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[00:00:00] Dr. Julia B. Hennermann: So hello to everybody joining this webinar. My name is Julia Hennemann. I'm a pediatrician by training, specialized in inborn errors of metabolism with a special focus on lysosomal storage disorders and alpha mannosidosis. And I'm very happy to welcome you together with Sarah Haupenthal, who is also a member of our team, which is located in Mainz in Germany. She's a psychiatrist. And she will be here in the second part of this webinar, an overview on the psychological aspects of alpha mannosidosis. So I'm very happy that you are all joining this webinar. First, before we are starting, I would like to give you some housekeeping. So please don't take any screenshots. You are not allowed to reproduce any of the slides. We will give you a 45-minute presentation. And afterwards, you will have time to pose your questions. If you have any questions, you may submit them any time via the question panel. And now I would like to start with my talk, which will be on the role of enzyme replacement therapy in managing alpha mannosidosis. Sorry, I'm a little bit too fast. So here you can see our center, which is located in the middle of Germany.
And I would like to start, first of all, with my disclosures. And now I'm coming directly to the enzyme replacement therapy. There's only one enzyme replacement therapy available for alpha-mannosidosis. This is the first human recombinant form of alpha-mannosidosis, which is Velmanase alfa. It is applied once a week in a dose of 1 milligram per kilogram of body weight per infusion, as all the other enzyme replacement therapies you know in lysosomal storage disorders. And it has been approved in Europe in 2018. And followed by approval of the FDA two years ago. But it is also approved in Brazil. And we know it's now approved in more than 30 European countries also in UK. It is approved for the treatment of the non- neurological manifestations of mild to moderate forms of alpha-mannosidosis in pediatric patients as well as in adult patients. And it has been used also for treatment before and after stem cell transplantation, which is another treatment option for some of the patients with alpha-mannosidosis dose. So here you can see how the enzyme replacement therapy works. On the left side of the slide, you can see the lysosome which is engorged in a patient cell with alpha- mannosidosis. You can see the accumulation of the substrate here. What is happening if you give the enzyme replacement therapy? The enzyme replacement therapy has an identical structure to the natural occurring enzyme. It then results in a kind of clearance of the mannosidase-enriched cells. And you see this kind of clearance of this accumulation of oligosaccharides. There have been a couple of different clinical trials with Velmanase Alfa. The first trial is quite a long time ago. It has been published 12 years ago. This was the first clinical trial in children. So there had been 10 patients included at the age of one to 17 years. It was a phase one, two open label trial. And what has been found in these children? In these children has been seen that there was a decrease of the oligosaccharides. This is what is increased as you have heard before in the other webinars in patients with alpha mannosidosis dose. And interestingly, there was not only a decrease of oligosaccharides in serum and urine. You could see also a slight decrease in the cerebrospinal fluid. There were further improvements. There were improvements in motor function as improvement in the three minute stair climbing test and improving in the six minute walk test. You can see the results were quite amazing. And there was also a slight improvement in the cognitive function. And the cognitive function has been measured by the Leiter-R test. I don't know if you are familiar with that test. It's a special test too. It's kind of non- verbal test of intellectual function in individuals being aged two to 21 years. So, the next trial, which had been published, was in 2018, so five years later. This was a placebo- controlled trial, Phase III trial. It took about 12 months, and there had been a couple of more patients being included, 23 patients. And you see, there were not only paediatric patients, but also adult patients, so the age range was from 5 to 30 years. And in this group, it was placebo- controlled. There was very well seen that, in comparison to the patients being treated with Velmanase Alfa, to the patients, to those patients who received placebo, there was a significant decrease of oligosaccharides in serum of more than 60%, and there was an improvement in the three- minute stair climbing test.
