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

Okay. So good morning, everyone. I would like to welcome you, those who made the effort and attend in person and to those who are participating virtually in today's investors event. It was a long successful journey that actually matured last month with 2 approvals both in the EU and the U.S. with the approvals of Elfabrio. We plan to continue this journey, going forward, and we hope to build a much more significant company. I would like to take this opportunity and thank the principal investigators and their teams, the Fabry patients and their families for their contribution and support in this journey and our achievements. A special thank you is also dedicated to our commercial partner, Chiesi, in particular to Giacomo Chiesi, who heads the Global Rare Disease division at the Chiesi Group, for their strong support and collaboration. Today, we are hosting Dr. Ankit Mehta, who participated in all of our clinical trials from the very beginning. Dr. Mehta will discuss Elfabrio's clinical program. And in addition, we will host Mr. Giacomo Chiesi, the Head of the Chiesi Global Rare Disease division, as I mentioned, and he will discuss the Chiesi Group and their preparation for the launch of Elfabrio. Dr. Mehta could not make it in person, unfortunately, due to weather condition, and his flight was canceled. But as you can see, he is on the screen connected to us. We will conclude the presentation with my presentation about Protalix's future and strategic plans. There will be a Q&A session after each of the presentations, both of Dr. Mehta and Mr. Chiesi. And of course, I urge you to participate with questions and answers. So thank you, everybody, for joining again. And please, Dr. Mehta, the stage is yours.

