CytoDyn Inc. (CYDY) Earnings Call Transcript & Summary

Greetings, and welcome to today's CytoDyn R&D Investor Update. My name is Diego, and I will serve as your moderator today. [Operator Instructions] As a reminder, this call is being recorded today, December 7. I'd now like to turn the call over to Cristina De Leon. Thank you. You may begin.

Good morning, everyone. Thank you, for joining us today. This is Cristina De Leon with CytoDyn. Joining us on today's webcast is our President, Cyrus Arman; and our Scientific Advisory Board members: Dr. Mazen Noureddin, Dr. Stefan Glück and Dr. Jonah Sacha. Before we begin, it is essential that we provide you with important cautionary language related to certain federal securities laws. Our remarks during today's webcast will include forward-looking statements. Forward-looking statements are not guarantees of future performance and involve known and unknown risks, uncertainties and other factors that are difficult to predict. Actual results may be materially different from any future results expressed or implied by such forward-looking statements. These risks and uncertainties include, among other matters, statements regarding leronlimab's potential efficacy in certain immunology and oncology indications, the company's ongoing ability to raise additional new capital that clinical trials may not commence or proceed as planned, products that appear promising in early trials may not subsequently prove to be viable on safety or efficacy grounds, products may not receive regulatory approval or market acceptance, competition may reduce the commercial potential of our products, we may experience product recalls, manufacturing issues or product liability, and our patents may be challenged or unenforceable. Although forward-looking statements help to provide complete information about the company, forward-looking statements may be less reliable than historical information. The company undertakes no obligation to update publicly these forward-looking statements, except as required by law. Please refer to our recent quarterly and annual reports filed with the Securities and Exchange Commission for more information about the risks and uncertainties that could cause actual results to differ materially versus our current expectations. I will now turn the webcast over to Cyrus Arman.

