Updates in Clinical Data for FDA-approved Disease-modifying Therapies for Spinal Muscular Atrophy

Supplements and Featured PublicationsAchieving High-Quality Patient Outcomes in Spinal Muscular Atrophy: A Review of New Data and Managed Care Strategies
Volume 27
Issue 1


Spinal muscular atrophy (SMA) is a rare, diverse group of inherited neuromuscular disorders that cause degradation of the lower motor neurons, progressive muscle atrophy, and weakness. The natural history of SMA has changed significantly with an increased understanding of SMA pathophysiology and new technologies. As a result, affected individuals now have 3 disease-modifying therapies available for treatment. Evidence suggests that these novel agents are more effective when started early in the disease process. This reinforces the importance of newborn screening as a mechanism for early diagnosis. Pharmacists are highly valued members of the healthcare team who play a pivotal role in the SMA care team. Therefore, pharmacists must be up-to-date on SMA’s medical management, including the most current efficacy and safety data to assist providers, caregivers, and patients in selecting these agents and ensuring patients with SMA receive optimal and timely medical care.

Am J Manag Care. 2021;27(suppl 1):S3-S12. https://doi.org/10.37765/ajmc.2021.88592


Spinal muscular atrophy (SMA) describes a diverse group of inherited neuromuscular disorders characterized by degradation of the lower motor neurons causing progressive muscle atrophy and weakness. Although SMA results in neuromuscular degeneration, it does not affect neurocognitive ability.1,2 The most common form of SMA (about 95% of cases) occurs due to a homozygous deletion (less frequently a point mutation) located on the 5q13 region of the survival motor neuron 1(SMN1) gene.1,3-8 The SMN1 gene is responsible for encoding SMN1 protein, ensuring alpha motor neuron fibers’ survival.3 The SMN2 gene is closely related to SMN1, but produces less protein than SMN1.9 The SMN2 gene still produces enough protein that the clinical severity of SMA is dictated by the number of SMN2 copies an affected individual with SMA has. The fewer the copies of SMN2, the more severe the SMA phenotype.10 Some forms of SMA are fatal without treatment, and patients diagnosed with the most severe form of disease will die of respiratory failure by 2 years of age unless they are provided continuous mechanical ventilation.9,11

SMA affects approximately 10,000 to 25,000 children and adults within the United States, making SMA the most common fatal genetic disease among infants.1,12 The estimated incidence of SMA is 1 in 6000 to 11,000 live births, and a 1 to 2 per 100,000 individual prevalence.1,2,13,14 Due to disease rarity and inconsistent newborn screening across the United States, these numbers have been difficult to ascertain. The first newborn studies conducted within the United States suggest a 1:40 SMA carrier frequency; however, reported frequencies vary based on ethnicity (1:48-1:97).

Over the past few years, significant changes have occurred with the licensing of disease-modifying therapies (DMTs) for the treatment of SMA. The medical management of patients with SMA has drastically evolved, along with the affected patient’s quality of life, survival outcomes, and parent and/or caregiver burden. Three agents are now commercially available within the United States, and pharmacists must have a thorough understanding of these therapies’ efficacy and safety data to help the SMA care team, patients, and caregivers obtain the best benefit from these therapies. Therefore, the purpose of this educational activity is to update pharmacists on the management of SMA, including classification, diagnosis, and screening. This activity will also review the most recent SMA standards of care, outcome measures, and safety and efficacy data for nusinersen, onasemnogene abeparvovec, and risdiplam.

Classification, Diagnosis, and Screening of SMA

SMA Classification

The clinical burden of SMA is highly variable. Historically, SMA was classified into 3 subtypes dependent on the affected individuals’ age of onset and highest achieved motor function (Werdnig Hoffmann disease [type 1], Dubowitz syndrome [type 2], and Kugelberg Welander disease [type 3]) outlined in Table 1.2 The classification system would then expand further (Table 12) to include congenital- or prenatal-onset (type 0, type 1 in later classifications) and adult-onset (type 4).15-18 However, the natural history of SMA has evolved significantly with additional clinical trials and the development of therapeutics resulting in previous classification systems becoming less practical.15 Treated SMA is now considered to lie on a continuum because patients frequently gain motor function versus progressive loss among those untreated. To address these changes, updates to the classification system categorize individuals with SMA as nonsitters, sitters, and walkers while focusing on current functional status and treatment response (Table 2).15,19-26

SMA Diagnosis and Screening

In the past, SMA was diagnosed once clinical signs appeared (such as proximal muscle weakness, motor delay, or regression).21 Now, if there is a high clinical suspicion of SMA, diagnosis occurs with genetic testing that may include multiplex ligation-depended probe amplification (MLPA), quantitative polymerase chain reaction (qPCR), or next-generation sequencing (NGS).21

