SMA therapies (a LinkAGE webinar)

Melody Redman: Welcome to our third Genomics Education Programme LinkAGE webinar. Really delighted to see so many people joining today.

Today we’ll be hearing about spinal muscular atrophy from Dr Louise Hartley, who I’ll introduce in a moment.

My name’s Dr Melody Redman. I’m a clinical genetics registrar in Leeds.

But before we start, I just wanted to cover a couple of bits of housekeeping. So firstly, just to say all of your microphones will be muted and your video cameras off throughout the talk. We do really want to hear your questions. So please, throughout the talk, pop your questions in the Q&A and we’ll come to those at the end where we’ll get the opportunity to discuss some of the questions that have come up.

At the end of the talk we’ll be sharing a QR code, which will be linked to the evaluation of today’s event. And we really value your feedback and we use this to improve future talks. So please do provide feedback at the end. Also, when you’re providing your evaluation, there’ll be an opportunity to tell us if you’d like a CPD certificate. The point to do that is at the point of submitting your evaluation.

So without further ado, it gives me great pleasure to introduce Dr Louise Hartley, who is a consultant paediatric neurologist at the Royal London Hospital. So Dr Hartley previously worked at the University Hospital of Wales, where she set up the paediatric neuromuscular service for Wales and initiated the treatment of SMA patients with nusinersen therapy.

And over the last year, she’s been with the neuromuscular service at the Evelina Children’s Hospital in London, providing Zolgensma gene therapy for children with SMA.

So I’ll now hand over to you, Dr Hartley. We’re really grateful to have you here presenting on this topic. Thank you.

Louise Hartley: Thanks, thanks for inviting me.

Yep.

So I’m Louis Hartley. I currently work at the Royal London Hospital. I’ve been here for five years. And before that I was in Wales for 13 years where I really did a lot of neuromuscular work.

In my current role, I just see a lot of general neurology, which includes a lot of neuromuscular work including SMA. But it’s very broad, my current role.

But I do some clinics at the Evelina, which is the – as you probably know – is one of the Zolgensma treatment sites. There are three in England, and one of them is at the Evelina. So I’ve a little bit involved with delivering this Zolgensma service (although my current job is very broad and not just neuromuscular).

So next slide.

Yeah, I’ve, in the past I’ve undertaken some consultancy for Roche. And then next slide then is the start of the talk.

Okay. So this condition we’re talking about it’s an autosomal recessive condition, and we’re talking about what we call 5q-spinal muscular atrophy. So the gene lies on the long arm of chromosome five.

There are non-5q-SMAs, which are super, super rare. And there are little, a little bunch of other diseases that can affect down to your horn cell. But this talk is about the 5q autosomal recessive SMA, which is actually common (relatively, you know, as recessive diseases go). And actually for me, working in a very general setting at the moment, not a dedicated neuromuscular unit, actually I see quite a lot because it’s a, it’s a common condition. Relatively.

About 1-in-6,000 to 1-in-10,000 births it’s due to mutations in a single gene, SMN1 and over 95% of cases the children have homozygous deletion of exon 7, sometimes exon 8 as well, but always exon 7 in the SMN1 gene. The other 5% or less will usually have an exon 7 deleted in one allele and a point mutation in the other allele.

But it is very unusual for us not to just easily find exon 7 bi-allelically deleted.

So the mutation carrier frequency is about 1 in 40. It might be a bit lower in some populations, but in most populations it seems to be about 1 in 40. So it’s pretty common after cystic fibrosis. It’s the next most commonly carried gene mutation. The result of this homozygous deletion of exon 7 in the SMN1 gene is that there are reduced levels of the protein that this gene codes for – and that’s SMN or survival motor neuron protein.

And that’s both in the central nervous system, but also in peripheral tissues as we’ll have a little look at.

But primarily the reason the disease manifests is because the lack of this protein in the central nervous system – actually in the nervous system – results in degeneration of anterior horn cells, loss of the lower motor neurone that comes from the anterior horn cell and then subsequent atrophy of the muscles that that lower motor neurone is innovating, which is where the name comes from. It’s atrophy of muscles with a spinal origin which is actually the anterior horn cell of the lower motor neurone.

So that’s what we see. Clinically what we’re seeing is this loss, sequally, of a loss of anterior horn cells and the subsequent muscle weakness and atrophy.

But it is actually ubiquitously expressed, it’s expressed in the central nervous system as well as all tissues, actually, all peripheral tissues. So that does have some implications now, particularly now we’re treating it. It’s not just a protein expressed in the anterior horn cell.

Okay, next slide.

As I said, it’s a homozygous deletion usually in (almost invariably of) exon 7 biallelically in the SMN1 gene. And the result of this is a spectrum of weakness. Any of you that are familiar with spinal muscular atrophy will be aware that it’s given a number according to the maximum motor milestone achieved.

So we have: (most commonly) type one, and by definition this is children who never sit.

And of course, these definitions were derived before we had the gene and understood how the condition arose and how the spectrum of weakness arose.

So type one was the clinical description of a child with severe spinal muscular atrophy who never achieved sitting as a milestone.

And the type twos sit, but never walk independently.

The type threes walk independently.

Then there are super-rare type zeros where there’s a prenatal onset. So the baby is already severely affected at birth. They usually have very severe joint contractures and are ventilator-dependent from birth.

And then there’s a quite rare type four, which has an adult onset.

So the majority of these present in childhood and they’re type one, two, and three.

The life expectancy – as you’d get the impression from the fact that the type ones are inevitably much more severe, they don’t even have the ability to sit – their life expectancy, untreated, is usually less than two years.

The type twos, historically, life expectancy is between 20–40 years.

The type threes will have a normal life expectancy.

So next slide.

So, to understand why we have this spectrum of disease severity, and also to understand how two of the three treatments that we have work, it’s really important to understand a little bit more about the genetics.

The area of chromosome 5q, where the SMN1 gene sits, the bunch of genes – that include SMN1 and some adjacent genes – over the course of evolution that area of 5q has duplicated and inverted. So it’s flipped over. And you get these phenocopy genes. So you get the SMN1 on the telomeric end, and you get a little group of genes which are almost identical, that have been duplicated and flipped over on the centromeric end. Probably there’s some evolutionary advantage, in general, for duplication of genes. And definitely in the case of SMA there’s a definite survival advantage to the fact that this duplication has happened.