Thank you, Cristina, and welcome, everyone, and thank you for joining us today. We are excited to take you through our R&D Investor Update. Our agenda for today is to review the company overview and background, discuss the previous clinical development programs and then have a discussion with select members of our Scientific Advisory Board to discuss clinical and preclinical data in prioritized therapeutic areas that the company intends to focus on in the future based on existing clinical data that we already have from previous programs. These speakers include Dr. Mazen Noureddin, who is currently the Director of the Houston Liver Institute and Former Founding Director of the Fatty Liver Program at the Cedars-Sinai Medical Center. Dr. Noureddin is a world-renowned key opinion leader in NASH, and he will be presenting on the potential role of leronlimab in treating NASH and nonalcoholic fatty liver disease. We also have with us Dr. Stefan Glück, who is a former Sylvester Professor at the Leonard M. Miller School of Medicine at the University of Miami in Florida. He has served in senior leadership roles at both Regeneron and Celgene, and he will discuss the potential role of leronlimab for -- in the tumor microenvironment for treating solid tumors. And finally, we have with us Dr. Jonah Sacha, who is currently a professor at the Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, both the Oregon Health Sciences University, where he conducts research on infectious diseases. Dr. Sacha will share the latest research developments with regard to leronlimab derivatives and the potential HIV cure. These are our SAB disclosures. So we're now going to talk a little bit about the company overview. Starting with CytoDyn's mission. So at CytoDyn, we believe that we have a moral obligation to generate therapies that improve people's lives. We think that we have a real powerful agent with leronlimab and that we have an imperative to develop this and get this product to market. Our path to doing so is through a focused and disciplined clinical development strategy that we're going to be discussing in more detail on this call. We think that by achieving that goal, we will be able to generate value and economic returns for our investors. So a bit on the company's history. So the company is headquartered in Vancouver, Washington. We currently have 15 full-time employees as of December of 2022. And CytoDyn was founded in 2002, about 20 years ago. And about a decade after that, it acquired the rights to PRO 140, now known as leronlimab. And a couple of years after that, in 2014, it began its own HIV treatment clinical program. It later expanded into autoimmune diseases and specifically to GVHD in 2016. And then later, again, also began studying leronlimab in oncology in 2019 and in NASH in 2020. In 2022, we put out our refocused development strategy to get to our next value inflection point. I want to take a moment to discuss our Board of Directors. So over the last year, we fully reconstituted our Board. They're now fully independent Board, and recent additions such as Steven Times and Ryan Dunlap further enhanced the independence of the Board and bring additional biotechnology industry experience onto the Board. Each of these individuals has a unique skill set and will be critical to the company's continued success and transformation, and we'll continue to expand our Board as needed in the future. So in terms of our critical partnerships, we have ongoing relationships with both AGC Biologics and Samsung Biologics, who have, in the past, produced drug supply for both clinical trials as well as [indiscernible] commercial supply ahead of a BLA filing for the HIV MDR population, which we pulled earlier this year in October. CytoDyn has also recently attended numerous medical professional society conferences where we presented our data in both NASH and oncology. And we continue to publish in academic peer-reviewed journals, and we expect to have an upcoming publication on our CD02 data coming shortly. We also continue to work with a number of academic institutions on various studies, including some preclinical studies that can inform future clinical trial design for our future programs. So I want to take a moment to talk a little bit about CCR5 as a target and about leronlimab. The CCR5/CCL5 axis has been a hot target for research for at least the last 20 years, primarily because it was identified initially, CCR5 was, as being 1 of 2 critical coreceptors in addition to CD4, and the other coreceptor being CXCR4, as being the portal through which HIV enters T cells. Once this discovery was made, a large research effort was taken throughout the industry to drug this target in an effort to try to develop therapies for HIV treatment. However, since then, it's also become apparent that this particular pathway has implications not only in infectious diseases, but through altering the pathway. It also has implications on cell proliferation, migration, angiogenesis, metastasis and survival, which are all important for treatment of oncology and solid tumors as well as it also has implications for autoimmune responses. What's also become apparent is that the precise binding location of a molecule on the receptor can have important downstreaming effects on immune function and downstream signaling. Now leronlimab is a humanized IgG4 monoclonal antibody that is directed against CCR5. And in 1999, it was first discovered that leronlimab actually binds to the extracellular domains of CCR5. And we'll talk about that in a little bit more detail shortly. Leronlimab is currently constituted as a once-a-week subcutaneous injection, but it can also be delivered in an IV form, if needed. Leronlimab has received fast track designation for both metastatic triple-negative breast cancer and HIV treatment. However, it remains an investigational new drug and is not yet approved or authorized by the FDA or any other regulatory authority for any indication. So taking a moment to look at the CCR5 inhibitor landscape. So we've identified a total of 28 unique different assets that target CCR5. As you can see from the graph here, the vast majority of these are actually small molecules, and only 3 of them are antibodies, one of which is leronlimab. The other 2 were formulated as IV and have both been suspended. So to our knowledge, leronlimab remains the only active subcutaneous antibody in development. And to date, only maraviroc has been approved as a CCR5 agent for the treatment of HIV. When we look at where these 28 unique agents have been studied in terms of which therapeutic areas, not surprisingly, we see that the vast majority of study has actually been in the HIV treatment and AIDS disease area. The next largest therapeutic area where CCR5 inhibitors have been studied as a group are solid tumors. And as you can see here, colorectal cancer, breast cancer, pancreatic cancer and urothelial cancer are among them. The remaining indications are comprised of neurologic, immunologic, metabolic and other infectious diseases. When we look at the active development pipeline, we can see that most of the treatments are currently in Phase II. And most of them are actually small molecules. And a vast majority of those total of 28 unique CCR5 inhibitors have actually -- are no longer in development. So you can see here that leronlimab, currently in Phase II for NASH and solid tumors. There are other agents from BMS, Merck and AbbVie that are also looking at solid tumors or other infectious diseases. So leronlimab, we believe, is unique in terms of the active development pipeline because of how it binds CCR5. So CCR5 is a G-protein coupled receptor. This is a seven-transmembrane receptor, which is typically very hard to fully inhibit with anything smaller than even a peptide. So a small molecule binder would typically bind deeper into one of these pockets that you can see here on the image on the right, whereas leronlimab binds to the N-terminus of the receptor as well as to the second extracellular loop detailed here. Now as previously discussed, where you bind can have differential effects on how the various chemokine ligands that interact with this receptor, can function and can ultimately lead to differences in downstream signaling. So looking at the clinical development history for leronlimab. So over the last decade, leronlimab has been studied in various therapeutic areas, including infectious diseases for both HIV treatment as well as COVID-19 treatment. Within oncology, for triple-negative breast cancer, with a basket trial as well that was looking at a total of 22 different solid tumor types. And we'll be talking a little bit about the colorectal cancer data that we collected from that basket trial later today. Within liver disease, we've run a single trial in NASH, which Dr. Noureddin will be taking us through momentarily, and also within autoimmune diseases for graft versus host disease. So this clinical development history represents over 20 