On the 19th of November the first spinal muscular atrophy (SMA) masterclass took place in Rome, Italy, organised by the neuromuscular network TREAT NMD. The meeting was designed to promote the new Standards of Care to those involved in the SMA field and to discuss the most up-to-date treatments and clinical trials that are currently taking place.
At the meeting were neurologists and paediatric neurologists, health professionals, geneticists, and pharmaceutical representatives. The majority of attendees were from Europe. This article summarises the topics covered within the masterclass.
The role of TREAT NMD
The first day began with an overview of the programme and an introduction to the neuromuscular network ‘TREAT NMD’. TREAT NMD is a not for profit organisation which aims to bring together neuromuscular experts for education and to promote research. Previously TREAT NMD have run a Duchenne muscular dystrophy masterclass, which is very popular and has acted as a way for local teams to receive teaching from experts in the field.
SMA and adults
The conference heard from Ms Ouillade, who is an individual with SMA Type 4, about the impact of SMA on adults and some of the controversies around treatment. Ms Ouillade spoke about the lack of trials for adults with SMA, except for SUNFISH, and the fact that nusinersen is not available for later onset Types of SMA (Type 3 and 4). There was also a feeling that SMA Type 4 was ‘relatively ignored’, with the majority of neurologists unlikely to know a great deal about this condition in spite of the fact they make up an estimated 10% of those with SMA. Ms Ouillade passionately advocated that adults with SMA don’t necessarily want to walk, but have more attainable goals such as being able to lift a spoon.
Diagnosis and genetics
The masterclass heard from Professors Aartsma-Rus and Goemans, firstly about how individuals with different types of SMA are diagnosed, and delays in diagnosis. Results of trials comparing life expectancy over long term periods suggested that the implementation of Standards of Care in SMA have led to a clear improvement in life expectancy1. There was a talk on the genetics of SMA, which suggested the best ways to investigate whether an individual has SMA. The talk detailed two gene changes which have been linked to less severe symptoms. The first is a mutation within SMN2 which has only been found in people of Spanish descent2. The second study looked at the positive effects of the gene Plastin 3, which has only been found in females and has been linked with less severe symptoms3. One study using gene therapy to insert Plastin 3 led to mice with SMA having less severe symptoms4.
The results of nusinersen studies suggested a better response to treatment if administered earlier. There is now increasing demand for newborn screening for SMA5. Increasing delays in diagnosis were associated with later onset types of SMA. For SMA Type 1, delays in diagnosis were 3.6 months on average, for Type 2 this was 14 months, and for Type 3 this was as long as 43 months on average. There have been several studies attempting newborn screening around the world; Taiwan ran a newborn screening programme from 2014-2016 which had a very high false positive rate of 50% (identifying newborns with the disease when they didn’t have it)6. Other countries (US, Germany and Belgium) have either attempted newborn screening or are in the process of developing this. The speaker relayed advanced plans for newborn screening in Italy which aims to perform blood tests on 70-80,000 newborns to identify an estimated 20-30 infants with SMA. This test is estimated to have a much better sensitivity rate (only 3% are thought to be missed by this test). The Italian newborn screening programme is planned to begin in January 2019.
The development of the Standards of Care
The next talk, by Professor Mercuri, outlined the process of how the Standards of Care were developed. The process is known as the Delphi process, and involves choosing experts within the field who then put together a working group of other experts in that field (e.g. breathing specialists). The studies were then discussed, and the group were canvassed as to their opinions and practice. Finally, a consensus was reached on the different topics under discussion, and the Standards of Care were developed7.
The second day of the conference began with a discussion of how muscle function can be measured by physiotherapists over time (functional outcome measures) in SMA. This is very important as this is the main way to show whether a treatment has worked. For infants the most commonly used measures are: Hammersmith functional motor scale- expanded (HFMSE), Hammersmith infant neurological examination (HINE), Bayley scale of infant and toddler development, and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). In adults or in older children, timed tests such as the six-minute walk test (how far you can walk in six minutes) may be used alongside other tools such as the revised upper limb module (an assessment of how to perform several different tasks with your arms) and the motor function measures tool.
