Morning. Today we will host Dr. Linhart. We will discuss the treatment landscape for Fabry disease, as well as perspectives on Elfabrio. Following Dr. Linhart's session, we are happy to host Dr. Schlesinger discussing the current treatment landscape for uncontrolled gout and the top-line results from our first in-human study. Following that, I will actually give an overview of Protalix and our strategic direction going forward. So just to add the questions and answers we can have, we'll be happy to have actually after each of the sessions, so please do. So Dr. Linhart, the stage is yours. Thank you very much, and thanks for inviting me. It's a pleasure to be here. Before I start, I would like to show you my disclosures. There are many, as you can see, and this is only logical if you are standing in the position I'm standing at, because we are involved in Fabry disease for more than 25 years, and we participated in the development of different drugs in this field, and running several registries, having some research grants, and being involved in a lot of different papers and publications, including the collaboration we had with Protalix. It was an exciting journey because from the very beginning we felt that there is an opportunity to have another alternative for our patients and improve the conditions that are not very easy for them. This is my history and my CV on a slide. As you can see, I'm a cardiologist. Only by chance, I landed in a field of Fabry disease because we are running the only center in the Czech Republic for this disease, following up more than 250 patients now, having a long-standing experience with that. And it's always a pleasure to deal with Fabry patients because they are really excited to have new treatments, new opportunities, and they are really dedicated to this because 25 years ago we didn't have anything for them. And the availability of the treatments is really changing their lives, even though we know they are not perfect, they are improving their quality of life, and they are improving lots of conditions. Okay, this is a necessary disclaimer. I would like only to mention that we will deal with Elfabrio. Elfabrio is a new drug approved for Fabry disease in Europe and the United States. There are a lot of expectations still because we have only concluded pilot trials for that drug, and we are not having such a long-lasting experience we have with the other enzymes. The data I will show you are looking very, very promising. Before I go to details about the drug, I would like to say a couple of words about Fabry disease because not everyone is familiar with that disease. It's a genetic disease that's leading to a deficiency of alpha-galactosidase A. It's a hereditary disease causing a deficient enzyme. This enzyme is normally working in a lysosome, and you can see the lysosome here on the left within the cell. On the right, you can see how it looks like, and it contains a lot of different enzymes. It's like a kitchen of your cell. It's cleaving and dicing different products to make them available again for the metabolic pathways. It has a very special environment in it, acidic environment. And a lot of different substances are being taken up and transported into the lysosome. So it's really an active environment. So when you have Fabry disease, what happens? This is electron microscopy of this lysosome. So what do you see inside are crystallized, stored substances, namely globotriaosylceramide. So imagine you have a lysosome, a compartment that's normally highly functional, filled with garbage. And I said it's a kitchen, so the kitchen would look like that, okay? I promise it's not my kitchen. Close to that, but not my kitchen. So it's obviously quite hard to cook in it. This is exactly what's happening in Fabry disease. Once you have the storage inside the cell, inside the lysosome, there is a cascade of secondary phenomena that's leading to cellular damage, cellular death, inflammatory changes. The pathophysiology is quite complicated. The disease is quite severe in those carrying so-called classic mutations. They are having really close to zero enzyme activity left in their cells. This is a journey of boys that are affected with the disease. It's an X-linked disease. I will get back to that in a minute. Females are not that much affected as boys or males. But here you can see what happens. They are starting in childhood having pain. We call it acroparesthesias. They have febrile crises. They can't exercise. They have GI symptoms, seeing a lot of different specialists being attributed, a lot of different diagnostics. An average of 12 years to make the right diagnosis, seeing 10, 20 specialists that are giving them diagnoses like juvenile rheumatoid arthritis or irritable colon syndrome, irritable bowel syndrome, and so on and so on. And then they are developing angiokeratomas, red spots on their skin. They have hypohidrosis. They are not sweating enough, so they can't exercise. But what is killing our patients is cardiomyopathy that starts to develop in the third, fourth decade, hypertrophic heart, which is leading to arrhythmias, heart failure, and eventually cardiac death, which is the most frequent death in Fabry disease. Renal disease starting like diabetic kidney disease with microalbuminuria getting to proteinuria and ending with overt renal failure, bringing our male patients on hemodialysis when they are 40, 50, and strokes. And those strokes are at variable age. They can start relatively early, but many of those patients are having them in their fourth and fifth decade of life, sometimes really debilitating strokes. So you can see this is a multisystemic disease, which is the classic picture of the disease. But now we know that there are some variants in the gene, some mutations that are leading to later-onset disease, which is manifesting itself mostly as a cardiomyopathy of the fourth, fifth decade of life. So a lot of different patients. And this pyramid on the left side of the slide, on the right side of the slide, is actually representing the pyramid of the severity of different variants and mutations. So some of those mutations are relatively benign. Some of those are giving you the late-onset disease, and some of them are giving you the severe disease. And then what I mentioned already, it's an X-linked disease. You can see where the GLA gene is on the X chromosome. Females are usually heterozygous. They have two X chromosomes, and one of them is usually healthy. We have a very rare case in our cohort of homozygosity, but this is really exceptional. Mostly they are heterozygous. They are keeping some cells that are keeping enough enzyme and staying relatively healthy. But then there is a complex mechanism of inactivating one of the X chromosomes, which is leading to