So SMN2 then becomes a really important gene to understand, and it differs from SMN1 by eight nucleotides across the whole gene.

Crucially, in exon 7 – which is the exon we’re particularly interested in in SMA because that’s the one that’s usually homozygously deleted in exon 7.

SMN2 has one, just one nucleotide that’s different. So there’s a C to T base change six base pairs inside exon 7. So very similar.

And the next slide.

The result of that nucleotide change is that exon 7 is usually spliced out. So usually SMN2 is behaving like an exon-7-deleted SMN1 i.e. it’s useless; exon 7 is spliced out and no functional protein is made.

But for some reason, about 10% of the time when SMN2 is transcribed exon 7 isn’t spliced out. So a copy of SMN2 will make about 10% of the 100% of SMN protein that you’d hope from SMN1.

This is crucial to understand.

So next slide.

So basically, you’ve now got SMN2 producing a small quantity of functional protein, and we have a varying copy number that explains the spectrum of disease.

So you have to have some.

If you’re homozygously deleted for exon 7 of SMN1, and you don’t have any SMN2, you’re not gonna survive fetal life. The embryo is not gonna survive very long at all. You need some SMN protein to produce, to survive fetal life, to get through fetal life.

The fact we have any postnatal experience of SMA is because of SMN2. Most children with type one SMA will have two copies of SMN2, as shown by these pie diagrams.

Most children with type two SMA will have three copies.

The one to two copies are gonna be making about 20% of the SMN protein.

Type two, most of them have got three copies, so they’re making about 30%.

And the type threes, three or four copies.

And so on.

You have to have some else you won’t survive to delivery. So if you’re born with SMA, you must have at least one, usually two or three or four copies of SMN2.

And that’s the reason you survive.

And that explains that the spectrum in severity.

So the next slide.

This is just to fill a little bit more, now, on that table we looked at earlier.

So, most of the children with type zero, which is very rare, will have one copy. They’ll have to have one copy. If they had zero copies they wouldn’t have got to postnatal life.

About three quarters of children with type one SMA have two copies. But a significant proportion, about 20%, have only one copy of SMN2 – if you look on the far-right column – and about 7% will have three copies.

You can’t completely predict the phenotype based on the SMN2 copy number. There is a variation. Some variability.

Most patients with type two, so 78%, will have three copies, but some have two or four copies.

And then the type three and four, you’ve got increasing copy numbers; even up to six or even more copies.

Next slide.

Okay.

So just breaking down a little bit more into the spectrum again. As we’ve become increasingly familiar with the disease and the treatments we recognise subcategories within this spectrum.

So if we look at type one, we now divide type one into A, B, and C. So one A are children that present within the first 50 days of life. So often on day one, they’ll have some head lag, they’ll be a bit weak and floppy. They’ve evidently got the disease by 15 days of age.

The type one B, which is the most common type of one, present before three months.

And the type one C, who are a little bit milder, present after three months.

Altogether type one makes up about 50% of all of SMA.

Then just looking at the type threes, you can see there’s a three A and a three B.

So the three As are the children that present before three years, and the three Bs after.

The ones that present before three years walk because, by definition, to have type three they must walk. But the ones we don’t detect before three years have a very significant risk of stopping walking with time because this is a degenerative condition.

Okay, so the next slide.

So this is just the classical phenotype of type one SMA, which as I said is about 50% of the total.

So these are floppy infants and they have proximal weakness.

They have these bright alert faces, so there’s no myopathic faces. They have normal eye movements; they look around, they are very alert and interested.

The things that distinguish them from other floppy, weak babies is that they have diaphragmatic breathing. You can get a slight sense of that from just these still photos. The belly is quite expanded because the diaphragm is descending within inspiration, which is a normal breathing pattern, but the chest is not – the chest excursion is very poor. So the intercostal muscles are very weak and all the breathing is happening with the tummy, with the diaphragm. So you get this: the chest starts to narrow and they get what’s called a bell-shaped chest, actually, and this baby’s got a little bit of pectus excavatum. So we only really see this SMA. If you see a baby with diaphragmatic breathing with poor chest excursion you’re ‘game on’ that this is gonna be SMA.

About a third of the children have tongue fasciculations, and that’s a feature de-innervation and re-innervation. It’s quite a hard sign, actually, but about a third will have that.

All the babies are areflexic. They never have deep tendon reflexes.

And then you have this quite interesting pattern of weakness where the legs are weaker than the arms. And you can get a sense of that with this baby – obviously it’s a still but – you can see that baby’s move, it has lifted the arms from the elbow. And the distal muscles are weaker than the proximal muscles. So they tend to sometimes have a little bit of movements at the feet, but not at the hips. They might wiggle their feet a bit, but not move their hips. And likewise they won’t really move their shoulders, but you can see this baby’s able to lift their arms at the elbow and they might have some reasonable hand movement.

And this is a curious pattern, and it’s to do with the pattern in which the anterior horn cells die. They degenerate caudo-rostrally and medio-anteriorly, and in the spinal cord it just happens those they take out the big proximal muscles first and the lower muscles, as in the legs, earlier than the shoulder muscles.

So that’s a very pathognomonic pattern. We don’t really see it in any other disease.

Once you’ve seen a case of type one SMA, it’s very easy to pin. There’s not really differential. It’s a very easy diagnosis to make.

Okay, next slide.

So as I mentioned, the tongue fasciculation is a feature of denervation and the dying nerve cells trying to sprout and reinnervate.

And that’s manifested in the type two and three SMA as tremor. So you’ll very commonly see a hand tremor in type two and three SMA, which again is a very helpful distinguishing feature because that’s an unusual feature to see in a child with a neuromuscular condition.

So the type two children, as we said, they’ll sit unsupported and often they’ll have normal milestones up to sitting. But then they might crawl or they might not; they might just sit and that’s the only milestone they’ll achieve, or they might crawl, they might even pull to stand, they might even walk pushing a walker, but they’ll never walk independently.

So again, these are all spectrums. Anything can happen between just sitting unsupported and almost walking independently. There will be a type two.

