Author: Joseph Krzeski
Editor: Ashley Aguillard
Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that causes early life mortality. Within the past decade, the Food and Drug Administration (FDA) has approved three novel therapeutics for SMA – Spinraza, Evrysdi, and Zolgensma. While challenges remain, these innovative therapies offer significant clinical improvements for individuals with SMA, marking a major advancement in the treatment of this devastating condition.
Overview of Spinal Muscular Atrophy
SMA is an autosomal recessive disorder that leads to progressive muscle degeneration and atrophy. Affecting ~1:10,000 births, SMA exhibits a heterogenous clinical spectrum. The disorder is categorized into five main types (Type 0 – Type 4) based on symptom severity and age of onset. SMA Type 0 is a rare and severe form that is fatal around birth. SMA Type 1 – Type 3 are the most prevalent forms, with Type 1 representing ~60% of all diagnoses. Life expectancy for SMA Type 1 is ~10 months, while life expectancy for Type 2 is ~20 years. Individuals with SMA Type 3 have a typical life expectancy, but experience pronounced muscle degeneration that impairs motor function. SMA Type 4 is a rare adult-onset form, marked by some muscle weakness and a typical life expectancy (Table 1).1,2
The genetic cause of SMA is connected to a single gene, Survival of Motor Neuron 1 (SMN1). The loss of functional SMN1 causes the degeneration of motor neurons, which are essential for controlling voluntary muscles involved in movement, breathing, and swallowing. As these motor neurons degenerate, significant muscle atrophy occurs and leads to early-life mortality. The severity of SMA symptoms, ranging from the fatal early onset in SMA Type 1 to the progressive muscle degeneration seen in SMA Type 3, is influenced by the presence of a second gene, Survival of Motor Neuron 2 (SMN2). Although SMN2 is nearly identical to SMN1, it contains a coding variant in exon 7, a critical component of the SMN2 gene. This variant causes exon 7 to be preferentially skipped during SMN2 mRNA splicing, which results in the production of only about 10% of functional SMN2 protein (Figure 1). While SMN2 protein can partially compensate for the lack of SMN1 protein, the degree of compensation varies with the number of SMN2 gene copies. Generally, individuals with SMA Type 3 have more copies of the SMN2 gene, which guards against more severe symptoms, while individuals with SMA Type 1 have fewer SMN2 gene copies, which contributes to a more severe manifestation (Table 1).1,2
Current Therapeutic Landscape
Historically, clinical care for SMA focused on symptom management, including physical and respiratory therapy, alongside palliative care. In 2016, the FDA approved the first disease-modifying therapy for SMA, Spinraza. Since then, two additional therapies, Evrysdi and Zolgensma, also received FDA approval. Two of these treatments—Spinraza and Evrysdi—enhance the production of functional SMN2 protein to compensate for the lack of SMN1 protein. The third therapy, Zolgensma, restores functional SMN1 to motor neurons.
Spinraza (nusinersen)
Background: Developed by Ionis Pharmaceuticals and Biogen, Spinraza was approved by the FDA in 2016 as the first disease-modifying treatment for SMA.3 Spinraza is an antisense oligonucleotide (ASO), or a short, engineered sequence of nucleic acids that can bind DNA or RNA. It is administered directly into the spinal canal, through an intrathecal injection.5 Spinraza requires an initial series of four loading doses. The first three loading doses are spaced 14 days apart while the fourth loading dose occurs 30 days after the third dose. Following the loading doses, Spinraza is administered once every four months as maintenance.4
Mechanism of Action: Spinraza was designed to bind to a specific region of SMN2 pre-mRNA, called the intronic splicing silencer N1 (ISS-N1). By binding to this region, Spinraza prevents splicing factors from excluding exon 7, thereby promoting the inclusion of exon 7 in mature SMN2 mRNA. This results in the production of more functional SMN2 protein, which compensates for the lack of functional SMN1 protein and mitigates symptom progression (Figure 2).1,5
Clinical Trial: The safety and efficacy of Spinraza in both early-onset and late-onset SMA was evaluated in the ENDEAR and CHERISH phase 3 clinical trials, respectively.4 Both studies were double-blinded with sham-treated control groups. In the ENDEAR trial, which focused on early-onset SMA (i.e., SMA Type 1 patients <7 months old), 51% of Spinraza-treated individuals showed improvements on the Hammersmith Infant Neurological Examination 2 (HINE-2), a scale that measures infant motor milestones such as head control, rolling, independent sitting, and standing. Additionally, there was a 47% reduction in mortality and permanent ventilation risk compared to those who did not receive treatment.6 The CHERISH trial, which examined later-onset SMA (i.e., SMA Type 2 and 3 patients 2-9 years old), found that 56.8% of Spinraza-treated individuals had clinical improvements on the Hammersmith Functional Motor Scale-Expanded (HFMSE), a scale that examines motor control in older individuals with SMA.7
Evrysdi (risdiplam)
Background: Evrysdi, developed collaboratively by Genentech, PTC Therapeutics, and the Spinal Muscular Atrophy Foundation, was approved by the FDA in 2020.8 Like Spinraza, Evrysdi increases the production of functional SMN2 protein. Evrysdi is a small molecule therapeutic that is administered daily as an oral solution in infants or as an oral tablet in older children and adults.9
Mechanism of Action: While Evrysdi also enhances the inclusion of exon 7 in SMN2, its mechanism of action differs from Spinraza. Evrysdi binds to two regions of SMN2 pre-mRNA, the 5′ splice site (just after exon 7) and the exonic splicing enhancer 2 (ESE2) region within exon 7. This binding stabilizes the interaction of splicing factors on exon 7, ultimately promoting its inclusion and the production of functional SMN2 protein (Figure 3).10
Clinical Trial: The safety and efficacy of Evrysdi was tested in three phase 3 clinical trials: RAINBOWFISH, FIREFISH, and SUNFISH.9 The RAINBOWFISH trial, an open-label, single-arm study, focused on presymptomatic newborns with confirmed SMA diagnoses. After one year of treatment, 96% of infants treated with Evrysdi were able to sit independently for at least five seconds.11 The FIREFISH trial investigated Evrysdi in infants aged 2 to 7 months with SMA Type 1 and was an open-label study. After two years of treatment, 84% of the patients were alive and showed improvements in motor function (i.e., ability to sit unsupported for at least 5 seconds) compared to the natural progression of SMA.12,13 The SUNFISH trial, a placebo-controlled study, tested Evrysdi in individuals aged 9 years or older with SMA Type 2 or Type 3. There were significant improvements in motor function, as measured by the Motor Function Measure-32 (MFM-32) and Revised Upper Limb Module (RULM), in individuals treated with Evrysdi compared to the placebo group.14,15 Collectively, these trials demonstrate that Evrysdi improves motor function and survival outcomes in a broad range of individuals with SMA.
