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[00:00:12] Dr. Florian Lagler: Hello, everybody. My name is Florian Lagler, and I am pediatrician by training. I'm taking care for patients with mucopolysaccharidosis and other lysosomal storage diseases in Salzburg, Austria, in the Children's Hospital, and I see adult patients together with my transition partners. It's my pleasure to give you a presentation on the clinical features, the challenges in diagnosis and enzyme replacement therapy in MPS today as part of this row at Excellence in Pediatrics webinars. So as housekeeping notes, I would kindly ask you to not take screenshots and do not reproduce the slides. Just use it for your own use, and the format is about 20- 25 minutes of presentations, and then I'm happy to answer your questions with regard to this presentation. You can submit your questions via the chat function of the webinar platform, and I will read out the questions and answer it to you later on. The webinar is recorded, so you can have a look at it later on as well. And with that, I'm happy to start now. This is my disclosure, and the agenda for today is I will start and give you a background on mucopolysaccharidosis as a disease group. I will show you the potential and the limits of enzyme therapy, which is available since many years now, and I will also give you a slight introduction in the strategies to overcome these therapeutic limits of enzyme replacement therapy. So on the background, if we are talking about mucopolysaccharidosis as a disease group, we have to face that there are about 5, 000 to 8, 000 rare diseases. Within this group, there are about 500 inborn errors of metabolism, about 50 lysosomal storage diseases within the metabolic diseases, and then we're talking about seven forms of mucopolysaccharidosis, but there are some subforms as well. Altogether, the cumulative prevalence of mucopolysaccharidosis as a group range is around 1 in 77, 700 up to 1 in 50, 000, depending on the publication that you take into account. Around about 70% of patients with mucopolysaccharidosis have a CNS involvement, and that contributes largely to the disease burden. The first report on a mucopolysaccharidosis patient, or better to say two patients, was published by Charles Hunter, and you will appreciate that we today speak of Hunter's disease when we talk about MPS type 2. This clinical description from 1917 included already the key features of the disease. He was describing brothers 8 and 10 years of age with hearing loss, short stature, as you can appreciate in this picture, macrocephaly, hypertrophic cardiomyopathy, umbilical hernia, joint contractures, skeletal anomalies, and unfortunately the two brothers died with 11 and 16 years of age. Today we not only know about Hunter's disease, but also Hurler's disease, which is MPS type 1 in the severe form, Morquio disease, which is MPS 4a, and Sanfilippo disease, that's type 3 MPS, Maroteaux–Lamy type 6. Scheie was formerly thought as an own entity, but later on upon enzymatic analysis discovered to be simply mild phenotype with MPS 1, and then we have MPS 7 and MPS 9, Morbus Sly and Natowicz disease. This is a busy table, but it should simply illustrate that we have different types of MPS, the bold written types MPS 1, 2, 4, 6, and 7. There is enzyme replacement therapy available today. We have the names of the syndrome, which is obviously the name of the physicians that describe the disease first. All of them are enzyme deficiencies with the respective lysosomal enzymes not working properly and all of them lead to storage of different glycosaminoglycans which have been called mucopolysaccharides in the earlier days and that's why the diseases are called mucopolysaccharidosis. You can see that there is different glycosaminoglycans and there can be different combinations of these in the specific diseases. Now towards the pathomechanism and the phenotype. To give a very short view on that, it's very easy. There is an enzyme deficient of activity in the lysosome that leads to storage of glycosaminoglycans in the lysosome. This leads to enlargement of the lysosomes and thereafter enlargement of the cells. The cells are not only enlarged, they also lose their function and therefore we end up with impaired organ function. That's pretty much the same pathomechanism in all lysosomal storage diseases including mucopolysaccharidosis. Here at the microscopic pictures that you can see in the background you have a normal cell and you have a cell with a lot of storage material in the cell. Actually this cell is a cell after enzyme replacement therapy. The enzyme replacement therapy generally can resolve this storage problem and therefore reintroduce normal function of the cell but not in all organs as we see in just a few minutes. This is a very short video of a patient with Hunter's disease MPS type 2 and you can appreciate that the patient is quite upset in a way. He is very active. You