Transgene SA (TRGNF) Earnings Call Transcript & Summary

Good morning, and welcome to the Transgene conference call. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Transgene website following the event. I'd now like to turn the call over to Lucie Larguier. Please go ahead, Lucie.

Thank you, Tara, and hello, everyone. Thanks for joining us on today's call, and we will discuss our new TG4050 Phase I immunological data. Today, you will have the opportunity to discuss with Dr. Alessandro Riva, our Chairman and CEO; and also, I'm glad to introduce Katell Bidet Huang our Head of Translational Medicine, who has presented a poster at SITC last week. In addition to the presentation being broadcast, you can also access the SITC poster on the SITC website and on Transgene's website. Alessandro and Katell will run through the data and how they fit within Transgene's strategy in the individualized neoantigen therapeutic vaccine field. And after this discussion, we'll take and answer your questions. So before we begin, I'd like to remind everyone that today's discussion contains forward-looking statements, which are subject to numerous risks and uncertainties. And with this, I now hand over the call to Alessandro.

Thank you, Lucie, and good afternoon and good morning, everyone. We will focus today's call on the promising TG4050 clinic data in patients with operable head and neck squamous cell carcinoma. As you know, we discussed a few times previously, TG4050 is our first individualized neoantigen therapeutic vaccine that is derived from the myvac platform. This tailor-made vaccine is based on the FDA as a viral vector that is a well-established backbone for vaccine development and demonstrated already strong immunogenicity and ability to induce a durable and specific immune response. In addition, the combination of AI-driven antigen selection with our own proprietary computational design engine and in-house manufacturing established TG4050 as a truly individualized therapeutic vaccine. If we go to Slide 5, you see the trial design, the study that we presented at ASCO. And as you know, we have evaluated TG4050 in a randomized Phase I/II study in operable head and neck cancer patients. The data that we are going to discuss today is focused on the Part 1, the Phase I part of the Phase I/II study. The ongoing Phase II trial is progressing at a very good pace, and we expect to complete the randomization in early 2026. Now as for the randomized Phase I part of the trial, we have enrolled 33 patients, of which 32 were available according to predefined criteria in the protocol, and we're randomizing 2 arms, one receiving TG4050 after the standard adjuvant therapy and the other arm being subject to watchful follow-up also after the standard adjuvant therapy. All the trial endpoints from the Phase I trial were met. Safety was very good. Immunogenicity has been demonstrated against the predefined neoantigens that we have selected for the vaccine. And the efficacy in the next slide also has been demonstrated, representing a very solid proof of principle for TG4050 in operable head and neck cancer patients. This data that you see in this slide were presented at ASCO. It represents 24 months follow-up for all patients. And you can see that with this relatively important follow-up, no patients randomized in the TG4050 arm experienced a relapse. So we have 100% of patients being disease-free. On the other hand, we observed 3 relapse among the patients that did not receive TG4050. In addition, the immunological data presented at the SITC conference this year, just last week, confirms the mechanism of action of TG4050 that results in the promising disease-free survival data that you can see in this slide. With this, I now hand the call over to Katell, who will present the immunological data in more details. Katell, please.

