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

Good morning, and welcome to the Protalix BioTherapeutics KOL webinar. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Protalix website following the conclusion of the event. Before we begin, please note that this presentation, including all verbal remarks contain forward-looking statements. The accuracy of which depends on future events outside the company's control, and therefore, might cause actual results to differ materially from those forward-looking statements. In the case of any questions or discrepancies, we defer to the company's public documents available from its website and filed with the SEC. I'd now like to turn the call over to Dror Bashan, President and Chief Executive Officer at Protalix Biotherapeutics. Please go ahead, Dror.

Thank you, Tara, and good morning and good afternoon to everybody who took the time to join the call. We are now -- actually organized this session, this KOL event with Dr. Myrl Holida, and I will refer to him in a couple of minutes in order to tell a little bit about our lead program, the PRX-102, for Fabry. About Protalix, Tara, if you can move to the next slide, please. I will share with you a little bit about Protalix. Protalix was established over 24 years ago. We're a biotherapeutics company. We have actually 1 drug approved for Gaucher. It's called Elelyso, it was approved already in 2012 and globalize are [indiscernible] Pfizer, and the further program is actually the last, if I may say, curved, hopefully towards maturity and approval by the second quarter of next year, hopefully. The Fabry program started then many years ago, of course, and we are now actually post all the clinical program and actually in the -- through the regulatory process with the EMA, the EU authorities and we have just announced this morning that we have resubmitted our BLA to the FDA and they got an acknowledgment and the PDUFA date is May 9, 2023. We have 3 main partnerships. Chiesi is our global commercial partner for the Fabry program. Pfizer is our global partner for the Gaucher program, the Elelyso product and Fiocruz is the name of the Brazilian agency, which actually gave us the license under an agreement to market our Gaucher program, Elelyso in Brazil. Protalix is established, actually, as it was established on -- based on the unique technology where we can express complex human protein for plant cells in suspension. It's called ProCellEx. This platform, actually, we have through this platform biological manufacturing client in our site in Israel. This site is being inspected by the different authorities like the FDA, the EMA and of course, our global partners periodically, successfully, of course. In addition, we have a small early pipeline. And the first and the more advanced program is Uricase for gout, where we -- our plan to initiate the Phase I with humans in the Q1 of 2023, which means in couple of months. Overall, we have a solid balance sheet, and we are now working together with our partner and the regulatory agencies, hopefully towards approval. I will turn now to Myrl Holida, who is our guest speaker and he is the KOL in Fabry. Thank you. Please?

