe more importantly, the peripheral neuropathy. So vast subset of patients will develop neuropathy after 6 or 7 months of treatment. So sometimes it could be quite serious. You can see here that Grade 3 and 4 occur actually in around 7%, 8% of the patient, but even a Grade 2 is a problem because you have to discontinue the treatment to reduce the dose and sometimes the patient is not willing to be treated with this drug anymore. So the most common treatment related adverse events leading to discontinuation of EV is indeed peripheral neuropathy and one priority in terms of clinical research as of today is how can de-escalate this drug because of the risk of neuropathy and how we can develop new agents without this risk of neuropathy. So of course, if we can develop new ADC with low risk of neuropathy because maybe we can use a payload that's different from MMAE, it could be something very important in daily practice. So the enfortumab vedotin is approved in bladder cancer. So it's validating the role of Nectin-4 as a target for ADC. But you have to know that beyond bladder in Nectin-4 is expressed in many other tissues in lung cancer, in breast cancer, in GI cancer. The thing is that there is no validated sign of activity of -- with Nectin-4 ADC so far. The response rate is quite disappointing in many other tumors, and so including again GI, breast cancer or lung cancer. So there is clearly opportunity and unmet need for all other tumor beyond bladder cancer. So there is a need development of next generation of Nectin-4 ADC to overcome some challenges that we are facing in daily practice. The first challenge that we have is the low and heterogenous Nectin-4 expressions in other tumors and also in bladder cancer. So what we need here, it's a new ADC that could target Nectin-4, but with a higher bystander effect to address this limits of the low and heterogenous level of Nectin-4. So number two, so the second challenge is how we can overcome acquired resistance and the resistance to the approved ADC, so with MMAE as a payload. So meaning that now what we have do and try to do is to develop different payloads and basically different payloads to address this question of primary resistance and secondary resistance to enfortumab vedotin. And the last challenge, as mentioned earlier, is the toxicity and how we can deal with the risk of peripheral neuropathy and skin toxicity. So meaning, again, that we have to provide patients with better ADC or ADC with better safety profile, limiting this risk of neuropathy.

