Finkel RS et al; Prenatal SMA Risdiplam Study Group. Risdiplam for Prenatal Therapy of Spinal Muscular Atrophy. N Engl J Med. 2025 Mar 13;392(11):1138-1140. doi: 10.1056/NEJMc2300802. Epub 2025 Feb 19. PMID: 39970420.

Portia 

Hello everybody and welcome to SMA UK’s latest webinar. Today we’re going to be talking about a really interesting topic which is prenatal treatment. We’re here today with three experts, really lucky to have them all here from Great Ormond Street Hospital and all of them have been working sort of internationally in this field. Now as a mum to a young man with SMA type 1, I know firsthand that there’s a chance that SMA can progress before a baby is born. And there’s many families out there, not me, that are still wanting to progress their family and thinking about family planning. And this is a really interesting topic that could be an option to consider. But it is very new. It’s an evolving topic. So I want to introduce you to our three experts. Shall we start with you, Professor Francesco Muntoni? 

Francesco 

Thank you, Portia. My name is Francesco Muntoni. I work at the Institute of Child Health and Great Ormond Street Hospital here in London together with my colleagues. 

Mariacristina. 

Hi everyone, I’m Mariacristina Scoto, I’m one of the neuromuscular consultant at Great Ormond Street Hospital working with Francesco Muntoni and Giovanni Baranello. 

Giovanni. 

Hi Giovanni Baranello, neuromuscular consultant at Great Ormond Street Hospital in UCL. 

Portia 

 Thank you. Now I’ve been following this for a while. There was news a good while ago now on social media about a family that had their baby treated prenatally in America. Francesco, can you tell us a little bit more about that early research and scientific evidence that made you think that this should be something that should be explored? 

Francesco 

Thank you, Portia. So, I’ll tell you how this came about. The observation is that newborn screening on the whole works very well. At the same time, it works statistically better for those kids who have three copy numbers, meaning the majority of these children will respond in a way that is full…that those in the children with two copy numbers, especially if treatment even after newborn screening is not initiated promptly or immediately, there may be a proportion of those kids who have delayed motor milestones. 

The, just to be clear, the majority of the newborn screening or the data on the newborn screening, of course, are evolving. The mean age of treatment in most of the newborn screening program is between three weeks, sometime even four weeks. So I think this is a plea, and I think here perhaps Mariacristina and Giovanni can also explain, to ensure that whenever there will be a newborn screening, this interval between the baby birth and that test, initiation of treatment, is as short as possible because clearly three weeks or sometimes four weeks is just too long.  

Another evidence indicates that many children, this is a study that had been done originally by one of the companies involved in the developing of therapies for and in newborns, that if you study one of the markers called neurofilament, that is a marker that indicates that there is already active disease. A proportion of children with two copy number at birth already had this marker that was elevated while essentially none of those children with three copy number had this elevated.  

I think essentially there is convergence of evidence that at birth this blood marker of disease already shows that there is some activity in a proportion of children with two copy number. If you wait three weeks or longer before start treatment then the proportion of children – they do well, but they don’t do as well as those children with three copy numbers, in whom the development appears to be normal. And therefore… Sorry…please carry on. 

Portia 

So, this is really for babies who you’re expecting to have the most severe type of SMA. So just for two copy number babies. 

Francesco 

That’s correct. 

Portia 

And the markers you talk about, this is something that you can look at and it’s like an indicator of how severe that baby’s going to be. Is that what a marker is.  

Francesco 

Think that the level are an indicator if there is active disease and yes, there is active disease, broadly speaking, the lower the level, the better and the higher the level, more pathology may occur. 

Portia 

Can you explain how you know the copy number of the baby if it hasn’t been born yet? Like, how do you find that out? That’s quite incredible. 