An individual must be missing both functional SMN1 copies to be diagnosed with SMA.21 If one functional SMN1 copy is present, additional testing should occur to determine if other mutations are present. Furthermore, if an individual has 2 functional SMN1 copies but has a strikingly typical SMA phenotype, additional genetic testing should occur to assess for rarer forms of SMA (or neuromuscular disorders) other than 5q SMA.21

An SMA diagnosis is commonly delayed for most people and can range between 4 months after symptom onset (SMA type 1) to greater than 10 months, or sometimes years, among people with SMA type 3.27-29 Per and colleagues followed 5 Italian centers and examined the limitations that led to delays in diagnosis.30 What the investigators found was that the mean time between symptom onset and diagnosis in patients with type 1 was 1.94 months, in type 2 it was 5.28 months, and in type 3 it was 16.8 months. Much of the delay in diagnosis is attributed to the age at which patients would present with symptoms based on disease severity and reinforced the importance of newborn screening as a mechanism for early diagnosis. In patients with delayed diagnosis, initiation of DMTs may not be as effective because significant degeneration of the non-regenerable alpha motor neurons has already occurred.30

Therefore, a greater emphasis on prenatal carrier testing and newborn SMA genetic screening has resulted in the hopes of identifying infants with SMA earlier so DMTs can be initiated sooner. In the United States, the federal Recommended Uniform Screening Panel added SMA in 2018, with 33 states currently adopting and implementing the recommendation (a full list of all states may be found at www.curesma.org/newborn-screening-for-sma/).31

Biomarkers are also another tool being investigated to help identify patients with SMA sooner, predict disease severity, and optimize therapy. More than 200 candidates exist focusing on SMN2 copy number and/or non-SMN-related biomarkers. A review of biomarkers is beyond the scope of this document but was recently reviewed by Kariyawasam et al.32

SMA Standards of Care and Scoring Tools

SMA Standards of Care

The 2018 SMA Standards of Care emphasize the importance of a multidisciplinary approach for the management of patients with SMA.20,21 SMA is a highly complex disorder that requires multiple specialties (eg, neurology, orthopedics, respiratory, nutrition and gastrointestinal, pharmacy) work in concert along with a coordinator and the patient’s family to provide the best possible outcomes for the affected patient.21

Before the approval of pharmacologic therapies, supportive care was the only option for patients with SMA, especially respiratory care as these patients will eventually progress to requiring ventilation. Airway clearance that consists of manual chest physiotherapy plus mechanical insufflation-exsufflation should be the primary methods used in patients who are ambulatory.20,21 Airway clearance measures must be implemented proactively based on a physical assessment to manage respiratory illnesses aggressively. Clinical assessment should include cough effectiveness, nocturnal hypoventilation, and any potential for infection among ambulatory individuals.33 Nutritional support in patients diagnosed with SMA has also been a historically important component of care. Hurst Davis et al published survey results in which all patients with SMA type I were found to require nutritional support via feeding tube, elemental formulas, probiotics, and bowel regimens.34 Orthopedic professionals will often be involved in the management of these patients due to progressive spinal deformities. These specialists may provide braces as palliation for spinal curvature and often perform surgical interventions to correct deformities.21 As stated previously, care of patients with SMA should be multidisciplinary and include other healthcare providers as required to ensure patients receive a comprehensive treatment plan.33

As more research has been conducted and SMA pathology is better understood, it has become clear that early treatment is critical to preventing the rapid and progressive nerve degeneration seen in SMA.27 For example, evidence suggests that more than 90% of motor units are lost within the first 6 months of age among patients with SMA type 1. Thus, as SMA still has a diagnostic delay and newborn screenings are not available everywhere within the United States, the optimal window for therapeutic intervention may be missed in many patients because treatment options can only be evaluated once the diagnosis has been made.27

In 2018, Glascock et al released a treatment algorithm developed for infants identified as SMA-positive via newborn screening based on their SMN2 copy number.27 The working group developed this algorithm to identify which patients should be treated immediately following a positive newborn screen.27 SMA is a disease state with a wide range of severity and acuity. Some manifestations of the disease are imminently life threatening, whereas others, while rare, may be completely asymptomatic. The working group that designed the algorithm consisted of 15 SMA experts who used a modified Delphi process moderated by a neutral third-party expert. Glascock et al recommended that infants with 2 or 3 copies of SMN2 should receive immediate treatment. Infants with 1 copy were recommended to be treated if they were truly pre-symptomatic, and if they had symptoms, it was up to the physician’s discretion. Similarly, among patients with 4 or more copies of SMN2, the working group recommended to monitor and begin treatment at the onset of symptoms. Also, routine follow-up care should occur every 3 to 6 months until the patient is 2 years old, and every 6 to 12 months after treatment if not started immediately. The working group also recommended follow-up tests such as electromyography, compound muscle action potential monitoring, myometry, physical examinations, and motor function scales in patients once they achieve the appropriate age.27 Finally, parents and/or caregivers should be educated to notify their primary SMA healthcare provider if they observe a significant change in their child (eg, movement, feeding, breathing pattern, increased fatigue, voice/cry changes).35