different clinical trials and over 1,500 patients. Some of these patients have been on treatment for many years, particularly within the HIV segment. And generally, what we've seen is that the drug is well tolerated at multiple doses that have been studied. Now that being said, we did receive a clinical hold from the FDA earlier this year. And I want to take a moment to talk about that in a bit more detail, because this is a really important issue that the company is working through currently. So as I said, in March, we did receive a full clinical hold for COVID-19 and a partial clinical hold for HIV treatment. We've voluntarily withdrew the IND for COVID-19, and we're actively working on resolving the partial clinical hold for HIV. Now how long it takes to get off clinical hold is dependent on what the agency is asking for and what data that the company has that's readily available at the time. Now in our case, the FDA requested 5 items: an updated investigator's brochure, which we submitted in September of this year; data safety update report, which we submitted in October this year; a safety management and pharmacovigilance plan, which we submitted in November of this year; and we continue to work on the remaining 2 items, being an aggregate safety analysis and a benefit-risk analysis. And we're nearing the end of the analysis for those 2 remaining items. Thus far, we have not seen any systemic concerns with how leronlimab has been tolerated across the previous 22 trials. And we look forward to submitting these final 2 items very shortly to the FDA. So turning now to future development. So as we previously presented, we're narrowing and focusing our forward-looking strategy to emphasize the highest value opportunities where we have the strongest supporting clinical data. So that's going to be in NASH and oncology. And again, we're going to present some of that supporting data on this call. And we're also still committed to HIV, but we're really looking at it more through the lens of developing longer-acting agents. And Dr. Sacha will be talking about that at the end of our discussion today. So within oncology, we're interested in studying what would be referred to as immunologically colder tumors. And Dr. Glück will present on what those -- what we mean by that later. But we think that these are areas where more recent advancements from checkpoint inhibitors have yet to really have a large impact in those markets. And so we think that there's a unique opportunity based on the data we already have in some of these colder tumors to make an impact. Within NASH, we're particularly excited about the data that we have there, and NASH will be our primary focus going forward. We'll also talk a little bit about a unique opportunity to study and look for the effect of treatment effect for leronlimab in people living with HIV who also have NASH. And we think that we might be in a unique position to address that population. So going forward, we're focusing on NASH, oncology and earlier-line HIV indications through longer-acting agents that inhibit CCR5. Again, we've already generated promising clinical signals in both NASH and oncology. And within NASH, we're exploring the opportunity to study a segment of patients of those NASH patients who are also living with HIV. Within oncology, we want to pursue colorectal cancer and breast cancer specifically. Within the colorectal cancer population, we want to focus on a micro-satellite stable group, which represents about 85% of all diagnosed colorectal cancers. And within breast cancer, we want to focus on the hormone receptor positive HER2-negative population, which is about 70% of all diagnosed breast cancers, and the TNBC population since we have data in that space. All of these are quite large markets. Looking at third-party market reports, we've estimated what the potential market size is out to 2028 for each of these groups. And as you can see, these are all large multibillion-dollar opportunities. To further substantiate that, we've looked at what the epidemiology is for each of these, and we use this information when we build our own net present value models. And as you can see, these are tracked out to 2046 over about a 25-year forecast period. And as an example, you can see that within the U.S. and the EU5 in Japan, which is where we do most of our modeling for NASH alone, there's roughly about 40 million patients that are going to have that disease during that forecast period. So taking a moment now to talk a little bit about NAFLD and NASH. So as we saw from the last slide, this is a highly prevalent disease, but there are currently no approved agents for -- to treat NASH. And NAFLD requires that there would be evidence of hepatic steatosis without any secondary causes of the hard accumulation on the liver, like heavy alcohol consumption, the use of any steatogenic medicines or any hereditary disorders that could lead to accumulation of fat in the liver. So in addition to being able to reduce that through therapy, also being able to demonstrate the attenuation or the reversal of fibrosis is critical since the extent of fibrosis is really what's linked to worsening outcomes for patients. And when we look at what the disease progression for NAFLD and NASH looks like, it looks like this. So roughly 15% to 30% of all people in the U.S. or in Western economies actually have the NAFLD. So again, very large numbers. Of them, somewhere around 25% at some stage of NASH. And it's generally believed that while you're in these stages, this can be reversed either through diet and lifestyle or potentially through therapy that would be related to weight loss. But the real challenge to date has been in being able to attenuate or reverse the inflammation and scarring in the later stages of NASH before it actually moves into [ surface ] or hepatocellular carcinoma, at which point, where it's generally believed that these are more difficult to treat and are potentially irreversible. So one of the exciting things that we're going to be looking at and that our early clinical data supports is potentially the ability to attenuate or reverse the fibrosis in the liver. So taking a moment just to talk about the HIV NASH population. So the burden of liver-related morbidity is especially high among HIV patients. And the impact of NAFLD is even more significant in that group where the prevalence can be as high as 50%. Now both the HIV infection itself as well as the actual treatments that the people living with HIV are taking can actually contribute to the development of NAFLD and NASH in various ways. Having HIV itself also makes you more susceptible to other infections like HCV, which, of course, is implicated in liver disease. But again, the anti-retroviral therapies that these patients are on, particularly the earlier generation versions, can also -- have also been associated with the development of NAFLD and NASH. Now what's really critical here is that this particular subset of patients who have NASH and HIV are typically excluded from other NASH clinical trials. So this creates a real clinical unmet need that isn't being addressed generally by the industry. And as far as [ railway ], there's really only 1 other company that's looking at this particular population in detail. So a bit on metastatic colorectal cancer. So this CRC is the second deadliest and the third most commonly diagnosed form of cancer worldwide. The most commonly prescribed therapies for the earliest lines of metastatic CRC are angiogenesis inhibitors like Avastin, which is [indiscernible], which is available for most tumor types in addition to various chemotherapy combinations. Other drugs such as Erbitux, BRAFTOVI, KEYTRUDA, OPDIVO and Jemperli are limited by gene expression, meaning that you have to have a certain genotype in order to qualify for that therapy. The most recent advancements in the colorectal sensor space that come in the last few years and come from the PD-1 such as KEYTRUDA and OPDIVO, but they're really only indicated for a subset of metastatic colorectal cancer patients that have microsatellite stability, high designations. And again, this is only 10% to 15% of all CRC. And the same PD-1 inhibitors have failed to show success in the larger microsatellite stable population to date. And this is the group that we're going to be potentially focusing on in future trials. Looking now at breast cancer. So hormone receptor positive breast cancer is the most common subtype, which is approximately 70% of all diagnosed breast cancers in the U.S. and western economies. This is actually the fourth leading cause of cancer-related deaths regardless of gender, despite the fact that most of these are actually caught very early on. They occur in such high numbers that for those who do progress to metastatic disease and ultimately [ DAS ], it is actually the fourth leading cause. All right. And with that, we're going to turn now to the presentation on NASH and leronlimab. Is Dr. Noureddin with us.

