Julie Parsons, MD

Gene transfer cannot be taken back once you give it; it is in for life, and hopefully it is durable in terms of this expression, although there are still some wondering about that. It does bring in the concept of the combination of treatment, in the sense that either you have received the gene transfer and then you add one of these other therapeutic options on top of it, or you try to use another combination of these treatments. I am wondering how that thinking is starting to evolve in your clinic [Children’s Hospital Colorado], since of course it is never sufficient to accept anything other than no symptoms at all with SMA [spinal muscular atrophy] for somebody living with that disease—if it is possible to get to that goal. How can we get there with these different treatments, in your opinion?

This is hard, because we are also asking insurers to pay a lot of money for these treatments. Gene transfer therapy, as we know, is over $2 million just for the gene transfer product, not for the delivery monitoring and appointments. The nusinersen is $125,000 for just the drug. Risdiplam is $350,000 for the year if we think about regular dosing. These are not inexpensive medications. I must be honest that many of the decisions are made based on what commercial payers are willing to do. But I think, as advocates for these kids, we all have patients who have not been great responders to any of these drugs. I think we owe it to our patients to be able to try either a new drug or a combination to see whether that will help them improve. I do not expect them to be typical, but taking care of these kids, we know when there is a patient who just does not seem to have a great response.

Speaking of response, there is the RESPOND trial, which is a rescue trial that is being undertaken right now, where patients who have had onasemnogene [abeparvovec] and have not been good responders can be “rescued” with nusinersen. That trial is ongoing. I think we will have some data on that scenario. There are patients, clearly, around the country who are being treated with risdiplam in conjunction with onasemnogene. I think that scenario is going to happen. I just hope that we can collect the data and information to find out whether these things are safe or whether there is any efficacy. Then we did not mention additional non–SMN-targeted therapy. For instance, there is a trial conducted by Scholar Rock [Inc] looking at a human monoclonal antibody for pro-myostatin. We look and say, “Are there going to be rational combination therapies where we say we are going to target muscle as well as SMN protein to improve outcomes?” To me, that is still the future. We are not done with treatment and trials for SMA at this point just because we have 3 approved therapies.

 We have to figure out how to best tailor what the optimal treatment regimen is for someone based on when we’re meeting them with their diagnosis of SMA. It matters whether we are seeing them presymptomatically or symptomatically, and where they are in their experience with the disease when we start treating them. Then, we see how they are responding and how we can best augment both the genetic deficiency that they have but also other tissues that are downstream that face consequences of that genetic deficiency. Is there a price at some point with having too much SMN toxicity with some sort of combination of these different therapeutic approaches and all their levels of tolerability? We may not be getting to a better place by having them heaped on top of each other. This is why I applaud things like the RESPOND study you mentioned or the JEWELFISH trial, where they are looking at risdiplam where there are combinations or switches going on in that study, too. They are getting objective data so we can make informed decisions about how to optimally do this with our patients. 

I have been trying to think of take-home messages to wrap up with here, and the point I want to highlight is that SMA is a disease that requires interdisciplinary care no matter what. You need to be associated with an SMA treatment center if you have SMA, regardless of whether you have been treated. We know from treatments that establishing this diagnosis early and getting people on treatment as soon as possible is critical. If you are somebody who is not as familiar with SMA and you have a patient you either just diagnosed or you suspect has [SMA], make that diagnosis early and get them referred to an SMA treatment center. Then those of us who are SMA specialists have an obligation to continue to try to understand how to best optimize all the different aspects of what we’re doing, both with targeted treatments and interdisciplinary care, to ensure that people living with SMA have the best life possible. Is there anything you want to add on top of that, Dr Parsons?

 No; I think it is an incredibly exciting time where one would think that, now that we have 3 treatments that are life altering, we would be complacent, but we are not. There are more questions and there are new phenotypes, and we are constantly looking at how to best provide care for these patients. What is the evolving phenotype going to be? I think it is an incredibly exciting time to be looking at this disorder.

Thank you so much, Dr Julie Parsons, my colleague, for joining me today for this wonderful discussion. Thank you to the audience for watching this 

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Videos

John Brandsema, MD, and Julie Parsons, MD, review the evolution of combination therapy in clinical practice for the management of SMA. 