In 2019, the SMA working group reconvened and determined sufficient new clinical data and real-world experience existed to justify reevaluating infants with 4 copies of SMN2 who were confirmed SMA-positive via newborn screening.36 Glascock et al updated their position, whereby, they now recommend immediate treatment for infants diagnosed with SMA from newborn screening with 4 copies of SMN2. In addition, the working group reaffirmed their recommendation for watchful waiting among infants with 5 SMN2 copies. All other recommendations remained the same as outlined in the previous 2018 treatment algorithm.27,36

SMA Outcome Measures

Historically, SMA muscle weakness was measured directly via assessments of strength, and those data were used to describe the level of impairment or disease severity experienced by affected patients.37 Today, outcome measures in SMA focus on the patient’s functional status and quality of life. Measurement tools that evaluate how well individuals with SMA function in their daily lives are considered more clinically relevant and meaningful. Furthermore, changes in strength can be evaluated more appropriately to assess how the change will impact a patient’s performance. Early tests such as the Test of Infant Motor Performance had good reliability but were poorly tolerated in patients with SMA type 1 due to the patient needing to be in the prone position, which taxed the respiratory reserve because of diaphragmatic breathing.38

With the promise of pharmacologic therapies on the horizon, SMA experts worldwide coalesced to develop and validate outcome measures that could be used for surrogate end points in clinical practice and clinical trials.37 Five of the most common outcome measures used in SMA research and clinical practice are outlined in more detail below.

Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)

CHOP INTEND is a validated 16-item scale developed to evaluate motor function in infants with SMA type 1.38,39 The tool was developed based on the natural history progression of motor function.37 The 16 items are graded on a scale of 0 (no response) to 4 (complete response) and are ordered to minimize position changes, the prone position, and purposely test least tolerated items last. The CHOP INTEND test takes approximately 15 to 40 minutes based on how cooperative the infant/child is. The maximum test score is 64.

Based on research using the CHOP INTEND scoring tool, children with SMA who are untreated have declining scores over time.37 Further, infants with SMA have significantly lower CHOP INTEND scores compared with age-matched typically developing infants over the same time.40,41 Infants with SMA type 1 who possess 2 copies of SMN2 have an average score of 20.2 and do not score above 36.37 Results of long-term data showed a mean change in the loss of −0.31 points/month (mild to severe phenotypes), −0.04 points/month (mild phenotypes), and −12.67 points over 2 years.41-43 The CHOP INTEND scoring tool was created to optimize the measurement of motor skills in the SMA patient population; however, further studies will be needed to continue to establish validity of this tool and quantify the sensitivity of this test to accurately measure change over time.39

Hammersmith Infant Neurological Examination-Section 2, Motor Milestones (HINE-2)

HINE-2 is a motor function assessment tool developed to evaluate infants’ motor skills and can be used to assess patients aged 2 to 24 months diagnosed with SMA. Section 2 of the HINE motor milestones is a brief (5-15 minute), standardized assessment tool that evaluates 8 motor skills (voluntary grasp, ability to kick, head control, sitting, crawling, standing, rolling, and walking) and their progression in healthy or high-risk infants. The milestone progression score shows increased levels of functional ability moving from left to right. The total score is the sum of points from each functional item and ranges from 0 to 26.

Despite HINE-2 not being designed for individuals with SMA specifically, it has been used in SMA clinical trials and was found to be both reliable and sensitive to change.37 HINE-2 was capable of detecting change over time in 16/19 infants with type 1 SMA (in all 8 motor skill domains).44 Improvements observed in HINE-2 were likewise correlated with changes in other neuromuscular outcome measures.44

Hammersmith Functional Motor Scale-Expanded (HFMSE)

The HFMSE scale is used to assess children’s (aged >24 months) ability to perform multiple activities in later-onset SMA types 2 and 3. The HFMSE scale contains 33 items, and increased functional ability moves from left to right. The maximum score is 66, with each item being scored from 0 to 2. It is recommended that the HFMSE is performed by a healthcare provider experienced in handling children and adults with SMA. The test takes approximately 10 to 30 minutes to complete. The HFMSE scale is highly correlated with the gross motor function measure and can help healthcare providers determine the SMA type and ambulatory and respiratory function.39

Revised Upper Limb Module (RULM)

