The diagnosis and treatment of a rare disease like spinal muscular atrophy (SMA) would benefit greatly from using implementation science to reduce the variation that exists in screening and therapy, according to researchers.
Although the field of spinal muscular atrophy (SMA) has advanced significantly in the past decade, thanks to 3 new approved treatments and robust infant screening programs, there is still a need to address implementation gaps to deliver the most effective care for these children, according to a recent article published in Frontiers in Neurology.
Those gaps include challenges with diagnosis, treatment, outcomes, cost and access, and long-term management, and the authors advocated for using implementation science to translate innovation to effective and multidisciplinary care.
“If implemented well, precision medicine approaches could have a significant benefit to patients with SMA and other rare diseases,” the researchers wrote. “However, biomedical science faces a formidable challenge in evaluating the clinical utility of scientific breakthroughs in rare diseases, especially if it follows the traditional path of innovation development, then efficacy and effectiveness studies, prior to implementation.”
SMA, a rare genetic disease affecting about 1 in 10,000 live births, can be detected in the first week of life. There are 5 different subtypes, with Type 0 being the most severe form and Type 4 being the mildest. Type 1 is the most common form, with progressive muscle weakness and atrophy.
SMA has 3 approved therapies: nusinersen (Spinraza; Biogen), the gene therapy onasemnogene abeparvovec (Zolgensma; Avexis), and risdiplam (Evrysdi; Genentech/Roche).
Nusinersen, an antisense oligonucleotide, increases the amount of SMN protein from SMN2, and is approved for all types of SMA. It was the first therapy to market.
Zolgensma, a gene replacement therapy, also increases SMN protein but from SMN1. It is currently FDA-approved for patients aged less than 2 years old and in type 1 for up to 3 SMN2 copies.
Risdiplam, a small molecule agent, is similar to nusinersen in that it increases SMN protein from SMN2; however, it is approved for all SMA types and infants less than 2 months old.
In the United States, newborn screening for SMA takes place for most new births. States are in charge of screening, and most programs already use multiplex testing, which is already used for severe combined immunodeficiency. The process of testing is influenced by a number of factors, the authors, noted including state size, demographics, health care infrastructure, social determinants of health, and factors unique to providers and practices.
The researchers said the gaps in the implementation of newborn screening include the 2 states that do not currently screen for it (Nevada and Hawaii), and variations in the numbers of specialists available to perform the screening, which could impact how long it takes to get a diagnosis and also to begin a treatment.
Another issue to watch, they wrote, is postmarketing safety monitoring. Given the short time that therapies have been on the market, long-term data is limited. Short-term side effects vary by the type or class of treatment. For instance, nusinersen is linked with proteinuria, thrombocytopenia and coagulation abnormalities, but these effects tend to be mild and are not do not change disease management.
The gene therapy Zolgensma is given through an intravenous infusion and has been linked with transaminitis, steroid responsive hepatotoxicity, complement mediated thrombocytopenia, and thrombotic microangiopathy; last year, the drugmaker, Novartis, updated the labeling for the therapy to note that fatal acute liver failure has been reported.
Risdiplam has been linked with diarrhea, rash, respiratory infections, including pneumonia during clinical trials.
Regarding patient outcomes, the authors suggested that patient registries could assist with decision making and optimize healthcare resource utilization. Most SMA studies focus on neuromotor achievements, time spent off a ventilator, and overall survival, but information is limited about how these treatments affect other outcomes such as improvements in dysphagia, sleep disordered breathing, and scoliosis.
The authors also noted the cost of these therapies and research into the cost of care beyond the actual treatment is limited.
“Evaluating the long-term cost, benefits and burden of these interventions requires transparent data sharing among centers and health care organizations," they wrote.
Moreover, a consolidated framework for implementation research, a key part of implementation science, could serve to guide improvement of screening programs as well as form the development of a framework of genomics and integrative research to improve the care of children with SMA.
Leon-Astudillo C, Byrne BJ, Salloum RG. Addressing the implementation gap in advanced therapeutics for spinal muscular atrophy in the era of newborn screening programs. Front Neurol. Published online December 12, 2022. doi:10.3389/fneur.2022.1064194. eCollection 2022.