Welcome, everyone. Thank you for coming, and thank you for asking me to speak about this investigational medication. I wanted to be there in person, but unfortunately, my schedule would not allow it. So there's a couple of things I'd like to accomplish. And the first one is that probably several or many of you don't necessarily have good medical knowledge about Fabry disease. So I want to give you a basic understanding of the disease and how it affects families. And then I'll tell you about the pegunigalsidase alfa that has been under study for many years. So next slide, please. This is my disclosure, typical for people who do what I do and next slide, please. So there's an extensive bio that you can see there posted, but there's a little bit more of the story that I wanted to tell you about. So I simply fell into taking care of Lysosomal Storage Disorder patients, which Fabry is a subclass of that, but I developed a keen interest and a passion for these patients, particularly with Fabry. So this is a bad disease typically affecting every generation in the family. So Gaucher disease was the first enzyme deficiency that had an ERT-approved, enzyme replacement therapy. And those patients were often diagnosed in pediatric cancer centers because they had manifestations similar to cancer, in that they had enlarged livers and spleens. So because of our experience with Gaucher, and we had several Fabry patients, a pediatric oncologist was approached to consider the agalsidase beta, the Fabrazyme extension trial, and we did bring that in, and I was asked to assist with that. The drug was then approved in 2003, and then we were able to identify those Fabry patients that have been lost to follow up because there was no treatment for them. And in addition to that, we were able to identify other patients that were previously undiagnosed, and we were able to start them on enzyme replacement therapy. So then the physician I worked with, in 2009, he left and shortly thereafter production of enzyme stalled. So there was an international shortage of Fabrazyme. So as one of the only prescribers in our institution, I was approached and asked to open a safety trial for Replagal, which since it's an unapproved drug in the U.S., you need to have a safety trial or other regulatory method to provide that drug and other pharmacologic therapies came under rapid development. So I then became a principal investor out of necessity and a desire to give my patients therapies. So we have since grown in our scope of research and clinical care since that time. So the next slide, please. So Fabry disease. It's a rare x-linked inherited progressive disorder of glycosphingolipid metabolism. So it's a deficiency or absence of that enzyme alpha-galactosidase-A. So if you don't have an adequate or have no enzyme you accumulate unmetabolized substrate in the tissue lysosome. It affects both males and females, but more so males, but in females, they can be as affected as males, but oftentimes, the effect is delayed roughly about a decade. So the unmetabolized substrates, globotriaosylceramide and globotriaosylsphingosine, which I will refer to as Gb3 and lysoGB3 because they're tongue-twisters. Anyway, they cause progressive organ damage over time, and the tissues most affected are included there on that schematic on the right, not necessarily in order of severity. So there is peripheral nervous system and central nervous system effects. Males in particular, can develop severe pain. It's a neuropathic pain, much like diabetes, only much worse. So sometimes these patients even require an emergency room visit because their pain is intolerable. Males also tend to stop sweating and often stop sweating completely, so they're not able to tolerate heat. The heart is affected, the heart and blood vessels, and it's a pan cardiac issue with the heart. Everything can be affected. The most common finding is left ventricular hypertrophy, where the substrate actually goes into the myocardium and enlarge as it -- and if it gets severe enough, you can actually have scarring in the heart muscle. The rhythm system is affected. These patients can have fatal arrhythmias. And so the #1 cause of death in these patients is probably heart disease from the standpoint of these rhythm issues or myocardial infarction. Because the blood vessels are affected, all of the blood vessels can have narrowing because of the depositions within the blood vessel. So the brain can be affected, and there's an increased risk of stroke, transient ischemic attack and white matter lesions. And that's because there's limited perfusion to those areas of the brain. The gut can be affected as well. These patients can have severe diarrhea, cramping. And this can affect them socially. They can't even necessarily go out to have a meal because as soon as they eat, they have to get up and use the bathroom. The opposite end of that spectrum in females, some females develop severe constipation, and they can go weeks without having a bowel movement. The kidneys can be affected in a major way because of the depositions within the kidneys. They will begin spilling protein in their urine and then can progress to renal failure and require kidney transplant or dialysis. So the only treatments in terms of enzyme replacement therapies are the Agalsidase alfa, which is Replagal and that's dosed at 0.2 milligrams per kilo and agalsidase beta or Fabrazyme, which is 1 milligram per kilo. Now there are some inherent issues with enzyme replacement drugs, that being because these patients don't have an enzyme level. They see that infused foreign protein enzyme is formed and develop antibodies against it. So you can also have neutralizing antibodies, in that the neutralizing antibody can essentially attach and take the enzyme out of circulation to varying degrees. So when you have antibodies, you also have an