quite heterogeneous presentation of this disease. Affected males, you can see the tiny Y chromosome compared to the big X chromosome, and we have only one. Unfortunately for male patients, it means that they don't have so much enzyme activity, and they are missing it. This is reflected by the severity of symptoms, but also by the life expectancy of our patients. So those are most recent data we have on life expectancy from Fabry Registry. And you can see that the lifespan of male patients was 58 years only. So if you compare it to the average lifespan of the population we were dealing with, it was 75 years. So substantial shortening. In females, it's not so prominent, but still five years difference in life expectancy, it's a lot. And the burden of the disease, especially when females are getting older, is also quite high. So that's why we were so eager to have Fabry-specific therapy, treating actually the base, the origin of the disease. And now we have two sorts of treatments. And if you divide the patients in those who are responsive to a small molecule, small molecular chaperone that's protecting the enzyme, misfolded enzyme from degradation, we call them amenable. Then they can be given migalastat, which is a small molecule, a chaperone, an iminosugar, which is a competitive inhibitor of the enzyme, allowing the misfolded enzyme not to be degraded in the cell and get to the lysosomes. It's an orally available drug. But still, for a lot of those patients, we are choosing the option we have for the non-amenable patients, and those are enzyme replacements. So the principle of enzyme replacements is to get the drug, to give it to patients intravenously, and let it enter the lysosomes of the cells and clear the cells from the storage. And those are data from agalsidase beta showing the proof of principle. I will show you the data also for pegunigalsidase alfa for Elfabrio later on. But this is how the first drug was approved on the market here in the States, agalsidase beta, more than 20 years ago, showing that we are able to clear some cells from the storage. And mostly those were endothelial cells. So you give the enzyme, you let it act in the lysosome, and then progressively there is a disappearance of those lysosomal inclusions, and this can be analyzed only by biopsy. So this is why those patients are so brave. They are undergoing serial biopsies of the kidneys, and they should be really thanked for that because this is a brave thing to do. But there are a lot of issues with enzyme replacement therapies, and nothing is solving them completely. But we know that the problem for the patients is that those drugs are given intravenously every second week. So every second week, the patient has to go to a center to get infused or have a home infusion, which is possible in many countries. Then the problem with the enzyme we had before Elfabrio was a short plasma half-life. So the question is whether it plays a role or not. This is still a question that's pending. But we know that for some patients, at the end of the dosing interval, they are feeling tired again, and they don't feel so well. So this is an important issue probably to see and watch in the future research. And then because you are giving a foreign protein, something a lot of patients were never in touch with, they may develop antibodies. And those antibodies may be so-called neutralizing. It means they are preventing the drug to act properly, to enter the cells, or to be enzymatically active. So those neutralizing antibodies are really a problem in some patients because they are also associated with infusion-related reactions that are obviously decreasing the quality of life of our patients. So now we are very happy to see any innovation. And there is one of the innovations that came on the market thanks to Protalix, and that's pegunigalsidase alfa. So pegunigalsidase alfa is a plant-based produced enzyme. So it's differently glycosylated than enzymes that are produced on animal or human cell lines. So this is one of the differences. And then what was done, there was an addition of PEG, polyethylene glycol, a small molecule, relatively 2.3 kilodalton. And as you can see, there is a binding of two subunits of the enzyme. So you are sticking them together with this kind of glue with polyethylene glycol, which means that there is a prolonged half-life of this enzyme. It's not so easily cleared from the circulation. It's highly stable in the environment that's simulating the environment of the lysosome. It also covers some parts of the enzyme from the antibodies. So it covers some epitopes. And this is also happening for those PEG subunits that are added on the lateral part of those two parts of the enzyme. So this is the innovation. And this innovation was, of course, tested in a clinical program. And the clinical program was very large. It started with phase I/II study where you are proving the concept. Then you are repeating a bit of what was done before, trying to see that you can clear the kidney from the storage on the kidney biopsies. And you can also see whether those patients are tolerating the drug and what are the side effects. So this was the first pivotal study on which there were an addition of three relatively large for this rare disease, large studies, Bridge, which was a switch over from agalsidase alfa, Balance, that's the pivotal trial, that's the most important trial. And we will be talking about it, and Bright, which is an attempt to show that this drug can be given every four weeks instead of every two weeks. So this is not the approved dosing, which is every two weeks. And this was on the basis of this trial, BALANCE trial. But first, let me review a couple of data from this phase I/II trial. So this is the pivotal trial for the lead or leading trial of the clinical development. And you can see that it proves that the enzyme has really a very long half-life, 80 hours. So far, the enzymes were going up to 2 hours. So 80 hours is the half-life of the drug. It circulates for a long time. And the uptake is probably different from those two enzymes we have on the market. And then I mentioned it's important to show the clearance of the storage from the tissue. And that was done by kidney biopsies. And there is a complex system evaluating the storage, which is called the Barisoni Lipid Inclusion Scoring System. And you can see on the right side of the graph is showing how much those inclusions were reduced in the kidney based on this scoring system. So again, the proof of concept and the similar data that are showing that this drug is doing exactly what the previous enzymes were doing, clearing the storage from the kidney. We are now using more and more biomarkers in Fabry disease. One of them is deacylated globotriaosylceramide, which is