And looking further, the next results, which had been published two years ago, were the results of a paediatric study, but very young paediatric patients. You see, they had been aged younger than six years. Only five patients could be included in that trial. It was also an open- label trial, Phase II trial, and it took about 12 months. And what was seen here, in these patients, that there was a significant decrease in oligosaccharides, also serum measured. It was up to more than 80% in some of the patients, and there was an improvement in this three- minute stair climbing test, nearly up to 30 steps. So there were very good results in these clinical trials, and I would like now to show you some of the results. Here you can see the decrease of the serum oligosaccharide concentration. This is very important, as we know that patients with alpha monocytases have an increase of these mannose-rich oligosaccharides all over the body. So if you see that there is a decrease of these oligosaccharides, you see that there's an effect of the Velmanase Alfa treatment. So ERT then led to a decrease of serum oligosaccharides in all patients. Here are the data of the second publication I just presented to you, and you can see here in the figure two different curves. In the bottom line here, you can see those patients being younger than 18 years, and here you see those patients being adult. You can see in both patients that there's a significant and very rapid decrease of the serum oligosaccharides. In contrast here, I would like to show you the data of the pediatric study, which had been published just two years ago, and you can see here the graphs of all the four children which had been included. You see that there is a significant decrease of nearly all oligosaccharide concentrations in the patients. You see there's one patient who shows a short increase within time of treatment, and this was a patient who developed different antibodies to the velmanase alfa. So this is the reason why there was an increase of the oligosaccharide concentration. Looking to further parameters, I would like to show you the data of the three- minute stair climb test. First, I would like to start again with the data of the placebo- controlled trial, which had been published in 2018. Here you can see again two different age groups. Here you see the group of the pediatric patients. Here you see the group of the adult patients. It's quite significant that there's a really very huge increase in the three- minute stair climbing test in the pediatric patients, whereas there's no good effect in the adult patients.
But I think this just reflects that adult patients often have a progress of the disease. That means the disease starts and if you start quite late treatment then patients may have already severe motor development. They may have ataxia and this is reflected by this results. And again I would like to show you the data of the pediatric patients and here you can see that in some patients there is an increase, an improvement, some we have a kind of stabilisation, but one patient it looks like that there is a severe decrease but in fact this patient really did not want to perform this examination. So this was the reason why there was a decrease of these results. In the following I would like to show you another model which is called the global treatment response model. As there are not so many data, we tried to figure out how we can evaluate the effect of the Velmona's alpha treatment much better.
[00:11:06] Dr Julia B. Hennermann: And so if you look at the pathophysiological background, first of all we have an accumulation of the amino- rich oligosaccharides and this accumulation which you may find in different organs or nearly in all organs leads on one side to an impairment of muscular and skeletal functions and on the other side of the respiratory functions. And this both then leads to diminished endurance and motor proficiency and this together then in diminished quality of life. So looking at the clinical effects, there had been established three different domains which were called the pharmacodynamic domain, the functional domain and the quality of life domain and different endpoints had been looked for. In the pharmacodynamic domain it was looked how is the effect of the Velmona's alpha on the serum oligosaccharides. I showed you some data before but also on the serum IgG because we know that patients with alpha mannosidosis may have decreased or very low level of serum IgG. Looking at the functional domain it was looked on the motor function and also on the respiratory function and the data which were used, the endpoints which were used were the three minute stair climbing test which I have shown you already, the six minute walk test, forced vital capacity and the BOT2.
And for quality of life there were different questionnaires used, for example the CHAQ Disability Index. For evaluating all the data I would like to show you the next slide, there were only these endpoints used, the reduction in serum oligosaccharides it was looked, so if patients may reach a normal value which is lower than 4 micromole per litre in the serum. On the functional domain it was just looked for the motor and respiratory functions and these data have been taken out of other clinical trials which had been used for approval of enzyme replacement therapy, for example for mucopolysaccharidosis or for Pompe disease. And for quality of life two different CHAQ tests were used and these data also have been extracted out of other clinical trials and they are quite well known for patients for example who have special form of arthritis. With that I would like to show you the results. If you use these, if you use these endpoints or these different pharmacodynamic or functional quality of life domains, it was looked for if patients have an improvement, have reached one of these endpoints and if they have reached this endpoint they were getting a point for pharmacodynamic domain. If they have reached one of these endpoints or one of these endpoints they have reached here this domain.
[00:14:35] Dr Julia B. Hennermann: So looking at the data, we have data of 33 patients, 19 paediatric patients and 14 adult patients and what you can see here that after a long- term period of ERT treatment, that means up to four years, while nearly all patients reached a positive response, that means they had an improvement in at least two of the three domains. You can see that all paediatric patients had an improvement and that at least 71 patients of adult patients responded to that. So, next, I would like to show you some newer data. They have been published this year, just recently. And what we have here now is an extended long- term data on the efficacy of velmanase alfa treatment. So, first of all, I would like to start with a six- minute walk test. Here again, you see two different graphs and what we can see here, again, this is the group of the pediatric patients and this is the group of the adult patients. Patients have, these are data of 21 patients and there had been 13 patients followed up for a period for 9 to 12 years, so we have quite long data. And here again, you can see that there's improvement in motor development, in motor function, but especially the pediatric patients show a very huge improvement. The same we can see here for the three-minute stair climbing test and then I would like to show you data on the respiratory function. I have not shown you any data on that before. And you can see here the data for the forced vital capacity. Again, we have here the adult group, we have here the pediatric patients.
