BioInvent International AB (publ) (BINV) Earnings Call Transcript & Summary

Good afternoon, and welcome to the BioInvent KOL webinar. [Operator Instructions] As a reminder, this webinar is being recorded, and a replay will be made available on the BioInvent website following the conclusion of the event. I'd now like to turn the call over to your host, Dr. Martin Welschof, Chief Executive Officer of BioInvent. Please go ahead, Martin.

Thank you, Tara, and welcome to everybody to the BioInvent webinar. Today, let me now will be focused on BI-1206. The next slide, please. So this is our forward-looking statements since we are listed in Stockholm. Next slide, please. And this is the agenda for today's webinar. I will go briefly over this. So at the beginning, I will have some introductory remarks, and then this will be followed by BI-1206 update [ and or summary ] of the ongoing study in Non-Hodgkin lymphoma. That will be done by Andres McAllister, our Chief Medical Officer. This will be then followed by Björn Frendéus, our CSO. He will give some updates around the mechanistic data, mode of action of BI-1206 and then lead over to our guest of today, which is Michael Wang from the MD Anderson, and he will talk about the treatment landscape. And then we end the meeting with our first data that we present today, which is still early days, but we believe, exciting on BI-1206 in solid tumors. And then obviously, we have a summary and Q&A. And this leads me over to the next slide. So just very briefly. And later, I think Björn will do a more detailed introduction to Michael Wang. So as I already mentioned, on the left-hand side, you will see Michael Wang. He is participating today, and we're really grateful that he supports us. He is professor at the MD Anderson and has published a lot of papers in -- regarding covering Non-Hodgkin Lymphoma. And as I said, so he will later will give a more detailed introduction. And then from the BioInvent team, we have today with us Andres McAllister, our Chief Medical Officer; Björn Frendéus, CSO; and myself, Martin Welschof, the CEO. The next slide, please. So just to remind the audience, and there might be also somebody listening for the first time. So by BioInvent is a publicly listed company in Sweden. We are focusing on immuno-oncology. And we're pushing ahead with a broad portfolio. So currently, we have 4 clinical programs that are actively ongoing. We actually just started 2 weeks ago. We initiated the program #5. We're a fairly integrated company. We have a discovery engine that provides targets and antibodies, who have our own GMP manufacturing capabilities in-house and, of course, also clinical development. The platform, as you can see, has been validated through a number of big pharma collaboration, most recently through Pfizer, but we also have antibodies in development with Daiichi, Bayer, Mitsubishi, Takeda, and CASI. We have a very strong international shareholder base. Our largest shareholder is Redmile, from the U.S. we also have Omega and Invus, and then also blue chip European investor, such as Van Herk Investments, HBM from Switzerland, [ Fourth Pension Fund ] Force Pension Fund, Swedbank Robur, Handelsbanken, and also [ Meru ]. I mentioned already earlier that we are listed on the Stockholm Stock Exchange, and we have a very solid cash position. Our current runway will keep us running on -- based on current plans until the end of 2024. Next slide, please. So I will not dwell on that. But at the core of the company, we have a very innovative screening platform, which is called F.I.R.S.T., and I will just briefly focus on the unique feature [ see it holds ]. The first one is that we can screen directly on human patient material. We have a very close collaboration with the local hospital here in Lund where the company is based. And we get fresh patient material on a regular basis that we then use to screen our n-CoDeR antibody phage library. And once we have specific bindings, we turn them into [indiscernible] and before we actually check what they bind to, we subject them to very vigorous phenotypic screening, and we would only then focus on those antibodies that have shown very strong therapeutic effects. And then for those who would also do the target identification. So this platform we have used in our collaboration and the collaborators, I mentioned already on the previous slide, but we also used it to build our own portfolio, which is on the next slide. So this is our current portfolio. As you can see, we have a strong pipeline with multiple value drivers. And we have basically 2 categories. So category #1 is focused on a very interesting target of the innate immune system at FcgRIIB. And there, we have currently 3 programs now. So BI-1206, which is the topic of today is currently running in 2 different trials, one for Non-Hodgkin lymphoma, the other one is for solid tumors, and we'll come back to that later in much more detail. And our second anti-FcgRIIB-antibody is BI-1607, and there we just filed the clinical trial application, a couple of weeks ago. Then on the low part of the slide deck, you've see then the programs targeting 2 very interesting targets on regulatory cells, TNF receptor 2 which is one of the hot and upcoming IO targets. And there we have 2 antibodies BI-1808 and BI-1910. 1808 also has initiated already clinical development, 1910 is still in preclinical development. And then we have one program, which we run in collaboration with transgene. And this is BT-001 where we combine our proprietary anti-CTLA-4. With their oncolytic virus platform. And this also has started clinical development at the beginning of this year. So that's the platform. And today, of course, we will focus on BI-1206 in combination with rituximab for Non-Hodgkin Lymphoma. And at the end of the presentation, we will also cover the solid cancer study. So with that slide, I will hand over to Andres. Please go ahead.