can appreciate also some of the clinical features of the disease which are summarized in the following slide. There are many, many symptoms that can lead to the diagnosis but in general it is in many cases a combination of skeletal anomalies with a shortness of stature, disproportionate because the spine is very short and dystrophic whereas the extremities, the arms and the legs, they are of normal length or at least in comparison with the spine length. So disproportionate shortness of length. As I said, 70% have CNS involvement and then we have a multi- organ symptoms in many of the patients including the typical facial stigma as well as impaired vision, glaucoma, corneal clouding, ENT. Symptoms are oftentimes the first symptoms that lead the patient to a physician because they suffer from enlarged tonsils and adenoids. There are airway problems which can be associated with substantial perioperative risks. There can be heart involvement, liver and spleen are normally enlarged that you can appreciate by the distended abdomen and diarrhea and other gastrointestinal symptoms can also be involved. With regards to the skeletal anomalies, we speak about dysostosis multiplex illustrating that basically all bones can be involved but the spine and the thorax are severely involved in many of these patients as you can appreciate in this scheme here. In the CNS, we normally have behavioral anomalies as you could appreciate in the short video and we have most of all cognitive impairment in the patients that have these signs. So a combination of skeletal anomalies, dysostosis multiplex together with a developmental delay or with one or several of these multisystemic symptoms should lead to the diagnosis or at least it should lead to a referral to a specialized center for rare diseases where the proper diagnostics can be made. To put it in a nutshell, and to make it easy to understand the differences between the different types of MPS, I put it in the following way. So, the type 1, 2, and 7, they normally have the skeletal system involved, multi- systemic symptoms as well as CNS symptoms. However, in MPS 1, 2, and 7, CNS involvement is not obligatory, which means that there is some patients that do not have the CNS involvement that show very normal cognitive development and no seizures and so on. Then we have MPS 6, which in the clinical picture is quite similar to 1 and 2, but all MPS 6 patients do not suffer from CNS involvement. So, these build one group, and from the stature and the joints, one can say these are the stiff forms because they are associated with a lot of contractures in the joints, particularly in the large joints. On the other side of the spectrum, we have MPS 4, which mainly has the skeletal involvement, never has a CNS involvement, and may have or not multi- systemic symptoms. MPS 3, on the other hand, can have very mild skeletal or multi- systemic involvement. It has mainly the CNS involvement with developmental delay, cognitive impairment, and seizures in the longer run of the disease. So, MPS 3 mainly CNS, MPS 4 hyperflexibility and mainly skeletal involvement, and 1, 2, 7, and 6 with a mixture of multi- systemic and skeletal symptoms plus minus CNS. All MPS forms share that they are chronic progressive diseases, as you can appreciate in this Hunter's disease. A patient of mine who looks pretty much normal at birth, but then thereafter developed macrocephaly, hydrocephalus, and here you can clearly appreciate the typical facial stigmata of the disease and already the beginning contractures of the fingers and the hand. All MPS forms share that they have a large spectrum from very mild to very severe forms. For example, in these three Hunter's patients, this patient can speak fluently three different languages, and this patient is severely affected and severely cognitively impaired. This patient has a somewhat impaired cognitive function, but he has a job, a special job though, but he comes along very well in his life. You can see that he has some skeletal problems. He has a little bit of contractures in the fingers. He has a stiff spine, and he has eye problems, hearing problems. So he presents with a multi- systemic skeletal and mild CNS involvement of MPS, whereas this patient is perfectly normal from his cognition, but only shows the skeletal involvement with the contractures in the hands and some other features, and this is a very severe type. However, sometimes to discriminate between severe type and mild type is not so easy because this patient of mine is about one meter of height, and this patient has the same height than me. She is running and even participating in charity runs recently. This patient needs the crutches to be mobile at all, so you cannot discriminate only by body size or skeletal involvement. Even in Marcuse disease, where the predominant features are the skeletal involvement, what is a mild or what is a severe case, every patient has his own history and his