Francesco 

So I think that maybe, I think that because this is linked to this theme in the cases that have had the prenatal therapy that we will be discussing. Those were not identified randomly. These were families where there had been a previous child affected and therefore these were at risk pregnancy and in those at risk pregnancy the family agreed to have a prenatal test. The prenatal test was done using one of the common tests that is used prenatally is usually the chorionic villus sampling and therefore with that test it’s possible to tell both if the fetus may be affected but also what is the copy number of SMN. But of course because there have been previous child affected families knew what may be the outcome. 

Portia 

And is that test just a blood test from mum? Do you have to get blood from the unborn baby? 

Francesco 

You don’t need to take a blood test from the baby. You need to take a small piece of the placenta. It’s a common study that is done. It can be done either by a small, if you like, needle through the tummy or through the uterus. It’s a very nice test that has been used now for decades. It can be done, you know, at…10, 12, 14 weeks. There are also tests that can be done later on. That’s called amniocentesis. But in a planned pregnancy, usually the chorionic villus sampling which is the first one I discuss, would be the one preferred. 

Portia 

Francesco, could you tell us a little bit about the research that happened in America that led to you guys thinking about bringing this to the UK? 

Francesco 

So one of our colleagues who has lot of experience with spinal muscular atrophy called Richard Finkel, he was following a family where a previous child had a severe form of spinal muscular atrophy. And by that time, the emerging data from the newborn screening that is available in the States indicate that only a proportion of those children with type, with two copy number of SMN at the severe end of the spectrum will have a full response after initiation of treatment.  

So, the mother or the family was quite informed and they grilled Professor Richard Finkel saying is there anything else that could be done other than just accepting that there may be a risk that even after newborn screening or after starting treatment in the newborn there may be not a positive outcome. And that was when Professor Richard Finkel first reached out to the company to understand better if there would be some potential risk for the child, for the fetus, but also for mum, then reached out to the ethics committee to see whether this, if you like desire of the mother and the family could be fulfilled in a way that was ethically and safe. She, you know, as a one-off, as what we call an N1 case, he did start the treatment. He was informed a lot from the company regarding what are the right levels to give because you’re giving the drug to mum hoping, and with the assumption that the drug will go to the fetus, but in actual fact, the dosage is a dosage that needs to be carefully understood. And therefore, he really put together the groundwork for this to be then pursued. Other cases that we’ll hear in a second also from Mariacristina have been pursued so far.  

So he presented the first time this data in October 2024 at one of the international meetings. He published the data in a leading journal and I think this really has given the inspiration and idea for other colleagues and other families to follow the same path. And I think Richard has been very generous with his knowledge to ensure that if you like whatever had been learned from his case could be shared with the community. 

Portia 

 Fantastic. 

And then I heard just on social media that this is starting to be offered in the UK, which was really, really exciting. So could you tell us Giovanni a little bit more about the processes involved? Like what do mums have to think about? Are there tests, assessments? How are you following this journey? How’s it happening in the UK? 

Giovanni 

So I am, let’s say that these are still early days because there is no, this is not somehow commissioned through the NHS. And the few cases that had been treated have somehow access a special pathway, which is either to an individual patient request or funding request or through compassionate use where basically there has been a sort of application, a discussion with the local ethical committee, individual hospitals, with an application to, in a specific case, to the company to provide for free, on a compassionate use basis, the drug. So it was very exceptional somehow. 

Portia 

It’s not a clinical trial, it’s not like an official clinical trial. 

Giovanni 

At the moment, no. At the moment, there is no clinical trial. And although there is ongoing discussion, because as you can imagine, somehow the pressure is increasing. And as you said, you know, it’s a hot topic of discussion among families. And I was also quite surprised to hear that many families who had already children with SMA would consider this option. 

So we are trying also internationally somehow to consider how to move forward because we need to provide evidence. Actually, if you look to the label of risdiplam, this is not recommended during pregnancy. So somehow we need to provide evidence that would be able to expand the label and to include also prenatal therapy for these selected cases, as Francesco was mentioning. 

Portia 

And I suppose it’s not recommended on the label because there’s no evidence, not because they found evidence that it’s dangerous in pregnant women, but just… Yeah. 