So hi, everybody. So I'm very pleased to be here with you today to present to you our preclinical data IPH4502 which is our drug conjugate of Nectin-4 ADC conjugated with exatecan. So next slide, please. So first, I will not be very long on that slide, which is more a reminder on the rationale why Nectin-4 is a very good target for ADC. So it's obviously a validated target, as PADCEV is approved. But just to remind you that it's a molecule which is part of the family of different Nectin molecule, which are adhesion molecule. And Nectin-4 has a very limited expression in normal tissue. Here, you have two examples of Nectin-4 staining in normal lungs. There is no expression. There is a little expression in some of the epithelial tumor tissue like esophageal or breasts and where, as you -- as was mentioned by Professor Loriot, there is the highest expression in the LC issue, is in the skin. Interestingly, and I will come back to that in a moment, it's overexpressed in a lot of different cancer like urothelial cancer, but also breast and lung cancer and has also been described in the past as being of poor prognosis, here you have like the retrospective study prospective in lung showing that when there is a high expression of Nectin-4, it's also of bad prognosis of this lung cancer patients. Next slide, please. So then what -- so what we did in order to address the limitation of the current Nectin-4 ADC compound and especially PADCEV. We looked at how we can really increase the potential of Nectin-4 targeting ADC and we looked first at where Nectin-4 is expressed. So I would say that urothelial cancer is a bit the outlier because it's really where the prevalence of high expression is really the most important. And that's where PADCEV is approved. But it's also approved in many more solid tumors, but that is low to medium expression level, like especially esophageal cancer, breast cancer, lung cancer as well. So we think that there are really here an opportunity to target all these non-bladder tumor type, which are showing a lower expression of Nectin-4, but also as mentioned by Professor Loriot in bladder, also to have a molecule that is overcoming the limitation of PADCEV, both in terms of therapeutic window and also different toxicity profile, but also addressing the relapse after the -- and the resistance mechanism after PADCEV. So next slide. So what we've done is that we have designed a proprietary ADC based on the proprietary antibody, which is binding a different epitope than PADCEV. And again, I will come back to that in a moment. So it's not competing with the binding for Nectin-4 with enfortumab. And it has also a competent FC which is able to mediate immune mechanism at some point. In terms of linker payload, we choose the exatecan, which is a very well-known topoisomerase I inhibitor which has the advantage of having a very good bystander effect. And we conjugated this payload to a drug antibody ratio of 8%. So really sticking a lot of exatecan to the antibody. And we managed to do that by using -- and this is a bit of our secret sauce, a linker that is very hydrophilic which is also very stable. That is allowing us to basically mask the hydrophobicity of the exatecan. Next slide, please. So here on the left, you can see the epitope that we have identified for the -- our drug candidate. It's at the inch between the distal C2 domain and the V domain. And actually, enfortumab but also almost all the antibody that we have looked at in different patents are really binding the V domain. So we are actually having a very unique binding epitope that all the others don't have. And also an important feature of our drug candidate is on the right, which is the hydrophobicity. It's hydrophobic chromatography here that you can see, which is basically a measure of the hydrophilicity of the molecule and the more the molecule is -- the peak is on the right, the more hydrophobic is a molecule. And you can see that enfortumab is far more hydrophobic than IPH4502, which is rather in the same range as trastuzumab at its take off, which -- and this is a very important feature because the more the drug is hydrophobic, the worst PK it will have. So I think an hydrophilic molecule here is important also for the manufacturing first, but also for having a good PK progress. Next slide. Then we characterized the efficacy of this molecule in very, I would say, classical in vitro and in vivo experiments. So we are having a very good subnanomolar killing activity of drug candidate, and we have characterized also the in vivo activity with a minimal effective dose of 4.5 mg/kg in xenograft model. But then -- and it's on the next slide, we have also, very interestingly, benchmarked the internalization capacity of our antibody compared to others. And you can see here in gray, the E curve, it's the enfortumab, so the parental antibody of PADCEV, and we have made also a homemade version of, which is LY here, which is the parental antibody of the Eli Lilly molecule. And you can see that we are having a far better internalization rate compared to this -- I mean, better than enfortumab, but really far better than the Lilly compound, which is also another molecule currently in Phase I with the exatecan linker-payload technology. And then what we have done and we have on the next slide, generated, again, a homemade version of the Lilly candidates using the parental antibody and the linker technology that they have published in their paper and poster. And you can see on the right that we are having a better killing capacity. We are having approximately one log better potency compared to their compound. So we are really comparing favorably compared to the Lilly topo-1 ADC. Next, we -- we characterize the efficacy of the IPH4502 in the panel of PDX model. So this patient derived tumor model. These are small pieces of primary tumors that are implanted in the mouse. And we have looked at this series of 14 different bladder cancer model in the mouse. And you can see on the left, the efficacy of enfortumab vedotin. So you can see that in some model, there is a very strong tumor regression, but some of them are resistant to PADCEV. On the right, you have the efficacy of the IPH4502, you can see that all the models are responding to IPH4502. So we looked at -- understanding this difference between the two compounds and on the next slide, you can see that one important fact is the level of expression of the Nectin-4. On the left part of the slide, you have a model, a PDX model where the expression is considered as high with the H-score, which is a way to quantify the expression, which is a -- by multiplying the frequency by the intensity. You can see that in this high expresser model, basically the efficacy of PADCEV and IPH4502 are rather similar. But when we are exploring the -- comparing the efficacy in MEDIUM-TO-LOW expresser model, and this intensity of expression is decreasing, you can see that PADCEV is not working at all. So this model do not respond to PADCEV whereas IPH4502 can induce complete regressions in this model. So we can really potentially address all the patients that are having a low-to-medium expression level of Nectin-4 where the PADCEV is not working. Next slide. We then looked also at another important factor, which is the heterogeneity of the tumor because you have the expression level, but also in some tumors, the expression is not completely homogeneous. So what we've done here is that we have recreated artificially a model where the Nectin-4 is expressed only on half of the tumor. So you can see that on the left side, so we took the Nectin-4 expressing cell line and treated with IPH4502. It's completely resistant; when we knock down, we crisper out the Nectin-4 from the cell line. The cell line is becoming completely resistant. So there is no nonspecific toxic effect of the ADC. So really, you need the expression of Nectin-4 to have the toxicity efficacy in this model. And when we mix in a 1:1 ratio and recreate a tumor model, which is expressing 50% of Nectin-4 and 50% of the clones do not express the Nectin-4, we have complete regression of the tumor in this model, really showing that the antibody needs to be internalized by the Nectin-4 expressing clones and then release the payload and kill the neighboring non-expressing cells. So it's really very important because it's allowing us to address the tumor-type where the Nectin-4 expression is more heterogeneous. Next slide. Then -- and it's an ongoing effort that we are having at it. We are exploring also the different type of solid tumor where IPH4502 is working. And here you have one of our first example, which is in TNBC. And again, the previous slide were on the panel of bladder cancer, we have very efficacy here in TNBC, we are also having a very good efficacy. And now we are working at accumulating this data in other tumor types. Next slide, Also, one important aspect that [indiscernible] underscored, while the emergence of resistance to enfortumab. And there has been a recent paper on a very limited number of patient cohort which is also a retrospective study. But I mean, it's something that is known that you have one of the mechanism of resistance to chemo is the upregulation of this ABC transporter, like the MDR1 molecule. And here you have an example on the left of one patient having a bladder cancer with the primary tumor expressing Nectin-4 and there is no MDR1 on the primary tumor. But then when they looked at the metastasis, there is a slight decrease of the expression of Nectin-4, so it's becoming, I would say, moving from high to medium expressor but there is also a very important increase of the MDR1. So this is very important also because many chemotherapy that are approved like [indiscernible] are known to upregulate the MDR1. And then they have correlated retrospectively the expression of Nectin-4 and MDR1. And again, I will not enter into the detail because it's more hypothesis generating than really the conclusive data. It's pretty clear that when MDR1 is expressed and here the PFS of the patient treated with enfortumab, there is enfortumab is not working at all in the patients that do have this upregulation of MDR1. So on the next slide, you can see what we have replicated, try to replicate that in preclinical model by using a very aggressive mouse tumor model that we have engineered to express Nectin-4 and which is known to express this MDR1. So we've taken this MC38 Nectin-4 expressing cells. And as you can see on the bottom line, we have [indiscernible] cells with enfortumab vedotin to PADCEV and I would say, as expected, it's totally resistant. So we have here a model of primary resistance to EV. And interestingly, when we treat with IPH4502, there are some responses in this model, and we even try to treat a mouse that were exposed to PADCEV. And when they were progressing, we treat them with IPH4502, and we can induce tumor regression even under the exposure of PADCEV in this tumor model. So really showing that we could really address this potentially, this primary resistance mechanism. Then on the next slide, we actually -- so this is one paper who is describing the expression of the Nectin-4 under enfortumab vedotin treatment. And it looks like the Nectin-4, I mean, even if it can be modulated, it's still expressed upon treatment with EV. And we then generated a model to address the secondary resistance, the acquired resistance to EV. And that's what we have done on the following slide. Next slide, please, where we have treated. So we have used a PDX model, which is on the left, which is sensitive to PADCEV and IPH4502. So when we take this PDX, we can induce complete regression in all the mice. And it has a pretty medium level of expression of Nectin-4 with H-score of 200. And by having this selection pressure by multiple injection of PADCEV, we are able to generate a model that is becoming resistant to PADCEV. The expression of Nectin-4 is conserved, so we are still having an H-score of 200. But this model is now relapsing when we are treating the mice with EV, whereas it's totally sensitive to IPH4502, really showing that we can address this secondary resistance mechanism by switching the payload to topoisomerase inhibitor. So then next slide. We then further looked at the potential application of the IPH4502. It's as Professor Loriot highlighted now EV is of course in first-line better in combination with [ prembo ]. So we really wanted to look at whether IPH4502 could at some point also eventually be combined with PD-1. You can see that this model is not very sensitive to EV. When EV is combined with [ prembo ], there are some complete responses. But when we look at the combination of IPH4502 with the PD-1, we are really having a very good complete regression in this mouse model, really showing that we can combine potentially IPH4502 with PD-1 at some point in the development of the drug. So then we looked at the tox and PK of our antibody, nonhuman-primate. Basically, we -- the findings were, I would say, what we expect with this class of drug mostly related to the exatecan from GI and hematological toxicity. We have like this skin hyperpigmentation, but really milder than what was described with enfortumab. We don't have this peripheral neuropathy issue because which is really related to the MMAE payload. And what is really important to keep in mind. So we treated this monkey up to 30 mg/kg. So we are having a very good exposure to the drug related to the hydrophilicity of the ADC. And what is really interesting is on the bottom of the slide on what is in red. So we have a very low release of free toxin or free exatecan. And you know that this is really one thing that you want to avoid to have this release in the circulation of the payload because it will limit the therapeutic window of the ADC. And we think that our data are good because we have benchmarked them and it's on the next slide with what the others are showing. So on the left, you have the data that are published for enfortumab, which has a very, I would say, a more narrower therapeutic window and because you know that with MMAE, we cannot dose really higher than approved dose for enfortumab vedotin's 1.25 mg/kg. But when we benchmarked our data with what we think is our closest competitor has shown, which is the molecule from Lilly and it's the data coming from their poster, we are having a far lower release of free exatecan in the non-human primate. So potentially, it's also another element of differentiation with the internalization, the better killing capacity and also the more stable linker-payload system that we are having. So next slide. And this is to conclude that I hope that we -- I managed to demonstrate you that with this IPH4502, we are having a very novel and very differentiated Nectin-4 exatecan ADC with high internalization capacity and bystander effect with the linker-payload that we are using, it translates into a very good exposure in the nonhuman primate and very low release of exatecan which is also an advantage for our drug, the efficacy, preclinical data package is showing superior efficacy over enfortumab vedotin with a broader spectrum of activity and especially in the low Nectin-4-expressing model as well as in some model of primary resistance, but also acquired distance to PADCEV and we are now showing efficacy also in other tumor types. We are now having data in TNBC, but as I said, it's something that we are continuing. And we are also having, but it's more for the long term, a very good combination potential with PD-1 blocker. So I will stop here and hand over to Sonia for the clinical development plan.

