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

Good afternoon, and welcome to the BioInvent KOL call on BI-1206 for relapsed or refractory Non-Hodgkin's Lymphoma. [Operator Instructions] As a reminder, this webinar is being recorded, and a replay will be made available on the BioInvent website following the event. I would now like to turn the call over to your host, Dr. Martin Welschof, CEO of BioInvent. Please go ahead, Martin.

Thank you very much, Sara, and welcome, everybody, to our KOL event today. Good morning, and good afternoon. And if you can go please to the next slide. So obviously, since we are listed on the Stockholm NASDAQ Stock Exchange, this is our forward-looking statement. And before we kick-off, I want to provide a brief overview, which is on the next slide, of how we structure today's call. So I will start with a brief introduction. And then Andres McAllister, our Chief Medical Officer, will give you the latest update on BI-1206 in Non-Hodgkin Lymphoma. And then we are joined by Mats Jerkeman, and we are really grateful to have him on the call. He will provide an overview about the treatment landscape in follicular lymphoma and marginal zone lymphoma and mantle cell lymphoma. And then at the end, we have Wei-Wu He, President and CEO of CASI , and he will basically let us know why CASI selected BI-1206 and then also elaborate a little bit on the potential for China. And then I have some concluding remarks, and then we start our Q&A. So the next slide, please. Just to introduce the presenters of today. So I'll start with Mats. So Mats is a professor in clinical oncology at the Lund University and very experienced in the area that we are working on with 1206. So he has coordinated several ongoing clinical trials in diffuse large B-cell lymphoma and mantle cell lymphoma. And he's the Chairman of the Nordic Lymphoma Group and also Editor of the ESMO guidelines for lymphomas. Then obviously, you know already Andres McAllister, who's our Chief Medical Officer since 2017. Before that, he was a CSO at Debiopharm and had a couple of other roles in large and small companies. And he has a PhD from the Pasteur Institut in Paris. Then as already mentioned, we're really happy to have Wei-Wu with us, the Chair and CEO of CASI. And we're really looking forward to his contributions. And with that, I would like to go to the next slide. Thank you. And before we really start about the main topic, BI-1206, just to remind everybody, so we are a portfolio company. We are not a top-of-list company, so we have a number of shots on goal basically. And just to briefly remind you, so obviously, BI-1206 was our lead program that we're currently running in 2 clinical studies. And then we just recently kicked off BT-001 in collaboration with Transgene, where we are starting to enroll patients any time point soon. And we have started to enroll patients for BI-1808, which is our lead program targeting for -- targeting TNF receptor 2. And then later this year, the plan is really to advance BI-1607, which is our second antibody against FcgammaRIIB. So as you can see, a very rich portfolio and as we always say, multiple shots on goals, which basically means multiple value drivers. But then today's topic, next slide, please, is obviously BI-1206 for Non-Hodgkin Lymphoma in combination with rituximab. And we released the data today already this morning, and we are quite excited because, as you know, we are targeting a very fragile and important patient population with a high unmet medical need. And then we could see already at this stage 6 responses, partial and complete, out of 9, and some of those responses are really long-lasting. And we'll get back to details in a minute when Andres gives you the more detailed update on the data, but quite exciting times. What I would like to do is briefly remind you of the biology of the target FcgammaRIIB, which is summarized on the next slide. And when you look to the right, you see the T cell checkpoints, so called, and you know they come in 2 flavors: inhibitory receptors such as CTLA-4 or PD1, but then also you have activating receptors and the most prominent ones are CD28, OX40 and GITR. And you have the same principle of -- on cells of innate immune system. So we have activating receptors on the left and one inhibitory receptor, which is FcgammaRIIB, which is the only inhibitor receptor which is known so far. And this is the target of BI-1206. And as already mentioned on the overview, so we have 2 different trials running. Today, we want to focus on the Non-Hodgkin Lymphoma study. And on the next slide, you get a very brief introduction to the mode of action. So obviously, the gold standard for treatment of Non-Hodgkin Lymphoma is anti-CD20-based therapy, and the main product which is currently used is rituximab. And it works as such that it binds to CD20 and then basically induces phagocytosis. We are making use of the FcgammaRIIB receptor, which is, in this case, expressed on the tumoral B cell as well. And it's actually part of the resistance mechanism. So when rituximab binds to CD20, it also interacts with FcgammaRIIB. And then this trimer gets internalized, and they would have then no activity anymore. In the lower panel, you can see with BI-1206, we can block this internalization. In addition, we also add a certain single-agent activity. So we have a bifunctional mode but obviously positioned as a combination agent because that's the best way to use 1206, and this will be now explained in more detail by Andres. So Andres, if you can take it from here.