increased risk of having a reaction to the drug. So next slide, please. So this is pegunigalsidase alfa, another tongue twister. So I'll refer to this interchangeably as PRx or PEG or Unigal, which has been cleaned. So it is the standard-based enzyme, agalsidase alfa, and it has a PEG unit attached to it. So it's polyethylene glycol. It sounds like antifreeze, but it's not. It's considered to be an inert substance. And it's been used for many years. The earliest in the 1990s when it was approved, and it's been attached to other therapies, and in particular, chemotherapies and hemophilia drugs, and there's a list of others as well. So the [ PEG MOD ] is attached via 2,000-Dalton size linker. And in this medication, Unigal, and in other medications, we typically will see an extension of the availability of that enzyme in the blood system. And it may help improve the tissue half-life as well. Next slide, please. So there's a robust clinical development program, and these are the studies that have been ongoing for several years. So the Phase I, Phase II or ERT-naive Fabry patients never been treated before, and this is a dose-ranging study. at 0.2 and 1 milligram, which are mimicking the Replagal and Fabrazyme doses, respectively, and also the 2-milligram dose was used. So we also looked at those substrate levels, the lysoGb3 and the Gb3, which were accumulated in these naive patients in a very limited manner. So this study looked at the safety and the kidneys and the cardiac and the substrate levels. And the substrate levels were looked at in both the kidneys and the bloodstream and these patients underwent biopsies. And I'll give you more information about that later. The BALANCE study is the study that's really in question that's being submitted because that's a direct head-to-head comparison with agalsidase beta, so these patients were randomized in a 2:1 ratio, and it's a double-blind active control and the number of unigal patients was about double those patients agalsidase beta. So all these patients had previously been treated with agalsidase beta. And the major requirement is that they had to have impaired renal function and renal function was the primary endpoint. The BRIDGE study is a Phase III open-label study. These patients switch from Agalsidase alpha at the 0.2 milligrams per kilo and went to 1 milligram per kilo of the PEG enzyme and were treated on that for 12 months. The BRIGHT study, this is one that's a little bit different from the standpoint that the dose is doubled at 2 milligrams per kilo but the medication is giving -- is given half as often. So it's given every 4 weeks. So it's important to note that all the patients in these studies completed these studies or those that did complete the studies, they had an opportunity to go on to open-label extension with the unigal medication. So next slide, please. This shows you the time line of those studies. The Phase I, Phase II, we had patients in that study. Our patients started, I think, late 2015 or early 2016. By the time all the sites had completed, it was 2018. And then you can see the years that the other ones finished their initial study. So the BRIDGE, the BRIGHT, the BALANCE. And then in terms of the regulatory, it is submitted to the EU and is under review and the BLA submission to the FDA in the United States was submitted, I think, on November 7, and there is an approved PDUFA date, which is yes, May 9 of next year. Next slide, please. So this is the Phase I, Phase II study, and you see the schematic on the left that shows the enzyme levels that were measured at various points after infusion and for those specific doses that were given. This did show us that the half-life of that enzyme was approximately 8 hours. Now later on, you'll see in the BRIGHT study, this data was extrapolated out to 4 weeks, so gave a good indication of what the enzyme level would be at the 28-day point. So that was part of the process of the birthing of the BRIGHT study, so to speak. So in terms of the safety of administering this drug, most of the adverse events, the treatment emergent ones were mild to moderate in severity, thought to be unrelated to the pegylated enzyme and antidrug antibodies were infrequent and transitory in most of these patients. In terms of the pharmacodynamics, there were kidney biops required prior to starting therapy and were originally planned to be done at every 6 months. However, the results shown at the 6 months, which are on the middle block there, showed a very good reduction of the Gb3 in the kidneys and it was determined and requested that we not continue to do kidney biopsies as that's an invasive procedure. In addition to showing a reduction in Gb3 in the kidneys, there's clear reduction of the substrate levels in the plasma. And those are -- in all of these show males, females and as a group. So nice reduction and continue on throughout. So 5-plus years in some of these patients. The mean absolute estimated glomerular filtration rate is also shown there, and that's fairly flat. There were no cardiac fibrosis that were seen over 60 months of treatment of 5 years and left ventricular mass index values were essentially within the normal range. So this data showed us that the long-term treatment with this thus far provides continued benefit for these patients, and it's based on these parameters that I've shown you, the cardiac, the renal and reduction of the substrate levels over the long term, thus far. And then the drug has been shown to be safe. Next slide, please. So this is the BRIDGE study. This is changing from Replagal to pegylated enzyme. And again, you see a reduction in the plasma lyso Gb3 levels and the interesting aspect of this study, and this was, I think, unexpected in those groups that work with Replagal, the reduction in the EGFR I think, was much more dramatic than was expected. We did not expect to