Thank you. So can we move to the next slide, please? So this is a study which is -- this is the poster we just sent to ASH last week, basically presenting the study and the first results from the study. If you move to the next slide. This is the study design. Basically, it's a very classical drug escalation of BI-1206 in combination with rituximab, a 3 plus 3 design and basically using the regimen that is usually used [ without rituximab ]. So -- and the patients are, of course, patients who have received previous lines for rituximab and have progressed on those rituximab containing lines. We are, of course, pursuing the -- to find the recommended Phase II dose. We are very close to doing that. As soon as we have that, we will move into Part B of the study, which is expansion cohort with the same patient population. This expansion cohort can be enlarged. It needed the idea here has been from the beginning to enrich that phase with mantle cell lymphoma patients. Given that we have a strong preclinical data showing that this combination could be particularly interesting in mantle cell lymphoma. So this is the study design. If we move to the next one. This is what we have seen. So we initially began with 30 milligrams. I think this has been disclosed in the past. We had some infusion-related reactions that were managed when we implemented a steroid regimen around the infusion that allowed us to pursue this study where we treated Cohort #5, 4 and 5, 70 milligrams and 100 milligrams flat dose. And right now, we are in the subsequent Cohort, which is 200 milligrams. And you will notice that it's a split dosing. We want to be very conservative in doing this and trying to manage infusion-related reactions. So we implemented the split dosing, which is now what we're using in this study. It's important to note that we have not observed any DLTs or any serious adverse events. And so what we were observing in the past was clearly managed with this steroid regimen. So if we move to the next one. Here is the adverse events that we have observed. So basically, as I mentioned, mostly infusion related reactions, but importantly, no major safety concerns, and everything has been managed adequately without really any concern. One important point that we want to point out is the fact that we feel that subcutaneous formulation will be something important. So we have been working very hard in developing that formulation. We actually were able to produce very high concentrated material that is actually ready to -- it's actually being tested in toxicology studies, and we have actually produced the GMP batch for him -- for the human setting, and these will be tested in second part of next year, if everything goes well, and things are moving forward really nice. So we intend to -- and the preclinical data actually shows that this is the best way to manage infusion-related reactions associated with BI-1206. So we are very comfortable in moving this forward. So we move to the next one. This is the data when we have -- in the patients that we have looked. And this is the data specifically looking at follicular lymphoma, where we think because that is the largest subset of patients, is very interesting. So out of 9 valuable patients, we have 3 complete responses that have lasted over 12, 24 and 36 months out after the beginning of treatment. We also have 3 partial responses and 1 stable disease, and fortunately only in only 2 cases of progressive disease, which is, of course, very early data, but it's pointing in a very interesting direction in the sense that we feel that we're really pushing the activity of rituximab enhancing the activity of rituximab in patients who have not -- who have progressed on previous lines of rituximab containing therapies. So if you move to the next one, this is the full data set. So just adding the mantle cell lymphoma patients. We had 3 mantle cell lymphoma patients. And 1 of those patients developed had a [ blastoid form ]. What we did see there is that partial response and in particular, that the infusion of BI-1206 is actually completely depleted circulating tumor cells. So that's very interesting. And of course, very exciting. So we move to the next one. Just a summary of where we stand. So we have interesting objective response rates. This is basically summarizes the data. So I will go through it again, particularly interesting because of the size of the data set in follicular lymphoma, but of course, this is, again, very early days. And I think, importantly, we are working very hard in developing this subcutaneous formulation, which we think is going to be instrumental in the development of this drug, which, of course, will make it very easy for clinicians to use it. So without any further ado -- I will turn it over to Michael [indiscernible]. Great. Sorry.