Okay. Thank you very much. Sara, if you can go to the next slide then. Thank you. So thank you very much. I'd like to share with you today exciting data that we're starting to see in our Phase I/IIa clinical study. And I'd like to start the presentation by briefly pointing out the value drivers of BI-1206. First of all, it's based on a very compelling scientific rationale and trying to understand why people become resistant to anti-CD20 therapies, et cetera, which has been a mystery. And I think we are putting the finger on what's important, and this is Fcgamma receptor IIB, the target of BI-1206. Of course, this is -- would be a part of a chemo-free regimen, sort of 2-antibody cocktail. So very interesting positioning with respect to safety and tolerability and of course, hopefully, in terms of efficacy as well, as we will see. I'll talk a little bit at the end about this capability of the addressable market. But it's important also to note that this is a first-in-class product, and probably best in class and as far as we know, only in class so far, trying to address this high-unmet medical need of chemotherapy-free regimens for second- and third-line treatments of these elderly population. Of course, we have obtained orphan drug designation, and we will look further into these options for the future. The types of patients that we're looking and that we're including right now are, as Martin mentioned, mantle cell lymphoma, follicular lymphoma and marginal zone lymphoma. Mantle cell lymphoma is quite an aggressive disease. It can be very aggressive. And many of these patients are very high expressers of Fcgamma receptor IIB. And we also know that high expression is actually correlated with poor prognosis, so showing really that the target is there doing something detrimental for the patient. So that's particularly interesting in particular because once these patients go through the first rounds of -- first lines and second lines of therapy, they can become resistant to, for instance, BTK inhibitors. They can progress very quickly, and there is not very much left to be done. Follicular lymphoma is a more indolent form of disease but also very interesting and also devoid of good treatments after rituximab or chemotherapeutic agents have become resistant to those patients. So that's the -- we are also targeting marginal zone lymphoma. It's a smaller indication but also treated similarly as the 2 previous ones. So if we can move to the next slide. This is the study design. This is -- it's an open-label Phase I/IIa study. It's divided in part A and part B. Part A is basically a 3 plus 3 dose escalation of BI-1206 in combination with rituximab. We use rituximab in the usual regimen that is used, so once weekly, every -- for 4 weeks, followed by 1 -- maintenance of 1 infusion every 8 weeks for up to 1 year. And of course, the main objective of this aside from the usual objectives of describing the first characteristics of the drug will be to determine the recommended Phase II dose. And once we will have found that recommended Phase II dose, we will move into part B, which is basically an expansion cohort looking at the same patients -- same patient population and using the same regimen. So the study objectives are quite classical for this type of study, so I won't dwell into that. But it's important to note here that the patients that we're looking into right now are patients who have relapsed or are refractory to rituximab. So they must have received previous lines of rituximab-containing therapies. So that's the study design. Can we move to the next slide then? And this is what we have seen. So these are the patient demographics of the study so far. We have been able to recruit 15 patients, out of which 3 are mantle cell lymphoma patients and 12 follicular lymphoma patients. The patient demographics resembles very much the patient demographics of this sort of pathologies, so slightly more frequently in males. The age are elderly patients. In our study, we have patients from 53 to 80 with a mean of 70 years old. This is very much what is usually seen in these diseases. The disease type, as mentioned, follicular lymphoma is a more frequent one; mantle cell lymphoma, less frequent. And the number of prior lines of therapy in our study is between 1 and 11, with a mean of 3.7. That's basically the demographics. If we move to the next slide. This is the way the study has rolled out. We started with a 30-milligram -- cohort #1, 30-milligram flat dose, where we already saw some interesting responses. We saw some mild infusion-related reactions. And so that -- we went up to 100 milligrams, where we saw, unfortunately, some of those perhaps stronger -- or stronger infusion-related reactions that led to 2 DLT. So what we did at that time was we lowered the dose to an intermediate dose of 70 milligrams. We started dosing patients at this dose. And unfortunately, we also saw 2 DLTs in these cohorts. We -- at the same time, we saw, again, 1 complete response, which already, of course, motivated us and the investigators to pursue trying to escalate further. So we basically did some clinical and preclinical work trying to understand and manage these infusion-related reactions. We came up with a new steroid regimen that we implemented in the clinic. And we tested, and it showed that it worked. And in parallel, we showed a very interesting data preclinically by Björn's team at BioInvent, and we were able to show that this new regimen was actually working really well. So we opened -- this was, of course, approved by FDA and European authorities. So we continued and opened a new cohort of 70 milligrams, where we already saw 3 partial responses, and then we saw that we didn't have the trouble that we were having at the beginning of the study. That went really well so we moved up to 100 milligrams. With -- that's the current cohort where we are, and we're looking to fulfill this cohort, which should happen very soon. And that will lead us to cohort #6, which should be the recommended Phase II dose or at least very close to it. So that's where we are. Just a word if you take one word about what we have seen in terms of where those DLTs were. So basically, they were the consequence of the infusion-related reaction. And what we saw is 2 cases of thrombocytopenia. Fortunately, it was only lab values with no clinical signs or bleeding. The patients recovered rapidly. And by 1 week, they were already doing well and where they were at the beginning. And similarly, we had 2 cases of liver enzyme elevations, ALT and AST. Again, only lab values, no signs or symptoms, no bilirubin increases or any sign of liver compromise. And the patients' values returned to normal very quickly. So for that aspect, everything was -- has been okay. So if we move to the next slide then. I think the most interesting part is what we have seen so far. So out of 9 patients where we have performed the assessment, we have seen 2 complete responses and 4 partial responses. Those 2 complete responses have been out already with a very nice duration. One of them is over 12 months, and the other one is 24 months over. So very nice and very nice duration. And interestingly, those complete responses started out as partial responses, then that converted to complete responses as we continued the treatment. So that gives us hope that in the other partial responses that we still have in the trial, they may convert into complete responses as we move forward. So that's where we are. Right now, we're looking to fulfill that final cohort and hopefully move into the recommended Phase II dose and move to the part B of the study. If you move to the next slide. I'll just basically mention a few of our upcoming milestones: so again, select the recommended Phase II dose; move to phase -- to part B of the study, same study patient population, as I mentioned. But something that, as you saw, very excited we are about is that now we will include China in our clinical global development strategy. We're working with our colleagues at CASI right now, and our idea would be to implement that as soon as possible so that we can gather data in patients of Chinese origin that we will have a very complementary development plan. We are looking to have an end of Phase I meeting with FDA, and this should happen somewhere between Q3 and Q4 2021. So this will also be exciting. We will be able to discuss the dose with FDA and potentially a pivotal study design in case we see that this data as we move forward becomes more robust. And just to -- you probably know that in these indications, open-label studies have been the benchmark for achieving registration. So that's what we're looking for, and that's what we would like to do. And I think the data seems to indicate that there will be an amenable way to pursue. We will -- for the near future as well, we're starting to implement those Phase II studies in the U.S. and Europe and also in China and again, as I mentioned, determine the quickest path to registration. And the final word that I would like to say is that, of course, if you move to the next slide, Sara, just a word -- Mats is going to speak very much about this, but we would just point out that we are, at the bottom of this slide, basically a late line of therapy. But as you can see in this algorithm of treatment by follicular lymphoma, you can see that rituximab-based therapies can be -- or are used at just about every line. So we believe that BI-1206 can go hand in hand in any one and scale up to treat patients in all those lines of therapy. And in the next slide, you can see a similar algorithm for mantle cell lymphoma. Again, rituximab is part of the treatment algorithm just about at every step. So our hope is that BI-1206 will enhance rituximab in each one of these lines and we'll be able to position the drug in all those stages. So with no further comment, I will hand over to Mats, who's going to speak about the treatment landscape of follicular lymphoma and mantle cell lymphoma. Thank you for your attention, and looking forward to the questions.

