[00:00:00] Prof. Mercedes Gil-Campos: Hello, I'm Mercedes Gil-Campos from the University of Cordoba in Spain and it's a pleasure for me to be with you this day to share some knowledge about the alpha-mannosidosis and in this time we are going today to talk about the holistic approach in the different specialties as a multidisciplinary team and the different treatment options and results for the management in this pathology.
[00:01:03] Prof. Mercedes Gil-Campos: So we are going to advance, I have no conflict of interest and at first we are going to talk about the Delphi consensus because we have some articles, some evidence in the literature about how to diagnose for alpha-mannosidosis, there are some algorithms but nowadays there is no guidelines for monitoring and management for patients with alpha- mannosidosis. So the aim in this Delphi consensus was to try to establish a monitoring and integrated care coordination for these patients, pediatrics and adults and the Delphi methodology was based in different gaps by gathering experts on different strategies. So here you can see the different articles or communications in some congress about this. So the potential impact areas to work in this consensus to try to establish the care process with different specialties were in some areas like different cares in eating, working, resting, different cares for activities work and also we know that these patients have some problems with the hearing so we are trying to establish some management in different complications or comorbidities related with pain, infections, some mental health disorders, sleep disorders or others. So this methodology was based in three rounds of online service in different specialist experts in this pathology. So the panelists were composed of 10 doctors, 11 pediatric doctors, 10 geneticists, 5 experts in metabolic diseases, 2 pharmacologists, and 1 internal medicine colleague. So the consensus was defined in different areas where we have more than 75% of agreement in the different panelists voting. So this is a picture that is published in the article that you can see below and there are different key areas we are going to focus our attention in area 2 and area 3. The area 2 is related with the routine follow- up care so you can see that this related with all the nervous system manifestations, psychiatric manifestations and also hearing ophthalmology and other organ pathologies related with pulmonary function or cardiac functions or skeletal abnormalities. So, this is related with different specialists, so we have to coordinate as the principal doctor with these patients, how we are going to do all this follow- up, also we must do some biochemical analysis, sometimes through their lives, and also an evaluation about immune functions or other manifestations. And the key area 3 is related with the follow- up for the treatment, so it depends if we are only doing supportive care- related monitoring, or the patient had a transplantation, but the most of our patients are now treated with enzyme- replaced treatment, so we have also to monitor all these results, all the evolutions, and the possibility of some complications or adverse events related with this.
So, here you can see in more detail all the key areas and what are the tools or the manifestations that we can have in consideration to evaluate, for example, pulmonary functions about different tools to evaluate the forced capacity pulmonary, or cardiac functions through electrocardiogram or echocardiography or other manifestation about biochemical analysis for example to evaluate kidney health or the oligosaccharides related with the diagnosis but also is maybe a tool to evaluate the evolution related with treatment. Here we have some monitorization, for example, in the enzyme- replaced treatment, we have also to evaluate if some antibodies appear or there are some adverse events, so this is an integral evaluation in which there are a lot of specialists that must be included in it. I would like now to talk about the different results for the treatment that we are using in these patients that was, some years ago, evaluated by different clinical trials that you can see here, and some of these patients that passed phase 1, 2, and 2b, and after that, some of them were in phase 3, that this was rhLAMAN- 05 trial, and some of these patients are now also in an after- trial care program, and most of them are treated with Velmanase Alfa. So, to evaluate the response in these clinical trials, and also now in this after-care program, we decided to create a multi- domain- based analysis to evaluate the integral response. First domain related to pharmacodynamic evaluation, in which the endpoints are the serum oligosaccharides and the serum immunoglobulin G. There is another functional domain in which we are doing some different tests, for example, to walk during six minutes, or to up and down stairs along three minutes, and some other respiratory tests. And the third domain is related with the quality of life, and some tests are done in the different patients to evaluate the disability, or pain, or the habitual quality of life. So, it's important to classify a patient as a responder if they reach at least two domains. In some pivotal studies, as rhLAMAN- 05, in which Velmanase Alfa was used in one group, and the other group was with placebo, you can see, for example, here in the first picture, a relative change in serum oligosaccharides in the first 12 months, and after that, when all the patients were in the aftercare program, how all of them were similarly responded. Here, on the right, we can see the different answer in pediatric patients compared with adult patients. We are going to see that, normally, pediatric patients have a better response in all the domains. Here, for example, we have the results for the tests for up and down stairs, and here you can see that the people treated with Velmanase alfa, that they are in blue, they have an increased response with more fast, and treatment later than children. Here, again, you can see the immunoglobulin G response, so you can see how it's an increase in the levels of this immunoglobulin in the group treated with the replaced enzyme, and you can see that in placebo there is no changes in levels of this immunoglobulin.