lyso-Gb3, globotriaosylsphingosine. And whenever you have a drug that works, we are seeing a decline of lyso-Gb3. There are exceptions from this rule. There are some outliers. But in general, we are seeing a decline. And that was exactly happening in this phase I/II study. I will deviate a bit because it's quite interesting. And I will show you long-term data from those two studies from this cohort because here we are going up to 60 months of follow-up. And we are following patients also from the perspective of the kidney. So the kidney is one of the target organs. We were talking about Fabry nephropathy. And it's very important to stabilize the kidney function with the drug. And that's exactly what's happening in the phase I/II study with this long-term follow-up. The pivotal trial was the BALANCE study. This is the study on which data the enzyme was registered here by the FDA and then in Europe by the European Medicines Agency. The study is a randomized study, 2-to-1 randomization, treating patients with exactly the same dose, 1 milligram per kilogram every 2 weeks by intravenous infusion. You can see there are different analyses that were done. The primary efficacy analysis was aiming for non-inferiority at 2 years. This is the key result. Those are data for eGFR, glomerular filtration rate, estimated glomerular filtration rate. You can see that those two curves are overlapping. The patients are doing basically the same with the two branches. What's really interesting and what really struck me is that those patients were on purpose chosen as patients who were previously already treated with agalsidase beta with Fabrazyme. They were on purpose chosen as patients declining their kidney function by 2 milliliters per year. All of a sudden, when included in a randomized trial, they stabilized. It shows also that you have to have a very controlled environment to get the treatment right. A lot of patients are skipping their doses in clinical practice. They are doing it because they have some side effects and intolerance. We will get to that in a minute. We were monitoring also plasma lyso-Gb3. There were some outliers, as you can see. Those outliers were usually patients having more proteinuria. It seems that there was, because this is a small cohort of patients that was surely randomized, but there were some imbalances in the randomization. One of the imbalances was proteinuria. There were more patients with severe proteinuria and neutralizing antibodies that were already pre-existing neutralizing antibodies in the branch that was treated with pegunigalsidase alfa. So when you take this into account, when you analyze data from taking this into account, proteinuria in particular, you can get different results. And I'm saying it because that was already done before in different clinical trials. This is not a statistical game. So it's legitimate to do that. And this analysis is showing that whenever you do that, you can get different results. And you can get the result that that's shifting the final result in favor of pegunigalsidase alfa. But as you note, no confidence intervals are outside of the line of zero. So there is always a line of identity between the two. So those two treatments are really not different. The difference was in infusion-related reactions and in treatment-emergent adverse events. Here, the data are divided between those who were anti-drug antibodies negative and positive. One of the things you can compare, if you look on the two columns and you look on the rate, which is more informative than the number, you can see that those patients who are positive in antibodies, they are having much higher rates of treatment-emergent adverse events and infusion-related reactions. Anyhow, there was a difference in infusion-related reactions, although the two drugs were tolerated relatively fine compared to what we have in clinical practice. But there was a difference that's quite interesting and needs to be followed up in real clinical practice. This brings me to immunogenicity of the enzyme. So if you give an enzyme, you can have anti-drug antibodies that are really decreasing potentially the efficacy of the drug. Not all antibodies are doing that. So some of those are really to be watched more carefully, especially those neutralizing antibodies. Some of those antibodies are relatively benign. Some of those antibodies are only transient. They are appearing and then they are fading away. So here, we divided the patients according to the presence of antibodies in those who developed de novo antibodies. So they were exposed to a novel drug, and they are developing it only against the novel drug. But because a lot of the patients in the trials, actually most of the patients in the trials were patients who were already experienced with the previous enzyme replacement therapies, they had a large proportion of them had anti-drug antibodies. And some of those antibodies can be increased further by the presence of the new drug, and some of those not. So let's have a look on what's happening. So you can see that about one quarter of patients were having anti-drug antibodies before entering pegunigalsidase alfa trials. Only a limited number of new patients developed anti-drug antibodies de novo. And you can see that there is quite a variable percentage of neutralizing anti-drug antibodies. It seems that the de novo anti-drug antibodies are not so much neutralizing as compared to those pre-existing anti-drug antibodies. So it seems that, at least based on this analysis, yes, there is an anti-drug antibodies response, but it seems that a lot of those patients are not having this neutralizing effect we see with the other enzyme. So there is also an interesting observation that some of these antibodies are directed against PEG, against the polyethylene glycol, a relatively small percentage, and some of them against the plant glycans, again, not such an important part of the antibodies. An interesting paper appeared about two years ago by Malte Lenders, one of the leading experts in the field of antibodies. He is working in Münster in Germany. He was analyzing the cross-reactivity of antibodies against different enzymes. He showed that the affinity of anti-drug antibodies towards pegunigalsidase alfa is lower as compared to affinity of anti-drug antibodies to other enzymes on the market. Ladies and gentlemen, let me conclude that we are really in the Fabry community happy to have a new option for our patients. We need to gather more data because, of course, the experience is only starting to accumulate. There are some follow-up studies that are planned with this drug. It was approved on the basis of quite a robust randomized balanced trial in the U.S. and in the European Union. So the advantage in pharmacokinetics and