Advances in multidisciplinary care over the past several decades improved motor function and extended life expectancies, but new medical therapies approved by the FDA since 2016 have created dramatic breakthroughs for caring for people with SMA (Table). Nusinersen, an antisense oligonucleotide intrathecal medication, was approved by the FDA in 2016 for all patients with SMA. Nusinersen modifies premessenger RNA (premRNA) splicing of SMN2, increasing production of a full-length SMN protein. Onasemnogene abeparvovec is a single-dose intravenous gene replacement therapy approved by the FDA in 2019 for treatment of children under age 2 years with SMA. Onasemnogene is a recombinant aeno-associated viral (AAV) vector with DNA encoding the normal SMN1 gene, producing a normally functioning SMN protein. Risdiplam is an oral therapy the FDA approved in 2020 for individuals age 2 months or more with SMA. Risdiplam also modifies SMN2 splicing to augment production of the full SMN protein. Each of these therapies is discussed in more detail below. Other therapies previously studied with no treatment effect observed include histone deacetylase inhibitors (valproate and phenyl-butyrate), which inhibit class I and II histone deacetylases and upregulate SMN2 expression in mouse models of SMA. Other medications that have been studied without evidence for therapeutic benefit in humans include hydroxyurea, quinazoline, prolactin, riluzole, and gabapentin.
Nusinersen. The pivotal nusinersen clinical trials were the ENDEAR study of infantile-onset (type 1) SMA and the CHERISH study in later-onset SMA. Nusinersen is administered intrathecally, starting with 4 loading doses followed by a maintenance schedule of infusions every 4 months over indefinite durentination. Thrombocytopenia, coagulation abnormalities, and renal toxicity were observed in a minority of study patients. In the first pivotal trial of nusinersen, the primary outcome measures were the Hammersmith Infant Neurological Examination (HINE) and event-free survival (ie, death or permanent assisted ventilation). Of the 73 enrolled infants, 51% achieved key motor milestones (eg, head control, rolling, sitting, or standing) vs 0% of the control group. Of the children treated with nusinersen, 39% died or required permanent ventilator support, compared with 68% of the children who received placebo. Statistically significant differences were recorded for both primary outcome measures. The second pivotal trial found a statistically significant treatment effect in later onset SMA based on the primary outcome measure, and the study was terminated early because of these positive findings. These results have been confirmed in clinical practice, but it has become increasingly evident that treated patients continue to have a significant disease burden, with variable levels of treatment responses.
Onasemnogene. A 1-time intravenous therapy, onasemnogene abeparvovec was investigated in children with SMA type 1. The main reported side effect was elevated liver transaminases, which were attenuated by prednisolone dosing. Onasemnogene is DNA encoding the SMN1 gene contained within a self-complementary adeno-associated viral serotype 9 (scAAV9) vector. The primary outcome was safety with secondary outcomes of time until death and the need for permanent ventilatory assistance. Exploratory outcomes of motor milestone achievements and the Children’s Hospital of Philadelphia Infant Test of Neurological Disorders (CHOP INTEND) scale were measured in 15 treated infants. At the end of the study, all 15 were still surviving without the need for permanent mechanical ventilation, in comparison to a natural history in which only 8% achieved this landmark. Most sat unassisted, with 9 sitting unsupported for more than 30 seconds. Over half developed expressive language ability, and 2 have learned to walk independently. Of the 12 who received the high dose, 11 were swallowing independently and 10 were without NIV support. These milestones were not seen in any historical cohorts. A potential limitation of onasemnogene is the presence of antiAAV9 antibodies in some individuals, which limited therapeutic efficacy in 1 participant in the study.
Risdiplam. Risdiplam was investigated in a 2-part trial in participants with SMA type 1 and another trial in people with SMA type 2 or nonambulatory SMA type 3. Risdiplam is a once-daily oral medication. Thrombocytopenia, coagulation abnormalities, and renal toxicity were observed in a minority of trial participants. The 2-part trial in SMA type 1 investigated low and high dosing and included 21 participants in the first part of the trial. In the second part of the trial, a high-dosing regimen measured efficacy over 1 year, with beneficial results similar to those found in the first part. The primary outcomes in the first portion were safety, pharmacokinetics, pharmacodynamics, and selection of appropriate dosing for the second portion, with an exploratory outcome of sitting without support for more than 5 seconds. Post hoc exploratory outcomes from the second portion were also applied to the first portion and included event-free survival without use of permanent ventilation, scores from CHOP INTEND, and motor milestones from HINE. Within the high-dose group of portion 1 of the trial, 33% of participants were able to sit without support, 43% maintained upright head control, and 1 was able to bear weight while standing. Furthermore, no infant lost the ability to swallow and most (86%) were able to feed orally. At the end of the trial, 90% of these children remained event-free. These measures were compared with historical cohorts of infants with SMA type 1, who are unable to sit without support and typically require NIV support. The trial in people with SMA type 2 and nonambulatory SMA type 3 is ongoing with 120 participants treated with risdiplam. At the 2-year interval analysis, there was a statistically significant change in baseline on the 32-item Motor Function Measure (MFM) scale between the study and control group, with more information to be reported at the end of the trial.
The care of patients with SMA has advanced dramatically over the last 30 years, changing the expected course of the disease when new therapies are applied. From the discovery of the associated gene in 1995, therapeutic clinical trials in the 2000s and 2010s, increasing standardization of multidisciplinary care, and most recently, FDA-approved therapeutic medications, the outcomes of patients with SMA have been revolutionized. Although nusinersen, onasemnogene abeparvovec, and risdiplam are breakthrough medications, these were only approved in the past few years, thus questions remain regarding the long-term benefits and potential side effects of these medications. Fortunately, there are several ongoing studies examining these long-term questions. The adaptation of newborn screening for SMA by many states has substantially shortened the lag from birth to initiation of treatment. The future is promising for further advances in the treatment of patients with SMA, and hopefully, an eventual cure.