The RULM scale assesses upper limb function among ambulatory and non-ambulatory children and adults with SMA.37 Both upper limbs should be measured and scored using the 19-item test. Items assessed are typically associated with activities of daily living such as pressing a button, placing hands on lap, and picking up a token.45,46 RULM has a maximum score of 37, with each item being scored from 0 to 2 (one item scored as can or cannot). The test requires 10 to 15 minutes to complete.37

6-Minute Walk Test (6MWT)

The 6MWT is an objective measure of functional exercise capacity among ambulatory individuals with later-onset SMA.37 The 6MWT measures how far an individual can walk in 6 minutes on a linear 25-meter marked course. The test takes approximately 10 minutes to complete and has demonstrated excellent reliability and convergent validity in patients with SMA.37

Bayley Scales of Infant Development (BSID-III)

The Bayley Scales of Infant Development (BSID) are now on their third iteration.47 The original BSID was developed out of the National Collaborative Perinatal Project and served as an important standard for the assessment of infant and toddler development between age 2 and 30 months. Now in its third edition, this scale assesses the development of infants and toddlers aged between 1 and 42 months. This assessment is completed both by observation and a caregiver questionnaire. Sections of this assessment include evaluation of behavior, language, and fine motor and gross motor development.47 Within the motor scale, patients will complete tasks such as grasping, stacking blocks, sitting, and climbing stairs. Items on this scale are scored as able or unable. Currently, there are no data to support use of the BSID-III specifically in the SMA population.37

Motor Function Measure-32 (MFM-32)

MFM-32 is an assessment comprising 32 tasks across 3 dimensions to assess a patient’s motor abilities.48 Dimension 1 assesses standing and transfers. Dimension 2 assesses axial and proximal motor function. Dimension 3 assesses distal motor function. Patients are scored based on a 4-point scale in which 0 means they cannot initiate the task or maintain a starting position and 3 indicates that the patient can complete the task fully and completely. Upon completion of the scoring tool, the lower a patient score, the more severe the motor impairment.48

SMA Treatment


Nusinersen is an antisense oligonucleotide that causes pre-messenger RNA (mRNA) splicing of the SMN2 gene to increase exon 7 inclusion in SMN2 mRNA transcripts, increasing production of full-length SMN protein.3,49 Nusinersen was approved by the FDA in 2016, making it the first disease-specific therapy for SMA.49 Nusinersen is indicated for the treatment of SMA in pediatric and adult patients based on results from 2 pivotal phase 3 randomized, double-blind, sham-controlled trials (ENDEAR and CHERISH).50,51 Both phase 3 trials were terminated early due to statistically and clinically significant differences demonstrated during an interim analysis of the nusinersen and control groups.50,51

Nusinersen is administered to patients intrathecally.49 Each dose of nusinersen is 12 mg (5 mL). When patients are initiated on therapy, they must complete a series of loading doses before moving on to maintenance therapy. The first 3 loading doses of nusinersen are administered every 14 days. The fourth and final loading dose of nusinersen is administered 30 days after the third dose. After completing the loading dose regimen, patients are started on maintenance therapy that includes 1 intrathecal injection every 4 months. Nusinersen is approved in pediatric and adult patients with SMA.49

ENDEAR (NCT02193074) evaluated the safety and efficacy of intrathecal nusinersen in 121 infants with infantile-onset SMA who were aged 6 months or younger.50 The primary efficacy end points included motor-milestone response, defined according to HINE, and event-free survival. An interim analysis showed that patients treated with nusinersen had higher HINE motor milestone improvement (41%) compared with the control group (0%) (P <.001). The nusinersen group had a prolonged time to death (hard ratio for death, 0.37; P = .004) or need for permanent ventilation compared with controls. Also, 8.2% (6/73) of nusinersen-treated patients could sit independently , and those with shorter disease duration had an improved response to treatment.50 Due to the overwhelming evidence of efficacy, ENDEAR was terminated early, and all patients were enrolled in the open-label extension study SHINE (NCT02594124) to further evaluate the long-term safety and tolerability of nusinersen in patients with SMA who previously participated in ENDEAR and CHERISH.20,52 Results of the final analysis of ENDEAR showed 51% of nusinersen-treated infants had a motor-milestone response compared with 0% in the control group. The nusinersen-treated infants also had a 47% lower risk of death or use of permanent assisted ventilation (hazard ratio, 0.53; 95% CI, 0.32.-0.89; P = .005).50

