Akari Therapeutics, Plc (AKTX) Earnings Call Transcript & Summary

Okay. We are ready to get started, and welcome, everyone, to the Akari Therapeutics Corporate Update Webcast. [Operator Instructions] Note that this webcast is being recorded at the company's request, and a replay will be made available on the company's website following the end of the event. At this time, I'd like to remind our listeners that remarks made during this webcast may state management's intentions, beliefs, expectations or future projections. These are forward-looking statements and involve risks and uncertainties. Forward-looking statements on this call are made pursuant to the safe harbor provisions of the federal securities laws and are based on Akari Therapeutics current expectations, and actual results could differ materially. As a result, you should not place undue reliance on any forward-looking statements. Some of the factors that could cause actual results to differ materially from these contemplated by such forward-looking statements are discussed in the periodic reports Akari Therapeutics files with the Securities and Exchange Commission. These documents are available in the Investors section of the company's website and on the Securities and Exchange Commission's website, and we encourage you to review these documents carefully. So joining on today's call from the Akari Therapeutics leadership team are Abizer Gaslightwala, he is President and Chief Executive Officer; and Dr. Satyajit Mitra, he is Head of Oncology. I would now like to turn the call over to Abizer. Please proceed.

Great. Well, thank you, Jenene, and welcome, everyone. We thank you for joining us today. Go to the next slide, please. So I'm just going to give you a brief overview of what we're going to talk about today. I'll just give some opening remarks and a corporate overview for Akari. Then we'll also get into the payload overview for ADCs, kind of what the landscape looks like, and how we are a little bit different, but then we're going to kind of roll that out a little bit more with Dr. Mitra. He's going to walk through some of the really interesting data that was presented at SITC, The Society for Immunotherapy of Cancer about 1.5 weeks ago in Washington, D.C., where he'll do a deep dive into our novel payload and talk about what's unique about it and interest to focus on our splicing targeting payload and the ADC data that we presented. And then I'll conclude with some follow-up steps on our lead asset, AKTX-101 and where we're going in terms of development plans and next steps, and we'll do some Q&A. And again, as a reminder, for Q&A, you'll be able to submit your questions through the webcast and our IR team will be able to field those to us. Go to the next slide, please. So I just want to give a high-level overview. Many of you might be familiar with this already, but just as a brief orientation within oncology, which continues to be the #1 therapeutic area in the pharma biotech sector, antibody drug conjugates, or ADCs, continue to be the most popular and exciting modality to treat cancer patients. These have continued to be prominent in this news, as you probably heard and seen. And as an example, there are over six, $1 billion, what we call blockbuster product, already that are ADCs across a number of different cancer indications, whether they're solid tumors or blood cancers, and this class is rapidly growing and accelerating as well with new products entering every day. And this market is expected to surpass over $30 billion shortly. And as we look at these ADCs, you hear some of these -- you see some of these at the bottom, some of the names you might be familiar with, you can see the different types of tumors to go after. You can see the respective sales just in 2024, cumulative sales worldwide, and these are continuing to accelerate. What's interesting when you look at the payload that's used on all these blockbuster ADCs and importantly, on the right, which is all the ADCs and early to mid-stage development, you see two payload classes dominating, DNA damaging agents and microtubule inhibitors. And those are two kind of biological mechanisms how these payloads were, which are very similar to how -- exactly how chemotherapy, traditional chemotherapy works. So yes, some of these ADCs use targeted chemotherapy, maybe different versions of the older ones. But these are the two payload classes that over 95% of all ADCs are using. And so although there's been tremendous success with these two payload classes, which again are versions of chemotherapy, and they've done a great job with the current ADC set, we want to walk you through why it's important to diversify this payload approach because as good as these ADCs have become, there's more opportunity to go beyond the current efficacy and safety profiles we see. So let me walk you through why that is. Can we go to the next slide. So in terms of Akari, we're advancing ADCs beyond today's efficacy safety limitations you see today with urgency and efficiency. So getting to that first point, payload innovation for ADCs. Why do we need that? Well, as good as those ADCs have been, that we just walked through, there are limitations. Let's take, for example, an ADC class called TROP2, it's a target on many different solid tumors. And when you look at some of the current ADCs approved in the U.S. market for TROP2, what you see is some interesting stats, you see the median progression-free survival, which basically is the amount of time someone as a cancer patient goes about their tumor progressing. That means 50% of patients get less of response. And this response on average for these current approved ADCs