Okay. Okay, good afternoon, everyone. This is Daina Graybosch. I'm a senior equity research analyst here at Leerink Partners, and I'm excited to host Innate Pharma many years in a row now at our global conference. This year we have Jonathan, Yannis, and Stéphanie. We have 30 minutes, which is not a lot of time. I wanna make sure we get through three of your clinical programs. I thought we would start with your Nectin-4 ADC, IPH4502, then talk about lacutamab, and finally spend some time on Monalizumab as well. With your Nectin-4 ADC, this targets Nectin-4 and brings a topoisomerase I payload, and you've pointed to it as your next driver of growth.
I wonder if you could talk about how this molecule first is differentiated from the other Nectin-4 Topo I ADCs in the clinic?
I think Yannis will probably start off and take this one.
Okay.
Thank you. Thank you, Daina. It's a very important question because there are several Nectin-4 ADC out there. I mean, most of them are with MMA. I mean, the next generation are with MMA, so they will obviously carry the same kind of liability as PADCEV, meaning the peripheral neuropathy, and we'll have the, hopefully the same limit in term of therapeutic window, even if there are some that are expanding it a bit, but hopefully they will not be able to treat patients in the post PADCEV setting.
Yeah.
With regard to the Topo, there is less competition in the Topo. We have spotted, I would say, two main asset that are in development in the clinic. I mean, there are really we have two, but their lead asset is using exatecan, so the same payload as us. We are very much differentiated about the antibody and the linker. We have a much better antibody compared to the Lilly. Lilly has a pretty weak affinity and also a poor internalization capability. We have replicated the Lilly antibody from their patent and benchmark head-to-head versus our compound in vivo models.
We have shown that, I would say in the easy situation, when there is a ton of expression on Nectin-4, both antibody, I would say compare similarly and also similarly to PADCEV. When it comes to the low expression, which is really a key advantage for us, we are really outcompeting the Lilly antibody and we have a much greater efficacy. We are having complete responses, whereas the Lilly antibody ADC is not working at all, nor the nor the PADCEV. This is for the for the Lilly. Also more recently, we have been able to benchmark our antibody against the Hengrui, which is developed in China and was published pretty exciting data at ASCO last year.
Even if in this patient population that was published, they were selected for expression of the Nectin-4, but still they have shown response rate ranging from 30%-50% in across several tumor type. Again, we have replicated the ADC based on their patent. It's using not exatecan, this one, it's using risatecan, which is a slightly less potent Topo I. And they are also using a GGFG, which is another linker than our, which is not as hydrophilic as the one that we are using. I would say same story. We have recently benchmarked in vivo the innate compound compared to the Hengrui, and we also out-compete the Hengrui again in the low expressors.
We really think that we have this two angle of differentiation compared to the, first, the MMA second generation, because we can address the post PADCEV setting, and also compared to the other Topo I, because Based on the antibody and on the linker, we have a much more efficacious drug. Also a last point, with regard to the Lilly, it's not available for the Hengrui, but the Lilly has published their non-human primate data, and when we benchmark our non-human primate data, we have a much more stable linker, which will allow us to have a greater, potentially greater therapeutic window than the Lilly, because there is less release of free exatecan in the circulation.
Got it. Might Lilly have better bystander effect because of that? There's always a balance with.
There's always a balance, but you want to have the bystander when the drug is released at the tumor site. You really want to have like on tumor and not off tumor effect. With the systemic release of the exatecan, it's something that may limit the dosage of the compound, especially with a weak, poor binder.
Got it. Given the differentiation is most likely to show itself where Nectin-4 is lower expression, what indications does that point you to where you could really rise to the top?
In our current development program, we have an ongoing phase I study in a basket of tumor types that includes most of the tumor types that are known to express Nectin-4. What we're actually trying to do in that study is to follow the data. It's an adaptive design study, what we're able to do is backfill cohorts when we see something that's interesting. That's exactly what we're trying to do is basically follow the data and build cohorts of patients in different tumor types. I think all things being equal, if we see good signals across most of the tumor types that we're exploring in that in that basket study, clearly, the indications that will be interesting will be the bigger tumor types.
