New therapies for spinal muscular atrophy: where we stand and what is next

Abstract

The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration. Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug’s approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.

Safety and efficacy of growth-friendly instrumentation for early-onset scoliosis in patients with spinal muscular atrophy type 1 in the disease-modifying treatment era

“…DMTs have changed the clinical phenotypes for all types of SMA, and the most dramatic improvement was seen in patients with SMA type 1. 19 When treatment is started very early, especially in the presymptomatic phase, prominent improvements can be expected. 20 However, newborn or prenatal screening is not universally available, and treatment is usually started after the onset of symptoms.…”

Respiratory morbidity in patients with spinal muscular atrophy—a changing world in the light of disease-modifying therapies

“…The two pivotal randomized controlled clinical trials with nusinersen (ENDEAR trial for SMA type 1, CHERISH trial for SMA type 2 and 3) documented great improvements in motor function and survival ( 9 ). In the ENDEAR trial, children in the nusinersen group had a higher likelihood of event-free (defined as being alive without permanent assisted ventilation) and overall survival.…”

“…There are currently three drugs approved for SMA. Nusinersen (Spinraza®) , approved in 2016 by the Food and Drug administration (FDA) and in 2017 by the European Medicines Agency (EMA) as the first drug for SMA, modifies SMN2 splicing resulting in an increased production of full-length SMN protein ( 9 ). Nusinersen is a hybridizing antisense oligonucleotide (ASO) that binds to the pre-mRNA and promotes the inclusion of exon 7.…”

“…In 2019, an intravenous (IV) gene therapy, onasemnogene abeparvovec ( Zolgensma ®), was approved for use by the (FDA), followed by approval in 2020 in Europe ( 12 ). Delivery of a single IV dose of a recombinant human SMN1 transgene by a viral vector (adeno-associated viral vector type 9, AAV9) that can cross the BBB, results in replacement of the mutated SMN1 gene ( 9 , 11 , 13 ). Lastly, risdiplam (Evrysdi®), a small molecule that acts as a splicing enhancer, was approved in 2020 in the US and one year later by EMA ( 14 ).…”

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia

“…Since antisense oligonucleotides do not pass the blood–brain barrier, the therapy is delivered directly into the spinal canal through a procedure that begins with the collection of cerebrospinal fluid (CSF) samples, which is a fundamental requirement for the therapeutic injection. Currently, the only clinical indicators of better response to treatment are a later age at disease onset and higher scores of motor function ( 9 ). Due to the increasing number of SMA individuals treated with Nusinersen, there is a growing need for sensitive, reliable, and objective biomarkers that can reflect short- and long-term therapeutic effects and potentially detect changes before they manifest in motor performance.…”