I am right here.

Great. All right. I'll advance your slide, Dr. Noureddin.

Right. Can you hear me well?

Yes, we can.

Perfect. So I think I'm in control of the slides. I'm going to move it. So Cyrus, it's thank you for having me here. Mazen or [indiscernible] from the Houston Liver Institute that I just arrived here in Houston after being a decade at Cedars-Sinai in Los Angeles, also United Methodist Hospital. And I'm going to just take you through some slides of NASH, which I have been doing for the last decade or so and publishing on it. But it's not a surprise anymore or it's a disease that is very prevalent. It's pandemic and waiting for treatment. And with the type 2 diabetes and obesity that have been increasing in the world, nonalcoholic fatty liver disease is the cousin of those diseases and affected by them. But it's a separate entity that it needs its own treatment. So what is fatty liver? Fatty liver is when the fat comes and deposit in the liver, and the liver cannot get rid of it. Over time, not all patients, but significant portion of them progress to nonalcoholic steatohepatitis. And what I tell my patients, it's easy. Like if you have it alone, it's probably okay. A lot of people have that. When you get inflammation, this is when the problem starts. It's kind of gas on fire. And the inflammation, at least the activation of inflammatory cascades and eventually [indiscernible] of fibrosis and cirrhosis as tired should one of the slides. Why this is significant? Because we do have a lot of patients nowadays dying from this liver disease, the leading cause of transplant in women from data we published and it's the most common liver disease. It correlates -- once you get inflammation on fibrosis stage 2 and higher, you are more likely to die and have morbidities. And this is why this disease has been under focus. I mentioned inflammation. But one of the key mechanisms of inflammation is targeting this chemokine [indiscernible] inflammatory signaling pathway, which actually can reduce both the fat inflammation and its chronic. And I will show you gotten in a second, walking us through the story. And let me reemphasize on the slide that Cyrus actually mentioned. So you have about 30% of the population, they have this yellow fatty liver at the beginning. And the problems start, and a subpopulation still a lot of people, millions, 12% to 14% of them may get now alcohol steatohepatitis. And over time, scarring forms and lead to fibrosis. It's not jumping from NASH resources all of a sudden. You get scarring, scarring, scarring. And then when you hit 2 and higher, this is when you get morbidity and mortality, and then you get to cirrhosis sources, which is 4 in the scale 0 to 4. So this is really important. Once you get the cirrhosis, it's very hard to reverse, if any. And you start getting eventually decompensation, meaning the liver stop working and liver failure and also a lot of patients have liver cancer. And NASH is actually now the most common cause of liver cancer. Let me walk you through this cartoon, and I want you to look at these pink cells. What happened in these pink cells once you start getting like the fat deposition and injury. What that accumulation do is failure stress. And you see that arrow, and that leads to release of this chemokine CCL2 or MCP-1. Once this is released, this is the bloodstream here on the top. What you see is these inflammatory cells, mainly circulating monocytes, start being recruited. And those are CCR2, and this is very important. And these inflammatory monocytes, when they get to the liver, they raise a lot of chemokines and cytokines such as TNF alpha, IL-18, IL-6, GLACITGMbeta. And what that leads is to, you see these yellow cells, the stellate cells, those are the problems. If they get activated, they get to this, I guess, let's call it the monster activated myofibrils stats. It gets strong and started secreting collagen, and collagen is the mechanism of a scar. Well, guess what? In these myofibroblast, you see you have the CCR5 inhibitor. But the -- you have the CCR5 receptor. So it's plausible that if you target that, you stop a lot of this cascading, including inflammatory as well as the fibrosis signal. You're kind of at the right spot. And CCR5 is expressed solid cells and gets involved in the pro-fibrogenic activation potation. So this is a key concept in the key area of the pathophysiology. So what's CCR5? It's a G protein coupled receptors, and it's the receptor for these chemo kinds, where they hit and affect the cascade especially the harmful casting. And its confluent ligands include CCL3, CCL4 and CCL5. And I showed you earlier that this important monocyte then that they turn into macrophages, and they activate the cascade inflammatory signal as well as eventually cell itself on myofibroblast [ CCR5 ] present on all these pathways, and it play a hero mechanism. And for us, mass researchers, it has been really a key mechanism that we're interested in, yet we still need more targets for that pathway. So what is the evidence? I already showed you the cartoons that the CCR5 evolves in monocytes and macrophages, but that had been shown in NASH patients, in particular, that the NASH patients have high level of CCR5 and [indiscernible] ligands. And thus, it's really appealing and attractive to target that pathway in NASH patients. That's why a lot of research and literature has been done on this, and that's why it makes sense to target that pathway by hitting that pathway. Now I don't want to go into animal models much, but in animal models of NAFLD the NASH, using CCR5 have led to improvement in steatosis inflammation and fibrosis. Well, let me take you through the human data. So this is the NASH -- CDI NASH 01 study using leronlimab. And that was initially designed as multicenter Phase IIa trial, which subsequently converted into explanatory study to evaluate the doses we needed to find a dose. It's efficacy and safety, we compare 700, 350. And on the part 1, there was a placebo. And that design helped us to discover the efficacy of all doses and in addition to their safety. So here at Part 1, it was the blinded placebo-controlled randomized, and then the treatment was received for up to 13, 14 weeks, and there was a follow-up period. And then the Part 2 had a single-arm open label of the 350 milligrams. Those are the demographics, nothing fancy or different from NASH trials that have been involved in. What you want to look at is the -- I guess, the red and blue, the 700-milligram and 350-milligram, and there were equivalent distribution in terms of race, ethnicity and gender. But let's look at an important concept, especially for liver disease and patients with liver disease. There were really no difference and adverse events in that trial between the 700, 350 milligram. And you will hear along this presentation that we have [indiscernible] patients were CCR5, because it could be there's a potential defect in some CCR5 receptors. So we did add additional precision medicine with haplotyping. So there was probably a little bit more GI side effects on the 700 milligrams, but that was not only different from others and did not -- was not overall safety signal or anything like that. Indeed, look at the number of adverse events, there was no statistical significance between placebo 700-milligram -- 350-milligram and 700-milligram haplotype patients. So that's good in terms of safety signal. Here is where the money is. Right now, what we use for Phase IIa data or proof of concept are 2 techniques. And I'm sure a lot of people on this call heard of them multiple times. Indeed, I was involved in the diverse publication of that fraction that when we said we got -- back in 2013 when we said it's going to help a Phase IIa study, and now it validated as a tool. And the FDA actually gave the thumbs up for this MRI-PDFF for Phase IIa studies. There's another tool also called MRI CT1. So they are the same MRI. You have 2 softwares. The first software is basically fat signal. So it tells you we measure 3 areas in the liver or more, and we tell you like the percentage of fat in these 3 areas, for instance. And what the radiologists do, at the end of the trial, they go back to these 3 areas and tells you if the fat was reduced in these areas. There's another technique that I told you about, again, at the same exam, different software CET1, which you mentioned both actually the fab and the inflammatory signal, which is very important. So that CT1, we used to do a liver biopsy only for the inflammatory signal. But with the CT1, now we're able to measure that inflammatory signal. And many companies now use CT1 in their Phase IIa study. So here, let's look at the full analysis set with PDFF. So what you see here, statistical significant drop in MRI PDFF in the 700-milligram haplotype, but not in the 700-milligram non-haplotype. But the pool analysis when you added [ 300 milligram ] was almost statistically significant. But let's look at the 350 milligram, which is a very attractive dose. So in this blue, the overall population is -- has reduced their MRI PDFF and was statistically significant compared to the placebo. But what we also did subanalysis, I guess, we looked at these patients on the CT1 that they have inflammatory signal, which is eventually the population we're going to target. So we used 2 numbers for inflammation on that [ CT1875 ] and then [ 950 ], both in the literature correlates with outcomes and more severe disease. So with that 870 -- or the 350 and the 875 inflammation signal, it was also statistically significant and thus with the more 950, showing you that these patients also reduced their fat on MRI [indiscernible]. This is the CT1, which is very good. You see here in the placebo. You look at the 700-milligram haplotype and you see statistical significant when compared to the placebo. The 350 had a reduction in the overall population. And those were more than 875, meaning more inflammation, it's even further. And with those more than [ 850 ], which is more inflammation group, it's even went top. The improvement was more pronounced. So which makes sense, more inflammation, people with on-time [indiscernible] antifibrotic drug here also to reduce fat, you see more improvement. But let's look at some of the data. To mention, not everyone started with elevated liver enzymes, but those that had elevated liver enzymes, there was a signal to increase liver enzymes. The [ outpost ] was significant in the 350 and at ALT and AST move the right direction as well, while the placebo did not have much reduction, if any, 4 compared to 29 units and their CET1 increased the placebo versus the others decreased. So you see here the inflammatory signal [indiscernible] in liver enzymes. Digging deeper into signals and mechanism of actions because we wanted to understand what's happening. So you see here the CCL3 as well as the CCL18 statistically significantly reduced in the 350-milligram arm by various sub-analyses. So those have been reduced. The CCL2 actually, which is important, you see here also a signal towards a reduction. And the red extras actually shows you a statistical significant. So a lot of biomarkers are being reduced. There is also more analysis, and this is important, VCAM, which -- VCAM is a recruitment of these inflammatory cells. It's a marker. So we're hitting that as well, showing that you reduce the recruitment of inflammatory cells, monocytes and other cytokines to the liver. And [ N rage ] is a very important market has been also decreased with these 350-milligram dose with various sub-analysis and those that they had fat and inflammation as well. More data on other chemokines and cytokines 1RA. You see [ R8 ] and TNF receptor to have all reduced, many are statistically significant, confirming the elementary fibrotic signal. And I showed you the fat reduction as well at the beginning. Keeping on that you see that this is more data on the implant cycles neutrophils, the tissue inhibitor metaproteins and we talked about the end rate as well as the [ Vica ]. So those are the conclusion. The design was conferred from randomized controlled trial into expiratory 1 exploratory design to study safety as well efficacy, and I showed you that in this slide. So treatment on leronlimab was tolerated in both Part 1 and 2. And although the 700-milligram did not reduce PDFF and CT1, the 350-milligram significantly had the reduction in PDFF and CET1 within 14 weeks compared to the placebo. There were tons of biomarkers that have been reviewed showing you the mechanism of action and important inflammatory signal in non-alcoholic steatohepatitis patients, giving you confidence that we're moving the needle towards the right direction. Definitely, this drug should be carried out into later stages in terms of trial designs, such as [ 2b and 3 ]. I think that is my part. And yes, we'll take it back to you, Cyrus.

