I think we can start. Good afternoon, everyone. Thanks for joining. Joining us with Jonathan Dickinson, CEO of Innate Pharma. Thanks for being with us. Maybe in case you didn't see about the company on this event, could you summarize what you're doing and your core focus?
Absolutely. First of all, thank you for the invitation to speak here today. A little bit about Innate Pharma. We're a company that today is very much focused on bringing to market a next wave of differentiated antibody drug conjugates. We have a historical background in antibody engineering, so we were a spin-out from the Marseille Immunology Institute. We've developed a range of products. Our lead ADC is IPH4502. This is a product against Nectin-4 that we're developing in solid tumors. We have a big data readout coming next week, on the 18th of November, which we'll be presenting at the Triple Meeting. Our other assets that we're focused on today are actually licensed. The first one is lacutamab, which is a KIR3DL2 targeted antibody, which we're developing in cutaneous T-cell lymphoma.
We have an accelerated approval pathway, a Breakthrough Therapy designation, and we're moving towards a BLA submission once we have a confirmatory study up and running. That's partnered with Sobi, who will take over the commercialization of the drug. The third asset that we're focusing on today is monalizumab, which is our NKG2A targeted antibody, which is being developed in stage III non-resectable non-small cell lung cancer. This particular asset has basically completed a randomized phase II off the back of that, in combination with AstraZeneca. It went into a large randomized phase III, the PACIFIC-9 study, and that study is projected to read out early next year, and on the primary endpoint. Important milestones coming in the very near term.
Thank you for that. We'll mostly deep dive on lacutamab and the ADC. First on lacutamab, so you're in CTCL, it's Sézary syndrome and mycosis fungoides, the two largest subgroups. How does the treatment need differ between those two populations, and how is lacutamab supposed to answer those two diseases?
Yeah. As you stated, cutaneous T-cell lymphoma, the two most significant segments of CTCL are Sézary syndrome, which is the smaller one, and mycosis fungoides, which is the bigger. In terms of treatment needs, Sézary syndrome is all of the patients are stage IV. There is a very high unmet medical need. The current standard of care today is mogamulizumab. Post-mogamulizumab, there are very few treatment options for patients. So, lacutamab basically is designed to work very effectively in Sézary syndrome, targeting KIR3DL2, and there is a large pool of patients who really need basically a next step. Mycosis fungoides is a little bit different. It is more of an indolent disease in the earlier stages, and the patients in the beginning are often treated with topical therapies in the earlier stages, stage 1A, stage 1B, sometimes stage 2A.
Systemic therapies tend to be used later in the treatment of the disease as it progresses through the different stages. This is where lacutamab can potentially have a very important role. Lacutamab, because it hits KIR3DL2, which is expressed pretty much only on malignant T-cells which are causing the disease, when you treat with lacutamab, all you are really removing are the disease-causing cells. This means the drug is very well tolerated. We have patients who have been on the drug from the phase I over seven years, patients from the phase II for over five years, and that means this is a drug that can potentially be used earlier because of this pretty benign safety profile wherever systemic therapies are not used.
If you look at the survival of mycosis fungoides patients, there is a significant drop-off between stage 2A and stage 2B when you see the five-year survival drop from 78% to 47%. Systemic therapies have not traditionally been used to try and prevent that because of the toxicities associated with those therapies. This is where really lacutamab is uniquely positioned to be able to intervene at an earlier stage, and potentially create a new market. So, very different in terms of Sézary and MF.
Yeah. But you already presented the data, right, of your phase II, TELLOMAK. Could you summarize what you have seen in the Sézary syndrome and MF, and how that makes a case for those?
Yes, I can. So if we look at the data, it's been presented at ASCO a couple of years ago and ASH, and what we were able to basically demonstrate was in Sézary syndrome, a very high objective response rate in the context of this disease, with patients being pre-treated with mogamulizumab, so it was 43% ORR. We see about just over an eight-month PFS, or 8.3 months PFS, and we see a very high clinical benefit rate of close to 90%, in this patient population with a very high unmet medical need. It's a little bit different in mycosis fungoides. So we see a 19% objective response rate, but also a very high disease control rate of close to 90% again, and a significant PFS, which is very important in the context of MF, of around 10 months. These were interesting data.
FDA was particularly interested in the data, and they used this data from the TELLOMAK II study to give the BTD designation for Sézary syndrome. Very important data.
That was the basis for TELLOMAK-3, which is your phase III that you start. You said it's going to be a bit different because in Sézary syndrome, you'll file for accelerated approval. In MF, it will be the registrational trial. Maybe it depends on the design. How does it differ from the phase II?