is only about 5.5 to 7 months. So imagine roughly about 6 months a benefit you get with these ADCs. Now it's better than where these patients are before. But 6 months doesn't seem to really move the needle for many patients and their families. We also see tremendous side effects still with these ADCs. As I mentioned, many of these ADCs use chemotherapy-like payloads, so you're going to expect chemotherapy like toxicities. And one of the more important things we look at both for a patient and a physician is dosing interruptions when a patient actually has to stop their dosing of a product because their toxicity is too bad. Well, that's bad because that means you're not treating the cancer. So when you look at the, again, current TROP2, ADCs, anywhere from 22% to 66% of these ADCs have to be dose interrupted in the clinical trials, where they were dosing patients. And that's a best-class scenario because clinical trials are just an objective experiment. So imagine, again, the tolerability and safety issues. So when you look across efficacy and safety, there's clearly despite progress by these current ADCs, there's clearly opportunity to improve on both. And that's what makes us excited about Akari's PH1 splicing modulating payload. It is totally different than those chemotherapies we've heard about and talk about. It is -- it has a 1, 2 punch, and we'll speak more about that in a second. It is cytotoxic, which means it kills the cancer cell that's targeted. But more importantly, it has a strong immuno-oncology action, dual action for the payload. And we know that immuno-oncology, the immune system is the best way to actually attack cancer, and we have a payload that does that in full totality. And we're going to talk about that data that was presented at SITC. So what you anticipate that very soon. We also know from our preclinical data, this payload PH1 is superior when we've seen in preclinical testing to some of the current ADC payloads, and we have a number of data, and we'll walk through some of that as well in terms of some of that data that gives us conviction and confidence in this payload performance. We've also seen in our initial safety testing that the payload for our ADC, this PH1 as a differentiated safety profile. We don't see some of the safety events and issues that we see with the current ADCs. And that gives us a lot of encouragement that hopefully we can improve that statistic around dose interruptions, and we can see better dose continuation, which means you're treating the cancer more readily. So this is the reason why we think payload innovation is needed in the ADC market to fully unlock the potential. And we have a great solution with our PH1 splicing modulating payload, which you'll hear more about. Well, what does that payload mean? Now that Akari has a first-in-class leading best-in-class payload, we can actually start applying that, and we have our lead asset, AKTX-101, it's actually going after TROP2 as well as a target, and we're going to speak more about that at the end of the presentation. We believe this payload can be leveraged not just for AKTX-101, but across many other ADCs to create a pipeline of ADC. So we think there is a pipeline in this payload opportunity. And we've already demonstrated preclinical experiments, and you'll see some of this shortly. We think this payload is super active in many areas. We actually filed some patents early this year because of that. We believe we're active in certain cancer mutations or oncogenic drivers of what they're called. They are pretty bad in certain cancer types. We actually find our payload is very effective against those, and we filed a patent around that. We also know our payload is very active in immune activation. We filed some patents around that in the fourth quarter, and you'll be seeing that data that was presented and part of that patent filing as well shortly. And the last piece I want to kind of differentiate Akari maybe from other biotechs. How do we think about ourselves in terms of not only this innovation, but how we're bringing this innovation to market, and we're doing it with urgency of speed and efficiency of capital. And how are we doing that? Well, we're going to be using a lot of partnerships to incentivize speed to get to the clinic. And you'll hear more about that on the 101 program shortly because we think that partnerships risk shares and opportunities to get people with the same incentives and alignment to deliver results is more important than just paying vendors to do work. That also allows us to defer capital outlays until we get to value inflection points. As we progress our pipeline, not only do we benefit but our partners benefit, and that's how it allows us to be more efficient with our capital. It allows us to advance our preclinical assets like AKTX-101 to the clinic at much lower cost than a traditionally seen from ADC development and really allows value inflection for Akari. If we can get these assets quicker into the clinic, we did get a valuation for Akari that could approach what clinical stage ADC companies are today, pending we generate positive Phase I data into the clinic soon, so that's the Akari story. We're really excited about the payload innovation, but how we're actually executing against that payload innovation to bring this new type of ADC to patients hopefully in the future. We go to the next slide. And with that, I want to transition to Satyajit, Dr. Mitra is our Head of Oncology, and he will walk you through the exciting data around the payload, set up some background as well as walk you through the SITC data that we just presented with great anticipation and excitement. Thank you.