Thank you, Yannis. And here in the next slide please, I hope we managed to convince you that we have a very differentiated asset here. All the data that Yannis has presented at CITC and AACR last year and the new data that have been presented today, form the basis for us to move in the clinic with this differentiated asset where we see that we really have an opportunity, an opportunity to have a broader therapeutic window, an opportunity to have a better safety profile than what has been shown for PADCEV and correctly highlighted by Professor Loriot, an asset that, yes, produce some efficacy at the cost of high discontinuation rate and peripheral toxicity. With exatecan as a payload, we should not have any peripheral toxicity because exatecan is an old molecule that's been used before. We know what the toxicity is for exatecan and peripheral toxicity has never been reported. We also have the potential to address not only the high expressor tumor like bladder, we really have the potential to address all the tumor types that address any level of Nectin-4, moderate, but even low. And not last, we have the potential also to address tumors that have been previously treated and with PADCEV and they become resistant. And so we can address tumors that have a primary resistance because perhaps they didn't have enough expression to be responsive to PADCEV or they upregulated the multidrug-resistant mechanism and became resistant to payload. And so for all these reasons that I highlighted here in the green part of the slide, we believe we have a differentiated asset, and we are very proud to have, let's say, started our first in-human trial at the end of January. In the next slide. Thank you. So we really capitalized the strategy of the clinical development is really capitalized on the two main factors. Indications like bladder that are resistant to PADCEV and in that respect, we can address a growing medical need in urothelial carcinoma. And eventually, quickly move to Phase I -- sorry, quickly move to first line also in combination with anti-PD-1 in this indication, but also expand in all the different indications that express Nectin-4 and are currently not responsive to any of the Nectin-4 ADCs because as Professor Loriot has shown, many tried to develop in different indication; lung, head, and neck, but the response rate has been at best disappointing. In the next slide, here, we are talking about unmet medical need in many different indications. You can see there are very common tumor types like non-small cell lung cancer that you may argue is really unmet. But still, there is a room to improve even in this indication; breast or colorectal cancer, where we are still using old-fashioned chemotherapy; Prostate, head and neck, ovarian, gastroesophageal junction, cervical, esophageal and also melanoma, even though fantastic immunotherapy has reduced the medical need in this indication. In the next slide is the study design for the first in-human trial that has started recruitment in -- at the end of January this year. And I'm also happy to say that we already treated the first three patients on this trial. And this is a dose escalation that is guided by Bayesian design. And so we are going outside of the classic 3 plus 3 that is a very rigid design to adopt a more flexible design using the BOIN statistical method and also have the possibility to enrich cohort or increase with backfill cohorts. And therefore, we will not pause the recruitment during the dose escalation, which is always a problem when we have, let's say, patients that may be lined up for treatment and also have the possibility to expand our knowledge and indication of interest. In general, we think we will recruit in total around 45 patients between the dose escalation and the backfill cohort and then move in a single indication to dose optimization. And of course, we can do dose optimization in more than one indication. The primary objective of this first in-human is as usual, safety and tolerability and the secondary endpoint is assessment of PK, immunogenicity and signs of activity, preliminary efficacy. Sorry, I keep moving. Next slide. Now we also have as part of the first in-human trial, a biomarker plan for two reasons because it is very important to assess the level of Nectin-4 expression at baseline in these patients. We do not prospectively select patients for expression of Nectin-4 because this would require a validated assay, would need a threshold of sensitivity for the assay and would take too long for patients that are critically ill that usually end up in a first in-human trial. But it's extremely useful to understand what type of tumors are we going to have effect upon? Because there are, apart from the negative that I described here, but let's say, the easy one are what you find in the top -- and then okay. This one, high and homogeneous. And these are the ones that usually should respond well to Nectin-4 ADC. Let's say, even like [indiscernible], high expression, homogeneous expression let's say, it's a given. Where we are going to test our hypothesis and where we consider we have a winning strategy is about tumors that have a low and homogeneous expression as you see on the top or like most of the times, we know that tumors are highly heterogeneous. We may have patches with high expression and other patches with either no expression or no expression at all. And this by standard effect that Yannis has very nicely described. It basically means that by binding to the areas that express for instance, even a low or high expression of Nectin-4, we have the possibility to, let's say, diffuse the payload to the adjacent cells that may not express the Nectin-4 and therefore, heal anyway, even, let's say, this highly heterogeneous and patchy tumors, because this is really the reality of patients. In the next slide, we also look, and this is, let's say, easier to do for soluble markers, like soluble Nectin-4 by having different samples during treatment, on treatment. And soluble Nectin-4 may be a useful parameter to follow because it has been shown, let's say, highly upregulated in cancer and versus healthy donors. And it may also decrease over time mirroring the clinical efficacy of patients. In the next slide, here is where we are at the moment, as I mentioned, we just started the study. We have completed the first cohort. And we -- since we have -- the sites are highly engaged with this program, we consider we may have data around preliminary safety and activity between the end of this year and beginning of next year. and immediately start with the dose optimization that since it is going to be in selected indication, will take time depending on whether the indication is more or less rare. At the same time, depending on emerging data, we have the possibility it will start more a basket trial in combination with standard of care with anti-PD-L1 or else and have an expansion cohort from selected indications as single agent, but this is going to be in 2027. And next slide, thank you very much to all of you for attending the meeting today.

