Transgene SA (TNG) Earnings Call Transcript & Summary

Hello, and welcome to the presentation of the Phase Ib/II data of TG4001 plus avelumab in HPV16-positive cancers. My name is Jess, and I'll be your coordinator for today's event. [Operator Instructions] I will now hand you over to your host, Lucie Larguier, to begin today's call. Thank you.

Thank you, Jess. Hello, everyone. I'm Lucie Larguier. Today with me are Philippe Archinard and Maud Brandely. And we are very excited to provide you with more details on the results we obtained with TG4001 in combination with avelumab in our Phase Ib/II trial. Before I turn the call over to Mr. Archinard, I'd like to remind everyone that today's discussion contains forward-looking statements, which are subject to a number of risks and uncertainties. The presentation and the webcast can be accessed via the home page of our website and also on our Investor page. If you are listening to this webcast via Internet, you will not be able to ask questions. [Operator Instructions] With this short introduction, I now turn over the call to Philippe Archinard.

Hello, everyone, and thank you for joining us. As you can imagine, I'm really happy to be talking to you today once more at the occasion of this SITC conference. I believe Transgene was able to impactfully showcase its virus-based expertise this year. We will mostly be talking about TG4001 today, which we believe established very encouraging clinical performance set for our virus-based approach in combination with immune checkpoint inhibitors and, of course, for the product itself. Most importantly, we at Transgene, together with KOL are working -- we are working with, are convinced that TG4001 can bring a real benefit to patients. The data Maud will go through also demonstrate the power of our vaccine platform that are able to elicit a strong and specific immune response resulting in clinical improvements. The other product we showcased at SITC this year is BT-001, our novel oncolytic virus co-developed with BioInvent. We have presented our new data that show its potential. In addition to the great antitumor effect and long-lasting immune response induction we have already presented, we now show our strongest abscopal effects. I'll briefly come back to BT-001 at the end of this call. But let's start with TG4001. As you know, TG4001 is a virus-based immunotherapy. It is a therapeutic vaccine based on our MVA platform and vectorizing well-known oncogenic protein E6 and E7 of HPV16 and [indiscernible]. It's been designed to educate the immune system against cancer cell carrying these [indiscernible] antigens. Here, we are targeting non-self-antigens that are known to elicit a stronger immune response than tumor-associated antigen, which are by definition closer to the cell. I remind you that we have already published very strong single agent clinical activity in pre-cervical cancer settings, so-called at CIN2/3, which is also caused by HPV chronic infection. We have shown before that TG4001 is able to elicit a specific immune response against HPV16 E6 and E7 antigen. The TG4001 induces long-lasting response that allow the control of the disease. We saw this in precancerous lesion like CIN2/3. And we also see this at the end stage of HPV-induced cancer in the current trial, as Maud will explain in greater detail in a minute. As you see on the table on the right part of the slide, when used as a single agent, TG4001 was able to reduce a total resolution of precancerous lesion, not just a mere regression, as many others have published, but a total resolution from CIN2/3 to CIN0 of this pre-cervical cancer lesion. I remind you that this was demonstrated in a large, randomized, placebo-controlled trial. Close to 200 patients were involved. Safety was also demonstrated, which obviously is critical when you think of combining a drug with checkpoint blockers. So this prior data, together with the high unmet medical need represented by these different HPV-positive cancers, convinced us to initiate a tumor site-agnostic exploratory trial combining TG4001 with a checkpoint blocker. As you can see, this would open up -- open us, sorry, a market of at least 25,000 patients that have no satisfactory treatment option nor in the U.S. nor in Europe. For this trial, we teamed up with Merck Serono, Pfizer, which provided its anti-PD-L1 agent, avelumab, for the trial, and they obviously also validated the trial design. With our Phase Ib/II trial evaluating TG4001 together with avelumab, we wanted to assess both the safety and efficacy of the combination in a diverse group of patients with different etiology and different advanced stages. So these tumor site-agnostic exploratory trial aim at assessing the safety of the combination as well as helping us defining the best way forward in the treatment of this advanced HPV-positive tumors. We are happy to report that the study has delivered very satisfactory answers to our question with promising both clinical and translational outcome. It is clear that the combination regimen compares favorably with published data from competitive approaches and very favorably with current single agent standards of care. It is clear that these results are paving very well the way forward. I will now hand over the discussion to Maud, who will give you a lot more specifics on the trial outcome.