And the type three children, as I said, walk independently but they’ll have signs particularly of hip-girdle weakness. So they’ll have probably a waddle and a Gowers manoeuvre would be classical.

But the tremor, there’s obviously quite a big differential for the type twos and threes. They’re a bit harder to spot because there’s quite a lot of other conditions that can present in this way, such as Duchenne for a type three a myriad of different neuromuscular conditions for type two. But if they’ve got a tremor and you can’t get reflexes, that’s a good helpful sign that this is likely to be SMA.

So next slide.

So this is just a summary slide of what I’ve just said.

So we’ve got a tiny percentage of type zero. Then 50% of type one, and the majority of those have two copies of SMN2.

About 30% to type two, and most of those have three copies.

Then it’s about 10% of children will be type three A, and they have a significant risk – 60% will lose ambulation over the course of their lifetime.

And then about 9% are the three Bs, who will continue walking but will have a waddle and the Gowers [manoeuvre].

Okay. So that’s just a little summary. Okay.

So the next slide then.

Just looking at type one, the most common cause of SMA. We know that by the age of six months, about 95% of the lower motor neurones have been lost just because of this anterior horn cell degeneration.

And we know that untreated, the median age of intervention is that the children need nutritional support by eight months. So although they don’t always have bulbar failure early on, they will develop bulbar involvement.

By 11 months, the children will be requiring ventilation support. And the median age of death (untreated) is 20 months.

Okay, so then the next slide.

Werdnig and Hoffman, which used to be the name for type one SMA, first described it in 1891. The gene was first identified in 1995 partly because of the understanding of SMN2.

Two treatments, nusinersen and risdiplam which are effective by their effect on SMN2, were trialled in the beginning of the 2010s, and Zolgensma [onasemnogene abeparvovec], which – they were all pretty much at the same time actually – is the gene therapy which is replacing the whole gene, trying to splice SMN2.

These three treatments have become available over the last decade and are now available in many countries, including the UK. They have been approved by Nice, and we are able to use all three of these treatments.

So I’ll spend some time now going into the details of these.

Next slide.

So I don’t know how much you are aware of these treatments but nusinersen, which was the first drug to have positive trials and be licensed, is delivered by intrathecal injection.

So it’s delivered by lumbar puncture and it increases SMN2, basically.

We’ll look a little bit how it does that.

Risdiplam is also increasing SMN2. It’s a daily oral dose, whereas nusinersen is an intermittent – it’s every four months – lumbar puncture.

These are treatments you have to have lifelong. You’ll stop making SMN2 if you stop taking them.

And then onasemnogene abeparvovec, which is Zolgensma, is a replacement of the SMN1 gene via a viral vector. It’s a single intravenous injection.

Next slide.

We’ll little look bit of how they work in a minute, but these were the pivotal trials in SMA [type] one. And this is where most of the trial work has been in SMA [type] one.

We can have a look at these in some of the subsequent slides, but we had trials of presymptomatic children who were pretty much all younger siblings of children in families who’d already had a child with SMA, and then went on to have another child and knew that they were at high risk and so had that child tested at birth.

So each of the drugs was trialled in presymptomatic children. We had the pivotal trials in the infants with SMA [type] one. And then there were these early trials of older children with nusinersen and risdiplam – so children with established SMA.

Okay, so the next slide.

So you’ll come across these motor assessments – these are the standardised functional motor assessments that have been used – and for the children, for the babies under the age of two the Chop-Intend (Children’s Hospital of Philadelphia, infant testing of neuromuscular disorder) is the is the scale that’s used.

For the older children, who can sit and do more, there’s the Hammersmith functional motor scale (HFMS/E) and the motor function measure score (MFM32).

So they’re in some of the slides we’re talking some about. Some of the trial outcomes, I’ll mention those functional motor assessments.

Next slide.

Okay, so this is nusinersen. This is an antisense oligonucleotide, as is risdiplam. So it’s basically a small string of nucleotides that target SMN2 pre-messenger RNA and prevent exon 7 from big spliced out. So it acts as a splicing modifier. It targets the intronic splicing silencer N1, and this allows SMN2 to prevent a full-length protein. It stops it splicing.

Rather than just that 10% of SMN being made it allows, maybe not a hundred percent but a lot more – well hopefully a 100% of SMN to be made.

So you get SMN protein produced from SMN2. You’re doing nothing with SMN1, you’re just working on SMN2.

Next slide.

So this was the hugely exciting moment in 2016 when the pivotal trial of nusinersen published this interim result.

They had an interim analysis, it’s a trial called Endear, and it was a double-blind, sham procedure.

So they gave two thirds of the children intrathecal nusinersen and then they had a sham blinded group who they just made a little pin prick in the back so that the treating doctors and parents wouldn’t know that they hadn’t had – they didn’t actually lumbar puncture them, but they made a little prick on the back and put a plaster on. So they wouldn’t know that whether or not they’d had a lumbar puncture.

And this, the interim analysis, the results were so good that what – we’ll move to the next slide.

So there were 122 infants from 31 centres worldwide in an RCT. Two thirds receiving nusinersen, and a third the sham procedure. These were all babies. They were seven months at screening, some were up to eight months, I think, by the time they were treated. They all had two SMN2 copy numbers who were predicted to have type one SMA.

And at the end of the study. So the interim results there was a significant improved in motor milestones.

So 51% had improved and the sham group, none had improved.

This is a disease that is relentlessly degenerative; the children don’t achieve any milestones, they just lose them. So the sham control group, none had regained any milestones. In the group receiving the nusinersen, 22% had head control, 10% could roll, 8% could sit, 1% could stand.

So this compared to the natural history of 0% of the children not receiving medication making any motor progress, this was an absolutely astonishing.

The risk of death or permanent ventilator usage was 50% lower in the treatment group. There was an improvement in the CHOP INTEND scale in three quarters of the infants.

The other thing that was striking was that the likelihood of survival and not requiring a ventilator was higher in the infants treated earlier. So in less than 13 weeks, which, is important.

Next slide.

As a result of that trial everyone got moved onto the treatment arm, after the interim analysis.

And in 2016 the company made nusinersen available on an expanded-access program to all type one babies while we waited for countries to fund it.

It is delivered by intrathecal injection.