own handicap or not. treatment challenges. As I pointed out earlier, there is enzyme replacement therapies available for some of the MPS forms and for the other forms they are under development. The approach is quite straightforward because, as we have discussed earlier, the deficiency in place is that the lysosomal enzyme involved is not active enough to clear the lysosome from the glycosamino glycans from the macromolecules that they should degrade and therefore it comes to accumulation. So the the use of recombinantly produced enzyme as an infusion in MPS, this is weakly infusions, is straightforward. However, one can see that the clinical effects of therapy involves not every aspect of the disease. So on the one hand, we have from this clinical development study a clear indication of glycosaminoglycans going down under treatment and in many patients this is even normalized. We have an increased mobility and endurance with a significant improvement in the six- minute walking tests and we have also visceral improvement quantified in an improved lung function. However, this is by far not guaranteeing a restitutio ad integrum. This is only slowing the progression and improving some aspects. Other aspects are not as well treatable as the endpoints I have just illustrated. By far we have more than 10 years experience with enzyme replacement therapy and we have in our registries more than 1, 000 patients and we can say that the therapy is really safe. It's also delivered in home therapy and this is safe and well tolerated. But on the other hand, as I pointed out earlier, we have clear improvement in some symptoms. We have partial improvement, for example, in spleen size, in cardiomyopathy, which is to some extent reversible but not fully reversible upon treatment. We have an improved walking ability but rarely a normalization of walking ability, lung function and endurance and also the joint range is only improved but rarely normalized and this applies mainly for the upper extremities, for the shoulders, whereas the lower extremities are, there are only minor effects. Moreover, at the bones, at the dystostosis multiplex, there is hardly any effect with the enzyme replacement therapy as well as with the CNS involvement, which of course is a pity. And if we think about how these limited therapy effects can be explained, there is on the one hand a pharmacological explanation to that. Obviously, this bone is very hard to reach as a bradytrophic tissue and then there is the CNS as well as eye, which is protected from the natural blood- brain barrier, which has a very positive effect in the prevention of CNS infection but in this case prevents the enzyme to cross or to get into the CNS neurons and therefore we don't reach the brain, the eye and the skeleton so well. On the other hand, we have infusions and even if it is weekly infusions, we have from the pharmacokinetic point of view a strong increase of the concentration in the circulation but then it goes down again and we are far away from the physiologic continuous level of enzyme activity in the body, so it may be that drug exposure in the target organ is simply too short in time. And then there is an aspect that has more to do with the diagnosis and that is that by the fact that the disease is diagnosed mainly in the second, third or fourth year of life, we start the treatment at this time, whereas the storage due to the enzyme deficiency, the lysosomal storage already starts in uterus or in the fetus already. So in any case, we are starting too low to get the optimum of treatment effect. However, in MPS2 and also in other disease types, there is some rare sibling studies where, for example, in this publication of Paula Tilsky-Szymanski, she showed that siblings that suffer from the same mutation leading to MPS2. led to a severely decreased IQ of 50 in an age of three and four years in this patient. This patient was later on started on ERT when she was seven years old because the treatment was not available at that time. She already had mild dysmorphia, joint contracture, sepidus splenomegaly in an age of three and four years, whereas the brother who was diagnosed by family history very early in life and could start on enzyme replacement therapy in the third month of life had a normal IQ at the age of three years, no dysmorphia, no cardial symptoms, no contractures and only very mild dysostosis. Interestingly enough he has a twin brother who has an IQ of 114. It's not identical twins, so this is a healthy brother of this patient, so it might be that an IQ of 98 already is a little decreased as compared to the brother, but that's not to be defined by a single case studies. In any ways the result of this shows us that if the enzyme replacement therapy is started very early we can even have nice effects on bone and other otherwise not very well treatable aspects of the disease. Of course there are new strategies under development to get a better efficacy