Great. Thank you, Dr. Noureddin. All right. Can I regain slide control, please? Thank you. All right. So I'll now be presenting our clinical data in metastatic triple-negative breast cancer and CRC, before turning over to Dr. Stefan Glück, who will present on the role of the immune system and the tumor microenvironment and treating advanced-stage solid tumors and who will provide a summary of our clinical data. So to set the stage here a little bit. So what we're going to present is a pooled analysis across 3 different studies that we opened for triple-negative breast cancer. The first one being a Phase Ib/II study that had 10 patients; the next 1 being a compassionate use study, also in triple-negative breast cancer that had 16 patients; and 2 patients from our basket study who had triple-negative breast cancer, for a total of 28 patients that are going to be in the analysis that we're going to present here. So all of these patients received at least 1 dose of leronlimab, and the total range of doses was anywhere from 1 to 33. One of the trials was a dose-ranging trial, and patients were escalated from 350 to 525 and had the ability to go up to 700. 4 of those patients did reach dose escalation per the study protocol. The average age for the patients was 52 years with a range of 33 to 75. 52 might sound quite young. However, triple-negative breast cancer typically does emerge in a younger population. So that's not too surprising. And all of this data was as reported as of August 15, 2021. I want to take a moment to highlight that we do use standard of care in sacituzumab as references to provide benchmarks for the study. However, neither of these were directly evaluated in a head-to-head manner in these studies. So they're really just used a historical control references. Across those 3 studies, a variety of drugs were used in combination with leronlimab as a background therapy. And all of these are already approved in the treatment of metastatic triple-negative breast. We've listed what those agents are here. At the time, atezolizumab was approved under an accelerated approval. This is a PD-L1 inhibitor. It is currently no longer available, but other PD-1 inhibitors are. No cross reactions were observed from a drug-drug standpoint. However, the sample sizes are small. So we don't draw any conclusions from that with these studies. So starting first with the safety data across this pooled analysis. So we looked at treatment-related adverse events, treatment-emergent adverse events and serious adverse events in these 28 patients. The distinction between treatment-emersion and treatment-related events are that treatment-emergent events are any events that occurred after the induction of the study, and the treatment-related events are those that can actually be tied back to the investigational product, in this case, leronlimab. So as you can see from the graph on the right, out of a total of 68 treatment-emergent adverse events that occurred, 8 of them were actually attributable to leronlimab, and only 1 of them was a grade 3, 4 event. When we look more specifically at the serious adverse events, which are the grade 3, 4 events, only 1 of them was related to leronlimab. And the vast majority of the serious events actually came out of the compassionate use study, which is not surprising as these are patients that were potentially more advanced in their disease. When we look at the top 13 treatment-related emerging adverse events by type, you can see them here. The majority of them were grade 1, 2 events. And in blue, the Grade 3, 4 events are in red. Only 1 Grade 3 or 4 event was attributable to leronlimab. And again, this was a gastrointestinal disorder, which is also what was a small signal for the scene in the NASH study that Dr. Noureddin presented. So overall, we don't see any -- in this pooled analysis of patients who are on therapy for a short period of time, we don't see major causes for concern with regard to safety. So then looking at the Kaplan-Meier curves and the survival curve. So all of these analysis is broken down into progression-free survival and overall survival. The progression-free survival standard for patients who have received third-line therapy or greater is 2.3 months, and the overall survival standard for patients who received 3 or more lines of therapies, 6.5 months. So the graph on the left here in blue shows what the Kaplan-Meier curve was for leronlimab in those patients. We got a median progression-free survival of 3.8 months, which again is greater than the historical control. Again, not studied in a head-to-head way, but just using a historical measure of what progression-free survival looks like in that population of 2.3 months versus 3.8 months in the overall survival group, it was quite similar to the standard of care at the pool level. When we look at a subpopulation of patients who did not have prior brain metastases, we had a progression-free survival of 3.8 months versus 2.3. And again, this is greater than standard of care from a historical control standpoint. When we look at the overall survival group, where the standard is 6.5 months or 6.6 months, more than 50% of the patients were still alive when the study ended, which is greater than the OS standard and is similar to sacituzumab. When we break down the same patient sets based on the dose they received, broken down into either the 350-milligram dose or the higher doses at 525- to 700-milligram doses, we can see that there's a clear trend for better survival at the higher doses with both progression-free survival as well as for overall survival. When we focus the study down just to patients who are on carboplatinum and leronlimab, the line in red here is the survival curve for the leronlimab patients. And what we can see here is that we got a median PFS of 3.5 -- of 3.9 months, which is greater than the standard of care, again, from a historical control standpoint. And on the overall survival, this population, the subpopulation did very well. In fact, they outperformed the historical controls for both standard of care as well as sacituzumab. So this may be a population that we would focus on in future clinical studies in those that would receive leronlimab in combination with carboplatin. So when we look at the changes in tumor growth by PET/CT, we see some very encouraging results here. So this is patients who received -- 12 patients who did receive scans that were then qualified using RECIST criteria. And what we can see is that all the patients had either stable disease or at least a partial response over the course of the study. And so those are very encouraging results. You can see from the waterfall on the right that the vast majority of the patients stayed within the stable disease range. Within oncology, this is a positive indicator that disease is not getting worse than with the subset of patients, the tumors were certainly getting smaller. When we look at the patients from just the Phase Ib/II study and then break them out by the dose they received, again, you can see that the majority of patients actually did see reductions in their tumors. Some of the patients actually discontinued carboplatin and remained on leronlimab as a single agent for some time. Interestingly, those patients did have the largest reductions in the MAX change in their tumor size. And then finally, what I'll present here before showing the colorectal cancer data is data from a poster presentation at the AACR conference earlier this year. So this looked at changes in circulating tumor cells that have been associated -- or can be looked at as a surrogate for progression of disease. And what you can see here is that the progression-free survival for patients who received at least 1 dose of leronlimab, they had -- and those that had an absence or a decrease in circulating tumor cells had a trend for better survival than those trying an increase in CTCs. And similarly, we saw a similar sort of trend on the overall survival curve. Now this is not surprising. Other agents that would look at a similar breakdown in terms of CTCs would see a similar effect. When we also look at tumor-associated cells, we see a similar trend towards better survival when the tumor-associated cells drop in the peripheral blood measures. I now want to show just a little bit of data on -- from the CRC patients from the basket study, where we had a total of 6. So when we look again at their tumor growth through the spyre grams and through the waterfall plots, that we only had 6 patients here. But as you can see, all of them remain within the stable disease and many actually achieve partial responses over the course of the short study. And of them actually had no measurable lesions on the PET scan at follow-up. And the remainder saw either stable disease or partial responses. I'll now turn it over to Dr. Stefan Glück, who will talk a little bit more about the tumor microenvironment immuno-oncology and the role for leronlimab in attenuating the tumor microenvironment. Dr. Glück, are you there?