CHERISH (NCT02292537) included 126 children with later-onset SMA defined as symptom onset after 6 months of age (age range, 2-9 years).51 The primary end point was the least-squares mean change from baseline in the HFMSE score at 15 months of treatment.51 Interim analysis showed that the nusinersen group had a mean 4-point increase versus a 1.9 mean decrease in the controls (P <.001) in the HFMSE score. A least-squares mean increase of 4.2 points in the nusinersen (−0.5 points in the control group) from baseline to 15 months using RULM score (P <.001) was also seen. The final analysis showed that 57% of patients treated with nusinersen compared with 26% in the sham group had a 3-point rise in HFMSE scores after 15 months of treatment. Like ENDEAR, the CHERISH trial was also terminated early based on these positive results, and all patients were enrolled in the SHINE trial. Moreover, this trial also demonstrated the capacity of nusinersen to effect positive meaningful changes on the clinical course of SMA among children with later-onset SMA.51

The SHINE open-label extension trial began in November 2015 and has an estimated completion date of August 2023. All patients enrolled in SHINE were moved to 12-mg intrathecal injections every 4 months. Data up to the October 2018 cutoff date showed 89 children moved from ENDEAR to SHINE from the nusinersen group and 24 from the control group.53 Among the children who originally received nusinersen in ENDEAR, 36% could sit without support, 8% could stand with assistance, and 5% were able to walk with assistance compared with 0% who received placebo in ENDEAR. The abstract did not include data from the 2019 cutoff; however, it is noted by the manufacturer that individuals who began nusinersen earlier in the disease process had the greatest benefit compared with those who started later and only had evidence of motor function stabilization or improvement.53 Similarly, CHERISH had 83 nusinersen and 42 placebo patients that transitioned to SHINE.54 Again, patients who were started earlier on nusinersen had better motor function evaluated using the HFMSE and RULM scores compared with the control group in CHERISH.54 Results from 5 young adults with SMA types 2 and 3 who began nusinersen treatment between the ages of 13 and 15 in the CS2 trial and open-label CS12 who moved to SHINE were also reported.55 Data using a 2018 cutoff found 3 patients who were able to ambulate were still able to throughout SHINE, and 1 non-ambulatory patient was able to stand with assistance, and the final patient was able to sit without support during SHINE.55

Nusinersen is also being evaluated in NURTURE (NCT02386553), an open-label interventional study assessing the efficacy, safety, tolerability, and pharmacokinetics of multiple doses of intrathecal nusinersen in genetically diagnosed pre-symptomatic infants aged 6 weeks or younger (at first dose) with SMA.56 The primary end point is time to death or respiratory intervention. Interim results from 25 infants found that four met the primary end point (ie, required respiratory support during a time of illness). All infants could sit without support, 22 were able to walk unassisted, and 17 could walk independently. These data emphasized the importance of newborn screening and early treatment as soon as a genetic diagnosis is made in pre-symptomatic infants.56 In June 2020, new NURTURE data (as of February 2020) reported that all 25 patients (median age, 3.8 years) treated with nusinersen were alive and did not require permanent ventilation.57 A notable finding as most children with SMA type 1 who are untreated rarely live to age 2 years. All children who achieved walking independently have maintained that ability from the first occurrence through their last visit. The study has been extended an additional 3 years to evaluate the participants through age 8 years and collect longer-term efficacy and safety data.54 The new estimated study completion date is set for February 2025.58

In March 2020, research of nusinersen was continued with a phase 2/3 controlled dose-escalating trial, DEVOTE (NCT04089566).59 The purpose of the DEVOTE study is to evaluate whether a higher dose of nusinersen will increase treatment efficacy (using CHOP INTEND) across a broad group of patients with SMA (including adults). The trial will be completed in 3 parts and include an open-label safety evaluation and a pivotal, double-blind, active-control randomized treatment period followed by an open-label treatment period. After the safety evaluation, 2 loading doses of 50 mg administered 14 days apart, followed by a maintenance dose of 28 mg every 4 months, will be evaluated.60 The third part of the trial will determine how to safely and efficiently transition patients from the current FDA-approved dosing to the higher nusinersen dose evaluated in the study. The study has an estimated study completion date of July 4, 2023.59

In July 2020, plans for a phase 4 trial, RESPOND, were announced to evaluate the benefit of nusinersen in infants and children treated with onasemnogene abeparvovec with unmet clinical needs after treatment.61 RESPOND will be a 2-year, open-label study that will evaluate change from baseline on motor function measures, other clinical outcomes, and caregiver burden. This trial will also use an exploratory biomarker end point (neurofilament levels) for biological disease activity. The trial estimates to enroll 40 infants aged 9 months or younger with 2 copies of SMN2 who received onasemnogene abeparvovec at 6 months of age or younger. The second study group will include 20 children and evaluate nusinersen in children up to 3 years old at the first time of nusinersen dose. The RESPOND trial sponsors expect to begin enrolling in the first quarter of 2021.61

