Paediatrics CME ACCREDITED Watch Time: 36 mins

touchPANEL DISCUSSION Taking the next steps to improve patient outcomes in SMA: Early diagnosis and treatment

Learn more about the early diagnosis and treatment of spinal muscular atrophy (SMA) in this discussion between three internationally renowned experts.
For subtitles in Spanish and Brazilian Portuguese, please click [CC] on the video player below.

Dr Julie Parsons

University of Colorado School of Medicine, Aurora, CO, USA

CHAIR

Panelists:
Prof. Eduardo Tizzano, Prof. Francesco Muntoni
 
Video Chapters
Introduction

Chair Dr Julie Parsons introduces the expert panel and agenda for this discussion on the early diagnosis and treatment of SMA.

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Video Chapters
What is the evidence for initiating treatment early in patients with SMA?

The panel outlines the rationale for initiating treatment early in patients with SMA and considers the clinical data for pre-symptomatic treatment with the available disease-modifying therapies.

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Video Chapters
How can SMA be diagnosed at the earliest opportunity?

The panel discusses the possible causes of diagnostic delay in SMA and how SMA can be diagnosed at the earliest opportunity.

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Video Chapters
How close are we to new biomarkers for SMA?

The panel highlights the possible role of biomarkers in SMA and provides an update on some of the most promising biomarkers being investigated.

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Overview & Learning Objectives
Overview

Learn more about the early diagnosis and treatment of spinal muscular atrophy (SMA) in this discussion between three internationally renowned experts.

This activity has been jointly provided by Oakstone and touchIME RESPIRATORY. Oakstone Publishing is accredited by the ACCME to provide continuing medical education to physicians.

Target audience

This activity has been designed to meet the educational needs of neurologists, paediatric neurologists, paediatricians, pulmonologists, neurology nurses and primary care physicians.

Disclosures

Oakstone Publishing has assessed conflict of interest with its faculty, authors, editors, and any individuals who were in a position to control the content of this CME activity. Any identified relevant conflicts of interest were resolved for fair balance and scientific objectivity of studies utilized in this activity. Oakstone Publishing’s planners, content reviewers, and editorial staff disclose no relevant commercial interests.

Faculty

Dr Julie Parsons discloses: Grant/research support from Avexis, Biogen, PTC Therapeutics and Scholar Rock. Consultant/advisory board for Avexis, Biogen, Genentech and Scholar Rock.

Prof. Eduardo Tizzano discloses: Grant/research support from Ionis/Biogen. Consultant/advisory board for Avexis, Biogen, Biologix, Cytokinetics, Novartis and Roche. He serves as a scientific/medical advisor for the following non-profit organizations: FAME Chile, Famiglie SMA Italy, Familias SMA Argentina, FundAME, SMA Europe and TREAT-NMD.

Prof. Francesco Muntoni discloses: Grant/research support from Biogen and Sarepta for investigator-initiated studies. Consultant/advisory board for Avexis, Biogen, Dyne Therapeutics, Novartis, Roche and Sarepta. Speakers Bureau for Avexis, Biogen, Roche and Sarepta.

Content Reviewer 

Walter Murray Yarbrough, MD, FACP, has no financial interests/relationships or affiliations in relation to this activity.

Touch Medical Director 

Hannah Fisher has no financial interests/relationships or affiliations in relation to this activity.

Requirements for Successful Completion

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Oakstone Publishing and touchIME. Oakstone Publishing is accredited by the ACCME to provide continuing medical education for physicians.

The European Union of Medical Specialists (UEMS) – European Accreditation Council for Continuing Medical Education (EACCME) has an agreement of mutual recognition of continuing medical education (CME) credit with the American Medical Association (AMA). European physicians interested in converting AMA PRA Category 1 Credit™ into European CME credit (ECMEC) should contact the UEMS (www.uems.eu).

Oakstone Publishing designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In order to receive credit for this activity, participants must review and complete the post-test and evaluation form. Statements of credit are awarded upon successful completion of the post-test and evaluation form.

Date of original release: 21 January 2021. Date credits expire: 21 January 2022.