Thanks, Abizer. Next slide, please. So Abizer talked about how exciting the ADC field is. And my first slide is about the limitations of ADC. So don't get me wrong. It's the fastest-growing plus of modality, which is upended traditional chemotherapy and appended many targeted chemotherapies on the way to success. So -- but as is often the case with something a modality that leapfrogs very quickly, it creates a vacuum in its space. So since 2013, HER2-positive breast cancer and gastric cancer patients were receiving the drug, Kadcyla. And many years later, this was replaced by a drug that performed better and HER2. Then the question immediately arises, what do you do in a post -- and HER2 setting? Is the target still relevant? Do the cancer patients still express HER2? Do we give HER2 ADCs with different payloads? Well, early studies seem to suggest that the resistance is due to the payload. So you can follow a HER2 ADC with another HER2 ADC of a different payload class and you can still expect activity. But if you follow the same -- different target, ADC against a different target, you have -- with the same payload or the same payload class, you may not capture that activity. So this immediately posed an important question, where do resistance -- where does resistance come from? Where are the mutations that give rise to resistance. And you can see in various patient pools, there are mutations in topoisomerase that make it refractory not only to the payload -- ADC with the same payload that it has been treated with, but also potentially to the payload class. So anyone who's been treated with an irinotecan version, the mutation makes it refractory to deruxtecan and reduces the binding affinity to something like exatecan. And this about 60 such topoisomerase is coming through the ranks in clinical studies. So this poses a big challenge in oncology, how do you sequence ADC after ADC? The other problem is when you look at the resistance per se, and you look at the toxicity profile. One of the toxicity problems is that there is toxicity with a payload class. So irrespective of whether you treat with them any version of irinotecan. You have nausea, vomiting, diarrhea. You have gut toxicity associated with that payload plus. You're not going to walk away from them. There is -- you get less or more of that toxicity. As you -- engineer incremental changes around the payload. You tweak a linker here or there or you make more changes about the payload, you are still stuck with the toxicity of the payload class. So how does one deal with that? You have to change the game. You can't play by the same rules and expect to win. So this screams out for the field to generate different payloads. And payloads of a different class altogether, different mechanism of action altogether. So what we did is we started working on a novel payload class. And we asked ourselves the question, what are some of these hallmarks that we should capture. One important hallmark is cytotoxicity itself. We should have the ability to kill cancer cells. In addition to that, we thought that there was no better modality than activation of the immune system. And looking at the success of checkpoint inhibitors across the spectrum in multiple indications where it brought out efficacy, unlocked efficacy of 30% of all patients, we decided to -- this is our Godzilla. We need to get this in our payloads. So we engineered and look for biologies that were compatible with this philosophy, and we discovered splicing at the heart of intersection of both these two, cytotoxicity as well as activation of the immune system. Then the problem with trailblazing and being first in class is you don't know what problems do you expect. And all the patients that are developing resistance to either microtubule inhibitor class or topoisomerase inhibitors class. They have a common problem, and that is overexpression of efflux transporters, you do your best to dose the patients get the drug levels to the extent that it causes tumor regression, but then the cancer cells adapt by overexpressing these drug Efflux Pump and pumps these payloads out of the cancer cell. By being second, what we can do is engineer our payloads and look for payloads that are refractory to drug efflux pumps. So we tackle this problem by basically stepping outside the box and going into splicing biology. Next slide, please. So what is splicing? You've heard the Central Dogma DNA to RNA to protein and -- but in that, a very key step is that of splicing. Splicing impacts about 80% of all human genes that have non-coding regions in them. And these are precisely spliced out before functional proteins are made. If these proteins are not excised properly. Then there's a gate check mechanism called nonsense mediated DK, which takes care of the proteins that are going to be misfolded or misspliced. And as a result of that, these never want to make functional protein. What we do with the splicing modulator payload, ADC, is that we throw a wrench in these works. By throwing this wrench, you are impacting hundreds of proteins that are vital to the cancer cell and therein is your cytotoxic mechanism. Some of these proteins will misfold and come up the endoplasmic reticulum and the protein factories. And that results in death by unfolded protein response or ER stress. Finally, if by some miracle, you do -- the cancer cell does survive this onslaught, then these misfolded proteins, these unnatural proteins called neopeptides, they are presented on the cancer cell surface. And these look like foreign proteins to the immune system. So they light up the cancer cell, like Christmas lights, and this activates the immune system and kicks it into high gear. Next slide, please. So we've heard the story of every chemotherapy or every ADC payload, basically saying we kill cancer cells and increase the level of immunogenicity, or it releases neoepitopes and activates the immune system. But the question is how much? How much do you -- purchase do you get when you tweak the biology towards production of these foreign proteins called neopeptides. So in this comparison, on the left, we want to look at a payload, which targets microtubule and this is called DM4, and it's found in the folate receptor ADC, ELAHERE. So we're able to look at how much new epitopes that ADC, that payload mix and compare it to ours, which is on the right. So this is a transcriptomic study. You're looking at all RNA species across the board in an unbiased manner. All the strike through the middle in black reflect genes that are unchanged, and anything above that is increased, anything below that has decreased. So in the blue, we appreciate all the genes that are going to