Thank you, Andres. So I'll give an overview of the current treatment landscape of patients with follicular and mantle cell lymphoma. So we can have next slide. These are some figures from the Swedish lymphoma register, which is population based and includes all patients nationwide. And so follicular lymphoma and mantle cell lymphoma are quite common subtypes of lymphoma. They are #2 and 4 in frequency, follicular lymphoma about 15% of the patients and mantle cell lymphoma about half of those. So we can have the next slide. And both of these are B-cell malignancies. There are similarities but also difference between these 2. They're both very sensitive to CD20 -- anti-CD20 immunotherapies like rituximab and obinutuzumab, which is important for the discussion today, I think. But they're also very radio-sensitive, extremely sensitive. They present always -- often in a similar way clinically with mostly lymph node involvement but also very often with bone marrow involvement. And another common feature is that both of these are incurable diseases. But mantle cell lymphoma is -- as Andres previously said, is more often a clinically very aggressive disease but not always. There are also differences in the sensitivity to novel agents. For mantle cell lymphoma, BTK inhibitors are particularly active, and also BCL-2 inhibitors like venetoclax are particularly active in mantle cell lymphoma. Whereas, in follicular lymphoma, the PI3K inhibitors are more active and more interesting as future novel compounds. So we can have the next slide. So I will give an overview of the current European ESMO guidelines, where there are -- there's quite recently published guideline for follicular lymphoma, where I've also been involved. And for follicular lymphoma, it's important to distinguish between patients with low tumor burden and high tumor burden when you discuss treatment. And for patients with low tumor burden, that is with small lymph nodes and a limited number of involved lymph nodes, patients with localized disease with only 1 or 2 lymph nodes involved, they can receive local therapy with radiotherapy, to the left. And patients with low tumor burden and no clinical symptoms usually don't receive any treatment. They are only watched, and we wait to see if they receive -- get any symptoms then before we start treatment. Some of these patients can receive rituximab monotherapy, only rituximab. Next slide, please. And if patients relapse with still low tumor burden, most -- in many cases, we defer treatment and wait until patients get symptoms. So this is a disease which you can live with. But in some cases, you can give low-dose radiotherapy, extremely low doses because this is such a radio-sensitive disease, so only about 4 Grays. But other options are also here at time of relapse, rituximab monotherapy. But also in this situation, rituximab can be combined with chemotherapy for some -- in some cases. So next slide, please. Patients with high tumor burden is more significant clinical problem. And here, there are some differences in terms of patient age because younger patients can tolerate more intensive treatments, such as high-dose chemotherapy. But both for younger and elderly patients, usually, the most common treatment is the combination of immunotherapy and chemotherapy. And the immunotherapy can be most commonly rituximab but also obinutuzumab. This is an option here. Another option is the combination of rituximab and lenalidomide, which has been shown to be noninferior to chemo-immunotherapy. Lenalidomide works as a chemo -- immunosensitizer in this respect. And for younger patients at relapse, there is a possibility of consolidation with high-dose chemotherapy with autologous stem cell support, also called autologous stem cell transplantation, but -- which is not an option for elderly patients. So we can move to the next slide. For mantle cell lymphoma, there are also European guidelines published a couple of years ago but that are still relevant. We can have the next slide. So in this slide, you can see to the left the algorithm for younger patients, in the middle for elderly patients and to the right for frail elderly patients. Because -- here, first-line treatment is very dependent on age because for younger patients, patients generally receive an intensive induction therapy, which includes doxorubicin, like R-CHOP, but also cytarabine, which is a very important component. And then they receive consolidation with autologous stem cell transplant. That's the current standard. And after autologous stem cell transplant, they receive rituximab maintenance for at least 3 years as this has been shown to prolong survival. For -- to the -- in the middle are the elderly patients, and the age limit is around 65, 70 years. Elderly patients receive more conventional chemo-immunotherapy. Most -- very common combination is the combination of rituximab and bendamustine, which is tolerated up to 80 years or so. Or R-CHOP is another option. And then they receive also rituximab maintenance in this situation. Frail elderly patients can receive mild chemotherapy like chlorambucil and rituximab. And at the time of relapse, a little further down, younger patients can receive another type of chemotherapy like rituximab-bendamustine for instance. An option is allogeneic transplant for these patients. For elderly patients, they are not eligible for that kind of therapy so they usually receive another type of also chemo-immunotherapy. And more and more commonly, patients in this situation also receive ibrutinib or another BTK inhibitor like acalabrutinib or zanubrutinib. So this is moving usually -- it's beginning to move earlier in the treatment lines. And at later relapses, patients can receive other types of novel agents such as lenalidomide, for instance, or combinations with pertuzumab or combination with BTK inhibitors. In the U.S. and also in the U.K., we also have the possibility to use CAR T-cell therapy in this situation, which has recently been approved. Next slide, please. So where can we use BI-1206 in this situation? I think it has potential as a sensitizer of rituximab and possibly more specific than lenalidomide, and it could be a component in chemo-free regimens. And I'm thinking especially of patients with low-burden follicular lymphoma, for instance, where we use rituximab as a single agent or rituximab in combination with lenalidomide. I'm also thinking about elderly patients with mantle cell lymphoma, both not-so-frail elderly but also the frail elderly, where patients can receive, for instance, combinations with ibrutinib and rituximab and possibly also BI-1206. Or in this situation, also rituximab and lenalidomide has shown to be a very active combination. So the -- we could use possibly BI-1206 instead of lenalidomide here. And in mantle cell lymphoma younger patients, we use rituximab as a single agent as maintenance, and this could also possibly be combined with BI-1206 in this situation. Next slide, please. So that was all for me. So I'll move on to the next speaker.