Thanks. That's all right, Andres. Well, if 2 slides back please. Yes, please. So yes. So one more back. So it's first, Björn, and then it's Michael. Okay set. Okay. Apologies for that, everyone. Anyways, thanks to Andres and Martin, for the introductions. Right. So FcgRIIB is a receptor that drives resistance to antibody-based therapy by several mechanisms, acting both on immune effector cells and tumor cells. So as shown in the left panel of this illustration, following rituximab binding to its targeted receptors on tumor B cells, rituximab's tail is able to interact with FcgRIIB, triggering the intronization and removal of rituximab molecules from the tumor cell surface. This means that binding and activation of immune effector cells is prevented. And so resistance is being developed. Now in contrast, and as illustrated in the right panel of this illustration, when rituximab is given with 1206, 1206 will bind to the FcgRIIB receptors, preventing its interaction with rituximab, effectively preventing intronization of rituximab and leaving greater numbers of rituximab molecules on the tumor cell surface. These rituximab molecules can then robustly bind through and activating immune effector cells, which in turn, attack and destroy the tumor cells. And so resistance is overcome. Next slide, please. This FcgRIIB mediated resistant mechanism appears to be highly relevant to the different types of lymphoma that have been studied. So what has been shown in independent retrospective clinical analysis is that those patients whose tumors express high levels of FcgRIIB, show poor survival in response to rituximab treatment or rituximab containing regimens. Relative to those patients whose tumors are negative for FcgRIIB or show low FcgRIIB expression. This has been observed both in mantle cell lymphoma, follicular lymphoma and most recently in 2 large cohorts of diffuse large B-cell lymphoma. Next slide, please. So on the back of our emerging very exciting clinical data and the strong rationale of targeting FcgRIIB to overcome rituximab resistance. It's a great pleasure to introduce this guest speaker. Dr. Michael Wang. As Martin said earlier on, Michael Wang is a professor in the Department of Lymphoma and Myeloma at MD Anderson. He obtained his MD from Shandong Medical University in China. He completed his clinical training, both at Norwalk hospital in Connecticut, and as a fellow in oncology and hematology at MD Anderson. Michael has, over the past 2 decades, been focused on translational, preclinical and clinical research, establishing for the first time in human primary mantle lymphoma animal models and bringing new targeted therapies like ibrutinib and acalabrutinib to patients, incorporating these drugs into the treatment algorithm. And of course, being a frequent publisher in the absolute most prestigious medical journals in the world, such as New England Journal of Medicine and Lancet. So Michael, it's our great pleasure to have you with us, and we're looking forward to you taking us through the treatment landscape, and in particular, pointing out how you feel BI-1206 can help patients. Thank you.