Thank you, Philippe. So as you know, there is no specific treatment for HPV-positive cancer. Current standard of care do not address specifically the viral origin of the disease. Checkpoint blockers are approved in first- and second-line treatment of head and neck cancer in Europe and the U.S. as well and in the second-line treatment of cervix cancer only in the U.S. In other anogenital cancer, second-line treatments are diverse and include mostly chemotherapy. And at advanced stage, and regardless of the indication, a minority of patients, in the range of 10% to 15%, respond to checkpoint blockers. PFS, as you can see on this slide, is around 2 months, and the median overall survival is less than a year. So there is obviously an urgent medical need for the 25,000 patients in Europe and in the U.S. who suffer from HPV-positive cancer. So let me move now to the Phase Ib/II trial evaluating TG4001 in combination with avelumab. As Philippe said, we assessed the safety and efficacy of the combination in a heterogenous group of patients with very advanced HPV-positive cancer, and Merck Serono provided avelumab for the trial. TG4001 was administered at 5x10^7 pfu subcu weekly for 6 weeks and then every 2 weeks up to month 6 and every 12 weeks thereafter. Avelumab was given at 10-milligram per kg by IV route, starting 1 week after the first vaccine dose. 34 patients with previously treated recurrent or metastatic HPV16-positive cancer were administered TG4001 in combination with avelumab. You can see the patient characteristics on this slide. Almost half of the patients, 44% exactly, had anal cancer. 23% had oropharyngeal cancer, and the remaining had cervix, vulvar or vaginal cancer. Besides local recurrence, patients presented with distant metastasis: in lymph nodes, for more than half of them; liver, 38%; and/or lung, 32%. Most patients had progressed or relapsed after 1 to 3 lines of chemotherapy given for their metastatic or recurrent disease. Note that there is a line with 0 lines of chemotherapy for recurrent metastatic, 4 patients. But actually, those patients did not even respond to first-line to chemotherapy given for the treatment of the locally advanced disease. So they were really refractory patients. So overall, this is a group of patients with very hard-to-treat HPV-positive cancer. So firstly, we observed that the combination of TG4001 with avelumab had a favorable safety profile, which is consistent. You remember with our previous Phase Ib data, most common adverse event being mild to moderate injection site reaction. Objective response rate was assessed by the standard RECIST 1.1 criteria. And among the 34 evaluable patients, 8 patients achieved a confirmed response, and 1 of them achieved a complete response. So the overall response rate was 23.5%, comparing favorably with single-agent ICI, which, as said before, ranged between 10% to 15%. Just a word about the patient with complete response. This patient had anal cancer with peritoneal extension, and all those legions disappeared, and the patient is doing well after more than 6 months of treatment. So as previously reported with single-agent ICI, we observed that liver metastasis has a major impact on outcome. Response rate was 34.8% in the 23 patients without liver involvement, while no response was observed in the small group of 11 patients with liver metastases. This difference was also seen in progression-free survival, where median stood at 5.6 months for the patients without liver involvement versus 1.4 months for the other group. Just more -- to be more specific on the incidence of avelumab. So this incidence is greater in anal cancer, an increase, of course, in advanced stage. Occurrence of multiple and on large liver met is associated with poor prognosis in general and poor efficacy, more specifically, of single-agent ICI. TG4001, being an immunotherapy, was also fully effective in this group of patients. So importantly, for our future clinical development, these findings are critical for refining the selection criteria of the patients we intend to enroll. Importantly, the response were durable. This is illustrated on the spider plot and the waterfall plot that you can see on this slide -- on the slide. And therefore, several patients are being treated, with one patient being followed now for almost 3 years. So let's move now to the immune response and the impact on tumor microenvironment we observed in this trial. So TG4001 was able to induce specific immune response in 7 out of 11 evaluable patients, meaning that north of 60% of patients can mount a specific immune T-cell response against HPV antigen. Interestingly, in the patients with complete response, the disappearance of lesion was accompanied by the development of a strong T-cell response against HPV antigen, of course. And this response developed as early as day 43 and sustained at 6 months after initiation of therapy. These results support the durable disease control. Moreover, on the next slide, you can see the impact on the tumor microenvironment with an increase of lymphocytic infiltrates and increased expression of immune-related gene and, importantly, higher PD-L1 protein expression across all patients during treatment. So those results suggest that our therapy is able to modulate the tumor microenvironment. It means that there is a switch towards what is the so-called hot tumor phenotype, which validates the use of a therapeutic vaccine or a therapeutic vaccine in combination with ICI. So in summary, these results compare favorably with the current therapeutic options, including immune checkpoint inhibitor as single agent. So I must say that KOL are very much interested in pursuing the clinical development of TG4001 in combination with avelumab. So we are currently discussing with them and external experts as well to finalize the protocol of an upcoming trial. We have designed a randomized, controlled trial that would take place both in Europe and in the U.S. So KOL, obviously are on board, and we are agreeing in refining the last detail of the trial in order to start submission to regulatory agencies before the end of the year. So now I will leave the floor to Philippe.

