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[00:00:27] Dr. Florian Lagler: Hello everybody it's my pleasure to give a webinar today on MPS and advances in treatments. My name is Florian Lagler and I work in Salzburg Austria and seeing MPS patients and other patients with lysosomal storage diseases. I'm pediatrician and pharmacologist by training and it's my pleasure to do this together with you with MPS Europe. Thanks for invitation with European reference networks and excellence in pediatrics. First of all some notes for you please don't take any screenshots, don't reproduce any of the slides or contents without express written permission of me. The format will be 30 minutes presentations and answers and questions. You can submit your questions using the chat function of the webinar platform. I will then read it loud so that I can answer it for everybody. You can ask any question that you want I will try and answer all of your questions. It is recorded the webinar and you will be able to replay it if you like and approach it online via the indicated web URL. Okay so let's get started and get into contents right away. Advances in treatments available for MPS and I'm going to give an overview on a short after a short introduction I will give an overview on the key limitations of current therapies, the state of development of emerging therapies. I will by that a little bit explain the active mechanisms and the expectable limitations of these new therapy forms. But first of all I would like to start with a short introduction. This is my disclosure slide. The background for the background of mucopolysaccharidosis. It's important to have in mind that we are talking about rare diseases, even very rare diseases. Next to the MPSs there are five to eight thousand rare diseases known and about 500 inborn errors of metabolism. Of course the number of identified diseases is increasingly is increasing very much. We know about 50 lysosomal storage diseases and within that group we have seven MPSs and subforms of these MPSs. The cumulative prevalence of the MPSs as a disease group is something around 1 in 8, 000 to 1 in 50, 000. So it's not too improbable that each of you will see MPS patients even if you are not in the field of lysosomal storage diseases in general. It's important to have in mind that about 70% of the patients have a CNS involvement and this is also important when we later talk about the therapy. The first cases of MPS II, Hunter's disease, really were described very well by Charles Hunter and already presented with a typical phenotype. He presented, he reported two brothers with Hunter's disease 10 and 8 years of age hearing loss, short stature, macrocephaly, hypertrophic cardiomyopathy, umbilical hernia, joint contractures and skeletal anomalias. Unfortunately they died young but the clinical picture described by Charles Hunter is really representative for the classical forms even today. Of course you know that there is several types of mucopolysaccharidosis and they are described as syndromes with the name of the physician that first described it. To start with Gertrude Hurler, MPS I, the severe form and so on. You can see that these forms have been described beginning with the early 1900s and MPS IX was described by Natowicz in the end of this decade, sorry, century. And here you see the physicians that described the diseases. This is our systematic nomenclature. Today we have MPS forms, severe Hunter, the severe form of MPS I is referred to as Hunter's disease and the mild form is referred to as Scheie disease but otherwise it's type I, II, IV, III, VI, VII and IX. In all of these MPS diseases an enzyme is deficient, and this is again important to understand the therapeutic concept, because what we nowadays provide is enzyme replacement therapy as the gold standard therapy. For the diseases where drugs with a recombinant produced enzyme are available, and this is the case for the bold written here- MPS I, II, IV, VI, VII and for the other diseases, therapies are underway and, as you will see a little later, there is also other therapeutic concepts. But in the first part of the presentation we will pretty much focus on enzyme replacement. So the enzyme that is deficient in the MPS can be recombinantly produced, using cell cultures of human cells, animal cells or plant cells even, but this is beyond the scope of this presentation. To give you a deeper insight into pharmaceutical production of this product, it's important that it's a causal therapy, because the defective enzyme is replaced by the enzyme replacement therapy, or also referred to as enzyme therapy. So it's important to have a basic understanding of the pathomechanism. These deficiencies of the enzymes, of the lysosomal enzymes involved in the different forms of MPSs, leads to accumulation of glycosaminoglycans, which have been named mucopolysaccharides in the past, and that's why we speak of call the diseases mucopolysaccharidoses. The storage of glycosaminoglycans leads to impaired cell function and impaired organ function. More or less every organ can be involved, but we have a strong affection of the skeletal system in general and, as I've said earlier, in 70 percent of the patients also the CNS. So in this very short video you can appreciate the phenotype of a typical Hunter's patient very shortly- sorry, in a very short video. What have you seen? Actually, what you can see, even in the picture, is that the complications of the symptoms of the disease affect mainly three systems, which is the skeletal system and the vast picture of dysostosis multiplex, so the involvement of many, many