Okay. Thank you. So what we'd like to do now is to open up the questions. So we have Professor Loriot on the line. Maybe we'll start in the room, Henry. Is that okay? Yes? So I think we have a question here. if you speak loud, maybe I don't have to repeat it. But if not, I'll repeat the question.

Sure. Justin from BTIG. Maybe a few questions here. Maybe firstly, aside from advisors compound, obviously, there's a few other developmental ADCs or in Nectin-4. Could you highlight just how do you see your [indiscernible] versus advance development currently.

Do you want to take that one Yannis?

Yes, as you have seen in one of the -- on the very first slide, there are I would say the first wave of second generation is Nectin-4 ADC, which are more based on the MMA payload like a bicycle compound, but also [indiscernible]. So all these agents will at some point and the same kind of limitation as [ Pat ] said, because it will have the same kind of -- maybe a different dose, but the same kind of toxicity profile because the peripheral neuropathy is related to the MMA. It will be sensitive to the same kind of mechanism of resistance because MMA is sensitive to MDR-1 regulation. And then there are the other -- the top 4. And in the U.S. and Europe, the only company that is -- we are competing with is Lilly. They have these 2 compound, one, which is -- which has started the Phase 1 in March. So we are a little bit behind. But as I showed during the preclinical portion of the talk. We think that we are having a better assets because internalization and clean capacity is reality key for the therapeutic index of the final ADC.