see that degree of change and improvement as the data is the data. So we don't have a good explanation for that. And in terms of safety, 2 patients did withdraw due to hypersensitivity reactions and only patients who had pre-existing antibodies from their previous enzyme replacement therapy were positive for neutralizing antibodies. Next slide, please. This is the BRIGHT Phase III. And the enzyme levels are shown out to day 28, and that confirmed what we originally thought from the Phase I, Phase II and you see the stable eGFR pretty much a flat line. Of note is that the mean change in the eGFR values was minus 1.27 just for a point of reference, people who have no renal disease just by age alone, that reduction is about minus 1, so very limited change in their renal status. And again, in terms of the safety data, this medication was well tolerated. There were no de-novo antidrug antibodies that develop. So nothing that happen out of the blue. Next slide, please. This is the summary of the BALANCE study. Again, this was double blind, randomized. Nobody knew which drug they were getting. And so approximately twice as many patients in the unigal group as the Fabrazyme group, and both groups were followed for 2 years and then the values were assessed. And the randomization was also stratified by urine protein to creatinine ratio at what level that was because that had an impact on what the renal function might be. Next slide, please. So this is the efficacy data. You can see that there is significant overlap between pegylated enzyme and Fabrazyme. If you did not have any color coating, you couldn't tell the difference. And the confidence interval, minus 3.788 and minus 1.24. At 24 months, the difference in the intention to treat population and it's important to look at the intention to treat population, so you eliminate any possible bias. And the lower confidence interval met that prespecified non-inferiority margin. And confidence interval included 0. So this showed us that there was no significant difference between pegunigalsidase alfa and agalsidase beta. Next slide, please. This looks at the immunogenicity of the 2 medications. So this data is presented as a percentage of the patients who are Ab positive or ADA positive and the green is the unigal, the blue is the agalsidase beta. And both groups had greater than 30% preexisting ADAs at baseline and again, due to their previous enzyme replacement therapy. The unigal reduction in the ADA positive was 35% at start to 23% at end, Fabrazyme was 32% to 26% and neutralizing antibodies in the unigal was 33% decrease to 15%. But in Fabrazyme, there was really no perceptible change from 28% to 26%. And in terms of the safety data, both groups experienced treatment emergent adverse events at about same rate. But if you look at the rate of related treatment events and you look at it from the perspective of events per 100 patient years, there was approximately a fourfold lower for the unigal group. And in terms of the infusion-related reactions, the number of events were lower for the unigal group to the agalsidase group, also by about fourfold looking at normalized data to per 100 infusions. No deaths were reported in either group. So this is a summary of the data compiled in the BALANCE study. So unigal was shown to be non-inferior to Fabrazyme based on the median eGFR annualized slope, and that's a key measure of Fabry disease progression in the kidneys and that's controversial in terms of how do you determine kidney function decline, and that's always been an ongoing discussion in these Fabry patients. But there were no safety concerns identified and the tolerability and immunogenicity profiles were favorable for patients in the beta agalsidase-based arm. Note that the unigal arm, there were 5 discontinuations, 4 were due to withdrawal of consent and 1 was due to a serious hypersensitivity reaction, and the group that remained on Fabrazyme had 1 discontinuation due to withdrawal of consent. And after study completion, 97% of these patients opted to continue treatment on the pegunigalsidase arm in a 6-month open-label extension study. Next slide, please. So this is the summary of the BALANCE, and this again is the study in question. So unigal showed no inferior aspect relative to agalsidase beta based on the median eGFR annualized slope and no new safety concerns were identified. Tolerability and immunogenicity profiles were favorable for pegunigalsidase alfa. And I provided you the information about those with withdrawals. Next slide, please. So this is the current status of the ongoing studies. So the F60 is the trial that many of the patients rolled into continuing at what is considered the standard dose of the pegunigalsidase 1 milligram per kilogram every 2 weeks, and there are about 90 patients. Some have been on therapy for greater than 6 years. The F51 is the double dosing every 4 weeks and some of these have been on for greater than 5 years as well. And in addition to that, there's an expanded access program with 32 patients that are enrolled. So over 140 patients have received at least 1 infusion of pegunigalsidase, and I'd like to note that I had a patient that was involved in a major automobile accident and was unable to continue. So that was a patient in the double dose group. Some patients have been treated with unigal for more than 5 years and the cumulative exposure is about 300 patient years at 1 milligram per kilo every 2 weeks and about 100 patient years at the double dosing every 4 weeks. And then next slide, if there is one, I think that might be the end. Is it correct? Is it the last slide? So all the data presented here today is under FDA review for this investigational medication. So we are awaiting that and the investigators and patients have high expectations of approval. So if there's any questions, I'll defer this back to Dror.