There’s a loading dose of four doses over two months. You have quite an intensive every couple (two or three weeks), over two months you’ll have four doses. And then following that, you need four monthly maintenance dosing forever. It’s very expensive and NICE agreed to fund it under a managed-access agreement with strict eligibility and stop criteria and with the collation of clinical data as we went with the treatments.

So next slide.

So the eligibility criteria are currently for nusinersen are that the children have to have definitely confirmed 5q SMA – can be type one, two, or three or presymptomatic. But if they’re presymptomatic, they have to be predicted to develop type one or two, which normally means two or three SMN2 copy numbers.

They have to have not be permanent ventilated or have a tracheostomy.

[Intrathecal] (IT) injection has to be feasible and that’s not always the case because some of them have had spinal fusion or – particularly the older children – they had severe scoliosis from their weak spinal muscles. So not all children, it’s not feasible in all children.

And if they’re type three, then as long as they’ve had symptom onset before the age of 19 years and they could comply with monitoring data collection and don’t have another life-limiting condition. So it’s actually very broad the eligibility criteria. Encompasses pretty much everybody.

Next slide.

And then the stop criteria is if there’s worsening in the motor score on two consecutive visits or ventilation becomes permanent or inability to deliver. They’re the stop criteria.

So next slide.

Okay, so we’ve now, as of last summer, we had about 13,000 people treated worldwide. So about nine years follow up. It’s very well tolerated. Some of the children need a general aesthetic because they don’t like having a lumbar puncture. And occasionally interventional radiology is needed to get into the fetal sac.

It is evident, as we’ve collected data and gained more post-trial experience, that, as that Endear [trial] showed, if you start the treatment later in the disease course it’s less effective.

And that would make sense because these anti-horn cells are dying and you need to rescue them before too many have died, rather than late in the disease course.

It also seems to be less effective for the bulbar and respiratory symptoms.

There’s also an emerging phenotype of treated children with speech-language delay which doesn’t just seem to be a bulbar problem.

And we wonder if actually SMN proteins, as I said before, is ubiquitously expressed, including in the central nervous system. We wonder how much the SMN protein is needed for fetal brain development. So now with this group of type one children, who previously wouldn’t have survived, we’re seeing that the children are surviving and that some of them have what seems to be a central speech-language delay.

Next slide. Sorry. Next slide.

This was just – oh, sorry. Thought I’ve added in a slide.

Okay, risdiplam is another antisense oligonucleotide. So this is orally administered and it’s a daily dose. Again, it’s a splicing modifier. Binds to two sites on SMN2 pre-mRNA, and it promotes the inclusion of exon 7 and full length of transcript with the SMN protein.

It crosses the blood–brain barrier, so that’s why it doesn’t have to be delivered intrathecally. And one advantage of the fact that it’s given orally is there, there’s a systemic delivery to all tissues. And at the moment, it’s not clear what that will mean. As I said before, we do know that SMN protein is expressed in all tissues, so it’s probably gonna be advantageous to promote its expression in more than just the anterior horn cells.

Again, it’s licensed in the UK, and Europe it’s licensed for type one, two, and three SMA over the age of two months old, providing they have between one and four SMN2 copies. In the [United States of America] it’s also approved now for under two months of age, but at the moment, we can’t use it in the newborn babies. We have to wait till they’re two months old.

Next slide.

So this was the Endear equivalent for risdiplam, Firefish. This was type one-B patients, so the ones that present before the age of three months. And they were dosed by seven months. And at three years, 96% were alive without permanent ventilation. Whereas, the natural history would be that, 99% of these children – a 100% actually – would be dead without any ventilation at this stage. And all would need some ventilation. So this was an astonishing result.

60% were sitting unsupported, and that increased over the three years of treatment. And the numbers sitting, they didn’t all start to sit immediately but they began to sit gradually.

Oral feeding was preserved in the vast majority.

So again, really astonishing good results.

Next slide.

And then the later onset SMA two and three, Sunfish and Jewelfish were the pivotal studies. The patients reported, and continue to report, stability in their in their disease. So not deteriorating as you’d expect. They don’t get worse, they stay stable on treatment. And often small-but-meaningful (for the patients) increases in strength and stamina. So it might be that they can perhaps lift a full cup where previously they couldn’t, they could only lift half a cup. There are things that – they can maybe open a can – things that are hard to capture in a functional scale but are meaningful to the children of families.

So the Sunfish showed an increase in the MFM32 (the motor function measure) by one to two points. So these are not huge increases, but they are, their stability, plus or minus some improvement.

And Jewelfish was a very broad group of patients, between the ages of 2 to 60, who’d previously had other treatments and they saw a stabilization in their motor function score. Roche were pretty pleased with that.

Next slide.

So the safety they seem to be very well tolerated, actually. There were some early reports with nusinersen of hydrocephalus, but they’ve been very few. I think they mean maybe between three and five, from 13,000 people treated.

So we’re not entirely sure what that is about, but it’s not been a consistent or very troublesome problem.

Some of the children get some mild thrombocytopenia proteinuria, but nothing clinically significant. Some get lumbar-puncture-related side effects. Obviously you can get headaches following the lumbar puncture.

And of course, there’s the problem of needing repeated general anaesthesia for some of the younger children who don’t like having a lumbar puncture, which is obviously not great.

Risdiplam. A lot of the children get a bit of diarrhoea and some skin rashes, which are usually don’t require the drug to be stopped. They usually resolve and are not too troublesome.

Risdiplam, there were some – in the preclinical animal studies – there was some retinal thickening in some non-human primates and some photoreceptor degeneration. In fact, this is partly why nusinersen got ahead of the curve, actually. Because they were being developed in parallel but risdiplam, when it was in development, got set back by a year or so while put the studies on hold while they investigated this. And as a result, risdiplam then ended up not finishing its trials and becoming licensed for a couple of years after nusinersen. Although it seems to be equipotent and we’ve got a lot of children on intrathecal nusinersen who probably would otherwise have been on risdiplam or – some are swapping over but I think risdiplam was a bit behind the curve because of this retinal thickening. But it’s been very carefully studied in the children treated, and none of them have had any problems.

It’s also got a potential effect on male fertility and potential embryo fetal toxicity. So adults taking risdiplam are advised not to get pregnant while they’re on it.

Okay, next slide.