Triple-negative breast cancer, prostate, non-small cell lung could be the types of places that we would like to go. Again, providing the data takes us in that direction and we see signals from that from that dose-finding study.
Is it large enough really to have a little dose finding and backfill? Couldn't you by luck end up in the wrong place?
I think it's large enough. We've recently expanded the size of the, of the study. I think originally we were projecting it was gonna be 185 patients in total, and correct me if I'm wrong, Yannis, it's now 120 something patients. I think if you're looking at the number of patients that will be at a pharmacologically active dose, we should get to 10, 15 patients in a number of different tumor types. I think it should be sufficient to be able to establish signals in the key tumor types that we're looking to establish.
Once you start getting to these other tumor types, though, like TNBC and lung, where there's other topo I ADCs far ahead of you, I mean, doesn't that come into play? Even prostate, with the B7-H3, two of them in phase III studies already. Like, you lose the advantage you have in bladder, where the established ADC is an MMAE, which gives you flexibility to go after it. How can you really go after those bigger settings, and are they really bigger when you account for prior topo I exposure?
Yeah. I mean, clearly, we have to be cognizant of that when we're developing the product. I think we have in the, for instance, the dose finding study prior exatecan usage now. We should be able to establish a signal. I think at the end of the day, it will boil down to the quality of the results, and if we're seeing a very strong clinical signal, I think that's what will dictate the success of the product. Yeah. Yannis doesn't agree with me.
Yeah. Also the resistance mechanism is not totally the same. The profile of resistance to exatecan is not exactly the same to other Topo I like the DXD, for example. There is like a MRP1, which is an ABC transporter, where exatecan is not sensitive at all, whereas DXD is sensitive to this resistance mechanism.
You might see some activity post. Interesting. You've expanded the study. Are we still on track to see data this year? Sort of can you help us know when and so the-.
Yep
nature of that data?
Yeah. We're still on track to see data. I think the study is actually progressing very well. We have a lot of demand in the study. Every time we open up a dosing cohort, we fill it literally within a few days. The study is moving forward very nicely and more or less exactly to the original schedule. We have a choice to make. We could release data sometime towards the end of Q2, if we choose to. Basically, it would be across a basket of tumor types, where we would see a response rate across that basket of tumor types.
We could choose to wait and have a more substantial data set where we basically have efficacy by tumor type, 10, 15+ patients in each of the individual tumor types with a response rate in each of those tumor types with longer duration of follow-up, more durability. That's a decision we need to make pretty soon as to whether we go with the original plan, which was to release data early, or we really wait for a stronger data set that I think would allow investors to make more informed decisions and have a better hypothesis on what the product could be when it comes to the market. I think we're erring towards the idea of waiting for a stronger data set.
I think the message is that we're on track in terms of exactly where we expect it to be at this point in time.
Is it all just how you're thinking about investors and physicians interpreting those two data sets? What else is going into that decision that could drive it one way or the other?
I think it's based around how I think the investors would receive that data.
Yeah.
I think if you have a more substantial data set with longer duration of therapy with more patients, I think investors can have more confidence that the signal is real, that they can also more easily make a thesis in each individual tumor type. I think when you have a basket of 10 different tumors.
Yeah
... you have a handful of responses across those 10 different tumor types, it's gonna be a lot more difficult to actually make an investment thesis. I think we wanna try and make it easy, and the way to do that is basically to wait.
This is really early for this, but I think it informs how you do this early investigation in bladder cancer. PADCEV pembrolizumab is now pretty clearly established in very adjuvant muscle-invasive bladder cancer, both cisplatin-ineligible and cisplatin-eligible. We just saw the data at ASCO-GU. How does that inform how you might develop in metastatic bladder cancer? Are you already enrolling some patients post-adjuvant PADCEV exposure that may be our first-line metastatic?
I don't think we're enrolling patients as a post-adjuvant PADCEV. We're certainly enrolling patients post first-line. The possibility we could recruit some patients post-adjuvant, but I think as that's a reasonably recent approval, actually having patients that have gone through the treatment and relapsed and come out the other side, there's not so many patients out there in that position today. I think as we continue to recruit patients into the study, there's a possibility we could recruit some of those patients. The way we're thinking about this, we are trying to enrich that dose-finding study for PADCEV treated patients that failed PADCEV treatment, so that we can really develop a very sound signal in that PADCEV failure group.
