Hello and welcome to our update on treatment for children webinar. I’m Portia, I’m Head of Advocacy and Community at SMA UK and also mum to a young man who lives with SMA type 1. Now if you haven’t seen the news lately, you may not have seen that on the 14th of May, NICE, which stands for the National Institute of Health and Care Excellence, recommended permanent NHS England funding for both nusinersen and risdiplam for people living with SMA. This is a super important milestone, and it has been a lot of work getting here. 

So, I’d like to take this opportunity on behalf of everyone at SMA UK, just a massive thanks to all the patient groups, all the clinicians that have worked tirelessly over the last 10 years to advocate for treatment access for us all. And of course, all you guys, the members of the SMA community who have campaigned, advocated, replied to surveys and taken part in everything that we’ve done for over 10 years to make sure that we’ve got access to these treatments. 

Today we’re going to be talking about the three disease modifying treatments for SMA that are now permanently funded by the NHS for children diagnosed with 5Q SMA. So that’s types 1, 2, 3 and type 0. Those treatments are nusinersen, and its trademark is Spinraza. So, all treatments sort of have two names, the drug name and the trade name. So nusinersen or Spinraza; risdiplam or Evrysdi and onasemnogene abeparvovec which is very hard to say so I’m going to use the trade names of Zolgensma for that one throughout this webinar. 

And we’re really lucky today to have our two experts. We have Jennie Sheehan here and Dr. Min Ong. I’m going to hand over to Min for you to introduce yourself first. Thanks, Min. 

Hi, thanks, Portia I’m Dr. Min Ong. I’m a paediatric neurology consultant and neuromuscular lead in Sheffield Children’s Hospital. 

And Jenny? 

 Thanks, Portia. I’m Jennie Sheehan, clinical specialist, physiotherapist in neuromuscular at Evelina London Children’s Hospital and also co-clinical lead for the neuromuscular service at Evelina. 

Fantastic. So you bring some really great expertise. We’ve got the neurologist’s opinion and we have the physiotherapist as well, specialist physiotherapist. That’s perfect. 

So we have split this webinar into three chunks so that people can listen to the sections that are of interest to them. For some, treatments might be new. So the first part, we’re going to talk about all three treatments for SMA: how they work, how they’re given, the more common risks, and what’s done to manage these risks. We’ll then talk about children who have been diagnosed because of their SMA symptoms, and we call these children symptomatic. 

We’re going to talk about which treatment they might be able to have and what their follow-up care looks like. And the final section we’ll cover which treatment babies who have been diagnosed before their symptoms start. And we call these babies presymptomatic. 

Part 1 About the treatments: 

• how they work and are given  

• common risks and how these are managed 

• ‘bridging therapy for Zolgensma’ 

So Min, could you give us a quick summary of the three treatments, how they work, how they’re given and any other important information about risks or something that may have to be managed.  

There are three approved SMA specific treatments available in the UK now. SMA patients produce less SMN protein and all three drugs work to increase SMN protein in patients with SMA. Two of these drugs work through increasing the SMN protein via SMN2 gene which is the backup gene in humans to make SMN protein. This is the nusinersen and risdiplam. One drug works through increasing SMN protein via providing working SMN one gene, which is missing in patients with SMA, and this is Zolgensma. So the first drug, nusinersen, works by increasing SMN protein via the SMN2 backup gene. 

And this is given by lumbar puncture, which is an injection into the lower spinal space. And this needs to be done in hospital, usually a neuromuscular centre. We’ve been using nusinersen now for a few years, up to eight years in the UK. And this is initially used by giving a loading dose of five mls of 12 milligram dose, four times on days 0, 14, 28, and 63. And then subsequently, maintenance doses of also 5 mls of 12 milligrams every four months thereafter. However, the new approval allows us to use a higher dose of nusinersen, which is a loading dose of 5 mls but 50 milligrams on days 0, and days 14, and maintenance doses of 5 mls of 28 mg every four months thereafter. So the higher dosing allows us to perform lumbar punctures less frequently as well. The risk for nusinersen is two types. There is the risk of the procedure itself, which is the lumbar puncture, and the risk from the drug. The risk from lumbar puncture procedures are general to all lumbar punctures, which are pain, bleeding at the puncture site, headache and vomiting post the procedure. And there is also a small chance of the clinician not being able to access the spinal space, sometimes due to scoliosis because of SMA. 