bone and of the bone development in general, affecting the spine but also the other bones, leading to dwarfism, disproportionate dwarfism as we call it, because we have a very short spine and in proportion, the extremities are normal or long in proportion with a short neck, kyphoscoliosis and so on. I will not go in too much into details, but it's important to have in mind that the skeletal system is affected very much: the CNS in 70 percent of all MPS patients, and then what we summarize as multi- systemic symptoms, which include typical face-eye involvement, ENT symptoms- very important also for perioperative complications- airways, the heart involvement, the abdomen with a large liver and large spleen, carpal tunnel syndrome and so on and so forth. So it's a very multi- system disease, but the pathophysiology should only be very shortly described so that you can understand the specific aspects of the therapy that we will discuss now. For the systematics, it's easiest if we put it in a nutshell as follows. So we have the different types of MPSs. In each type there is different enzymes involved and type I, type II and type VII are pretty much the same as they share skeletal, multisystemic and plus minus CNS symptoms. These are patients that suffer from strong cartilage contractures very much. So they have a strong skeletal involvement and multisystemic disease plus minus CNS symptoms. Type VI is also quite similar, but patients with MPS type VI, they never have the CNS involvement, at least not due to the fact of MPS type VI. They can of course have a different reason or different cause of CNS involvement. Then we have MPS IV, Morquio disease. The skeletal symptoms are very predominant. These patients do not have CNS involvement and rather mild multisystemic diseases. The other way around in MPS III, where we have predominantly the CNS symptoms and there can be skeletal and multisystemic symptoms, but they are not so strong as in the other forms of MPS. What do they share? In the clinical picture, all of the MPSs are chronic progressive. This is a Hunter's patient of mine. We also have a broad clinical spectrum from very mild to quite severe forms. This is again Hunter's patients and intermediate forms. Hunter's patients can be of normal height, for example, but they can be of short stature. This patient, for example, is very intelligent, speaks several languages, and this patient is very handicapped, as you can see. So we have a broad spectrum of severity, and it's not always easy to really say this is a mild case, this is a severe case. This is, for example, two patients with MPS type IVa, Morquio syndrome, and this patient is almost of my height, and this patient is around about one meter of height. So who is the most severe? Well, this one is very mobile, and this one needs the crutches, so it's not so easy. That's just to point out, it's not so easy to say severe phenotype, mild phenotype. That's why we normally refer to, in the other MPS forms, not in the MPS IV, in the other MPS forms, we say it's a Neuronopathic with CNS involvement form or a non- neuronopathic form. Good. What are the treatment challenges of enzyme replacement therapy? As I said, enzyme replacement therapy was for a number of lysosomal storage diseases the first causal therapy available, and it was a very fascinating history of medicine and pharmacy, one has to say. It's really great that we have these therapies available, and as you have seen for many, many forms of MPS, we already have enzyme replacement therapy available. It is normally provided in weekly infusions, well tolerated, and it's effective and safe. However, of course, there is some shortcomings that need to be kept in mind. So first of all, let's start with the clinical development program and the data that has been provided for the market approval of, in this case, the enzyme replacement therapy for MPS II. What did they show when the drug was approved? Glycosaminoglycans go down from an elevated level to normal or near-normal concentrations in urine and blood. Then mobility and strength is increased and was measured in a six-minute walking test. This was significantly increasing, and the same is true for the lung function. Meanwhile, for the example of Hunter's disease, we know about more than 1,000 patients documented in the registries, and we know that the enzyme replacement therapy is efficient and is very well tolerated. The main side effect to be kept in mind is infusion reactions, which is acute reactions upon infusion, during the infusion, or right after that, and they can be very mild, which is the case in most infusion reactions. In infusion, it's only a mild rash or it's itching sensation. can be a slight cough, but it can go up until anaphylaxis in very rare and very strong situations. So the team that is providing the enzyme replacement therapy should be aware of these complications. And that is why we, together with Christina Lampe, Matthias Schaferand some other colleagues, set up emergency training and effusion complication training in our simulation center. But if you're aware about these potential complications of the infusion therapy, then it's really, really safe to be provided. And the infusion reactions can be stopped by stopping the enzyme and, for example, antihistamines and so on. So the safety and the efficacy is really very, very positive. However, there is some limitations to be kept in mind. Whereas the GAG concentration and the liver size goes down quite nicely upon therapy. Spleen volume is only partly improved in many patients. Cardiomyopathy and cardiac function improve, but they may not