Medical Care
Nusinersen
In December 2016, the FDA approved nusinersen (Spinraza), the first drug approved to treat children (including newborns) and adults with SMA. Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. [45]
Nusinersen approval was based on the ENDEAR trial. The ENDEAR trial (n=121) is a phase 3 randomized, double-blind, sham-controlled study in patients with infantile-onset (most likely to develop Type 1) SMA. At a planned interim analysis, a greater percentage of infants treated with nusinersen achieved a motor milestone response compared to those who did not receive treatment (40% vs 0%; p< 0.0001) as measured by the Hammersmith Infant Neurological Examination (HINE). Additionally, a smaller percentage of patients in the nusinersen group died (23%) compared to untreated patients (43%). [46]
Interim data from another phase 3 trial, CHERISH, included 126 nonambulatory patients with later-onset SMA (consistent with Type 2), including patients with the onset of signs and symptoms at >6 months and an age of 2 to 12 years at screening. Prespecified interim analysis demonstrated a difference of 5.9 points (p= 0.0000002) at 15 months between the treatment (n=84) and sham-controlled (n=42) study arms, as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From baseline to 15 months of treatment, patients in the nusinersen group achieved a mean improvement of 4.0 points in the HFMSE, while patients who were not on treatment declined by a mean of 1.9 points. [47]
Onasemnogene abeparvovec
Onasemnogene abeparvovec (Zolgensma) is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human survival motor neuron (SMN) protein. It is indicated for gene replacement therapy in children aged 2 years or younger with spinal muscular atrophy (SMA) type 1 (also called Werdnig-Hoffman disease) who have biallelic mutation in the survival motor neuron 1 (SNM1) gene.
Approval was based on the ongoing phase 3 STR1VE trial and the completed phase 1 START trial. Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. As of the data cutoff, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone. [48]
Interim data analysis from the ongoing phase 3 STR1VE trial described 21 of 22 (95%) patients were alive and event-free. The median age was 9.5 months, with 6 of 7 (86%) patients aged 0.5 months or older surviving event-free. Interim results also showed ongoing improvement of motor milestones (eg, holding head erect, rolling over, sitting without support). [49, 50]
Risdiplam
Risdiplam (Evrysdi) is a survival of motor neuron 2 (SMN2) mRNA splicing modifier designed to treat mutations in chromosome 5q that lead to SMN protein deficiency. It is indicated for spinal muscular atrophy, including types 1, 2, and 3, in adults and children aged 2 months or older. The indication was expanded to include children younger than 2 months in May 2022. Approval was supported by results from several phase 3 trials (FIREFISH, SUNFISH, JEWELFISH, RAINBOWFISH).
FIREFISH is an open-label, two-part pivotal clinical trial in infants aged 2–7 months with Type 1 SMA. Results showed 41% (7/17) of infants achieved ability to sit without support for at least 5 seconds and 90% (19/21) were alive without permanent ventilation at 12 months. After a minimum of 23 months of treatment and reaching an age of 28 months or older, 81% (17/21) of all patients were alive without permanent ventilation. [51]
The SUNFISH study was a two-part, double-blind, placebo-controlled pivotal clinical trial in children and young adults (aged 2–25 years) with Type 2 or 3 SMA. A clinically meaningful and statistically significant improvement in motor function among children and adults was observed as measured by a change from baseline in the MFM-32 total score. Improved upper limb motor function compared to baseline, as measured by the Revised Upper Limb Module (RULM), a secondary independent motor function endpoint of the study, also showed statistically significant improvement. [52]
JEWELFISH is an open-label exploratory trial in people with SMA Type 1, 2 or 3, aged 6 months to 60 years who have been previously treated with SMA therapy, gene therapy, or olesoxime. Recruitment is complete with 174 people enrolled.
RAINBOWFISH is an open-label, single-arm, multicenter study, investigating the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in babies (~n=25), from birth to 6 weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study is currently recruiting.