Thank you. Thank you for that introduction, and thank you, everybody for coming. As you've heard, my flight got cancelled, and so we're doing this online instead of actually doing it in person. If there are any A/V issues, please interrupt and let me know, so we can address them right away. Okay. So with that, I'm going to get started. So I'm going to talk about some of the data that led to the Elfabrio clinical approval, and we'll discuss it in detail as we go on. Next slide, please. So in the interest of time, I only am going to talk about certain parts of the clinical development program. There's a lot more information available with the full prescribing information on the FDA's website as well as the approval packages. So I refer you guys to these resources for any further information. Next slide, please. So that's me. I have been involved in Fabry for a while. Before that, actually, let's talk about -- I went to medical school in India. I did my residency, internal medicine residency and nephrology training at Baylor University Medical Center in Dallas. And then I'm here at Baylor University Medical Center involved in education for -- of residents, fellows, even medical students. I've been here for a while now, almost 20 years, and I've worked as a nephrologist with Dallas Nephrology Associates. Today's presentation has nothing to do with Dallas Nephrology Associates or Baylor, it's about my experience and my interest in patients with Fabry disease, and that's what we're going to talk about. Next slide, please. I'm going to have this up for a minute, but taking to the next slide. So let's start with a little bit of background about Fabry disease. Fabry disease is a multisystem progressive, X-linked disorder. Originally, it was thought that the X-linked disorders only affect men, and that is completely wrong. There are plenty of women who have Fabry disease and symptoms and disease progression from Fabry problems as well. The only difference is women are a lot more variable in their presentation, sometimes later in presentation and variable organ manifestations than men in Fabry disease. The basic genetic problem in Fabry is a defect in the GLA gene. This GLA gene actually quotes for an enzyme called alpha-gal. Alpha-gal enzyme normally breaks down lysosome of products in the cell. So when a patient with Fabry disease doesn't have any alpha-gal enzyme or makes them misfolded alpha-gal enzyme, it cannot break down the lysosomal byproducts and they accumulate. The 2 most commonly looked at are Gb3 and lyso-Gb3. Gb3 and lyso-Gb3 tend to accumulate in patients with Fabry disease. This accumulation leads to a multitude of problems, and it's shown in a graphical format on the right. But symptoms typically start in childhood, with neuropathic pain in the peripheral nervous system has involvement. The heart is involved and the patients start having arrhythmias, thickness of the left ventricular, it's called the heart muscle, left ventricular hypertrophy is one of the manifestations. In fact, the commonest cause of death in Fabry disease is an arrhythmic cardiac event. In the central nervous system, patients start having strokes earlier in life. I'm talking about strokes in 20s and 30s. And then if we look with an MRI, you would see white matter lesions. In the GI tract, many Fabry patients will have episodes of abdominal pain and diarrhea, sometimes nausea, vomiting. And in the kidney, these patients started to have -- start having protein in the urine earlier in life that progress to chronic kidney disease and end-stage kidney disease, needing transplant or dialysis later in life. There are over 1,000 mutations in the GLA gene. And the prevalence is quite variable, depending on what study you look at, but it's thought to be about 1 in 40,000 to 1 in 60,000 in men. So it's a rare disease. When Elfabrio was being developed, 2 enzyme replacement therapies were already available to our Fabry patients, and these are agalsidase alpha and agalsidase beta. Algasidase alpha is not available in the U.S., but algasidase beta is available in the U.S. Next slide. So let's talk about Elfabrio itself. So I may frequently go back and forth between pegunigalsidase alpha and Elfabrio and unigal, they are all the same chemical compound. So how is it made? So if you look at the graphic on the right, you see that there are 2 alpha-gal subunits that are linked covalently. So one of the advantages here is when you linking them with short PEGs, you are increasing the half-life. These alpha-gal subunits are actually expressed in [ plant ] cells, and that PEGylation actually increases the half-life, and I'll show you some pharmacokinetic data that shows a longer half-life. The [ type ] with the longer half-life is you would have a steady concentration of the drug, and that will help with first better tissue penetration and outcomes from tissues organ's standpoint, but also immunogenicity impact. So the PEG-ed molecules would cover some key epitopes on the alpha-gal subunit. Epitopes are areas that induce antidrug antibodies, and they lead to hypersensitivity. So having these PEGs would cover up those episodes and the [ totes ] that would help with immune tolerance over time. Even in patients that have a pre-existing antidrug antibody, covering these epitopes would be helpful. This demonstration initially started in Phase I/II studies and -- where it was shown that human blood samples have quite a bit of substrate reduction. And in kidney biopsies as well, there was substrate reduction, and I'll show you some of that data. Next slide, please. So here's the clinical development program for pegunigalsidase alfa. It starts on the left side with the Phase I and II studies. Phase I and II are open-label studies that are [ naive ] Fabry disease patients. And multiple doses were looked at, 0.2 milligrams per kilogram, 1 milligram per kilogram and 2-milligram per kilogram, every 2 weeks. The duration for -- was about 12 months, and the primary endpoint was safety. So Phase I and II, the goal was looking at safety events and dose finding. There were 18 patients enrolled in this F1, F2 or F3 Phase I and II studies. Next column is BALANCE. The BALANCE study is a Phase II -- Phase III. It's a double-blind, randomized, active control study. And the dose that was looked at was 1 milligram per kilogram every 2 weeks for 24 months. The primary endpoint in BALANCE is an annualized change in GFR or the slope in [ eGFR ] kidney function at 24 months. And there were 77 patients that were in the intention-to-treat analysis. The study after BALANCE is BRIDGE. BRIDGE is another Phase III study, but this is an open-label. 1 milligram per kilogram every 2 weeks for 12 months. And I'm going to discuss BALANCE and BRIDGE as well in subsequent slides. The primary endpoint in BRIDGE was safety with 22 patients in the study. The last one on this slide is BRIGHT. BRIGHT is also a Phase III open-label study, the dose that was studied was 2 milligrams per kilogram every 4 weeks for 12 months. The primary endpoint was again safety, and there were 30 patients in this study. So if you think about it, there are over 140 patients with up to 7.5 years of follow-up that have been studied. Over 400 patient years of exposure at 1 milligram per kilogram every 2 weeks, while over 110 patient years of exposure at 2 milligram per kilogram every 4 weeks. And I know we talked about a bunch of different dosing, but I want to clarify that the approved dose of the drug is 1 milligram per kilogram every 2 weeks. Next slide, please. So this is the timeline of development for pegunigalsidase alfa. And from 2012 to '18 are the Phase I and II studies, and these are 18 patients, and these are, again, in [ naive ] patients. I mean enzyme-naive patients with Fabry disease. And these studies are dose finding and looking at safety. BALANCE was enrolled between 2016 and 2022. There's a Phase III study, randomized control trial, active control arm, and we're going to discuss that in the next few slides today. BRIDGE was between 2017 to 2020. Again, a Phase III switchover from agalsidase alfa that was done outside of the U.S. BRIGHT was Phase III, with 30 patients from 2017 to 2021. All the regulatory applications were made in 2022, and the FDA approved as well as the EMA approval was earlier in 2023. Next slide. That's cute. So let's talk about the Phase I and II studies. I know this is a busy slide, so I will help you guys walk through this. So a reminder, this was done in patients that were ERT naive or patients that did not receive ERT for at least 6 months. So on the top left, we start with pharmacokinetic data. The 3 doses that we looked at were 0.2 milligram per kilogram, 1 milligram per kilogram and 2 milligrams per kilogram. And as you can see with the graph, there is enzyme activity at all 3 doses up to 14 days, so the X-axis as days after treatment, and there's enzyme activity for 14 days. The half-life calculates to about 80 hours. Okay. Let's look at the middle column, the pharmacodynamic data. The first part is reduction of Gb3 in kidney. So these patients had kidney biopsies before. And after 6 months of treatment, and there was a significant fall in the Gb3, which is one of the byproducts and accumulates in patients with Fabry disease. There was also a reduction of plasma lyso-Gb3. So if you check lyso-Gb3 levels in the blood, there was a significant drop along the study. And on the right side, you see clinical activity data. The top part shows eGFR values over time. And the annualized eGFR slope at 16 months was about 1.6 mL per minute for 1.73 meter square per year. So I want to take a step back, most adults will lose about 1 mL per year of kidney function on an average. And so in this study, there was about a loss of 1.6 mL per year when you combine men and women together. One more caveat up there, most of the patients were actually enrolled for about 3 years. In the last 2 years, there were not as many patients. But nevertheless, data is up there. There was also a cardiac data that I'm not sharing in the interest of time, that showed the left ventricular mass was stable. So from a safety standpoint, most treatment-emergent adverse events were mild to moderate in severity, and they were unrelated to pegunigalsidase alfa. One patient did have a severe hypersensitivity reaction, it was a bronchospasm during the first infusion and was withdrawn from the study. [ ADAs ] were infrequent and trends in 3. So the summary of these Phase I and II study was that long-term use of pegunigalsidase alfa provided continued benefits in patients with Fabry disease. Next slide. So that brings me to BALANCE. BALANCE is a Phase III randomized, double-blind, active-controlled study, and the goal was to assess the safety and efficacy of pegunigalsidase alfa in adults with Fabry disease with deteriorating kidney function. So the main inclusion criteria of the study is not only patients with symptomatic -- adults with symptomatic Fabry disease, but adults with symptomatic Fabry disease that had a rate of decline of kidney function that was significant. And what I mean is the rate of decline was worse than 2 mL per year. And these patients had to be compliant on treatment prior to inclusion in the study. So they were on treatment with algasidase beta for at least a year and 80% compliant over the past 6 months before they were included. The main exclusion criteria are also listed up there. The biggest one is patients with hyperfiltration. And what I mean by that is if you have a screening GFR, kidney function between 91 and 120 and you have a historic kidney function greater than 120, then you're excluded. That's because of the hyperfiltration of kidney that's detrimental. The second group that was excluded as patients with urine protein/creatinine ratio greater than 0.5 gram per grams which basically means you have significant protein in the urine, and you've not treated with the standard of care, which are [ ASMRO ], then you're excluded. So investigator started with about 127 patients that were randomized 2:1, so 2 patients getting pegunigalsidase alfa while 1 getting agalsidase beta. And there were 78 patients that were randomized, 53 to the pegunigalsidase arm and 25 to the algasidase arm. One of the patients in the pegunigalsidase arm withdrew consent before the drug was given, so the number of patients that were exposed to treatment was 77, 52 in the pegunigalsidase arm, while there were 25 in the agalsidase beta arm. These patients got the treatment for about 24 months. And then intention-to-treat analysis, there were 77 patients that we're going to discuss the results. Next slide, please. So the top left shows eGFR values over time. Along the x-axis is the study duration, so there are weeks. And you don't have to be a statistician, but the 2 curves or lines are basically overlapping each other, right? The pegunigalsidase alfa line is in blue, while agalsidase data line is in orange. When you actually do the statistical analysis and calculate the slope of 2 lines, both of these lines, and see what is the difference between them, the difference in this slope is negative 0.359. While the confidence intervals for this difference, 95% confidence intervals, range from negative 2.4 to positive 1.7. And since the confidence intervals crossed 0, there is a statistical difference between these 2 groups. Next slide. This shows plasma lyso-Gb3 concentration over time. Again, pegunigalsidase is in blue and agalsidase beta is in orange. And just to orient you guys, again, time is on x-axis, it's in weeks. The boxes are [ medians ], while the lines, the whiskers, are quartiles. And the outliers are these dots that you see. So first plans, these dots, the outliers, [ both ] have a significant influence over this data. So that's the first takeaway from the slide. But to me, there's overlap observed in the plasma lyso-Gb3 concentrations in both the arms, right? If you actually do statistical analysis, you see that the Elfabrio arm, the pegunigalsidase arm had a slight increase of 1.15 nanomoles with the lyso-Gb3, while the agalsidase data arm had a small drop of 1.5 nanomoles of the lyso-Gb3 concentration. Next slide. Let's talk about the safety. So first, I'm going to go over the discontinuations. There were 5 patients in the unigal arm that discontinued. One withdrew consent before first infusion. 4 withdrew throughout the study, 2 due to adverse events, 1 of which was actually drug-related. One patient in agalsidase beta arm discontinued. If you look at treatment-emergent adverse events. I'm going to draw your attention to the right side of the table and the second row, which says treatment-emergent adverse events related to drug. So if you look at the pegunigalsidase alfa arm, out of the 52 patients in that study, 21 had treatment-emergent adverse events, and there were 42 events. And then you move over to the agalsidase beta arm, out of the 25 patients in the study, 11 patients had treatment-emergent adverse events, and there were 76 events in those patients. There were no deaths in the study. 1 patient, actually in the unigal arm, had a serious treatment-emergent adverse event, they had a hypersensitivity reaction to pegunigalsidase alfa infusion. The bottom table on the right shows infusion-related reactions. And if you look, most infusion-related reactions are mild to moderate in severity [indiscernible] table. There was 1 severe infusion-related reaction in the pegunigalsidase alfa arm, and that's the patient that had hypersensitivity reaction. As planned, there was a significant drop in premedication use in both the arms at 24 months. That was the design of the trial. Next slide. So let's look at the immunogenicity assessment. Again, I know a busy slide, but I'm hoping I can walk you guys through it. So the first point I want to make here is almost 30% of patients in both arms had pre-existing antidrug antibodies, so 30% starting off the bat at pre-existing antidrug antibodies. And if you look at the top right, that's the pegunigalsidase alfa, a graph. The bars represent what happens to antidrug antibody concentration over time. So they start off with 35% patients that were [ ADA ] positive and end with about 23% that are [ ADA ] positive. And if you look at the line, the line actually in that top right shows neutralizing antibodies, while neutralizing antibodies dropped from 33% to 15% at the end of the 2-year study. The bottom right shows similar data for agalsidase beta. So the bars again show total IgG antidrug antibodies, and they change from 32% to 26% over the course of 2 years, while the neutralizing antibodies is a line that changed from 28% to 26% over the course of 2 years. If we look at just treatment-emergent [ ADA ] positivity during the study, it was about 12% at pegunigalsidase arm and 20% in agalsidase beta arm. Next slide. So here are some summary statements from the BALANCE data. First, from an efficacy standpoint of kidney function, there were similar eGFR values in the 2 treatment arms. And if you actually do the annualized eGFR slope, statistical analysis suggested that there's no difference between the 2 arms. From a pharmacodynamic standpoint, if you look at lyso-Gb3, again, there was a lot of overlap in the values of plasma lyso-Gb3 between the 2 arms. There was a slight increase from baseline in the Elfabrio arm and a decrease in the agalsidase beta arm. These changes were not thought to be clinically significant. From a safety and tolerability standpoint, it's generally consistent with other enzyme replacement therapies. So I want to say from an infusion reaction and treatment-emergent-adverse event standpoints, it's [ still very ] consistent. There was 1 patient that had a hypersensitivity reaction in BALANCE, and I've talked about that when we were discussing that. From an ADA standpoint, antidrug antibody standpoint, most patients coming into the study had significant -- 30% of them have antidrug antibodies, and the immunogenicity profile is very comparable in the 2 arms. I want to remind everybody about the discontinuation. The pegunigalsidase alfa arm had 5 discontinuations, 4 withdrew their consent, 1 due to a severe hypersensitivity reaction, but the agalsidase beta arm had 1 discontinuation. At the completion of the study, 97% of the patients actually went on to an open-label pegunigalsidase alfa extension study for another [ 16 ] months. Next slide. So I only have one slide about the BRIDGE. First, BRIDGE was a switchover from agalsidase alfa to pegunigalsidase alfa. And just as a note, agalsidase alfa is not approved in the United States and the study was actually done outside of the United States. So my European colleagues are quite excited about this data. So the left side of the graph shows what happens to lyso-Gb3 over time in these patients that were switched from agalsidase alfa to Elfabrio. There's a 31% drop in lyso-Gb3 at 12 months, 31.5% drop to be exact. That's significant. In the middle, you see what happens to eGFR annualized slope. These patients that were on agalsidase alfa had an average loss of 5.9% per year -- 5.9 mLs per year of kidney function. And at 12 months, that changed to 1.2 mL per year. So there's a significant slowing in rate of loss of kidney function. From a safety standpoint, most treatment-emergent adverse events were mild to moderate, again, in severity, and all AEs were transient. 2 patients withdrew from the treatment due to hypersensitive reaction, these resolved following the withdrawal, and only 2 patients with preexisting ADAs were positive for neutralizing antibodies. Next slide. So here are the main conclusions from the overall clinical program for Elfabrio. First, it's approved in the U.S. and EU. This approval is based on the clinical program that included over 140 patients that received at least 1 infusion of pegunigalsidase alfa. And some patients have been on treatment for over 7.5 years. From an efficacy standpoint, there's a substantial reduction in Gb3 deposit in the ERT-naive Fabry disease patients. When you look at kidney biopsies at 6 months compared to baseline -- I actually wanted to put up a slide with kidney biopsies that I figured that it might be too nerdy and the only people who would care about it would be kidney doctors like me. And so we decided not to include the kidney biopsy pictures here, but you can look at the data and see yourself. From an efficacy standpoint, the eGFR slope showed stability and high similarity between the 2 arms. When you compare pegunigalsidase alfa to agalsidase beta, that's the BALANCE data. From a pharmacodynamic standpoint, treatment actually resulted in reduction of plasma Gb3 -- plasma lyso-Gb3 in ERT-naive patients, and I showed you that data earlier. And when you look at lyso-Gb3 in agalsidase alfa or agalsidase beta [ pretreated ] patients then switching to Elfabrio, the effect is variable. From an immunogenicity standpoint, there's a low ADA prevalence and potential to become ADA negative when treated with Elfabrio, mostly existing ADAs in ERT pretreated patients enrolled in the study when neutralizing. And from a safety standpoint, it is similar to what's out there, what's available for other enzyme replacement therapies. Currently, there are about 100 patients still active in open-label extension studies with pegunigalsidase alfa. Next slide. So I -- this is taken from the prescribing information for Elfabrio, and I want to just leave up the indication and some important safety information out there for everybody to review. Full information seen in the packaging side. Thank you. Any questions? Anything I can help address.