Onasemnogene abeparvovec

Onasemnogene abeparvovec is an adeno-associated virus type 9 (AAV9) vector-based SMN1 gene therapy that replaces the SMN1 gene encoding human SMN protein.62 Onasemnogene was FDA approved in May 2019 for the treatment of SMA in pediatric patients younger than 2 years with bi-allelic mutations in the SMN1 gene.62 Approval for this agent was granted based on a completed phase 1 and an ongoing phase 3 clinical trial in infantile-onset SMA. The FDA-approved dosing for onasemnogene is 1.1 x 1014 vector genomes per kilogram of patient’s body weight. Onasemnogene is administered as an intravenous infusion over 60 minutes.62

The START phase 1 trial (NCT02122952) included 15 infants with SMA type 1 who had 2 copies of SMN2 in a single-arm, open-label, ascending-dose study.63 The purpose of the study was to evaluate the preliminary efficacy and safety of onasemnogene.64 Safety was the study’s primary outcome (defined as any treatment-related adverse effects, grade 3 or higher), and time until death or the need for permanent ventilation was the secondary outcome. An amendment to the study protocol was made after an elevated serum aminotransferase occurred in the first patient (cohort 1) to administer concomitant oral prednisolone. At 2 years post-infusion, 1 participant in the low-dose cohort met the end point of permanent ventilation, but the ventilation requirement was reduced by 25%, and all patients in the high-dose cohort were free from permanent ventilation. Also, 9 of 12 participants (75%) in the high-dose cohort could sit independently for more than 30 seconds; 2 participants (16.7%) could stand and walk independently. CHOP INTEND scores increased by 9.8 points after 1 month and 15.4 after 3 months in the high-dose group compared with a decrease in untreated SMA type 1.64 Furthermore, all 15 patients achieved 20 months of age and did not require permanent ventilation compared with 8% of participants in the historical cohort who were free from permanent ventilation at the time of data collection. There were 56 serious adverse effects (AEs) reported in 13 participants across both cohorts. Two AEs were treatment-related grade 4 elevated serum aminotransferase levels. Another 241 non-serious AEs occurred, with just three being treatment related. Fourteen participants also experienced respiratory illness in the treatment group. Overall results showed that a single onasemnogene intravenous infusion positively affected survival and motor function among infantile-onset SMA.64 A subsequent follow-up study is underway assessing long-term safety among 13/15 of the participants who received onasemnogene and will be followed for up to 15 years.65

Another study comparing untreated patients with SMA type 1 in the NeuroNEXT (NCT10736553) trial had a 100% survival rate among infants treated with onasemnogene compared with 38% in the NN101 cohort.41,66 The baseline mean CHOP INTEND score was 28.2 and improved to 56.5 in the onasemnogene group compared with 20.3 with a decrease to 5.3 in the NN101 group after 24 months. Furthermore, 92% of the onasemnogene patients could sit independently for 5 seconds or more, 83% for 10 seconds or more, 75% for 30 seconds or more, and 17% (2 people) could stand and walk unassisted. In contrast, CHOP INTEND scores in the NN101 cohort did not suggest any motor milestones being achieved.66

Results from the STR1VE-US trial (NCT03306277) evaluating the safety and efficacy of onasemnogene used in symptomatic patients with SMA type 1 (aged <6 months with 2 SMN2 copies) were recently reported.67-69 This phase 3, open-label, single-arm, single-dose, gene replacement trial administered onasemnogene via intravenous infusion and 91% of patients met the co-primary efficacy end point of event-free survival at 14 months and 59% met functional sitting for 30 seconds or longer at 18 months of age (P <.0001 vs. natural history).69 Also, 68.2% of patients remained free of noninvasive ventilation during the study, and 81.8% were free of ventilation at 18 months of age. Twenty-one patients achieved CHOP INTEND scores greater than or equal to 30, and fourteen achieved a score greater than or equal to 50.67 This study also was the first to introduce the “ability to thrive” composite measure defined as the proportion of infants able to maintain a healthy body weight without nutritional support. Of the 22 participants, 40.9% (P <.0001 vs natural history) demonstrated the ability to thrive at 18 months of age, with 19 participants not requiring a feeding tube, 14 maintaining a good weight, and 12 able to tolerate thin liquids.69 There was 1 AE reported in all 22 participants (12 that were deemed treatment related). The most commonly reported AEs were pyrexia, upper respiratory tract infections, constipation, and scoliosis, considered manageable and consistent with the drug safety profile.67-69