Thank you, Alessandro. So now I will go through in the next few slides through the data that we presented last week. And so basically, the aim of all of this was to confirm or get insights into the mechanism of action of TG4050. Our working hypothesis that TG4050 by delivering these patient-specific sequences encoding the tumor neoantigens can induce T cell responses that are specific to these neoantigens. And this -- when these T cells encounter their targets, so tumor cells that present the antigens, they will be able to kill them via the release of cytotoxic mediators and eliminate them. So we examined several aspects of this model experimentally. And then we found specifically that TG4050 can indeed induce T cell responses to the vaccine neoantigen, that's point one. Also that these responses persist beyond the end of treatment, that's point 2, that the functional profile of the cells is what's called cytotoxic and tissue resident, point 3, and that also TG4050 triggers an expansion and a diversification of the tumor-specific T cell repertoire. So together, this data really comforts us in the fact that we have a strong rationale for the TG4050 mechanism of action. Next slide, please. A few more words about the methods that we use to establish this. So we had a mixture of established and more cutting-edge methods. First of all, the T cell response was quantified by 2 complementary methods in the blood. So we had interferon gamma ELISpot without prior amplification, and we also had peptide MHC Class I tetramers. And these 2 methods are complementary and they allow us to get a very broad overview of the T cell response to treatment. We also then monitored the persistence of the T cell response by this peptide MHC Class I tetramers. And then we isolated the neoantigen-specific T cells and analyzed their functional profiles by flow cytometry and by single-cell RNA sequencing. And then finally, we tracked the origin of the T cells by TCR sequencing by comparing what's happening in the blood after treatment and what was present in the tumor before treatment. So first, on the next slide, we will look at the T cell response to the vaccine neoantigens, and this is comparing baseline so pretreatment and at day 64, so after 7 doses of TG4050 by ELISpot and tetramer. When we take into account the 2 methods, we observed that 11 out of the 15 patients for which we had evaluable data had responses in Arm A. So that's 73% of the patients. We also observed that these responses were often polyepitopic, meaning that we had multiple responses to different neoantigens in the same patients. And we saw that this could go up to 16 out of the 13 neoantigens in the same patients. And importantly, we also saw that all responding patients except one had at least one de novo response, which means that it was a response that was not present before treatment, but was detected after treatment. So this really confirms that TG4050 can prime the immune system against the neoantigens and generate this robust and broad T cell responses to the -- what we included in the vaccine. Next slide, please. So we were happy to see that we could elicit T cell responses at early times after vaccination. But if we want to have long-term protection in the patients, we have really to determine whether these responses are long-lasting. So that's what we did by tetramer, and we followed the kinetics of the response throughout the treatment for 6 patients that had between 1 and 5 tetramer each. What we saw is that the patients treated with TG4050 as this single agent developed CD8 T cells to the neoantigens quite rapidly after the start of treatment and reached a peak by the end of this induction phase. But what was quite striking was to see that until the end of treatment, so what's on the graph here up to day 240 and beyond. And even after the treatment was stopped, so these points that are month 18 and month 24, so up to 1 year after the end of the dosing, we could still measure the sustained CD8 T cell responses and the levels were still really close to what we observed at the peak. So this showed us that TG4050 has induced really durable antitumor immunity and so that we have the potential to provide long-lasting protection against a relapse. Next slide, please. So next, we focused on the function of the T cells that were induced. And we know that T cells with antitumor activity should have cytotoxic effect of functions. And so we determine if we could see this in the T cells induced by TG4050 using 2 methods. What you can see on the left panel is flow cytometry. So there, we used at classical CD8 sub-cell markers. And then we saw that all the neoantigen-specific T cells were either from the T effector memory subsets or the terminally differentiated effector subset like T-MRA. And importantly, that this effector phenotype was maintained at this M24 point, so 1 year after the end of treatment. So this indicates that we have -- we can expect long-lasting functionality of the cells. On the right side, what we can see is single-cell RNA sequencing, and we use this to dive even more in-depth into the functional profile of the CD8 T cells. And as a control, we compared the neoantigen-specific T cells to other cells specific to viral antigens such as CMV, flu and MVA in the same patients to really be able to compare what we were seeing. And what we could observe is that the neoantigen-specific cells were the one that expressed the highest level of markers associated with cytotoxicity, such as granzyme B in all the subsets, but also that they express this marker that's characteristic to tissue residency. Here, it's ZNF683, that's the main marker compared to other subsets. And so what it tells us is that the neoantigen-specific cells are likely to be able to go in and out of tissue, and they should be particularly effective at patrolling these tissues and where they can scout for the target cells and then kill them. What we could also see is that the neoantigen-specific T cells express high levels of markers that are commonly associated with chronic antigen expression -- exposure, sorry, that is seen usually in the context of tumor immunity. And those are PD-1, CTLA-4, CD39 and TIM-3. So through this, we can hypothesize that some of the neoantigen-specific T cells have indeed previously encountered their targets in the context of the tumor and are being recalled by vaccination. Next slide, please. To go through this in a little bit more detail and determine whether indeed TG4050 could recall preexisting tumor-associated T cell clones, we turn to TCR sequencing. And there, we examined the changes in the neoantigen-specific T cell clones in the blood during treatment and compare them to the T cell repertoire that was found in the tumor prior to treatment. And the first observation was that multiple T cell clones, indeed up to 19 were induced for each responding neoantigen. So we had a response that were both polyepitopic and polyclonal. But also when we compared the T cells that were expanded in the blood to the T cells that existed in the tumor prior to treatment, we found that TG4050 induced both new T cell clones that you can see here in the blue lines on the graph, but also expanded pre-existing tumor infiltrating T cell clones that are here depicted in as red lines. And we think this is a really important observation because it highlights the relevance of the predicted neoantigens we selected in the context of antitumor immunity. So therefore, the conclusion of all this analysis is that TG4050 treatment induces an expansion and the diversification of the T cell repertoire, which lasts until at least 1 year after the end of treatment and that the cells have effector cytotoxic and tissue resident profile, showing that they have all the attributes that are expected for being able to kill tumor cells. And we think that this is very encouraging data and consistent with the model we proposed earlier in which TG4050 induces this tumor neoantigen-specific cytotoxic T cell responses, which can then prevent tumor recurrence. So with this, I now hand the call back over to Alessandro to give more perspective on what it means.