So, if we consider all the multi- domain analysis, we have most 87 percent of patients responders with Velmanase alfa compared with only 30 of patients responders in the placebo group. Here, we have also another study that is called rhLAMAN- 10. This is related with the after- trial care program, so all of the patients were included in treatment. You can see here the characteristics of this sample of patients More or less, there are the pediatric patients before 18 years and other group of adults, and with different genotype group. This is important because maybe we have different phenotype and different clinical answers, and it is also related not only with the treatment, but also with this type of mutations in the gene MAN2B1. So, in this study, when we evaluate the multi- domain analysis, we have little higher responders in the last section with all the patients included and the 80% of them respond in two or three domains compared with the other group that was analyzed at month 12. And here for example we can see the response in serum oligosaccharides. So, we can show that the pediatric group has more change in a decrease of this level compared with the other group, but also in the last observation, the group in rhLAMAN- 10 has a better response compared with the group in month 12. Here we have some results related with the quality of life, focus on health from a person working at or the necessity to have a wheelchair.
So, in the pediatric baseline, there were, for example, five patients with mobility assistance, and in the last observation two of them were able to not require this assistance. And also in the group of adults we have the same evolution. So there are some patients that are not worse, also they sometimes improve in some areas. Here in the rhLAMAN- 10 study, we can compare with the pediatric group and you can see that 100% of pediatric patients respond at least in two or three domains and in adults, this answer is a bit lower and also is influencing the total results. So the early treatment is more beneficial in pediatrics groups, and contributing to the improvement in children. However, we can see that in adults there is a measurable benefit. For this evaluation I would like to comment on some results in this patient. He was one of the first patients in the clinical trials in phase 2 and he was diagnosed at 4 years and with 10 years, he was included in the clinical trial and he has continued this enzyme replacement during all of his life until nowadays with this velmanase alfa weekly without any stopping. Also in COVID pandemic, he has been receiving this treatment. So maybe some of these results that I'm going to comment with you are related with his phenotype, but when he was younger, he had a lot of comorbidities, a psychomotor retardation and some hearing impairment. So we didn't know how it will be this evolution, but now he is 24 years old. He completed secondary studies with some support, obviously, and adaptation, but he has passed all the subjects. He has learned with some difficulties and with some deficit attention, but he didn't need any medication for it. And now he's doing things that he likes. He plays football. He is doing daily exercise like paddling and he says that he has no pain, he doesn't express difficulties to move and to do any sport, he has some skeletal abnormalities and there had been some factures but he persists his quality of life like the maximum, he has no special socialization problems, he is autonomic in the daily habits, he has no digestive problems, he is a little overweight and he is controlling now his weight. In all this time we have no presence in serious infections process or that require hospitalizations and he has no problems with sleep or psychiatric symptoms. So maybe these beneficial results, these surprisingly results are related with his phenotype but also I think that we have to take in consideration that this child started with this treatment very early and maybe is one of the effects of this weight evolution. So my final comments are that there is a potential benefit with this treatment mainly observed in pediatric patients but also in people that are with a long- term treatment more than 12 months.
So we have some limitations with the sample size because this is an ultra- rare disease. So we are doing a study called SPARKLE to follow up all the European patients for at least 10 or 15 years to capture clinical improvements and to have and holistic approach about how to do the follow- up, how to do the follow- up in treatment and also to know the natural history for this disease and to integrate better the care and the support for all of these patients because maybe we are not considering all the specialists or we know all the comorbidities that could appear. So it's important to evaluate this patient in an integral, global response to evaluate the multiple disease domains and to consider that there is a heterogeneity of this disease so the diagnosis should be at early but not always in the pediatric stage. And we have also to consider that there are some adults that have this alpha-mannosidosis disease and maybe we have to take attention in these patients to evaluate all the clinical signs but all to take into account that most of these specialities must know about this disease to have the opportunity to do a diagnosis.