normalize. Walking ability, lung function, endurance, joint range of motion in the upper extremities get better, significantly shown in the studies. But this is not a normalization that we appreciate in the cases that are treated with two, where the treatment starts with two or three years, as this might be the average also in your countries. Very minor effects are seen in joint of range of the upper extremities on the bones and on the CNS. And it is important that you understand the potential reasons for that. Enzyme-infused, the recombinant drug is a rather large molecule with physical chemical characteristics that leads to the fact that they don't pass the blood-brain barrier. So if you infuse the enzyme intravenously, then it cannot go across the blood-brain barrier. That's why in these 70% of patients that have CNS involvement, the CNS involvement is hardly treatable with the infusion therapy, with the enzyme replacement therapy. The same is true for the eye. There is also anatomic barriers. And the same is, of course, partly true for the bone. Bone is a bradytrophic tissue, which is not very well reachable for the enzyme. The other thing is that in physiology, that means in humans without an MPS, the enzyme is produced quite continuously. Whereas if we give an infusion, then the halftime is quite short. So we have a substantial peak right after the infusion, and then the concentration go down. And this might contribute to the limits of efficacy of these drugs. And then, of course, this is not the pharmaceutical aspect or pharmacological aspect. This is a clinical aspect. Many of the patients are diagnosed only in the second, third, fourth year, or even later. I have, I follow one patient that was sent to me by colleagues. He's a very mild MPS. One patient was diagnosed only with 30 years of age. So the diagnostic delay can be substantial in the mild forms of the MPS forms. And then, of course, it is more successful if you start treatment early. So early diagnose and early treatment start is very important to have the optimum of efficacy and efficiency. There is even sibling studies out there published. I will not go through this in very detail, but sibling studies where you find siblings that share the same MPS genotype, the ones that are diagnosed late, in this case with seven years, or that receive therapy start only late in the first decade, in this case with seven years, they show. Much stronger phenotype as the ones that are the siblings that are diagnosed right after birth and then can receive the ERT very early. But honestly, this is only few cases and this is not very strong evidence, but it gives us an insight into that. The fact of bone is hardly reached and the brain is hardly reached. This is a little relative if you have a few on these patients. So in any case, we should take this as a strong motivator to try and contribute to a early diagnose and early treatment of these patients. So of course, medical and pharmaceutical research goes on and it's directed to improve the therapy available for patients with rare diseases and also for MPS patients. Of course, it is not a given that we cannot reach the point- the brain, that we cannot treat the brain and the bone. There is some strategies that try and do better and if I want to structure these efforts, then there is two fields that have to be kept in mind. So drugs- try new drugs, innovative emerging 30 approaches aim for improved target exposure. So brain, bone, eye and so on should be reached by the active compound better and additionally, as a second point, continuous sufficient concentration of the enzyme is expected to be key for well treatment if for optimum of treatment effects. And using this schematic, I will now introduce it to some of the most interesting emerging emerging therapy concepts for the treatment of MPS. So this is a schematic picture of the blood-brain barrier. So here you have a vessel, you have the blood- brain barrier, here you have the CNS, which of course includes the brain and the spine marrow to reach the brain or the intrathecal space. Of course it is quite straightforward to inject the drug into intrathecal, which can be done by lumbar puncture or can be even done by intrathecal injections. There are several programs on on the way for MPS I, II & III, and I think this is a very promising approach that is has already been studied in in clinical trials. The results are very promising. However, it is not so easy to show treatment effects because it's also very much dependent on the time point when you start the intrathecal therapy. This is very important for the aspect that can the effect that can be expected. So in this systematic figures I will show you the black references here in the case that it's studied in clinical trials, and there is also the gray citations which indicates that it's preclinical data, so far only, which is animal models and other preclinical experiments. There is another interesting approach, which is called the chaperone approach. So chaperones are small molecules that bind to the defective protein, in our case to the defective enzyme, lysosomal enzyme, and by binding specifically to this protein they improve the three- dimensional structure. We call that folding, so the folding of the protein from misfolding to functional folding. And this is used in many other diseases as well. For example, there is an approved drug on the market for phenylketonuria which acts as a pharmacological chaperone. The beauty on this approach is that the small molecules have a high probability to pass the blood blood- brain barrier and, as you can see, there is some studies