So then Zolgensma [onasemnogene abeparvovec] is a viral vector gene therapy.

So this is a copy of the SMN1 gene packaged into an AAV9 virus, which is a pretty benign virus which affects all cells, including crossing the blood-brain barrier and getting into the spinal cord and the brain.

The DNA doesn’t, the SMN gene doesn’t integrate into the genome of the patient. It gets into the nucleus and it is then transcribed and makes SMN protein, but doesn’t get incorporated into the patient’s genome.

Next slide.

So this is licensed for genetically confirmed type one, clinical diagnosis of type one SMA.

So this is in the UK. This is children under six-completed months of age with a clinical diagnosis of type one, or if they’re 7 to 12 months of age and a national team (which sits very frequently) of experts considers that they’re about 70% likely to keep sitting, they’re allowed to have it. But mostly it’s the younger children; it’s usually the under six months that have it. And there’s also now weight cut off. And they also need not to be trached [had a tracheostomy] or ventilated for more than 16 hours. That’s an exclusion criteria. And also presymptomatic children with up to three copies, with known biallelic exon 7 deletions in SMN1, and up to three copies of SMN2.

So those are the group of children that are in eligible for Zolgensma.

Next slide.

And we have about seven years now of both clinical trial and subsequently real-world data. The clinical trial the children – so that was the Sprint [trial], I think it was – I showed it in the earlier slide.

The children were under six months at dosing. Actually in the real-world data, older children have been treated up at the age of five. Again, the greatest benefit it seems to be when it’s administered prior to symptom onset as a, we mentioned at the beginning in these type one children that are receiving as Zolgensma, 95% of their motor neurons have been lost by six months. So we need to try and get in before they’re losing that number of neurones.

The children, although this is a benign virus and is not known to cause disease in regular life, the number of particles given are absolutely astronomical and there are some […] to that. The children need steroids.

In fact, show the next slide I think we’ve got the, yeah.

So the children very frequently have some fever and vomiting as they get this huge infusion of virus for the first few days. And about a third of patients get hepatotoxicity, which is then monitored for 12 weeks.

So they have weekly bloods for about 12 weeks.

A lot will get a transaminitis, but this usually resolves by a couple of weeks. However, there have been two fatalities from hepatotoxicity, so they’re in Russia and Kazakhstan. A 28-month-old and a 4-month-old baby developed acute liver failure, six to seven weeks post the gene therapy.

1. Yeah, sorry, I that I’ll move on that type of the next slide. I think so.

So a lot of them, many of them get some thrombocytopenia but that resolves spontaneously. There’s sometimes asymptomatic, transient rise in cardiac enzymes and there have been four cases of thrombotic micro angiopathy, so it’s not a completely benign treatment. So this has to be monitored quite carefully.

Next slide.

And because of the hepatotoxicity toxicity in particular all the children are pre-treated with prednisolone. And of course that then has, potential side effects. It risks the children getting adrenal suppression if they end up on, on several weeks or even months of prednisolone while we wait for their liver enzymes to settle.

This is a young population who are likely to be chickenpox and measles naive. And so we can’t give their live vaccines while they’re on prednisolone. So the immunization schedules delayed.

The hepatotoxicity is currently being investigated by the MHRA. It does seem to be a more of a risk in the heavier children and in UK now as of a few weeks ago, previously there were some children who were older than 12 months were being treated or heavier. But now the limit (at the moment) is under 12 months and less than 13.5 kilos. So the older children or the heavier children are not being treated. The theory being that if we’re giving the doses dependent on your body weight. So obviously giving much bigger doses to the heavier children.

Next slide.

So one thing that children have to not have is AAV9 antibodies. They have to be tested before they’re treated. Obviously, if they have got antibodies either from their mum via trans placental transfer or that they’ve seen a AAV9 in the few months they’ve been alive, they can’t have it.

If it’s trans placental then we can wait for the AAV9 antibodies to go away and give the gene therapy later.

Of course, the other flip side of that is that once they’ve had AAV9 therapy, they can’t ever have it again because they’ll have antibodies and they’ll reject it. So this is a once-off treatment.

If they’ve got intercurrent viral illness or a pre-existing liver disease, then again it’s put on hold until that’s sorted. So not everyone can have it.

Next slide.

So all three of these drugs, they improve motor function and motor-milestone acquisition.

They all improve event-free survival.

They all help maintain oral feeding and the ability to come off ventilation.

Next slide.

The most dramatic results have been in the presymptomatic trials. So Sprint was the presymptomatic trial for Zolgensma. They gave 14 babies – who were siblings of other previously diagnosed children, all of whom had two copies of SMN2, were diagnosed at birth – they were all treated before the age of six weeks. None of them, at 14 months, needed pump ventilation. I don’t think any of them even now have, and we’re now several years down the line, actually. None of them required feeding support. 11 out of 14 were standing and many walked.

Most of these babies look completely normal. Most of these babies have got no symptoms from their SMA. So, treating these babies before the age of six weeks with a gene therapy has been absolutely dramatic.

Next slide.

And then Nurture, which was the presymptomatic trial of nusinersen. 15 children with two copies of SMN2 and 10 with three copies of SMN2, again, all treated before six weeks of age. All of them were sitting. 22 out of 25 were walking independently.

Absolutely dramatic results for children that, without treatment would’ve achieved absolutely no motor milestones, and in fact would’ve been deteriorating and losing skills such as self-ventilating.

Next slide. Sorry.

Then Rainbowfish was the risdiplam presymptomatic trial, and they had six children with two or three copies of SMN2. And again, a 100% were sitting. 67% were standing, 50% were independently walking. After 12 months really all of these drugs are amazing if they’re given presymptomatically.

Okay, so next slide.

So we have three licensed drugs currently. Obviously the approval is very broad, or particularly for the antisense oligonucleotides (risdiplam and nusinersen) it’s much broader than the population that were in the clinical trials. Of course, the trials inevitably had a relatively short observation period, and we’ve now got, up to nine years of observation in the real world.

And there are no head-to-head comparisons. We haven’t had any trials that head-to-head compare these three drugs.

So I’ll look a little bit more at the treatment landscape, which is dynamic. There are other treatments being developed and there’s also the really important possibility of newborn screening. There are also trials looking at treatment switches and combination therapies, and I’ve got a few more slides on that we can have a look at.