The procedure needs to be done aseptically, means cleanly and to avoid introducing infections. The drug itself is an antisense oligonucleotide drug, which if given subcutaneously or intravenously has been known to cause bleeding or clotting problems and / or kidney problems. And also the need for repeated lumbar punctures, it is good to know that there is no clotting problems beforehand, and also to check intermittently for kidney problems. So in essence, when someone uses nusinersen, we would typically check for clotting and blood count, as well as kidney function. 

However, problems with clotting ongoing and kidney function is not typical in patients receiving nusinersen over the years.  

Patients receiving nusinersen. And nusinersen is generally a very safe drug. The second drug, risdiplam, works also on increasing the SMN protein via SMN2.  

There are two forms of risdiplam. Initially there was the liquid form and now a tablet form is available. The liquid and tablet form can be taken orally, so through the mouth, or the liquid form could be given through a feeding tube. The tablet dose and form is only for those who are at the maximum dose, which is 5 milligrams when they are greater than two years of age and a weight of greater than 20 kilograms. The solution form could be adjusted according to the weight and age of patient. Risdiplam is given at home or wherever the patient is once daily. The tablet form has a shelf life of three years and the liquid one a shelf life of 64 days in the fridge but maximum of five days outside the fridge is allowed.  

For the risks of risdiplam, patients on risdiplam are advised for contraception during treatment for both males and females. There has been indications that male fertility may be compromised while under treatment, and so sperm preservation prior to treatment and recommendation of contraception during treatment is made. 

Treatment, however, can be stopped temporarily if the patient wishes to have children. It is also not recommended to be used in pregnancy or breastfeeding. There are side effects to risdiplam and the very common ones are diarrhoea and rash. The diarrhoea is more pronounced with the liquid form because of added ingredients to the liquid form that is required to maintain its stability. 

Risdiplam however, is generally a very safe medication as well. 

 So the third and final drug is Zolgensma. And this works through introducing the functional SMN1 gene into cells to provide a source of SMN protein. So patients with SMA are missing the SMN1 gene that is working. This is a viral gene therapy and it is a single one-time treatment via injection through the bloodstream over one hour. This can only be given in the hospital. As treatment cannot be undone, given, families need to be counselled adequately prior to treatment to ensure that this is the right treatment for them at the right time. There is also a lot more preparation that needs to go into  

Zolgensma treatment to ensure that this is given as safely as possible compared to the other drugs. The preparations include checking for bloods. So this includes AAV9 antibody testing. AAV9 is the virus that the drug uses to bring the genetic product into the cells. We also check blood count, liver function and kidney function, cardiac enzymes and clotting.  

We would also go through the history, particularly for vaccinations, infections, recent ones, especially breathing, feeding, medications, family history of other medical problems to make sure that this is the right treatment for the patient. 

We generally like the patients receiving Zolgensma to be at their optimal state of health because this treatment can lead to serious systemic, meaning whole body, immune response. 

Zolgensma also requires pre-treatment with steroids orally 24 hours before Zolgensma is actually given. And the steroids need to be continued for at least 30 days and then subsequently tapered down to stop when it is safe to do so. There are several specific risks to having Zolgensma treatment. 

The first is, and very commonly, fever in the first week of post-treatment, as if the patient has had a bad viral infection. In the first two weeks, they can also feel quite nauseated and vomit. 