pharmacodynamics, we can see that this enzyme is able to reduce plasma lyso-Gb3. It can reduce also storage within the kidney as expected from an enzyme that's efficient. The efficacy was confirmed with comparable data to agalsidase beta Fabrazyme, which is the reference on the market and the only enzyme available here in the United States. eGFR is stabilized. And now we have the long-term data showing that the stabilization goes over five years, at least in those patients who were treated for so long. And there are some more data showing that, for example, switching those patients from agalsidase alfa to pegunigalsidase alfa has been associated with stabilization of their kidney function and further reduction of lyso-Gb3. From the perspective of immunogenicity, yes, this drug can induce immune reactions. I shouldn't forget to say that there were four cases of IgE-mediated hypersensitivity during the first infusion. Those patients had a severe allergic reaction. They can't get on the treatment anymore. So this is one of the precautions. But it seems that a lot of those antibodies are transient. And there is a lower affinity on pre-existing anti-drug antibodies to Elfabrio. And the last but not least, infusion-related reactions and treatment-emergent adverse events are at acceptable rate. And the safety profile is really very promising. With this, I would like to conclude my presentation. Thank you for your attention. So thank you, Dr. Linhart. Naomi, please. I would like to invite Dr. Schlesinger to the stage. Actually, I'll get back from the discussion. OK, I'll get back from the discussion. OK, I'm sorry. That's fine. OK, hold yours. Good morning, everyone. It's a pleasure being here and talking about my favorite topic, gout. So we're going to be talking about gout and treatment with uricase approved and under development and maybe make it a bit more crystal clear. So we're talking about gout because it's common. It's the most common inflammatory arthritis in mankind. Over 5% of Americans suffer from gout. 10% of white Americans over 65 suffer from gout. 15% of Asian Americans suffer from gout, a very common disease. The main risk factor for gout is an elevated uric acid or hyperuricemia. This happens at a level of 6.8 milligrams per deciliter. You can see here that a third of people over 65 suffer from this elevated uric acid pool or hyperuricemia. So gout is a disease of purine metabolism. Xanthine oxidase is the rate-limiting enzyme on this cascade. The end product is uric acid. We, as humans, lack an active uricase that converts uric acid to allantoin. Hence, most of the uric acid is reabsorbed. Only a very small proportion of it is excreted in the kidney. The uric acid pool, about two-thirds, is from breakdown of cells and about a third from diet. So diet is important, but only to a small effect. What we have learned is the higher the serum urate, the higher this uric acid in the blood, the higher the risk to get gout. When we talk about gout, we talk about different disease stages. We talk about the hyperuricemic, the person that has an elevated uric acid pool. We may see microscopic or imaging evidence for gout. But really, they usually declare the disease when they have a flare. A flare is a severe pain attack, extreme pain. I'll show you some pictures and describe it further. It is interleukin-1 mediated. It's a pro-inflammatory cytokine. Between flares, patients mostly have chronic ongoing inflammation due to interleukin-1. Then we have the advanced patients, the very severe patients, those that have tophi. A tophus is a chalkstone. These chalkstones or tophi lead to erosions in the bone. They cut in the bone. There are also long-term complications, including cardiovascular disease, kidney disease, and so on. I'd like to suggest that both hyperuricemia and inflammation cause this cascade called gout. Here are some of my patients with acute gout flares. You can see here, this is called podagra, podos being foot, agra, seizure. It has all the signs of synovitis or inflammation of the joint. This is in the first MTP, first metatarsophalangeal joint. It's red. It's warm. It's tender to touch. It's swollen and decreased range of motion. Patients have asked me to cut their limb off. It's very painful. Women have told me that an acute flare is worse than giving birth. This is extreme pain. And then you can see here inflammation in the skin, what we call cellulitis. Usually, that's due to an infection. But here, I like to suggest that it's due to the monosodium urate crystals. The uric acid pool, when it's elevated, causes crystals to deposit in joints, around the joints. And I'd like to suggest that this is actually inflammation in the skin due to these monosodium urate crystal deposition. So now that we've diagnosed gout, we need to treat gout. Meisner, a poet, in 1623 stated that love and gout are incurable. The gout and venere alone will not the physician or condone. However, things have changed since then. We have treatment both to lower the uric acid pool and to combat inflammation, both that of acute flares and also chronic inflammation. Optimal outcomes are when we lower the uric acid. We give anti-inflammatory drugs. But we also look at their underlying comorbidities. Our patients with gout have multiple comorbidities. Most will have four or more comorbidities and other drugs they're on. And this leads to best treatment. So here we are, the same diagram, urate-lowering therapy. And again, xanthine oxidase, the rate-limiting enzyme. We have allopurinol and febuxostat, which are xanthine oxidase inhibitors. They're oral. And we have probenecid, which is a uricosuric. It lowers uric acid reabsorption in the kidney. Not highly used, though. Very few thousands in the States are treated with probenecid. And what we have is a uricase. We have one on the market that converts uric acid to allantoin, the soluble form. This is given IV. Let's talk about uricase. Humans lack a functional uricase. The uricase in humans and some primates, for instance, the chimpanzee in the Philadelphia Zoo, suffered from recurrent gout flares. We used to visit her. It was inactivated primarily to nonsense and frame-shift mutations in the gene many millions of years ago. The uricase is an enzyme that converts, as I said, uric acid to allantoin, which is 10 times more soluble in water and hence in urine. Hence, the uric acid can actually be excreted as opposed to most of it being reabsorbed by the kidney. Here are just some of my tophaceous gout patients, severe tophaceous gout. On the top is a 36-year-old that came to me from South America. On the left, the patient, this is just going forward. Sorry about that. A patient with AIDS and tophaceous gout. And here, a woman that was very, she was five feet, but with the huge tophi