Using Small Molecule Treatment for SMA Management


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.

John Brandsema, MD: 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?

Julie Parsons, MD: 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.

John Brandsema, MD: 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?

Julie Parsons, MD: 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.”

John Brandsema, MD: 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.

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Transcript Edited for Clarity

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