be depleted from the system and cause cytotoxicity. And you can find that there's a three-fold increase in the number of depleted genes by our payable. So 199 versus 660. So what we see here is a more potent cytotoxic mechanism with respect to the DM4 payload from the splicing perspective. Now if you look above and look at our focus on the red dots, here, we are asking a question, where are the proteins that are not found in the human proteome, so these are like foreign proteins. These are like neoepitopes. And when you look at these sequences, you find that there is almost a tenfold increase in the payload induced neoepitopes. What that means for us is that while our payload is also cytotoxic and will create neoepitopes by all the classic mechanisms that other chemotherapies and ADC payloads do, we will produce a different class of neoepitopes of the frame shift category. So now let me talk you through how these two are different. Neoepitopes from cancer cells are generally something a carbohydrate residue that is higher in cancer cells versus normal cells, or it is a property of two sequences coming together. And you have a two amino acid difference at the junction. But a splicing modulator causes a frame shift for all the amino acids downstream of that where you throw the wrench in the works. So it has the impact of creating hundreds of amino acids that are different. So what I'm telling you is that all neoepitopes are not created equal, and this class of neoepitopes or frameshift neoepitopes, which are induced via payload increase the antigenicity and these basically kick the immune cells into high gear. Next slide, please. So this is one of the slides that we presented at SITC. And here, you can appreciate what this payload, how it changes the characteristics of the same antibody. So this is -- we have now -- we spoke about Kadcyla, right? Now we're going to go head-to-head against Kadcyla, plus/minus anti-PD-1. In a colon cancer model, which has HER2, so what we have done is we've treated these mice bearing tumors for a period of only 14 days with the ADCs, and we followed it for a period of 5 months to see tumor regression. And when you get tumor regression, you want to know the mechanisms behind it. If there's an immune mechanism. You want to know what that is. If you see different rates of complete regression, we want to understand why that is. So over to the right, you see all the individual tumor growth curves in our mice experiment. What we see is that our ADC called Tras PH1 gives you nearly the same efficacy, captures the same efficacy of that of Kadcyla and slows down tumor growth. But in addition to that, it causes a small rate of complete regression, about 11% of the mice. And this results in the tumors going away completely. That's what we call complete regression. Now in this experiment, the checkpoint inhibitor, anti-PD1 worked really well and cured 33%, 1/3 of the mice of their tumors. And even in that backdrop, our ADC combined very well with checkpoint inhibitors unlock further efficacy. So if you look at our combination, Tras PH1 plus anti-PD1 and compared that to Kadcyla, we find that there is a near doubling of complete regressions, 14 out of 19, 74% versus 42%. This was behind some of the efficacy that we observed. So now let us find out why we saw this efficacy. By doing something called immuno profiling, looking at the immune cells, when the cancer aggressions were happening. And we find that each arm was associated with a different immune mechanism. Next slide, please. So our single-agent ADC did something, which was really unexpected. As expected, we reduced the frameshift neopeptides. That's the mechanism of the payload. But as a result of increased neoepitopes we found all the antigen presenting cells, the macrophages responding and getting activated. These then presented these antigens to B cells and B cells made anti-neoepitope antibodies that was the primary mechanism in the Tras PH1 alone arm. We saw some changes, and these were anti-neoepitope based changes. There were no surprises in the anti-PD-1 arm. The anti-PD-1 arm had an effect on T cells. It unlocked and unleash their activity. And that is pretty much expected from anti-PD. But when we put anti-PD-1 and Tras PH1 together, we not only saw both the individual activities of anti-PD-1 and Tras PH1. We saw something in addition to that. And that is in our jargon is what we call true synergy. We saw activation of a kind of lymphocyte called gamma delta T cells. And gamma delta T cells are the 1 of 2 lymphocytes, other than natural killer cells that are capable of finding tumors and killing them without the need for antigen-presenting cells. So they are epitope-independent. These -- there is an entire industry of people who make gamma delta T cells, train them and reintroduce them back into cancers to unlock efficacy. And we are getting those gamma delta T cells activated downstream payload. So basically, I want to summarize this section by telling you. In terms of getting differentiated efficacy and differentiated safety, one has to venture out of the box, to get outside the safety zone of the conventional payloads. You have to try something different. You cannot get the same activity. You cannot expect different things by doing the same kind of sequence. Incremental changes are not going to bring about unleash a totally different spectrum of efficacy or a different spectrum of safety. And by working on this payload over the years, we have found that this payload irrespective of which target, we hook this payload onto. We captured the immune phenotype as well as the cytotoxicity. So we are very, really excited to try this in multiple cases. So we presented this data at SITC, and it was received very well. I mean in the -- at the talk, there was the first person of the mic said just spontaneously this is ingenious. And then followed with a tough question. You would expect that. We got an overwhelming response at our poster session. All the usual suspects from pharma, came to a poster looked at it, something new and novel on the horizon. We excited academics as well as MDs alike. We had people from academia offering ideas and suggestions by the minute. And they just couldn't help themselves. They're going on and on with these suggestions and making mental notes. And KOLs, very reputed KOLs who done 50-plus clinical trials. When are we going to get our hands on this ADC, on this payload to try this for our patients. And all I could say is soon, soon, soon. So anyway, luckily, I didn't have -- I mean, I don't have -- I didn't have an answer for them then, but Abizer has an answer for you now. So I'll hand it back to you, Abizer.