Another phase 3 trial, SPR1NT (NCT03505099), is an open-label, single-arm trial evaluating the safety and efficacy of onasemnogene pre-symptomatically in infants with SMA younger than 6 weeks old with 2 or 3 copies of SMN2 (similar to the NURTURE trial).70 Interim data analysis with a December 31, 2019 cutoff was conducted to determine preliminary results. Results of these data showed that 57% (8/14) of participants with 2 copies of the SMN2 gene could sit independently for at least 30 seconds, and 28.5% (4/14) could walk independently.69 All participants with 2 SMN2 copies achieved or maintained CHOP INTEND scores greater than or equal to 50 (with 13 ≥58). Among SMA type 1 natural history patients, individuals rarely score 40 or above on CHOP INTEND. Also, 26.5% (4/15) of participants with 3 copies of the SMN2 gene could stand independently for at least 3 seconds, and 20% (3/15) could walk independently. AEs were reported after administration in all participants with 17 deemed treatment related.69 The most common AEs were pyrexia, upper respiratory tract infection, constipation, and nasopharyngitis. Six patients had serious AEs, but they were not deemed to be treatment related.69 For this 2019 analysis, many of the patients who had not yet achieved certain motor milestones were still within the appropriate age range for continued development.62 As the data continue to be collected, the results from the study may become more robust.62

START Long-Term Follow-Up (START LTFU) is an ongoing observational, long-term follow-up study from the patients who completed the phase 1 START trial and received onasemnogene.69 As of December 31, 2019, ten of the 12 participants from the second cohort of START who enrolled in the LTFU study were alive and did not require permanent ventilation. Also, there were no previously achieved motor milestones lost during the follow-up period. Two patients achieved a new milestone of standing with assistance (and did not receive treatment with nusinersen during the follow-up period). None of the patients who were free from ventilation at the end of START have had to initiate new ventilation support during the follow-up period. Also, 60% (6/10) of participants also do not require daily respiratory support after more than 4 years from receiving their onasemnogene dose. No new treatment-related severe adverse events or AEs of note occurred during the long-term follow-up study.69

Onasemnogene has also been studied for intrathecal administration.71,72 The phase 1/phase 2 trial STRONG investigated the safety of 2 different doses of onasemnogene when given via the intrathecal route. A total of 32 patients were enrolled in the study. Two groups were created, those older and younger than 2 years. Participants’ ages ranged from 6 months to 5 years. The STRONG trial has been on hold since October 2019. In preclinical data, there was inflammation found in primates secondary to the intrathecal administration of onasemnogene. Although this has not been seen in any of the human participants, the FDA is conducting a full investigation of the preclinical findings.71,72

Overall cumulative safety data from all trials and postmarketing surveillance suggest that patients experience AEs from onasemnogene, but they are generally manageable and not serious.69 One potentially serious AE is liver injury.73 Liver transaminase elevations need to be monitored via liver function tests and should be managed with prophylactic prednisolone started 1 day before treatment and continued for at least 30 days.73 Liver injury and hepatotoxicity can be serious without appropriate monitoring and intervention.74 Feldman and colleagues reported 2 cases of transient drug-induced liver failure with use of onasemnogene. Teams considering use of onasemnogene in their practice may want to consider inclusion of a hepatologist in the patient care team. Thrombocytopenia has also occurred but usually is transient and resolves without intervention and monitored via platelet counts. Postmarketing surveillance has also noted reports of heart rate changes and laboratory anomalies that are not explained clinically. Therefore, troponin I should also be monitored in patients receiving onasemnogene. No dorsal root ganglia inflammation has been observed clinically at this time. No new deaths have been reported in either the STR1VE-US or STR1VE-EU trials; the 2 reported deaths were determined to be unrelated to drug therapy based on autopsy findings.69


Risdiplam is the first oral, small-molecule, SMN2 splicing modifier that increases functional SMN protein.75 Risdiplam is approved in patients aged 2 months and older and is available as an oral liquid that can be administered by mouth or via feeding tube.76 Dosing is both weight and age based for risdiplam. Patients between 2 months and 2 years of age will receive 0.2 mg/kg of their body weight of risdiplam regardless of weight. For patients 2 years and older, dosing is 0.25 mg/kg body weight with a maximum dose of 5 mg recommended in all patients 20 kg and greater.76 Risdiplam is dispensed in amber, glass bottles for protection from light and pharmacists will need to dispense the appropriate amber syringes for the patient’s dose. Risdiplam is manufactured as a 0.75-mg/mL oral solution. It was FDA approved in August 2020 to treat SMA in patients aged 2 months and older.77 Approval of this agent was based on 2 pivotal trials: FIREFISH and SUNFISH.