Understood. And Yannis, could you speak to any differentiation that you might expect on the dose or dosing administration profile compared to other agents.

Potentially with less -- again, it's potential but with less release of [indiscernible], we can potentially dose higher than the Lilly one. And also one key differentiation. So it's a linker payload. We are not using the same linker. We think our one is more stable. And the Lilly compound is the Fc silenced. So that it does not engage in any immune mechanism. So it's a pure targeting. So -- that we are targeting, but we can also have the effect on the ADCP and ADCC mediated by the antibody. And that's something that our antibody can do.

And Jonathan, if I may maybe one question, Sonia.

I think we have to repeat the questions apparently because it's not coming up through loud on the [indiscernible]. Maybe I can repeat it after you.

Yes. My question is, I understand that you first dosed your patient recently. Congratulations. When do we might see the first data from those programs?

Can we just repeat the question. So the question was that we understand that the first patient has been dosed. And the question is when we might see the first data?

Well, as I mentioned previously, we hope to have all the safety and initial, let's say, antitumor activity. by the end of 2025. But as always the caveat in first in human is that anything can happen even a [indiscernible] may slow down the recruitment. The sites are highly, highly engaged. As I said, we -- in one week, we have filled the first cohort, which was great. But I cannot guarantee that it's going to be the same all the time. But outside that we are optimistic on this.

And clinical side, just how many that you have [indiscernible]

We are recruiting in the U.S. we have opened two sites in U.S. in December already. And we will have 4 sites in the U.S. and some sites in France.

So I think that Yigal was first. The hand went up a little quicker. So the question is, are we trying to enroll patients who had PADCEV or both. So I mean, Sonia if...

We do not have any exclusion for patients have been previously pretreated with PADCEV. On the contrary, we are welcoming, let's say, the enrollment of patients who had primary resistance or secondary resistance to us. The only thing is that there may not be so many patients available. But there is no exclusion, let's say, in the protocol.

Another question. [indiscernible] your Nectin-4. So are there other Nectin-3 there. Are there ones that you go after, so much profitable?

Yes, it's a family. There is Nectin-1, Nectin-2, Nectin-3.

Not from our actual analysis.

Can you maybe call or you can talk about the benchmarks that other ADCs have seen outside of urothelial carcinoma. Can you speak to whether they -- those benchmarks were enriched for Nectin-4 expression. And without any enrollment for Nectin-4 expression, what gives you confidence in these 45 patients you'll be able to see a signal that's more attractive than what those competitors saw. If you end up enrolling, let's say, 30 CRC patients with very low Nectin-4. Maybe like the worst-case scenario.

Of course, we will try to prevent that any skew of a particular indication in the study. And so it is, let's say, highly unlikely that we are going to have the situation of 30, let's say, CRC patients in the study. And this is the reason why we have excluded, for instance, pancreatic cancer from the list despite pancreatic cancer express Nectin-4, because the moment you have pancreatic cancer in the study, you are fully loaded with only pancreatic cancer. And so we would like first to have a good signal before eventually opening to pancreatic, which is for sure a high unmet medical need, but extremely difficult to treat for different reasons. In terms of patient selections, there are different reasons for not going at this stage in a patient selection. And of course, I appreciate your concern, which is actually also our concern, a retrospective analysis may lead to a higher than envisage number of negative patients. In that case, we have, let's say, time to optimize the method for selection, but also the issue, especially in first line -- sorry, in the first in-human trial, where we have patients that need to be treated as a matter of urgency because they have exhausted by protocol, any standard of care, and they are extremely, let's say, ill. The time for turnaround, having first a positive trial screening that basically means they are eligible for the study. Having the biopsy, analyzing the biopsy and have the result will take so long that the patient will progress. And on this -- on this, I actually would welcome Professor Loriot to comment because he has been an investigator on the trial. Yohann, how do you see this topic.

So yes, it's very challenging to now to envision some bar marker in the field of EDC and especially for, let's say, EV. The data that we have from EV-301 and even 302 trial showed that actually in bladder cancer, most simpler express Nectin-4 has different level. And the -- the level of expression is not clearly correlated with the response. So there is no need based on this data to select patients as on Nectin-4 expression. As you know, there is -- and as I discussed earlier, ADC has 3 different components. So to envision a biomarker, a good biomarker in the field of ADC priorly we have to take into account for the expression of the target, of course, but also maybe the internalization, the migration of the ADC in the metastasis, the sensitivity to the tumor cells. So that's why -- so except some very limited ADC in oncology, like in breast cancer with trastuzumab, [indiscernible]. There is very, very few ADCs that are approved with a good bar marker.

Obviously, the molecules don't have great activity outside of bladder. Is that impacted by Nectin-4 expression.

Do you mean in different indication?

Yes, the competitor ADCs. Just to help us contextualize that bar.

Yes. To my knowledge, there is no [indiscernible] to my knowledge, all the data that was wrapping together in this time, there is no consideration of patients based on [indiscernible] it's that you have certain type of tumor where [indiscernible] are more coherant and [indiscernible]. But in other tumor types, the expression is really more viable and the proportion of patients with low medium expensive level of Nectin-4 is better. So you have a higher probability of showing a lower response rate in this tumor type.