Zolgensma (onasemnogene abeparvovec)
Background: Zolgensma, developed by Novartis Gene Therapies (previously AveXis), was approved by the FDA in 2019.16 Unlike Spinraza and Evrysdi, Zolgensma reinstates the functional SMN1 gene directly in neurons. Administered as a single intravenous injection, Zolgensma’s effects are enduring, presumably lasting an entire lifetime.17
Mechanism of Action: Zolgensma utilizes adeno-associated virus (AAV)-mediated gene transfer to directly deliver the functional SMN1 gene into neurons. AAVs are small, non-pathogenic viruses that can be engineered to carry therapeutic genes. In Zolgensma, the SMN1 gene is packaged into a specific AAV, called AAV9, that allows it to enter neurons. Once inside a neuron, the AAV particle releases the SMN1 gene for expression. AAV9 cannot replicate, which ensures a safe delivery in neurons (Figure 4).18
Clinical Trial: The safety and efficacy of Zolgensma for SMA Type 1 was evaluated in the STR1VE clinical trial, a phase 3 open-label, single-arm study.17 The primary outcome measures included survival at 14 months of age and the ability to sit independently for more than 30 seconds at 18 months of age. The STR1VE trial found that 91% of individuals with SMA Type 1 treated with Zolgensma were alive at 14 months, and 59% were able to sit independently for over 30 seconds.19 These results demonstrate that Zolgensma significantly improves survival and motor milestones in infants with SMA Type 1.
The Road Ahead
Spinraza, Evrysdi, and Zolgensma have all leveraged cutting-edge science to develop disease-modifying therapies for SMA and demonstrated clear benefits that improve motor function and/or reduce the risk of early mortality and permanent ventilation. However, some challenges persist. Spinraza requires intrathecal injections every four months. While these injections are routine procedures, they require a specialized medical team and are associated with side effects such as intense headaches and nausea.20 Adherence to Spinraza has been lower than anticipated, potentially due to difficulties associated with these injections.21,22 Evrysdi must be taken orally by individuals with SMA, which can be challenging for those who have difficulties swallowing. Zolgensma is an AAV-mediated therapy and may not be suitable for all patients. Because AAVs are naturally-occurring viruses, previous exposures can result in the development of neutralizing AAV antibodies. As a result, Zolgensma is not typically administered to individuals with detectable AAV antibodies, as these antibodies could trigger immune responses. While prior screening for AAV antibodies prevents this issue, it results in the exclusion of individuals from receiving Zolgensma.18 Overcoming these challenges will broaden the number of individuals that can be treated. Despite these obstacles, Spinraza, Evrysdi, and Zolgensma have significantly improved the quality of life for individuals with SMA and ushered in new medical standards.
Early intervention is optimal to prevent SMA symptom progression.23 As a result, the ideal time to treat individuals with SMA is prior to motor neuron degeneration and symptom onset, as it becomes challenging to regenerate neurons and muscles once atrophy has occurred. Since 2018, all newborns in America are screened for SMA, and prenatal testing is available for parents with known SMN1 mutations.24 Early screening evokes the possibility of treating SMA individuals in utero and/or immediately after birth. In fact, Evrysdi was recently administered to a pregnant woman carrying a fetus diagnosed with SMA (likely SMA Type 1). After birth, the infant continued Evrysdi treatment and, at two years old, has shown no symptoms.25 While this is only a single case and not conclusive, it heralds a new frontier for treating SMA. Prenatal treatment carries risks and opportunities that will likely vary on a case-by-case basis. Specialized medical teams will need to review each case independently to weigh the risks and benefits of prenatal treatment. Whether Spinraza or Zolgensma can also be administered safely and effectively in utero remains undetermined and will require special considerations for each therapeutic modality.
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