Thank you, Myrl, and thank you, everybody, again. We are now -- we will now take questions, of course. So I suggest we will start.

[Operator Instructions] Please go ahead, John.

Good morning, everyone. And Myrl, thanks for giving us an update or a rundown of all the data. Just wanted to ask a little bit about the competitive environment. There are a few gene therapies out there in development. And some of them have fallen by the wayside. How do you see that emerging over the coming years and the drugs that are already available and, of course, picking the agalsidase alfa. How does that all fit together? Do you think when -- assuming it's approved.

Yes. I mean I think it has to do with as it is with any disease, medications get developed, and it's really more about the time line of what happens and the success of each one individually. Some medications are better than others. Gene therapy in some of those trials is looking very promising. So yes, we're involved in one of them. And I think you just have to see how it plays out. And there will be some competition. And there will be controversy about what is better, what is not, what are the issues involved with each medication. And I think particularly in a new investigational medication, there will be more questions that oftentimes are answered later on in post marketing information, but you don't necessarily want to strain a medication if it appears to be working very well. So we just have to see how it plays out.

Got it. And my sense is maybe that the FDA looks at gene therapies differently when there are already options available out there. Obviously, if there's no treatment, the bar is a little bit lower but there are several treatments available and more on the way. Does that -- do you think that affects the possibility of gene therapies being successful in the future?

There's good background on gene therapy, for example, like in the hemophilia population. Some of that has been very successful. And now using different vectors and changing some of the things that they do with these gene therapies, they're looking pretty good. I mean, this is essentially a constant infusion enzyme pump. I mean, one of the downsides, depending upon which vectors used is that you still not -- may not be able to get the drug to cross the blood-brain barrier because it's too large a molecule. So -- but again, I think it will just pull out the way it plays out.

Got it. And then looking at the risk profile for just all the available options out there, any thoughts on that? How that might affect the competitive environment, assuming approval and other assets that are in development as well?

Well, since you look in the U.S. anyway, we only have 1 drug as an enzyme therapy that's approved, and we have the oral drug, but that has a very limited usage based on percentage of patients. And oftentimes, it's regional. They use -- excuse me, I have to switch this off. So the comparison -- or say, for example, the pegunigalsidase alpha, there are some suggestions from this data that there's better immunogenicity and it's thought that the PEG component is protective in terms of shielding or masking the epitopes, so that may limit the availability of the antidrug antibodies to attach and cause issues. But again, that's things that needs to be proved. The effect of the drug seems to be very good with patients on therapy for 5 years or longer, and they're doing well. And there's some anecdotal information that suggests that these patients are feeling better, but that's not assessed and it's not looked at statistically so you can't really comment on that. So I hope that answers your question.

Yes, that's helpful. And still looking at the competitive environment and understanding, obviously, that we only have 1 drug available in the United States, Fabrazyme. Might we see -- assuming that's expanded, we see approvals, might we see certain Fabry products gravitating towards specific patient populations now we have Galafold for those with alpha mutations and then perhaps others for more or less severe disease. Do you see that happening as we get more products out there available for patients?

I mean it does have that potential, but you're looking at a population of a rare disease, and it takes many years to assess those subpopulations that may respond. I mean the Galafold, there is an assay where we can predict with good quality whether the patients will respond. And additionally, you could make the argument that with Galafold, it's a very small molecule and crosses the blood brain barrier. So it probably does impact the brain more than other therapies, but there's not enough data to prove that thus far. So with the limited patient population and the difficulties in running trials to make these assessments, I think that's going to be a difficult thing that could take a long time.

Right. That makes perfect sense. And that almost might seem to suggest that things might be a little sticky, I guess, in the space. I mean what would affect that stickiness do you think that a patient or a physician would be willing to try something new would put over the edge to do that?

I think in general, most physicians kind of look at the gold standard therapy. So it may be that some physicians may not be interested in changing patients over to pegunigalsidase if it gets approved, and some may be full court. They would do it with many of their patients. I think that's individualized. And I think we see the same thing with velaglucerase for Gaucher disease and taliglucerase. Some of it is somewhat reliant on insurance because sometimes they drive which therapy you provide. And sometimes it's driven by what type of support services that those individual pharma provide.

Yes. I mean, my thought was if there's some kind of side effect profile that's not good or just response isn't very good, they're willing to try something else. Obviously, that's always going to be the case. Last question is just on potential for combination therapies. Is that something that may come along? And I know a lot of my questions are kind of looking ahead maybe too many years. But any thoughts on that, that you have and the potential benefit that it might provide to patients using more than one of the potentially available?

There was some data that was done using combination therapy with Fabrazyme and Galafold and that did show some increase of enzyme levels and skin and blood and some of it was somewhat surprising data. But I think there are confounding factors that -- that I don't necessarily know about. For example, cost of this combination therapy would be exorbitant and although you hate to look at cost for effectiveness because you want to be sure that patients have the best therapy. Again, I think that's going to be probably the major factor and the degree of effectiveness that you add by combining those therapies.

Boobalan Pachaiyappan from H.C. Wainright.