Thanks for the great presentation. A few questions from us. So how would you characterize some of the inherent issues associated with standard of care? And how Elfabrio could potentially address some or all of the issues? So that's the first question. And then secondly, with respect to long-term safety profile and based on the severe hypersensitivity reaction that is observed, so what we should expect from real-world patients as they gain access to treatment? That's the second one. And thirdly -- sorry, a lot of questions. With respect to comorbid status, so I wanted to know how many drugs does a typical Fabry patient takes? And then how taking Elfabrio would meaningfully alter their medication regimen?

Okay. So I'll start from the last one. So comorbid status, how many drugs does a typical Fabry-disease patient take? I'm going to -- I mean this is completely on my clinical assessment. I don't have any solid data to point you to. But in my practice, I would say, probably 5 to 7 drugs. But you have to remember that Fabry disease is a lifelong disease. And so I have some very young adults with Fabry disease who are not on many other drugs and have some older adults with Fabry disease who are on multiple other drugs, just like general population. So I would say, it increases over time as we all get old and we get high blood pressure and diabetes and all the other illnesses as well. So yes. So the other prior questions were how many other drugs? And so -- I'm sorry, what were the other questions? One was about...

Hypersensitivity.

Hypersensitivity reaction, yes. So the -- I mean the risk with hypersensitivity reaction remains, there is no doubt about it. It's showing up with Elfabrio and other studies like old studies. There is a risk for hypersensitivity reaction. We just have to be careful about it with infusions. Current enzyme replacement therapies that are out there also have that risk for a hypersensitivity reaction. And the way I tell my patients as this is an infusion and with every infusion comes to risk, and infusion reaction and hypersensitivity reactions are real, and we have to watch out for that.

Thank you. Any other questions? Chuck, any...

Some of the patients in the studies were able to go from 2-week infusions to 4-week infusions. Was that an incremental change, 2 to 2.5 weeks to 3 weeks to 4? And why did it stop at 4?

No, let me clarify that. There was a different study that had every 4-week infusion, and that was an open-label study. Just to look at safety data, most infusions are every 2 weeks and the FDA-approved dose is also 1 milligram per kilogram every 2 weeks. That there is -- we did not do an incremental infusion dose or infusion duration change study.

Any other questions? Okay.

All right. Thank you, everybody. Following me, I have Giacomo Chiesi, who's going to share some of the things about Chiesi. So Giacomo, take it away.