FIREFISH (NCT02913482) was an open-label, 2-part phase 2/3 trial in infants with SMA type 1 aged 1 to 7 months.78 Part 1 (N = 21) included a dose-finding study and a safety evaluation. Part 2 (N = 41) evaluated the efficacy of risdiplam. The primary efficacy objective was measured using the proportion of infants sitting without support for 12 months of treatment and longer using the Gross Motor Scale of the BSID-III.78 Part 1 results showed that key motor milestones were met after 1 year of treatment with risdiplam.79 Of the 17 participants who received the part 2 study dose, 41.2% (7/21) were able to sit independently for a minimum of 5 seconds. Also, 64.7% (11/17) could sit with or without support, and 52.9% (9/17) achieved upright head control after 12 months of treatment measured via the HINE-2. One infant was also able to stand by 12 months. Part 1 also used CHOP INTEND to assess motor function. Of the 17 participants, 58.8% in the risdiplam group achieved a CHOP INTEND score of 40 or more points. The CHOP INTEND median change from baseline to month 12 was 17.5 points. Among all 21 participants, none of the infants lost the ability to swallow, required tracheostomy, or permanent ventilation. The most common AEs were pyrexia, upper respiratory tract infections, diarrhea, vomiting, cough, pneumonia, and constipation.79 Preliminary final results of part 2 were recently presented and showed event-free survival time was vastly improved among those treated with risdiplam compared with natural history SMA.80 The majority of infants also retained their ability to swallow and feed. Almost half of the risdiplam-treated patients did not require hospitalization up to 12 months.80

SUNFISH (NCT02908685) is a second phase 2/3, randomized, double-blind, placebo-controlled extension study evaluating the safety, tolerability, and effectiveness of risdiplam in SMA types 2 and 3 in individuals aged 2 to 25 years who are not ambulatory.81 Part 1 (N = 51) examined the safety, pharmacodynamics, pharmacokinetics, and optimal dose of risdiplam. Part 1 showed treatment with risdiplam resulted in a median 2-fold increase in blood SMN protein levels after 4 weeks, which were sustained for a minimum of 24 months.82 Motor function measure (MFM) total change from baseline at month 24 was also larger in patients treated with risdiplam (3.99-point difference, 95% CI, 2.34-5.65; P <.0001). Part 2 of the SUNFISH trial results were recently presented. A change in baseline of the MFM-32 scale was significantly greater in risdiplam-treated patients compared with placebo (−1.55-point mean difference; P = .0156). The greatest response in MFM-32 was observed in the 2- to 5-year age group versus placebo and disease stabilization in the 18- to 25-year age group. The safety profile was consistent with other risdiplam trials, and the most common AEs were upper respiratory tract infections, nasopharyngitis, pyrexia, headache, diarrhea, vomiting, and cough.81

JEWELFISH (NCT03032172) is a phase 2, open-label exploratory trial in patients with SMA types 1 to 3 between the ages of 6 months and 60 years who have also received previous treatment for SMA with nusinersen, onasemnogene, or olesoxime.82,83 The study enrolled 174 participants with 76 previously treated with nusinersen and 14 with onasemnogene. The other 83 participants had been treated with other compounds under development by the manufacturer. The most common AEs observed were upper respiratory tract infections, headache, fever, diarrhea, nasopharyngitis, and nausea. No drug-related safety findings have led to withdrawal from JEWELFISH to date, and AE profiles are consistent with those found in risdiplam trials with SMA-targeting therapy-naïve patients.82 This study is ongoing and has an estimated study completion date of January 31, 2025.

RAINBOWFISH (NCT03779334) is an open-label, single-arm, multicenter study that is ongoing and evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of risdiplam in infants from birth to 6 weeks old genetically diagnosed with SMA and pre-symptomatic.84 RAINBOWFISH is currently recruiting and is expected to enroll 25 participants. Each participant will be given oral risdiplam once daily for 2 years and then enrolled in an open-label extension and follow-up. The estimated completion date is July 22, 2026.84


In summary, SMA is an inherited neuromuscular disorder that results in a wide variety of clinical burdens. Disease severity correlates, although imperfectly, with SMN2 copy number. Before 2016, there were no disease-modifying therapies, and patients and caregivers relied on supportive care. The natural history of SMA has evolved over the years as additional research and technologies have improved our understanding of the pathologic mechanisms responsible for SMA. Increased understanding has also resulted in the development of novel disease-modifying therapies that have led to patients achieving motor milestones and survival outcomes never before possible. There are now 3 disease-modifying therapies FDA approved and commercially available for use in patients with SMA. Therefore, it is crucial that pharmacists, as integral members of the SMA care team, have a thorough understanding of efficacy and safety data for these agents to improve clinical decision making and outcomes among affected patients with SMA.

Author affiliation: Dr Bisaccia is a clinical pharmacy specialist at Rush University Medical Center in Chicago, IL.

Funding source: This activity is supported by an educational grant from Biogen.

Author disclosure: Dr Bisaccia has no relevant financial relationships with commercial interests to disclose.

Author information: Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; final approval of manuscript.

Address correspondence to: elizabeth_k_bisaccia@rush.edu

Medical writing and editorial support provided by: Brittany Hoffmann-Eubanks, PharmD, MBA.


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