Protalix BioTherapeutics, Inc. (PLX) Earnings Call Transcript & Summary

Good morning. Today, we will host Dr. Linhart, who will discuss the treatment landscape for Fabry disease as well as perspective on Elfabrio. And following Dr. Linhart 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, answers, we can have -- we'd 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. And before I start, I would like to show you my disclosures. And 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 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 and including the collaboration we had with Protalix. And 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. So this is my history and my CV on a slide. And as you can see that 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 are 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. And there is a lot of expectations still because we have only concluded [ pivotally ] trials for that drug. And we are not having such a long-lasting experience we have with the other enzymes. But the data I will show you are looking very, very promising. So 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. So it's a hereditary disease causing a deficient enzyme. And 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. So 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 [ steward ] 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. And this is exactly what's happening in Fabry disease. So 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. So the pathophysiology is quite complicated. And 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. And 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. So 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 acroparesthesia. As they have [ Fabry ] crisis, they can't exercise. They have GI symptoms, seeing a lot of different specialists, being attributed a lot of different diagnostics. An average 12 years to make the right diagnosis, seeing 10, 20 specialists that are giving them diagnosis 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 skins. 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 third, fourth decade; hypertrophic heart, which is leading to a arhythmias, heart failure and eventually cardiac death, which is the most frequent death in Fabry disease; renal disease starting like a diabetic kidney disease with microalbuminuria, getting to proteinuria and ending with [ overt renal ] failure, bringing our male patients on hemodialysis when they are 40 or 45 -- say 50; and strokes. And those strokes are at variable age, they can start relatively early, but many of [ dialysis ] patients are having them in their fourth and fifth decade of life, sometimes really debilitating stroke. So you can see this is a multi-systemic disease and -- which is the classical picture of the disease. But now we know that there are some variants in the genes, 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 later-onset disease, and some of them are giving you the severe disease. And then what I mentioned already, it's an [ X-cell ] disease. So you can see where the GLA gene is on the X chromosome. So females are usually heterozygous. They have 2 X chromosomes, and one of them is usually healthy. We have a very rare case of our -- in our cohort of a homozygosity, but this is really exceptional. Mostly, they are heterozygous. So they are keeping some cells that are keeping enough enzyme and really 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. So unfortunately, for male patients, it means that they don't have so much enzyme activity, and they are missing it. And this is reflected by the severity of symptoms, but also by the life expectancy of our patients. So this is -- those are most recent data we have on life expectancy from Fabry registry. And you can see that the life span of male patients was [ 50 80 ] years only. So if you compare it to the average lifespan of the population we were dealing with, it was 75 years. So a substantial shortening. In females, it's not so prominent. But still, 5 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 2 sorts of treatments. And if you divide the patients and those who are responsive to a small molecule, small-molecular chaperone that's protecting the enzyme, misfolded enzyme from degradation; we call them amenable. And then they can be given migalastat, which is a small molecule, a chaperone and iminosugar, which is a competitive inhibitor of the enzyme, allowing the misfolded enzyme not to be degraded in the cell and gets 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 nonimmunable 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 these 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 end of 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 [ series ] of 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 slowing 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 cell -- 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 2 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. And it also covers some parts of the enzyme from the antibody. So it covers some epitopes. And this is also happening for those PEG subunits that are added on the lateral part of those 2 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 and you are repeating a bit 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 in which there were an addition of 3 relatively [ large ] for this rare disease [ launch ] studies, BRIDGE, which was a switchover 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 4 weeks instead of every 2 weeks. So this is not the approved dosing, which is every 2 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 [ leader ] -- 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, so far, the enzymes, we are 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 2 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 [ barinzonilipid ] 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 the scoring system. So again, the proof of concept and a 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, and one of them is [ deescalated ] 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 a long-term data from those 2 studies from this cohort. Because here, we are going up to 60 months of follow-up, and we are following patients so 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. But the pivotal trial was BALANCE study. So this is the study on which data, the enzyme was registered here by FDA and then Europe by European Medicines Agency. The study is a randomized study, 2:1 randomization, treating patients with exactly the same dose, 1 milligram per kilogram every 2 weeks by intravenous infusion. And you can see there are different analyses that were done, but the primary efficacy analysis was aiming for noninferiority at 2 years. And this is the key result . So those are data for eGFR glomerular filtration rate, estimated glomerular filtration rate. And you can see that those 2 curves are overlapping and the patients are doing basically the same with the 2 branches. What's really interesting and what really strucks me is that those patients were on purpose chosen as patients who were previously already treated with agalsidase beta, with Fabrazyme. And they were on purpose chosen as patients declining their kidney function by 2 milliliters per year. And all of a sudden, when included in a randomized trial, there -- they stabilized. So it shows also that you have to have a very controlled environment to get the treatment right. And a lot of patients are skipping their doses in clinical practice, and they are doing it because they have some side effects and intolerance, and we will get to that in a minute. We were monitoring also plasma lyso-Gb3. There was -- there were some [ outliers ], as you can see, and those [ outliers ] were usually patients having more proteinuria. And it seems that there was -- because this is a small cohort of patients that was, sure, randomized, but there were some imbalances in the randomization. And one of the imbalances was proteinuria. And there were more patients with severe proteinuria and neutralizing antibodies that were already preexisting 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 all -- 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's shifting the final result in favor of pegunigalsidase alfa. But as you note, no confidence intervals are outside of the line of 0. So there is always a line of identity between the two. So those 2 treatments are really not different. The difference was in infusion-related reactions and in treatment-emerging adverse events. Here, the data are divided between those who were antidrug antibodies negative and positive. And 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 [ 2 ] 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 antidrug 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, antidrug 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 1/4 of patients were having antidrug antibodies before entering pegunigalsidase alfa trials. Only a limited number of new patients developed antidrug antibodies, de novo. And you can see that there is quite a variable percentage of neutralizing antidrug antibodies. It seems that the de novo antidrug antibodies are not so much neutralizing, and it's compared to those pre-existing antidrug antibodies. So it seems that, at least based on this analysis, yes, there is an antidrug 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, relatively small percentage and some of them against the plant glycans, against -- again, not such an important part of the antibodies. So an interesting paper appeared about 2 years ago by [ Multilenders ], one of the leading experts in the field of antibodies. And he's working in Münster in Germany, and he was analyzing the cross-reactivity of antibodies against different enzymes, and he showed that the affinity of antidrug antibodies towards pegunigalsidase alfa is lower as compared to affinity of antidrug antibodies to other enzymes on the market. So 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, and there are some follow-up studies that are planned with this drug, but it was approved on the base of quite a robust randomized trial, [ BALANCE ] in the U.S. and in the European Union. So the advantages are 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 the 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 5 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 4 cases of IgE-mediated hypersensitivity. During the first infusion, those patients had a severe allergic reaction, and 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 that there is a lower affinity on preexisting antidrug 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, and thank you for your attention.