So thank you, Björn, for that kind introduction. I'm Michael Wang from MD Anderson. I'd like to share with you how excited I am with the BI-1206. I have done quite some preclinical research work and has been involved with this compound for a while. And you can see that Björn has described you the fascinating mechanism of action of how it can help rituximab [ it serves its function ]. I also want to share with everybody that rituximab has been widely used in all kinds of B-cell lymphomas. And at amazing factor is that if the patient received 3 prior lines of therapy, either for follicular, mantal, or large cell lymphoma, marginal zone lymphoma, they almost always contain the rituxumab. So if we are able to find a mechanism enhance the performance of rituximab. As you can see from the F.I.R.S.T. data, it just does so the implications and the applications of this technology or this drug or immunotherapy mechanism will be far-reaching in all the B-cell lymphomas. Next slide. So as you can see, for mantle cell lymphoma, we used to treat it with chemotherapy. And again, this chemotherapy absolutely have the rituximab unit. This is a comparison in mantle cell lymphoma for VR-CAP and R-CHOP in newly diagnosed elderly mantle cell lymphoma patients. As you can see, the [ reduction ] in measurement and improved, and in VR-CAP, we improve the R-CHOP therapy over -- show the benefit over R-CHOP therapy. Next slide. So -- that's for the standard therapy for the elderly patient and for the young patient with the newly done mantle cell lymphoma, we always use an induction therapy followed by the Nordic therapy developed by Northern European scholars. So this is a standard therapy for a young patient with mantle cell lymphoma. As you can see, it contains rituximab in almost all parts of the therapy. Next slide. So the newest therapies, so it would be the BTK inhibitor. It has [ combined ] into BTK inhibitor including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib, but a new class of BTK inhibitors are emerging, these are reversible BTK inhibitors and such as LOXO-305, which is now called pirtobrutinib. I just presented the data, the Phase II international clinical trial data at the day passing in the past week at ASH in Atlanta, very exciting class of drugs for B-cell lymphoma. Next slide. So ibrutinib could be used in the first relapse of mantle cell lymphoma. As you can see, the response rate, there is a retrospective of U.K. and as we are seeing the overall response rate of 69%, CR at 27%. Next slide. Please remember, I published another study with rituximab, ibrutinib, with the addition and the [ aplha rituximab ], the response rate was much higher. The duration response was much higher as well. Acalabrutinib is the -- another FDA-approved BTK inhibitor and it when used alone, it has over responsible 80%. But if we are doing a study with rituximab with acalabrutinib for elderly patients. And think about it, if we use the BI-1206 and to enhance the performance of rituximab, acalabrutinib. I think the response rate, the tolerability will be very promising. Next slide. Zanubrutinib is not the FDA approved BTK inhibitor. Next slide. And the BRUIN study, like I presented last week at ASH, and this is ASH '20, but we have new updated data from ASH '21. The -- basically, the response rate still remains at 52% of the 3 prior lines products therapy. As you can see from the water plot, the majority of the patient enjoy the tumor reductions. Next slide. So management of mantle cell lymphoma, as you can see on the right side, ideally, we use combinations and pretty much all the combinations are very effective, especially with the rituximab continuing combinations. Next slide. So the very beginning of the chemo-immunotherapy was the R2 therapy. Of course, it has rituximab added to the REVLIMID or we call it lenalidomide. The overall response rate was 57% of the 3 prioe lines plants of therapy and the [ progression-free survival ] was very significant at 12 months. Next slide. So the ZUMA 2 study is when all the therapies, including BTK therapies would not work, and the patients with mantle cell lymphoma become very malignant with the broad [indiscernible] tolerant and also after 3 prior lines of therapy. As you can see, the CD19 CAR-T cell therapy called the best [ chimeric antigen autolus ] induced a response rate of 93%, and a CR rate of 67%. The failure-free survival, the overall survival is very favorable so far. Next slide. The VLS-101 is another antibody therapy that's against the direct of -- against ROR-1 antigen, which links to a -- by a linker to MMAE as the immuno drug conjugate. And this drug has been very effective in mantle cell lymphoma