We are aware of the need to collect additional real-world evidence. Many countries have registries with mandated collection of data on treated patients which should allow us to begin to detect differences in the efficacy of these three drugs in the real world over the five to nine years we’ve been using them – or increasingly you as you use them. So certainly in the UK, any child receiving any of these treatments has to be part of a managed access agreement, and they have to attend, the six monthly – or whatever the mandated follow up is – and have a very thorough assessment. The condition of continuing treatment is that they remain in a registry with mandated collection of data so we can see what is going to happen long term.

Next slide.

So this is an example of a recent – it was February, in Brain (just last month) of group from Germany and Austria and think of another country. So some of Northern European countries, where they have mandated collection of data on all their type one babies treated with nusinersen for up to 38 months. So this is the real-world data as opposed to the limited trial data.

In the children who have started under the age of two years, there were major improvements in motor function with a third achieving independence sitting, however, not such a good improvement in the bulbar/respiratory function as there was in the motor skills.

The motor improvements seemed to be greatest in the first 14 months. And then plateaued with stabilization – they’re not deteriorating but stabilizing.

This is compared to the presymptomatic children, many of whom in the trial have age-appropriate motor … sorry … in this study, as well, the children that were treated presymptomatically have had age-appropriate motor development.

The children that were treated after two years didn’t achieve any new motor milestones. Some of them did get a small increase in their Chop-Intend score, but none of them sat, stood or walked where they weren’t already doing that. And the concern about the fact that bulbar/respiratory function is not improving as much as the generalised motor function has led people to wonder if actually there’s a gravitational effect of nusinersen; that it’s delivered into the lumber thecal sac and it’s maybe, even though of the children have the lumbar puncture, there’s a concern that maybe they’re not getting enough nusinersen to thoracic and bulbar regions.

So there’s a current trial called Devote which is a trial of higher-dose intrathecal nusinersen to see if they can get better bioavailability of the drug into the bulbar and cervical motor nuclei. So that’s current.

Next slide.

It is evident that bulbar function in SMA does remain a problem. A lot of these children, despite treatment, have impairments in swallowing. They have a restricted range of movement and strength of the mandible. They get jaw contractors. Many of them will get, have a weak suck. Recurrent lower respiratory tract infections.

And of course they’re at risk, before treatments, of losing anterior horn cells in the cranial nerves. Speech is also affected, so a lot of these treated children now have quite a lot of speech difficulties and some of that is bulbar, so articulation. [They do not have] sufficient respiratory support for speech. Often, not-great resonance with hypernasality from poor phonation, pitch volume control. But also, as I mentioned earlier, there does seem to be some children who have more of a cognitive central speech problem. Not just a bulbar in articulation or, lower motoneuron problem.

So it does seem that, oh sorry. Next slide. Sorry.

The most benefit is seen by the younger children with severe forms of SMA, particularly if they’re treated early in the disease course or ideally, presymptomatically.

Older children and adults may accrue and some benefit also, in particularly, they may experience stability. And actually for patients, stability is really important in the context of a neurodegenerative disease. Not losing skills, even if they don’t gain any, not losing any is huge for them.

These are extremely expensive drugs and it’s really important that the standards of care and this sort of multidisciplinary approach are maintained and that there’s active intervention with therapies that nutritional status is maximised.

It would be a disaster to spend all this money on the drugs and then not provide the therapeutic and nutritional and so on, support that the children need to keep themselves in good shape.

Next slide.

So I mentioned earlier that, you know, SMN is not just expressed in anterior horn cells. It’s required for the viability of all cells and restoring the full length SMN protein seems safe and effective, but in a lot of children it’s not a cure. And we’re increasingly, understanding what the biological functions of SMN are. So it has canonical roles in RNA processing and splicing and non-canonical roles in ribosome, mitochondrial, and proteosome function.

It might be that it has tissue-specific functions that vary across the lifespan and different organs might be affected at different times, both pre and postnatally, including the brain prenatally. In a way, particularly because SMA [type] one is the most severe of these and is the most common of these and – prior to treatments – we didn’t have longitudinal, the children didn’t survive for us to have any idea as to what this disease … how this disease might affect them across their lifespan. Whether other tissues are going to manifest your problems.

It’s obviously really important to understand the role of SMN protein in different tissues and at different times.

And we’re also aware that the timing of treatment is really important. And that a lot of these, although the children treated presymptomatically have done brilliantly, a lot of the children who are treated symptomatically have already lost a lot of anterior horn cells and while they achieve stability, they’re not getting huge gains. There are trials looking at complimentary treatments, combination therapies that might address other defects. So next slide please.

Melody Redman: Just to let you know, it’s 25 minutes past. So I’m not sure if you have many slides left, but just so we have time for discussion.

Louise Hartley: Okay. Okay. Okay. I’ll speed up.

Okay, so this is just this is another recent paper looking at the concept of a prodrominal –

just on this slide, just to point out that we have, increasingly we have biomarkers that allow us to detect what’s happening to the anterior horn cells, even in presymptomatic children. NfL, phosphorylated neurofilament levels, which are a marker of axonal degeneration. We know they’re very high in presymptomatic SMA [type] one patients. So we know that, that’s a marker that their anterior – their axons are dying, their nerve cells are dying even before they’re symptomatic. And also CMAP (compound muscle action potentials) and MUNE (motor unit number estimation), which are electrophysiological tests – we can see that, even before the children have any clinical manifestations, these are decreased with high NfL levels.

Next slide.

And there’s this concept now of a presymptomatic and a symptomatic phase whereby within the presymptomatic phase, there’s a clinically silent phase. And then a prodromal phase when possibly a very experienced clinician might pick up a mild problem.

And then a conversion to a clinically manifest phase.

Next slide. Sorry, I’m gonna whizz through the last ones.

Yeah.

So we know that these presymptomatic babies have a reduced pool of motor neurons because we know that their NfL and their MUNEs are reduced. They might look normal, but they’re at risk of developing: muscle fatigue, weakness, motor impairment later in life (at some point) when they tip over, become prodromal and the pool of motor neurones is reduced, and then a threshold is reached where they become weak.

So finding an optimal window of time following birth before significant motor neurones are lost is key.

