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[00:00:17] Dr Francesca Fumagalli: So, welcome to everybody. Thank you for joining the last webinar of this series and on the early signs of MLD. This last webinar will be focused on established and emerging treatment for metachromatic leukodystrophy. Before starting, I have to recall you not to take any screenshot, not to reproduce any of these slides. I will present you a content of this webinar in 20 to 25 minutes and you can text your question through the chat and then I will try to answer at the end of my presentation. And you can review this presentation and the previous one of these series on the website. Here you should see the link. I will give you an overview of the treatment option currently available and look into the treatment under development or, emerging in the last few months. Since this is in order to really well understand the meaning of early diagnosis and the importance of an early diagnosis to start early treatments of MLD. Previous speakers give you an excellent introduction to the disease and to the challenge for an early diagnosis. So, I don't need to come back to the disease but to physiology. I just recall you that the disease can be considered a continuum based on activity levels and different genotypes but the classification of the different variants is really imoprtant when we look to treatment options. And in particular, I want to underline that we can identify early onset variants that are very aggressive, very rapidly progressive and late onset variants that appear with very subtle and indolent cognitive symptoms leading to pre- diagnostic delay.
[00:02:52] Dr Francesca Fumagalli: As you see in the picture that I present from a paper that CARE recently published on neurology, you can in particular focus on the fact that early juvenile and late juvenile form that are usually considered a unique group have indeed a different progression of motor symptoms with very rapid progression and reaching severe disability for early juvenile and the late infantile form while the late juvenile and adult form have a very slow progression of motor symptoms and sometimes maintain good motor function for the long term, even if not treated.
[00:03:47] Dr Francesca Fumagalli: If we look to available management option for MLD, we have to say that for many years, treatment has been only supportive based on palliation of symptoms while recently more option became available. In fact, the most important challenge in the development of effective treatment for MLD is represented by the need to cross blood- brain barrier and target the central nervous system. I will summarize for you today approaches established such as allogenic hematopoietic stem cell transplant and treatment under study that try to deliver the enzyme to the brain through different route, such as, intra brain delivery of vectors or intrathecal delivery of enzyme or vectors. Before showing you causal treatments, I have this slide to underline the importance of an early treatment for each MLD child. In fact, even if we diagnose a child that is too late for a causal treatment, it is important to ensure also to him the best quality of care and the best quality of life. In particular, we should think to an early psychological support starting from the phase of diagnosis offering as soon as possible physiotherapies and specific devices to allow the posture prevent retractions or any discomfort. Think to occupational and speech therapists to allow these children to communicate. Looking to support networks at local levels in term of educational support,treat spasticity, treat epilepsy but also think to the neurological sympotims suchs as metabolic acidosis or gallbladder abnormalities that can be a proble for these children. We also have to think to swallowing impairment since the first phase of the disease, think about looking to caloric intake of children, speak with parents about the needs of gastrostomy soon after diagnosis and think to needs of physiotherapy in terms of respiratory physiotherapies and prevention of infection at the respiratory airways in order to prevent this kind of complication and ensure better quality of life. Going to causal treatment, what is already established is a allogenic hematopoietic stem cell transplant. There are some papers published in the last few years and in particular allogenic hematopoietic stem cell transplant has been examined for a lot of lysosomal disorders.