Thank you, Maud. So based on these promising findings, we believe this data establish the strong potential of TG4001 in combination with an immune checkpoint inhibitor in this patient population with HPV-positive cancer. So as Maud said, we are finalizing the study protocol with KOL, interacting with external experts, interacting with Merck and actively preparing the necessary filings both in the U.S. and in Europe. We will give you more specifics on the upcoming study when regulatory submission are advanced enough to provide you with the protocol -- the final protocol of the trials and the time lines, more importantly, that you expect. We are working hard to make sure we move fast and give TG4001 the best chance of reaching approval. We believe that we have the right virus-based candidate with the right antigen positioned in the right indication and in the right patient population. As a result, we intend, as Maud said, to continue the clinical development in a larger controlled, randomized study. We will keep the right of this product till the next set of data readouts in order to create more value for our shareholders. You probably have seen that we also presented a poster at SITC on BT-001. I'd like to spend bit of time on this presentation -- on that one. So this novel oncolytic virus has been engineered based on our proprietary oncolytic viral platform, Invir.IO. It includes an anti-CTLA4 antibody developed from -- by BioInvent, and we are co-developed -- that we are codeveloping together this product. I encourage you really to look in detail at the poster. The preclinical data show very strong antitumor activity, thanks to the combined effect of the oncolysis and the expression of the antibody. We have shown that the antitumor response is notably CD8 T-cell dependent, more so than CD4 T-cell dependent. We have shown the induction of an immune memory response and very importantly, a so-called bystander effect of BT-001. In other words, when the drug is injected in a lesion, this lesion is destroyed as well as others or distant tumors. All of these data confirm the strong immune modulating effect of oncolytics in general and of BT-001, in particular, and support the launch of the clinical development of BT-001 with a clinical trial that we expect to start by the end of the year. So that's ending the formal presentation, and it's time now for the Q&A session.

[Operator Instructions] The first question comes from the line of Jean-Jacques Le Fur from Bryan Garnier.

Congrats for these results. Good news for Transgene, obviously. I have 2 questions. The first one is looking at the data presented in the poster at SITC, which were on your slides today also, it appears that the genital and cervical cancer respond better than the anal and oropharyngeal, both on objective response rates and progression-free survival. So is there any particular explanation there? And my second question is regarding the disease control rate, which was quite nice with 43% at 12 -- no, sorry, 56% at 12 weeks. Do you have the split between the different type of cancer? And did you observe the same trend, as I explained, with genital and cervix cancer responding better than the others?

Thank you, Jean-Jacques, for asking your question. So I must say that we should be cautious before concluding that the activity is better in cervix cancer, vulvovaginal cancer because as you have seen, the number are quite low. And this is -- even if it's very encouraging, obviously, it's the reason why we really need a larger trial with stratification by tumor type, so that we will be in a good position to -- really to see whether there is a difference between the different tumor location. And I must say that anal cancer, we're particularly in advanced stage. And there was one with mostly liver lesion, as I said. So it's also a little bit hard to conclude that they are doing -- they are responding less than the others. So I would be very cautious to conclude that this here, the PFS or the response rate is different depending on the tumor type.

[Operator Instructions] The next question comes from the line of Sebastiaan van der Schoot from Kempen.

Congratulations on the data. I was wondering whether you could provide a little bit more color on the number of patients and the specific cancer types that you're going to target in the next trial. And if you could indicate whether you are going to also group certain types of [ invasive ] cancers?

Well, it's still under debate because we want to have the right number of patients, not too small but not too big, because we would like to have enough patients and demonstrate a good difference between the group of patients treated with single-agent ICI versus the combination of TG4001 and the ICI. So -- and we also plan to perform an interim analysis to be sure that we are going in the right direction. So I would say that we are in the range of something like 100, something like that.

Okay. And if I may, will you also look at other factors like biological indicators or [indiscernible] factors in the tumor itself?