You can see there is quite a long time of stabilization. Then you have the impression that there is a decrease in the adult patients that might be, but to our experience, it's also very complicated due to the compliance of the patients and the older the patients get, the more complicated for them it is to really do that respiratory function test. So sometimes there might be also false bad results for that. And then at last, I would like to show you the data on the serum IgG. I told you that there are low values for the majority of patients with alpha-mannosidosis and we see that here, that in both groups as well in the adult and pediatric patients, we have a significant increase of the serum IgG. And sometimes it is reflected because we see that patients have much less often infections if they are on ERT. So what are the limitations then? What are the side effects of velmanase alfa, the only ERT we have for alpha-mannosidosis?
[00:18:00] Dr Julia B. Hennermann: So first of all, as we know from other enzyme replacement therapy, it does not cross the blood- brain barrier. This means there is no effect on the cerebral manifestations of alpha-mannosidosis. And I have shown you the data of one pediatric patient who had developed an anti- drug antibody. So this is one of the side effects. And another side effect that there might be hypersensitivity reactions, also including anaphylactic reactions. But in the clinical trials, hypersensitivity mainly was shown as signs of nasopharyngitis, pyrexia, headache, and arthralgia. And it occurred a little bit more often in pediatric patients than in adult patients. But anyhow, none of those treatment- emergent adverse events lead to a discontinuation in the clinical trials. With that, I would like to show you some also newer data which have been published just recently on the function and quality of life of patients with alpha-mannosidosis. And I would like to show you just a short, well, some, a few data on this survey.
These were data from 51 patients. Some had been on enzyme replacement therapy. Some patients had received stem cell transplantation. And there had been some untreated patients. And it was asked, how was the state five years ago? And how is the state of the patients today? Here, first of all, I would like to show you the data on mental health, so a little bit difficult to get through it. Here, you can see everything on the left side is an improvement, everything on the right side is worsening, and in the first rows, you can see just the data on ERT. There have been 22 patients on ERT, then it is splitted in the younger children, as in younger patients, then in the adult patients, then in the ERT length, and then in the bottom, you see those patients who had received stem cell transplantation and those patients who are untreated, and you can see here concerning mental health, there's a quite stabilization in the whole group of those patients being on enzyme replacement therapy, in contrast especially to those patients who were untreated. Looking further, I have chosen to show you the data on pain and discomfort, and again, you see here the data on the ERT patients, here you see the data on the transplanted patients, and here the data on the untreated patients, and I think it's quite clear to see that those patients, especially the younger patients, the pediatric patients, who received enzyme replacement therapy had more improvement in pain and discomfort in contrast to the untreated patients. And finally, I would like to show you some data on self-care. Self-care, I think, is a very important point for quality of life of patients, for their social independence, and you can see here, there is, well, quite, well, no real changes in the patients with enzyme replacement therapy. You see that patients who received a stem cell transplantation have a better self-care, but the group of untreated patients have really worsening of their self-care. I think these are very important data to see how do patients, how do families feel with the different forms of treatment.
[00:22:03] Dr Julia B. Hennermann: And with that, I would like to summarize these effects of ERT and alpha-mannosidosis. What do we see with the ERT? We have a decrease of mannose-rich oligosaccharides, especially in serum, and we have an increase of IgG concentrations, which is associated with a decrease in infections. We have a decrease of organomegaly. I have not shown you the data, but it is described. We, there is no improvement of cognition, although in the first trial there was a slight improvement in the Leiter-R test, there's no really improvement of cognition as the ERT does not cross the blood- brain barrier. But on the other hand, we have an improvement of motor and respiratory function, and we have what is very important, an improvement in quality of life for these patients. So, looking at this actual treatment, I would like to shortly mention new treatment, emerging disease- specific treatment for alpha mannosidosis, which is a new development. First of all, I would like to mention the fusion protein. You might have come across with other lysosomal storage disorders where it is already used, for example, in mucopolysaccharidosis. What is this fusion protein? This fusion protein is fused from a certain enzyme domain where we have this enzyme, which is now infused alone. This enzyme as fusion protein is fused with an antibody, which is the IgG domain, and this antibody is directed against receptors, which are located at the blood-brain barrier. These receptors may be, for example, transferrin receptors or insulin receptors. What is happening is that this IgG domain, this antibody is binding to the receptor at the blood-brain barrier, and with that, this fusion protein might pass the blood-brain barrier and the enzyme might then work in the brain. So, it is already tested for some MPS types. It is already approved for one MPS type, for one MPS form, not here in Europe, not in the US, but in Japan. But there is, this might be a potential option for treating the neurological manifestation of alpha-mannosidosis.