Great. Thank you, Satya. That's a good segue of where I'm going to go through. Let's just stay here on this slide for a second. I just want to recap, Satya, thank you for that really comprehensive overview of the history of ADC payloads, the limitations and the whole design principles of you and the R&D team of why you came up with something to go after RNA splicing biology and the payload that's been developed through years of testing and these fantastic results. I think if I were to take a step back, I would say these results are unprecedented for any ADC payload because in any of the literature you look at, no payload has demonstrated this type of immuno-oncology effect is very unique. This is charting new ground, which is why the SITC organizers wanted us to have a main oral presentation and a poster. And what I think is really interesting just to kind of -- I'm not an immunology expert, but when I look at it, I think of these as two puzzle pieces. When you think about our ADC payload and what it does versus the checkpoint inhibitors, which are the most successful class of agents in oncology at $50 billion plus and growing. Our agent activates this innate kind of immune system, which is one type and the antibodies, the humoral B-cell antibodies as well. And then the checkpoint inhibitor are the T cell. So when we marry them all together, we're getting this really unique response of innate adaptive, which are T cells, innate the macrophages and neutrophils, the adaptives of T cells and the humoral of B cells. I don't think any payload with any immunotherapy has ever demonstrated that kind of pleiotropic broad-based effect, which gives us continued excitement around we have something novel, and how we want to progress it. So thank you for putting that in really simple terms for us to understand. Now the question is how are we going to take this in? As Satya said into clinic and start demonstrating these results as Satya said this payload dynamics can be generalized to any antigen target. Hence, why we're really excited. The data that Satya just presented was an HER2 antibody that we put our payload on. That was a test prototype. Let's go to the next step and talk about AKTX-101. This is our TROP2 directed ADC. We have a lot of good translational data preclinically that gives us good insights into where we want to go, and what we want to do is we actually want to take this product now and do the final stages of manufacturing -- final manufacturing scale-up, and what we call our toxicology final safety studies. We've done preliminary studies. And that is at the last step before you enter human clinical trials. These are the big steps. These means that you have a really good molecule and you're ready to go prime time in a sense. So that's what we're starting. We call them clinical trial enabling activities or what your IND enabling that's a filing with the FDA to kind of start clinical trials. These are the activities you see on the top, the CMC and nonclinical based, manufacturing and final safety studies. And then that will lead into us hopefully starting this Phase I initial first in human, that's FIH study in late '26, early '27. And our target area where we want to go into, in particular -- sorry, we would do this first in human and then potentially expand this into a really specific tumor type. In that specific tumor type is urothelial or bladder cancer in the second-line setting. So what I want to kind of emphasize there's a couple of points. If you remember at the beginning about what Akari is, we're not only about payload innovation, we're also in a sense, trying to rework the biotech model innovation on ADCs. We want to get there in a very accelerated time line. If you were to just ask other ADC companies, this is a pretty accelerated time line to get to where we are now from a lead product candidate to actually starting a clinical trial within a year. But we're also doing it in a way where we're bringing partners in to help us defer capital outlays and does it in a very efficient way relative to the traditional model of our products are brought into the clinic. So we're excited that we're not only bringing innovation on the ADC side. We're also just trying to innovate how we actually -- on the business side, how we progress things in different ways with risk sharing with partnerships, with shared incentives and capital efficient ways as well. And so we're really excited about this kind of process to get to the first-in-human trial specifically. So with that, let's go to the next slide. I'll just kind of summarize. So I think as you heard, we'll tell you again, why they need for novel payloads. Well, as you heard, as I mentioned and Satya really talked in detail, when you look at the current ADCs as good as they are, there are limitations, both on the efficacy and safety side, and we use the TROP2 ADCs as an example in terms of the efficacy limitations and safety tolerability. This is true of other antigen targets, other antibodies and those payloads, which are only 2 classes. And that leads us to why we have a splicing modulating payload and what we put on to AKTX-101, our lead molecule directed against TROP2. We think there's continued unmet need in this TROP2 expressing cancers. And as I mentioned, maybe early in the slide, we talked about the urothelial second line. Well, the reason we're thinking of second line is exactly the reason Satya mentioned because many of the patients in the front line have developed resistance or lost efficacy to the first-line ADC, which uses a microtubule inhibitor. So exactly the reason we're seeing Satya talk about that theoretically is playing out in the market, and we see a growing pool of these refractory bladder cancer patients. We think that's a unique opportunity for us to go after. But we're not done there. We think TROP2 has a lot of lives. We know we could potentially go in gastric cancer. We have some really compelling data. And lung and breast are also known as potential strong areas that we could take our ADC into as well. And that's based on the robust efficacy we've had. So a lot of broad potential for our lead ADC. And that time line, I talked about to get to the first-in-human clinical trial data. We'd like to hopefully get more in the 12 versus 15, but we think that's the window and that's on a very accelerated time frame in a capital-efficient way. And I think the take-home is ultimately, we get into the clinic. We prove some of this preclinical data in a human clinical trial setting. We think that is a really attractive value inflection for Akari that gets us into a different space, comparable to other early-stage clinical ADC companies. So with that, I really want to thank you for your time today. And we're going to open it up for questions and Q&A. And Jenene from JTC will help us navigate that.