taller. Currently, we have on the market, we have pegloticase, which is indicated for gout patients, not first-line treatment, in whom oral urate-lowering therapy and other interventions have failed to achieve a serum urate target and continue to flare, which is two or more flares a year, and have non-resolving subcutaneous tophi. So, tophus is a chalkstone. And in these tophi, we have these crystals, the monosodium urate crystals, chalk-like crystals. So we have pegloticase that's approved by the FDA and on the market. It's a very common modified mammalian uricase. However, as you heard in the previous talk, it has poor solubility, short half-life, and immunogenic. Hence, they needed to conjugate it to PEG moiety. And in the pivotal trials, rapid reduction of hyperuricemia, complete resolution of tophi in months, not in years, as we see with oral urate-lowering therapy, and improvement in quality of life. However, as you heard in the previous talk, antipegloticase antibody developed in the pivotal trials within two to three months of treatment. And they lead to failure to achieve sustained serum urate lowering and infusion reactions. We have learned, looking at these trials, that serum urate is actually a biomarker and predicts infusion reactions. And hence, we need to monitor the serum urate before infusion with pegloticase. We've learned the combination of immunomodulation with pegloticase is now clinical practice. And the FDA in July of 2022 advises us to use pegloticase with methotrexate, an immunomodulator. We have to screen for G6PD deficiency in all patients getting uricases, especially African Asians and Mediterranean males. The G6PD deficiency can cause hemolysis and methemoglobinemia and is dangerous. In the trials of pegloticase, 3% in the treatment arms had mild to moderate anaphylaxis. Then we have the SEL-212. It's under development. And it just completed phase III studies. It's the combination of sequential infusion of a pegylated uricase, pegadricase, and SEL-110, which is an immunomodulator, rapamycin, that is coated in nanoparticles. So just a high view of the phase III dissolve studies. So what they did is they compared placebo to high-dose rapamycin and low-dose rapamycin with the same dose of pegadricase, same dose of uricase. And their studies met the primary efficacy endpoint of achieving and maintaining a serum urate of 6 milligrams per deciliter or less. We want it to be less than the 6.8 milligram per deciliter, which is hyperuricemia, for 80% of the time during the 6 treatment period. What they found is the high-dose group, which is the high-dose rapamycin group, 56% and 46% in the two trials responded to treatment. In the low-dose group, it was lower, 48% and 40%. 3.4% of these patients have a severe adverse event. 4 of them suffer from anaphylaxis. Here we are in the PRX-115, phase I, top-line results. This is an interim analysis of cohorts 1- 7. This is a double-blind placebo-controlled single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic properties of PRX-115 in adult volunteers that have elevated uric acid levels. The primary objective was to evaluate the safety and tolerability of PRX-115 after a single ascending IV infusion dose in adults with elevated uric acid levels. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics, as well as immunogenicity of PRX-115 after a single ascending IV infusion dose in adults with elevated uric acid. Here we are. This is a dose escalation study. You can see here the different cohorts, 8 participants in each cohort, 6 are active and 2 placebo. For subject safety, each cohort starts at least 7 days from the last dosing of the previous cohort. You can see here the follow-up is for 85 days, so almost 3 months. Who is recruited? Who is the study population? Adults, 18 years- 65 years of age, serum uric acid 6 milligrams per deciliter, although reduced to 4.7 milligrams per deciliter at screening. That was found in five patients. Body mass index in the range of 18.5 kg/m² -40 kg/m². They had no gout flares prior to enrolling in the study and no clinical evidence for subcutaneous tophi. As this is the first human trial, no formal sample size determination is appropriate. Eight participants, as I told you, in each dose level are considered to be adequate to detect adverse events and safety signals of PRX-115. So who's recruited? Well, the mean age was 36. 70% were male. 70% were whites. Weight was 90 kg. That was the mean. The mean body mass index was 29. The serum uric acid was 7.5 mg/dL, with the highest serum urate level of 12.2 mg/dL. PRX-115 was well tolerated. All randomized patients completed the study. There was one patient that experienced an anaphylactic reaction immediately, within 6 minutes following the commencement of the infusion. The reaction was resolved. He actually continued in the study for follow-up safety assessments. No other serious adverse events were reported during the study. No related adverse events were repeated for the higher doses, cohorts 6 and 7. How about immunogenicity? You heard about treatment for Fabry. Here, preliminary anti-drug IgG antibody assessment revealed that many subjects developed positive low-titer IgG response following a single administration of PRX-115. PRX-115 immunogenicity is still under evaluation, including correlation to PK, PD, and safety. Taking under consideration that this is a single-dose study, it would need to be evaluated the immunogenicity following repeated dosing of the drug. Here you can see the mean PRX plasma concentration on the y-axis over time, over the 85 days, almost 3 months. You can see here that exposure of PRX-115 increases with increasing dose. Detectable exposure beyond day 56 is observed in plasma of treated patients in the cohorts 6 and 7, which is the higher doses. Here you can see the mean uric acid concentrations in milligrams per deciliter. In the y-axis, again, the x-axis is over time, three months. You can see here that in the low doses, there's a dip. You can see here in the blue, there's a dip. But then it comes back over 6 milligrams per deciliter. But as we go up with the dosing, you can see that not just that there's a dip, it's 1 milligrams per deciliter. You can see here in the higher dosing. But it also stays below the 6 milligrams per deciliter. So administration of PRX-115 leads to a rapid reduction of plasma uric acid. The effect of PRX-115 on plasma uric acid levels and duration response is dose-dependent. Nicely, it lasts beyond the 4 weeks. In summary, we found that all randomized patients complete the study. PRX-115 is found to be well tolerated in this study. There's 26% of patients report study drug adverse events, mostly mild to moderate in severity, with the exception of this 1 patient that develops this anaphylactic reaction within 