And low platelets, which is a type of blood cell to prevent bleeding, can occur. And there is a chance, a risk of bleeding as the platelets become low in the first two weeks after Zolgensma. There can also be liver problems. And this can happen in the first two weeks, but can also occur later on. Sometimes, steroid doses need to be increased to counteract this or another medication may be required to be added in. We also check the heart enzymes as this can be elevated after treatment with Zolgensma. 

 Saying all this, all the risk that I’ve mentioned will be higher if there is concomitant infections or vaccinations around the time of dosing. And so it is very important to avoid infections around the time of dosing and also after dosing. And so families are generally advised to try to keep infection risk as low as possible, almost like shielding. 

 I would also like to stress that it is very important to attend monitoring reviews after Zolgensma treatment. And this can be as frequent as one to two times a week initially and continued for several months, particularly when the patient is still on steroids, as we need to monitor whether the dose is correct and when we take patients gradually off steroids. Steroids themselves can have side effects.  

The risk of steroid side effects increases with the duration and increase in dose of the steroid itself. One other thing that needs to be mentioned also with Zolgensma treatment is that it is because Zolgensma uses a virus to bring in the genetic product into the cells of the patient.  

The virus itself sheds from the patient within the month of receiving Zolgensma. And so good hand hygiene is recommended and also careful disposal of waste of bodily fluids is required.  

That’s all. 

Thanks Min. There’s a lot for families to think about with all these treatments and it sounds like there’s a lot of risks but I do want to reassure people that these risks are low and these treatments have been assessed as being safe. My son is on Spinraza and he breezes through his lumbar punctures three times a year.  

For all these treatments, evidence has shown that the earlier they’re given, the better the treatment outcomes. And you spoke about all these tests that are required before Zolgensma gene therapy can be given. And I presume that takes maybe a number of weeks for those tests to happen. And that means a delay to access to that treatment. Can you tell us how clinicians are approaching this problem and making sure that children are getting treated as soon as possible after diagnosis? 

Yeah, so we do what we call bridging, and this is defined as a short-term arrangement, three months or less, until definitive therapy is given with Zolgensma. And there is convincing evidence that the earlier initiation of any SMA treatment, as you mentioned, is associated with better outcome. 

So the timeframe between diagnosis and starting of treatment should be as short as possible, particularly those with two or less copies of SMN2 gene. 

And if the parents and carers preferred option is actually Zolgensma treatment, then bridging treatment can be recommended while we work up to preparing for Zolgensma treatment. 

That’s really great. Jennie, in your role as a specialist physiotherapist, you must work with children who are on all of these treatments, all three of them, assessing them through physio assessments and supporting them in their physio routines. Have you seen any evidence as to which treatment is best? 

Yes, at Evelina we see children on all three treatments. First to say there is no comparative clinical trial evidence and in the real world we see that all three treatments are working. I can’t honestly say that any one is better than any other and it’s important to make the right decision for each family. 

And that is based on the age of diagnosis and what works for the family. So when we’re looking at doing the assessments to see any progress, we have to remember that the children are all starting from a different point, have all started treatment at a different point. So it’s really important not to compare with other children. Obviously, we have to in terms of real world evidence. 

But I would strongly recommend that parents don’t compare with peers because everything is not the same. But the short answer is I don’t think there’s any evidence of any one treatment being better than another, either with clinical trials or in the real world. 

And is there any evidence that dual therapies or having two treatments at the same time is any better?  

Again, no, there isn’t any evidence. There have been a couple of trials, but that’s been more looking at safety. But there’s not any current evidence that dual treatment is beneficial.  

Thanks, Jenny. 

Part 2: Children who have shown symptoms and been diagnosed with SMA: 

• which treatment is possible 

• follow up assessment and care 

• making a treatment decision 

In terms of access to treatment, children who have been diagnosed symptomatically, so that means they’re diagnosed once their symptoms have been noticed by parents and picked up by those frontline clinicians. And if I could just cover first that children who have been diagnosed with type 1, 2 or 3, they may have nusinersen or risdiplam wherever they live in the UK. 