[Operator Instructions] So our first question is from James Molloy. He's a research analyst with AGP. So these are -- there's three questions here or three parts to it. I'm going to read all of it and then we can break it down because I think it's important to put it all together. So the question comes in, how would you characterize the current partnership environment? Are there any partners currently in the data room or under NDA. And there's been some recent high-profile M&A in the oncology space, J&J and Halda and for $3 billion, Genmab and MRUS for $8 billion and has this activity increase interest around AKTX's portfolio.

Sure. So I think I remember the second and third. Can you remind me the first -- sorry, the first one was...

Sure. How would you characterize the current partnership environment?

Yes. So I think the partnership environment continues to evolve. I think you're seeing a variety of different partnerships you're seeing outright licensing and acquisition molecules. You're seeing company acquisitions, the Genmab one was mentioned as well. So we think there's actually increasing deal flow and activity, maybe it gets to the third part of the question. I think in particular, you see ADCs in oncology is still bright spot in the biotech sector, which gives us a lot of excitement and excitement in our plan to move forward. You saw a lot of ADC deals in the first half of the year, just recently in the last 4 to 6 weeks, if not broader, you've seen a number of deals on the ADC, whether they're financing, whether they're acquisitions or licensing by big pharma or not. I think it continues to show the excitement around targeted therapies, ADCs, in particular. So we're pretty encouraged. I think the second part, obviously, you cannot disclose confidential information around partnership discussions we have. What I can say is we enter a lot of both nonconfidential, and we do have a number of confidential discussions we're having with potential pharma partners. Obviously, I can't give any more details than that, but we are active. And I would say the reason we're active, and you can imagine how many inbound some of these pharma companies get. It's a splicing modulating payload. What Satya just talked about, that is stopping power that gets people to look at it again, and that's why people talk to us both on a non-con and confidential basis to explore more about what does Akari have and why does it look different? And wow, this does feel different. And these aren't companies that are new to ADCs. These are companies that have experience with ADC. So the fact that we're getting our foot in the door and having these conversations, again, speaks to the uniqueness and novelty and innovation on this payload. And I think [indiscernible] commented on some of the deals, I mean, I think you look at the Genmab deal, obviously, but that was a Merus was a bispecific, I believe, a little bit different technology begin around targeted therapies in oncology. But I'll just mention Genmab in general, some of the bets they made may not be playing out. And I'm not saying they made a wrong bet, but just the ProfoundBio acquisition they did a couple of years ago, they've discontinued 2 out of 3 of those ADCs. So I think even the thesis on how some of these traditional ADCs have played out, either due to the limitations Satya mentioned or competitive dynamics of competing against the same types of ADCs. Some companies are finding they need to change the playbook a little. And we think that's exactly a good segue for why our novel payload is changing the playbook for ADCs and gives us excitement. I think I got them all. Did I get all?

I think you did. Yes. Great job. Okay. Our next question is, can you speak to the unmet need of bladder cancer and the market opportunity?

Yes, sure. I think it's a great question. And one might ask and if you're familiar with the bladder cancer metastatic, so there are many different types of bladder cancer. There's muscle invasive, non-muscle invasive. We're going to focus on the metastatic, which is the most severe unmet need, which essentially means the bladder cancer is spread, metastasis, other parts of the body, that's where the prognosis is the worst for patients due to the overall tumor burden. In that setting, there has been significant advancements. So let me just kind of characterize. And after I give this, I'll have Satya to add any things I might miss on this. But when you think about this metastatic bladder cancer patient therapies like cisplatin, which is a platinum-based therapy, effective, but super toxic and limited efficacy, subject to resistance mechanisms as Satya mentioned for chemotherapy. That's been the frontline setting forever using cisplatin, maybe combinations of cisplatin. And then there's a bit of a revolution or change that happened in the bladder -- metastatic cancer and bladder cancer market. In ADC product called Padcev, enfortumab vedotin uses a microtubule inhibitor actually change the landscape. And this is, again, I think, a success of ADCs that you had a targeted agent like enfortumab vedotin that went into metastatic bladder cancer showed some great data, both as a single agent in combination with a checkpoint inhibitor. And that is approved in the frontline setting and Padcev, enfortumab vedotin is more than a $1 billion drug, and it's on its path to do even more. It's moving into earlier lines, what we call a neo-adjuvant setting, which is when the cancer is a little less spread. And so it's a great success story. That being said, as great as the data is, and what Padcev, enfortumab vedotin has done, it targets an antigen called Nectin-4, which is different than the target we're going after, both targets are highly expressed Nectin-4, and TROP2 are very highly expressed in bladder cancer. As good as that data is when you look at what we call, again, the median progression-free survival from their pivotal trial data on combination therapy, it's about 12 months. And that is a big advancement from where cisplatin was, which is about under 6 months. So it has made significant inroads, but think about 12 months for a cancer patient. When we say median, that means 50% of patients relapse less than 12 months and 50% relapse later than 12 months, that's median. So if you're a cancer patient, yes, that's an advancement, but you're only talking about maybe less than a year for half -- you're 1 out of 2 that may be less than a year before your tumor is going to continue to progress. And that's not a great long-term prognosis. So we want to change that. So there is now a growing pool of patients that have taken Padcev and Padcev have another combination agents and are probably relapsing. And we know this pool is growing. And so that's exactly that target population. And it's similar to what other companies have done and strategies that you go after refractory populations with super high unmet need that are not refractory to an ADC, refractory to chemotherapy. And again, as Satya mentioned, going after those same patients with the same payload like a microtubule inhibitor, probably not going to work because they become resistant. So that's exactly the perfect setting for us to take a splicing modulating payload like ours into and we have a tremendous amount of preclinical data that's probably our strongest potentially in this setting for bladder cancer. So hopefully, I gave some perspective of the unmet need, and why we're excited, Satya, I just want to turn it over to you to add additional thoughts and ideas on that.