We have never seen really a direct correlation that has been presented, at least by others that, let's say, even the 10% response rate that they observed was due because a higher expression compared to the patient that did not respond. To my knowledge, this has not been [indiscernible].

[indiscernible]. Even though topoisomerase inhibitors are being used the chemotherapy for a long time, why does [indiscernible] not really looked at as a payload when MMAE has always been payload choice?

Yes. I don't know if you heard that Professor Loriot, but I think the question was why topoisomerase inhibitor is not being used as a payload or in the past or looked at in the past and it's always been MMAE. You're on mute Professor?

Yes. It's a very relevant question. Actually, it was based on the profile and the clinical profile of this patient treated for metastatic urothelial carcinoma. Usually, it's not the case. But historically, these patients were quite old with a lot of comorbidities. And so this patient were previously treated with platinum-based chemotherapy. And then there's nothing. So historically, there was some clinical trial with [indiscernible] and they were not able to receive anything further. So the clinical trial that could investigate topo-1 inhibitors were very limited due to the rapid progression of the tumors, number one, and number two, that they were not fit enough to receive topo-1inhibitors historically in third line, on fourth line because performance studies was quite bad with a high risk of toxicity and especially with regard to the neutropenia.

Was there any rationale not to go to an exatecan payload earlier versus MMAE?

In terms of -- in the context of ADC, no, there was so -- I mean -- so the first -- the first going in the field of urothelial carcinoma with the Enfortumab Vedotin because we knew from the past that [ tumor ] inhibitors could be active in bladder cancer because we have some clinical trials suggesting that MMAE would be something important for bladder cancer. So that's why the first ADC, so EV was associated was built on MMAE payload. But as I said before, so in preclinically, so in preclinical model, we know that bladder cancer model are sensitive to topo-1 inhibitors. So why we don't have any clinical trial with topo-1 inhibitors historically, it's just because of the difficulty and the challenge in the past to conduct trial with such agents in bladder cancer. But it doesn't mean that topo-1 inhibitors are used less in bladder cancer.

If you look at the Innate's technology field. For many years, the paradigm was to go with the ultra potent payloads. And before Daiichi and DXd, everybody was or looking at either more potent toxin with other lower bar potentially like some PDs, and it's really the NR2 showing that it's better to stick more molecule with lower potency and less molecule with a high potency that could work. And I think this is one turning point, the success of NR2. And second thing is also a technical point in that [indiscernible] it's not that easy to stick exatecan on an antibody without having an aggregation of the product. So you really need to work on the linker to mask this hydrophobicity to be able to have something that is soluble and monomeric and not just create aggregates.

Can I follow up with a quick question? What gives IPH45 the ability to target low expressing Nectin4 tumors where EV doesn't seem to be a function.

Yes. Repeat this question first, Yannis.

Yes. Yigal was asking why we think that IPH4502 is able to get low expressor Nectin-4, where EV is not in or working? I mean we have some hypothesis. I think first, the epitope, which is different, might be an explanation. We still don't understand exactly why, but it might be an explanation. And also the fact that with different sensitivity of the payload might also explain why we can capture this low expressor with IPH4502.

Kelly [indiscernible] Jefferies, and thank you for [indiscernible] I have two questions. First, on [indiscernible] does actually IPH4502 also respond [indiscernible] in low-expressing tumor types other than bladder cancer model. And secondly, for your Phase I data readout,readout, do we anticipate or do you prefer to have a sizable patient subgroup who had a prior [indiscernible] experience.

So the -- I will take the preclinical question. So the question was whether there is activity in PDX model other than bladder in low expressors, and this is an ongoing work. So we are currently accumulating there, and we did not disclose yet, but it's an ongoing effort.

And regarding the question, the clinical data, the question was whether we prefer to have PADCEV pretreated patient rather than other indication, let's say. We do not have, let's say, at the moment, a preference. We do not exclude any -- as I mentioned before, we do not exclude patients with [indiscernible] that have been previously pretreated with PADCEV. And actually, this may constitute, let's say, a quick way to move forward if we had enough patients that are experienced on PADCEV and they respond to IPH4502. And so this would be great to have. But the idea is really do fast on this first-in-human and only in a second time, produce once we have evidence of safety and hints of clinical efficacy, really to try to shape the clinical development in one indication rather than another depending on business case or faster speed for approval. We would leave this up at the second step.

Two quick ones from me. [indiscernible] from H.C. Wainwright. You spoke a little about our enthusiasm for the epitope and the high affinity that you have to target. Of the different cancer subtypes you're investigating, are there differences in epitope expression of Nectin-4? And if so, we do the modeling or preclinical work that would indicate your target epitope, there might be higher affinities for certain tumor type?

So the question was -- I will shorten it a bit. The question was whether the epitope targeted by the IPH4502 is different. I mean there is different expression of the epitope in different tumor types. And so far, we don't know exactly. So we have looked at that, but we don't see any difference. It looks like it's the same Nectin-4 molecule Express in every tumor type. So that's why I'm saying that we don't know exactly -- I understand exactly the molecular advantage of this.