Learning Objectives

After watching this activity, participants should be better able to:

  • Recall the outcomes associated with early treatment initiation for patients with SMA
  • Discuss strategies for diagnosing SMA as early as possible
  • Describe the latest research findings for biomarkers in SMA
Faculty & Disclosures
Dr Julie Parsons

University of Colorado School of Medicine, Aurora, CO, USA

Julie Parsons is Professor of Clinical Pediatrics and Neurology at the University of Colorado School of Medicine in Aurora, CO, USA. She holds the Haberfeld Family Endowed Chair in Pediatric Neuromuscular Disorders and is Co-director of the Neuromuscular Clinic at Children’s Hospital Colorado. read more

She was awarded her MD from the University of Colorado School of Medicine, followed by residencies in paediatrics and child neurology, as well as a fellowship in neuromuscular medicine at the University of Colorado. Dr Parsons has an enduring interest in medical education and served as the child neurology residency programme director for 9 years.

Dr Parsons’ clinical interests include a wide range of neuromuscular diseases, such as muscular dystrophies, spinal muscular atrophy and myotonic dystrophies. She is an active participant and principal investigator for many clinical trials.

Dr Julie Parsons discloses: Grant/research support from Avexis, Biogen, PTC Therapeutics and Scholar Rock. Consultant/advisory board for Avexis, Biogen, Genentech and Scholar Rock.

Prof. Eduardo Tizzano

Hospital Vall d’Hebrón, Barcelona, Spain

Eduardo Tizzano is Head of Pediatrics and Director of the Clinical and Molecular Genetics Department at the Hospital Vall d’Hebrón, Barcelona, Spain, where he is also coordinator of the rare diseases programme and orphan drugs. He is also head of the Genetic Medicine Group at Vall d’Hebrón Institut de Recerca (VHIR). read more

His main areas of research include the characterization of spinal muscular atrophy (SMA) during human development, genotype–phenotype correlations and the validation of biological markers. He is very active in academic and research activities at national and international levels, collaborating with different neuromuscular and genetic centres, and has close links to regional and national patient support groups. He was awarded the Queen Sophia Prize for his cumulative clinical, research and social work in SMA, and coordinates the SMA Registry, Biobank and clinical research to define therapeutic targets.

Prof. Eduardo Tizzano discloses: Grant/research support from Ionis/Biogen. Consultant/advisory board for Avexis, Biogen, Biologix, Cytokinetics, Novartis and Roche. He serves as a scientific/medical advisor for the following non-profit organizations: FAME Chile, Famiglie SMA Italy, Familias SMA Argentina, FundAME, SMA Europe and TREAT-NMD.

Prof. Francesco Muntoni

UCL Institute of Child Health and Great Ormond Street Hospital for Children, London, UK

Francesco Muntoni is Professor of Paediatric Neurology and Honorary Consultant at the UCL Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH) for Children, London, UK. He is also Head of the Dubowitz Neuromuscular Centre. read more

He is Theme Lead in novel therapies for childhood diseases for the NIHR Biomedical Research Centre at GOSH/ICH and Developmental Neurosciences Theme Lead at the UCL ICH.

Prof. Muntoni has authored more than 400 peer-reviewed manuscripts. His main areas of research have been focused on the genetic heterogeneity of neuromuscular disorders and on translational research aspects related to neuromuscular disorders.

Prof. Francesco Muntoni discloses: Grant/research support from Biogen and Sarepta for investigator-initiated studies. Consultant/advisory board for Avexis, Biogen, Dyne Therapeutics, Novartis, Roche and Sarepta. Speakers Bureau for Avexis, Biogen, Roche and Sarepta.

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Question 1/5
The phase II NURTURE trial assessed the use of nusinersen in infants with genetically diagnosed spinal muscular atrophy (SMA) who had no clinical signs or symptoms suggestive of SMA and who received their first dose of treatment at ≤6 weeks of age.

Which of the following statements is true regarding outcomes at 2.9 years of follow-up?
Correct

The NURTURE trial is an ongoing, phase II, multisite, open-label, single-arm study in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while pre-symptomatic. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. Interim outcomes reported as of 29 March 2019, at a median 2.9 years of follow-up, showed the following:1

  • At last visit, children were median 34.8 months of age (range 25.7–45.4) and past the expected age of symptom onset for SMA Types 1 or 2
  • All were alive and none required tracheostomy or permanent ventilation
  • All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently

SMA, spinal muscular atrophy; SMN, survival motor neuron.