Role of Combination Therapies in SMA Management 

I do think another area that is interesting to consider here is compliance and adherence to therapy. With nusinersen, we are very sure people are getting their maintenance doses because we are controlling that when we give the lumbar puncture. We know if somebody is little late, we can start asking them, “When you are coming in? We need to get you scheduled.” Everyone is nervous about people not taking risdiplam because of the daily need for this steady state. There is also concern about how long you can have no access to this before your motor neurons start to become unwell—whether it is because the medication did not get delivered to you properly, you are unwell and cannot swallow and are vomiting for a period of time, or you just have decided you are too cool for your medication and you are 14. Whatever the reason may be, I think there is no forgiveness here. If someone with epilepsy does not take their medication and they have a seizure, you can say, “You really need to take your medicine.” Here, if you lose motor neurons, we cannot get those back once you are not taking your medication. I have been trying to think a little about other areas where we have a lot of experience with this, like in the cases of transplant and other things. How do you ensure that you have a good therapeutic alliance with your patient, that you know for sure they are getting access, and that they are appropriately maintaining their therapy?

Going back to one of your other points, John, with the other drugs, which I am really interested in, we have talked about the intrathecal medication to target the motor neurons without a lot of systemic involvement. With risdiplam, you are choosing to give a medication that you know is systemic. Is that an advantage or disadvantage, or do we even know at this point?

 That is such an interesting thing to discuss; we could spend the whole rest of the day on this because in other tissues besides motor neurons, the manifestations of this disease are not very obvious, unless patients have a very severe early onset. We know they can have cardiac disease, and dysautonomia occurs in patients with early onset. There are some liver and immune system things that have been established in the literature, but we do not tend to see things in our monitoring of these more stable, especially higher functioning, patients that are really important to recognize in terms of other systemic involvement.

Thank you to the audience for watching this 

John Brandsema, MD, comments on the importance of patient compliance to therapy to manage spinal muscular atrophy. 

SMA: Patient Adherence to Therapy 

The most recent addition to our armamentarium, which we have in our clinic [Children’s Hospital of Philadelphia] now, is small molecule treatment. This is in the form of risdiplam, which was approved just last year, in 2020, for us. The concept here, again, is targeting that SMN2 gene, which all people living with SMA [spinal muscular atrophy] still have at least 1 functional copy of, so everybody can be treated by this sort of approach. We are trying to increase the amount of SMN protein the SMN2 gene is able to make through this targeted small molecule approach. There are other development programs with other small molecules still underway, but risdiplam is our first clinically approved treatment. Right now, it has been approved for those over 2 months of age, although there is an ongoing presymptomatic trial looking at safety for the younger babies and how to dose them. 

This involves a daily dose, orally if the patient is able to swallow, or via G-tube [gastrostomy tube], which in the research trials, looking at the FIREFISH study for infantile onset, and then the SUNFISH trial, looking at the higher functioning patients, showed quite good efficacy. Regarding this approach, in terms of having a response to treatment, in many people’s opinion, this roughly parallels what happened with nusinersen. There are differences in the baseline populations that were included; there are differences in the functional scales that were measured in the different cultural context of how these trials evolved between North America and Europe. The development program for risdiplam had a bit more focus on some of the bulbar function than the nusinersen development programs did. It is a little hard to directly compare the two. Essentially, what we are looking at now in the United States is that, for someone less than 2 years old but over 2 months of age, we now have 3 potential options for treating that patient. Then, after 2 years of age, we have nusinersen and risdiplam as potential therapeutic options. I think it becomes very complicated with patients who are treatment-naïve in terms of trying to decide between these things. It is also complicated for people who are already on one established treatment who may want to consider changing to another. I will start with the patient who is treatment-naïve, who is between 2 months and 2 years of age; what has your experience in the clinic been like with the 3 options for that patient, as opposed to your experience with patients over 2 years of age with 2 options?

Most patients who are 2 months to 2 years of age still have been interested in, for me, gene transfer therapy, and a couple are interested in nusinersen. We have not had anybody in that age group who has opted for risdiplam. One of the issues is that, on the label, as you know, it talks about potential for male infertility issues. This was determined by looking in animal studies, but there has not been anything done to test that in humans. There is a concern in our community about whether, particularly for baby boys, this is going to be something that has real implications. That has at least been my experience with the families; they are still a little anxious about that. The gene transfer with a single IV [intravenous] infusion has probably been the one that most of those families have defaulted toward.