Mehta, great to see you today. Hope you're doing well. All right. So good morning or good afternoon, everyone. It's -- Dr. Mehta's presentation is always excellent. So it's a tough act to follow, but I'll do my best. I am Giacomo Chiesi, and I lead the Chiesi Global Rare Diseases, which is a business unit of Chiesi Group, which is a private company. We're now going to zoom out a little bit from the Fabry talk that we just had, in the Elfabrio talk primarily because we're coming from the assumption that a lot of people here in the room are not familiar with Chiesi as a company. We think Chiesi a significant company, and therefore, we're going to start by giving you a background about the company itself, the organization, then zoom in into the business unit and then speaking a little bit about highlights and our intentions about Fabry disease. So on the next slide, I'm going to cover the basics of the company. Company is a family business, 100% owned by the family. We are -- we've been in business for 85 years now. Company was founded in 1935. We've always been very focused on the patients, very dedicated to the patients. As a family business, we have a long-term orientation. I'll get back to it in a minute, where I'm also going to speak about the fact that Chiesi is a Benefit Corporation and a B Corp. We have about 7,000 employees today in the company, with a significant focus on research and development. A lot of our treatments have been developed in-house at Chiesi. But lately in the last -- about 10 years, we've also devoted a lot of our efforts to acquisitions, partnerships and inorganic growth. Company is divided into 3 main strategic areas, which you can see the pic at the bottom of the slide. AIR, RARE and CARE, that's how we call ourselves. AIR is respiratory treatment, RARE is what we're going to be speaking about, and CARE is essentially specialty care treatment and acute cardiovascular therapies. So in the next slide, I'm going to focus a bit on the geographical presence. Sorry about the format there, but I'll walk you guys through the numbers. So Chiesi had about $3 billion in sales in 2022, EUR 2.8 billion, depending on your exchange rate, but it's about $3 billion. We are a global company, with a direct presence in more than 30 countries and an indirect presence in about 70 countries via distributors and other partnerships. As I mentioned, the company has about 7,000 employees. We continue to grow profitably with about 30% in EBITDA. And the breakdown of the therapeutic areas is about 70%, 75%, respiratory, about 12% rare diseases and the [ balances ] represented by specialty care. So in the next slide, you'll see the focus on sustainability. We're a Benefit Corporation, and we're also a certified B Corp. To bring this down and make it simple, we believe strongly in sustainability. We believe that it makes a lot of sense to be a good citizen. And therefore, in 2018, we obtained the certification of Benefit Corporation and B Corp with collaboration with B Lab. This means that we adjust all of our processes and decision-making in pretty much everything that we do to high sustainable standards, which means transparency, which means accountability. And it also means for us that we want to be sort of a good citizen. So we -- and we take things very seriously. So we hold ourselves accountable to high standards, which means for us, also measuring the impact on social and environmental level that we have on society and on the communities that we impact. Not only we measure ourselves, but we also want to set the bar higher and higher. And therefore, we continue to work with B Lab and other organizations to score ourselves against specific sustainability standards. In the next slide, I'm going to continue on and speak a little bit about the focus that we have in the 3 different areas in rare diseases. Specifically, rare diseases in 2022 represented about 12% of the company's turnover, the overall revenues. We expect that in 2023, this is going to be a much higher percentage, also thanks to the recent acquisition of Amryt Therapeutics that we completed in April this year. If you take a look at the rare disease products, you'll see many of them, including Elfabrio, front and center. But you also see the legacy Chiesi products, which are so meaningful for us, including respiratory franchise [ UpTop ] with Foster and Trimbow as well as some of the CARE products at the bottom. So in the next slide, we now transition and speak about the business unit, which I lead. And in the next slide, we get to the mission. We launched Chiesi Global Rare Diseases 3 years -- actually 4 years ago now, almost. Actually no, 3.5 years. And initially, it was a very small endeavor. We are now about 700 people in the organization. The DNA of the business unit as well as the company is to be really committed to the patients and be there to always make a difference for the patients. And the way we see it is that we want to make a rare difference in the lives of people with rare diseases. As a family business, we will continue to deliver innovative therapies and solutions for people with rare diseases, respiratory disorders and other disorders that we focus on. We will also continue to focus on equal access because we're going to want to provide patients with the therapies regardless of their economic situation. We're very passionate about what we do. We're compassionate about all the individuals that we serve. We serve people humbly. First of all, we listen. We sit down, we listen, we understand, we take time to really deepen our understanding of the needs of the community. We think that we're privileged, we deem ourselves privileged to serve the patients, and we aspire to continue to make a difference for them and to humbly support the patients through other journey. We also want to sit down and learn from their ability to face their condition every day. We're committed to removing the obstacles that separate the patients from the therapies and we're also committed to providing the patients and the community with more and more tools to deal with their conditions. We're a highly entrepreneurial company, and this is coming out of a family, somebody is not going away any time soon and we have a highly entrepreneurial spirit. We want to continue to make a difference. It's very simple. So in the next slide, please. We now focus on the Global Rare Disease leadership team. And this is a team of leaders that we assembled. A lot of them came from Chiesi, a lot of them came from other companies, including companies that we acquired. We think we've done a good job in the last 3 years of putting together our team that has a good mix of DNA of people with a lot of seniority, a lot of capabilities coming from different companies. Some of them come from big pharma, others coming from specialty pharma, and others are legacy cases. So a good mix, we think, overall. In the next slide, we turn to, again, formatting issues. Anyway, so we turn to a little bit of the history of Chiesi Global Rare Diseases. We set up the business unit about 3.5 years ago, and we've gone through a number of inflection points. A lot of these inflection points were related to acquisitions. I mentioned the acquisition of Amryt that we completed 2 -- about 2 months ago. But I can also focus on the many inflection points from a clinical and a regulatory standpoint. I'll focus on a couple of them. One is related to the completion of multiple clinical trials that Dr. Mehta alluded to or describes -- actually well-described, elegantly described in his presentation, with pegunigalsidase alfa in collaboration with our partners at Protalix, with whom we obviously have a great relationship. We go back a long time with Dror Bashan and his team. But we also were able to take Lamzede and other enzyme replacement therapy through FDA approval recently. Lamzede was approved for alpha-mannosidosis and other lysosomal storage disorder in February this year by the FDA. And another example relates to our presence in thalassemia and sickle cell disease, where we have been active for many, many years now in commercializing Ferriprox, which is an iron collection therapy. That was also approved with a new formulation, twice-a-day formulation by the FDA in 2020. And then we extended -- several months ago, we also extended the indication to sickle cell disease. We're going to move to the next slide, hopefully, no formatting issues in the next one. Here, we just wanted to provide everyone with a glimpse of the Global Rare Disease business unit at Chiesi. Essentially, the business unit can move very fast and can be competitive in clinical development and regulatory development, also in acquisitions and integration because it's essentially self-contained. It includes all the important functions that allow an organization to develop therapies, take them through regulatory approval -- clinical trials first, regulatory approval and then all the way to the patient. So we're fully integrated. We have everything that matters from patient [ efficacy ] to medical affairs to marketing, market access, commercial operations, patient services. So it's a fully fledged rare disease organization. And with full P&L responsibility and a lot of managerial latitude, these are the assets that allow us to move expeditiously to make a difference in the life of people with rare diseases. So in the next slide, we're going to transition to the products. And this is public information. So a lot of you are hopefully familiar with this, but there have been a few changes recently in virtue of the recent Amryt acquisition. So I'm not going to spend too much time on this, but just suffice to say that we're focusing on a few areas. The first and foremost is [ imbernerasa ] metabolism or actually lysosomal storage disorder. I mentioned Lamzede. Elfabrio is obviously what we're discussing today and then [ processes ] for which we have the ex-U.S. or ex-North America rights from Horizon Therapeutics. I mentioned Ferriprox under hemato immunology. We also commercialized another enzyme replacement for ADA-SCID named Revcovi. We have a partnership with Santhera on Raxone, which is an [ oral ] formulation for [ Leber's ] optic neuropathy. We have recently acquired Amryt Therapeutics, as I mentioned, which takes us also to endocrinology with a few specific therapies as well as one [ dermatological ] treatment. So hopefully, that provides a good overview for everyone on products. And then moving on to the next slide, I'm now going to speak a little bit about patient advocacy. We have a lot of very well-established relationships with patient advocacy groups, when it comes down to lysosomal storage disorders. And in particular Fabry disease, we have service relationships with pretty much all the organizations around the globe and also in the United States, including FSIG, National Fabry and also Canadian Fabry and associations in many other countries, certainly including Italy. I didn't mentioned that we're headquartered in Italy, and it's also where I am connected from, today. So moving on, we're now going to speak a little bit more specifically about Fabry disease. If I'm not mistaken, hopefully the slides are going to come up in a second. Thank you. So I'll just give a few highlights because I think Dr. Mehta described the product and the clinical development very clearly. So certainly, cannot do a better job than he has done. And there are 3 players in the European market and 2 players in the U.S. market, which you guys can see in the slide. And in the next slide, you'll see sort of the breakdown of what's happening at a worldwide level. And these data, I believe, comes from IQVIA's, so it's basically the best that we were able to get. And the market overview is relatively simple. It's a very interesting market, with more and more patients that we get to see on an every day, on an annual basis, thanks to continued diagnosis as well as a continued penetration of therapies. As we mentioned in the next slide, I suppose the next couple of slides, enzyme replacement continues to be -- actually, can we go back, please. And the replacement continues to be the most widely used treatment. As you can see, the market leader is Fabrazyme, on the left, and -- for worldwide sales. But in Europe, we actually have 2 approved enzymes and -- Replagal and Fabrazyme. And there, we see that actually, Replagal is a larger competitor. We also see that the [ alpha ] is doing well, which is good, obviously, for the patients. And then in the next slide, you'll see the heterogeneity of -- in particular, the European market, where you see that products essentially contain the market in multiple different jurisdictions, and you see that Replagal seems to be the market leader in some markets, whereas Fabrazyme and Galafold are market leaders in others. This just gives you a bit of a perspective on the fact that we're very vigilant as to what's happening on the market as we continue to prepare for the launch and continue to work on the launch activities. In the next slide, we focus also on the pipeline. There's a bunch of competitors that are in clinical trials. Hopefully, this provides everyone with a good baseline about the opportunities for Fabry patients in the future. While there are several approved therapies now, including 3 enzymes in Galafold, there is a number of therapies undergoing clinical trials that you guys see there. It's not lost on us that some of these therapies eventually will come to the market and we'll provide patients with new opportunities. So in the next slide, we focus a bit more on our strategic imperatives. I'll be very brief and telegraphic on this one. There are 3 strategic imperatives for us. The first one is to work with the patients and the community and the healthcare practitioners to build advocates and demand for Elfabrio, which we think is going to be an attractive therapy for many patients. The second one is to prepare the product by working to establish Elfabrio as an attractive therapy. And then the third one is to prepare the payers to ensure that patient access is provided to all the patients without hiccups, any issues. And we're also going to continue to work on the therapy itself via real-world evidence in the new clinical trials in the future. In the next slide, you see a glimpse of our [ branding ] campaign. Now, Elfabrio has been approved by the FDA several weeks ago. So we're starting those specific activities. And then in the next slide, I also wanted to provide you guys with -- actually, let me stop here. We're a very compliant organization in whenever we present our products, we do so by being very balanced in terms of the advantages and the drawbacks of the therapy that we present. And because we're very compliant, we always present the safety information related to the product. So I'll give the audience maybe 15 seconds or maybe 30 seconds to look at this. And then I'll move on. Good. So hopefully, the audience has been able to read through this. In the next slide, we wanted to provide you guys with a high-level perspective on some of the things we're doing with our medical affairs team. In general, there are 4 priorities: The first one is to continue to engage the key opinion leader and continue to generate insights about the disease and about the product, about Elfabrio, per se. We think we're getting a lot of receptivity, a lot of good reception by the community and the medical community and the patient community. We're going to continue that. Additionally, we are establishing capabilities for real-world [ evidence ] this generation. And this is a small group within the company, and we're expanding it right now. We have a lot of interesting ideas in terms of real-world evidence studies that we might want to do in the future. We're also going to continue to guarantee a lot of presence at conferences and a solid publication plan across multiple areas, and we're establishing a very efficient patient services program that will span across multiple services, which I'll cover in the next few slides. In the next slide, we focus on one of these examples. We have continued to engage the community in a continual way. As I mentioned, we continue to receive a lot of good reception by the community and a lot of the feedback, and this is just one example. We have created community surveys and also went into the depth of understanding how mental health is important for patients, particularly patients with rare diseases and particularly patients with Fabry disease. So we ran a mental health survey with more than 400 respondents with the collaboration of some of the groups, included in the slide. And asked patients questions related to how Fabry disease has affected their mental wellness. And we've uncovered that mental health is actually an area of unmet need, based on our survey. And therefore, in the next slide, we'll see how we're planning to help the community and the patients cope with that. So we have struck an alliance with NAMI, which is the National Alliance on Mental Illness, to provide support to families with rare disease in relation to alleviating some of the stress of rare disease, which relate to the emotional impact of a delayed diagnosis, the uncertainty about the treatment options, coping with the symptoms and the complications, the difficulty of maintaining personal relationships and so on, right? And we have come up with an initial estimate that about 62% of the individuals with Fabry disease experience mental health issues, including depression, often as a result of neuropathic pain. So we think that this is a significant need for the patients. And in the next slide, we have decided to commit to help address mental wellness with the rare disease community, and we're providing tools to the patients, they are Mindfully rare. So if you want to go to mindfullyrare.com, you're going to be able to see how NAMI can help you there. So in the next slide, we also focus on Chiesi Total Care. I mentioned the development of patient services, which is -- obviously, they are very important for the patients. And we want to make sure that the patients that will go on to see the Chiesi products, including Elfabrio, will be served with a 360-degree approach. Chiesi Total Care, in particular, has a care team, which is dedicated to the patients and healthcare providers using the Chiesi treatments with dedicated line, phone and fax numbers and so on. We're engaging in this. We're organizing the service via Eversana, which is a specialty pharmacy focused on rare disease and rare disease medications, and you can see some of the credentials there. In the next slide, I'm going to give you a glimpse of what support services are specifically. I mentioned that we want make sure that patients that go on to receive Chiesi products, including Elfabrio, are provided with great services. And these are the examples. So we dedicated program enrollment support with benefit verification, Copay Assistance Program and so on, right? So from this, you can get a good glimpse of all the services that we're going to be able to provide. So this concludes the presentation. As I mentioned at the beginning, we zoomed out Fabry disease a little bit to give you a sort of a glimpse of Chiesi as a company, a glimpse on to Chiesi Global Rare Diseases and some highlights at a high level about what we're going to be doing in Fabry disease. So happy to take any questions.