Hello. I'm Wei-Wu He, CEO of CASI Pharmaceuticals. It's really -- we are very delighted to have a chance to partner with BioInvent. Next slide, please. CASI is a NASDAQ publicly traded company, so the forward-looking statement. Next slide, please. So I think the -- a few words about CASI. CASI is a company that leverages kind of the Chinese fast-growing pharmaceutical market as our initial market, but we really are trying to partner with global innovators like BioInvent to source innovations. CASI is already a commercial-stage pharmaceutical company. We launched our first drug, EVOMELA, which is a reformulated melphalan used for autologous transplant. We launched that drug. The full year launch was 2020, and we actually are doing extremely well with that launch. And that also gives us the core competency of having a drug approved by the Chinese NMPA, the Chinese FDA. And also, we have almost now 100 sales rep in Chinese market, detailing all the physicians in hematology/oncology space. And we also have a very strong clinical development team in China. This is why we're so excited about this FcgammaRIIB inhibitor, because we believe this is really the first-in-class monoclonal antibody targeting this very important checkpoint for monoclonal antibody treatment. We think actually the FcgammaRII receptor has -- is a broader target. It can -- by blocking this antibody, it will actually have broader biological activity to the other monoclonal antibody therapeutics. And next slide, please. And so the -- our strategic partner with BioInvent will be -- I personally think it will be a very important innovation in today's pharmaceutical development. Some of the large pharmaceutical company actually obviously uses a lot of clinical resources in China to develop innovative therapeutics. For instance, Pfizer used -- their ALK inhibitor, they used actually more patients in China than in the rest of the world to develop an ALK inhibitor. We think this kind of strategic partnership will be actually used more and more in the coming years. It's simply -- it's a very simple rationale. China has more cancer patients than any other country in the world. And there's also a lot more naive patient in China than a lot of other countries. So that's really the -- we think this partnership is going to be extremely exciting. So we are actually planning to work with BioInvent to use Chinese clinical resources potentially to really accelerate the development of this program. But we also -- potentially, we can use this compound to explore other indications in combination with a different antibody, including some of our own antibodies. And obviously, CASI has exclusive China development and commercialization rights. Next slide, please. And so the first indication, obviously, will be what we talked about today. It's in the Non-Hodgkin Lymphoma market. And we believe there's also other indications in China which could be huge. For instance, in combination with PD-1 for non-small cell lung cancer, which is China has probably the most number of lung cancer patients in the world and also in liver cancer, which is also China has a huge potential market. But more importantly, CASI has what we think one of the best-in-class CD38 antibodies for multiple myeloma. And we will be also exploring the possibility of using BI-1206 with our CD38 antibody for multiple myeloma, which CASI has a franchise in China. Next slide, please. And so this is actually -- again, we're extremely excited about this opportunity to work with the BioInvent team. I think there's 2 ways we can add clinical capability to this molecule. One is now it's actually quite easy for China to become part of the global trial. Since China now has been part of ICH, there's a lot of harmonization of clinical trial data. So we can easily become part of BioInvent's global clinical trial. So we can actually enroll up to potentially 50% of patients in China in a global clinical trial. But on the other hand, we can actually start a brand-new R&D in China. And that process in China is really accelerating right now. So we actually -- if we take that route, I just talked to our team, we believe we can get an IND filed this year and create a clinical trial approval probably by end of this year or early next year. The beauty of that trial is we can also potentially initiate some exploratory clinical trial. For instance, in combination with CD38 or in combination with PD-1 for lung cancer. Next slide, please. So just to kind of emphasize, China really is a country with the largest number of cancer population. And by leveraging the Chinese market and Chinese clinical resources with global innovation like BioInvent, we think we're creating a brand-new business model to do a global innovation. Next slide. Yes, this is really a repeat of what the BioInvent just talked about. We're so excited about this data. Out of the 9 patients, we see 2 CRs and 4 PRs. We truly believe BI-1206 is really just another weapon physicians can use to manage this deadly disease. Next slide, please. I think that will be my presentation. Thank you very much.

