July 27, 2021

Biology Reporter

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New oral treatment option for spinal muscular atrophy

New oral treatment option for spinal muscular atrophy

Recently, patients with SMA have access to many treatment options. In addition to intrathecal nusinersen, there is intravenous gene therapy, and oral therapy has recently appeared. On May 15, the Ministry of Health received a compensation request for the SMA drug – risdiplam. To which patients this drug is intended – says Prof. Doctor Hub. n. med. Anna Kostera-Pruszczyk, Head of the Department and Clinic of Neurology at the Medical University of Warsaw.

ANNA KOSTERA-PRUSZCZYK: At the moment, we do not have a biomarker that could indicate that one or the other drugs would be optimal for a particular patient from the point of view of, for example, the expected efficacy threshold. Since the drug is taken orally, and spinal muscular atrophy is inherently associated with significant curvature of the spine in some patients, my medical intuition tells me that the oral route of administration would be preferable in patients whose lumbar puncture may be difficult.

AGATA MISIUREWICZ-GABI: Clinical trials – RAIBOWFISH, FIREFISH, SUNFISH and JEWELFISH – have shown that risdiplam is safe and effectively improves the health of participants: children, adolescents and adults with various forms of SMA. Please familiarize the readers with this study and tell us how it improved the vital functions of patients on the CHOP-INTEND scale?

AK-P.: We have four studies named after exotic fish. The RAINBOWFISH study is for asymptomatic children who begin to sit up and do all the other things that would never have happened without drug therapy for SMA. Remember that most children with SMA1 and SMA2 without drug treatment develop severe symptoms as early as 1 to 2 years. age.

The FIREFISH study includes children with SMA1 who also note an improvement on the CHOP-INTEND scale. Their prognosis improves, and thanks to treatment, a significant percentage of them develop the ability to sit independently without drug intervention. There will be other observations from this study.

Patients with SMA2 or SMA3 aged between 2 and 25 years at the time of study enrollment are enrolled in SUNFISH. They were by definition non-infantry. They also see very good results and improvement on the MFM-32 scale, which is a slightly different scale than the one we use every day in the B.102 program, the Hammersmith Motor Efficiency Scale (HFMSE). Another perspective on the performance of SMA patients is also very important, which is the assessment of the independence scale. Each of us desires to be as independent as possible. A person in a wheelchair is almost always dependent on the caregiver and their environment. In the SUNFISH study, we see that patient independence is clearly improved after 12 months of use, with this good effect persisting even after 2 years of the study.

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Another open-label study is JEWELFISH, where patients are enrolled in a wide range of ages – from infancy to over 60 years of age. These are patients who, by definition, have previously received another treatment that can modify the SMA pathway, ranging from a molecule that was in clinical trials with a slight positive effect on the SMA pathway, ie oloxime, to nusinersen, or even gene therapy.

In the studies with risdiplam, we have a very wide range of symptom severity at the time of administration and a large age range for patients. We also have a very convenient security profile. When it comes to efficacy, we note a repeat of what we already know from other previous studies, for example, nusinersen, that is, it is higher in patients with presymptomatic symptoms. That is why it is my personal medical pleasure that newborn screening will begin in Poland and that we will treat Polish children before symptoms of spinal muscular atrophy appear. So when treatment is able to change their lives as much as possible for the better.

I believe the results of these studies are very consistent across all age groups, including the severity of symptoms when drug therapy is started. Of course, we follow all subsequent reports, and also collect our own experiences.

AM-G.: The Risdiplam Early Access Program has ended. It was launched before the drug was registered and 50 patients were sent to it. What are the inclusion criteria for the program?

AK-P.: The Early Access Program, due to its legal structure, provides a short time window during which, if there is a decision from the drug manufacturer, access to treatment between US registration through European registration can be achieved. The program ended in March of this year at the time of European registration. In order for other patients to have access to this treatment, we will have to wait for the decision to reimburse the drug.

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In the case of nusinersen therapy, a lumbar puncture may be a potential difficulty or inconvenience associated with its administration in some patients with severe scoliosis. At the center I run, we are 100% effective in administering the drug intrathecally. There is a group of patients, due to the condition of the spine, the only possible form of administration is a suboccipital puncture. For these patients in particular, the oral route of administration is the optimal approach. Fortunately, the proportion of patients waiting for drug treatment is declining. If we count people already treated under the drug program, including those treated under the early access program and patients participating in the ongoing clinical trials in Poland, this would be a large group of patients. We can say that we already treat all patients who want to be treated.

AM-G: SMA screening exams have been successfully introduced in Poland. As of April 2021, the program has been gradually extended to other regions. Will screening tests and effective drugs prevent disabled children with SMA in Poland within a few years or tens of years?

AK-P .: I would like to know the exact answer to this question. We already have results from more than 5 years of observation of the asymptomatic children who were included in the NURTURE study. There are also reports from a clinical trial in children treated with gene therapy before symptoms. We also have recent reports from the RAINBOWFISH study of asymptomatic children who received Risdellam. A very large group of these children develop properly. This is especially true for patients who have three copies of the SMN2 gene, and who acquire their developmental milestones in the age range in which we would expect them to be perfectly healthy children. This is something that still cuts my voice a little bit in 2021. We’ve been able to get to a level of efficacy on this horrible, deadly disease, which until recently was beyond my imagination and I also think beyond the imaginations of all serious people dealing with SMA for years.

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Do all the kids run and do flips? – I do not know. Remember that there are some modifiers of the phenotype. We do not know all of these phenotype rates. We know that if a child with predictive therapy has two copies of the SMN2 gene, then in all the studies we’ve talked about today, developmental stages are delayed compared to children who have three copies of the SMN2 gene. However, we must not forget one thing – how untreated spinal muscular atrophy was, especially SMA1. We know it was a tragic and fatal disease. I would like to remember that thanks to the tremendous efforts of doctors, patient organizations and the wonderful people from the Ministry of Health who understood how terrible this disease is, we are now leaders in Europe when it comes to newborn screening and access to treatment. Pediatric neurologists all over Poland are doing a good job. Thank you very much for that.

However, we still have at least 1,000 people with SMA who started treatment during the symptomatic period. We are obligated to provide all of these patients with multidisciplinary care, regardless of how advanced the disease may be. Remember, SMA patients are wonderful people who, as Father Kaczykowski once said, live off a full-on fireworks. Despite their disability, they sometimes achieve their dreams in a way that is beyond our imagination for healthy people. And we can effectively help them with this now.

AM-G: Indeed, patients with SMA are wonderful people, and we have often seen the accomplishments of these people who are constantly struggling and trying to make their dreams come true. We keep our fingers crossed for all of these patients, as well as for the doctors who show great commitment and help.