Yeah. So, basically what we have is the TELLOMAK-3 is a randomized study. It's controlled. We have two statistically powered cohorts in the study, one for Sézary, which is basically confirmatory of the accelerated approval, which we're expecting to get. In that particular arm, all of the patients are post-mogamulizumab. It's a head-to-head study of lacutamab versus romidepsin, an HDAC inhibitor, basically to confirm the accelerated approval. Then from a mycosis fungoides perspective, we have another statistically powered cohort of patients where we go head-to-head of lacutamab versus mogamulizumab. The endpoint of both of these cohorts is a PFS by blinded independent review. Key secondaries in Sézary is overall survival, which is important in the context of the severity of the disease, because all of the patients are stage four.
And then, if we look at MF, it is PFS as the primary, but then health-related quality of life assessments as the key secondary endpoints. This was something important, which I did not mention in terms of the results from the phase II. What we were able to demonstrate both in Sézary syndrome and mycosis fungoides was excellent improvement in quality of life for patients. These patients, particularly the MF patients, have problems sleeping, they have severe itch, and what we saw in the phase II was that the quality of life goes from poor to good within a very short period of time when you administer the lacutamab treatment. So really improving patients' wellbeing and quality of life.
So you have durable response, you have tolerability. In terms of where you put the treatment from a physician perspective, so SS, it is post-mogamulizumab, the setting is quite clear, although there could be a case of moving it earlier into the line of treatment. I think MF, there is more heterogeneous treatment. There is not a line as mogamulizumab that is clearly established. What is your aim with that phase III? Is it to make it sort of like become the first systemic therapy for MF patients?
Yeah. So, the design of the study basically is around proving superiority over mogamulizumab. So the idea here is that basically you would be the first systemic therapy that physicians would look to in mycosis fungoides, and to establish lacutamab as the standard of care in MF. And I think particularly what we want to be able to do is to position the drug in those earlier stage patients that I mentioned, this transition between stage IIA and IIB and the drop-off in survival. If we can position lacutamab to be used in stage IB or stage IIA patients to prevent that progression of survival, that will have a huge impact for patients. But it will also open up this potential new market where mainly topical therapies are used today, and this is actually where the MF patients are diagnosed.
This is the opportunity to intervene early when the patients are diagnosed and hopefully change the treatment course for those MF patients. Also for Sézary, we will come post-mogamulizumab. Our expectation, based on the discussions we have had with U.S. physicians, is that lacutamab will be included in the NCCN guidelines for Sézary, and it will be in a very open context. So physicians will be able to use the product at any stage and potentially use it earlier. So, we may see a situation where physicians choose to use lacutamab even ahead of mogamulizumab, based on the better tolerability profile of the product. So, I think that is important. Maybe another important consideration is that we have also been told that lacutamab will also go into the NCCN guidelines at the accelerated approval for Sézary for MF.
Despite not having an approval in mycosis fungoides, physicians may choose off-label to actually use lacutamab in mycosis fungoides based on the accelerated approval in Sézary syndrome.
It is always good for physicians. I think if you are thinking from a promotion perspective, there is a very large overlap between the physicians treating Sézary syndrome and mycosis fungoides. It is pretty much the same customer. In the U.S., we know that the majority of patients are treated in 50 centers. Basically, any work that you are doing in terms of promoting in Sézary syndrome is actually doing the pre-approval promotion for mycosis fungoides. Yeah.
One of the main events on that was the deal, Phase III study, because it is what allowed you to progress with your Phase III. Can you maybe come back on the terms, how you divide the responsibility from now in the Phase IIIs, the filing, and then-
Yeah. The deal was very important for lacutamab. Basically, the deal with the EUR 75 million upfront and the EUR 14 million in potential short-term milestones associated with the accelerated approval in Sézary syndrome, it's allowed us to initiate the TELLOMAK-3 study, and basically take that forward. In terms of responsibilities moving forward, we will continue to run the phase III confirmatory study. That's very important that we have that in our control. The reason for that is that we have the expertise in CTCL. We've run the TELLOMAK study. That was a 160-patient study in nearly 50 centers. We have a lot of knowledge of where and how CTCL is treated, so we are ideally placed to be able to drive forward the TELLOMAK-3 study. Then, we will also be in control of submission of the BLA for the accelerated approval.
