Gene-Targeted Therapies and Palliative Care in Children with Spinal Muscular Atrophy Type I: No Intrinsic Contradiction

Dear Editor:

Type 1 spinal muscular atrophy (SMA1) is a progressive life-limiting neurodegenerative disorder that results in bulbar and respiratory insufficiency and without treatment in death in infancy. Consensus statements for standards of care in SMA highlighted the international lack of consensus and the controversies on palliative versus interventional approaches. The authors emphasized the multidisciplinary approach as a key element in the management of patients with SMA. ¹ Although many aspects of care for children with SMA have dramatically improved in the scope of new therapies, resulting in longer survival and better quality of life, respiratory morbidity and bulbar insufficiency remain the hallmarks of the neurodegenerative clinical course.

US approval of Nusinersen as first gene-targeted therapy in December 2016 and of Onasemnogene Abeparvovec as first gene replacement therapy in May 2019 have altered the phenotype of SMA and the perception of caregivers, families with SMA, national authorities, and payers, and gave rise to an increasing uncertainty regarding previous treatment pathways. Subsequently gaps in palliative care evolved, e.g., lacking of insurance company approval of concomitant gene-targeted therapies and palliative care, although longitudinal data on the clinical course and the survival are still missing. It has been shown clearly that the effect of all existing disease-modifying treatments depend on the age of first application and the degree of neurodegeneration at time of diagnosis. Sustainable efficacy, safety, and, therefore, long-term evidence of gene-modifying therapies have yet to be shown. In the analyses of the phase III clinical trial with Nusinersen of 121 infants, 39% of patients with Nusinersen treatment had died or were on permanent assisted ventilation, compared with 68% of the control group. ² After the phase I trial with Onasemnogene Abeparvovec for 18 months, ³ no further clinical data have been published so far on the long-term clinical outcome. After the Food and Drug Administration (FDA) approval, three young children died after treatment with Onasemnogen Abeparvovec. All three cases were finally declared as unrelated to the gene replacement therapy. ⁴

The authors represent a group of pediatric neuromuscular and palliative care specialists being involved in primary care of infants with SMA1 from various sides. They postulate the ongoing need of a holistic approach for families with SMA1, including a standardized cooperative integrated model of pediatric palliative care at the time of diagnosis. The authors see the fundamental need for a coexisting multidisciplinary care model, including palliative care and targeted therapies for children with SMA. Societies have to enter a multilevel discourse on ethical issues about care access, drug availability, and monitoring against the background of a socioeconomic context. Treatment algorithms and communication strategies between caregivers and the families have to be redefined in the era of novel targeted therapies. The authors propose the development of a systematic quantitative online survey on the necessity and indication for concomitant care of children with SMA1 treated with disease-modifying therapies in specialized neuromuscular centers and by specialized pediatric palliative care teams. The results of this multicenter survey may evolve into a standardized treatment algorithm in SMA1.