Yes. Can you hear me?

Yes.

Wonderful. So sorry for the initial hiccups here technically. So I joined a few minutes later, but I am here. I do see the slide, and it seems like you're hearing me, and thank you very much for giving me the opportunity. Quick introduction. I have been practicing medical oncology for 38-plus years. The last 12 years, I was the Director of the Breast Cancer Program at the University of Miami, but practice also other actually even hematology, not only oncology patients. But my research is focused on breast cancer and all its molecular subsets, including microenvironment. So I can tell you about it a little bit. And I believe you will be pushing the slides forward. So next slide, please. I think what we have learned, and I'm intentionally very broad here. I'm not going too much detail. I just want you to understand why I am so excited about the concept using CCR5 as a target, particularly having a monoclonal antibody like leronlimab. What we have done over decades, we targeted the tumor cells in cancer patients and try to eliminate and cure patients. And I think it is a good start, but now we are focusing more on the immune system, which consists mainly of a variety -- a huge variety of lymphocytes, which are those immune cells that are learning to target unknown tissues like tumor cells; and metro kinases, so which are the first line or part of the first line of immune system, which are targeting anything and everything. So they are quick, fast and effective. Next slide, please. And this all happens in the tumor microenvironment. The tumors are not growing simply where they arise, let's say, lung cancer in the lung or breast cancer in the breast. But they actually create a variety of very different cytokine releases, an environment which makes the environment reasonable and favorable to growing cancer sales. And this environment, very briefly, very simply depicted here, includes a number of cells that are important. And some of them are macrophages and natural killer cells, as you see on the right upper and right side. Now these are those cells that immediately react and do not need learning to attack the cancer. They attack it immediately. But some of these macrophages and some of the natural killer cells actually have a phenotype, which is suppressing the immune system. And that's exactly where the CCR5, and we heard it just 20 minutes ago from Dr. Noureddin, impacts on the variety of cytokines. And actually, it is very much related to the liver disease that we heard about. Now I will not focus on the other -- on the T-cells, on the middle and left side. I will not focus on the very important fibrotic tissues that are equally important for the micro environment, but I will focus on something different. Next slide. And now what we can skip it because I just said it basically, in other words, so without this picture. Yes. So the immune cycle, where the cancer is being actually actively destroyed needs a number of steps. And this is one of the most known slide of the immune cycle from 2013, so almost 10 years old. And what we need to take home here that usually the gray tumor cells on the lower part needs to release something, which we call neoantigens. These are proteins or betas that are not recognized by the body as cells. And the recognition happens in the step #2, the so-called cancer antigen presenting cells APCs like dendritic cells. That's why they have to then drive these fingers. And they gave the immune system, the T cells, the whole story and show them, attack this tumor if it has this particular neoantigen. And then these cells go to the blood vessel and integrate in the step #5 into the tumor, and then they recognize cells. And there are 2 or 3 different stopping proteins, so-called anti-PD-1 and PD-L1 inhibitors on the set #7. And these are upregulated by cancer cells. So this system stops working. Next slide. And in order -- and this system was discovered by 2 now Noble [indiscernible] a few years back, 4 years back, [ Generis ] from MD Anderson in Houston, and Natasukind Honjo from the Tokyo University, and they identified these 2 pathways. And at the same time, they postulated if we stop these stopping pathways, the immune system can work again. And you will see why I'm mentioning. It is so in detail. Next slide. The reason is very simple. We have huge success using anti-PD-1 and PD-L1 monoclonal antibodies and anti-CTLA-4 antibodies. And it's a multi, multibillion-dollar enterprise. For example, if you look at the right side, that you will see non-small cell lung cancer, renal cell cancer, esophagus cancer, gastric cancer and melanoma. And these cancers together alone create more than $50 billion revenue, the lung cancer alone, $12 billion. Breast cancer, not much yet. And what this slide shows you is the following. The huge success, which is the response rate in dark blue, it's a miniscule, small, very small part of the cancer continuum. There's many other cancers that do not actually respond to these treatments. And many cancers, they do respond, but only a [ 10 50 ] up to 20% of all patients. So the vast majority is the grayish or light blue portion, and that's where that means huge unmet need is. Next slide. And the unmet need can be discussed by the immune microenvironment. Those tumors, like on the lower left side, it show pre-existing immunity, which is no more than 40% of all cancers are actually of all immunologically active cancers on the right side of this previous slide. They show that these cells are present. They include macrophages, matricular cells and T cells. But sometimes, they are being stopped and are not functioning like on the second panel on the left lower side. And these cells are still present but are nonfunctional. And sometimes, like in pancreatic cancer, they are excluded. These cells cannot penetrate into the cancer. So see the margin on the third side -- slide in a lower panel and do not benefit into the cancer tissues. And finally, there's an even [indiscernible]. There is some cancers, they don't have any immune reactions, and this is the vast majority of cancers. And these may be so difficult to treat because they are not even targeted -- or sorry, responding to chemotherapy. Next slide. So that's where chemotherapy and the immune system moves to be activated. If you look at the chemotherapy in the middle, and you just heard from Cyrus that the combination of leronlimab and carboplatin, which is a typical chemotherapy agents for triple-negative breast cancer, actually works extremely well. Overall survivor, you heard from Cyrus, is more than a year, unheard of in simple negative breast cancer, even in first and second line. The survival is barely a year in first line, and the survivor is about 6 months in second and third line. So incredible data, sure, small numbers, very early studies, but shows you the progress of the promise of this type of treatment. And one more thing, the polarization of regulatory cells, such as PH1, CTS, Tregs, [indiscernible] tumor cell -- myeloid DRAD stem cells and finally, NK cells and macrophages, are being up-regulated in the right direction, down-regulated for the suppressor and up-regulated into the inducer efficacy of the immune system, just a beautiful biology. And we have to prove it in clinic that it's to the indication so far into the negative breast cancer are here. Next slide. So these are -- in summary, what I said, data support -- sorry, statement supported by data. The macrophage [indiscernible] to non-suppresses function is clearly demonstrated in preclinical model. It's demonstrated very clearly that the metastatic tumor volumes are reduced, including the size and number of metastases. The CCL5, the ligand, so CCR5 [indiscernible] promotes another interesting item, which is the VEGF angiogenesis. Angiogenesis has been successfully utilized as a target and with VEGF receptor and VEGF antagonists. And may I remind you, all these compounds that are very effective and [indiscernible] and nontoxic are monoclonal antibodies, whereas TKIs, as a kind of inhibitor and other small molecules that target VEGF and VEGF receptors, do not function well. And if they do, they are very toxic. So if you go to one of the first slides that we heard from Cyrus, that there is so much competition, so many compounds in combination, actually, there is none. Because all these TKIs to small molecules are not really competition due to the lack of efficacy and the higher and much higher toxicity. The efficacy is, if anything, short-lived. And then the other 2 monoclonal antibodies, they have been regard from on development because they don't show the signal that you have seen as presented by Cyrus in 2 diseases, hard to treat diseases. And finally, the CCL5 suppresses also decide the toxic the set that I mentioned, hence, promotes the growth of Tregs regulatory cells and TH responses, which means it suppresses the immune system. And there you go with leronlimab binding to the CC across this breast cancer cell and cell lines and up to almost, not quite, 100% efficiency. Next slide. So I will not repeat the role here. We have seen at the transmembrane molecule 7 times through the membrane and can be easily targeted by amount and a large amount of different molecules, but I think the monoclonal antibody concept is the single best one that we have seen so far. Next slide. Now in these 28 patients that Cyrus presented, those 2 in the basket study and compassionate use and [ 2 to 10 ] patients on a Phase Ib study, they show us the data that we learned. Progression-free survive seems to be so much better. And remember, this is a high unmet need in breast cancer, triple-negative patients. If they already have 1, 2, 3 therapies like these patients on these studies and compassionate use, they have progression for 2, 2.5 months and they live no more than half a year. Whereas on these studies using leronlimab, particularly in combination with carboplatin, you reached again at least a year. Now these are usually younger patients. So every single week almost, I would say, definitely every single month, longer survival counts here. Next slide. So these are some of the diseases studies that you've also heard. But I would like to emphasize that circulating tumor cells, which actually I published in the '90s, I was probably the first one published on CTCs in breast cancer, show 2 things. Number one, if you can detect CTCs and peripheral burden, so in liquid biopsy, either alone or in combination with a cell-free DNA, and there are some tests that are available now, they are very sophisticated, then they have a worse prognosis. But if after treatment, even only 1 dose of a given treatment, the CTCs fall down or disappear completely, then the survival of these patients is much better, much longer. And I would argue, there will be some patients that actually might be even cured or have a long-term survival like measured in years and not months anymore. And this is the number of 2 points here, the absence. Now if they increase, then, of course, the survival is not worse. So as you saw, very small studies, but extremely promising, and the signal for an oncologist like myself is so strong that I'm enthusiastic about it. We, as oncologists, need to be positive because otherwise, we cannot treat patients and tell them something better is coming. The leronlimab decrease of these tumor cells actually did relate both [indiscernible] and in colorectal with improved survival. That's amazing. Next slide. So [ carbon ], as I mentioned before, is a very typical compound for triple-negative breast cancer. And it is being used in the first or second line, and this was used here in patients who have heavily pretreated. So they progress on treatment to more progress on treatment already. And in all 3 dose levels, it was well tolerated. As predicted, leronlimab is not toxic like TKIs or small molecules. It doesn't have liver toxicity, which would be for the other diseases that we heard before the NASH and NAFLD, very detrimental sequences. And it does not. So this is very good. And you have seen very early preliminary but extremely promising data in 2 different diseases. And for cancer, unlike for liver disease, the weekly 700 milligrams dose is probably the best. Now whether or not they continue with exceeding the carboplatinum a week or to reduce it also to weekly with a lower dose and therefore, even further reduce toxicity remains to be seen by the studies that are being planned. And that, of course, many patients will want to participate because for them, there's not much annotate is left. Next slide. So conclusion from my side here. I think we have 28 patients, as you have seen. The median provisions survival is at least as good and in some instances, particularly in combination with carbo more than a year, unheard of in the past. The medium over survival, #2 here, that received higher doses is also impressive. And finally, the medium progression-free survival, which is a surrogate, is not so important. And the FDA doesn't like it too much for some -- for a number of reasons, I can definitely mention and discuss with you if you wish. But it is important for the individual patient. So remember, a patient has, let's say, stage 4 triple-negative breast cancer and being started on something which gives her 2 or 3 months progression-free survival, and progression-free survive usually means also good quality of life or gives us 6 months like here, [ second half ], 5, 6 months of progression-free survival. So she lives longer and better quality of life, particularly now in this time of the year, holiday seasons coming up. And patients want to spend maybe the last Christmas or last Hanukkah or whatever they do with their family because they may not be alive next time in the holiday season. So if they survive, it is better progression-free survival without symptoms and not in a hospital, how good is that. And the FDA is forgetting this starting endpoint. Now lastly, the vast majority of patients or measurable reasons, and it's important for clinical trials to measure the reasons, why? Because you can actually quantify they are going down, they are stable. And even stable disease for patients means they change or we change with treatments like leronlimab hopefully soon, the aggressiveness of the disease and the patients are dying from growing by -- overgrown by the tumor to something chronic. So it's a stable disease, if the tumor stops growing is already success. So let me tell you, stable is much more important than the clinical trials indicate. So if I see the waterfall plot from Cyrus that you have seen a few minutes back, and you see the vast majority of patients have either responses, maybe complete responses, but also a lot of them no growth of disease, and that's very important for patient's outcome. I think this is my last slide, it's the next. Not quite. Yes, the last slide I would like to remind you, the whole marks of cancer includes many, many things. And now since this year, they have been added 2 more such new dimensions, if I may. And this includes now clearly the tumor-promoted inflammation. And I think Dr. Noureddin will love it that I'm saying it because that's exactly what also causes the disease that he's treating, NASH and similar, but it causes also cancer. And obviously, on the other important portion of this cycle is the immune regulation. So they're avoiding immune destruction and avoiding the immune escape. We call it escape. This cancer cell escape our immune system. It's not with compounds that are targeting CCR5,and you heard why I believe leronlimab is the one, probably only the one winner once we have further Phase II and hopefully Phase III studies, is targeting these 2 new things in the hallmarks of cancer. And I finish here with the slide then.