[00:07:39] Dr Francesca Fumagalli: This is a way to overcome the blood- brain barrier because hematopoietic stem cell progenitor can cross blood- brain barrier and reach the brain where they can deliver the enzyme to the surrounding cells and we can exploit the mechanism that is the so- called mechanism of cross- correction because the donor cell can delivery the enzyme that can be reuptake by surrounding cells through specific receptors that are on the cell membrane surface and that can deliver the enzyme to the lysosome where the enzyme is needed. The limitation of the published studies, the small sample size, they are studies on single- center course. Sometimes, there are different definitions of symptomatic sample and pre- symptomatic patients and there is no distinction between early juvenile and late juvenile patients as it was anticipated before. All the studies used different outcome measures. This leads to not yet an international consensus reached on which patients can benefit from allogenic transplants. Anyway, in this slide I try to focus on two of these studies but there are a lot of other studies published in the last 10 years and you can review them. The first one i mention is the group of Escolar that used umbilical cord blood transplantation. And as you can see in this graph, you can see that late infantile variant can not be treated with an allogenic bone marrow transplant is not able to stop the disease progression in this variant particularly in most pre- symptomatic and asymptomatic status. While allogenic transplant can slow down disease progression in early symptomatic status particulartly in the late onset variant. And as shown by the German group in this work in German neurology the patient can benefit from transplant and in particular patient in pre- symptomatic phase with gross motor function level 0 to 1. That means patient is still able to walk independently and with higher IQ so a normal IQ and with an onset after four years or so with later onset. In particular, they also suggest that patients that can benefit are patients with low severity score brain MRI. It has to be recalled that allogenic transplant related mortality and morbidity that maybe has been optimised the latest years throughout optimisation of transplant protocol. If we look to this recent study published again by the German group, they suggest in this small cohort of patients that there are patients with a rapid progression just after treatment and other patients that can be considered not progressive and in this work they try to understand which are the patients that rapidly progress after transplant and in fact they are patients treated with a normal motor function with higher MRI severity score. While it seems that age of onset and age of transplant as well as severity of peripheral nervous system involvement but also IQ are not related to rapid progression after treatment. The authors speculate that the reason of this rapid progression is that patients are at that time point entering the rapid phase of progression and probably the conditioning regimen has a neurotoxicity per se and can lead to an acceleration of disease course at time of treatment, even more rapid compared to the natural course of the disease and we have to keep in mind that while thinking and proposing an allogenic transplant to diagnosed patients. We have developed and I am an investigator of trials on hematopoietic stem cell and gene therapy. we have developed this approach in order to reduce risk of allogenic transplant and improve benefit profile. Autologous hematopoietic stem cells are corrected from affected child and are modified in vitro using lentiviral vector that transfers into stem cells one or more copies of the lacking ARSA gene. The corrected cells are infused after busulfan conditioning that is made in order to make space in the bone marrow to the new cells and follow migration of the new cells across the blood-brain barrier. As you can see in this picture cells modified are able to cross the blood-brain barrier and then here they can become microglial cells able to deliver functional enzyme to the surrounding cells. The surrounding cells reuptake the enzyme and again has in the allogenic transplant through the mechanism of cross- correction but hematopoietic stem cell gene therapy is able to deliver a supernormal level of enzyme to the surrounding cell and this is what we want to obtain to reach a higher level of efficacy. Two years ago a step of cryoconservation was introduced to allow completion of quality check of tests before infusion. And the first clinical trial started in2010 and to go along the pathway its approach reached full approval in Europe last December. So it is not an emerging treatment but an approved and established treatment for early onset MLD. I will go through the clinical trial to show you the current indication of this medicinal prouduct. The patients that were included in the clinical trial were pre- symptomatic late infantile and pre- symptomatic or early symptomatic early juvenile. The early symptomatic status was defined as IQ above 70 at the beginning and able to walk 10 steps independently but then restricted to IQ above 85 and able to walk longer distances. The objective of the study was to evaluate the safety of the procedures and efficacy in terms of improvement of motor function and restore of performance at normal to supranormal level compared to baseline.
[00:16:17] Dr Francesca Fumagalli: We also evaluated treatment effect on cognition, brain MRI, and nerve conduction velocities. Long- term efficacy data are available on 29 patients treated with the fresh formulation. And to be noticed that all the late infantiles but one were treated when pre- symptomatic a natural history cohort of patients. As you can see in that slide, all the patients show engraftment of corrective cells ranging from 20 to 90% of progenitor corrective cells in the bone marrow. The transduced cells were detectable starting from one month for gene therapy, so really early, and they were stable throughout the follow up.This results in ARSA activity in peripheral blood and cerebrospinal fluid in the normal range or even at higher compare to normal range. In term of clinical efficacy gross motor function measure is a scale going from 0 to 100. 100 is the normal function of a child that is 5 years old. We found significantly higher score in treated children with respect to the natural course of the disease two years and three years after treatment. In green, the late infantile cohort. In blue, the early juvenile cohort. In the EJ cohort, the difference was not significant two years post- treatment but increased three years compared to natural history suggesting a slowdown in disease progression. It is to be considered that in the early juvenile cohort, some of the patients were already symptomatic at the time of treatment and they experienced some degree of deterioration of motor function with respect to baseline. Defining severe disability, a score of 5 of gross motor function classification that the previous speaker explained, meaning the capability to remain able to sit independently and move around, we could prevent severe motor impairment in the majority of late infantiles so all the late infantiles except for the patients treated at disease onset, treated in symptomatic phase and in the majority of early juvenile patients at long term. Concretely, what this graph means? If we look at this child treated in pre- symptomatic phase, late infantile, treated 15 months old you see that he developed some degree of passive parapheresis but 8 years post gene therapy seemed able to walk at an age where his older sibling already died and reached severe motor impairments so has been driven by the age of four years old. This second patient, seven year post gene therapy with completely normal function and his older sibling experienced very rapid disease progression with loss of all motor function by the age of 3 and a half. The third patient is an early juvenile subject, 4 years post- gene treatment therapy. Completely normal motor function. He is performing motor tasks of our motor skills while his older sister unfortunately was bedridden by the age of 7 years old. Even these samples from our patients particularly regional subjects and some late infantile treated after 12 months experience some degree of motor impairment, the majority of our patients maintain good cognitive capabilities along the follow up. In particular, they remain in the grey area, so the normal cognitive development and continue to acquire cognitive skills along the follow- up. These clinical results were supported by stabilisation of instrumental tests. The brain mass score stabilised at a very low score. It means that we could prevent, as you can see in the picture on the right side, white matter abnormalities, both in pre- symptomatic patients and also in early symptomatic patients, and we prevent demyelination and also development of brain atrophy. In terms of peripheral nervous system involvement it is well known that the late infantile form is characterised by very severe peripheral neuropathy early in the disease course. It is not prevented, it is not corrected by allogenic transplant. In this graph you can see that untreated children in light green develop very severe peripheral neuropathy. Treated children decline worse in the first months after treatment but stabilise at long term follow- up in better nerve conduction velocities compared to natural history cohort of patients. Yes, they don't reach normal nerve conduction velocities but these velocities are sufficient to maintain good locomotor skills. Reviewing our data, we focus on some failures and I want to underline this because this is important to stress the importance of early diagnosis.