and large cell lymphoma. Next slide. So rituximab, ibrutinib, for [ untreated ] mantle cell lymphoma, a response rate of 92% in elderly patient, which -- with the first front line. This has been publish in the [indiscernible] from my group. And I really think that if rituximab, ibrutinib, looking at 92%, if you integrate the BI-1206 compound, I think there will be a very promising trial to do. And I think the therapy will be very potentially very positive. Next slide. So how about the follicular lymphoma. Follicular lymphoma is also -- has also enjoyed a lot of progress. For example, the BR versus R-CHOP trial because it had rituximab and therefore, amenable for 1206 clinical trials. The BRIGHT study is BR versus R-CHOP versus R-CVP and the GALLIUM study with R-chemotherapy versus obinutuzumab, which is another CD20 drug that we can potentially use with a combination with 1206. The RELEVANCE study is basically a international Phase III trial with rituximab [indiscernible] versus rituximab plus chemotherapy. The result has been identical in 2 arms in terms of efficacy, but with the toxicity profile [indiscernible] arm. And there is the PRIMA study with rituximab maintenance study is also a very quite possible trial for the follicular lymphoma. Next slide. As you can see, the most recently, quite a few therapies has been approved for follicular lymphoma, including idelalisib a PI3 kinase inhibitor, obinutuzumab is a CD20 monoclonal antibody, copanlisib combines with PI3, PI3 or 2, which is an immunomodulation, umbralisib, another -- another PI -- new therapy, and axicabtagene ciloleuce, which is a CD20 studies in the ZUMA-5 clinical trial, which was also updated last week at ASH. And then there's the easy R2 inhibitor, the tazemetostat is also one of the newly additions approved by FDA for follicular lymphoma. As you can see, many of those therapies could be combined with rituxumab and [ partially ] be studied with 1206. You can see -- you can feel that how widely -- a widespread implications that 1206 could indicate. Next slide. So this is the AUGMENT study, we should randomized the R2 with R-placebo to try to see to study the R2 regimen and which is REVLIMID lenalidomide. Next slide. As you can see, the Failure-free survival is a statistically different figure in the R2 or R-placebo and over survival favouring, the R2 arm as well. Next slide. The obinutuzumab with plus lenalidomide is also quite an effective therapy with a very impressive overall response rate and also failure-free survival so far has to which has not showed a significance, but as the study is ongoing. Next slide. The MD Anderson, obinutuzumabme with the lenalidomide study showed a response rate of 96.6%. And the -- also the duration of response, failure-free survival, very impressive. Next slide. The PI3 inhibitors in follicular lymphoma already outlined that including 4 of them with good comparisons, they work in the different sub units, and then we all combine with the rituximab. Next slide. The CHRONOS study, which is R2 copanlisib versus R2 with the placebo, very, very positive study entering right action with copanlisib, the standard therapy that's a prolonged, not only failure-free survival, but also overall salable, very impressive study. Next slide. The UNITY trial which is umbralisib plus the BTK or the PI3 inhibitor also have impressive overall response rate and duration of response as low as 27.7%. Next slide. ZUMA-5, as I alluded to earlier, is the CAR -- CD19 CAR-T therapy for follicular lymphoma and marginal zone lymphoma, which has a good response rate with also duration of original response, very impressive. Next slide. Progression-free survival and overall survival with ZUMA-2 is also very impressive. As you can see, they are long-lasting patients remissions. Next slide. So this was -- this efficacy and toxicity was updated last week by [ Dr. Caron Jacobson ] and indicating continued success in -- with CAR-T cell therapy in follicular lymphoma and in marginal zone lymphoma. Next slide. In conclusion outcomes for the majority of the patient with the follicular lymphoma are favorable but we need balancing the goals of therapy with patient-specific features generally inform the patient selection. And there's unmet clinical need is to identify more therapies to enhance the current therapies is in combination or through an immune system such as the current immune system that are employed by 1206. The goal of the treatment to achieve a normal life expectancy without too much toxicity. Next slide. There are so much of therapy, so mantle cell lymphoma, follicular lymphoma, and I only touched a little bit and to give you a little flavor. Thank you very much.