And then second point, we talked -- a couple of other questions were already on patient selection and you sort of described that strategy. Are you trying to or -- of your 45 patients trying to wait at all towards a particular indication like that Nectin-4, you see of those 45 [indiscernible] are there another cancer subtype where Nectin-4 is not kind of approved target, but do you think there is a lot of possibility there. Let's make sure we have 5 there so we have statistical significance [indiscernible]

Okay. Well, the question and I summarize here, whether we are trying to shape the recruitment in the dose escalation. And again, here, the main objective is really to grow as fast as possible. And therefore, we don't want to really hold a dose level because we are not having, I don't know, the melanoma that we had in mind. The idea is really to move faster, and we have this backfill cohort that is, let's say, optional, so to speak. And so we can really -- they are shaped and for instance, ask the investigator, can you please get patients who head and neck. And in that respect, we can perhaps wait, but not in the dose escalation, as otherwise, I'm sure that when we are at the end of 2025, we won't be happy that we don't have results.

[indiscernible] based on your [indiscernible] model, understanding that the IPH4502 will be closed once 3 weeks for the first 4 weeks, and then [indiscernible] basically be translated to [indiscernible] cost revenue compare to [indiscernible].

If you're talking about the dose regimen that we used in the study, we for a Q3. And so an administration every 3 weeks, that is from the beginning until progression or toxicities.

[indiscernible]. So can you give some color on the weight loss impact on the [indiscernible].

There was no particular toxicity on the weight loss in the PDX. I mean we are using doses that are tolerated by the mice.

[indiscernible] is there [indiscernible] suggesting overlap between [indiscernible] being this week? And then how do you think about competition [indiscernible].

Yes, yes. To my knowledge, but it's something -- there is no association with these receptor. So yes.

Second question was will show that [indiscernible] disease. I believe that lines message for high cell line, but regarding [indiscernible] you have announced is global [indiscernible].

No, it's question. So the question was whether the so we have benchmarked the IPH4502 again, the Lilly antibody in a cell line that is a high expressor whether we have similar data in low expressor and it's something that we are currently doing.

A couple on the Phase I trial enrollment. I asked it a kind of a different way than it's been asked before. I know you speed is sort of part of the objectives. I don;t want to bias too early but how many patients do you need to be comfortable in selecting a tumor type for extension hypothetically, you have 11 tumor types, 4 of each be about 45 patients. They have different Nectin-4 and different dose levels. I mean, is that enough to have confidence in your tumor type selection, did that sort of getting to like really want to bias that or restrict that to sort of have that confidence and you get that signal. And then -- my second question sort of the biomarker. Bicycle report it's been early, but potentially trading correlation with Nectin-4 gene application and activity in this basket solid tumor context and do you consider looking at that in your biomarker [indiscernible]

Do you want to start, Sonia?

Sure, sure. Regarding of how to define the signal, considering that the number is relatively small. First of all, it's not a given that we are going to have all the patients that are listed. And it is very likely. Every time that there is, let's say, a basket trial where you have, let's say, 10 indication in reality, you are going probably to get 5 because plus let's say, one patient in the other indication, which does not constitute, let's say, a significant number to make any decision in that respect. We always have the possibility based on, for instance, a pharmacodynamic changes to have some hypotheses and in that respect, use the backfill cohort. And bear in mind, there is always a possibility to amend the protocol to expand, I don't need to, let's say, a quote for instance, the initial PD1 trials, the first in human, they ended up with 1,300 patients not in this situation, of course. But to have a protocol amendment to have another, let's say, in 40 patients in case we want to expand, would certainly be not an issue. Anyway, we can really expand in this indication where we think we may have something and see whether that materializes or move to a different indication. In terms of this gene amplification. This is something since we have, let's say, peripheral sampling that is taken on treatment. This is something that we can always test. But perhaps you want to expand on this. We may not think it might be really significant for our study.

Yes. It's something that we follow and [indiscernible] assuming a coalition between the normal expression and this gene amplification [indiscernible], it's shown in urothelial, but also in other different tumor type. So we will follow that. But again, we think that we may be active in lower expressors. So that's why it might not be needed.

One quick follow up there. Where do you think investigator bias from an enrollment perspective? I know that's sometimes a case where they look forward a certain product or drug for clinical trial perspective, do you think it will, maybe that's why it could go bladder? Or do you think the investigators are kind of trying to look to see how Nectin-4 may be brought into other tumor types?

Are you asking if there is a bias from the investigator perspective?

Yes, like in which tumor and why they want to enroll [indiscernible]

Well, I think -- and here, I would also like to ask Yohann Loriot for this because he is an investigator. But let's say, from my 20 years' experience, of course, very often, there is a kind of bias because if you're asking -- if your investigator is a specialist in GU, it is very likely that it's going to be a patient in the GU space and not a patient with lung cancer. It is quite rare that, let's say, the Phase 1 unit is totally, let's say, indication agnostic. But please Yohann, expand on this because...

Yes. So you're right. I think there is a risk, but to me, it's very minimal because the different Phase I unit that has been selected are quite agnostic. Just for example, our unit here. We are -- in our units, we are drilling all the tumor types, including hematology, so lung, breast, GI, [ GY ], bladder, of course, prostate. So we won't have any bias. But of course, in this context of this specific if a patient has been, for example, treated with EV and [indiscernible] our center to find in the trial, I think it is very well with the trial because there is a strong rationale to give this new ADC for a patients who has been previously treated, but generally speaking in department where all the tumor type are represented, there is no bias or very limited bias.