Give me just one second here.

David [ Gara ], Spartan Capital. You said your commercial capabilities and acquisitions a lot of times. Is there a number in your head that you're thinking?

I'm sorry, I missed the question.

Yes, sorry. In your presentation, you said commercial capabilities of the company and also said acquisitions much many times. Is there a number in your head that you're thinking when you're looking for new companies as you're rolling out over the next year?

Interesting question. So we don't have a number of companies per se. In terms of what we're going to be doing strategically, I can answer that question. As I mentioned, we're focused on 3 areas, which are respiratory, specialty care and rare diseases. So far, in the last few years, we developed a few billions dollars in rare diseases. And I mentioned the last acquisition of Amryt, which was a full company acquisition to a total of $1.2 billion in upfront, plus contingent payments. And that was a 300-person company, which brought to us also a significant and sizable commercial operation across both sides of the pond. I will say that from my perspective, I believe we're going to continue with acquisitions, maybe not as large as Amryt, but it's likely going to continue with companies potentially on the smaller end, potentially half of that size in terms of the values. But it's certainly going to continue, and it's going to continue across the 3 different areas.

Boobalan from H.C. Wainwright. So three questions from us. So firstly, maybe on a high level, as you think about your launch preparations, so can you comment on potential synergy with existing drugs that you have, and how you plan to leverage that to maximize Elfabrio adoption in the U.S.? So that's the first one. I'll just go ahead and say all the three. And the second, as you think about the ramp trajectory, are there potential lessons that you learned from existing Fabry drugs that you could apply in the present case to maximize the market penetration of Elfabrio? If so, what are the lessons? And then finally, the obvious one, how are you thinking about the pricing for Elfabrio? And any potential discounts and all that, that you can expect? And where you are in terms of payer engagement?