Thank you very much, Michael, for this very comprehensive overview. And for pointing out where BI-1206 could be positioned nicely. And before we move over to the solid tumor part. So just to highlight again from my perspective, obviously, we're still early days in Non-Hodgkin Lymphoma study, but we already have a very impressive overall response rate. And I think what I'm very concerned with is also the quality of responses that we're seeing in some -- in one case, even more than 3 years and 2 years after concluding the study without further treatment. So I think that quality of response speaks also for itself. And as you said also in one of your slides and also during your conclusions, Michael, is that, of course, also the quality of life is important because there are a lot of therapies currently out there that are quite efficient, but also quite toxic. And I think we offer a very nice safety profile, which, of course, would also contribute to the quality of life of the patients at the same time what I am seeing long duration responses. So thank you very much. And I think now we'll move over to BI-1206 with pembrolizumab in solid tumors. So this is, of course, even earlier, but I think still quite exciting. And Andres, please go ahead.

Thank you. May we move to the next slide. Yes. So basically, this is the description of the study design. Of course, the mechanism of action of BI-1206 in combination with anti-PD-1 targeting antigens different from what we saw in Non-Hodgkin Lymphoma. This study, we're basically escalating, using an adaptive design. And we, of course, we have been escalating. And as soon as we find the recommended Phase II dose, we will move into the second part of the study, where we currently have 3 cohorts, one in lung cancer, one in its metastatic melanoma and one basket where we will include patients with different types of malignancies. So a little bit of a signal seeking study design. If we move to the next one. So this is what we have observed so far. So we started out with the same, see we are observing the same sort of infusion-related reactions that we observed in the Non-Hodgkin Lymphoma study. We started at 1 milligram per kilogram. We again implemented the steroid regimen around the infusion, and that actually helped quite a bit in the sense that we were able to continue escalating. We have now fulfilled 1 milligram per kilogram cohort. The last patient is about to finish this DLT period, and then we will move forward in January in cohort #4, where we'll move up to 2 milligrams per kilogram. So that's currently, where we stand. Basically, what we have seen is sort of the same observations. So these infusion reactions that are quite transient, and patients get well our receptors with infusion. So nothing to be very much concerned about. Everything has been adequately managed in the clinic. So we -- in terms of safety, other than that, there is nothing else to report. We haven't seen anything else so far. If we move to the next slide. Basically, what we have seen in terms of efficacy is we have seen 2 patients that have responded. The first patient was a 35-year-old patient with sarcoma metastatic sarcoma with metastasis to lungs and bones, who had received several lines of previous therapy, including 2 anti-PD-1 targeting agents. The patient was not in very good condition, and had a very cough for a number of months and pain in the bones that was -- the patient was basically on OxyContin for many months. After entering the study, the patient clinically was doing very well, started to -- the pain was subsided could actually relieve pain relievers and in the patient improve his breathing capacity. So was able to go back to work, et cetera, that was very good. It was reported as a stable disease. Fortunately in the next scan, the lesions appear bigger. But the patient was doing clinically very well. So the patient was taken off the study, unfortunately, because of what we started at that time, being disease progression. In fact, it was a classical case of pseudo progression. And actually because the patient was doing so well, the treating investigator decided not to give any more and basically wait and see how that would evolve. And the CT scan that was performed in September 2021 show actually that many of the metastatic lesions had actually disappeared. Some were smaller and no new lesions could be detected. So a very clear case of pseudo progression. So we have actually opened a compassionate use, and it's now approved. So for the time being, the patient has not received anything else is doing very well, and we will retreat the patient in case the investigator decides to move forward in that direction. And the second patient that has responded to therapies, a 69 year old patient with uveal melanoma with metastases, again to the lung, pericardium adrenal gland, liver and peritoneum. Again, previous 4 lines of previous therapy, including 1 Anti-PD1 targeting agent to which the patient had reported to progress versus at treatment. In the first evaluation at week 9, the patients showed decrease in lesions of 28%, which was a stable disease. And then second, the patient continued on treatment and the second evaluation at week 16 showed a decrease in target lesions of about 39.7%, which is actually a partial response. So that's very exciting. The patient is still in treatment, doing well, and has had several new infusions. And so we are very excited to see those patients responding. And of course, this is anecdotal, early days, but interesting things since these patients had received previous by Anti-PD1 antigens. Can we move to the next one? So what will we be doing next in the Non-Hodgkin Lymphoma study, we will have 1 additional cohort. But basically, we're working hard in preparing for the meeting and the Phase I meeting with FDA, where we'll be discussing our strategy and basically, of course, we would like to discuss with FDA the possibility of moving forward BI-1206 in Non-Hodgkin Lymphoma with a single-arm, potentially registrational study. So we will be discussing that. We're also working very hard with our Chinese collaborators, CASI pharmaceuticals. We're working together in order to implement this study in China as soon as possible. And we recently have received CASI received an IND approval for the submission. So that's very exciting, moving forward well. And last but not least, we have been working very hard on the subcutaneous formulation, which we feel will actually be extremely important to be able to develop this in the best manner to put that to patients. And in terms of the combination with pembrolizumab, we will continue dose escalation, hopefully, find the recommended Phase II dose and move forward in that direction as well. Can we have the next slide?