going on for MPS II, III and IV with pharmacological chaperones that can be applied even orally or as an infusion, and then bypass from the venous system into. They bypass the blood- brain barrier and reach the brain, the CNS. Then there is another very, very interesting treatment approach and I use this maybe funny looking figure here for you because this approach is called the Trojan horse approach. What is it? So there is even larger molecules that are able to open the blood-brain barrier in a way so that even large molecules can cross the blood-brain barrier. This has some physiological functions and is the case for example for the insulin receptor and if you produce an insulin fusion protein, so a large protein of insulin receptor molecule together with the enzyme that you want to transport across the blood- brain barrier. This is referred to as a Trojan horse approach because maybe you are aware with this history of the Trojans that used the wooden horse to enter Troy, oh it was to Greece, sorry, to enter Troy and the soldiers were in the trunk of this horse. In this case, it's not in the trunk, it's just fused to this transport molecule, if you may, the insulin receptor and the transferrin receptor acts in the same way. So there is some studies going on where an enzyme is fused to an insulin receptor or transferrin receptor and the transferrin receptor and insulin receptor docks in the blood-brain barrier, opens the blood-brain barrier and then it's permeable for the large molecule of enzyme so the enzyme can reach the CNS. All what you see here obviously is aiming for a better target reaching, a better target concentration of the enzyme or of a functional enzyme that is already there. Now how to get the continuously and sufficient concentration in the target organs?
[00:27:25] Dr. Florian Lagler: Of course, if you talk about genetic disease, then it's very straightforward to have gene therapy in mind and whereas 10 years, 20 years ago we were mainly talking about gene therapy, gene therapy now is really available and in clinical development for a number of diseases, even approved for some of the diseases and there is some very interesting clinical programs going on for MPS I, MPS VI and also for MPS III meanwhile. So gene therapy means that a mutation in the gene is corrected and that physiological protein can then be read and produced of the organism itself. You can however also use a mini bioreactor in a way if you use encapsulated cells that are not detected as foreign by the body and therefore not induce immunological reaction and that produce the enzyme like a mini bioreactor and that can be used. But interestingly enough, even if you do systematic gene therapy in the organism provided by infusion for example of a vector in vivo gene therapy or corrected DNA in an ex vivo approach, these infused vectors, infused ex vivo gene therapy products, they don't reach the brain. If you don't inject them directly into the CNS. So this is the blood brain barrier is still active in gene therapy and so it's important to provide the vector for example for an ex vivo approach directly to the CNS. But this is done even in clinical trials believe it or not and it's very promising to do that. Those who are aware about the zinc finger nuclease approach, this is also involved in this treatment approaches and as you can see there is gene therapy clinically under investigation and that's very promising of course for the future time. Because in gene therapy as well as in this micro-encapsuled cells, you can expect the continuous production and continuously available functional enzyme for the organism and so. You will if you reach the brain and the bone and so on have sufficient enzyme in place to prevent the accumulation and by that prevent the organ dysfunction. So overall this is very promising and I want to conclude with a short summary in times of enzyme replacement therapy. But the same will be true also for the innovative emerging therapy approaches. Early diagnosis is critical because otherwise you have irreversible organ involvement that cannot be treated very well with whatsoever therapy. The recognition of the clinical pattern is the key for early diagnosis and besides the causal therapy may be enzyme replacement therapy or one of the other therapy approaches that I've just shown. Comprehensive supportive therapy is very important. This was not in the focus of this presentation I have to say because it's not possible to keep all the supportive therapy options together with what I presented today. But this is why an MPS patient should always be followed in a specialized center because it's always a multidisciplinary approach to treat these patients. You need ENT specialists, ENT surgeons, neurosurgeons, the metabolic pediatrician of course, neuropediatrician, orthopedic and so on and so on. And in only very few centers worldwide you have centers where you have for each discipline a real MPS experience expert. That is why there needs to be a team leader of this multidisciplinary teams and this team leader should know MPS the best.