in these diseases and as I said the problem is in target exposure and continuous sufficient concentration and therefore all the treatment approaches can be grouped in this way. So I will now give you an overview on new therapies that aim to guarantee an improved target exposure with regard to the brain. You can see a symbol of the brain here and this is the blood-brain barrier. So obviously as in oncological diseases the drug could be applied intrathecally so it can reach the brain and this is under development in MPS 1, 2 and 3 in clinical studies and there is preclinical studies also in other forms of the disease. Besides enzyme replacement therapy there is the possibility to improve the enzyme function by using an approach that is called pharmacological chaperone therapy and these pharmacological chaperones are normally small molecules that can pass the blood-brain barrier, cross the blood-brain barrier and then there is a very interesting treatment approach as well. You can open the barrier of blood-brain barrier by utilizing physiological effects of for example insulin receptors that open the blood-brain barrier and therefore you can build infusion, you can build fusion proteins of the enzyme that is therapeutically needed and an antibody that opens the blood-brain barrier by binding to the insulin receptor and so you can shift in the enzyme and that approach is called the Trojan horse approach. That's why we have this symbol here and this is under development as well in clinical studies. On the other hand it is obvious that in a genetic disease gene therapy should be one option to go for and there is clinical studies in MPS 1 and 6 already and preclinical studies also in other MPS forms. Another approach that aims to establish a continuous secretion of enzyme into the organism is the use of micro-encapsuled cells that are implanted into the patient. There is only preclinical experiments going on there but in other words this is a very tiny bioreactor that is micro-encapsuled so it prevents immunological reaction towards the foreign molecules in the body. Interestingly enough it has been shown that gene therapy only reaches effects in the CNF if it is applied into the CNS and there are studies going on with the injection of ex vivo. ex vivo gene therapy vectors that are directly brought into the brain. So that is the future, but I think that's the near future in which we will hopefully be able to improve the target, the concentration of enzyme at the target and a continuous availability of a functional enzyme. So to conclude this very short overview presentation, I want to express very clearly that MPS, mucopolysaccharidosis, are complex diseases that need early diagnosis, that need the ability to recognize the clinical pattern. It's not, in most of the cases, it's not one single symptom that is leading towards the diagnosis, but the combination, the clinical pattern of skeletal, CNS, and Marti system symptoms that direct us to the diagnosis, or at least to the suspect of a genetic disease and further workup in a specialized center. Early causal and also supportive therapy is critical for the patient because many disease complications can be improved by very comprehensive supportive therapy, and this needs a competent multidisciplinary team, including a metabolic pediatrician, neuropediatrician, orthopedics, and so on and so on, ENT surgeon, many disciplines are involved, and therefore MPS expert always needs to be a leader of a multidisciplinary team that provides best care possible for the MPS patients. There is innovative therapy approaches on the way, which hopefully will bring better efficacy in the near future to most of our patients. And with that, I close the presentation and I'm happy to receive your questions and answer them. So we have one question here. What is the key symptom that should direct me to the diagnosis of MPS? So as I pointed out earlier, it is rather the pattern. So the combination of symptoms in the skeleton, as well as multi systemic symptoms like the ENT problems, for example, or hydrocephalus as a CNS problem that should direct us to the diagnosis. However, as a rule of thumb, we can say that if there is these three systems, the skeleton, as well as the CNS, as well as visceral organs are involved, we should suspect a genetic disease and we should direct the patient to a specialist for rare diseases, endocrinologist or metabolic pediatrician to do the further workup. If there is, if I should pick one single sign that can direct directly to the diagnosis of MPS, I have to say that the carpal tunnel syndrome, for example, that is a result of the storage into the soft tissue that is rarely occurring in other diseases in childhood. It's very common in adults, but in a child that has a carpal tunnel syndrome, you should always suspect MPS. And on the other hand, the contractures of the fingers, we call it the claw hand, can also be a very early symptoms, sometimes