6 minutes. Following the commencement of the infusion, the reaction is fully resolved. The patient continues in the study for safety assessments. No other serious adverse events were reported. Interestingly, no adverse events reported in cohorts 6 and 7, the higher doses. As far as the PK, increased exposure with increasing dose, PRX-115 was detected beyond day 56, which is 8 weeks in cohort 6 and 7. Regarding PD, administration of PRX-115 leads to a rapid reduction of plasma uric acid. The effect of PRX-115 on plasma uric acid levels and duration of response is dose-dependent and lasts beyond four weeks. Cohort 8 completed recruitment and now is in the stage of follow-up. So thank you so much for your attention. Thank you. So thank you, Dr. Schlesinger, and thank you, Dr. Linhart, for your presentations. If there will be any questions, we follow my presentation. Clearly, we will answer them. I would like to give an overview of Protalix and our strategic direction going forward. We'll start with a couple of highlights. We have two approved drugs. One is ELELYSO for Gaucher and Elfabrio for Fabry. We have a platform, ProCellEx, which is validated. We express complex human proteins through plant cells in suspension. It is approved by the EMA and the FDA. We will continue to use this platform. We have strong partnerships with Chiesi, Pfizer. We have an agreement with the Brazilian government where we market ELELYSO in Brazil. Protalix is a 30-year-old company. Along the years, Protalix had a long learning curve and accumulated a lot of experience with regard to clinical and regulatory affairs, experience with the genetic space. We have a small development pipeline, which we elaborated earlier about the gout program. We have some earlier preclinical programs that we will update you when due. Protalix has three streams of revenues from Chiesi, from Pfizer, and from Brazil. The intent is indeed to grow these revenues and finance this company going forward. Overall, I will just say that certainly we have achieved in the last few years, and certainly after the approval of Elfabrio, a much stronger foundation to build the future of Protalix. You can see here at the pipeline, as I mentioned, we have two approved drugs. One was approved already in 2012 by the FDA; it's ELELYSO. And then in multiple other markets, Elfabrio was approved actually a year ago, 13 months ago, in May of 2023, both by the EC and the FDA. The gout program, we are actually at the last curve of the phase I. We are already in the planning of phase II, which is planned to be initiated mid next year. We will consult, of course, with the regulatory agencies, both here in the U.S. and markets in Europe. We will move on. On ELELYSO, just to add a couple of things, as mentioned, this was actually the first plant cell-derived protein that was approved by the FDA. It was done 13 years ago. ELELYSO is approved for Gaucher disease. It's a rare lysosomal storage disease, one in 40,000 people. As mentioned, ProCellEx system. The standard of care in Gaucher disease are ERTs. There are three ERTs in Gaucher. And commercially, we're approved in 23 different markets worldwide. We have exclusive agreement, commercial agreement with Pfizer. Brazil is the only place we have our own sales force. We operate there through a license from the Brazilian government. And we sell between $10 million-$12 million a year with about 25% market share. There are about 900-950 diagnosed and treated Gaucher patients in Brazil. With regard to Fabry and ELELYSO and Elfabrio, I'm sorry. So actually, this was the second time the FDA approved a product from Protalix based on our platform. Fabry is an excellent lysosomal storage disease, one in 40,000-60,000 men. The standard of care in Fabry is mainly ERT. And I will show in a minute in the next slide. And we think today the Fabry indication is about $2 billion. It will be estimated to be $3 billion by the end of the decade. And I think Chiesi has expanded significant resources, both at the commercial and medical fronts, in order to penetrate into this market and have Elfabrio available to as many patients as possible. This is the, I would say, the competitive landscape in Fabry. Fabrazyme, Replagal, ERTs were approved over 20 years ago. Fabrazyme is approved globally. Once in two weeks, ERT, which is there is an infusion. Replagal is approved everywhere outside the U.S. Galafold is a chaperone technology by Amicus, which was approved 6 and 8 years ago in the U.S. and the EU. Elfabrio, as discussed, was approved recently. We truly believe that it's a very good alternative for the patients. A little bit about Chiesi. Chiesi is a private Italian company. They are based originally in Italy. They are spread worldwide. Chiesi is a group. They sell about $3 billion in sales. They have established their rare disease business about 4 years ago. They bought, licensed a couple of small assets. They invested heavily in Elfabrio and this program. Now, post the approval, I think the risk is partially reduced. Still, a lot of efforts are being put into it. They bought Amryt about a year and a half ago. So they put a lot of resources and thoughts into it. As for us, as we look at the partnership with Chiesi, we are very much pleased. It's a committed partner with a well-experienced commercial team with strategic focus in rare disease and specific sub-indications. Clearly, one of them is Fabry. Per Chiesi, Elfabrio is a top priority asset. They do well on the market. I'm sure we will be pleased going forward as well. About the 115, I think there are 2 slides here that I think are a bit repetitive. I will skip them as Dr. Schlesinger reviewed them. Just to summarize, indeed, it's a pretty big market of gout patients in the U.S. and worldwide. As mentioned, we are finalizing our phase I. The last 8 participants of cohort 8 were infused. No AEs. Now we are at the follow-up period, which is about 85 days, I believe. So I think we will have a CSR, the plan by Q4 of this year. It will be October-November. In parallel, we meet with the regulatory authorities, as mentioned. And then we plan to initiate the phase II mid next year. I would like to describe a little bit about our strategy going forward. In the last few quarters, we went through a very detailed process together with outside consultants and consultancy firms and, of course, with our internal team. We have fine-tuned our pathway going forward. And we have enhanced our research strategy, I would say, with a greater focus. So we'll continue to leverage our ProCellEx platform, as well as explore and prioritize certain rare disease indications. And it will be based on our research strategy and our R&D team. Now, with regard to the platform, we explore expansion of the platform, adding additional value to