I think you captured most of it. The only thing I would add there is in -- the mechanism of resistance there, the reports are basically not you have some amount of nectin-4 loss, you have MDR overexpression. So it's a good thing that this payload has been optimized for nonbinding to MDR. And it's against a different target, which overlaps in expression in about 80% of all urothelial cancers that express nectin-4, so that being the case, you have now an opportunity to treat patients where there is inflamed setting, which responded to PD-1 and increase the neoepitopes in that setting, so to unlock further efficacy. So it's a good place to be in, in terms of frequency of high-expressing target. And it's a good place to be in with respect to the -- how hot the cancer setting is.

Yes. That's a great additional point, Satya, although we might look initially as a single agent in this population, it gives us optionality to actually bring forward the combination data with an anti-PD-1 or checkpoint to get the kind of results we saw preclinically, we'd love to replicate because that could be the long enduring efficacy we could see and the unique kind of profile of our payload really comes to fashion. So again, that's exactly the vision we want to go. We want to go into these hot tumors, which are more immunoactive and bladder cancer is one of these. So thank you for adding additional perspective that builds on the SITC data.

Next question comes from Aydin Huseynov, he is a research analyst with Ladenburg Thalmann. His question is, can you help us better understand the differentiation of AKTX-101 from Trodelvy and given both our TROP2 target, where do you think AKTX-101 presents the best opportunity?

Yes. I'm going to give maybe a high level, and I'll ask Satya to walk through the more details. So Trodelvy is a TROP2 directed ADC. It was the first approved. It's actually a pretty successful drug. But if you look at it's over $1 billion in sales, it's approved in the breast cancer setting, two major areas, triple-negative breast cancer and then another subset of breast cancer called hormone receptor-positive, HER2 negative. What Trodelvy is, it is an antibody against TROP2, it uses the payload called the -- it's a topoisomerase I inhibitor. It's a cousin of irinotecan, which I think Satya mentioned has its own toxicity. So by definition, that payload will have very similar toxicities. When you look at its package insert, it's got Grade 3. So to get to the differentiation point, it's got great box warnings for neutropenia, which means low white blood cell count high infection rates, potentially, it has high rates of diarrhea, and some other GI issues, those are Reno-TCAM-like side effects, if you're familiar with that chemotherapy. It's a similar set of side effects for this payload. And there's also a linker that they use that I'll let Satya explain that's different than the way we're using. So it's around the payload is very different, has some of those historical legacies of topoisomerase I and the linker strategy they're using, we would probably say and others would agree is maybe not optimal that creates other side effects, but I'll let Satya maybe describe in more detail.

So there are a number of differences and in our approach to Trodelvy. Trodelvy is basically the active moiety of irinotecan. SN-38 booked onto an hRS7 antibody via a CL2A linker, so this linker is acid-labile. And by the nature of the release of the payload is in the extracellular million. So whenever you go into a tumor, the environment is generally more static than the rest of the body. So it deploys there. But no matter how good you are at deploying the payload at the decided location, there is always leaching of payloads from the tumor and exposure to organ. So you get organ tox and some of the gut tox is what Abizer rightly pointed out. Our ADCs are non-cleavable. And they only deploy in context of the target that is expressed only on the cancer cells. So we are trying to partition the payload specifically to the cancer cell. And we've taken a lot of precaution to prevent this payload from causing systemic issues. And this is because of, obviously, of the immune phenotype. We want to make sure that there is no off-target effects. So you get a lot of off-target effects in Trodelvy, which is in tune with the bystander killing, but we have reduced that in order to get less immune flare-up. We do get bystander activity separately from immune system when we bring immune cells into the tumor, they take care of the heterogeneity problem. They target the tumor -- the target non-expressing cells as well as the target expressing cells, both equally. So in that way, we countered bystander problem in a different way through an immune bystander approach. So very differentiated.

So I'd maybe add a couple of points. Thank you, Satya, for giving it a little bit more technical scientific explanation. So essentially, we avoid collateral damage, the way we've engineered our linkers and payloads. We try to avoid that collateral damage. And we also -- because of our payload, we actually cause immune activation in a different way, hence, the kind of responses we get. And just to kind of bring that home, when you see we've done some head-to-head work against Trodelvy and in the gastric cancer model, just looking at the pure side of toxicity. We have superiority to Trodelvy, in a gastric cancer preclinical model. So that gives us a lot of conviction that yes, this payload is super active, and it's capable of being the lead TROP2 agent at least in this preclinical model of gastric cancer.

Our next question is from Viju Gupta. He's a translational scientist. I just lost my screen, there we go. At WashU, Viju says great information, there are two questions. Number one, is your mouse model, a subcu model or orthotopic? And number two, PH1 being related to statins, do you anticipate effects of cholesterol pathway?