 It has been similar in our clinic also. I think we do have options for how to preserve that ability. If someone is an older patient, and interested in risdiplam therapy, we can do sperm banking. We have talked about cryopreservation techniques that can be done for patients as young as 2 years of age in terms of harvesting cells that will eventually become sperm from a person for storage. Part of the nuance, at least in this country, for that is that you may initially have the original procedure covered, but often the insurance does not cover the long-term storage of that material for the person. There are real financial implications for the family, even if they were interested in this potential option for preserving fertility. For women, it seems like there is not an issue with their own eggs, but if they were to become pregnant, there is a teratogenicity concern with risdiplam. Patients who can become pregnant are expected to be on some method of birth control if they are actively taking risdiplam and sexually active because they need to stop the risdiplam before pregnancy if they are interested in becoming pregnant while on that medication. I think in most of our clinics, most of us have had our patients on established nusinersen treatment since around 2017, 2018, when they started this medication. This other option came into the field, risdiplam, so what kind of patient scenarios are you thinking about where risdiplam might be a preferred option for a family? How is that coming up in your day-to-day clinical care, and how would you approach a patient if they are already on nusinersen?

 This has been interesting. I think it breaks down into the younger kids and the older kids, and one wonderful thing about the risdiplam trials is that they are looking at older populations. In the JEWELFISH trial, they are looking at patients up to the age of 60. It is wonderful to be able to have some data on the older patients, which we have not done, obviously, with the gene transfer or with nusinersen yet. There will be more data available, but it is not robust enough yet to be able to help with medical decision-making. The patients in our older population who have had problems with post-LP [lumbar puncture] headaches, or just think it sounds better to take an oral medicine, have been the ones who have asked to convert. In a really interesting turn of events, I thought many patients would say, “I want an oral medication; I do not want to have an LP,” but teenagers and my young adults—it’s fascinating. They will say, “Why would I have to worry about taking something every day when I can just have a spinal tap 3 times a year? It is not a big deal for me, and I am doing really well. Why would I change?” I do think, in the interest of transparency and full disclosure, that at clinic visits we need to discuss the options and we need to discuss that there are different treatments available. We need to enquire whether it is something the patient and family feel as though they want to change or to think about. The younger patients have not wanted to change so much, which is interesting. For the latency age kids, nusinersen is working: “It is great; we are used to it; we’re fine. We are going to keep going for a little while until we know more about this drug, about risdiplam.”

I think the safety profile certainly has been pretty remarkable with risdiplam. There has not been much of a signal for anything that has come up in terms of things to monitor. There have maybe been a bit of skin reactions or GI [gastrointestinal] upset for some patients in trials, but in the clinic so far, I have not run across too much with my patients. I did hear, anecdotally, of 1 situation with urinary tract infections. They are noted in some of the research trials to be more frequent, and there was 1 patient I heard of who had a series of urinary tract infections when that was not something they had experienced before on risdiplam. That was the reason they decided not to continue. But most anecdotal things I have heard so far have been about the successful changing of treatment, if that is something people are interested in.

Experts in pediatric neurology share insights on the role of small molecule treatment for SMA through the recent FDA approval of risdiplam and discuss factors to consider when tailoring therapy for individual patients. 

Using Small Molecule Treatment for SMA Management 

A couple of years after the original foray into targeted treatment, we then had onasemnogene abeparvovec approved for our patients, which I am going to refer to now as “gene transfer” because it is very hard to say that very long name repetitively. The concept behind gene transfer is that you give back an SMN1 functional gene to the motor neurons you are targeting, but perhaps other tissues also, through a single intravenous [IV] dose of medication. This, again, was developed through a parallel development program where we are still actively learning about these patients. There have been data updates now in all of the programs; we have learned about presymptomatic dosing, dosing in symptomatic infants, and dosing in people with milder forms of SMA [spinal muscular atrophy] and how they have been doing in long-term follow-up. How has the introduction of gene transfer evolved the thinking from 2019 or 2020 in your clinic [Children’s Hospital Colorado], now that you have 2 options, especially for the youngest patients?