not detected. So if you have an eye on that, you may be able to find the diagnosis very early. Let's see if we have another question. It's the question, is it possible to treat with enzyme fetus? If yes, aren't there any consequences or complications in the future? So yes, of course, this is a straightforward approach. I'm not aware of any clinical trial that has done this before, but in the first page, this would for now mainly apply for siblings of patients that have been diagnosed earlier. And yes, we can do a prenatal diagnosis. And in these cases, in theory, the intrafetal infusion would be an option. But on the other hand, of course, it's a true challenge to do this on a weekly basis, because as I've pointed out earlier, we need a continuous, sufficient concentration of the enzyme in the organism, in this case, in the fetus, and weekly infusions, I think, is still in our days a true challenge in prenatal medicine. But in theory, yes, this would be an approach. Let's see if we have another question. MPS6 nugleosyme and pretreatment with antihistaminics and ibuprofen. So I guess the question means Is this necessary? What do I think about it? So this question obviously comes from someone who has experience with the treatment. The treatment, the weekly infusions with enzyme replacement therapy can lead to infusion associated reactions. The clinical picture of these infusion related reactions, they are similar to allergic reactions. However, the mechanism is slightly different. So these allergic reactions or pseudo allergic reactions can include flush and itching, but they can in the extreme case, which fortunately is very rare, lead into an anaphylactic situation with shock of the patient. So it is important to prevent this as good as possible. Pretreatment with antihistaminics and ibuprofen is one option that we can use. We can also use steroids, cortisone as a pretreatment to reduce the probability of infusion related reaction in the patient. Normally with nuglosyme and in MPS6, we start the infusions without pretreatment, but if we recognize infusion related reactions, we use antihistaminics and steroids and in an extreme case epinephrine as an intramuscular injection as an emergency treatment and thereafter, if when we restart the treatment the week after, we also use this medication, not the epinephrine, but steroids and antihistaminics and also ibuprofen as a pretreatment. There are other factors that can lead to a reduced risk of infusion reaction, which is very careful handling of the enzyme while dilution because the enzyme is a very complex molecule that suffers from heating, for example, or rapid movement. Don't shake the infusion. Use large needles if you dilute the enzyme and be very careful with that. That also contributes to a low probability of infusion reaction. So, if a patient reacted once, we need to be very careful. Reduction of infusion rate can also be one method to increase the risk of, to decrease the risk for a further reaction and overall, we can say that all patients can receive the enzyme even if they showed infusion related reactions with acute treatment, with pre-medication, with reduction of infusion rate. Every patient should be treatable in the long run, but it may be necessary to start slowly and with pretreatment after a patient reacted. Okay, I hope this answers your question comprehensively. Is there any event or training that provides further information on diagnosis and management of MPS? Yes, of course. There are many conferences going on. There is a yearly conference of the International Patient Organizations held in different places and we serve together with other leading experts in the field including Dr. Cristina Lampe, Matthias Schäfer, Maurizio Scarpa, Christoph Kampmann. So, with international colleagues, we provide MPS preceptorships. That's a three-day training that includes a lot of clinically relevant presentations, overview presentations, case presentations by the participants and the faculty and there's a very special format. We also include simulation training where we simulate emergency situations including infusion reactions, but also other emergency situations. We simulate this by using patient actors and simulation robots and we provide by that opportunity to gather experience in the treatment of patients. So, altogether these preceptorships are very intense and very informative three days programs and if you're interested, you are very welcome to send me an email and I can see when we can invite you for one of these trainings. Let's see if there are further questions. I can see that there is no more further questions and with that I want to thank you for your participation and I hope this presentation and the questions and answers were helpful for your clinical practice and I'm looking forward to meet soon on one of the conferences or one of our trainings. Enjoy your work with the MPS patients. Have a nice day. Thank you very much.