So thank you, Katell, for this very promising data that, again, supports the mechanism of action of TG4050 and the approach of individualized neoantigen therapeutic vaccine. Now moving forward, this slide summarizes the main catalyst that we plan to share with the community during the next couple of years. And just I would like to focus on the critical one and specifically for the next year. So first of all, we are going to end the randomization of the randomized Phase II study that is expected to be completed by Q1 2026. There was a slight delay versus what we previously announced due to administrative issue related to the Christmas and the end of the year holidays. for scheduling and visit for patients for the follow-up assessment. So that's number one. And then we plan to have the 3-year disease-free survival analysis presented in second half 2026 from the Phase I trial. And then with regards to the Phase II part of the trial, we plan to present the first immunogenicity data by the end of 2026. As for the efficacy data for the ongoing Phase II trial, you remember the primary endpoint is 2-year disease-free survival and the data will become available as soon as patients are available for 2 years disease-free survival with either an event that is defined as relapse or death or a 2-year follow-up, whichever occurs first. This can be expected either by the end of 2027 or at the early beginning of 2028. In parallel, with advancing TG4050 in head and neck cancer, we continue to prepare a new Phase I study in a second solid tumor indication, one with a different biological profile from the more immunological called head and neck tumors that we are currently treating. We aim to initiate this study as soon as all regulatory process is completed and all the financial condition, of course, are met. So we expect to start it very soon. And for this trial that is going to combine TG4050 with an immune checkpoint inhibitor we would expect to complete recruitment and obtain immunogenicity data within 12 months after trial initiation. Now I'm on Slide 16, Lucie. Just a kind of conclusion before opening for Q&A. As you have certainly understood during this presentation, we are building on the strong momentum that is around our myvac platform. And our vision continues to be focused on advancing the individualized neoantigen therapeutic vaccine in operable solid tumor patients. The field of INTV, as you know, continues to mature, and we believe that it starts to be kind of derisked from both a scientific and clinical point of view. And the data presented at ASCO in head and neck cancer with 100% of disease-free survival at 2 years provide a very solid proof of principle for TG4050 in an indication where a significant medical need still exists despite the advances from also the immunotherapy, including checkpoint inhibitor. The Phase I study delivered translational data that Katell has presented that are consistent with the model in which TG4050 induced tumor neoantigen-specific cytotoxic T cell responses that may help prevent tumor recurrences. And our myvac platform has the broad potential in early tumor setting that goes beyond head and neck, and we intend to continue, of course, to leverage this potential for the best of operable solid tumor patients that are at risk of relapsing. We continue to remain focused on the strategic imperatives that I just summarized. And with our key milestones ahead, we are confident that we will position the company for the next stage of its growth. Katell, Lucie and I now are available for answering all your questions, and I hand the call to the operator to -- for the Q&A. Please, operator.