Yes. Thank you very much, Andres. Pretty exciting days indeed. It though still early. So that was the presentation. And now we would lead over to Q&A. So maybe the next slide, please. In order to introduce Q&A. Thank you. And thank you very much for Michael, for your very detailed and comprehensive presentation. Of course, thanks to Andres and Björn. So we can start the Q&A session now, Tara.

[Operator Instructions] So our first question comes from Dan Akschuti at Pareto.

So I have quite a few questions. So I'll just try to pick a few to start. So currently, as I understood, you are going to increase the dose in solid tumors to 2 milligrams per kilograms. Do you see any signs of side effects building up in -- like going higher in the doses, any signs of potential neutropenia? And -- that's the first part. The second part, the responses that you have, you mentioned there are also 4 other patients still on treatment. Are they a bit earlier, especially in light with the kind of response progression that we've seen at 9 weeks, 28% at 16 weeks, 40% for the uveal melanoma are the other ones earlier? Or are they already longer on treatment?

Yes. So thanks, Dan. Yes, actually, those patients are earlier, and that's the reason why they are still on treatment. They will be achieving their standpoint relatively soon. But I have not done it yet.

And the first part was the tolerability. And of course, before maybe we go into this, I think, it's quite important also to stress again. So one reason, obviously, that we have developed a subcu, which is actually already quite advanced, just to remind everybody. We have produced the batch that we can test it from the -- second half of next year. And we're quite excited about this because this is, of course, quite important in order to manage 100% on completely any infusion-related reaction that should remain. But I think we are also currently -- in the current study quite under control. So...

Yes, so it's difficult to speak about the future. But what we have seen is infusion-related reactions that actually subside very quickly and managed at the bed side without any trouble. Patients have gone home without any trouble after the infusion. So difficult to say what will happen at 2-milligram per kilogram and -- or beyond. But aside these infusion reactions, we haven't seen any major issues, so no safety concerns. And what we saw at the beginning, so platelet drops and liver enzyme elevations. While we may still see them, they are now much less important. So really not concerning as it used to be.

That sounds very promising. And on the uveal melanoma patient, a follow-up, has the response stopped? Or would you say that you could see a continuous ongoing response there still?

We'll see. We'll see. I think it's -- we're all super happy to see a tumor regress, and now the regression is quite important. So I think we're excited. We'll see how it goes, difficult to speak about the future, but hopefully, the patient -- the tumor will continue regressing.

Yes. And of course, as I think you mentioned it but also to stress again, so this indication is very, very difficult to treat. Maybe you can comment on that as well.

Yes. It's melanoma. It's difficult to treat in this sort of disease. The overall survival is counted in months. So any delay of progression is already a great accomplishment. So we're super happy about this.

Okay. And of course, in these kind of early trials, it's also very interesting to learn from those patients that have not responded. So do you see any correlation regarding, let's say, sigma expression and the responses that you have seen from the patients? Do you think you're -- you can already take some learnings into the designs of the next trials? Or which patients you want to go for? I would say, I guess uveal melanoma looks very promising, but they see also maybe where it doesn't work and where you're kind of -- going to steer the upcoming trials towards...

Yes. So something that we're working very hard on is trying to understand the expression the FcgammaRIIB in those tumors and of course, try to correlate that with potential responses. That's something that the team is working hard on. And that would be, of course, the idea of perhaps not only we're doing that with RNA so that we perhaps can follow the expression of FcgammaRIIB, but perhaps other markers of immunity. And Björn, you may want to add something?

No, I think that's a super good question and it's very important, of course, to find a biomarker that can help find patients to treat. So like you said, we're doing it by measures of RNA quantitation. And in 1 slide I had shown in the latest study, there was actually an equally strong correlation between FcgammaRIIB and poor outcome on rituximab treatment, whether protein-based immunohistochemistry or gene expression-based RNA Seq analysis were used. So yes, I think that's super important. Of course, we're still -- I keep coming back to an early stage. You need some good number of patients actually to make that correlation in a robust manner. But a very important question, and this is what our focus is on right now, getting more patients to treat and correlating with FcgammaRIIB expression levels.