Okay. Thank you for the presenters. Thank you, Wei-Wu, very inspiring. And thank you Mats for giving this context from the patient perspective. And Andres, obviously, a brilliant presentation of the very exciting data. And I think, just looking at the time, we should probably immediately go into the Q&A session. So what I would ask is that the people participating in the Q&A session on our side maybe switch on their cameras, so that everybody can see them. And then maybe, Tara, you can go through the logistics, how we deal with the Q&A session. Tara, please.

Great. Thank you, Martin. So at this time, we'll be conducting our question-and-answer session. [Operator Instructions] So the first question comes from Dan Akschuti from Pareto Securities.

Can you hear me?

Yes.

Perfect. Congratulations first for the outstanding data that you have presented. We have been waiting for that, and I think it was positive surprise. So I have a few questions first on the data and then some others, just tell me if it's getting too much. So just on the side effects, again, have you seen any other side effects after you mitigated the infusion-related ones with the steroid regimen that you implemented? Anything concerning on hematological values, for instance? Or has it been good since?

Yes. So basically, as Andres -- and Andres, I give the word quickly to you. As Andres presented on this slide, where we showed how we developed the new safety protocol, since then, it's looking good. But Andres, maybe you can elaborate a little bit more.

Yes. You just basically said it. No, we have not seen any concerning issues. We have seen moderate placer drops and things like that, but nothing that we have not been able to deal with or even -- I mean, no concerns. And more importantly, no other type of safety concerns. So I think that's also what's super important.

Thank you, Andres.

And from the current partial responses, are they all on maintenance? And can you still see improvements? Can you still see a trend in these patients that they are improving, the responses?

Andres, please?

Yes. We don't really know. What we do know is that some of the patients that these 2 patients have developed a complete response. They started out with a partial response at the first analysis. And then as we -- they moved through treatment, they developed a complete response. So what we can hope, definitely hope, is that some of these partial responses that we are still -- there are still on treatment may evolve to a complete response. And of course, given that we're trying now higher doses and will be trying higher doses of BI-1206, that may -- has probably a higher risk of getting there.

Okay. And do you see any trend in terms of time and how long it takes for a partial response to become a complete response depending on the type of NHL?

It's difficult to comment in terms of there's been few numbers. Usually by the second analysis, patients have developed a complete response in the few -- of 2 patients. So just very few number of events. So by the second assessment, they have developed complete responses.

Okay. And do you have any kind of concrete idea when you expect to start the expansion?

Yes, we will -- hopefully, we do need to do a little bit of homework in terms of determining what is the best recommended Phase II dose for future studies. Hopefully, by mid of this year, we should be there, I believe. It's -- looking to the glass ball, but I think, hopefully, mid of this year we should be there.

Okay. And Wei-Wu mentioned the broader potential that BI-1206 kind of shows and mechanistically compared to others that are currently in the pipeline, and I wonder what your takes are on the data that was presented at ASH by IGM Biosciences on their drug, where we saw slightly less impressive data, but nevertheless they had 2 partial responses out of 14 patients. And I think in total, including after cutoff, 2 complete responses. Their stock gained more than $1 billion in market cap in that period, where you -- I think they are targeting more the kind of T cell with the CD3 that they combine with the CD20 and you're kind of coming from another side with CD32B. I'm kind of interested in what you kind of see there. Also what Wei-Wu said with the broader potential and also in terms of market.

