Welcome to our update on treatment for adults. I’m Molly, I’m SMA UK’s junior researcher. I have SMA type 3. I’m currently on risdiplam, but I’ve also been on nusinersen in the past. So if you haven’t seen the news over the past few weeks, on the 14th of May, the National Institute for Health and Care Excellence recommended permanent NHS England funding for nusinersen and risdiplam for people living with SMA. This marks a hugely important milestone. Today, I’ll be discussing what this means in practice, as well as access in Wales, Northern Ireland and Scotland with our expert panel. 

Before I ask them to introduce themselves, everyone at SMA UK would like to extend their sincere thanks to all patient groups and clinicians, advocates and members of the SMA community who have campaigned and advocated for more than 10 years for this outcome. Our thanks also to all the organisations who have worked tirelessly to help make this possible. Over to you, James. 

  

Hello everyone. So yeah, my name’s James Lilleker. I’m a consultant neurologist. I work in Manchester at the Muscle Diseases Unit, Salford Royal Hospital. I run the SMA service up here with my team. And yeah, it’s my pleasure to join you today, Molly and Rob, and talk about the exciting news that we’ve just had over the last week. 

Thank you, and Robert. 

  

Hello, name is Robert Muni Lofra, my consultant physiotherapist here at the John Walton Muscular Dystrophy Research Centre in Newcastle –  which is a mouthful. I do see patients with all neuromuscular conditions & have a special interest in SMA from paediatric to adult range, but I’ve been also been the lead physio for the SMA-Reach adult network and also part 

  

of the clinical panel that has supported the implementation of the Managed Access Agreement. 

  

Thank you. So the guidance that I just mentioned means that there are no longer Managed Access Agreements for these two drugs anywhere in the UK and the funding will be ongoing. Who can potentially access which ones will vary throughout the UK and I’ll be asking our panel about all of that. But first of all, I’m very aware that these treatments will be new to some people listening. So James, would you mind giving a quick summary of how they work, how they’re given and any other important information about risks that have to be managed? 

  

Yeah, thanks Molly and I would certainly echo what you said there about the fantastic work that SMA UK has done getting us to this point. So just in terms of the summary of how these drugs work and I’m mainly focusing on nusinersen and risdiplam. 

  

And what I always say to my patients is that the end result of these drugs is very similar. And they both work to try and improve or increase the amount of functional SMN protein in your nervous system. And we know that in people with SMA, the problem is that their SMN gene isn’t working properly. They’re not producing full length SMN protein and that affects the function of the motor nerves. So what the drugs do, you know, 

is take a backup copy of the gene that we’ve all got SMN2 and they enable the cell to produce a full-length SMN protein from that backup copy of the gene. Nusinersen does that directly if you like, it’s injected into your back, into your lower back via a lumbar puncture. 

and gets into the cells, the motor neurons directly there and has its effect. Risdiplam is taken orally and that’s either as a liquid or a tablet. And that’s actually disbursed throughout the whole body and could also have effects on other parts of the body as well. But ultimately what happens is that you start to produce a full length SMN protein, which can then start to hopefully have beneficial effects in terms of that, 

the function of those motor neurons. So as I mentioned, nusinersen is injected into the back. And this is the key difference really between the two treatments. It’s an injection. There’s a loading period. And then you have it three times a year via a lumbar puncture injection. There’s a slight change perhaps coming as a new option for us to use higher dose nusinersen. This is the same drug, but given at approximately a double dose. 

  

The loading period is truncated because you receive a higher dose but fewer of them. And then it’s the same protocol of having injections three times a year but of a higher dose. And that’s come from evidence that suggests that perhaps in some people the effectiveness of nusinersen can be maximized by having a higher dose. And that’s something that may and is very likely to become available if you’re receiving nusinersen now. 

And there’ll be some transitional arrangements in place at your local centre. And I would contact your neuromuscular team with regards to that. Risdiplam, the big change there recently, prior to this recent announcement, was the availability of the tablet, which many people have switched over from the liquid to the tablet. And have found that that fits into their day-to-day schedule in a much easier fashion. It’s just treated like any other tablet, And it’s much more shelf stable. You don’t have to keep it in the fridge. You don’t have to measure out liquid. 

and things like that. In terms of like the risks and things like that, this is what drives the decision making about which treatment people choose to be on. The main issues with nusinersen aren’t really side effects of the drug itself, but they’re perhaps more to do with how it’s administered via the lumbar puncture. And you can have sometimes complications of lumbar puncture, it can be difficult to get the needle in. Risdiplam is different. It’s taken orally. And sometimes there are other issues that people experience because of that. 