That's really one of the, I would say, the more detailed approaches in terms of where we're going. We see that as one of the key pillars of the future development program. We see potentially a single-arm phase II, potentially an accelerated approval in that setting, a relatively fast track to market in that PADCEV-resistant population. I think the way we want to try and develop this is in a way where wherever PADCEV ends up, you would use IPH4502 following PADCEV. If that's in the muscle-invasive bladder cancer setting, then it could be in the first line setting that you could be using IPH4502. If it's in the first line, it could be in the second line setting, et cetera.
That's the type of label I think we will be looking to try and achieve is just really a post-PADCEV label.
Not a PADCEV combo label?
No.
You're both going after Nectin-4, but is that possible?
I think it's feasible, but I don't think that's not the way to do it quickly. I think the way we see of bringing the product to market quickly is to go in the post-PADCEV setting where there is a really high unmet medical need, where you can actually do a relatively small development program, and you can go very quickly.
Why do you think that there's any opening for single-arm accelerated approvals? I thought the shift was to be all front-runner randomized response rate going to Overall Survival in the same trial.
Yeah. I think some of the discussions we've had sort of point us in that direction. We haven't had that discussion with FDA yet, that's a discussion we will have to have, and we'll have to get their commitment to that path. All of the advisors and the key people we've spoken to see this as a potential. They see a very high unmet medical need for this particular patient group. There's really no real standard of care post PADCEV pembrolizumab, and this could fit that high unmet medical need and could really add some value for patients. We'll pursue that and we'll see where we're able to go.
Let's talk about lacutamab. This is your lead program, wholly owned. It's a KIR3DL2 monoclonal antibody. You're developing it for cutaneous and peripheral T-cell lymphomas. Let's just start with status of the program, 'cause you have a lot going on preparing for a confirmatory trial. Also you've been in strategic partnership discussions for a year, a couple years. Just give us an update of where that is.
lacutamab is actually quite advanced. We just took a little bit of the history. We actually got the BTD from FDA at the end of February last year. Off the back of that BTD, we've been able to have substantial discussions with FDA to really facilitate a really good dialogue over the last year. In that dialogue, we've been able to agree on an accelerated path to approval for lacutamab. More recently, we've been able to agree and align on the phase III confirmatory study that will be required to support that accelerated approval.
That study is quite interesting, what we've aligned on is basically an umbrella protocol with two statistically powered cohorts, one for Sézary syndrome, which is where the BTD is and where the accelerated approval would be, and then another cohort in MF. The Sézary cohort would confirm the accelerated approval, and then the MF cohort would provide the data for the full approval in mycosis fungoides. We're going head-to-head versus an active comparator in both of those cohorts. In the Sézary cohort, we go head-to-head against romidepsin, an HDAC inhibitor. Primary endpoint is PFS by blinded independent review, a key secondary Overall Survival. In MF, we go head-to-head against mogamulizumab. Again, primary endpoint, PFS by blinded independent review, and then key secondary endpoints, health-related quality of life outcomes in MF.
The quality-of-life aspect is really important, and we know we have excellent data with lacutamab from a quality-of-life perspective. We have the confirmatory study in place. FDA gave the green light for that study after a series of dialogues and basically incorporating all of their comments into the phase III program. They gave us the green light to initiate that confirmatory study for the accelerated approval process. That really starts the countdown because now what we need to do is to get that confirmatory study up and running. We've basically gone through feasibility. We have a CRO lined up. We're ready to sign the contract.