Giovanni 

Yes, because there is no evidence and because the limited data that they run, you know, that every time that you try to develop a drug, you need to do some toxicology studies in animals and also to study the risk for pregnancy, during pregnancy. So the limited data that they did just for the purpose of, you know, developing and bringing the drug into the humans, identified there could be potential risks in the early stages of the pregnancy.  

And this is why, you know, based on the data that they had, I think it was from rats, you know, the evidence was not to use or the recommendation was not to use in pregnancy, because also this was somehow outside of the purpose, you know, treating babies after birth. And this is why also the few cases that have been treated now, during pregnancy, where receiving the drug at the later stage of the pregnancy – so in the third trimester, where let’s say all the possible side effects or toxic effects of the early treatments might be reduced, you know, and nearly equal to zero. 

Portia 

Okay, so you’re only treating that last trimester. Mariacristina, could you tell us, I mean, if I was pregnant, you know, I know I’ve had an SMA child before, how would I go about getting access to this prenatal treatment and what sort of tests and assessments might I expect on that journey? 

Mariacristina 

Thank you, Portia. first of all, as my colleagues already mentioned, this is a very early stage of treating patients prenatally. In my experience, if you like, the request came from the family. Probably you know already that there are a couple of families that have received prenatal treatment already in the UK. And the first one was with us and the mother of two children that we already follow in our hospital with SMA contacted me early in the pregnancy to let me know that she was pregnant again. And at that time last year, the paper that Professor Muntoni mentioned before about the first treated cases just came up.  

So, I mentioned different options to this family in terms of…we could try to treat the baby as soon as the baby is born, we will follow you all the pregnancy, et cetera, et cetera. But there was this, you know, in the background, there was this knowledge, because it’s been already presented in some conferences, so the families knew about this potential prenatal treatment. And at that time, I wasn’t sure if this was possible. There was only one case and there was never…the request in UK.  

So, I told the family, let me investigate, let me see what can be done. So, and what was my experience? It was partially replicated by the second consultant who treated a case and now there is a third one who is treating a pregnant mum. So what I had to do as a clinician was first of all to look at the potential safety for both mum and the baby. And this was done with several consultations with my colleagues, neuromuscular colleagues, but also I inquired to our own ethics committee whether there was an ethic background to treat this baby knowing that the two previous siblings had SMA Type 1 and had two SMN2 copies. So we were pretty sure that this baby would have had the same genetic makeup. 

And I had several conversations with Dr. Finkel, who was the one who treated the first baby. And also I reached out to other consultants in Europe who were starting thinking about that or they started treating other mothers. So through all of that, I had clearly a positive response from a clinical point of view. My colleagues that is committed, colleagues in US, in Europe, that this was something potentially feasible treating the patient, the mother with the risdiplam. And that was also with a good follow-up, there was some good safety net that we could use in terms of following this mum.  

And an important step, Portia, was the collaboration with the fetal medicine team because this mother was already pregnant, she was already getting to the fourth, fifth, sixth month of pregnancy, she was already followed by a fetal medicine group. So the important thing was to have this group on board. So to understand that there was my part, which was informing them about SMA, about the treatments, about what I was trying to do and provide all the scientific information to this group. And then there is the very important part of the fetal medicine colleagues who ultimately are the one who are following the mother during the pregnancy in this third trimester. Are going to do all the safety assessment for the mum and the baby during the last trimester of pregnancy. And because mum is an adult and I’m a paediatric neurologist, they are also responsible for prescribing the treatment to mum and monitoring all potential adverse events. All in collaboration, of course. 

And we follow protocol to do that, which was the same protocol that was followed by Richard Finkel for the first case. And we created our, if you like, in-house consent form, where there was in detail what was known in terms of the potential effect of a risdiplam in an adult with SMA or in healthy volunteers, because this is something that always happens before clinical trials, some healthy volunteers are treated with the compound. And what was the more intense follow-up that this mother has to follow in terms of visits to the fetal medicine, which is on a weekly basis, basically. And what was the plan at the delivery of the baby and how we would have treated the baby ⁓ after the baby was born.  