Gastrointestinal issues, for example, is something that sometimes people experience. And the fact that you have to remember to take it every day and other things like that. We also think about how it interacts with, say, if you’re planning to start a family or breastfeed or other, you these are all the issues that we take into account when choosing between the two treatments. 

  

Amazing. Is there any evidence at the minute to which of the two is most effective? 

  

I think the short answer to that is no. My feeling and from looking at the patients I’ve treated over the years and looking at the evidence that’s out there is that the treatments work very similarly in terms of their effectiveness. And I think the thing really that should drive the decision making around which treatment is best for you is thinking about how it fits into your life. And as I say, that difference between taking something as a tablet or liquid each day versus having those injections into the back. 

And there’s pros and cons from each approach. I have patients that really love their nusinersen because they can just forget about the treatment for the periods between the injections. Other people, particularly since the risdiplam tablet has become available, you know, this is just now like taking any other tablet. So it’s those sort of things that are really guiding the decision making rather than the effectiveness of the treatment. And what I’ve seen really is that both treatments 

  

do tend to stabilize the condition on average. So instead of their condition getting worse each year I see them, more people are experiencing stability of their condition. I think that’s a really beneficial outcome from treatment. It can be quite difficult to quantify. People often say, well, how would I have been if I’d not been receiving this treatment? Obviously, that’s impossible to answer. But we often look back at 

their scores, their motor scores on the test before the treatments were available and sort of how they were tending to get worse each time. Whereas now I’ve been seeing people since 2020 or so receiving treatments, often stable now for many years at a time. So they’re the sort of things I talk about when we’re choosing which treatment to have. 

  

That’s great, thank you. Would you be able to talk us through which treatment adults in England can now have? 

So adults in England can have either nusinersen or risdiplam. There’s a little bit of nuance around the availability of risdiplam, particularly for people with SMA Type 4. So SMA Type 4 is adult-onset SMA. This is onset after the age of 18. So it’s quite a small proportion of people overall with SMA, but nevertheless an important group and a group that up until now, we haven’t been able to offer them any treatment. 

  

But now nusinersen has become available for SMA Type 4. And again, if you have that particular subtype of SMA, then that’s something you may now wish to discuss with your neuromuscular team. Now, because of the way that risdiplam was licensed, they specified sort of in detail the Types of SMA that the drug could be used for. And they specified Types 1, 2, and 3. And unfortunately, that’s now had this effect where because Type 4 

wasn’t mentioned in the licensing, it isn’t available for the treatment of SMA type four. So there’s a slight nuance for that small group of patients with SMA type four, but otherwise there’s fairly broad and open access between risdiplam and nusinersen for people living in England. 

Brilliant, thank you. Would you like to tell us a little bit about access in Wales and Northern Ireland and how that differs from England at the moment? 

So in Wales and Northern Ireland, my understanding is that they would usually follow NICE. And whilst we haven’t had the full confirmation of that as yet, given that this is hot off the press, we’re hoping that that will follow quite soon. 

  

Okay, brilliant. How about Scotland? 

In Scotland, again, the situation is a bit more complicated and this particularly relates to access to nusinersen. I think the reality is and I don’t work in Scotland, but what I gather is the situation is that Centres currently don’t offer nusinersen and anyone wanting to receive new scenario would have to obtain that elsewhere. 

  

Technically, my understanding is that nusinersen is now approved for use in Scotland, but only for SMA Types 1, 2 and 3. So if somebody with SMA Type 4 was exploring the option of treatment with nusinersen, again, that would be something where they’d have to think about trying to obtain it elsewhere. And there are complexities there around the funding arrangements and making sure, for example, if you were going to travel to a site in England, that they’re 

  

the appropriate reimbursement is set up by the healthcare system. 

  

Now at the moment, higher dose nusinersen isn’t currently available, although Biogen are working with the Scottish Medicines Consortium, who make the decisions in Scotland to try and ensure that equitable access across 

across the UK and in Scotland in particular. So that’s something we’ll have to wait and see the outcome of. 

  

Perfect, thank you. So both nusinersen and risdiplam have shown for adults that they mainly contribute to stabilizing the progression of the condition. Are there any current effects that you’ve seen in adults beyond motor function? Robert, if I go to you for that one. 