Yes. Thank you for asking because, of course, one thing I didn't mention, we induced the expression of PD-L1. So this is something which is important to check. So obviously, we will characterize -- not include the patient depending on PD-L1 expression because we did observe response in PD-L1 negatives, so in PD-L1 negative patients. And therefore, we will characterize to make sure that we have a baseline and during treatment that at day 43 or later, the level, the measurement of the level of expression of PD-L1, so that we can support the rationale for the combination, obviously.

Thanks, Maud. Maybe indeed, so PD-L1 will not be an inclusion criteria but will be a marker that we will follow in the longitudinal assessment of the patients. So that's clear. I think you also asked a question, Sebastiaan, regarding the -- whether or not we will be centered and focused on one indication or more tumor-agnostic. So I think we can say at this stage that we will certainly not be focusing the enrollment in just one specific population, but rather try to follow the path, if at all possible, of the tumor-agnostic type of approach for HPV-positive cancer. That's where we are aiming at. And again, that's really a matter of days or weeks to finalize this whole thing and to get the right sales plan. But we are nearing the filing timing now.

Okay. And if I may ask one question on the BT-001. I see that you're -- in the preclinical data set, you use intratumoral injection. Is that also something that you're going to do for the final indication, seeing that you also, with TG4001, do an intravenous injection?

Yes. To start with, but the protocol in its development encompass single agent and combination and, indeed, over time, based on the outcome of the ongoing 6002 trial. As you know, we are assessing IV, IHA. We will have all these data by next year. And obviously, this data will inform us on the best way forward. So indeed, should we see an interesting signal, which we hope with 6002, and so far, it seems to trend in that direction, we will certainly take this into consideration to further broaden the scope of potential indication that we will be targeting with BT-001.

Your next question comes the line of Jean-Jacques Le Fur from Bryan Garnier.

So a follow-on to Sebastiaan, one on the next trial. First of all, to be sure I well understood, will it be a pivotal trial? Or will it be a sort of Phase IIb and you will need after that a Phase III? And I understood that you will not be focused on one tumor in this next trial. Isn't it at any risk to have a sort of dilution in the number of patient you will recruit? Let's assume that you posted 100 patient, for example, that you will have too many -- too low number of patient in each tumors to -- in order to have seen statistic significance. So trying to understand why not focusing on 1 or 2 tumors only? And my last question is a nonscientific question. Is there any reason -- on Slide 8, I saw that the HPV16-positive cancer, 75% of patients in the EU and only 25% in the U.S. Why is that?

So regarding your question whether the trial is pivotal or not, as I mentioned, what is planned is that we perform an interim analysis. And so at this point, we would be in a good position to see whether there is a behavior -- a different behavior between the different tumor location. And we intend that if, of course, the interim analysis is positive to -- at this stage, to meet the authorities and discuss with them how to meet their expectations for this trial to become pivotal. So it's too early to say that it's pivotal. But of course, if the interim analysis is positive, this is obviously a question we will discuss with the regulatory agencies, so FDA and the EMA. That was the first question. So the second question, as I said, so by stratifying according to the tumor location, we'll be -- I'm focusing also more our selection criteria so that we have less earlier disease stage patients in better condition. So that we will have a better vision of what the combination brings to each tumor type versus the ICI single agent. And so if needed at the time of the interim analysis, we can decide to drop tumor type and to focus on a single or 2 tumor locations, for instance. And maybe your third question, I'm not sure I can answer why there is a different incidence of cancer between U.S. and Europe. Do you know, Philippe?

No. I guess it's behavioral, the occurrence. That's the only rational explanation for that because at this stage, we can't say that, for instance, the prophylactic HPV vaccine has yet any bearing in term of incidence of cervical cancer. Over time, maybe there will be some explanation there. But at this stage, I think it's just behavioral and possibly some screening, which is better than in the U.S. than it is in Europe. And we see also in Europe a big difference between Northern Europe and Southern Europe. So I mean it's particular, let's say. Jean-Jacques, is it properly answering the questions?

Yes. Fully.

The next question comes from the line of Martial Descoutures from ODDO.

So I'm sorry, but I have also another question on the next step of the Phase II. Just to understand the strategy of the company, could you confirm us that Merck and Pfizer will be interested by another collaboration on this development? Or maybe could we think that you could find another collaboration or another partnership to share the cost of the next step? And is it possible maybe to have a guidance or time lines to have more details on this new phase?