Next slide.

So we have new phenotypes on treatment. We now we have children with different ages of symptom onset and diagnosis. They’ve received different treatments. They have different levels of need and access to therapy.

We have children who – a treated type one child will not look like a type one child anymore, but they might not even look like a type two child. They have their own phenotypes really. So there’s a lot to, to navigate for, for the treating teams and for the families.

Next slide.

And really importantly, treating these children when they’re already very symptomatic is the ideal way to go. Many countries are now screening: Ukraine, most of the US, about 50% of Europe, they’re now screening at birth.

So they, with the Guthrie heel-prick test, they’re looking at exon 7 deletions and SMN2 copy number.

Belgium have been screening since 2018 and have a lot of data. One thing that they’ve picked up is that, of course the type 1a patients as you predict, because they’d present before 15 days of age, even on newborn screen they’re already symptomatic. There’s a real pressure to get these treatments in early.

There are some pilots of screening in the UK at the moment. It’s likely that we’ll start screening nationally next year.

Families do need to understand that particularly children with two copies of SMN2, they are likely to have had some, even prenatal, onset of the disease. Even if they’re not clearly symptomatic or very minimally symptomatic then they’re not necessarily going to have a normal outcome because they’ve already lost anterior horn cells.

Next slide.

So that’s just, this is just to give a sense of other treatments that are being developed.

Next slide.

The combination therapies.

So at the moment, there are three trials of myostatin inhibition. This is a negative regulator of muscle growth, and blocking myostatin increases muscle size and function.

There are three trials at the moment in children. Some of children who’ve been previously developed, treated with, or are currently being treated with risdiplam, or have had risdiplam or nusinersen.

And also trial in children who’ve had any of the three, including Zolgensma.

So the hope that these children who’ve not had a great outcome, they’re stable following the treatment, but have still got quite a lot of weakness, the aim is to see if we can get their muscles bulked up and working better with myostatin inhibition.

And then – next slide.

That’s just a scheme of the current trials which include the higher dose of nusinersen and there’s a trial of intrathecal Zolgensma and then these combination trials.

Okay. So that’s the last slide.

So should we spend the rest – sorry, I can’t share my screen, I can’t show you the videos.

I’m really sorry about that.

I just had some videos to show.

Melody Redman: Thank you so much. That was such an interesting talk and it’s really inspiring to see the really dramatic impact of these therapies on children who’ve received them.

I’m just gonna encourage people – so if people are able to stay around for a couple of questions, then please do, because obviously if people have to drop off then we understand. Please pop your questions in the Q&A box.

While people are typing them in. I just wondered if I could kick us off by just asking, you very briefly touched on this, but do you think these therapies are likely to have an impact on morbidity and mortality in the later onset types of SMA?

Louise Hartley: Yes. So I mean that there are adults are being treated – older children and adults are being treated.

Yes.

There are some that gain skills most will not lose skills.

Stability as I mentioned, is really important. Some will gain motor skills that we can detect on something like the NfM. Others will have small gains that are not detectable on the measures we have, but will be clinically meaningful. The child will be able to, or the adult will be able to, open a jar, lift a something up higher than they could do so they’ll be able to. And often they have more stamina.

So yes, across the board, most people get stability plus maybe a small benefit.

So again, a lot of older children and adults are treated now.

Thousands. Around the world.

But they, obviously the most benefit is for the babies, particularly if they’re treated early.

Melody Redman: Thank you.

I’m gonna read out another question in a moment, but just while I do, just to remind attendees, there’s the QR code on the screen, or also in the Q&A box, there is a link that you can go to for evaluation. We’d really appreciate your feedback and it also gives you the opportunity for a CPD attendance certificate.

So the next question is from Professor Kate Tatton-Brown, who’s just asking about the health economics of the treatment. She’s wondering if you have any evidence about the, how much the therapies are saving compared to the interventions and support that would be needed for children affected with SMA?

Louise Hartley: Yeah, I haven’t got any figures at my fingertips, but –

I mean the children that are treated early, and/or have a good response at any age, clearly they’re gonna have much lesser health needs and much-lesser therapy needs and live independent lives.

I think the problem is with the children who are being treated. The SMA [type] one’s who are being treated late because, actually, they’re surviving and of course you can’t really put a cost on that. They’re surviving, but often with a huge amount of disability – the children that are treated late – and which is why we need to screen. Waiting until the child’s already six months age and has lost 95% of their anterior horn cells, and then rescuing 5% – we’ll keep them alive; it’ll stabilise out their respiratory function, they might need NIV, but they will remain alive.

But they will probably not feed orally and they might not achieve head control or sitting.

(Some do, but not all do.)

If they didn’t have the treatment they would’ve died. They would die. So that’s a difficult – you know, that’s – what cost you put on that? It is difficult, I think, and I think because a lot of these children are now surviving with a severe amount of disability and they would’ve previously died. It’s a no-brainer to screen.

It’s a shame we’re taking so long to do it.

I know they’re very strict pathways in the UK for getting screening.

Laurent Servais, he’s a professor of neuromuscular in Oxford now. He was in Belgium and he set up the trials in Belgium, and newborn screening in Belgium. He’s really frustrated that the children were treated and diagnosed in Belgium since 2018. They’ve been diagnosed at birth and they’ve been treated, whereas we’re waiting until they’re quite advanced, when they present. Because there’ll be people who haven’t realised.

I saw one last week and the parents just hadn’t – they came for an incidental thing and someone just called me to say they’re a bit worried about them. They came for an echo and that they’d been worried for three months. But I don’t know, they just hadn’t got their act together to go and ask anyone for help.

In fact, she’s quite much. She’s a type one C, so hopefully she’ll – she’s having gene therapy this week, actually she had it yesterday or day before.

Picking these cases up, if we are not screening, they’re inevitably going to be treating them late. I think it is a bit depressing because these are very expensive treatments.

Melody Redman: The next question actually really fits nicely with that. From Sarah Stanley, who’s asking, how quickly does treatment usually start once the genetic diagnosis has been made?

Louise Hartley: Pretty quickly. Yeah. Within a couple of weeks.

The videos I was gonna show you actually, one was this baby we just saw. We saw I think, three weeks ago. She just was in having a routine echo and we saw her and realised it was SMA and got the gene back within a week.