 In England, Wales and Northern Ireland, a baby with the very serious and rare type 0 SMA, may also be able to have nusinersen. And this would be with a conversation with their health professionals.  

And the last treatment, Zolgensma, is only available for type 1 patients in the whole of the UK. There is also weight restrictions of 21 kilogram maximum  

recommended for this treatment in the whole world. And ideally in the UK, we try to give this to patients less than seven months old, as we know that the heavier and older the patient is, the risk increases from the treatment itself, including the use of steroids.  

And for people currently on risdiplam and in nusinersen, like my son, now that we’ve got these treatments approved by NICE, will anything change for the people who are on treatments currently, be it in access or in their monitoring or in our clinics?  

So nothing has changed in terms of access.  Patients now Nice has allowed treatment without the same stopping criteria as the Managed Access Agreement. So actually, it is now potentially more available than previously. And if a person is on any of this treatment, that there’s currently no change required for the patient or the clinician to make unless there is a new reason for it and this can be discussed with your clinical team.  

Fantastic. And are we free to switch between treatments?  

Yes, so patients on nusinersen and risdiplam can switch between treatments. Obviously, you’ve already had or patient already has had a Zolgensma treatment, this is still the same. So second treatment following successful Zolgensma treatment is not allowed. And the definition for an unsuccessful Zolgensma treatment is a reduction in motor ability and/ or a deterioration in respiratory function. And there are different parameters where we have to assess patients on in these two fields before we can say that they have had unsuccessful treatment with Zolgensma. 

 I know also another thing you mentioned was stopping rules and I know there were these rules attached to the Managed Access Agreement and one of those was over 16 hours of ventilation and if that was the case you couldn’t access treatment. Jennie what does the guidance now say about access for the ventilated population? 

So that guidance, previous rule has now been removed and all children that are on ventilation, whether it’s full-time ventilation can still access treatments. So even children with tracheostomy are now able to access treatment. In the past, some were through compassionate use, but now everybody can through the NHS. 

Great. 

 That’s such fantastic news that it’s no longer a stopping criteria. I always thought how awfully unfair that was. 

I forgot to add in that, you know, we have seen with children that are having treatment that they still benefit from the treatment and I think that has been recognised now by NICE. So even if children have had a difficult start in life and requiring a lot of ventilation, having treatment has enabled them to reduce ventilation and children that are on full-time ventilation are still seeing benefits on the motor function. 

When my son first got treatment, he was permanently ventilated in intensive care and now he’s nine and he has it overnight. So it shows that it definitely does have an impact on use of ventilation. Another thing we used to have to do as parents throughout the Managed Access Agreement for risdiplam and Spinraza was come into clinic every six months and have some quite rigorous assessments. We used to have to get scores on the outcome measures and it really took a lot of clinic time. Is that something that will continue? What’s it going to look like in practice for people living with SMA on these two treatments? 

 So the pressure is off in that you’re not having to make sure that you haven’t reduced two points on any of the outcome measures. So it takes away the panic of the stopping criteria. And sometimes there was a reduction for maybe a child wasn’t very well on that particular day. So it’s taken away that. However, outcome measures are still really important. They’re important for research. They’re important for real world evidence. 

But more importantly than that, they help us manage that particular child. So for example, if they’re doing the upper limb assessment and something is becoming more difficult, we can consider whether any aids or equipment can be beneficial. So there’s still a need for the assessments. The pressure is off, but they are still important. And it’s also in the current standards of care which are due to be updated, but that is still recommending standardized outcome measures.  

Okay, that’s good to hear. I’ll be a bit more relaxed.  