[Operator Instructions] So our first question comes from Chiara Montironi at Kempen.

Congratulations with the beautiful work, really elegant way to get insight into the mechanism of action. So I was wondering if you could put the data in perspective of using TG4050 in combination with immune checkpoint inhibitors. And also if you could talk about the next step for TG4050 in head and neck, whether you still intend to talk about pivotal plans next year?

Yes. Thank you, Chiara. So I mean, your first question about the potential of TG4050 in the context of checkpoint inhibitor. So we believe that essentially, there is the possibility to have a profound synergy between the 2 approaches for the simple reason that an individualized neoantigen therapeutic vaccine increase the diversity of the neoantigens that is going to identify by the immune system. And of course, if you add then a checkpoint inhibitor that take out the break of the T cell, you can imagine that, that diversification is further potentiated by the addition of a checkpoint inhibitor. So we believe that for the right indication, where a checkpoint inhibitor makes sense, the addition of TG4050 increase significantly the neoantigen availability for the immune system and therefore, create synergy and potentially a good outcome for patients. As we mentioned in the presentation, Chiara, so we are now preparing a new study in a new indication where we are combining TG4050 with checkpoint inhibitors. And as for the head and neck cancer development, we are assessing with the panel of experts in head and neck. The next step after the Phase II study that is going to be completed by beginning of 2026, the next step in the context of all innovation that has been presented at ASCO with the checkpoint inhibitor. So more to follow. And of course, we are committed to share with you as soon as we have a clear path forward. But certainly, checkpoint inhibitor will represent a critical milestone for that approach. And then I answer also your second question was the next step for TG4050 in head and neck. Hopefully, Chiara it is clear.

Our next question comes from Amara Singh at Intron Health Research.

Following this promising data for TG4050, what feedback have you received from KOLs and clinicians?

So I mean, the feedback from the clinicians and the head and neck experts and the scientists too have been quite good, I would say, excellent. So they were impressed and they are and they continues to be impressed by the clinical data. And of course, after the SITC presentation with the data that Katell has shared with us, they have been even more impressed because everything is going to be kind of connected, right? So now there is a reason why we are seeing in clinical setting what we are seeing because we are demonstrating that really the vaccine is able to induce a specific immunogenic response to the pre-identified neoantigens. And also the phenotype that has been described by Katell, this effector memory phenotype and the tissue residency and the cytotoxicity. I mean everything speaks about the fact that the vaccine is doing a good job. Of course, we need further confirmation in the randomized Phase II and for the immunogenicity data that we will disclose in 2026. But the community across the board, Europe, United States of America is very excited about what's going on.

So I'm now going to turn the call over to P.J. Kelleher at LifeSci to read the written questions.

[Operator Instructions] Alessandro I'll start with a few that have come in so far. Can you talk about any of the data you guys have on control arm patients?

Yes. In the control arm patients, we have not assessed any translational medicine immunogenicity data, right? So this was not planned in the randomized Phase I. And for the randomized Phase II part of the trial, perhaps Katell, you may want to take this question.

Yes. So we are indeed planning to look at it in the Phase II part of the trial. So obviously, we do know that there are some spontaneous T cell responses to tumor neoantigens. That's what the checkpoint inhibitors work on actually. And so we want to check whether what we see in the treated patients is very specific to the vaccination. However, given the profile of the response that we see, so the fact that they are induced at quite strong level within weeks after vaccination and then they are sustained until the end of treatment, we don't think that's really something that would happen with spontaneous responses that are likely to be of lower -- lower level of responses and maybe more fluctuating as well, especially when we measure them in the blood. So short answer is, yes, we will do this, and we will show the results as soon as we have them.

Yes, by the end of 2026, so preliminary results, as we mentioned. Thanks, Katell.