Yes, sure. Absolutely. Three great questions. I want to start from the last one. The pricing is, for now, confidential. And we'll look at it that for now, but you'll see it very soon across both sides of the pond. Obviously, pricing negotiations and assessments are ongoing within multiple jurisdictions following the EMA and the FDA, basically concomitant approval, they sort of approved within the span of a week or so. So the pricing will remain confidential. And the first question is about the comment on synergy with existing drugs, so that's an interesting question. Yes. So we have synergies on a few things. I mentioned that we have a portfolio of 3 different drugs in lysosomal storage disorders. I mentioned that one drug is indicated for alpha-mannosidosis, that's another enzyme replacement therapy. And with that drug, we have established a pretty significant presence ex U.S. first. And then now we're actually launching [ Lamzede ] also in the United States. So that helps us because one of the many prescribers or prescribing specialties, I suppose, for the [ aforementioned ] treatment is the [ genetic ] system. And so with that, we've created a community, and we've established a Chiesi Global Rare Disease presence. And again, as I mentioned previously, ex U.S. and then now also in the United States. So there's a lot of synergy with that drug. The additional synergy that we have, and this is primarily ex-U.S., is with [ Procysbi ], which is the drug that I mentioned that we in-licensed from Horizon Therapeutics. [ Procysbi ] is indicated for cystinosis, nephropatic cystinosis. The primary prescriber of [ Procysbi ] as well as other cystinosis drugs is the nephrologist. And so there are obvious synergies on the nephrology side of things, so between Elfabrio and [ Procysbi ]. So we definitely see a lot of synergy there. More broadly, the way that we have built our rare disease presence is modular, meaning we've acquired product after product. But every time we've done a deal, we have taken very seriously and then cautiously into consideration the synergies we had with the previously established presence within rare diseases. So we do expect synergy there. I will say that the synergy comes from the perspective of continuing to establish the brand and the reputation of Chiesi and Chiesi Global Rare Diseases, more specifically within the space of rare disease, with the medical community, meaning -- I mentioned that Chiesi is a -- it's a 7,000-employee company, right? And rare disease is not a question of commercial muscles, right? It's more of a question of credibility, reputation, scientific rigor, being close to the patients and their families and so on. And so we're obtaining synergies, we're obtaining synergies on those areas, in those areas from the other drugs that I mentioned, right? So it's not a question of commercial synergy per se, right? Although there is some of it, but it's limited. On the ramp trajectory, lessons from existing Fabry drugs, it's a very fascinating question. We have definitely studied the story and the history of the other Fabry drugs. I will say that we are in a bit of a different situation because we're coming very late in the game compared to some of the other treatments that have been approved in certain jurisdictions for as long as [ 22 ] years, right? So there are certainly lessons that we have taken about things that we want to do similarly and things that we might want to do differently, which we're going to apply. I will say that one of the lessons that -- I will say that one of the products that we feel are obviously different than ours is Galafold because it's an oral treatment. It's indicated only for a specific -- have a patient with a specific [indiscernible] mutation and so on, right? So maybe that lesson does not translate directly to Elfabrio per se, but I've seen -- we've seen a lot of lessons that we've taken from the other 2 drugs over a period of multiple years that we're going to apply in the future.

Any other questions from the audience? Here we go, Chuck.

Okay. A couple of questions online for Giacomo. First, are you planning any additional markets for Elfabrio outside the U.S. and EU?

Yes, that's an excellent question. Yes, we're -- let me think about it. So we have a full geographical expansion plan that spans most of the countries. We're -- at a minimum we're -- other products have already been approved. I will say, and this is publicly available information that we set up Chiesi Japan sometime ago to also develop some of the rare disease products in Japan as well. Certainly looking at other jurisdictions as well in Far East, the Middle East and Latin America.

Okay. Thank you. A few more, if you don't mind me just running through these. Do you plan to pursue a label update for 4-week dosing in the U.S. and EU?

That is a great question. I'm going to leave the answer to that as a confidential one with a smile.

Okay. What trials are you planning to make for Elfabrio available for children with Fabry disease?

I'm sorry, you're seeing more both trials?

What trials are you planning to make Elfabrio available for children with Fabry disease? I guess, [ pediatric disease ] studies.

Okay. So for the pediatric population, you're saying, right? Yes, that's a good question. Yes, we're definitely going to comply with some of the regulatory post-marketing commitments that we have with some of the regulatory agencies. And so we're starting the study. Actually, let me take it back. So we're starting a couple of studies. One is a pregnancy study. And then we're starting a pediatric study as well, yes.

Okay. Next is what percentage of patients from the clinical studies have been converted to the commercial drug? I guess, it might be a little bit early for that.

Yes, yes. That's ongoing. It's going -- we're very happy with what we're seeing, but it's still ongoing at this point in time. We continue to see patients flip from the open-label extension and the expanded access programs over to commercial, also depending on the speed of the negotiations with the payers, which in some jurisdictions, as you know, will take years. In other jurisdictions, will take several weeks.

Okay. What is physicians' awareness of Elfabrio in the EU?

We would find it satisfactory at this point in time. We've done a lot of activities in preparational launch in the last few years. And we've also -- well, I would say that the Protalix team did an excellent job involving the community and some of the key opinion leaders in the clinical trials, so we leverage their work, and we expanded upon that. So we are happy with what we're seeing right now. We -- as I mentioned, we're seeing a lot of good reception, a lot of good feedback, a lot of good expectations, perhaps trepidation as well by some parts of the community. So we're happy with what we're seeing.

Okay. What is your timing for a commercial launch in the U.S.?

We're talking weeks. I think we're going to have a product very, very -- already -- if it's not already in the U.S., it's going to be there very soon.

Okay. One additional here, it might have already been addressed, but given your company's experience in the rare disease market and the competitive products in Fabry disease, how do you anticipate Elfabrio will be received in the global market?

I would say that it's going to be looked at a very attractive opportunity, therapeutic alternative for a lot of patients. One of the feedbacks that we've received over the last several months and years in fact, as we have continued to speak to the community relates to the fact that there is a lot of curiosity about a new available therapy after the community didn't have anything particularly new for at least in the space of the enzymes for the longest time. And so there is a lot of intrigued -- a lot of people are intrigued with the therapy per se as well as with some of the specific features of the product that Dr. Mehta alluded to previously.

Okay. Additional question. Do you have any goals for market penetration or market share?

Of course, we do, and that's how we operated, but we're not disclosing them today.

Fair enough. There's a couple of more. I'm still going through. Monique I'm not sure if there's anymore.

All right. Any other questions in the room? One back here.

Earlier in your presentation, you mentioned sickle cell that you were looking to get involved in that area. Could you give a little more detail in terms of what your plans might be?

Of course, I'm happy to. We are involved already. As I mentioned previously, we have acquired a company in 2020. It was a carve-out -- company was called Apotex. We carved out a part of Apotex, company based in Canada, and we carved it out their pharmaceutical company. Apotex is essentially a company in the generics business. We -- but they had essentially invested in a non-generic business, in branded business. And they have developed a product in Ferriprox, deferiprone for thalassemia. And so we took the company over. We took ApoPharma over that's how the pharma company, the biopharma company or business unit was called in 2020. We took Ferriprox and basically completed the studies in sickle cell disease and then Ferriprox was approved several months ago by the FDA with the indication of sickle cell disease. So it's an iron chelation therapy indicated for patients who have undergone iron transfusion and who have iron overload. And we've extended the indication from just thalassemia to also sickle cell disease and other anemias. So we're going to continue to take this therapy to the patients. Ferriprox has been approved in different formulations. I want to say maybe 70 countries, 80 countries. So it's a very well established therapy, and we're going to continue to take it to the patients around the world.