What we need to do now is to have the funding to be able to do that study, and that is now the rate-limiting step to initiating that particular study. That is coming hopefully quite quickly. The moment we can get that phase III confirmatory study ongoing and recruiting patients and underway, we can then submit the BLA to FDA based off the existing data from the TELLOMAK-2 study. We have a six-month approval clock on the accelerated approval. We hope that we'll be able to get that study up and running middle, I would say now probably early second half of this year.
six months to get all of the centers up and running, enrolling patients, which would allow us to submit the BLA hopefully sometime early in the first half of 2027, which would lead to the approval sometime in towards the end of the second half of 2027. That's the study, the confirmatory study and where we're at. In terms of strategic partnerships, we have a lot of avenues on under discussion at the moment. We're deep in discussion with potential partners from a BD perspective. We are also deep in discussions with Royalty Pharma financing for lacutamab to be able to take the study forward ourselves if we chose to do that.
We're also considering the possibility of an equity raise, and we're running the numbers on those different possibilities, and we'll choose one or two or maybe three of them to move forward to be able to fund the program and take the next steps for the programs.
Are the BD global partnerships or geographic?
No, global.
Global. Got it. I think in this confirmation study, the head-to-head versus MOGA is pretty bold, and it's exciting to take on like a real modern standard of care. What gives you confidence that you can beat MOGA?
I think if you look at our results, that gives us the confidence. If you look at the primary endpoint of the confirmatory study, it's PFS by blinded independent review. If you look at our results from the TELLOMAK study in mycosis fungoides, we have a PFS over 10 months. If you look at the MOGA results from the MAVORIC study in a line of therapy earlier than we studied with lacutamab, we see about a five-month PFS. We're roughly doubling the PFS in our TELLOMAK study in a line of therapy later in a very similar patient population from a characteristics perspective.
We would anticipate based on looking at our results on how the patients who'd had less intense therapy, how they did from a PFS and objective response perspective, they did better. We would expect when we're treating earlier stage patients that we'll see our PFS increase slightly. I think that gives us a reasonable level of confidence that we'll.
Yeah
we'll have a positive study.
Is there a role for lacutamab even earlier?
Yes.
We have to wait.
Well, yeah. I mean, again, if we, if we look into delving into the lab data, particularly MF here in mycosis fungoides. If you look here, the earlier the patients are treated, the better the results are with lacutamab. So if you... And then we've had a lot of discussions with physicians about when patients are treated. And if you look at something that's really important to physicians, it's if you look at the five-year survival of patients, when patients progress from stage two A to stage two B, you see a significant fall off in five-year survival. It goes from 78% to 46%. Physicians would like to be able to prevent that progression.
Today, they don't have a systemic therapy available that they can use in all of their patients that allows them to do that. They tend to treat those earlier stage patients with topical therapies, and they don't prevent the progression of the disease. The reason they don't use those other systemic therapies like MOGA is because they have skin toxicity as the main side effect. If you look at MF, it manifests itself in the skin in the early stages of the disease. They don't want to treat a patient with those systemic therapies that exacerbates the existing condition.
Yeah.
Basically, there are exceptions where there are exceptions where they treat earlier stage patients, but they tend not to in the real world. If you look at lacutamab and you look at the safety profile, we're basically targeting KIR3DL2, which is only expressed on malignant T-cells. and a small number of NK cells, but we know that NK cells don't take out NK cells. Basically, we don't have off-target toxicity with lacutamab. We're just basically taking out the cause of the disease, the malignant T-cells. That means the patients stay on drug a long period of time. We've got patients on drug for over five years from the phase II, over seven years from the phase I.
This is a product that you can use in those earlier stage patients in stage 1B, stage 2A, and potentially prevent that progression to stage 2A. That's something that when we're talking to thought leaders, the NCCN guideline committee, they get super excited about that and the potential that maybe lacutamab can be a game changer here and basically create a market that doesn't exist today because there aren't really systemic therapies used in those early stage patients. You can imagine you can build it on the back of topical therapy and again, hopefully have a very significant impact for these patients. We're very excited about that, and it potentially makes the sales potential of the product.
Yeah
...significantly higher as well.
Is that gated by the confirmation study? Are you starting investigator trials for these earlier patients?
No, that wouldn't be gated by the, I mean, it would be confirmed in the confirmatory study.
Yeah.
We would look to do investigator-initiated studies to start to establish that concept.
Got it. What's the current outlook in PTCL? I know that's been more led by an investigator study. That's a big market with pretty high unmet needs, important data.