ProCellEx. We are evaluating, as we speak, plant-based drug delivery systems that will allow a protected delivery of different modalities into specific tissues. So this is an addition, if I may say, in order to, I would say, to bring an edge to the platform in addition to what we have so far, together with the chemical modifications, which are actually the PEGs that we have with Fabry and with the gout program, and hopefully, additional indications. Now, to further explain how we are, I would say, sharpening our focus. So first of all, we have conducted, I would say, a systematic analysis to identify potential key areas of focus in the rare disease space, both genetic and non-genetic opportunities. We will prioritize rare renal diseases as the core of Protalix's development pipeline. We will address high unmet needs of renal diseases, which include very specific sub-indications like ADPKD, Alport syndrome, et cetera. Second, with respect to BD&L, I think we will take, I would say, a systematic approach in addition to our own capabilities at home through the system itself. Now, equipped, I would say, with the new strategic or enhanced strategy, we believe Protalix will continue to enable and address high unmet needs. I think that when you look at the track record of ELELYSO and Elfabrio, in the next few years, we hope, and certainly, this is a very successful track record, bringing two drugs to the market. In the next few years, we plan to focus into the pipeline and hopefully to have an additional program from discovery to phase II, including the gout, of course. We will continue to use ProCellEx and hopefully to expand it to additional modalities. We will work also with inorganic moves as M&A. Again, I would say smaller ones as fit to our budget, of course. And overall, we hope that in the next few years, we will have a much more significant innovative rare disease pipeline. Now, as we hopefully see fruits to these moves and to these efforts, we think the goal is indeed to have a bigger company with a pipeline of innovative rare disease clinical programs with fully integrated end-to-end capabilities and then with a commercial, of course, infrastructure to support these products. So this is, in a nutshell, actually to bring all these to the market and, in parallel, novel technologies to enhance our platform within the rare disease space. From a financial point of view, we reported end of Q1 that we see by the end of March with $48 million in cash. As mentioned, we have three streams of revenues from Chiesi, from Pfizer, and from Brazil. We expect them to grow going forward. From a cash runway point of view, we have sufficient cash not only to support the debt repayment. We plan to pay the $20.4 million by September 1st. Actually, it's in two months' time, but also to maintain our operations. But this is inclusive of the phase II in gout. This is very important. The debt, as I mentioned, will be zero very soon. So we will end the year with zero debt, with three streams of revenues, with cash. So I think it's a much stronger company than it was in the recent years. I would like to explain that actually, in the next few days, I will mark five years in Protalix. Over the last five years, I think together with the team, we have sharpened the focus. We increased capital to enable the next phase of pipeline development. You can see here on this slide on different aspects. Elfabrio got to the finish line. Debt is being reduced, actually, to zero soon. We sit on cash. From a strategic focus, in the past, Protalix was based its pipeline on ProCellEx's platform, which is agnostic in essence. Going forward, we will mainly, I would say, focus on rare disease, especially in the renal area. And hopefully, we'll be able to mature additional drug delivery modalities in addition to the current platform and the PEGylation. So I think this sums the journey that we have done now. We have a lot of work ahead of us. Clearly, we will build a much more significant company going forward. I would like to say and thank the team. We have an experienced and talented leadership team. I would also like to thank the board of directors. We have an accomplished board of directors that support us. We work very closely together and transparently together. I think it works well. So thank you very much. So Lorraine, I think if there are any questions to Naomi or Aleš or to myself, please. Yes. So thanks, everyone. We'll now be taking live questions here from anyone that has them. If you have a question, go ahead and raise your hand. Then we'll bring over a microphone so that you can ask your question. Any questions? Jeff Levine, OMERS Life Sciences. Thanks for the presentations, both Dr. Linhart and Schlesinger. Maybe a question for Dr. Linhart. On thinking about where you would use Elfabrio in your patient population, what's kind of the low-hanging fruit? So I will describe my own personal experience with Elfabrio because we were part of the clinical trials running, actually, three of them in our center, altogether 12 patients. All of them were tolerating the treatment very well. All of them are stable. Three of them are still in a clinical trial that requires them to travel long distances for getting infused. And they are still ready to do that. So they are all experienced patients. They had a treatment before with different sorts of drugs on the market. And they report clinical stability and improvement. Of course, you can't never say this is not a bias induced by being part of the clinical trial. We see it with different drugs. Our patients are feeling very well on the therapy. We have the impression that, if anything, they are getting stable. The problem of Fabry disease, it's a very slowly evolving disease. Sometimes you need to wait for a significant amount of time to see whether the biological phenomenon is not prevailing over the treatment. It seems that in this case, we are reaching a very good stability of our patients. Some of them are staying on the therapy already five years, being included among first in different clinical trials. For further evaluation of those patients, we need real-world data. You will never gather enough clinical data in a randomized trial that lasts for a short period of time. What I would like to stress out, what you have seen in the BALANCE trial, I didn't mention it in my presentation. The important feature is this is actually the first treatment trial with an active comparator, choosing so far the strongest drug we have on the market as a comparator. So the final result is quite a success because to beat something that really works well is always very, very difficult. And now we have to see what are the indications, where are the fields where Elfabrio should be the first choice of the therapy. And of course, it's