Okay. I think regarding the mechanistic part of the question, maybe that would be a good question to answer by Björn Frendéus, our CSO. Please, Björn. Just have to unmute.

Right. So obviously, that's a rather different kind of beast, for lack of a better word. So we all know that re-engaging T cells can be a very powerful strategy. I think I'd like to come back to Andres' comment on chemo-free regimens, that still may be very powerful. And obviously, I'm representing the preclinical side here. So I think for whatever mouse models can be worth, we have demonstrated some very convincing enhancing effects in patients that include those that are resistant to anti-CD3 or CD3-reengaging types of therapies. I do not dare to look into the crystal ball with respect to clinical development. So I don't know if, Andres, maybe do you have any comments on sort of patient population-wise? Does this answer your question, Dan?

Yes, partly.

Yes. I think that CD3, it's interesting, as Björn said. Of course, what we see in the clinic is a more less-tolerable regimens, so with a number of safety concerns, et cetera. We'll see how -- what the future tells us. It's a competitive environment. But I think here, what's super important about this drug is that for years, people have failed to understand why people relapse or become refractory to rituximab. And I think we and Björn's team and his work, they have put down the finger on one of the reasons or at least one of the reasons, and I think that's why we see these responses.

Great. Thank you. So the next question comes from Sebastiaan van der Schoot at Kempen.

Sebastiaan?

We cannot hear you. [Technical Difficulty] So we'll move on to Leland Gershell at Oppenheimer.

Great. I hope you can hear me. Congratulations, great data. Just a couple of questions from me. Just since you're seeing already signs of response at the low dose, I think at 30, we had seen a CR and the PR, and obviously you're going up on dose. Just wanted to ask what's the binding kinetics of the antibody to the receptor at these doses? Are we already approaching what would be kind of saturation? Or do you think there's a lot of room to run there as you bring the dose further up above 70 and 100 and so forth? Maybe a follow-up as well after that.

Andres, please.

Yes. So -- and Björn, please comment because they have -- basically what we see already at 30 milligrams very shortly, but we do see very high receptor occupancy measured on circulating B cells. So we don't -- we think that we are not very far from covering the weak period at least, or not very far from 100% receptor occupancy. So I don't think we need to escalate a lot more to be covering the same regimen that rituximab is given. Now the question will become do we want to escalate further in order to explore how different regimens, et cetera. But we are 100% receptor occupancy. So I don't think there will be a big sink after that.

Okay. Great. And maybe a question for Wei-Wu. Just as we think about Rituxan and rituximab biosimilars in China, just wanted to know if you can provide some commentary on what that landscape looks like and how we should think about the evolution of that going forward?

Yes, there's actually quite a few rituximab kind of generic or need better actually in the pipeline, which I think is good for us to develop this molecule because we can team up with different partners potentially in China. So -- but in the end, having another molecule like BI-1206 really just adds another arsenal to the physician. Personally, I believe that there's probably, in the future, a position kind of cocktail for people to understand the people who are more suitable to this type of combination therapy, because obviously, in the future, we'll be using CAR-Ts and different strategy. But I think for different population, this combination probably will be extremely powerful. That's my kind of futuristic prediction. I don't know if I answer your question. So -- but in China, in general, if there's a hot molecule like PD-1 or rituxin herceptin, there's always going to be, in the next few years, quite a few generics or need better in the pipeline. And so -- yes, so which is good for this molecule because we -- actually, I saw some of the question. We do not see any molecule in the Fc inhibitory receptor front in China yet. So we will be probably the first in class in this space.

Got you. And then one -- actually, one last question, if I may maybe back to the BioInvent team. If you were to predict what might be a compensatory mechanism that might allow escape after treatment with the combination, would there be one that might be obvious? Or there's a multitude of possibilities there and it's hard to really know what you want to look for post Rituxan with BI-1206?

Yes. Thank you, Leland. So that's a very good question. Obviously, more crystal ball type of a question. So Andres, do you have any comments?

No, I don't. And I think that it's difficult to predict. As I mentioned, I think FcgammaRIIB biology is one that had been a little bit put aside because people didn't manage to get antibodies that were sufficiently selective and specific, and the BioInvent team was able to do that. How will somebody escape -- tumor will escape from that, I don't know. I don't really -- I don't know. What we do know, though, is that we have Pdx, so cells derived from patients who have become resistant to just about every drug, including venetoclax, lenalidomide, CAR-T cells, et cetera, and they have all responded to the combination treatment. So that's super exciting. That was published at ASH by Björn and his group. But I will yield the word to Björn because I'm sure he probably has some good ideas.

Well, crystal balling is -- it's not my sort of favorite topic, but I do understand the importance of your question. And I think remains to be demonstrated. But one of the really interesting things I think we have seen is that -- again, I'm talking about preclinical now, across the different samples we have looked at, and that includes patients that did respond to rituximab and more interestingly, those that have failed to respond to rituximab -- and actually, this is also done in collaboration with [ Allo and MasTecs Group ], had received 1 or 2 or 3 courses of rituximab-containing therapies or open rituximab or ofatumumab. They all seem to be sensitive actually to our drug and then when recombining with rituximab. So to me, it's kind of like introducing or eliminating resistance to antibiotics as a great problem, and rituximab perhaps is an antibiotic of several types of cancer. So perhaps a bit naively, but I think very compellingly, from a mechanistic perspective, there should be good utility if our preclinical data translates into the clinic.