Awesome. And then a follow-up question. How do you compare these data presented with other individualized cancer vaccines out there?

So you're talking about the immunogenicity data, I assume?

Yes.

Yes. So Katell, do you want to start and then maybe I continue.

Yes. So that's obviously a question we've been asking ourselves many times. And I would like to point out first that it's very difficult to compare across trials, mainly because of the different methods that are being used. So for example, we use this ELISpot method without expansion and then some others use ELISpot that have pre-expansion steps. So then this will change dramatically the magnitude of the responses we obtain. So if we look at the competitors that have used the closest methodology as we have, this would be the BioNTech studies. And there, we see that basically the responses we measure in our patients are in the same ballpark, both in terms of magnitude and also the breadth of the response, which is the number of neoantigens that are reactive per patient. So they have reported for pancreatic cancer patients and also for their larger solid tumor indication that they had a median of 2 reactive neoantigen per patient, and that's also what we see. So at this point, we are confident that we are at least comparable to what others are doing.

Yes, that's -- I think I don't have anything else to add.

Awesome. And then a question on the Phase II trial. Do you plan to generate similar data in the Phase II trial, including a control arm here?

Yes. The answer -- the short answer is yes, right? So -- and again, we plan to show the first data set from an immunogenicity point of view by the end of 2026.

Awesome. And then kind of a follow-up in the same vein on the Phase II trial. what are you guys looking to see in that Phase II trial? And is it a replication of what you've seen so far in this data set?

Yes. Essentially, yes, the answer -- again, short answer is yes. The beauty of this Phase I, Phase II study that it will also bring some statistical power to the overall disease-free survival because we are going to combine Phase I and Phase II data. So we expect a kind of a similar magnitude of difference, but this time with some statistical power again that -- and statistical considerations that will strengthen further the Phase I data.

Awesome. And then maybe a final one here on the next trial, but in the next planned trial for a new indication in combination with the immune checkpoint inhibitors, will we be able to determine whether the individualized vaccine synergize with immune checkpoint inhibitors at the mechanistic level?

I mean the answer is yes. And of course, I cannot disclose yet the trial design, but I can reassure you that we will be able to answer to that question. Based, and when you will see and we can announce the trial and the study design, you will understand in a second.

Fantastic. That concludes the written questions in the queue. Alessandro, I'll turn it back to you if you have any closing remarks here.

Yes. So thank you, everyone, for the question. Just as a closing remarks, Transgene is ideally positioned to deliver multiple clinical milestones during the next, I would say, year, but also up until the end of 2027, as you have seen in the slide that I presented. the past year has been very intensive, and it allowed us to focus the organization on this important technology and important individualized therapy for patients. We believe that this approach can represent a new step forward in the context of immuno-oncology and specifically for operable solid tumor patients that are still at risk to relapse despite innovative treatments are available to them. So TG4050 and the myvac platform will be able, of course, to deliver promising therapies beyond the head and neck cancer, of course, focus on head and neck cancer, we need to make sure that -- we continue to accelerate the program and go into a registration trial, but also we believe that we have an obligation for the community to show the potential of this technology in other operable solid tumor patients. And you will hear from us as we move forward. So we also think that we are building up all the critical pillars that are necessary to show that Transgene is one of the key actor in this field with other actors, as you mentioned during the Q&A. And we believe that the need is extremely high in -- when we talk about operable solid tumor patients that there is the space and the -- for everyone, right? So to improve outcome again for patients. There is some differentiation that we are showing that differentiation will come from -- of course, the viral vector will come also from the algorithm and the platforms that we have developed by NEC, but also developed by Transgene VacDesign and also the in-house manufacturing that will position us in a very, very strong position for continue to deliver this portfolio for patients. So the journey is exciting, is at times challenging. But when we see these results that Katell has presented and we presented at ASCO I mean, we think that perhaps all these efforts are worth. And therefore, of course, we thank you for being with us, listening to us and supporting us in this journey and have a great rest of the day. Operator, please?

Great. Thank you, Alessandro. So this concludes today's event. You may now disconnect.