And what else do we have? There are some developments to augment the stem cell transplantation with changing of conditioning and other things. I don't want to go further into detail. And there are also some preclinical experiments, especially in the animal models where we see that the gene therapy might help quite well. So with that, I would like to conclude the enzyme replacement therapy results in a reduction of oligosaccharides, improvement in motor and respiratory function, reduction of organomegaly, increase of serum IgG, reduction of infections and improvement of quality of life. But it has side effects as infusion related reactions and antitrack antibodies. And as already shown, it does not cross the blood brain barrier. So treatment decision really depends a little bit. What is the actual situation of the patient? What is the age of the patient? And so we always find an individual multidisciplinary approach to decide which kind of treatment and if we should start treatment. And for sure, I have shown you that the outcome is dependent on the age at start of treatment. And we see that there are also new treatments in development. With that, I would like to thank you very much for your attendance and I'm happy to take questions later. And here is a photo of our team. Thank you. So, Sarah.
[00:26:39] Dr Sarah Haupenthal: Thank you. Thank you very much for your very interesting presentation. And yeah, for me, of course, the psychological part is always the most interesting part. You mentioned a survey which focused on mental health and quality of life of the patients. There were also caregivers included, I saw in the slides. Are there also any results for the caregivers that would be quite interesting if so?
[00:27:11] Dr Julia B. Hennermann: Yeah, thank you very much. Very good question. Indeed, in this questionnaires, there were two parts of the questionnaire. One was just concerning the patients and one was concerning the caregivers. And there were similar results. So first of all, those patients being on ERT, mental health and all these different aspects, quality of life, was quite stable in the parents, especially in those patients who were on treatment for a shorter period of time. The worst index was shown for all caregivers being parents of untreated patients. So this is a huge problem. And I think, yeah, if you see patients and if you see the natural cause of the disease, the patients, they get worse and worse and they become ataxic. They have special, well, it's very difficult for them to walk anymore without help. They are needing help in all daily activities. And I think this is becoming more and more severe for the parents. And- I can imagine. Yeah, yeah. And for sure, the social life and also the family life is very much influenced by the clinical status of the patients. So are there any, so if you have any questions in the chat, please put it on the question line. Very happy to take any further questions. If not, we may do a Q&A session after the talk of Sarah. And I will be very happy to hear new news on the holistic approach on psychological aspects of alpha mannosidosis. Sarah has very long experience with that. And I'm happy she's giving us an overview.
[00:29:32] Dr Sarah Haupenthal: I'm really happy to speak a little bit about the psychological aspects. As Julia mentioned earlier, there is a huge impact. So, first of all, what is my part in mannosidosis? So, the main goal in psychological care is coping with and processing illness. Here it's important to look a bit closer to who am I addressing. First, there's a group of the parents or the caregivers, then there's psychological support for the patients themselves. And here it's important to focus on the children and the adolescents, because it's a quite different approach to adult patients. So, I would like to start with the caregivers. My work starts at the time of the diagnosis. So, we wanted like a standardized psychological support. That means I'm involved from the beginning on. Why that? The diagnosis is a huge shock for the parents. Yeah, we experience a lot of feelings for the parents. Usually, their whole world falls apart. And also, the setting of this conversation itself, it's really frightening and overwhelming for the parents. Sometimes, it even can be traumatic. And the parents and caregivers, they often say they see me as an anchor in this conversation. First of all, I'm not a doctor, so I just wear normal clothes. They say, yeah, there's another friendly face in the room that already helps. And my part is actually quite small. I usually just ask questions like, did you understand everything what the doctor said? It's quite a lot. Do you need a break? Do you need something to drink? Like really small things. But this makes it easier for the parents, for example, ask questions to the doctors. They don't need to feel ashamed. Oh, I didn't understand what the doctor said. So it makes it easier for them. Also, there's still a huge stigma of mental illness. And the parents already are stigmatized. Their children have a severe disease. And then on top of that, there are some psychologists. In the beginning, it's a bit irritating. Why psychologists? My children don't have mental illness. So to avoid this stigma, it's a good thing that I'm there from the beginning on, that I see, oh, she's just a friendly person. I can ask questions to them. And also I have the possibility to initiate assistance or help. So what happens after that diagnosis? As I mentioned, there's a huge shock, which is very overwhelming, but there are also other emotions. For example, there can be guilt, especially because there is a genetic component. And parents often ask, is there something wrong with my DNA? Did I cause this to my child? Could I have done anything different during pregnancy, for example? And that leads to huge feelings of guilt, for example. Some people feel offended. Oh, there's the disease. Why? Why in my family? They struggle with it. Why is it my child? That's not fair. There can be anger because, yeah, like I said, it's not fair. Also, shame is a huge emotion.