And all of that came with also some consideration in terms of, again, replicating the little experience that was there, which was both the other two people, one in Europe and one US, that were treated. The delivery was induced at 38 weeks, so there was a bit of control of when the baby was born. 

And then there was the discussion about starting treating the baby. So we replicated what was already done by other colleagues and did the same ⁓ with our case. And this, without saying Portia, came with a lengthy discussion with the family, with the father, with the mother, ⁓ as I said already with several consultants. And eventually this family knowing very well SMA, having already two children, they were really interested and they felt that this was something they wanted to try and we gave all the information to them. We had several consultations with them before starting treatment and then mum started treatment around the 32 weeks and five days. So again in the time window that Giovanni mentioned before, which was the one that we had some knowledge already and we knew it was done before and it was safe. 

Portia 

Yeah, I suppose it’s always a risk benefit decision, isn’t it, for any family?  Yes. And when you know the outcomes of SMA, then, the really huge benefits to be seen. Were there any risks? Are there any risks throughout this process for… 

Mariacristina 

Yes, of course, Portia, there is always risk. Risdiplam is not labelled, is not approved for ⁓ prenatal treatment. And therefore, there was, I cannot hide, and I know it’s the same for my colleagues who are treating other patients. There was a lot of, I was really, really careful with the follow up with mum. 

We expected some potential side effects which are the one for mum, the one that are typically seen in adult who are taking this treatment for several weeks, which could be gastrointestinal side effects to start with, you know, nausea or diarrhoea. But the reality is that this compound is taken from mum through the placenta goes to the baby, which is exactly what we want to do. But we don’t know if it might target other things and this is why the pregnant women are followed on a weekly basis.  

Basically, one week there is a number of safety assessments that are done on the mother and the following week there are assessments done on the baby, including scan and including brain images during the pregnancy as well, not because we expected in the third trimester that there was some fetal toxicity as such, but because of the only reported case so far where at birth there were some central nervous system ⁓ abnormalities, we were all looking into that and trying to be very, very careful. 

And of course, you look at the parameters of the baby, if he’s growing well, if there is any problem with the growth of the baby. And again, fetal medicine colleagues are exceptionally good in that. They do prenatal treatment for a number of other conditions. They really know how to follow this mother. So the collaboration was vital in this case. And the mother is followed after birth as well. There is another ⁓ couple of visits with the mother just to make sure that there are no residual problems.  

And luckily, Portia, my family did tolerate risdiplam well. They had to adjust the way they were taking risdiplam. With breakfast, there was a little bit of ⁓ nausea, but taking with ⁓ later, with tea, et cetera, it was much better tolerated. And there were no other potential alarm bells during the pregnancy that something was going wrong with mum or the baby. And then there was a plan after the baby was born and the plan was to treat the baby soon after birth.  

So the baby was seen actually by Giovanni when he was only three days old. And we did some baseline measurements, some of the biomarkers that Professor Muntoni mentioned before. And then by the third day, of life this baby started the oral treatment. And in the meantime, there was already a conversation, a discussion about whether the baby would remain on one treatment or switch to a different treatment. And this is something that we do all the time Portia, it’s not new. The consultation about treatment after birth is not a new thing. And the plan was for this family to have gene therapy eventually.  

So we started the oral treatment for the baby and in the meantime, we prepared the baby for gene therapy, which was given after two months of life. And we continue to monitor the baby more than what we would do, Portia, with the typical babies after we start risdiplam. We try to monitor the baby every week or every other week, just to make sure again that there were no alarm bells in terms of safety and there were none. 

And clinically, the baby looked normal, didn’t have any sign and never showed any sign or symptoms up to the gene therapy and up to now. 

Portia 

Sorry to interrupt. Did you as clinicians, do you notice any difference between the one baby you’ve seen treated prenatally and from what you’ve heard to babies that are treated through newborn screening? Are you seeing better outcomes from that prenatal treatment? 