[00:23:15] Dr Francesca Fumagalli: In fact, we observe a failure in the patient that was pre- symptomatic at time of screening but by the time of treatment developed some symptoms of the disease. So he was enrolled in clinical trial 22 months old and treated 24 months but in this time frame, he started to progress and following treatment, he experienced very rapid deteriorations following the natural history trajectory of decline. We concluded that late infantile patients should be treated pre- symptomatic and the pre- symptomatic status... treatment phase to avoid treatment, too late treatment and inefficacious treatment in patients developing first symptoms of the disease. Regarding early juvenile patients, we feel that the disease is a little bit slowing in progression but still we need to treat the patient really early. In fact, we notice benefit in patient treating when they have good motor capability, able to walk independently for long distances and without cognitive decline. So, with an IQ at time of treatment about 85.
[00:24:51] Dr Francesca Fumagalli: I don't have time to explain you the safety profile of gene therapy that is now called Libmeldy but you can look to the SMPC that is now public but keep in mind that we didn't have any treatment related mortality. Some patients developed some degree of antibodies against ARSA but we doubt any impact on the clinical outcomes. There is a risk of malignancy but we never observed it in the clinical trial but we are forced to follow patients for a long time and we have to keep in mind the risks related to the chemotherapy but in comparison with allogeneic transplant we have to remember that gene therapy does not need immunosuppressive drug after treatment because it is an autologous transplant and you don't have risk of graft versus soft disease or risk of rejection of autologous cells. Treatment will be soon available in different expert centers, experts in the disease and experts on transplant around Europe.
[00:26:19] Dr Francesca Fumagalli: Looking to emerging treatment, I'm moving to the last part of my presentation. Here are the trials done in the last few years on going. In particular now gene therapy is under evaluation for late- onset variants so a trial is open to the treatment of late juvenile MLD. While in the past, an approach of intracerebral injection of adeno- associated virus has been tried, but the trial closed because the treatment was inefficacious on a late infantile and early juvenile patient. The intrathecal enzyme replacement therapy is the most advance treatment under development. First trial with intravenous infusion of the enzyme failed because as you know the enzyme does not cross the blood- brain barrier. But as you see in the following slide a trial, phase one trial was done and published in 2020. Using a new method of infusion of the enzyme. It is infusion intrathecally through a device that allowed the infusion of the enzyme in the spinal space intrathecally periodically in a selected dose. The phase one clinical trial was designed to study safety of these methods and using increasing dose of the enzyme. 24 patients were enrolled in this trial with different doses. And the enzyme was infused every other week. In terms of safety, a number of patients and the serious adverse events related to the device and the methods of the infusion, such as infection of the device, means of replacement of the device, but there was no serious adverse events related to the drug product. Some patients developed antibodies but again this seems not an impact on the clinical function or not leading to serious adverse events. It is important to notice that the patient treated with the higher dose of the enzyme can reach normal levels of sulfatase in the cerebrospinal fluid, in the patient treated with the higher doses. In terms of motor function we know that this study was not developed to study efficacy, but a trend of less decline in motor function in patients treated with the highest dose was observed. This is the reason why a new clinical trial is now ongoing to evaluate the efficacy of this approach using a higher dose and more frequent administration, so administering the enzyme every week. This study is aimed to demonstrate improvement of motor function respect to the natural history of the disease. In this study we enrolled patient with the late infantile variant at a different level of severity. At the end of my presentation, we have not yet data on this trial. The enrollment is closed because they have reached the number of patients expected and the follow up is ongoing. We will see but we will expect the major benefit will occur in patients treated in the earliest phase of the disease because we know how rapidly the late infantile form of the disease progresses. I want to stress again, to finish, the importance of the early diagnosis. In fact, we have to look and to focus on the first months of life of children. The early signs of late infantile MLD appears before regression of motor capability. The first symptom is stagnation of motor development as previous speakers told you so please look to stagnation of motor development and if you as a pediatrician see very mild neurological abnormalities please refer to expert