Thanks, Björn, and thanks for the questions, Leland. So we'll go back to Sebastiaan van der Schoot from Kempen and try this again.

Can everybody hear me?

Now we can hear you.

Great. Great. Congratulations on the results. Yes, and I was wondering if you could please indicate what the breakdown is of the responses between follicular lymphoma and mantle cell lymphoma? I just wanted to say, my Internet is a bit on wonky, so I broke off and maybe you guys already talked about June numbers.

Yes, we're happy to address that again. So Andres, maybe you can do that quickly.

Yes. So the 2 complete responses that we have seen are in follicular lymphoma. It was a surprise. It's a more indolent form of disease, so you have more time. We did see one patient with mantle cell lymphoma who developed a partial response. And we saw that circulating cells of that patient were completely depleted after a single injection of the BI-1206. So very encouraging early data. And we have had, of course, very little experience with the mantle cell lymphoma patients.

Okay. And previously, you indicated that you would saturate from mantle cell lymphoma patients, especially in the dose-expansion study. Can you maybe comment on how you will foresee how to do that in the future because it's more difficult than recruiting for follicular lymphoma.

Yes, absolutely. It is more difficult. Basically, what we are hoping we will be able to do is to engage clinicians like Professor Jerkeman, who are experts in dealing with mantle cell lymphoma particularly. We work also together with Michael Huang and [indiscernible] who is of course, a well-known person in the field and who has performed a number of these studies that I mentioned in collaboration with Björn's team. So basically -- and of course, last but not least, our colleagues in China with our CASI collaborators. We hope to be able to identify clinicians who are confronted with mantle cell lymphoma patients and engage those physicians into our trial. That's basically the one I hope to be able to do that.

Okay. And then for CASI, did I understand correct that you want to file an IND near year-end? And for which indication would that be for the 12 or 6 rituximab combination or something else?

We probably -- can you hear me?

Yes.

Yes. Yes. Great, yes. So we probably will go first with an indication which we already see some response, obviously, non-Hodgkin lymphoma. So the data from the BioInvent will be extremely helpful. But just to give you some color, CASI actually already launched our first drug is EVOMELA, which is really a more stable form of melphalan for autologous transplant. And because of that product launch, we -- because that product is used for lymphoma autologous transplant, we actually know quite probably some of the best KOLs in China in the lymphoma space. So -- and we also work with extremely good institutions like Tianjin Hematology/Oncology Institute, which is always ranked #1 in China. And we are also developing a CAR-T therapy in Tianjin in China, which we have beautiful data and all that. So I think one of the beautiful collaboration between wonderful innovators like BioInvent and CASI is we can put a team together and say, hey, after we initiate R&D, and figured out a dose, we can probably start 5, 6 exploratory trials. And that probably, I think, is -- we're really looking forward to explore that type of trial. But initially, we most likely will go after an indication we already see a good clinical responses. Does that answer your question?

Yes, that answers my question. And then one last question is regarding the position in follicular lymphoma. There also have been investigational agents that -- like biospecific that show high overall response rates. How do you see the field progressing in the future? So if you don't look at the current treatment paradigm more what is in the pipeline in the future? And where BI-1206/rituximab will take place?

Andres?

Yes. Maybe I would like to ask Mats just to -- because he will give you his perspective and then I will comment on what he says.

So maybe also Wei-Wu.

Biospecifics are very interesting agents in both follicular lymphoma and in diffuse large B-cell lymphoma, extremely promising. So -- but possibly, these can be combined with BI-1206 as well as sensitizers to these agents as well. That remains to be seen, of course. But there are many possibilities for novel immunotherapy combinations in both in follicular lymphoma and diffuse large B-cell lymphoma, from my perspective. Interesting.

Sorry, Mats. I didn't want to cut you. It seems that Mats has concluded. So Andres?

Sorry, yes.

Yes. So I think that I agree, and I think that time will tell what the best option will be. I think that BI-1206 has the immense opportunity of just going hand-in-hand with rituximab. So a 2 antibody cocktail with a really well-known safety profile. I think that just think about those 2 patients that developed a complete response, how they had received chemotherapy with all the difficulties that, that entails and likewise, quality of life. And then all of a sudden, you get a 2 cocktail -- 2 antibody cocktail and you walk away with a complete response. And if that is a durable response, that's super interesting. So I think in terms of safety and in terms of quality of life, we are really well positioned. And again, this can go in anywhere rituximab is positioned. And so one of the questions addressing, can we think that this would also work with obinutuzumab, we have data to show that it does. So I think definitely, that's how I would see this. But it is a competitive field, and we just want to -- I think we have a very strong case.

Thank you, Andres. Wei-Wu?