She was then screened with AAV9 antibodies and liver function and she’s had her gene therapy this week.

So it was three weeks from being seen. It can be quicker than that.

Melody Redman: Wow, that’s amazing.

Louise Hartley: But it needs to be, because there’s no point in giving someone nearly 2 million pounds worth of gene therapy if you made them wait three months while you – but it is beholden on clinicians to see these kids promptly.

When they rang me from cardiology, I just said: “just send them down.” There’s no point in them waiting a week to see me. I may as well just see them now because if there’s any risk that that’s what they’ve got, the sooner we see them – there’s no point in holding up these kids.

The other, but the other baby…

… you’re saying: “how soon do they work?” No. You’re saying: “how she’d be treated?” Yeah.

So in fact the other baby I was gonna show you actually was a type one A who’s a little boy who had congenital cardiac disease. It was picked up on day two of life. He was dusky and, post-op, was found to be floppy.

So he was a week old and was found to be floppy.

So he had SMA diagnosed at 10 days. Well, suspected at about 10 days of age.

In fact, because he’d had cardiac surgery, they weren’t very keen to give him gene therapy immediately. So he had nusinersen like three days later because nusinersen there’s no real build-up, whereas gene therapy you do need to check their antibodies and does have some toxicity. Nusinersen really doesn’t.

So he was loaded with Nusinersen a few days after the gene came back.

And then, once he’d been loaded and everything was stable and they were happy that his cardiac enzymes were normal and he wasn’t at risk from giving him a massive dose of this virus, he then had gene therapy.

But having said that, his respiratory effort is much better, but he’s not really got head [control]. He’s got a bit of head control. Not gonna have a brilliant outcome. He’s gonna survive and survive quite well, but he’s not gonna have a great motor-outcome. But then [again], he was very severe. Even if we detected him at birth, he was picked up at eight or ten days anyway, even if we done screening he would’ve taken that long, wouldn’t it? By the time they’d taken the blood and sent it to the lab and got [back the results] it’s gonna be a couple of weeks, isn’t it?

He’s had the best outcome he could have done.

Considering he’s been loaded nusinersen and had gene therapy, it’s a bit sad that…

…anyway, it’s great he’s gonna survive and his parents are very happy.

Yeah.

Melody Redman: Then the next question, as well, follows on nicely from that. Someone’s asking if there’s any prospect of prenatal treatment in utero?

Louise Hartley: Pass.

I’m not sure.

I think…

… at the moment, would we screen for SMA when we do Downs screening?

These become quite ethical questions, don’t they? How much we screen?

There are lots of things we could screen for a Nutra, aren’t there?

I don’t think anyone’s working at the moment on any treatments would potentially be given antenatally. I’m not aware of anything.

Melody Redman: Okay. And the next question is, what are your thoughts regarding prenatal genetic testing versus treatment for families where parents are non-carriers? So perhaps if there’s already been an affected child.

Louise Hartley: Yeah no, they should definitely. Yeah, definitely. Yeah. Yes, definitely.

If you know that you can test the baby, if you know that the baby’s at risk and test them prenatal, then you can be ready to give the gene therapy the day after they’re born.

So yes, it would be a really good idea. Where I work, we have a very high rate of consanguinity, actually. That’s partly why we have quite a high rate of – to be fair, the kids that we’ve diagnosed haven’t been from a consanguineous families actually. But in theory, we were at areas where there’s high consanguinity, obviously a higher risk of diseases like SMA.

There are lots of rare diseases, aren’t there, that we could be screening parents to be carriers for.

We do stray into ethical territory (don’t we all) as to how much we screen and what we do with that information.

But yes, definitely.

If you know your carriers and then we make complete sense to test the fetus and be ready to treat.

Actually I got asked by a medical student the other day whether it would be ethical for parents to terminate if they knew, now that we have treatments, whether it’d be ethical for parents to terminate a fetus known to be affected, which I passed on. Because at the moment we don’t test foetuses, but if we were test foetuses, that would be an ethical dilemma, wouldn’t it? Whether the parents would be allowed then to terminate or whether we’d say you can’t, because we’ve got a treatment.

Melody Redman: These are big ethical questions coming out, so we’ll just end on one question. If we could just briefly answer this, for the last question.

The last question is who decides which treatment or drug the baby will get?

Louise Hartley: Yeah, so there’s a committee, an MDT committee, that looks at the cases. Basically. At the moment, the babies can’t have [this drug] anyway until they’re two months old. But if they’re not suitable for gene therapy, for whatever reason, many will get started on risdiplam, once they’re two months old.

Because, actually, it looks to be, the trials, very similar really. They look all to be pretty equally efficacious, really. And nusinersen, such a problem to have to give repeated lumbar punctures. But if they’re [like] my baby that had the congenital heart disease, he couldn’t have risdiplam because he wasn’t two months old so he had to have nusinersen.

Most babies are getting gene therapy, unless there’s a reason to delay it, and they might get risdiplam/nusinersen while they wait for the gene therapy. Most will get gene therapy now, most under six months old. And over that, then it’s a discussion often with the families. Most people I think now would take risdiplam.

Nusinersen, because that’s what we had first, a lot are on nusinersen and a lot don’t want to swap because they’re on it and it seems to be working and they don’t want to risk coming off it.

Some families or patients like knowing they just have one-off four-month treatment, and then they can not think about it for four months instead of having to remember every day to take medicine.

Increasingly we probably will swap over to risdiplam, because it’s so much less arduous and the data seems to be very similar efficacy for all three drugs.

The other thing with gene therapy is we don’t know what will happen long term. We assume that the anterior horn cells will keep on churning out SMN protein forever. But we don’t know that. We don’t know whether – oh, of course we won’t be able to have it again because they’ll have antibodies. So, if in 10 years time or something, 20 years time, whatever, [the drug] starts to lose its efficacy they’ll have to have another treatment.

Melody Redman: Thank you so much Dr Hartley, for a really interesting talk and a huge virtual round of applause.

Just a final note to all attendees. Please do fill out the evaluation using either the QR code or the link in the chat. And thank you so much for joining us today.

We hope that we’ll see you at future LinkAGE webinar events.

Thank you all very much.