Reference

  1. De Vivo DC, et al. Neuromuscul Disord. 2019;11:842–56.
Question 2/5
The phase III SPR1NT trial assessed the use of onasemnogene abeparvovec-xioi in pre-symptomatic patients with spinal muscular atrophy and two or three copies of SMN2. Patients were ≤6 weeks of age at the time of receiving treatment.

Which of the following statements is true regarding outcomes at the interim analysis with a data cut-off of 31 December 2019?

SMN, survival motor neuron.
Correct

The SPR1NT trial is a phase III, open-label, single-arm study of a single one-time dose of onasemnogene abeparvovec-xioi in pre-symptomatic patients with SMA and two (n=14) or three (n=15) SMN2 copies.1

Interim outcomes reported as of 31 December 2019 at last follow-up visit (at 11.2 months for infants with two SMN2 copies and at 9.7 months for infants with three SMN2 copies), showed the following:2

  • All patients were alive and none required ventilation support as of last visit

Among patients with two SMN2 copies:

  • 8/14 infants achieved independent sitting within the normal age interval
  • 4/14 walked independently within a normal age range
  • All patients achieved a CHOP-INTEND score of ≥50 points

Among patients with three SMN2 copies:

  • 4/15 achieved independent standing within the WHO reference window; 3 of these also achieved independent walking

CHOP-INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; SMA, spinal muscular atrophy; SMN, survival motor neuron; WHO, World Health Organization.

References

  1. NCT03505099. Available at: ClinicalTrials.gov (accessed 14 December 2020).
  2. Strauss KA, et al. Neurology. 2020;94(Suppl. 15):2384.
Question 3/5
A 4-month-old baby is brought in to see you by her parents because they have noticed that she is “floppy”. She appears bright and responsive. On examination, you find she is weak. What do you do next?

SMN, survival motor neuron
Correct

The diagnosis of SMA is based on molecular genetic testing. Genetic testing of SMN1/SMN2 is highly reliable and it is the first line of investigation when the condition is suspected in a typical case.1

Unless there are previous familial cases, the diagnostic process is generally prompted by the clinical signs. Clinically, these infants present with hypotonia, progressive symmetric and proximal weakness affecting the legs more than the arms, sparing of the facial muscles but often with bulbar muscle weakness. There is also weakness of the intercostal muscles with relative sparing of the diaphragm, which results in the typical “bell-shaped” chest and paradoxical breathing pattern.1

SMA, spinal muscular atrophy; SMN, survival motor neuron.

Reference

  1. Mercuri E, et al. Neuromuscular Disord. 2018; 28:103–115.
Question 4/5
Your patient has been diagnosed with spinal muscular atrophy via newborn screening. The patient is currently asymptomatic and has two copies of the SMN2 gene. According to expert consensus, how would you manage this patient?

SMN, survival motor neuron
Correct

With the advent of newborn screening for SMA, SMN2 copy number is emerging as a vital marker to guide the type and extent of intervention and stratify newborn patients to differing treatment arms. For example, there is consensus among experts that pre-symptomatic infants with ≤3 copies of SMN2 should be promptly treated with disease-modifying therapy, as they are predicted to have early onset forms of SMA. However, SMN2 copy number has limitations, lacking precision as a biomarker of disease onset and prognosis.1

SMA, spinal muscular atrophy; SMN, survival motor neuron

Reference

  1. Kariyawasam DST, et al. Front Neurol. 2019;10:898.
Question 5/5
Which biomolecular biomarker has demonstrated potential prognostic and predictive ability in the nusinersen clinical trials in spinal muscular atrophy?

SMN, survival motor neuron, mRNA, micro-ribonucleic acid
Correct

Neurofilaments are cytoplasmic proteins abundantly expressed in axons that have recently been recognized as promising diagnostic, prognostic, and monitoring biomarkers in a range of neurological disorders associated with axon loss.1

Across large nusinersen clinical trials with SMA Types 1 and 2 and pre-symptomatic infants, plasma pNF-H differentiated SMA individuals from healthy controls. Treatment initiation with nusinersen was associated with rapid decline followed by stabilization of pNF-H at levels close to those of healthy controls. However, the small number of healthy age-matched controls, and the fact that pNF-H declined with advancing age in untreated patients, raises uncertainty about its utility as a biomarker, and further evaluation is required.1

pNF-H, phosphorylated neurofilament heavy chain; SMA, spinal muscular atrophy.

Reference

  1. Kariyawasam DST, et al. Front Neurol. 2019;10:898.
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