So thank you, Dr. Linhart. Naomi, please. I would like to invite Dr. Schlesinger to the stage.

Good morning, everyone. It's a pleasure being here and talking about my favorite topic out. So we're going to be talking about gout and treatment with uricases approved and under development, 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 gout and [ 15% ] of Asian Americans suffer firm 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. And you can see here that 1/3 of people over 65 suffer from this elevated uric acid pool or hyperuricemia. So gout is a disease of pure metabolism. Xanthine oxidase is the rate-limiting enzyme in this cascade. And the end product is uric acid. We as humans lack an active uricase that converts uric acid to [indiscernible]. And hence, most of the uric acid is reabsorbed and only a very small proportion of it is excreted in the kidney. The uric acid pool, about 2/3 is from breakdown of cells and about 1/3 from diet. So diet is important, but only to a small effect. What we've learned is the higher the serum urate, the higher the 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 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, and I'll show you some pictures and describe it further. It is interleukin-1 mediated, it's a pro-inflammatory cytokine. Between flares, patients have -- most have chronic ongoing inflammation due to interleukin-1. And then we have the advanced patient, the very severe patients, those that have tophi. [indiscernible] is a chalkstone. And these chalkstones are tophi, lead to erosions in the bone, they cut in the bone. And there are also long-term complications, including cardiovascular disease, kidney disease and so on. So I'd like to suggest that both hyperuricemia and inflammation cause this cascade called gout. And here are some of my patients with acute gout flares. You can see here, this is called Podagra [ Podus ] being foot [ agra ] seizure, and 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. This is -- 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'd 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. Mesner, a poet in 1623, stated that love and gout are incurable. The gout and venery alone will knock the physician [indiscernible]. However, things have changed since then, and we have treatment both to lower the uric acid pool and to combat inflammation, both out of acute flares and also chronic inflammation. And optimal outcomes are when we look -- when we lower the uric acid, we give anti-inflammatory drugs, but we also look at their underlying comorbidities or patients with [ gout ] -- multiple comorbidities. Most will have 4 more comorbidities, and other drugs that are on, and this leads to best treatment. So here we are, the same diagram, urate-lowering therapy. And again, xanthine oxidase, the urate-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, and this is given IV. So let's talk about uricase, so humans lack of functional uricase, the uricase in humans and some primates. For instance, the chimpanzee in the Philadelphia Zoo suffered from recurrent gout flares, and we used to visit her. And it was inactivated primarily to [ nonsense ] and frameshift 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 10x more soluble in water and hence in urine -- and hence, the uric acid can actually be excreted as opposed to most of it being reabsorbed by the kidney. And 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. The patient with [indiscernible] and tophaceous gout. And here a woman that was very -- she was 5 feet, but with the [ heltophi taller ]. And currently, we have on the market, we have pegloticase, which is indicated for gout patients, not first-line treatment. In-home oral urate-lowering therapy and other interventions have failed to achieve a serum urate target and continue to flare, which is to -- or more flares a year and have nonresolving subcutaneous tophi. So tophus, in latin, 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 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, anti-pegloticase antibody developed in the pivotal trials within 2 to 3 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 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 FDA, in July of 2022, advises us to use pegloticase with methotrexate 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 it's 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 just completed Phase [ III ] studies. It's the combination of sequential infusion of PEGylated uricase, pegadricase. And SEL-110, which is an immunomodulator, rapamycin, that is coded in nano particles. 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 sixth treatment period. What they found is the high-dose group, which is the high-dose rapamycin group, 56% and 46% in the 2 trials responded to treatment. In the low-dose group, it was lower 48% and 40%. And 3.4% of these patients have a severe adverse events, 4 of them suffer from anaphylaxis. So here we are in the PRX-115 Phase I top line results. This is an interim analysis of cohorts 1 to 7. So 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. And 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. So here we are. And this is a dose escalation study. You can see here the different cohorts, 8 participants in each cohort, 6 in the active -- 6 are active and 2 placebo. And for subject safety, each cohort starts at least 7 days from the last dosing of the previous cohort. And you can see, the follow-up was for 85 days, so almost 3 months. So who is recruited? What was the study population? Adults 18 to 65 years of age, serum uric acid 6 milligrams per deciliter, although reduced to 4.7 milligrams per deciliter, screening, and that was found in 5 patients. Body mass index in the range of 18.5 to 40 kilograms per meter square. They had no gas 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, the termination is appropriate. And [ 8 ] 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 white. Weight was 90 kilogram, that was the mean, and the mean body mass index was 29. The serum uric acid was 7.5 milligrams per deciliter, with the highest serum urate level of 12.2 milligrams per deciliter. So PRX-115 was well tolerated. All randomized patients completed the study. There was 1 patient that experienced an anaphylactic reaction immediately within 6 minutes following the commencement of the infusion. The reaction was resolved, and he actually continued in the study [ for ] follow-up safety assessments. No other serious adverse events were reported during the study, and no related adverse events were repeated for the higher doses, cohort 6 and 7. How about immunogenicity? You heard about [ tune ] for Fabry. And here, preliminary antidrug IgG antibody assessment reveal 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. And taking under consideration that this is a single-dose study, it would need to be evaluated, the immunogenicity, following repeated dosing of the drug. And here, you can see the [ mean ] PRX plasma concentration on the Y axis over time, over the 85 days, almost 3 months. And you can see that exposure of PRX-115 increases with increasing dose. And detectable exposure beyond day 56 is observed in plasma of treated patients in the cohorts 6 and 7, which is the higher doses. And here, you can see the [ mean ] uric acid concentrations in milligrams per deciliter in the Y axis. Again, the x-axis is over time, 3 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 a 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. And nicely, it lasts beyond the 4 weeks. So 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, and the patient continues in the study for safety assessment. No other serious adverse events were reported. And interestingly, no adverse events report in cohort 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. And regarding PD, administration of PRX-115 leads to a rapid reduction of plasma uric acid, and the effect of PRX-115 on plasma uric acid levels and duration of response is dose dependent and last beyond 4 weeks. Cohort 8 completed recruitment and now is in the stage of follow-up. So thank you so much for your attention. Thank you.