And of course, I think the important thing, and I think that sort of transpires from Michael's presentation is that if you are able to enhance the activity of rituximab, rituximab is used so widely. And so it's such a great drug that if we can cherrypick the patients, we can go to more difficult-to-treat diseases such as DLBCL. And as Björn showed in one of the slides, there is a couple of cohorts already showing that FcgammaRIIB expression is a poor prognosis in DLBCL. So we could specifically choose the patients that would be likely to respond. So I think that's also very important and interesting.

Okay. I would have more for solid tumors, but I think I'll go to the liquids. So to sum up, basically, you are in the current cohort if 4 patients out of 5 still on treatment with potential responses going on and you're increasing the dose with no dose-limiting toxicities with the steroids. So that's -- I would say, very promising, and I looked a bit at other companies as well during ASH that were presenting data in lymphoma. There was, of course, quite a lot of data there. And it was interesting to see that these new approaches from Allogene, CRISPR Therapeutics, Precision, Bioscientists, they had quite a lot of relapses early. I think Precision had 8 out of 12 relapsing within 6 months; CRISPR 11 out of 14 within 6 months; and Allogene 12 out of 24. If you compared a bit your responses that you have to these, and from what I see, I think the main benefit is probably the patients in terms of like actual lung in during nonrelapsing complete responses.

Exactly. I think you've summarized it, Dan, I think it's early stages for those projects as well. But clearly, with -- when you compare data with data, the CHRONOS-3 study or the relevant study, et cetera, you see that patients -- when you treat patients, we're getting a lot better responses and actually comparable to those other drugs just by enhancing the activity of rituximab. So I think that's -- if the trajectory continues, I think we are in a very good shape. And this, of course, we still need to tweak the dose and be able to do it ideally optimally. And then I think we will have a very interesting way to enhance the activity of CD8, 20 targeting agents such as rituximab, but also perhaps with obinutuzumab and the others.

Maybe that's also a good point for Michael to provide a comment.

Yes. So I think the follow-up of TAM is not that long, and the number of patients on the trial is still in the early phase. I do believe that with more time on it, we will show more durability, but that requires the time. But usually, uveal-related drugs last a little longer than about the chemotherapy or targeted therapies. That's how I feel, especially you combined the -- with rituximab, their mechanism. I really think the duration should also be promising in relation to the response. So only time could help.

Maybe one last question to Michael. Considering the efficacy that BI-1206 is showing, what is your take on the kind of mild treatment you're actually getting with [ rush ] rituximab plus BI-1206 compared to this chemo CAR-T therapies or others? It seems to be a much milder treatment.

It is. We do -- yes, so we do need the milder treatment. Rituximab is mild -- is used in maintenance therapy. So we -- all kinds of [indiscernible], we have [ retired ] maintenance. I think if we combine the [ 2 ] 1206 and that a combination continued -- could be -- continue to [ divide], not only in the therapeutic time period, but also in the maintenance time period. And also, we can use the combination together to combine with others to treat even the very aggressive disease as well. So it can be used to be almost every -- any setting that you can imagine on B-cell lymphomas.

Our next question comes from Sebastiaan van der Schoot from Kempen.

He is probably on mute.

So we'll go to the next question from Richard [indiscernible] from Redeye.

I'd like to start with a question for Michael Wang. A bit somewhat repeat from previous question, but I think it's worth underlining or stressing this. How would you rank the preliminary results from BI-1206 in lymphoma, admittedly early and a few patients compared to standard second-line treatment? And also if you -- as I understood that the -- it's main advantage. Would that be -- could that be better toxicity or better efficacy or both?

Okay. So because the patients not too many yet and the follow-up time is relatively short, it is really very hard to compare with the FDA-approved therapies at the first-line relapsed B-cell lymphoma. But I feel that with the time, we will be able to provide this data, I think -- although it's early, the message is very clear, this is an effective combination. And the toxicities, we do have some infusion related to toxicities. However, this can be mitigated by developing the subcu injection. So I really believe that I've been in the clinical trials for so many years. And I feel that my intuition is that this is going to be some very -- some efficacious combination be -- that can be used alone in combination and with the other studies. So it is impossible for now -- for me now to compare with the standard therapies yet. We are not there yet.

Thank you, Michael.