[00:32:10] Dr. Florian Lagler: Maybe it's you in your center. So if you're so far only focused on your metabolic or rare disease expertise, please keep in mind your patients need you also as a competent team leader for a multidisciplinary team approach. And this is why in our preceptorship programs and in our simulation programs we very much stress this as well and show how an MPS expert should also involve other disciplines. In emergency situations of course this might often be the intensivist or the anesthetist to be in a way guided and led by the MPS expert that may be you in your center. So there is innovative therapy approaches on the way. And I hope that I could give you a good overview on what is there on the way and I could give you an insight into how they work and what we can expect of this innovative therapies and what we can of course expect also of the already approved and available therapies. And with that I'm looking forward to your questions. Thank you very much. So we have the first question here. What is the earliest age enzyme replacement therapy can or should be considered? Actually this can be considered from birth on. There is my friend and colleague Christina Lampe described some very interesting cases where enzyme replacement therapy was started very early. It's well tolerated and you should start right after therapy. Sorry right after the diagnosis has been made. We have the next question here: who would you include, as a minimum, in a successful multidisciplinary team and the wider team when administering treatments? So I think this question has two parts. I want to start with when administering treatments. So I understand this question in a way: who is needed to provide the therapy now, once the diagnosis is made and confirmed and you are just about to start the enzyme replacement therapy? The summary of product characteristics says there needs to be a physician available experienced with enzyme replacement therapy, and this, of course, is maybe not under discussion. But actually providing the therapy is quite a simple thing you have to have in mind to prepare the infusion very carefully. Use large needles, for example, for the syringes that you use to prepare the infusion, so that the protein, which is very susceptible to physical and thermic stress, is not stressed. What I mean is handle it with care, don't shake the bottle and be very careful and read the summary of product characteristics, where this is also described. Let me use the chance and also underline that you should not heat up the infusion, but also from the temperature, be very careful with the infusion, but if this is kept in mind, then it might be the metabolic physician that provides the infusion and so on, and if the infusion is well tolerated, you don't need any other discipline. On the other hand, if you have a patient that already presents with symptoms of the disease, then you will need an interdisciplinary team, and that should, in any case. I mean it's a little dependent on the MPS form that you're dealing with, but I very much benefit from my colleagues in orthopedics, for example, in neuropediatrics- orthopedics for the skeletal problems, for the osteosis, for example, and so on, and the neuropediatrics patients can have seizures and for the developmental and behavioral aspects of the disease, as well as the neurosurgeon. Those patients can have a hydrocephalus and so on and so on. So I think to give a comprehensive list for all the disciplines that are involved normally is really beyond the focus of this presentation. It is also very much dependent on what your patients, what complications, what symptoms your patients present. Do they all have to be an expert. Seeing a defined number of MPS patients well, it's a benefit, of course, but most importantly is that you know your patients very well, you know MPS very well, you know the standards very well and if not, then reach out to one of the centers and then keep your colleagues informed. One critical aspect of cooperation, for example, is the preparation of an MPS patient for an elective surgical procedure. It's always a challenge to inform the anaesthetists about the specific risks and needs of these patients, which can include, for example, large tongue, narrow airways and so on that need a fiber optic intubation and so on. So it's important that you, who knows MPS very well, make your colleagues, your interdisciplinary colleagues, aware of the needs. I hope this answers your question halfway sufficiently because I want to continue with the next question. How does enzyme treatment differ between mild and severe cases, length or treatment or strength of infusion? Well, actually, in MPSs we normally use the standard concentrations. In the mild as well as severe cases that we are treating, it is more a question of starting and quitting treatment. So I have experienced very mildly affected patients that after some years of treatment, asked for quitting the infusion or themselves stepped back from treatment because they said I cannot see the benefit. And even there is, as a matter of fact, there is very mild cases where you may dispute if there is only bone involvement that cannot be reached very well with the enzyme replacement therapy, whether or not to continue with the enzyme replacement therapy. But those would still be the same, but whether or not to continue might be a question in these very mild cases. And it might also be a very difficult discussion in the very severe cases where you have more or less a palliative situation. This is hard to decide, always needs also a team approach and much experience and well knowledge about what you can reach with enzyme replacement therapy and whatnot. So if you are in this situation to consider and quit the enzyme replacement therapy after many years of treatment, for example, and with progression, then you should reach out to an expert that sees a lot of patients. Okay, I would like to continue with the next question. When you talked about Hurler patients, have they had a bone marrow transplant? So that is a very good question. Of course, enzyme replacement therapy is not the only approved therapy for MPSs. There