Other Therapies
Medications such as valproic acid, phenylbutyrate, hydroxyurea, and albuterol have been shown to increase SMN transcription in laboratory studies, but clinical trials have not demonstrated significant improvement in disease progression. The SMA CARNIVAL trials (parts 1 and 2) [53, 54] found valproic acid and L-carnitine ineffective with regard to strength or functional improvement at 6 months and 12 months in both ambulatory and nonambulatory children. Adverse effects were reported in 85% of patients. [53] Gabapentin, riluzole, and olesoxime have been studied for their suspected neuroprotective properties, without significant clinical benefit noted. [38, 55, 56] Treatment with creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, and hydroxyurea have also proved ineffective. [55]
A randomized, double-blind, placebo-controlled trial in male subjects with genetically confirmed spinobulbar muscular atrophy (Kennedy disease) using oral dutasteride (a 5-alpha-reductase inhibitor that reduces dihydrotestosterone) did not show a significant effect on the progression of muscle weakness. [57] Failure of this treatment trial in spinobulbar muscular atrophy may in part be attributed to the underpowered study and the relatively short period in which treatment effect can be accurately measured because of the slowly progressive nature of this disease. These results also suggest that the role of androgens in spinobulbar muscular atrophy is complex.
Supportive treatment should be aimed at improving the patients' quality of life and minimizing disability, particularly in patients with slow progression.
The goals are to maximize the patient's independence and quality of life at each stage of the disease.
The treatment of patients with adult-onset spinal muscular atrophy is similar to that for amyotrophic lateral sclerosis (ALS), except that the course and life span in spinal muscular atrophies is considerably longer.
A multidisciplinary approach is essential. Once diagnosis is reached, overnight oximetry, respiratory muscle function tests, cough effectiveness, forced vital capacity (for patients >5 years), swallow study with video, physical and occupational therapy assessments, assistive equipment evaluation, and hip/spine radiography are appropriate. Recognition of mandibular dysfunction manifested as limited mouth opening is an important factor in prevention of aspiration. [38, 58]
Interventions such as chest physiotherapy, assisted cough, nocturnal (+/- daytime) noninvasive ventilation, and Nissen fundoplication for nonsitting patients may be considered. Gastrostomy placement is often pursued at the time of diagnosis for SMA1. [38]
The use of splints, bracing, and spinal orthoses can be customized to each patient. [59] Wheelchair use should be determined by patient’s level of fatigue with activity as well as their rate of falling. [38]
Women with SMA who become pregnant have no increased risk of miscarriage or hypertensive diseases. Higher rates of caesarian delivery (42.5%) and preterm deliveries (29.4%) have been observed. Approximately one third of patients noted deterioration of symptoms during pregnancy. [13]
Patients and families can also be directed to ongoing clinical trials for the treatment of spinal muscular atrophies. Descriptions of various trials can be found at the following Web sites:
Surgical Care
Surgical revision may provide stable correction of the spine, and early orthopedic intervention may be indicated in patients in whom prolonged survival is anticipated. Hip subluxations and dislocations are common. Nonsurgical treatment is generally preferred unless pain is severe, owing to the high rate of repeated dislocation. [60]
Noninvasive ventilation and percutaneous gastrostomy reportedly improves the quality of life with no effect on survival. These modalities may be most effective in prolonging lifespan in patients with slowly progressive disease, whereas they may provide comfort care in rapidly progressive infantile forms. [61]
Consultations
Consultations for ancillary evaluations and treatments are appropriate. Consult the following specialists as needed: physical therapist, occupational therapist, speech therapist, dietary or nutritional therapist, social service staff, pulmonologist, orthopedics, and gastroenterologist. Palliative care consultation may be considered upon diagnosis of SMA1. [38]
Diet
Ensuring optimal caloric intake enables patients to use weak muscles to their maximum capacity without incurring obesity as a comorbid condition.
Activity
Encourage mobility. The goal of active but nonfatiguing exercises is to maintain range of motion, increase muscle flexibility, and prevent contractures. These exercises should not produce pain or exhaustion. A small series showed that the risk of falls is strongly correlated to stride-length variability, so this variable should be a focus of physical therapy programs. [62]
Preventing spinal deformities (eg, scoliosis) and joint contractures is important. This goal is accomplished by using range-of-motion exercises, knee-ankle-foot orthoses, specialized wheelchairs and seats at home and school, and home assistance devices.