Thank you. Great. Thank you, Dr. Glück, for your thoughts on leronlimab in the TME, the immune cycle, and for the summary of the clinical data. Okay. So we are now going to pivot to our last portion of the R&D update call, which is with Dr. Jonah Sacha to discuss the role of CCR5 in HIV prevention and cure. Dr. Sacha, are you with us?

I am.

Excellent.

Great. Thank you for that introduction, Cyrus. Good afternoon -- good morning, everyone. My name is Jonah Sacha. I'm excited to present some data to you today that it's from our preclinical nonhuman primate, our [ besisMcac ] model, which I think will help illustrate why we are so excited about the potential of leronlimab to positively and significantly impact the HIV epidemic by slowing and limiting further spread of the virus. Next slide, please. And for those of you who don't know, CCR5, as Cyrus alluded to earlier, was discovered in 1996. And in that same year, a flurry of papers came out because it was shown to be the major co-receptor of HIV. And in fact, it was quickly found as individuals that naturally bear a 32 base-pair [ deletion ] in CCR5, and therefore, don't express CCR5 on the surface are highly resistant to sexual transmission of HIV. And this is due to the fact that when HIV infects new individuals, it almost exclusively uses CCR5. Even though the individual transmitting the virus may have both R5 and export tropic viruses, it's usually 99.9% only the CCR5 tropic HIVs that transmit. Next slide, please. And it was because of this known protective ability of CCR5 deficiency that Dr. [ Garo Heter ], who performed the first allogeneic bone marrow transplantation to a patient, shown here Timothy [ Rebrown ], the Berlin patient, used a stem cell donor who was CCR5 deficient. And Tennessee Ray Brown was in HIV remission over 13 years. Next slide, please. And unfortunately, he died in 2020. But before he died, he was joined in his cure brotherhood by Adam Castilla, the London patient, who also received a CCR5 deficient allogeneic stem cell transplantation. Next slide, please. Now there are currently 3 other unpublished case reports that will be coming out very shortly, where these -- there's 3 further individuals who are also cured by receiving a stem cell transplantation from donors who are CCR5 deficient, most excitingly is the first woman who's ever being cured of HIV. And so I think what this does is set the stage to really show the power of how central CCR5 is the biology of HIV. And when you starve the virus of its ability to interact with CCR5, you can actually do the previously thought unthinkable, which is cure HIV. Now these case studies really had illustrated the power of targeting CCR5. And so there is now a flurry of activity around lots of gene therapy approaches to try and edit out CCR5, which is a very tall order. Next slide. And we pose it actually, that instead of going through this ability, you can simply use leronlimab and give it to a patient and block HIV and the reason that is, is shown here. As you can see, HIV binds to its major co-receptor, CD4. But in order to enter cell, it also has to interact with CCR5. And you can see on the right-hand side, leronlimab binds to the exact same domain of CCR5 that HIV wants to use. And so in contrast to the allosteric small molecule inhibitors like maraviroc, the virus can't interact with CCR5 at all because leronlimab is sterically hindering. It's sitting in the site that HIV wants to use. And this is a very potent mechanism of action. We know that maraviroc has failed as a prep agent because the virus, for whatever reason, can just simply adapt to the maraviroc bound form, as they'll continue its infection. And so leronlimab is a competitive inhibitor, which I believe will allow us to mimic the CCR5 Delta [ 30 ] phenotype. This is the CCR5 deficient phenotype. Next slide. And so we tested this in our nonhuman product model with [indiscernible] is a previously published study in Nature Communications, where we dosed, unaffected [ attacks ] with a low and a high dose. And that resulted in statistically significant and full sterile protection, respectively, from acquisition of Shiv, that's semi and human immunodeficiency virus. That's [indiscernible] SIV or HIV that carries the actual HIV envelope, and this is important because it's the HIV envelope that is binding to CCR5. And what this does is it shows us this leronlimab can really pharmacologically mimic the CCR5 Delta 32 phenotype, and this is really critically important. And I will stress that all of this is done preclinically in nonhuman primates that [indiscernible]. But for those of you who don't know, we refer to macaque as the gatekeepers with the clinic, many FDA-approved substances will be first tested in macaque for safety and efficacy, as you will see with a long-acting [indiscernible], which was recently approved for prevention of HIV. Next slide, please. And as I just mentioned, the field has really gone from taking a pill every day to longer-acting injectables. And the reason is because patients really don't want to take a pill, a daily pill. This is -- there's both a stigma attached to it and also many patients forget or they feel side effects. And so there's a real movement towards long-acting injectables. And long-acting means greater than weekly. So once a month, once every 2 months. And as I mentioned, with cabotegravir, which is a integration hit on the left, this approach using long-acting cabotegravir was first tested in macaque, the exact same model that I just showed you on the previous slide. And this eventually resulted, as you can see on the right, in the FDA approval last year of a long-acting cabotegravir for HIV prevention or our prep-pre-exposure prophylaxis. Next slide, please. So how can we take leronlimab, which is currently a once weekly, which is great, but how can we make it longer. And what we did is we made a tool compound for our macaque studies. So we took the -- we call the FC, the comp in a crystallizable fragment, that's the bottom of the Y here. And we've swapped out the human version of the molecule for a version. And there's many ways in which you can extend the half-life of antibodies in circulation, but we chose what's called the LS mutation. That's simply 2 amino acids that you replace in the same region. And what this does that allows the antibody to escape the natural recycling mechanism. So instead of being recycled and degraded, the antibody can escape from that pathway and then to put back out in circulation. And so this -- we chose us because there's been a lot of FDA-approved drugs that have used this most recently. Next slide. And so I want to show you is some data where we've made a long-acting version of leronlimab that I think really shows the power of this approach. So what you're looking at here are 4 RESIST macaques. We gave a single 10-mg per kg or low dose of -- subcutaneous dose of the long-acting leronlimab. You're looking at the plasma leronlimab levels on the y-axis versus days post injection. Now when we give these macaques a single dose of the parental leronlimab, it's clear from circulation by about 20 days. Here, you can see that we have a detectable leronlimab plasma out to [ 100 to ] 160 days. So about 4 months from a single small dose injection, that's quite promising. Next slide, please. But with leronlimab, what you really have to look at is what we call receptor occupancy. And in this bottom left, what you're seeing in red is how much CCR5 is coated and covered up by leronlimab on the surface of CD4 T cells, the target of HIV in peripheral blood. And what we see is there's 1 animal in the circle that dropped out and lost its leronlimab by about 100 days, but most of these animals maintained it for 140 to 160. So 100% receptor occupancy. This is well past our target, which was 90 days or 3 months. On the bottom right, what you're looking at is the amount of antidrug antibody or ADA. And what that is, is the body making its own immune response against the drug or against leronlimab. And you can see, essentially, we were able to avoid the elicitation of antidrug antibodies. Next slide. But what I find most exciting -- I'm sorry, can you go back one? Unfortunately, it appears the last graft did not render, which is unfortunate. But what the last slide, which you can't see, unfortunately, is we took biopsies of the rectum. And we saw -- and we looked at the receptor occupancy of CCR5 on CD4 T cells in the rectum. And this is important because that's the major site of a sexual SIB transmission. And there in all of these macaques, we saw full receptor occupancy that was maintained for 90 days in that site. So what that means is that with a single dose, we were able to get coverage of about a 3-month window where individuals would be protected from sexual transmission. And these press studies are ongoing. I've recently presented these data actually on Monday at the HIV DART meeting in [ Tabo set ] Lucas, and we'll also be presenting these results next week at the Miami Reservoirs meeting. So these are really breaking data that is very exciting for both us and the field. Next slide, please. So that's why we think that leronlimab can help with PREP, our pre-exposure prophylaxis, what about cure? Now as I mentioned, all the individuals to date that have been cured of HIV were cured through allogeneic stem cell transplantation. That is not a process that we can simply roll out and universally do. It is very expensive, is very dangerous. It has a mortality rate of about 40%. And so we want to ask the question, if we're going to cure HIV, it has to be something that patients would want to do. So ask yourself, if you had HIV and you wanted to be cured, would you go through a bone marrow transplantation? I've got a wager that the answer would be no. However, would you be willing to go in and get a single intramuscular injection? I bet you would. I know I would. And on next slide, please. And so really looking forward to where this -- where the field is going. This is in vivo gene therapy. And currently, the state-of-the-art is AAV vectors or adeno-associated virus. And what you can do is you can actually take leronlimab in sequence. You can put it into this vector, you can then inject that into the muscle. And these myocytes, muscle cells will pick up the AAV vector, and they will then turn into a little antibody factories and produce leronlimab for the rest of your life. Next slide, please. So we tested this proof of concept in an animal that is shiv infected. So the animal was affected with simian human immune efficiency virus. So remember, this is the HIV envelope. On the top left, we're looking at the amount of leronlimab following a single injection of this AAV vector. And you can see that the animals muscle cells are indeed making leronlimab. We can detect it in the plasma over time. These are still an ongoing study. We're only about 12, 13 weeks out. On the bottom left, you can see that 1 week following this injection of the AAV gene therapy vector, we get full receptor occupancy. Leronlimab made by these muscle cells is fully coding CCR5 on CD4 T cells, the target of the virus, thereby blocking access of the virus to infect these target cells. On the top left, what you can see is a little anti-drug antibody response that happens about to week 3 through 6. And this is interesting because if you look at the bottom right, what we've done is I've overlaid the receptor occupancy of the targets of the virus in blue. It was the virus load on the right. You can see shiv. This is a log scale. So prior to the injection, this animal had about 1,000 to 10,000 copies of the [indiscernible] circulating in its blood. Following injection of leronlimab when we get 4 receptor occupancy, as you can see here at week 0, the virus then decreases down. At week 3 and 4, it's fully undetectable. And then remember, we had the sort of antidrug antibody response. What this means is that a little bit of the leronlimab being made is being cleared. And you can see a little bit of receptor encoding begin to happen at 4 weeks. And you see this little peak of virus that comes back. But look what happens when this goes away at about week 8 or 9 when the antidrug antibody disappears. It goes -- the virus load, shown here in black, goes back to 0. And so this animal is currently fully suppressed. There's no virus replicating in it following a single injection of an AAV vector expressing leronlimab. Next slide, please. And so this is why we are so optimistic about the future of leronlimab long-acting for HIV prevention and cure. So we think a long-acting molecule like this where a patient could, at home, subcutaneously dose themselves once every 3 months or perhaps even longer, will have very high uptake and will be very attractive to patients. And for functional cure, by that, I mean control of viremia, the goal here is to develop something where you could just go in, get a single shot. And you have coverage of -- your own body will make leronlimab. And this is only possible because leronlimab appears to be very well tolerated in patients and also in our preclinical studies. And I believe that's my last slide. Thank you.