All right. I see another question.

This is for Dror and maybe one for Eyal. So Dror, as we think about Elfabrio market penetration in the U.S., so what percentage of real-world patients in the U.S., they qualify or they fit in the exclusion criteria?

Can you repeat the question? I don't think that I fully understand.

So what percentage of real-world Fabry patients in U.S. meet the explosion criteria?

I think it's hard to tell. Giacomo, are you...

I don't fully understand, I'm sorry. Maybe we can take it offline, but I don't know what you mean.

Yes. So I'm just trying to understand what percentage of patients are eligible for Elfabrio treatment in the U.S.

So Elfabrio is approved for all adult Fabry patients right now in the U.S.

So based on exclusion criteria you mentioned in the label...

Once the pediatric study will be done and approved, and also children can be added to that, to the label but there were no limitation, if I may say, of men, women or something else.

So Eyal as you think about milestones remaining that are to be received from Chiesi, so maybe can you remind us what are the expected milestones as soon as the drug is launched and as soon as the first sales are recorded?

Yes. So the milestones are redacted as you know. We only disclosed the total potential license, which goes up to $1 billion for both regulatory and commercial license. And the tiered royalties that goes from 15% to 35% on sales conducted outside the U.S. and 15% to 40% for sales conducted within the U.S. So nothing we can say more than this at this point.

If there are any further questions to Giacomo before he needs to go back to his meetings, please, Giac? So Giacomo, thank you very much for everything. We appreciate it. We'll take it from there.

Well done. Thanks, Dror. Thanks, everyone.

So again, I want to ask to say thank you to Dr. Mehta and to Giacomo Chiesi on their comprehensive presentations. And we will move into -- a view into Protalix and what we plan to do in the future. So please, next slide, please. These are the forward-looking statements, and I think we can go into the presentation. Thank you. So Protalix, as you know, was established, I think, something like 30 years ago. And Protalix is based on unique technology when we express complex human protein for plant cells in suspension. Today, we can say we after a very, I would say, exciting milestone where we achieved the approvals both in the U.S. and the EU. The Protalix is indeed, as you can see here, sits on a strong foundation to further expand into the rare disease area, in the rare disease space. We have 2 approved drugs. We had a long history of developing trials and with 2 major successes. One is Elelyso which is an approved ERT for Gaucher. And the second one is Elfabrio as we have just discussed. ProCellEx is our unique platform. We express our protein for plant cells, as we mentioned. It's unique as the rest of the system they do for mammalian cells. We have a biological drug substance line in our facility where we produce the drug substance for both drugs, for Elelyso and now we already started, of course, to prepare for Elfabrio. Just as a note, we have enough capacity to produce Elfabrio for many years down the line. So there should be no concerns about that. This facility is inspected periodically. We just passed, of course, an FDA inspection ahead of the U.S. approval because it was also inspected by the EMA or the European authorities about 2 years ago or a year ago, I think, in 2021, 2 years ago, right? Time goes fast. And of course, with many other agencies. Elelyso, which is the first drug is approved in the U.S., an additional couple of dozens of countries and again, also by our partners. So we have 3 main partnerships. One is with Chiesi as was just described, of course. Pfizer is our global commercial partner for Elelyso, the ERT for Gaucher. So these are clear respectable partners. And Fiocruz, what is in parenthesis here at the bottom left is the name of a governmental Brazilian agency that actually gave us the license to market in Brazil. We have our own face in Brazil. So this is the agreement with them. You can see we have a pretty strong partnership, which is a nice achievement by itself that 2 big pharma companies signed commercial agreements with us and pleased with it. Protalix today as a long term of clinical and regulatory expertise in the genetic space developing drugs, biologics and I think we have a very special focus into the lysosomal storage diseases. We have a pipeline in addition to the 2 approved drugs and will review in a minute, which PEGylated Uricase for the treatment of severe gout patients. And we have additional couple of earlier stage programs. The one is here is PRX-119 for the treatment of NETs-related disease. From a financial point of view, we expect stream of royalties from Chiesi and milestones from the Elfabrio, of course. And in addition, we have sales to Pfizer for Elelyso in Brazil directly. This is the product pipeline. All right now is based on our ProCellEx systems. We can see here Elelyso and Elfabrio, which are approved which by itself is a major achievement to have 2 drugs developed from A to Z, if I may say, and get to the market. We have uricase for severe gout. As I mentioned, we expect we are now -- we enter the Phase I study, and we expect results by the first quarter of 2024. And then we have PRX-119 for NETs-related diseases and additional research programs. Okay, about a bit about Elelyso. This is the first product that was approved. It was approved in 2012 by the FDA and then by many other agencies around the globe. It's a rare disease lysosomal disease, the product -- the brand name is Elelyso, again, manufacture for our platform. It's approved, as you can see in 23 markets. We have a global exclusive agreement with Pfizer, they hold the commercial rights. We have one market. We have our own face in Brazil. We said about $9 million to $10 million a year in Brazil with our own team and our market share in Brazil is about 25%. Elfabrio is for Fabry. Fabry is a rare X-linked disease, again, another lysosomal disease. Elfabrio is actually pegunigalsidase alfa. It was approved for marketing, both in the EU and the U.S. about 6 weeks ago, the beginning of the first 10 days of May of this year. Commercially, the Fabry indication overall is about $2.1 billion, supposed to grow and reach around $3 billion by the end of this decade. It's the biggest indication lysosomal storage diseases from a value point of view. And we hope that, as you saw, Chiesi is putting it at the top priority, and we believe Chiesi is a very good partner to Protalix and treat it very seriously. We plan a very deep medical plan. And we hope that with a good probability they do good on the market for the patients of the families as well. And hopefully, they will get a decent market share down the road. Chiesi, as Giacomo explained in detail, and clearly, you have -- you can ask further questions it's a private Italian company. It's about $3 billion in sales. They grow, they are profitable, they operate in over 30 countries around the world. As you could see, they are very serious about what they are doing. They have established their rare disease business about 3.5 to 4 years ago. It's based in Boston. They are now, as you mentioned, 700 employees including employees from the Amryt move positioned well. They are based both in Europe and in the U.S. and in some other countries, and they plan to enter to others a way either directly or for distribution agreements. They have a clear strategy into the rare disease business and Giacomo is managing it very well and we are very pleased with this approach, of course. Elfabrio, they put into Protalix into this for pre-program, if I may say. A lot of money we speak about something around the $200 million, I believe, at risk, which is highly appreciated. They have been a very supportive and, if I may say, close partner to us. And clearly, we hope that it will be a very strong franchise. They have a deep medical plan, as I mentioned, you saw a couple of studies are already planned and others are under consideration. As we move forward and we expected, of course, approval. We didn't know, but we expect the approval already a while ago. Late last year, we polished our strategy going forward, and we establish our pathway forward. It was discussed, brainstormed and agreed and recommended to the Board and accepted by the Board to continue and develop and be active in programs within the lysosomal storage diseases and the rare genetic disease and the rare disease area, as you can see in these circles. This will be the focus going forward. We expect -- we plan to at least and I hope we will be able to deliver to have around 4 to 6 programs from discovery to Phase II within the next 2 years and I hope I will be able to stand here in 2 years and report to you where we stand. So our strategy is to focus into the rare disease space, both genetic and nongenetic opportunities. Clearly, we are looking at opportunities from early stage to clinical. And right now, we have initiated, if I may say, a BD&L process in the last 2, 3 months. And since approval, if I may say, we have changed the gears to some extent, we work more extensively to review and evaluate and explore. And we will hope that we'll be able to do, if I may say, twofolds: one, organically to use our platform and bring in new early-stage programs for the platform itself for Protalix, if I may say, for the plant cells. And second is actually a program that we will license in or we will buy, there must be a fit to what we are looking for, must be something that we can bring added value to that. And what we can say that we bring the experience, as I mentioned. And of course, the fact that experience with successes, not only scars, if I may say. And in addition, the commitment, Protalix is still a small company. So actually any program that we will bring in will get the highest priority. When we look again into where we plan to do into the future and also 10 years ago or about 11 years ago, Elelyso ERT focus share was approved by the FDA and the other agencies. So this was, if I may say, the first stem of our capabilities and system and this was the initial success. And today, when we stand at the end of the -- of June of 2023, following the 2 approvals of Elfabrio, I think this is the second stem which is very much important. It was approved in both continents, which gives a very, if I may say, a good ramp-up for Chiesi to move to start from. The next steps in the next 2 years, as I mentioned before, we plan to have a more significant pipeline within the rare disease space. We will look into protein discovery. We will use our protein discovery capabilities with our own system, and we'll use inorganic moves, and we will actually running a process, which I hope will yield couple of programs into the pipeline, either through licensing, collaborations or buying an asset or so. The intention is to have innovative solution that mainly address real unmet needs. This is the target. And clearly, we look also into future technology platforms that we can bring or collaborate with the Protalix team for new products. This will be for early stage, of course, but we speak about a very innovative technology that we're looking into. And the vision, if we look 5 and 8 years down the road, we plan to work, I hope with a lot of brainstorm and consultation and some brain, if I may say. And hopefully, with some success as well in order to build a significant pipeline with multiple clinical rare disease programs, it will be a fully integrated company. The intent is indeed to have down the road and again, I'm speaking about beyond the next 5 years, also commercial infrastructure to support the novel products or the new products and to leverage our technology platform that we will collaborate with. Financially, we have finalized to keep first quarter, which ended in the end of March of 2023 with $33 million, we received $20 million milestone upon U.S. approval from Chiesi. So we see it, give or take, as we speak today, about $50 million in cash. We have a cash runway, if I may say, under the current cash and cash equivalents, as we can see until mid of 2025. This is without doing any other move on the market. We have an ATM, which is operating with H.C. Wainwright. Our revenues for 2022 is about $25 million. We expect it to grow with building, if I may say, stock for Chiesi, of Elfabrio. And our burn rate is actually around 0, you can see 0 to $1.5 million per quarter. So as long as the focus that we see from Chiesi will mature, if I may say, I think Protalix is self-sustained under the current pace of R&D expenses, which I think is a rare situation for Protalix, if I may say, not because we are in rare disease area, but it's a good achievement for us. Our debt as of Q1 of 2023 was $28.75 million convertible notes that are due September of 2024. So I think this is it as a nutshell. I'll take questions, if it's okay.