  

Yes, thanks. So that’s very true with the implementation of the Managed Access Agreement and treating our patients. What we’ve seen is that disease duration is a key factor. So for how long you’ve been suffering symptoms, having symptoms because of the lack of SMN protein is a key factor of what will be the outcome of this treatment. So overall, it’s fair to say that what we’ve seen is stabilizing the slow deterioration. 

that adults were showing prior to any access to treatment has been the main topic. I always remember that sentence of our patients being able to do the same things, but for longer. And this has been translated mainly in a big word that is ‘fatigue’, but also it seems that the effect of the disease modifying treatments has a particular key effect in bulbar function, in the ability to swallow and to speak, especially in the severe end of the. 

of the phenotype of the condition. This is very important and very relevant and can have many implications for the day-to-day activities, but also in the quality of life of our patients, be able to eat safely and for longer has a huge impact on your nutrition, et cetera. And so these have been the key aspects that we’ve seen beyond motor function and of the effects of the treatments. 

  

Fantastic. Thank you. Now we won’t have Managed Access Agreements, will you still be monitoring the impact of these treatments? And if so, will you include looking at these sort of additional improvements? 

Yeah, absolutely. It’s, this is a huge milestone that we’ve achieved with the approval of this treatment, but it’s extremely important to understand the need and long-term effect of this treatment. This is not all important for our patients and to inform what’s the benefit of these treatments, but also to understand what’s the duration are we going to see the effect of these treatments for a very long time when it’s expected to have some sort of… 

  

acceptable deterioration despite of the treatment. So understanding this mid long term effect when again, disease duration has been significant before the start of the treatment is really, important. We want to focus on different aspects and as I said, fatigue is a big word that includes a lot of, let’s say dimensions. And I always tend to split fatigue in a very pragmatic way. We can be tired of 

reading, we can be tired of being at work and be very, you know, looking forward to get out of work and, you know, go walking back home. so mental fatigue is one thing, physical fatigue is another thing. And this is relatively easy to understand when we put specific examples, but when it comes to measure it, this is a huge challenge. 

  

So we would definitely would like to look into fatigue and what’s the impact of treatment. But when we measure it, we need to find the right way to do it. Traditionally, fatigue has been measured in what we call performance fatigability. If I asked you to do a task, repetitive task, you will get to a point everybody gets to a point that is unable to do that task that is, you know, the performance fatigability. How long are you able to do a specific task over a period of time? And that’s one way of measuring. 

Another very important one, I would say is even more relevant for the SMA community and for the implementation of treatment is what we call the perceived fatigue. How do you feel tired? What’s your perception of our specific task? And if I ask you, you know, how fatigued you feel after, you know, doing this activity for a certain amount of time, you might have the exact same level of ability from 

  

somebody else, but your perceived fatigue can be hugely different. And this has been, I would say, the key difference in the impact of the disease modifying treatments, how people feel like that they’re helping them and being able to measure this is one of the aims in the near future for understanding, again, mid and long-term impact of the new treatments. 

  

Okay, thank you. I think the next one might be a question, probably a little bit for the both of you. Have you seen any shift in adult attitudes treatments over the last few years? And if you have, particular things have you noticed? 

In our case, always said that we have that first meeting when the first, you know, announcement of the treatments being accessible for the SMA patients. And we sat down and we asked our patients and what will be their priorities and how to implement these new treatments. And I was very touched by our adult cohort of patients that said, please focus on the kids and just get the kids sorted and we’ll come. 

  

come later. The fact that the treatments are widely available, this has been of course a great improvement in the quality of life but also the expectations of the community. So I would say all adults are now, all those adults that won’t have access have access and it’s a great achievement. Again, what James was saying, I think that… 

what works for each individual is different and the way you have access to the treatments, the lumbar puncture or oral treatment is a very personal choice, but I think having wide access has been the main thing. 

  

Yeah. 

No, I’d agree, Rob. And I think it’s amazing how things have changed where when you think, you know, my patients now, many of them have been on some form of disease modifying treatment since, you know, since about 2020. The sort of discussion in clinic and the assessment clinic now is very much different. It really used to be 

  

entirely focused on management and of decline in essence. But there is now this hope with these treatments that the condition does appear to be stable in many cases. Some patients have also experienced improvements. And here obviously, just to emphasize again, we’re talking about adults who you know, the first time they received any treatment often in their 20s or 30s, you know, it’s been started very late in that grand scheme of things. So the effects have been more modest, but stabilisation of the condition is something that we’ve certainly seen. And yeah, the assessment in clinic is very much about understanding that effect, tracking that change over time, a really more kind of active 

assessment of their condition. And yeah, that’s put a whole new spin on clinic, a much more positive spin on clinic. And it’s really exciting now that things continue to evolve and perhaps even new options coming down the line in the future. 