And it also depends on the culture. There are cultures where diseases still are very stigmatized. And so it's very, very difficult for the parents to admit, okay, my child has a disease. And of course, there's a lot of grief. You can imagine that like a circle, like in the beginning there is shock and then the parents need to process different emotions. In ideal they experience all the emotions, that would be the best case. It's of course a very very hard and painful process. But if they are able to feel all the feelings, it gets easier in the end. Otherwise it can happen that they may stuck in one state. For example, me as a mother, I always feel guilty. Oh, I caused mannosidosis to my child. And that could lead to problems in, let's say, setting boundaries for my child. Because I feel so guilty all the time. But I will come to this later on again. Just remember there are a lot of emotions in the beginning. And it's my part to lead the parents through those emotions. And it's not just an act of kindness to help the parents, but it also has impacts on the affected child. Children always are emotional representatives of their parents. And to explain that a bit, I quoted a study here. I just will explain it very quickly. Maybe you heard from Peter Kornagy. He's a very famous psychoanalyst. And he did a lot of research in transgenerational trauma. And he found out that children of Holocaust survivors have symptoms of trauma, like PTSD. They themselves, the children, never experienced Holocaust. But they have the same symptoms as their parents. And that's quite remarkable. Because you can see how strong the impact of the emotions in the parental state is on the children. Also, in the psychoanalytic theory, we speak of parental representations. That means me as a child, I have an imagination of my parents. And, for example, if my mother is always very, very anxious, I get the imagination of, oh, okay, the world is a really, really frightening place. And maybe I'm not able to go through the world without being anxious. Part of that, of course, parenting is always challenging for every parent. But if you have a child with mannosidosis or another severe disease, there are, of course, more challenges. But you still have to go through all the phases.
[00:38:35] Dr Sarah Haupenthal: And to explain it to the patients a bit and lower the pressure, I like to talk about the concept of the good enough mother. It's from Winnicott. It's also a psychoanalyst who did a lot of research on attachment. And this concept says, okay, what do you have to do as a mother that your child will have a, let's say, happy life? And they found out you don't have to do everything perfect as a parent. It's okay if you are good enough. So if you translate it in a school grade, like you could say, yeah, in Germany it would be a four. You could say, yeah, you don't need a one or a plus. So good enough is good enough. And that usually helps the parents. And I say, okay, even though my child has a really severe disease, I don't have to do everything perfect. Thank you. Plus, for the development of a child, it's necessary to experience frustration. So every child needs boundaries, and of course that's frustrating, but it's for the development necessary. And what we also experience quite a lot is the fact that a chronically ill child stays a child.
What does that mean? So the child maybe comes to our center when it's, let's say, three years old and stays there until the child is an adult. But the parents very often treat that child, the adult child, still as a child. Because, of course, there are boundaries in the life of the child, but it's still an adult. And to keep that balance, it's often quite difficult for the parents. Now we turn to the patients themselves, but first to the children. Of course, it's really important to explain everything in an age- appropriate language that the child needs to understand what I'm saying. Also it's important to promote compliance, because Julia said before, there's a treatment once a week, and there is needed compliance. But you just have to be a bit careful with the autonomy process, like I said before. Don't push your child too hard. And then, of course, I do interventions when there is a crisis, when there are very difficult situations, when, for example, the symptoms are worsening, then there's my help often needed. Also, it helps a lot if there's a playful processing of experiences. Because as you can imagine, being in a hospital with all the doctors, all the treatments, it's really scary for a child. So it helps if you can go through it in a playful way. Also, of course, I try to strengthen self- efficiency and the self- esteem. And, yeah, quite a lot of studies found out that it's also important to involve the child in the decisions. Like a few years ago, they said like, yeah, the child does not need to understand what's going on.