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 2 approved drugs. One is Elelyso for Gaucher's and Elfabrio for Fabry. We have a platform, ProCellEx, which is validated. We express complex human protein for plant sales in suspension. This is approved by the EMA and the FDA, and we will continue to use this platform. We have strong partnerships with Chiesi, Pfizer. And we have an agreement with the Brazilian government, where we market Elelyso in Brazil. We gained -- Protalix, it's a 30-year-old company. And along the years, Protalix has a long learning curve and accumulated a lot of experience with regard to clinical and regulatory affairs experience with the genetic space. And we have a small development pipeline, which we elaborated earlier about the gout program. And we have some earlier preclinical program that we will update you when due. Protalix has 3 streams of revenues, from Chiesi, from Pfizer, from Brazil. And the intent is indeed to grow these revenues and finance this company going forward. Overall, I would just say that certainly, we have achieved in the last few years and the day 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 2 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 2, 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, and 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 a approved for Gaucher's disease. It's a rare lysosomal storage disease, 1 in 40,000 people. As mentioned, expressed to our system, the standard of care in Gaucher's disease [ our ] ERTs, there are 3 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 [ face ]. We operate through a license from the Brazilian government, and we sell between $10 million to $12 million a year, with about 25% market share, with about 900 to 950 diagnosed and treated Gaucher's patients in Brazil. With regard to Fabry and Elelyso -- [ Elfabrio ], sorry, so actually, this was the second time the FDA approved a product from Protalix based on our platform. Fabry is an X-linked lysosomal storage disease, 140 to 60,000 men. The standard of cares 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 2 weeks ERT, which is -- there is an infusion. Replagal is approved everywhere outside the U.S. Galafold is chaperone technology via [ Mikus ], which was approved 6 and 8 years ago in the U.S. and the EU. And Elfabrio, as discussed, was approved recently, and 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 in -- originally in Italy, they are spread worldwide. Chiesi as a group, they set about $3 billion in sales. They've established their rare disease business about 4 years ago. They bought, licensed a couple of small assets. They invested heavily in Elfabrio, in this program. Now post the approval, I think the risk is partially reduced. And still, a lot of efforts are being put into it. They bought Amryt about 1.5 years ago. So they put a lot of resources and thoughts into it. And 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, and they do well on the market, and I'm sure we will be pleased going forward as well. About the 115, I think there are two slides here that I think are a bit repetitive, so 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. And now we are in 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 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. We -- 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 Protalix platform, as well as explore and prioritize certain rare disease indications, and it would 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, bring an edge to the platform in addition to what we have so far, together with the chemical modifications, which are actually the PEG that we have with Fabry and with the gout program and hopefully, additional communications. Now to further explain how we are, I would say, sharpening our focus, so first of all, we have conducted this, I would say, systematic analysis to identify potential key areas of focus in the rare disease space, both genetic and nongenetic opportunities. We will prioritize rare renal diseases as the core of Protalix development pipeline. We will address high unmet needs of renal diseases, which include very specific sub-indications like ADPKD, the Alport syndrome, et cetera. And in -- and second, with respect to BD&L, I think we will be -- we will have -- 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 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 2 drugs to the market. So in the next few years, we plan to focus into the pipeline and hopefully, to have 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 BD&L. Again, I would say, smaller ones has 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 a fully integrated end-to-end capabilities and then with the 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 3 streams of revenues, from Chiesi, from Pfizer and from Brazil, and 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 1. Actually, it's in 2 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 3 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 -- actually, in the next few days, I will mark 5 years in Protalix. And over the last 5 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 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 [ PEGulation ]. So I think this sums the journey that we have done now. We have a lot of work ahead of us. And 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. And 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, and I think it works well. So thank you very much. So Lauren, I think if there are any questions to know me or [ I'll ask myself ], please.