[00:25:02] Prof. Mercedes Gil-Campos: So now I'm here to comment with all of you in the chat. We can also answer to some questions or to share what you want. So thank you very much for your attention. Well, here there is a first question.
[00:25:57] Prof. Mercedes Gil-Campos: They are asking about, does the Delphi survey put more focus on the enzyme replacement for alpha-mann than is currently established, or there is any other specialist that who should now have a bigger role in alpha-mann treatment? Well, I think that always there could be a coordinator about these patients, and it depends on the hospitals and the centers. In some centers, there are some units that are specialized in metabolism diseases. So, maybe these doctors must be the coordinators for this Delphi survey or this follow- up in these patients, but in other times, and in other times, there are neurologists specializing in children, and in adults, it's a big difference. Normally, there are some general doctors, like internal medicine specialists, but I think that we have the responsibility to share all of this knowledge with all the specialists that could be interested in this disease and could be involved in it, in the follow- up or in the treatment.
[00:28:19] Prof. Mercedes Gil-Campos: So we did in the Delphi survey a panelist with 20 experts, but it was because in this time, we were the only specialist that we have some experience with this disease, but I hope that in the future, the group could increment. Well, another question is that in rhLAMAN- 10, wheelchair use improvement of 40% in children and adults. Well, We know that this is a progressive disease, so the treatment is not the best. The best is it could be to have maybe a genetic solution, so it depends on the phenotype, and it also depends on the adherence to the treatment or different comorbidities, so it is difficult to know the future and to know if in the child, if we are going to have an improvement or an increase in the using of wheelchair. Probably, yes, because it's a progressive disease, but some of our patients with this treatment use the wheelchair lower than before, and some of them now, they are adults and they have no wheelchair yet. So, maybe it's a good evolution, but we cannot respond to all of them. Well, another question is that 100% of all children in the study improved on two and three domains. True. So, what was the spread of improvement, mainly in the same area? Well, we have to consider that in the domains, we have the pharmacodynamic area, and we know that most of the patients that started with the treatment, for example, lowered the oligosaccharides in serum and increased immunoglobulin G in serum.
So, this is a standard response, but we don't know if these biochemical answers are sufficient to improve the integral patient, because you know that oligosaccharides cannot load in central nervous system with the treatment, and this is doing some pain, some heart, and maybe some of these improvements should be discussed, because I think that pharmacodynamic response, it should be maybe separated from the real clinical answer. Another question, or some comments, or some experience with these patients? Well, another question, how long a period is the study currently covering? Two, three years? Well, I don't know if you refer to the SPARKLE that I named before. Now we have the SPARKLE that is for all the patients, treated and not treated, all the patients in Europe that we know, and they accepted to be in this registry. So, we have now data for three years, and we expect to be until 10 or maybe until 15 years. So, I am sure that we are going to know many new things about these diseases, evaluating all these patients, because there are some patients older now, and maybe they are going to express new comorbidities that nowadays we don't know about it. But we now are covering about three years. Well, another comment, condition at time of treatment has an impact of disease, alpha-mannosidosis progression in these patients? Yes, of course. So, how was that factored in for the results? Well, I think that we have been commenting about it, but I can focus on that. As earlier, as we start this treatment with our patients, it's better, you have seen in the results, but also the time, the longer time to have good results is also considered. So, you have seen in rhLAMAN- 10 that when we measure results after one year, we have some improvements, or we have no evolution. But it's important to have adherence to this treatment, and to have weekly infusions, and to evaluate all this response, mainly about six months or twelve months in the clinical visits maybe in adults at least one a year or twice a year, and in pediatric patients, of course, more frequently.
[00:36:18] Prof. Mercedes Gil-Campos: Okay, I think that there is no more questions. So, I would like to thank the audience for your attention, and I will be... webinar, and I hope that we can see in other occasions, and that you really like this presentation. Thank you very much.