We have a good relationship with FDA under the BTD designation. We've had multiple backwards and forward interactions with FDA, and as I said, have a really good working relationship with FDA. So again, based on our knowledge of the data and the studies that have been done so far, we're again in the best place to be able to pull together the BLA submission package, to file that, and to bring the product through to the accelerated approval. That's the point then when Sobi will take over the commercialization. As I think you're all aware, Sobi has a world-class expertise in rare orphan diseases, and in particular in oncology hematology. So really, they're the perfect partner to take forward the Sézary syndrome indication, which is a rare orphan disease, and then the mycosis fungoides indication when the registration comes through.
Sobi have already started the pre-commercialization work and are working diligently to be ready to be able to market the product at the accelerated approval. So, we expect to have the first patient initiation in the TELLOMAK-3 study in Q1 next year, BLA submission in the second half of next year, and then the approval early 2028. So we're in the countdown and in that pre-commercialization period now from a Sobi perspective.
Just to close on the timeline, so you have the filing approval. What about the Phase 3 results? When should we expect those things out?
Yeah. The plan is, as I said, first quarter we have the first patient initiation. That will allow us to establish a recruitment trajectory pretty quickly into the study, which will allow us to file the BLA submission and then the BLA approval early next year. Then in terms of the timelines, we are expecting roughly 15-18 months recruitment period for MF. MF will be quicker. Sézary will take a little bit longer, and then we roughly need 12 months follow-up after the last patient initiation.
So-
Basically, you are looking in the 2029 timeframe to have data, full approval in MF sometime 2030, Sézary syndrome a little bit later because it takes a little longer to recruit the patients because it is. If you look at the incidence prevalence of the two diseases, in the U.S., for instance, we have about a 300 patient incidents per year with about a 1,000 patient prevalence pool, whereas MF, we are looking about a 3,000 patient incidents and 12,000 patients prevalence. So, you can go quicker in MF than you can in Sézary.
In here.
Yeah.
Okay, perfect. Maybe we can move to the IPH4502, which I think is most exciting from an investor perspective. So we know that Nectin-4 is already a validated target, but that is on the market. What have you done differently with 4502, and why does it matter clinically?
Yeah, that's a really good question, and we spent a lot of time designing IPH4502 as a second-generation Nectin-4 ADC to overcome the limitations of the first generation. What does that mean specifically? First of all, the epitope that we hit with the antibody is non-overlapping with PADCEV, with EV. What does that mean? It means that we have activity from a preclinical perspective, not only in the high Nectin-4 expressing tumors, but also the low and moderate expressing tumors and those with heterogeneous expression of Nectin-4. That means that it could potentially open up opportunities to go into different tumor types where you have lower levels of expression of Nectin-4. Also from an internalization perspective, the antibody has demonstrated better internalization. That's important from a payload perspective and tumor cell killing.
If you combine that with the binding affinities, then we think we're differentiated on that particular part. The next level of differentiation is around the payload, and we have basically switched out the payload versus PADCEV. So instead of a tubulin inhibitor with an MMAE payload, we have a topoisomerase I. In this case, we chose exatecan. That gives us the ability to overcome the resistance in patients to the failing PADCEV. They have an upregulation of MDR1. Exatecan is not subject to that resistance mechanism, so we're able to go potentially post-PADCEV and generate activity. This is something that we've been able to demonstrate pre-clinically, but also more recently, we've disclosed that we have seen responses post-PADCEV in our phase I dose-finding study. The final level of differentiation is around our linker. We have a proprietary linker.
We very tightly bind the payload, and that means we have low levels of free circulating exatecan, which helps to improve the tolerability of the product. Again, something that we've communicated from our dose-finding study is that we've seen very low levels of hematological toxicity, which will be the expected off-target tox associated with an exatecan payload.
That's an excellent transition for my next question about the data you'll be presenting at ENA. You'll have 76 patients, 11 tumor types, very broad, I'd say. But what will it say about your therapeutic window? How low you can start seeing activity and how high you can go in terms of dosing?
Yeah. We basically have completed the enrollment in the dose-finding study. We completed in July this year. We have 76 patients, as you mentioned. What I would emphasize is this is a basket study tumor approach, so there are over 10 different tumor types in the study across a range of different doses. What are we going to be able to see from this data? Clearly, we will be able to profile the safety in a very effective way, and that will be one key thing that will be presented at the ENA meeting next week. The second will be around the PK, and this is important from a free circulating payload perspective, which is associated with potential toxicity, so we will be able to very nicely profile the PK.
Then the final piece is we will be able to see signs of activity in a very heavily pre-treated patient population. What we will have to do is to look at the totality of the data, because you can imagine with 10 different tumor types across a range of pharmacologically active doses, with maybe a handful of patients in each of those different subgroups, it will be very difficult to draw general conclusions on individual doses or individual tumor types, probably even more complicated. From a totality of data perspective, we will be able to see the level of clinical activity and how that changes by dose.