Yeah. It's a very big market with a very significant unmet disease. It's again, and one of those very aggressive tumors. Basically where we are, we have single agent data which shows activity of lacutamab. We have a phase II investigator-initiated study ongoing with the LYSA group, which is the lymphoma group in France. The study is investigating lacutamab in combination with GemOx chemotherapy in heavily pre-treated patients in latter lines of therapy, and it's basically GemOx versus GemOx plus lacutamab. We expect to have data from that study sometime before the end of the year. Hopefully, it will be at ASH. We're not sure about that yet, but hopefully it will be at ASH.
We know that the LYSA group are very excited about what they're seeing, and they would like to take lacutamab forward and build what they would call an L-CHOP regimen in the first line setting for PTCL. A little bit like R-CHOP in non-Hodgkin's lymphoma. Just as a coincidence, it was the LYSA group that did the original registration study for rituximab in aggressive non-Hodgkin's lymphoma.
Mm.
that led to the global registration of the product. They have a reputation for creating very good data. Certainly that's the next step that we would like to see move forward and develop that first line combination for PTCL.
Have you seen the data?
We have seen an interim analysis of it, yes.
Got it. Has regulators seen the data?
Nope.
Yeah. Got it. That's exciting.
Yep.
Okay, another exciting one we've been waiting a long time for is Monalizumab. Is it right that AstraZeneca contract that the study with Monalizumab plus Cetuximab as chemotherapy maintenance in early stage lung could read out this year?
Yeah.
Like, I think maybe you have thought about it definitely. Why should we be excited that that is successful?
Yeah. Maybe I will start with this one because we think that, first, I mean, the biological rationale for combining Mona to durva is really high because, you know, NKG2A is expressed on NK cells, but also on CD8 T cells that are infiltrating the tumors. It's expressed on T cells, it's expressed with CD1, so you really need to block both one and NKG2A to unleash the full effect of NKG2A. That's first on the mechanism and also on the setting because AZ has shown that in the post chemo/radio setting, basically the PACIFIC setting, there is an upregulation of the NKG2A HLA-E pathway. HLA-E being the ligand for NKG2A.
There is this increase due to the to the radiation in the chemo with increase in infiltration of the CD8. We really think that's from a mechanism of action, it's really a very nice setting, which is also backed by three different phase II in early lung. You know, the one in the in the adjuvant in the neoadjuvant setting, but also the COAST data, which is like a small PACIFIC-9 trial with a 60 patient per arm. You know that the PFS has shown that by adding Mona, we can really increase significantly the PFS over over durvalumab. Now it's event-driven.
There has been no recent update, so we are still on track for our primary completion in by end of June and potentially, data release in the second half of this year.
Is it fair to say that that will be the final analysis? Has Astra disclosed if there were interims?
No.
No disclosure?
No.
Not fair to say anything? June. Got it. That, that won't be gated by... 'cause that PACIFIC-9, sort of like your lacutamab study, is two sub-studies, right?
Yeah.
Cause they still have the Oleclumab.
Yep
arm in there. Could that be slowing anything down?
The statistical analysis is designed in a way that each experimental arm are compared to the control arm, but not together.
They could each hit events separately.
Yeah
We could get press releases at separate times. Got it. Got it. Okay, one last question in the last minute. We talked about, you know, three pretty substantial clinical programs. I know 1's in the hands of AstraZeneca. You currently have cash runway through third quarter of this year. I wonder how you're thinking about financing, particularly if it'd be great if Mona read out and you got a big milestone from that. Other than that, yeah, any update on extending that?
I think as I told you earlier, I think we're exploring all options at the moment to extend our cash runway, and we have some significant CD discussions going on. We have very good discussions from a royalty financing perspective for lacutamab. We're considering an equity raise as well. I think we'll do at least one of those at some point in the future. Maybe we'll do two, maybe we'll do all three. We see a clear pathway to extend the cash runway in the coming months and then be able to successfully take forward all three of the programs.
Okay. That's great. Thank you very much. I appreciate it. Thanks everybody for your attention.
Thank you.
Thank you.