It has been life altering as well. It is a sexy option because it is a single IV infusion, but also the safety issues are real with the gene transfer. I think we are learning more about this. There have been fewer patients who have been treated. I am not certain of the numbers right now, frankly; I think it might be about 1200 patients, perhaps a little bit more globally. It is definitely a smaller number of patients who have been treated. I think what we are experiencing as a community is that the younger the patient is—maybe from birth to 6 months—it seems a little easier with less complicated delivery than it does when treating patients who are from 6 months to 2 years of age. As you know, onasemnogene is indicated for children under the age of 2. We are able to treat them from the newborn period up to 2 years of age. The treatment itself is relatively easy because it is an IV with a gene transfer product; it is given once. However, there are implications in terms of some immune issues with patients. To be able to be treated, patients cannot have an elevation of AAV9 titers—adeno-associated virus [serotype 9] capsid—which is utilized to transport that gene transfer product. If a baby has elevated AAV9 titers, they are not able to have the product infused. We must think about that piece of it.

Then, we know in the first trial that was done, the START trial, babies had marked elevation in transaminases as they were treated as the liver was hit and there was a decrease in their platelets, or thrombocytopenia. Babies are pretreated with steroids on a schedule, and then if their laboratory and safety values have stabilized or are normal, those steroids are tapered off. They do have steroid treatment, which is something families need to know about. I think the issue of monitoring, babies with SMA, as I said, [have veins that are hard to find]. There is a lot of laboratory monitoring. There is a lot of looking at platelet counts and liver function studies to be able to see whether this is safe. There have been a couple of other issues that have come up, with some microangiopathy as well, in patients who have been treated. I think we are seeing this along other disorders, neuromuscular disorders, being treated with gene transfer therapy, there is a potential for severe liver injuries, liver failure, thrombocytopenia hitting the bone marrow, as well as microvasculature. This, to me, is also evolving, but for parents to be able to say, “You just get a single IV for your little baby and they are fixed,” is very attractive. For the newborns, that has emerged as something parents are pretty happy about, as opposed to having spinal taps.

I think, going back to our earlier conversation, in the basic science model, not every motor neuron gets transduced when you give gene replacement. You do not tend to see totally asymptomatic people after gene therapy treatment. It is very important to still have that follow-up because we will need to support all of these different aspects of care that we keep emphasizing. The efficacy data from the original START trial, going into the STRIVE trial, looking again at the infantile onset patients, has been quite promising. There has been a significant improvement; however, there is a separation when you look at even the presymptomatic patients in the…. 

 The SPRINT trial is the one I am trying to think of. When you look at the SPRINT trial, 2 copies versus 3 copies of SMN2, there is still a difference in the development of those patients, even if they are treated during the same period early on, in terms of their response to treatment. It is also interesting that, around the world, it is not always by age. There have been approvals in other countries that go up to a much higher weight than what was originally studied in the index trials here. As we start to understand better some of these very rare but real complications we can see, such as the hemolytic uremic syndrome or sustained liver inflammation that can happen in some patients, the thought is that there may be a point at which intravenous dosing is not the preferred option, and we may give our patients intrathecal dosing to try to limit the amount of viral vector being delivered directly to the targeted motor neurons that need it the most. 

The challenge there, in the STRONG study that was being developed, is that there was some preclinical concern for dorsal root ganglia toxicity in some of the animal models. Right now, as of the time of this taping, that trial is on hold by the FDA while this gets sorted out. That leads to a challenge in the United States in terms of anybody older than 2 years of age having access to the gene transfer treatment. There is hope that we can understand how to either safely dose at a higher rate or figure out the safety aspects of this intrathecal delivery over time, so that we can give more people access to that treatment option. Is that something your older patients are still asking about?

 Thank you to the audience for watching this 

John Brandsema, MD, leads the discussion on the concept of gene transfer for the management of SMA and the recent approval of onasemnogene abeparvovec-xioi. 

Julie Parsons, MD

Articles

Role of Combination Therapies in SMA Management

SMA: Patient Adherence to Therapy

Using Small Molecule Treatment for SMA Management

Role of Gene Transfer Therapy in SMA