We have to just do what's best for the child. But they found out, yeah, it is really important for the children to be involved and being asked if you're okay with this treatment. Yeah. And another thing that can help a lot is teaching different techniques, for example, relaxation techniques or imagination techniques to help through frightening situations. Now I can go to the next slide. Okay. Yeah. As I said before, age- appropriate language is really important. How can I do that? For example, if I use different terms, I don't talk about cells and enzymes, I can talk about, for example, a garbage can and the enzyme is the garbage disposal. And the cell deposits is the garbage overflowing. That is really understandable even for a young child. Here's a bit of literature. It's all in German, but maybe you can still understand a bit. For example, here, right in the corner, it's a book about body diversity. And this is really, really helpful to see, okay, there are different types of bodies. I'm not like the strange unicorn in the world. Yeah, there are particular challenges in adolescence, I would like to talk about. First of all, puberty is always a really challenging phase in life. And especially if there's also a disease on top. Usually adolescents have a desire for equality. They want to be like their friends and their class. They don't want to be the child that has to go to treatment once a week. They want just to be normal. Plus they search for identity like every growing person. And if there's also mannosidosis on top, it can be challenging. There is needed a special focus on autonomy, because let's imagine a 16- year- old person. It would be strange if this person is all the time with his parents.
Also I talked about compliance earlier. In puberty, it can happen that the patients show harmful behavior. Sometimes they refuse therapy. And that can be interpreted as an expression of rebellion against parents. Because maybe they don't have the chance to go partying with their friends. And I don't know, drink alcohol a lot. So this is their only way of rebellion. It's just important to keep that in mind. And in general, it's important to consider the normative development processes in this really special phase. Now I come to the adult patients. For them, of course, it's also the main goal to be supported in coping with and overcoming the illness. I also offer crisis interventions. Sometimes they have acute psychological stress. As you can imagine, the normal life is happening as well. And there are quite a lot of challenges. Also, the terms of self- efficiency and self- esteem are really, really important. And for the adult patients, the grieving part is a bit more important. Because children, they are used to the disease. They don't know another life. But especially if patients are diagnosed very late, they have to let go of the imagination of a healthy life. Even they might have symptoms their whole life. But the imagination of, yeah, I'm a healthy person, they have to let go of that. For the adult patients, it's also very important to give them information about mental illness. Because maybe they already have a severe depression. And so it's important to know what's going on. And if needed, to offer psychotherapy. So most of patients, they live really far away from our center. So my goal is to refer them to institutions close to home. That might be psychotherapy or a rehab or a counseling center. What else can be useful? I really like to teach skills. Maybe you are familiar with the term skills. It's invented by Marsha Linehan. It's a psychotherapist who treated patients with borderline personality disorders. But it's also a useful thing for everyone. It's used when you're in a very high state of tension. So those skills, maybe you know some of them. For example, like left here in the corner, that's a ring made of metal. And you can put it on your finger and it helps to relax.
For example, like I said, the diagnosis is a huge shock. And then you can use those skills to calm a bit down. Of course, also for the adult patients, there are relaxation techniques which are really, really helpful. Such as yoga, autogenic training, qigong or imagination techniques. There are a few further psychological services which I offer, such as cognitive tests. There are a lot of them here. I chose one, WISC is one of the most common tests. What is the goal of this testing? First of all, I would like to record the status quo and, depending on the age of the patient, find a suitable type of school. You can also identify if there is a possible progression on the disease. A part of the testing, there are various clinical studies, which usually is also a psychological part included. I do a lot of cooperation with non- clinical institutions. For example, I talk to the teachers of the patients, to the social pediatric center, for example. And not to forget the healthy siblings, because they very often are like the forgotten siblings. But they are also very important to focus on how they can process the disease of their sibling. Here are small insights into a psychological working day. It includes a lot of playing, which is also fun for me. Here I'm playing a board game with a young patient. If you are playing, it's a lot easier to ask questions than just sit on the table very stiff and ask, how are you feeling today? So a lot of playing. Here are a few take- home messages. What are the most important parts of my work? If possible, it's great to have a psychologist who is present during groundbreaking discussions. A second child or the patient sets the pace, even if that might be difficult in reality. Always obtain consent. That's really important. Consider the age of the child and the associated developmental steps. Then actively address the patients, even if they are young and the parents are present. And keep in mind that the clinic is not a normal setting. For us it is, because we work there and maybe we worked there for years already. But for the family, it's not a normal setting. And this may explain strange behavior, for example. And last one, find out how you can refer those relatives to psychotherapy or counseling centers in your country. Because in Germany, we are lucky that it's all for free. We don't have to pay for psychotherapy, but I know that's different in other countries. So yeah, find out how it works in your country.