Thank you for interesting points. I think this is question for you again, James. So are there any more developments with the current drugs for SMA, including the gene therapies or Zolgensma that is only for children with type 1 or pre-symptomatic babies with 1 to 3 SMN2 copies? 

So in terms of adults, so at the moment, the key options that we’ve got, as we’ve talked about earlier, are risdiplam as a liquid or the tablet, the nusinersen at the kind conventional dose, and then the new kid on the block, if you like, is the high dose. That’s what we have right now in terms of disease modifying therapy. In the future for adults, we may get access to gene therapy, but instead of 

  

the current way that that’s administered to the children as you just described Molly, this would instead be administered intrathecally. So that’s into the, via a lumbar puncture injection into the back in the same way as nusinersen. So intrathecal gene therapy. So that’s quite exciting. And I think we don’t know where we are with that yet in terms of availability. It’s going through the regulatory process at the moment, but might become an option for some people in the future. 

And in effect, that would replace either nusinersen or risdiplam. You would have this as a one-off treatment instead. That would be the plan. The other thing that might come down the line in the future is a kind of upgraded version of nusinersen called salanersen. This works in the same way, but the molecule has been modified so that it sticks around for much longer. 

and you only have to actually receive that once a year. So people that really like new to nusinersen, but they don’t like having lumbar punctures. Perhaps this is another thing to think about where having it once a year might be more doable. And there are other people looking into different ways of administering nusinersen as well, be that through intrathecal ports and other options. So there’s a lot of different things to consider now. And like we talked about before, it’s how 

really how it fits into someone’s lifestyle, the risks that they are willing to consider and others that they might want to avoid, how it fits into planning their family and fertility and those sort of issues as well as often very important and plays into the decision making process. So yeah, if those two options come along in the future as well, I think it will give us even more choice for people, which is very exciting. 

  

Interesting, thank you. Kind of on the same note really, obviously we recently had the disappointing news that Roche was no longer following up on its Manatee trials of the drug emugrobart. This was an investigational anti-myostatin antibody that was designed to target skeletal muscles, potentially increasing their size and their growth. Is that the end of anti-myostatin do we know or is Scholarock still pursuing apitegromab? 

  

  

Yes ,Apitegromab. No, no one can say that, including me. So I don’t think it’s the end of myostatin inhibition, but I mean, this has been a long process and I was involved in a trial of a myostatin inhibitor for a completely different disease. There’ve been efforts to try and find a place for myostatin inhibitors for, you know, for over a decade now. So we all have a sort of natural signal as we get older. 

  

  

where the level of myostatin increases and essentially stops your muscles growing anymore. So it’s a sort of natural break on further muscle development when you reach adulthood. There are genetic variants of myostatin affecting other animals other than humans I mean, so for example, there’s a cow called the Belgian blue cow, which has really humungous muscles. 

and there’s other, other animals as well. And it was sort of noticed that the reason that this, this cow had massive muscles was because of this issue with the myostatin inhibition. So basically the myostatin wasn’t working properly so the muscles were allowed to grow, much bigger than they would have done otherwise. And that’s how these therapeutics came about. And you can imagine a situation where you’ve modified the disease, the causative disease process. So you’ve sort of fixed. 

  

or altered or improved the genetic issue that’s causing SMA. But what we all recognize, particularly in our adults who started treatment later on in their life, that they’re still got very atrophic and wasted muscles. And unfortunately, as things stand, that damage is permanent. But you could imagine perhaps a situation where if there’s a combination of 

  

treating the underlying cause of disease plus stimulating the growth of muscles and that synergistic effect might be beneficial for people. I think this is still under investigation. I think the Scholarock drug has shown some promising data. It isn’t something that we can access currently in the UK, but I don’t think it’s sort of off the table entirely. So yeah, I think that’s one to sort of watch for the future. 

Okay, thank you. Again, to both of you really, are there any more innovative treatments on the near horizon that you know of? 

  

So Rob, don’t know if you know more about this Argenx approach. 

  

I’m not much aware of the trial, but I’m not entirely sure about the rules. 