So, yeah, as you say, it will be a handful of patients per tumor type, but you will have to take the drug somewhere, obviously, in it. First, do you have any internal benchmark of efficacy to get further, or would you go, for instance, post-PADCEV because there is where the strong rationale is, you have some responses, so it would also make sense to go for that indication. So the question is, what is your thinking for taking the drug a step further?
Yeah. The thinking around taking the drug into the next steps, there are basically a number of aspects to that. Clearly, there are some benchmarks out there. EV-302, the PADCEV study, in the patients who failed the therapy, they went on, a good proportion went on to receive platinum-based chemotherapy. That really provides, I would say, an evidence base for what chemotherapy can deliver post-PADCEV, and it is around a 20% objective response rate. Clearly, that is the lower end of the benchmark that you need to be able to achieve moving forward. You need to be able to beat that. If we look at some of the data sets that are out there that have come from potential competitive products, you are looking in the 30%, low 30s that you would need to be able to get to.
We need to be confident from our data set that we can deliver at least that level of efficacy to be able to move into the next steps, which would be dose optimization and taking the product forward to those next steps. You will be able to see this data at the ENA presentation next week.
We will have the next steps.
We also plan to illustrate the next steps. We have an investor event which we will do post the data presentation at the Innate meeting in Barcelona. We will do this event in London at the Jefferies Conference off the back of it.
We will basically have a standalone investor event, where we will have a KOL who will be discussing the data and the context and where this can go next.
EV-302 is a good benchmark in terms of what you want to achieve, but there are also other Nectin-4 ADCs. Most of them are around the same stage as you, so phase I, phase I/II. What would you need to demonstrate against those comparators you can use against, obviously? Is that mostly in prospectives? Is that tolerability? Is that the broad application on solid tumors? What would be the angle for this?
I think there are a number of potential angles here that would basically allow us to go forward. I think what we need to be able to demonstrate first of all is that we have a reasonable level of activity, or we have a way to get to a reasonable level of activity. That is critical. If we look at the other Nectin-4 ADCs that basically are being developed, particularly with a Topo 1 payload, most of them seem to have fallen by the wayside recently. We saw at ASCO that Lilly had two assets that they presented. One was discontinued, the product with the exatecan payload. The product with the camptothecin-98 payload seems to at least be on hold.
It does not seem to be making the next steps, and that is maybe because of the metabolism issue they have with camptothecin-98, which is linked to CYP2D6 metabolism, where there is genetic variation, and they saw extreme toxicity in the low metabolizers. That does not look to be moving forward at this point in time. The Merck product seems to have been discontinued, as we found out last week when it was dropped from their portfolio. The only exatecan-based ADC that is left is the Hengrui product, which is being developed in head and neck cancer. It is predominantly with Chinese data today, so I mean, it is a different benchmark. We have benchmarked internally versus that from a preclinical perspective and shown superiority over the Hengrui compound. I think we feel quite confident that we have a good path forward where we will have differentiation.
It is probably a mixture of the tumor types we choose to take forward, and really seizing, I think, the obvious opportunities as we move forward.
Yeah. Quite a clear path for the moment. You have your partner that said, you have lacutamab with Sobi, now with AstraZeneca. When would be a good time to bring a partner for IPH4502? How far are you willing to go on your own?
Yeah. It's a very good question. I think what we're doing is basically very much keeping our options open here. We're funded to be able to make the next steps in terms of moving into the dose optimization phase for IPH4502. I think what we need to do is look at the data and look at what makes the biggest business sense for our stakeholders. Is that developing across multiple tumor types based on the data and having a very extensive program, in which case maybe we need a partner, and maybe we need a partner reasonably quickly? Or is it that we focus on driving maybe a urothelial cancer indication post-PADCEV, which is maybe a simpler and easier route to take initially, and certainly something that we could do ourselves?
But I think the key thing here is that we evaluate the options, and we'll make the decision that's really best for the product, for our shareholders, and for the patients.
And you can keep generating more data in that sense.
Absolutely. Yeah.
A bit of flexibility. We have 20 seconds left. Can you summarize the key milestones in the next, let's say, 12, 18 months?
Yeah. Key milestones. First of all, we have the data readout for IPH4502 next week, ENA. We then have lacutamab, first patient initiation, Q1 next year. Then the submission of the BLA for accelerated approval, second half of next year. Then accelerated approval, first half of 2028. From a monalizumab perspective, we have the key readout of the PACIFIC-9 Phase III in the first half of next year.
Very clear. That's a wrap-up. Thank you very much for-
Thank you.
taking the time.