Yes. I'm probably going to be a little bit more optimistic and more futuristic. I think the future cancer treatment should be really looking at each individual. It's the auto position medicine, right? When we look at the CAR-T therapy, for instance, we now can use single-cell technology to really predict which patient will respond and which patient will not. So for -- if you see a 55% ORR for biospecific, but if I'm that patient, I may be that -- 45% don't respond to it, but I might be that -- maybe our 1206, I might be the perfect responder in the 1206 population, okay? So in that case, statistic doesn't really apply to me as an individual. I think in the future, we really need to figure out the most precise way of treating that patient. That's kind of a little bit more futuristic. But it really is happening. We are actually doing trials in China for CAR-T 19 therapy using single-cell sequencing technology to predict which patient will respond to the therapy because CAR-T therapy is so expensive, you don't want to give the drug to nonresponders, right? So that's -- I think whether it's biospecific or an Fc receptor inhibitor, I think the physician will love all these weapons available. And in the future, we biologists need to figure out for each individual patient, what is the best combination of weapon. Depend on their biology, their physical strengths, the age, the -- and I think that is ultimately the -- personalized medicine.

I agree. And just to add more specific 1206 perspective, 2 things from my end. So first of all, just adding to what you have said, Wei-Wu, is obviously, as you know, at BioInvent, we have a signature development program to really narrow down the patient population that we want to treat, such that we can really focus on those who will benefit most. And I also want to go back briefly to what Andres was saying. So I think also the toxicity profile is something very important. Because some biospecifics, at least, they're quite toxic. So they have good efficacy, but they're also quite toxic. And I think at the end, it's really the balance that you have to strike with good efficacy with the right patient population, but also with a high-quality of living. And I think that's what we're trying to do.

Thanks. So I think we have time for 1 or 2 more questions. So the next question will come from Joseph Hedden.

Just initially, what was behind your decision to do the trial in indolent NHL subtypes rather than the larger DLBCL indication? Just out of interest on that one.

Andres, do you want to address that?

Sure. Yes. So that's a super important question. And of course, a huge -- DLBCL and large B-cell lymphoma, it's a huge unmet medical need. But it's also a more difficult disease to treat and it's also a more difficult place to develop drugs. Indolent lymphoma, you have a little bit of time to explore how your drug works. You can see what we're seeing now. In -- with large B-cell lymphoma, even though the drug may be efficacious, you may run into trouble because you lose the patient as you're treating him or her in your clinical study. So just the fact that it is just a much more aggressive form of disease makes it more difficult. So that's where we decided to start with indolent non-Hodgkin lymphoma, and I'm happy we did that because I think it's proven to be a good strategy. Now -- and to tie up with the previous discussion, our goal is to develop a signature that would be able to identify patients likely to respond. And we know that those patients can also have large B-cell lymphoma. So as soon as -- and we're doing this with a company called Skyline Diagnostics who have experience in this. And what we're trying -- what we'll be trying to do is to identify those patients. And then specifically go after those patients in those more difficult-to-treat indications.

Thank you, Andres. Good point.

Thank you. So the next question and final question comes from Niklas Elmhammer from Redeye.

Niklas?

Yes. My questions have been asked already, but I was just curious if any of the patients have been treated with ibrutinib previously, because that would be an interesting observation?

Andres?

No, they haven't been. They have received previous chemotherapy and rituximab-containing therapy. There was one patient who received their PK inhibitor, that I can remember from the top of my head. But I don't believe any of the patients. But I can check that and get back to you.

So Martin, now turning the call back to you for closing remarks.

Okay. So I think that was a very comprehensive presentation. It worked quite well with all the different presenters. So thank you very much to Andres, Mats and Wei-Wu and obviously also to Björn, contributing to the discussion. So I think we are -- as Wei-Wu and some of the other speakers also stated, we are at the beginning of a very exciting path with 1206. And we were actually internally also very surprised to see those strong results that early, which is obviously quite promising. And we're really looking forward, especially then also with the help of CASI to kick this program as quickly as we can. Because as Wei-Wu was pointing out, obviously, by having access to those patients that you described, Wei-Wu, in China can give a big push to the program, can be a big accelerator. And I'm really pleased also to say that so far our interaction and our collaboration is running very well. So also to mention that here at that place, so I'm really happy to have you on board. And I think it's good to work in a team in order to be stronger and to generate results quicker. So with that, maybe Wei-Wu, you also want to have some closing words, and then we can end this session.

Yes. No, thank you so much, Martin and the team. We are extremely excited. I think we found you guys as one of the most innovative biology antibody developer and really, really have deep insight into the biology. I invested in Fc receptor 20 years ago in a company called MacroGenics, okay? So -- and I'm a big believer in this -- the Fc biology. And I think CASI is going to do our part. I think it's -- we already have a very strong hematology/oncology commercial franchise. And China obviously has more cancer patients than any other country in the world. If we work together, I think we will make this drug a wonderful weapon for doctors like [ Mats ] to help patients. Really, this is really -- I think it's going to be an exciting few years for this compound, and working together.

Yes, absolutely. So thank you very much, Wei-Wu. So on this high note, I think thank you very much to everybody who has attended, and also thank you for all the good questions. Obviously, we couldn't address all the questions. That's not possible in this amount of time. But I'm sure we will have other occasions where we can do that. And yes, have a good evening. Thank you very much.

Bye-bye, everybody.