Can you talk about -- this is Daina Graybosch from Leerink Partners again. Can you talk about the soluble Nectin-4 and whether you're ADC binds that or there's differences based on your epitope binding that from the ADCs?

Yes. So Daina is asking whether the IKH4502 is binding to soluble Nectin-4. Yes, I mean, to our knowledge, it should bind because it's cleared at the -- near the membrane. So the epitope is -- we didn't check on the -- cancer patient. It's something that we will do. But in all likelihood, the antibody should bind the soluble Nectin-4. But please keep in mind, if you look at the dosage that we are presenting, they are in the nanogram per ml. And given the dose that we are considering, we will be 4 to 5 log more drug than the soluble Nactin-4. It's unlikely that it's acting as a sink for the drug. But it may be well like Sonia presented, an interesting biomarker to follow to look at the, I would say, the tumor load in these patients.

What kind of [indiscernible] auction break.

Well, as you know, we do not have an anti-PD-L1. And therefore, we have to rely on, let's say, approved drugs. It is very difficult at this stage to say the preferences for one or the other. There is no reason why, let's say, one anti-PD-L1 should be more effective than the other in combination with the ADC. And as you know, I think this all depends where we can find the collaboration.

Okay. We've got some questions on line. So Chang Li at Oppenheimer. Do you think there's an accelerated approval path for IPH4502 in PADCEV refractory urothelial cancer on cancer patients. For non-UC tumor types, what type of which tumor are you more excited about? Yes. And I think the other questions have been asked.

I'll take this. Certainly, for the parts for refractory patients IPH45 efficacy in this patient would constitute a Fast Track for registration. And so on the first part of the answer is, yes. And what tumor times we are most excited. Well, there are many with high unmet medical need. And outside, for instance, colorectal is certainly one where we are still using kind of old-fashioned therapies. No real breakthrough recently in colorectal. But I wouldn't exclude any indication that are all unmet medical need at the end of the day. Yohann, do you have a preference.

No, no. So -- so there is -- so as we mentioned earlier, there is no Nectin-4 agents approved in other tumor types, except -- so bladder cancer. So there is a need for many other solid tumors and especially, for example, lung or breast cancer and especially triple-negative breast cancer where to topo-1 inhibitor could be something very important to consider. So I think here, it's probably 2 important solid tumor to consider. Regarding the first part of your question, and the possibility to get an accelerated approval definitively, yes. As you know, there is no standard of care for patients previously treated with EV and pembro. So the level of evidence is for platinum-based chemotherapy or [indiscernible]. So clearly, there is a past year.

And then a follow-up. Yes.

You mentioned it looks like with dose escalation, you're not doing the 3 plus 3 typical you [indiscernible]. So what's the least number of patients you could have to enroll for those? Like how much faster could you go and get to your recommended [indiscernible] versus the standard?

The question is around the dose escalation and the statistical method. The number of patients that we recruit for any dose is 3. And so in that respect, it may look similar to the 3 plus 3, with the exception that in the classic 3 plus 3, the moment you get through the LT, this is the end of the escalation with the [indiscernible] design, you have the possibility to expand the cohort and still escalate to the next level. And so basically, it prevents stopping the dose escalation due to [indiscernible] DLT.

And then a follow up question from Chang Li with Oppenheimer. Will Nectin-4 receptor [indiscernible] affect the bindings like 502 or Nectin-4 ADCs? Are you planning to use prophylaxis in the Phase I study for potential [indiscernible].

Yes. I mean, yes, I mean if Nectin-4 is cleared, there is -- there will be no binding to the tumor cells but binding to the [indiscernible] Nectin-4. But again, that's something that has been shown in the literature that Nectin-4 is highly expressed in primary tumor, it's still expressed on metastasis. So it should still be in tumor and to metastasis.

And there is no prophylaxis reduced. So far, we need to build a safety package to understand if prophylaxis is needed.

And then a couple of more questions online. Is the primary catabyte of after linker exatecan? Or is it chemically modified version [indiscernible]

It's exatecan.

And what sort of -- I think you covered this a bit, but what sort of drug sink effects are you anticipating, given Nectin-4s high expression in skin and other healthy tissues? might this affect be more pronounced or reduced with different epitope than PADCEV.

We expect to have the same -- same sink effect than with PADCEV, except that we don't use the same linker payload for a different mechanism in the [ tox ] study in nonhuman primate. We didn't really observe. I mean, except some Hyperpigmentation in the skin, which has been described with other and which is reversible after the -- after the recovery period. So we do not -- we expect less toxicity than what is described with PADCEV.

But in the clinical trial on the other hand, we have a full list of, let's say, expected toxicities and the skin toxicity is one. And so we just need to monitor.

Okay. I think that's it from a question specific. So I'd like to thank everybody here in the room for attending everybody online for attending. Thank you for your time. I hope it's been useful and you've got some valuable information, and we'll be looking forward to moving forward on our Nectin-4 journey with you and keeping you informed as we go through the next steps. Thank you.