Yes. So thanks, everyone. We'll now be taking questions, live questions here from anyone that has them. So if you have a question, go ahead and raise your hand, and then we'll bring over a microphone so that you can your questions. Any questions?

Jeff Levine, OMERS Life Sciences. Thanks for the presentations, both Dr. Linhart and Dr. Schlesinger. Maybe a question for Dr. Linhart on thinking about where you would use Elfabrio in your patient population, what's kind of low-hanging fruit?

So I will describe my own personal experience with Elfabrio because we were part of the clinical trials running actually 3 of them in our center, altogether 12 patients, all of them were tolerating the treatment very well. All of them are stable. 3 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 sort of drugs on the market. And they report clinical stability and an improvement, of course, that you can't never say this is not a bias induced by being a part of the clinical trial. We see it with different drugs. But our patients are feeling very well on the therapy, and we have the impression that if anything, they are getting stable. So the problem of Fabry disease, it's a very slowly evolving disease. So sometimes you need to wait for a significant amount of time to see whether the biological phenomenon is not prevailing over the treatment. And 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 5 years as being included in 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. But 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 result -- 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 we 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. But having this 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. 1 in 40,000 was an estimate based on the classical disease. But we are trying. We are still discovering more and more patients, especially among cardiac patients that are having this later-onset disease. And 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. So we are now estimating that the clinically significant disease is occurring in 1 in 10, potentially 1 in 15,000 maximum. So the problem is much larger. And 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 or known. 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 and 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 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. And 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.

Hello. This is Daby Carreras from Spartan Capital. I'm 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 overall cash position, stock price, I'm very encouraged.

So thank you. We have -- we discussed in [ 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 solution, which address real unmet needs. And indeed, the company is, you can see, 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 year, the company has strengthened itself from a business point of view. I mentioned earlier, we can finance our operation, going forward, inclusive of the Phase II of Fabry -- of gout, an additional earlier-stage program, by ourselves. So -- and people can see it on the market. We did not raise any money recently. We'd not take advantage of certain events. This is not the intent.

Any other questions?

Two questions that are related actually to the gout project. What -- 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?

I'll start with KRYSTEXXA, but this is me, Schlesinger. I don't know if this is to my hypothesis. So when they did the pivotal trials, they didn't do such a good job. And then they looked -- and they analyzed their data, and they took 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 and -- KRYSTEXXA. An IV infusion is around $20,000 to $28,000. And it's every 2 weeks. So insurances don't always okay it, although it works. That's the problem. And 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 1/3 of patients. In Europe, maybe less tophi. It's different -- a little bit different diseases. And gout is not treated very well. And the market is huge for now. So it's a very large market. It's over diagnosed, under-diagnosed. In Asia, very common. So 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. And I just moved to Utah. And there, we have the fourth largest community of Pacific Islanders, 15% of them have gout and very severe gouts. I'm seeing very young patients with these tophaceous deposits very early in life, 20. We've seen very severe gout. Yes. 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 yes, it's gradually penetrating into the market in the -- 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 1 or 2 days. It's -- I assume, to have $100 million revenues, you need to cross the 15% market share. We are pretty much positive that we'll do it, of course, and we estimate that we'll 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.

So it will be very short. So thank you, everybody, for coming and participating through Zoom 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.