You mentioned plants that has come from plants. Are there any specific plants that you're using or specific type of plants. Can you give us the name of a plant? Or just is it kind of like generic any plant in general? I'm kind of interested from botanical standpoint. Thank you.

So Elelyso is expressed through carrot cells and the rest of the pipeline going forward since then is done with tobacco cells, it's BY2 cells which we apply different modifications and techniques as any other company does.

So you said carrot cells. Can I assume carrots?

But we don't use carrots as carrots. We speak about carrot cells. Tobacco, we don't grow them on the ground. We just -- it's different.

So speaking of modalities outside of proteins, so what type of molecules are suitable for ProCellEx? You mentioned about cell and gene therapy. So I'm curious if you could expand a little bit more on that. Are they going to be developed with ProCellEx platform? Or are they going to be standalone therapies?

So this is a very good question. Anything that will come through ProCellEx has to come from very early-stage discovery, early preclinical in order for us to express a cell line. So therefore, proteins can -- or different type of protein can be expressed for our system, anything that will be licensed, both collaboration with on a later stage, will not go into our system, okay? We will use our long-term experience developing drugs and also the regulatory path to move them stride-by-stride ahead. So this is it now. When we focus into the genetic and the nongenetic rare disease space, the modalities can be small molecules. It can be proteins, could be others. Currently, unless it will be changed, but the agreement or the discussion within the company and the Board that will not go into cell and gene therapy. We do not have as of yet the capabilities for that. And again, we should be proud but modest with what we are doing. So we will focus where we think we can bring value.

Any other questions? Chuck, were there any written questions? Hang on, we have another question back here.

Can you please tell me about your commitment to being EPS positive in the next few years?

So Eyal would you like to take it?

Sure. So as Dror mentioned and as illustrated on the slide, the company is self-funded generated company based on the projections that we have for Chiesi at this point. In terms of the EPS, obviously, is a development company, and we keep on -- and we'll keep on growing our pipeline and investing. But over time, obviously, if I had to guesstimate, I think that 2025 will be like EPS positive, again, subject to the execution by Chiesi. But from a cash perspective, I think that we're like neutral even 2023.

Okay. There are a couple of questions online. How many patients to date have been treated with PRX-115 in your Phase I trial for severe gout?

We've just initiated the enrollment to the study. I don't know if it's even public, we have about 12 patients. 12 patients were involved, so now it's public. There are a number of cohorts, if I may say, so it will be up to 56 subjects.

And the next question is probably for Eyal, what you project the burn rate to be going forward?

The burn rate. So I think that we just touched it and it's even on the screen. So we project the anywhere between breakeven, which is a 0 to positive, again, subject to and based on the projections that we have from Chiesi, which is really the -- I think, the big ice here.

Next question is, what is your manufacturing capacity given your multiple commercial and clinical drugs?

So we have a drug substance manufacturing line in Protalix. The fill and finish is done for Elelyso is done with Pfizer and for Fabry one, I mean for Elfabrio, it's done with Chiesi. At our site, which is actually the majority, if I may say, of the manufacturing process, we have capacity, I think, close to up to 50% of the global market consumption. So I think this is not an issue at present. So it will never be an issue. We can always build a new facility.

Okay. Next question is what other drugs or indications are you investigating for your proprietary plant protein technology?

So I think we have discussed this. We have a Phase I in PEGylated uricase for severe gout patients. We have a couple of earlier-stage programs, one of them is PRX-119 in NETs-related diseases, and we will update, of course, accordingly once we will progress on our process.

Okay. Last question here online. Is there any plans to use the ProCellEx platform for manufacturing of biosimilars or specialized generics?

No, not at all. We are not in any price war business. This is not for us. Protalix is a totally different company. We develop innovative drugs, which address real unmet need, needs for the patients, if I may say.

Any more questions in the room?

By the way, it is just impossible to do biosimilar at Protalix, regulatory-wise. It's a different manufacturing method.

Can you explain some of the covenants that come along with the 2024 notes? Did that covenant, any restrictive...

Yes, please go. Eyal, maybe you can address the issue.

So I think the main covenant is a $7.5 million that we need to keep cash at all times. Other than these, there are all kinds of leans on the IP, but that's not the covenant that you're probably alluding to, I guess that based on the ending cash balance, as Dror mentioned, I don't think that, that's going to be an issue. And please understand that the conversion price of the notes is 180 and the noteholders can at all times, issue a conversion, a notice to the company, we assume there's a good reason to assume that the noteholders will follow the share price. But I guess that at least most of them as we go closer to the maturity, we'll probably elect to convert based and subject to the share price.

And one last time for questions in the room? All right. Dror, I'll turn it back over to you.

Okay. So I asked to thank you again to everyone that attended here in person and everyone that attended virtually. So thank you very much, and we will continue to update on our progress. Have a great day. Thank you.