very important to have something in your hands dealing with the patients, showing them there are multiple options, that they are not just stuck with one therapy that's available on the market. For a lot of them, this is important. And we are not pretending this is the ultimate solution of the problem. There will be still a lot of pending questions, unsolved issues. Having these multiple choices in our hands for the patients, it's an important advantage. It's an important improvement of the care. What was said, the prevalence of the disease is probably underestimated. One in 40,000 was an estimate based on the classical disease. We are trying; we are still discovering more and more patients, especially among cardiac patients that are having this later-onset disease. It's a big challenge because those patients are developing their disease later in life. They are not suffering those classical signs and symptoms, but there are many more of them. We are now estimating that the clinically significant disease is occurring in one in 10, potentially one in 15,000 maximum. The problem is much larger. We don't know why this, especially this gene, is so vulnerable. Can you imagine when I started in Fabry disease 25 years ago, we knew about 250 different mutations of this gene. Today, about 1,200 different mutations on our own. So this is an evolving area of a rare disease that's becoming not so rare at the end, and where we are having different competitive drugs. So the field is actually really expanding because we are trying to find more patients to offer them in a timely fashion an efficient therapy. So the strategy is to start the treatment as soon as possible when they have clinically relevant signs and symptoms or something wrong going on on the level of their heart or kidney, even without symptoms, because we are having more and more data, especially from registries, that the preventative way of the treatment is more efficient than a late treatment of an overt disease. From that perspective, I think having a therapy that's associated with a very acceptable rate of infusion-related reactions, having a very good tolerability for an enzyme that's given intravenously, it's of tremendous importance. Thank you. you. Hello. This is Daby Carreras from Spartan Capital, a retail broker, and very much heavily invested in this company for a number of years. I love that we have a short limited time to acquire more as the company is doing very well. I'm just interested in a little bit about your future pipeline. You spoke a little bit about 115, also about 110, a little bit more about the 18-patient trial in Japan. And just the overall cash position, stock price. I'm very encouraged. Thank you. Thank you. We discussed the gout. Earlier programs are, I would say, pretty early. Once we have something substantial to share, we will share. It's better not to speak on something which is way too early when we don't have enough evidence. But we will focus on, or we are focusing on, innovative solutions which address real unmet needs. And indeed, the company, as you can see, is stronger and can finance itself. So I think this is many people will ask about the share price, which clearly is understandable. But we can see that along the years, the company has strengthened itself from a business point of view. I mentioned earlier, we can finance our operations going forward, inclusive of the phase II of gout, an additional earlier stage program by ourselves. And people can see it on the market. We did not raise any money recently. We did not take advantage of certain events. This is not the intent. Any other questions? Thank you. Two questions that are related actually to the gout project. According to your estimation, what is the number of patients or percentage of patients that can be described as uncontrolled gout? That's question number one. I assume that the number is relatively high. And the related question would be, why KRYSTEXXA, at this point of time, is quite limited in their sales? Thank you. Okay. I'll start with KRYSTEXXA, but this is me, Schlesinger. I don't know if this is true. My hypothesis. So when they did the pivotal trials, they didn't do such a good job. And then they analyzed their data, and then another company bought it. And it's taken time to go up. Although the last few years, it has been going up. People are using more and more KRYSTEXXA. The problem is it's very expensive to use KRYSTEXXA. An IV infusion is around $20,000-$28,000. It's every two weeks. Insurances don't always okay it, although it works. That's the problem. Then the first question, a patient with tophi, gout is not one disease. I've opened a gout center in China, and there I see a lot of tophi. In the States, a lot of tophi, about a third of patients. In Europe, maybe less tophi. It's a little bit different diseases. Gout is not treated very well. The market is huge for gout. It's a very large market. It's overdiagnosed, underdiagnosed. In Asia, very common. It has a big potential. I mean, I showed that we have drugs, but really, we need more drugs. I mean, we need more medications, both anti-inflammatory and uric acid-lowering drugs because of the vast majority. I just moved to Utah. There we have the fourth largest community of Pacific Islanders. 15% of them have gout and very severe gout. So I'm seeing very young patients with these tophaceous deposits, very early in life, 20. I'm seeing very severe gout. Yeah. So the market is vast. There are lots of gout patients. Other questions from the audience? Okay. We do have folks who joined us on the webcast that were able to submit questions. So I'm seeing one here is related to revenues. So the question is your market cap as it relates to 2025 revenues. So if things go as planned, when do you anticipate breaking $100 million in revenues? Okay. Thank you. I think ELELYSO is gradually penetrating into the market. And following that, our revenues or royalties that are reflected as revenues, in addition to what we have in Brazil and Pfizer, will grow. It will not be a matter of one or two days. I assume to have $100 million revenues, you need to cross the 15% market share. We are pretty much positive they will do it, of course. And we estimate they will do more. But this will take a couple of years. But we are certainly on the right way. Okay. Great. I'm not seeing any further questions here from the webcast. Are there any last questions here from the audience? All right. Thanks, everyone, for joining. Dror, I'll hand it to you for just closing remarks. Thank you. So it will be very short. So thank you, everybody, for coming and participating through Zoom or webcast. And thank you, Dr. Schlesinger and Dr. Linhart, for making it here in person. And we will continue to update you. Thank you very much.