[00:53:50] Dr Julia B. Hennermann: Thank you very much, Sarah. Great data, very vivid talk. Thank you.
[00:53:57] Dr Julia B. Hennermann: I think it's very important also if you are on the doctor's side to see also the psychological aspects. I was wondering, as you showed all the different emotional processes at the time of the diagnosis. So perhaps it's wrong view from a doctor. But sometimes I have the impression that parents or patients might have kind of relief because they were looking for years for a diagnosis and then they have the diagnosis. Are you coming across with that also?
[00:54:33] Dr Sarah Haupenthal: Yeah, it depends. Like you said, if they are already looking for a diagnosis for years, then, of course, there is also a big relief. Maybe I should add this to the emotions because, of course, relief is a positive emotion. But usually after the relief, there are coming the other emotions anyways.
[00:55:02] Dr Julia B. Hennermann: Yeah, that's true. Are there any questions from the audience? I don't see. Here's one. Sorry. Okay, the question is, given the benefits shown in younger patients, what is the current consensus on the optimal age to initiate velmanase alfa to maximize long-term functional outcomes? Well, this is a very difficult question and unfortunately, I think we cannot answer that at the moment. There are no guidelines, there are no really published recommendations on the treatment of patients with alpha-mannosidosis. We know at the moment that if patients are very young, transplantation might be an option. There are quite new data showing that the side effects are comparable to the side effects of transplantation in MPS I and in all other patients. We start as early as we can. I hope this helps. So, the next question is, considering the data on skeletal endpoints, which bone- related complications shows the most consistent and clinically meaningful improvement with ERT? So, I think the problem is with the bones. We know from the other ERTs that we do not really reach the bone, but the bone is not a major problem in alpha-mannosidosis as it is, for example, in MPS IV. So, it is completely different. We have more, I think the problem is more the ataxia, which gets worse the older the patient gets, and then what we have are the arthropathy, which patients develop, and I think we will not change that with the ERT at the moment. So, there's a question for you, Sarah. Are there any red flags or specific developmental milestones that should trigger a review of the patient's psychological care plan and autonomy? Quite difficult.
[00:57:34] Dr Sarah Haupenthal: Yeah, that's a difficult question. I would say if the patient out of the sudden acts totally different than before, that could be a red flag, and you always should ask what's going on there. Is it just puberty or something else?
[00:58:04] Dr Julia B. Hennermann: Yeah, I always ask myself, what about the red flags of the parents, you know, because we see that parents, yeah, sometimes you have shown that very nicely, the problems of the parents, and what I often see that, you mentioned that quite nicely, that the patients have to stay a child, but always what I see is that parents do not give boundaries to their kids.
[00:58:31] Dr Sarah Haupenthal: Yeah, let's say the parents could be a red flag, and then it's important to just address maybe the patient alone, without the parents, that could help.
[00:58:46] Dr Julia B. Hennermann: Yeah. So, there's another question concerning the oligosaccharides. It's asked which oligosaccharide biomarker is being most reliable as showing the therapeutic response to ERT. Well, this is quite easy to answer because in the clinical trials, they had been used, in the New York trials, they had been used different oligosaccharide biomarkers, but well, for the clinical use, I think most hospitals do not have access to this measurement. So, what we are doing is just measuring the oligosaccharides in urine. I think that's what the majority of hospitals are doing at the moment, until we have new methods or new labs available to do that assays. Okay, yeah. So, if there are no further questions, I thank you, the audience, for listening. I thank you for your questions, and I thank you, Sarah, very much for the cooperation, for the nice webinar, and thank you for the organization of this webinar. Goodbye.