Thanks for the informative KOL event and congrats on the BLA acceptance. A few questions from us. First, for KOL. So based on the totality of the data, you have seen about PRX-102, do you anticipate any fresh regulatory hurdles or challenges for approval, sort of pushback from the FDA or...

That's always a crapshoot. I mean I think they will look at the data and they will assess it on its merit and they may have further questions. They may say, oh, we need more information about this or that. I mean the data that I'm aware of looks pretty good. So other than that, I don't think I have a good answer for that.

All right. Understood. And then how would you characterize the general physician awareness of PRX-102?

I'm sorry, say that again, please?

How would you characterize the awareness of PRX-102? Position awareness.

Within the Fabry community, most of the physicians that treat, we all know each other. I mean, it's a relatively small world. I think they're looking at it, but being involved in it and I think general physicians, I think there's very limited awareness. But in terms of those who treat, I think they keep on top of that and they're looking at it. So I do think those treaters are aware.

All right. Got it. And then how many drugs do normal Fabry patients take to manage the disease?

That's variable, quite variable. A good percentage of them will be on some type of hypertension medication, and it's not necessarily for hypertension. It's for proteinuria because you want to control the proteinuria, and we know that if you can control the proteinuria in combination with enzyme replacement therapy, those patients have better outcomes. So drugs like ACE inhibitors and ARBs, which are angiotension reuptake blockers. Those medications do that well, and they can also provide some protective heart effects. So in addition to that, treatment of pain with types of neuroleptic medications. It can be antidepressants, which work for that, things like carbamazepine, and some of the other anti-depressants can help with pain. So oftentimes, a pain med or blood pressure med for the renal effects, and then it can be a variety of things dependent upon their gastrointestinal symptoms, which are quite variable. So most patients are on at least 5 medications. That's probably as close as I can get it.

Okay. That's very helpful. And then for you, Dror, so firstly, what are your preliminary expectations in terms of the label?

Boobalan, this, we are now under , if I may say, regulatory processes, as you know, for both -- in both continents with the EMEA. And as of this morning, we have announced on the acknowledgment of the FDA. So I don't think we will refer to further questions on that. We will have to see. This is the process. Clearly, the target we mentioned, the intent is to, hopefully, to get approval for all adult patients in Fabry.

Okay. And then maybe I'm just jumping a little bit ahead here. I know PSA is your partnership, but just curious, what kind of information do you get from Fabrazyme commercial sales that can help you device PRX adoption?

All I can say that as is -- they work very hard and they have established their own infrastructure, of course, they hold the commercial rights. They work professionally and I'm sure they know what they are doing.

All right. One final question from me. What's your confidence level in terms of getting approval for PRX-102?

I'm optimistic. This is -- I think it goes without saying. We believe we have a robust program, and we would work with the agency, hopefully, to get approval.

[Audio Gap] Our Q&A session. I'll now turn it over to Chuck Padala from LifeSci Advisors to read the remainder of the questions from the webcast.

Okay. Thank you, Tara. First question for Myrl is can you please comment on how PRX-102 compares to Galafold? And what percentage of Fabry market each drug can address?

First of all, there's really no official comparison. And that's a very limited space. I think they say the number of Galafold patients who have a minimal mutations, I don't know, 30% to 35%. And I think that's somewhat regional. Our population is probably about 10% of patients or less. And to make that comparison, I just don't think is really very possible.

Okay. Fair enough. The next question is there are limited therapies available in the domain as a whole. However, options are even more limited for adolescents and pediatrics. When can we see PRX-102 being made available for these patients?

I think I should defer that question to the Protalix folks. I mean this is a discussion okay.

It's okay, Myrl.

Okay. It is so...

Thank you, Myrl. I will take it. What I -- we will say that as part of the post-approval commitment, Protalix and Chiesi will conduct a pediatric trial in order to obtain the approval for pediatric Fabry patients. Right now, the resubmission of the BLA and the [indiscernible] that was submission -- submitted, I'm sorry, to the EMA, targets all adult Fabry patients, the 1 milligram every 2 weeks and 2-milligram every 4 weeks.

Okay. Thank you. That is the end of our Q&A. Dror, I'll hand it back over to you for closing remarks.

So thank you, Chuck, and thanks again, everybody, for joining. I would like to thank, especially to Myrl Holida, that joined us today. Thank you. And we wish everybody a happy holiday season. Thank you very much.

Thank you.