Thank you, Dr. Sacha. Very exciting data, potentially game changers for patients living with and certainly has applications beyond HIV as well further diseases where CCR5 is a promising target. Okay. So we're not going to conclude the presentation with some closing thoughts. So coming back to our -- focusing on the pipeline on the highest value opportunities. So we've gone through our clinical rationale for why we're focusing in on NASH and oncology. We've seen from Dr. Sacha, this exciting opportunity for a longer-acting molecule that can play a role in HIV prevention as well as cure and potentially other indications as well. So we continue to believe that leronlimab and CCR5 blockade through leronlimab can be a promising mechanism to treat each of these diseases that have continuing high unmet needs. So in terms of how we want to get there. So with NASH, we intend to raise capital and execute trials. With oncology, we do see opportunities with co-development partnership. And within the development of longer-acting agents, we intend to invest in the future there and continue to try to advance these approaches. So in terms of what potential time lines can look like, I think it's really important to highlight that from a value-creation standpoint, and I've mentioned this before, we truly do need to generate a large robust and what I call unequivocal data set that will leave no questions left on the table, right? And that a strategic partner would find attractive and attractive enough to do a real value-accretive deal with the company. And so we've gone through and knocked out what the potential time lines are across each of the different areas that we presented on today. And we're -- as I mentioned before, National Oncology are our priorities. However, because this is all going to be funding dependent, we're going to focus on NASH initially and work with co-development partners to the extent that we can to develop in oncology. So what do we expect in 2023? So our largest priority is the removal of the clinical hold in HIV. This is essentially a gating step for us to be able to get back to normal operations as a company and do what biotech companies do, which is advanced therapeutics and try to bring them to market. Following the lift of the clinical hold, we expect financing to fund operations and to achieve this value inflection point that I've just alluded to. We intend on initiating a new NASH trial. We would like to commit to an investment in and advance longer-acting CCR5 molecules, as this is potentially the future of at least certainly HIV therapy, as Dr. Sacha presented. We continue to contribute in medical meetings and peer-reviewed publications. Again, the CD02 trial data is in process for that right now. We're going to continue to reshape our team and our capabilities in order to meet our goals. And at some point following the achievement of earlier metrics listed on the slide, we're starting a corporate rebranding as well. So to conclude, I want to say thank you to everyone for joining us on this call. We hope that the presentation of the clinical rationale for our development strategy was insightful and helpful. And as I mentioned, we will be fielding questions in our upcoming quarterly investor update that will be occurring in the new year. Please feel free to submit questions to us via the website as many of you have done in the past, and we will incorporate them into our discussion on the next regularly scheduled quarterly investor update. Again, thank you all, and that is our presentation for today.

Thank you. That concludes today's webcast.