is also bone marrow transplantation, but it is important to know about bone marrow transplantation that not all MPS forms benefit from them and it's important to start very early. So the best experiences have been made with MPS I. That's why the participant asks about Hurler's disease. So if you diagnose a Hurler's patient within the first year or manage to provide stem cell transplantation, bone marrow transplantation within the first two or some recommendations say two and a half years, this is a very good option because this can also improve the CNS situation. So if you manage to diagnose a Hurler's patient's MPS I severe form early enough, then stem cell transplantation or bone marrow transplantation is recommended. Not after the third year, fourth year and so on, because then the risks and the expected benefits don't have a very well ratio, a very good ratio. Also true for the other MPS forms, but it's unclear why, for example, Hunter's is different. One thing that is different between Hunter's disease, so MPS II and MPS I, is that Hunter's disease is often diagnosed too late as if to have a strong benefit from the bone marrow or stem cell transplantation. There is some clinical data published about bone marrow transplantation in other MPS forms, but the most convincing data comes from MPS form. Okay, here's the next question. After osteotomy operation for Morquio A, will the knocked knees turn knocked again? So the knocked knees, genu valgum, is a problem that affects different forms of MPS, but very strong, it's seen in MPS for Morquio A disease. And these can be fixed by a surgical procedure, which can have very nice results. However, it can also reoccur, so a continuous multidisciplinary care for these patients is very important. You cannot expect that it stays forever after a correction. The same is true also for other operations. This is why prospective regular follow- up investigation that includes, of course, the skeletal system as well as the other organs that can be involved, is of paramount importance for these patients, and it's provided in MPS centers, of course, so that not only when there is negative signs like pain or other complications, but you should be proactively identifying and treating the disease complications that can occur despite enzyme replacement therapy. Would you treat with ERT patient with MPS II with neurological involvement? So this is now a chat question with roughly 12 words or something like that and of course this is too few information to answer it right away. It is dependent also on the other complications. It is important to have in mind what ERT can reach and what not. As I pointed out, the bones and the CNS are not very well reached by ERT, by enzyme replacement therapy. So neurological involvement cannot be treated with a systemic enzyme replacement therapy. Should be possible to have benefits from infra-thicker but the question is asked because you can dispute if a patient with a CNS involvement should receive the enzyme. But the enzyme is not only treating this CNS involvement, it's treating also other aspects of the disease, the high frequency of ENT infections, the complications arising from the swelling of the mucosa in the airways and so on and so on. So to answer this question actually you have to have in mind the specific patient, you have to have in mind which symptoms and disease complications are present in this patient and which of these complications can be reached with the enzyme replacement therapy. And upon this information in the dialogue with the patient or patient parents, you have to find the best decision between palliative situation where you also can consider to stop the enzyme replacement therapy or a continuation of the enzyme replacement therapy. To be very clear, CNS involvement is not a 100% contraindication for enzyme replacement therapy but a desperate case might be a different story. So you need to see the patient. What do you think about adding ERT after bone marrow transplantation and hematopoietic stem cell transplantation? So this is of course very difficult to answer with good clinical data but the recommendation out there based on the cases that we know on the registries that we analyze on the research data that we analyze, we believe that in preparation of bone marrow or stem cell transplantation it's beneficial to receive enzyme and thereafter as well for a certain period. It is for sure not necessary to continue enzyme replacement therapy in a patient that was early diagnosed, early transplanted and had a good response to this transplantation. So the standard protocol says that we follow as well is in the preparation of the transplantation enzyme replacement therapy shortly after and then you can quit the enzyme replacement therapy upon good response to transplantation. Have you seen or considered Abeona Therapeutics data in IIIA and IIIB here in IV administration across the blood- brain barrier? I would ask you to approach me directly for this question because I'd say this goes beyond the focus of this webinar and we are already short in time. This needs a little broader discussion but please feel free and use my email address which should be available via Excellence in Pediatrics and we discuss this right away. No problem. Okay and I can see that apart from the last question there are no further questions. I very much thank you for participating and by raising these interesting questions. I hope it was any helpful for you and I hope to see you soon in one of the conferences again if this is possible again. Stay healthy, take care and see you next time. Thank you very much.