center patient to pediatric neurologist children, not to physiotherapy and not orthopedic evaluation because sometimes these symptoms lead to physiotherapy and orthopedic evaluation instead of neurological evaluation and brain MRI or nerve conduction velocity studies. And please keep in mind that a diagnosis of late infantile at 2 years old is better than at 3 years old. Also because we have to remember that we can treat pre- symptomatic younger siblings with gene therapy. So younger siblings can benefit from treatment with gene therapy and can benefit from early detection. Looking in the end to early symptoms to the juvenile variant please look for early signs such as tremor, fine motricity, abnormalities that appears after a normal period of development. Please look to uncertainties around 4 to 5 years old, clumsiness in playing at the playground. Please look to early and sudden strabismus or impairment of high movements. Please look to children with gallbladder abnormalities that are quite rare. And in the end, I want to recall you that for following and taking care of a late MLD child, a multidisciplinary team is necessary.
[00:34:21] Dr Francesca Fumagalli: And I want then to thank the team of our hospital San Raffaele in Milan. Sorry, maybe if I beat a little bit longer than what expected. I'm now available to answer your questions. So please write the questions in the chat. I am going through the chat to see if we have any question. Yes, we have a question regarding the fact that there's also you showed that allogenic transplant and gene therapy are more beneficial if performed in pre- symptomatic patients. So what about newborn screening? Yes, it's a very, very important question. In fact, yes, for sure, especially for the late infantile variant, the pre- symptomatic treatment is fundamental and the new screening is under development. Some pivotal studies are starting for example in the US and going to start in Germany. The techniques are under development. Before enlarging the national panel, adding MLD, we have to complete the validation of the newborn screening techniques and to perform pivotal newborn screening trials. But we are almost ready to go to newborn screening for late infantile and for all the variants of MLD. We have another question. Is it possible for the infantile MLD to manifest earlier than six months of age with slight motor delay and stagnation? In fact, it is not described the manifestation before six months of age. In my experience, usually the stagnation occurs between six months and 12 months, or maybe between nine months and 12 months. If we look backwards, some children around six months, some MLD children, are not able to sit on their own at six months, but it's still normal. But some children six months old or eight months old are a little hypotonic. Again, it's difficult to send every child that's not sitting independent to six months old to a child neurologist, but keep in mind not to wait too much. Please review him one or two months later, instead of an approach of waiting and see, please review your child, your patient, and if at eight months you still see hypotonia, for example please think to send him to a neurologist. Bone marrow, what is your view on bone marrow transplantation in patients in a more advanced stage? The problem with the treatment in a more advanced stage is that it has been demonstrated in these papers that sometimes there is a stabilization of this in very advanced disabled condition. So it is a matter of ethics, it is a matter of parents' decisions sometimes regarding treatment in more advanced stages. We usually carefully discuss with families and parents risks of allogenic transplants, risk of mortalities, risk of suffering and long hospitalization and risk of morbidity, and the risk also from the accelarating disease progression in advance stage of the disease. And then we carefully decide with the patient, with the family in this case, and also look if we have a good donor, for example, a sibling for transplant or not. It is a difficult decision the transplantation in advanced phase. Last question maybe. We have a question regarding how quick gene therapy allows to reach normal level of enzyme? We know that cells, corrective cells are there one month after treatment, we know that the level of enzyme starts to increase really soon and we usually reach a good level in three to six months after treatment. We see enzyme activity also in the cerebrospinal fluid three months after treatment. Levels stabilize between 6 to 12 months after treatment, but I think in my experience gene therapy starts to act even before 12 months of treatment. There are no other approaches to accelarate ARSA levels. High level of conditioning, so myeloablative conditioning is the way of accelerating, but we usually use that both for a gene transplant and gene therapy. I think we can end our webinar. There are no more questions. I thank everybody for attending to this last webinar. If you want to review the previous webinar on early signs of MLD, you can find it on the website. Thank you, everybody, for following this interesting and challenging series. Thank you to the organizer, too, for offering us this excellent opportunity. So, goodbye, everybody