Can I also add? Yes. The recommendation for continuous monitoring will also benefit the patient because if they are receiving ongoing treatment, say with nusinersen or risdiplam, we would like to know whether actually that particular treatment is still useful and benefiting the patient because potentially if it’s not, then they could swap to the other treatment. And also, even if patient has had a once-off treatment like with Zolgensma, we would like to know whether there is still ongoing benefits because we do not know what the longer-term outcome is, say in 10 years time after Zolgensma, whether this is a sustained benefit and / or if there are potentially even side effects from Zolgensma treatment after that period of time. So I think being engaged with the clinical team would still be beneficial for patients. And also we do not currently, while we understand SMA quite a lot now compared to before, there is still a lot that we do not know. So like what I’ve mentioned, real longer term outcomes, 10 plus years, 15 plus years, any other associated health issues that were not previously known to be seen in patients with SMA. So potentially bone problems, metabolism problems, orthopaedic management, and whether or not the drugs that we give now actually help them in those ways as well. So I think the assessments will probably change over time. And I agree with Jennie, it should suit the different needs of the different patient groups. And this could be like a pre-symptomatic patient group, a symptomatic patient group; and also dependent on their age, the age of the patients and what the patients actually need going forward.  

 I think it will be a little bit more individualised than it has been. 

 Yeah, which is great. 

  That’s what we want, I think, as patients, that’s what we want. So we don’t have newborn screening yet in the UK. We’re still having children diagnosed symptomatically. And with all these three treatments to choose from now, they’re all equally as good as each other. How do you work with a family to support them to choose a treatment for which one will work best for them?  

So we try to provide information to families and patients such that they can make an informed decision. And this will be different for different people. Some will want and need more information and others actually simpler information is better. Different people and families also may value different aspects of care or management differently. And there may also be practical issues that need to be accounted for in the different families like transport, other children in the family etc. So patients with SMA can also be quite different with different symptom severity so like some will be maybe a little bit more severe in their breathing but not so much affected if they’re feeding or movement and vice versa. So even if having the same SMA type, patients can be different. So each patient is an individual and it should be discussed with the patient in mind specifically. And so we try to work together with the families and patients to help come up with an individualized decision making on treatment, but also on the management of other aspects of SMA, not only with drug treatment. 

That seems like a really great approach, it’s about the whole family unit isn’t it and how it impacts everybody. 

Yeah, so while drug treatment is important and we know that the drugs are effective and do improve outcomes, the associated care that goes with looking after a patient with SMA is also as important, meaning the respiratory care, physiotherapy, and even ensuring that the patient has the right nutritional requirements. 

Fantastic. Jennie anything to add? 

Yeah, absolutely. I think there is a thought sometimes with families that they’ve had treatment and that’s it. All sorted, particularly with gene therapy. So it’s very important to remember that unfortunately it’s not a cure, it’s a therapy and everything else needs to go along with it. So for example, you may improve some strength with treatment but it’s not going to undo contractures, it’s not going to undo a scoliosis. So all the other physiotherapy management, orthotic management, everything that Min mentioned is still really important. And also to keep in mind, you know, with other treatments developing, everybody wants to be in the best state, if you like, and functionally, but also to be in the best state for if something else comes along. 

Part 3 Babies diagnosed before symptoms show 

• how do clinicians know how a baby’s SMA will develop if they don’t have treatment? 

• what treatment is possible? 

So we all know that the best outcomes for treatment for SMA are seen when treatment is given before symptoms start. And there’s two ways that this can happen. The first way, and what is happening right now, is that when SMA is already in the family, a sibling might be diagnosed with SMA pre-symptomatically. And also, when we have newborn screening this might also happen as part of that newborn bloodspot screening. It’s being trialled currently in Scotland, which is great news, and from October it’s going to slowly roll out in parts of England as part of the National Screening Committee’s In-Service Evaluation. This evaluation is to see if it is cost and clinically effective and should be permanently part of the UK’s national bloodspot screening? 