No, 

  

no, and it’s one of these interesting, it does link into what you were saying about what we mean by fatigue and fatigability. And, you know, some people talk about fatigability and just in terms of that very molecular issue at the neuromuscular junction. I think what Rob was saying very, you put it very nicely about it. It’s a big word, actually. Fatigue means lots of different things to lots of different people. And I don’t think there’s, I don’t think anyone is expecting the drugs that work at the neuromuscular junction to suddenly cure all fatigue. 

  

but they might sort of help enhance the function of the neuromuscular junction. This is where the sort of nerve comes into the muscle. And then instead of it connecting directly, there’s actually a little gap and you release a neurotransmitter and then this crosses over and binds to the muscle and that’s how you get muscle contraction. So there’s drugs that can essentially sort of help that process work more effectively. And again, I think it’s looking at combination approaches where 

some of the therapies that work on the genetic causes of the disease could be used in combination with something that either stimulates muscle growth or helps with neuromuscular junction function that could ultimately benefit people. So I think these two last discussions are very much things that are still in the research phase of their development and are probably several years off hitting the clinic. 

  

But certainly interesting things to keep an eye on for the future. 

  

Definitely something to keep an eye on. To kind of summarize everything we’ve talked about today then, is there anything that either of you think we haven’t covered about treatments for adults that you think would be of a particular interest to the SMA community? 

  

As a non-prescriber, I must say that the arrival of the Managed Access Agreement has allowed us to set these adult network and many adult patients that were just reviewed by the GP or a local neurologist with not a particular interest in our muscular diseases has… 

  

helped us to map out what’s the reality of many adults living with SMA in the UK and the realities that many didn’t have the right access to the standards of care. So I have to say that moving forward, this is one of my main focuses trying to make standards of care accessible for all adults living with SMA in the UK. And by doing this and enhancing the 

  

potential effect of disease modifying treatments, access to respiratory support, et cetera, are the very basics that seem to be covered, but many adults weren’t even seen by neuromuscular physiotherapist or didn’t have access to the right equipment. So definitely, definitely there’s a lot of work to be done in that sense. And of course, exercising and going back to the… 

  

to the point in how the access of disease-modifying treatments has changed the conversations in clinic. I do remember the beginning of disease-modifying treatments. I’ve done many, many more exercise routines that I’ve ever done for SMA patients because exactly this is the change of paradigm and the discussion of what I’m going to get out of these treatments. I want to get the most out of it and people really willing to be 

  

more physically active and doing exercise. All of this, again, from the non-prescriber perspective is definitely a huge amount to be done in that sense. And the potential effect of the disease modifying treatment is that the survival of the paediatric population has increased dramatically. We’ve seen in early figures that around 30% increment of the 

  

population of SMA in the UK since the arrival of disease modifying treatments and this is of course mainly paediatric patients but these paediatric patients will reach adulthood so we do need more people that understand SMA and more people to provide these services and standards of care for the adult population. 

No, I completely agree with you, Robert. The very frustrating thing is that we’ve got this sort of nice problem now. We’ve got availability of lots of different disease modifying therapies. You can’t get away from the fact this is really exciting. But a lot of money, a lot of resources has been spent on the pharmaceuticals. 

  

But it isn’t necessarily being matched with the support services, the physiotherapy, access to, you know, exercise programmes, physiotherapy, hydrotherapy, occupational therapy, psychology. And still a lot of that is being covered through charity organizations like SMA UK who do a fantastic job. But, you know, I sometimes ask myself, why is a patient having to apply for a Smart Moves grant? And yet I can prescribe them as sort of a very expensive genetic therapy on the 

on the NHS, but they can’t access a wheelchair without a grant from a charity. So I think there’s still a lot of work to do there about the bigger picture without sounding too sort of cheesy. If you do a big sort of pie chart, the pharmaceutical part of the management of SMA really is only a relatively small part of that pie. 

  

when you sort of think about everything else that needs to be covered in it as part of a standard of care as Robert described. So I think, yeah, I think that’s the work that we’ve got to do now over coming years. If someone’s going to have a really innovative genetic therapy for their condition, it should at least be matched with that support to go with it to make sure that the full benefit can be realized for each person that receives it. 

  

Thank you. Well, thank both for taking the time to come on to the webinar and for how informative this has been. If you do want to find out any more about anything we’ve spoken about today, you can go to the SMA UK website page on ‘Access to Treatments’ or talk to your own individual clinician.