Mariacristina 

So, this is a difficult question to answer now because the baby I treated, we treated, is now eight months. The other baby, the second baby treated, is probably four to five months, five months old or something like that. The third baby is to be born. So this is a little bit difficult – Time will tell –  to completely answer. And the reality is that we have some siblings that we have treated with two SMN2 copies and we treated them very early around a week ⁓ of age and actually to be honest some cases are not doing so well despite starting treatment around a week or 10 days of age which is actually earlier than what you would expect with newborn screening. It will be interesting and probably important to follow these babies for the long term and continue with some biomarkers as well that can give us some indication and clinically.  

But yeah, I mean, my personal feeling, I would have not gone through so much difficulties and getting this treatment for this mother if I wasn’t convinced together with my colleagues that this was the right thing to do for this family. And each family will have a his own process. I mean, it might not be the right thing for everyone. 

Portia 

Well, they always say, don’t they, that days are neurons. So the earliest possible opportunity to treat these babies must be a good thing. How do you see this going in the future? Is this going to be an opportunity that stays open? Will it become a clinical trial officially? Might there be a world where we can do gene therapy in the womb? Where do you think this might go? Anybody who wants to answer that one. 

Mariacristina 

I let Giovanni go into that because he has a strong interest in what’s going on now. 

Giovanni 

Shall I? Yeah. Just because we are trying to connect, you know, international with other initiatives. think that, you know, following what Mariacristina was saying, it’s an option that many families would like to try because again there are also as you know ethical considerations and I as I said I was struck by knowing or becoming aware of how many families actually would like to give a try to this option.  

Again because we know how much we are advocating and fighting for newborn screening so definitely that is the next step. At the same time as you said every day matters and we know that by the time we have a final confirmation and we start a treatment there are some delays. So going back to where Francesco was starting, the two copies may still have some unmet need, you know, where we need to intervene even earlier. And this is where the prenatal therapy could come into play.  

But we need to build up more evidence. We need to develop more evidence. We need to collect long-term data. So we will use the SMA REACH Registry. And actually, I can probably share a couple of slides that I have here just to show you.  

This is the map of the SMA Reach network, which is the national network that gathers together all the neuromuscular centres that follow patients with SMA. And those in yellows, you see there is quite a wide distribution across the countries, are those neuromuscular centres who have already made a good connection with the local fetal therapy centre because we need to create a network of fetal therapy centres that are able to immediately step in and monitor these families, monitor these pregnancies and so on.  

The idea would be now, I mean for some time, Roche put on hold somehow the programme because they wanted to understand more what data we have in terms of safety, how safe is it for the baby and so on. Now we are exploring potentially to have a proper study either to continue to collect this data as they come along, you know, we have, as Mariacristina was saying, there are already a few in the UK.  

There are others in other European countries and also in the US and worldwide. So we are trying to put together this data to see how these children are growing, what are the biomarkers, when they reach the milestones, how they potentially compare with those treated postnatally after newborn screening and so at the same time, we need to generate evidence because, as we said, at the moment it’s not recommended for use in pregnancy yet through the NHS, so we need to tick those boxes that will allow us basically to prescribe this in the real world for… So there are still a number of steps, but we are moving forward to have a more coordinated effort, not only in the UK, but linking with other initiatives. 

Portia 

That’s incredible. So the future really does look bright for, you know, early treatment and getting the best outcomes as we can out of these incredible treatments that we have.  

Thank you, everyone, for coming to chat with us today. Really, really appreciate it. And it’s really great that we can get the sort of latest information on the new, exciting stuff that’s going on in the UK. If anyone’s watching this that ⁓ is pregnant or you’ve already got a child with SMA and you’re thinking about, you know, planning to make your family bigger, we have lots of information on SMA UK’s website on family planning. Do reach out, have look at our website or contact the support team. Thank you guys. was great. 

Thank you