So Min, when you have a baby with no symptoms but a diagnosis of SMA, this is because of their SMN1 gene test. But how can you tell how their SMA would develop if they didn’t have treatment? 

So, SMA typing that we’ve been using is based basically on the development of the maximum motor ability of the patient and it is a clinical typing based on what one sees as we examine the patient. However, if babies are diagnosed before symptoms start or before they achieve their maximum ability, we cannot then type them in a traditional way. And so we rely on the SMN2 copy numbers of the patient, as this gives us a general indication of how much SMN protein they would be able to make without any drug treatment. The higher the copy number of SMN2, the more likely the person would be able to produce more SMN protein of their own. So this usually is, but not exclusively,  type 1 patients generally have two SMN2 type 2, patients have 3 SMN2 copies and type 3 patients 3 to 4 SMN2 copies and type 4 greater than 4 SMN2 copies. So SMN2 copies can be tested soon after birth in the whole of UK and so this is generally used to determine, to predict the severity or the anticipated type of patient the baby will become if no treatment is given to them. 

That’s really helpful and explains what NICE has said for England, and that Wales and Ireland are likely to follow. If I can summarise what they say, there’s a lot of information, so I thought this chart might help. Pre-symptomatic babies with between one and three copies of SMN2 may have any of the treatments, but they have said that if Zolgensma is suitable, risdiplam can only be used as a bridging therapy. It can’t be used as an ongoing treatment. 

If a pre-symptomatic baby has four copies of the SMN2 gene, they may have risdiplam or nusinersen. And what is new is that if a pre-symptomatic baby has four or more copies, nusinersen could be possible. And that’s because the overall license for this treatment allows it to be used for all 5Q SMA, whereas risdiplam is specifically licensed for only one to four SMN2 copies. 

Scotland is different at the moment, as nusinersen is currently not possible pre-symptomatically, but it is currently being assessed by the Scottish Medicines Consortium, the SMC, with a decision expected in late 2026. This means that the possibilities are risdiplam or Zolgensma for pre symptomatic babies with one to three copies of SMN2. Risdiplam can be used as a bridging therapy or as an ongoing treatment if preferred. And risdiplam is the only option for pre-symptomatic babies with four SMN2 copies. I hope that summarizes it and it’s a bit easier to understand. 

How do you work with families? Because it must be very difficult for families diagnosed presymptomatically. They have a baby that in essence looks completely fine, like doesn’t seem like a poorly child. How do you work with those families to make a decision about treatment and how do you support them? 

So we try to provide information to the families and patients, well, families mainly because the patient is a baby, such that they can make an informed decision in a timely manner because we know that earlier treatment, the better the outcome. And sometimes this is quite a lot of information to the family, particularly if the family was not expecting a diagnosis of SMA. Most patients now who are pre-symptomatic and identified are actually family members of a patient with already SMA. And so giving information to families who already know of SMA is easier. In the future, when newborn screening comes, many families are not expecting SMA in their baby and will be starting to be trying we will have to start with trying to get them to understand the condition and the reason for us wanting to treat their baby earlier. It also may be quite difficult for these families to accept that their child has SMA as a lot of the times the baby may appear well to the family. So I think information sharing will be different for different groups of patients, and also different families value different aspects of care and management differently and practically some treatments may pose difficulties to some families in the immediate period because like Zolgensma will require the families to come in quite regularly for assessments and monitoring. 

Things need to be individualized for the patients and families with regards to information as well as management and treatment. 

Yeah, for sure. Well, there’s been a lot of information given in this webinar. So I want to thank you both so much. And if ever anybody wants to have a quick look on our website, we’ve got three new treatment information sheets. One for adults and one for children in England, Wales, and Northern Ireland, and one for children in Scotland. So do go on our website for any more information. 

I want to thank you both, Min and Jennie, so much for coming and giving up your time to speak to us today. It’s been really, really informative, and we look forward to seeing you again on the next one. Bye-bye. 

Thank you. 

Thank you.