I'll defer these to Satya. Why don't you go ahead take them, Satya?

Sure. The first part of the question, we typically test our ADCs against tumors that have grown subcu, although we are not opposed to doing the old orthotopic experiment. But in this case, whether we're doing urothelial models or gastric cancer models, these are typically subcu. The second question, whether PH1 being related to statins. So I don't see a lot of similarity in the molecules per se. The cholesterol molecules will have that perhydrocyclopentanophenanthrene link system. This is very different from that. And even when we have done our nonhuman primate studies, we haven't seen any changes per se in cholesterol level, that seems to suggest that the cholesterol pathway may be important.

Our next question is how does PH1 perform if it's used alone without PD-1? And in a clinical setting with the sequencing of therapies affect its efficacy.

I'm going to let Satya maybe take that on, and I might add some following comments.

Sorry, I lost audio for there for a bit, Jenene, can you repeat that?

No problem. I'm happy to repeat it. So how does PH1 perform if it's used alone without PD-1. And in a clinical setting with the sequencing of therapies affect its efficacy?

That is actually a brilliant question, and that's front and center on everybody's mind, right? So the first part of the question, I'll try to break it up is, when you use this as a single agent, you do capture the cytotoxic efficacies. And you also see the effects on the innate immune system because that's their in mice in humans at baseline. So you see the effects on macrophages, you'll see the effects of neutrophils. So there will be some baseline killing and some baseline immune activation. You won't get the purchase of T and B cells, most likely you won't get the activation of T cells without the anti-PD-1, but you do get activation of T-cells and anti-neoepitope antibodies, even in the absence of PD-1. So that was behind the mechanism, if you remember, in the Tras PH1 story. So we do get some activity. We do get long-term activity that we have seen in our HER2 models, which are xenograft. So by xenograft means they don't -- we use new mice there to allow the human tumors to grow out, and they don't have an immune system. So in those experiments, we do see very good killing, and it is in one of these experiments that we performed equally or slightly better than Trodelvy in the gastric setting, as Abizer pointed out. So the second part of the question is about ADC sequencing and why that matters. Typically, when you administered anti-PD-1 and you give ADC, you're performing concomitant dosing and concomitant dosing means you're giving both these agents so that there is maximum overlap between the exposures of anti-PD-1 and the ADC. And this is to make sure that there is -- it unlocks each other's efficacy. We have done experiments in urothelial bladder setting, where we have given a dose dense regiment of anti-PD-1 following the ADC treatment to see if the effect of neoepitopes translates to activation. So in these experiments, anti-PD1 did not give any efficacy on its own. The tumor growth curves were similar to control, but you get about 50% TGI where you treat with the ADC alone. But when you add anti-PD-1, following the ADC treatment, you see the curve dip. And basically, you get -- you're unleashing more activity from T cells in this setting, even though the anti-PD-1 arm by itself did nothing. So I think there is an opportunity with this payload to sequence anti-PD-1 after ADC treatment to get some kind of activity. And we have seen that in preclinical experiments.

Yes. And I'll just add a couple of points. I think that's a great explanation on the sequencing because that data was pretty unique when we did before and after kind of regimens, and you saw a unique difference. I think the other thing I'll just add on the single agent what also impresses me like, obviously, the B cells, and we activate the B cells, that's very unique to our single-agent activity. The macrophages, which are those immune system cells in the tumor microenvironment. What's interesting around cancer is that cancer is very smart. It finds a way to take those macrophages, which are typically the first responders in a sense to any kind of things different. And it subdues them into becoming tumors impressive. So they actually don't do their job. If cancer kind of signals to them not to do their job. And what we found is that we actually were able what we call repolarized those macrophages to do their job. So we got them to wake up from their trans and the cancer cells put them in, and we found as a single agent, they got repolarized to do their job, which then starts again create activity of the immune system. That was as a single agent, again synergized, when we add a checkpoint inhibitor. So again, we have potent single-agent activity, whether it's cytotoxicity or immune activation, it just gets to really see the full light of day with the checkpoint inhibitor, Satya mentioned.

Great. Okay. These are -- we have about 2 minutes left. So I wanted to give you the opportunity for some closing remarks before we end the webcast.

Sure. First, I'd like to thank everyone for joining the call today. Hopefully, you walk away with more information around why we're excited around this novel payload, the need for novel payload. ADCs are hot, and how we can continue to build on that and take ADCs to the next chapter and change outcomes for cancer patients. And hopefully, you walk away with a clear conviction of the plan we have to get there. This is not great science for the sake of science. It's science that we're going to apply to get to the clinic and make a difference for patients that we have an accelerated plan to get there as soon as we can in a capital-efficient way. So I want to thank all the participants for joining us. Thank you, Satya, for a great presentation. Thank you, JTC, for organizing and helping us today.

Great. Absolutely. So this does conclude the webcast. As a reminder, the replay will be available on the company's website. We did have some additional questions, doesn't have time for them, so we will get back to everyone that submitted questions following the call. All right. Thanks, everyone, and have a great day.