Abstract
Dear Editor:
In early 2018, Cure SMA convened a group of expert clinicians and scientists to develop a treatment algorithm using a reiterative surveying modified Delphi technique for infants diagnosed with spinal muscular atrophy (SMA) via newborn screening (NBS). The findings and recommendations of this group were previously published here in May 2018 [1].
The working group first developed a treatment algorithm for the administration of an SMN-upregulating treatment based upon genotype following a positive NBS result. The initial decisions for this algorithm were based on the correlation of SMA genotype to phenotype across multiple studies. SMA types 1 and 2 represent a large majority, greater than 90%, of SMA cases and account for the bulk of those who have three or fewer copies of SMN2. The working group unanimously recommended immediate treatment for individuals predicted to manifest SMA with the qualifying genotypes of two or three copies of SMN2, as supported by the strong positive results arising from pre-symptomatic infants in the NURTURE trial [2].
In September 2019, Cure SMA reconvened our multidisciplinary working group to reassess the treatment algorithm for newborns with SMA identified through newborn screening based upon new experience and therapeutic options. We now wish to address the changing landscape of potential burden and benefit associated with early treatment of infants diagnosed with SMA via newborn screening who have four copies of the SMN2 gene.
Previously, the working group did not reach a consensus, and thus, did not issue a recommendation on whether to immediately treat or conduct watchful waiting for infants with four copies of SMN2. The group was nearly equally split on this decision and, therefore, referred the decision to the infant’s healthcare provider (n = 13). Our recommendation was for a personalized decision about which course to take for these patients by their parents and physicians.
When the working group reconvened, there was agreement that there was sufficient new clinical data and real-world experience to warrant revisiting the previous lack of recommendation for infants diagnosed with SMA via NBS who have four copies of SMN2. Reiterative surveying was conducted as detailed in the original publication and a meeting was held to discuss the recommendation.
The working group noted that the recent publication of data from Biogen’s NURTURE clinical trial shows the dramatic impact from early nusinersen treatment, with data showing that treatment under six weeks of age in patients with two or three copies of SMN2 is significantly better than treatment after six weeks of age [2]. Patients enrolled in this trial with two copies of SMN2 have a dramatically altered disease course with 100% alive, 100% sitting, 88% walking with assistance, 77% walking independently, and none needing the use of permanent ventilation assistance. Critically, disease has been largely prevented in the patients with three copies of SMN2, as these patients have met motor milestones on schedule and currently do NOT manifest clinical signs of SMA. The working group argues the same predicted outcomes would apply for patients with four copies of SMN2 as to those with three copies. With early treatment, disease would be mostly eradicated in presymptomatic patients with four copies of SMN2. Additionally, the SMN1 replacement gene therapy onasemnogene abeparvovec is now approved for all genotypes of patients under two years of age, also pushing toward treatment instead of waiting. The working group also noted that the presence of anti-AAV antibodies may preclude treatment with onasemnogene abeparvovec and children are more likely to develop antibodies as they age.
Decisions about initiation of treatment, when not done immediately, are still dependent on the presence of any clinical or subclinical signs of SMA, such as weakness or decrease in amplitude of the compound muscle action potential (CMAP). These symptoms are reflective of already occurring motor neuron dysfunction or loss. The working group recognizes the potential use of neurofilament as a predicative biomarker for SMA, once further validated, but this is not yet utilized in clinical practice. Critically, the working group notes that the loss of even a small number of motor neurons is unacceptable when effective treatment is available, as this loss cannot be reversed after onset but can be prevented with earlier treatment.
The working group does acknowledge that current laboratory assays designed to detect SMN2 copy number often have difficulty distinguishing high copy numbers of SMN2 and that many laboratories report results as four or more SMN2 copies, being unable to give an exact number. Recognizing this fact, the working group encourages follow-up with a laboratory able to distinguish exact SMN2 copy number. Many genetics laboratories are currently working to improve their SMN2 copy assays and the group is confident these assays will improve.
In summary, the working group is issuing this letter to update our recommendation for infants diagnosed with SMA via NBS with four copies of SMN2 to immediate treatment.
Sincerely,
Cure SMA, Elk Grove Village, IL, USA. Stanford University, Stanford, CA, USA. Washington University School of Medicine, St. Louis, MO, USA. Department of Neurology, Boston Children’s Hospital, Boston, MA, USA. Nemours Children’s Hospital, University of Central Florida College of Medicine, Orlando, FL, USA. Miller School of Medicine, University of Miami, Miami, FL, USA. Genzyme Corporation, a Sanofi Company, Framingham, MA, USA. Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA. Department of Molecular Pathology, Ohio State Wexner Medical Center, Columbus, OH, USA. University of California Los Angeles, Los Angeles, CA, USA. Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD, USA. Generation Bio, Cambridge, MA, USA.