The next topic discussed was nutritional management in spinal muscular atrophy. The talk outlined the various problems that may occur in infants and children with SMA, including reflux, constipation, reduced growth and reduced bone health. The talk also outlined the various measures that can be begun to try to resolve these issues. In terms of growth it was stressed that it is important to measure body fat and muscle composition using the same method each time and not to rely on simple measures such as height, weight and body mass index (BMI), as these can be poor predictors. Also discussed was the importance of adequate fluid intake, particularly when unwell. Individual dietary plans should be assessed by a dietician; this is particularly important with early onset Types (i.e. SMA Type 1 and 2).
Clinical Trial outcomes
Professor Servais spoke about the findings of previous clinical trials with negative results such as those into hydroxyurea, and valproic acid. He went on to discuss the findings of the nusinersen trials, including discussing the findings that earlier treatment may lead to a greater effect, showing a video of differences between two siblings: one treated after symptoms began, the second before symptoms. Professor Servais discussed that in the CHERISH trial there was a placebo effect that lasted for one year but then reduced. He also discussed findings and case studies from the latest trials run by the pharmaceutical company ROCHE. Professor Servais outlined the results of the expanded access programme for nusinersen in Germany, France and Belgium8.
Emergency and respiratory care
Professor Simonds discussed emergency care and the new guidelines for respiratory care. This included an overview of current findings on types of ventilation, the importance of emergency planning (also called anticipatory care), the need for appropriate vaccinations and the importance of early treatment of suspected chest infections.
Involving people with SMA in therapy development
The next topic presented by me (Dr Alex Murphy) was how individuals with SMA are involved in therapy development. This included an overview of the drug development pathway and how long it takes on average for the European Medicines Agency (EMA) (306 days) and the Food and Drug Administration (FDA) (383 days) to approve a medication. A model of healthcare called ‘Shared decision making’ was outlined, which encourages discussion and deliberation of options for treatment between patients and health professionals9. The talk pointed out the main ways families, parent groups and charities can be involved in therapy development: as participants, as a source of funding, by signing up to registries, surveys and research, by lobbying for treatments and as ‘expert patients’ for organisations such as the National Institute for Health and Care Excellence (NICE). The talk finished by discussing how, on an individual level, choice of treatment in an emergency can be influenced using emergency health plans (EHP); these can be made available when needed using the EHP app.
Access to treatments
The final lecture was by the president of SMA Europe, who discussed the challenges faced by families in accessing new commercial treatments such as nusinersen. The talk highlighted that there are still significant unmet needs of the SMA population, such as restrictions due to price, restricted access, and the fact that nusinersen is a treatment not a cure.
The meeting was aimed at increasing the knowledge of specialists looking after individuals with SMA in the new Standards of Care and the most up-to-date research. The talks were varied, interactive and well received.
1. https://www.ema.europa.eu/documents/presentation/presentation-natural-history-sma-impact-standards-care-survival-motor-function-richard-finkel_en.pdf Accessed 27th of November 2018.
2. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85(3):408-13.
3. Oprea GE, Kröber S, McWhorter ML, et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science. 2008;320(5875):524-7.
4. Kaifer KA, Villalón E, Osman EY, et al. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy. JCI Insight. 2017;2(5):e89970. Published 2017 Mar 9. doi:10.1172/jci.insight.89970
5. Mercuri E, Darras BT, Chiriboga CA, Day JW, Campbell C, Connolly AM, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. New England Journal of Medicine. 2018;378(7):625-35.
6. Chien, Yin-Hsiu et al. Presymptomatic Diagnosis of Spinal Muscular Atrophy Through Newborn Screening The Journal of Pediatrics, Volume 190, 124 - 129.e1
7. Eugenio Mercuri, Richard S. Finkel, Francesco Muntoni, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscular Disorders, 2018; (28): 2, 103-115. https://doi.org/10.1016/j.nmd.2017.11.005.
8. Pechmann A, Langer T, Schorling D, et al. Evaluation of children with SMA type 1 under treatment with nusinersen within the expanded access program in Germany. J Neuromuscul Dis 2018; 5: 135–43.
9. https://www.enmc.org/publications/workshop-reports/position-neuromuscular-patients-shared-decision-making-sdm. Accessed 5th of November 2018.