So regarding Merck Serono, as I said, we are interacting with them. Clearly, they are a natural player to piggyback on where we stand to amend the trial rather than to fight for a new one. So if we think of timing and moving fast, this is the logical step. So clearly, this is what we want to do. Having said that, that does not exclude potential other collaboration eventually with anti-PD-1 owner on slightly different type of approaches. But for the trial that Maud is talking about, we are talking about tonight, this is still part of it. By definition, we need to finalize the protocol and to have a joint agreement on this protocol. So you will understand that we are nearing this stage, but we are not -- we are 98% there but not 100%. So -- but this is clearly the objective we are pursuing. And regarding timing, as I said, we are -- will be filing this protocol before year-end. At least, this is our intention today, as soon as we have, let's say, the first feedback from these agencies. And you know very well that may vary from one territory to the other. We will give you, obviously -- so I'm hopeful that in Q1 next year or so, we should be able to get at least some early feedback from some territory and be able to tell you with more precision the specific of the design and the timing of the first inclusion.

The next question comes from the line of Arsene Guekam from Kepler Cheuvreux.

To follow up with a previous question, is it possible to leverage these results with another ICI? This is the first one. The second is how do you explain the shift from cold tumor to hot tumor? And is it tumor-specific, this effect? And the last one, have you seen any abscopal effect in some patient with metastasis?

On the leveraging of this data with others, this is -- I mean we know that there are differences from 1 anti-PD1 -- from 1 ICI to the others. Having said that, if you look at the data in this indication, it may differ, it may vary from indication to indication. And maybe this is where you can see a clearer differential of performance between the ICI. But if you look at all data, we have provided you with many different table, comparative table, nobody can say that there are the striking differences from 1 antibody to the other when you look at the HPV-positive cancer. So clearly, we think that, indeed, the data that we have obtained and will obtain could certainly speak not only in term of potential of synergizing with avelumab but with other ICI, clearly. Regarding switching the tumor phenotype, I mean, that's clearly what's expected from a vaccine or eventually from an oncolytic virus. I mean as soon as you end up stimulating the immune system, you create an army of T-cells that migrate to the tumor type and infiltrates the tumor microenvironment. So that's clearly nice to witness, but totally in line with the expected mechanism of action of our viruses. So specifically toward the metastasis versus the primary centers, we do expect because it's a systemic immune response that, indeed, this effect is seen or happening in -- both on the primary site and on the tumor metastasis. But that can -- that is not so easy to objectivize because obviously, the challenge is getting the tissue basically from the different sites and specific. So it's not always easy to fully objectively demonstrate, but this is clearly what we expect. I don't know, Maud, if you have something to add to that.

Well, personally, I was impressed to see that, for instance, if we -- I mentioned this patient with a complete response, so this patient had several peritoneal lesions around -- on her peritoneal cavity, and all of them disappeared. So it's quite impressive. So it means that really, the lymphocytes are circulating and doing the job to destroy the cancer cells. And we have seen also a reduction in size or even disappearance in some patients of lung metastasis. So meaning that we let, again, lymphocytes, activated lymphocytes circulate and doing the jobs we are expecting they usually do, and they are not inhibited. So that's what I was impressed by.

[Operator Instructions] There are no further questions in the queue. So I'll hand the call back over to your hosts for any closing remarks.

Thanks. So just a few concluding words. As you've heard, we are very proud of the data generated by 4001. What we described today really makes us confident that TG4001 could contribute to changing the treatment landscape for patients with HPV disease. Addressing this patient population and its diversity through a targeted approach could be a first type toward precision medicine. In our vaccine platform, TG4001 is paving the way for of TG4050, and I'm very confident in the potential of this personalized neoantigen-based cancer treatment. We have assembled the best possible partners with NEC, Hypertrust, Traaser, BostonGene, to name a few. We are working with the best cancer centers in the world like Mayo Clinic, Institut Curie and Toulouse-Oncopole. We are progressing very well in term of enrollment. All signals are in green, as I speak. And regarding Invir.IO, the recent data published by -- for TG6002 are also opening up the way for systemic administration of oncolytics, while the BT-001 preclinical data just presented at SITC are clearly showcasing its incredible potential efficacy. So we are really looking forward to treating the first patients with BT-001 and to give you more specific on this front. I believe that Transgene was able to impactfully showcase its virus-based expertise at SITC this year. With its unique know-how, Transgene has built a coherent portfolio of immuno-oncology products. Our approaches, I am convinced, can make a difference for patients. And we, scientists and expert at Transgene, together with clinicians around the world, are strongly committed to make significant progress in the fight against cancer. And with this, I would like to conclude today's call. Thank you, and wish you a good evening.

Thank you for joining today's call. You may now disconnect your lines.