Nusinersen (Spinraza)

Number: 0915

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses nusinersen (Spinraza) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of nusinersen (Spinraza) is required of all Aetna participating providers and members in applicable plan designs.  For precertification of nusinersen, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes^® Gene Based, Cellular and Other Innovative Therapy (GCIT^®) Network. For nusinersen (Spinraza), see Aetna Institutes® GCIT Designated Centers. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a physician who specializes in treatment of spinal muscular atrophy.

2. Criteria for Initial Approval

   Aetna considers nusinersen (Spinraza) medically necessary for treatment of spinal muscular atrophy (SMA) when all of the following criteria are met:

   1. Member has type 1, type 2 or type 3 SMA; and
   2. There is genetic documentation of 5q SMA homozygous gene mutation, homozygous gene deletion, or compound heterozygote; and
   3. Member is not dependent on either of the following:
      
      
      1. Invasive ventilation or tracheostomy; or
      2. Use of non-invasive ventilation beyond naps and nighttime sleep; and

   4. Submission of medical records (e.g., chart notes, laboratory values) of the baseline assessment for at least one of the following assessment tools (based on member age and motor ability) to establish baseline motor ability prior to therapy initiation:

      1. Hammersmith Infant Neurological Exam Part 2 (HINE-2); or
      2. Hammersmith Functional Motor Scale Expanded (HFMSE); or 
      3. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND); and
         

   5. Member meets one of the following criteria:

      1. Member has not previously received gene replacement therapy for SMA (e.g., Zolgensma); or
      2. Member has previously received gene replacement therapy for SMA (e.g., Zolgensma) and has experienced a worsening in clinical status since receiving gene replacement therapy as demonstrated by a decline of minimally clinical important difference from highest score achieved on one of the following exams (based on member age and motor ability):
         
         
         1. HINE-2: Decline of at least 2 points on kicking and 1 point on any other milestone (excluding voluntary grasp); or
         2. HFMSE: Decline of at least 3 points; or
         3. CHOP-INTEND: Decline of at least 4 points; and
            
   6. Member will not use Spinraza and risdiplam for oral solution (Evrysdi) concomitantly (see Pharmacy CPB for Evrysdi criteria); and
   7. If the member has not received a loading dose, the loading dose will be dosed at 12 mg (5mL) on Day 0, 14, 28, and 58.

3. Continuation of Therapy

   Note: Members who were previously established on nusinersen (Spinraza) and subsequently administered gene therapy replacement (e.g., Zolgensma) must meet all initial nusinersen criteria prior to re-starting therapy on nusinersen.

   Aetna considers continuation of nusinersen (Spinraza) therapy medically necessary for the treatment of SMA when all of the following criteria are met:

   1. Member has type 1, type 2 or type 3 SMA; and
   2. Member is not dependent on either of the following:
      
      
      1. Invasive ventilation or tracheostomy; or
      2. Use of non-invasive ventilation beyond naps and nighttime sleep; and
         

   3. Submission medical records (e.g., chart notes, laboratory values) of the most recent (less than 1 month prior to continuation request) assessment documenting a positive clinical response from pretreatment baseline to Spinraza therapy as demonstrated by at least one of the following assessments:

      1. Hammersmith Infant Neurological Exam Part 2 (HINE-2):

         1. One of the following:

            1. Member exhibited improvement or maintenance of previous improvement of at least a 2 point (or maximal score) increase in ability to kick; or
            2. Member exhibited improvement or maintenance of previous improvement of at least a 1 point (or maximal score) increase in any other HINE-2 milestone (e.g., head control, rolling, sitting, crawling, standing, or walking) excluding voluntary grasp; and

         2. One of the following:

            1. Member exhibited improvement or maintenance of previous improvement in more HINE-2 motor milestones than worsening (net positive improvement); or
            2. Member achieved and maintained any new motor milestones when they would otherwise be unexpected to do so (e.g., sit or stand unassisted, walk); or

      2. Hammersmith Functional Motor Scale Expanded (HFMSE):

         One of the following:

         1. Member exhibited improvement or maintenance of previous improvement of at least a 3- point increase in score; or
         2. Member has achieved and maintained any new motor milestone from pretreatment baseline when they would otherwise be unexpected to do so; or

      3. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorder (CHOP-INTEND): 

         One of the following:

         1. Member exhibited improvement or maintenance of previous improvement of at least a 4- point increase in score; or
         2. Member has achieved and maintained any new motor milestone from pretreatment baseline when they would otherwise be unexpected to do so; or
            

      4. Member was prescribed nusinersen (Spinraza) due to clinical worsening after receiving gene replacement therapy (e.g., Zolgensma) and there is documentation of stabilization or improvement in clinical status with Spinraza therapy (e.g., impact on motor milestones); and

   4. Member will not use Spinraza and risdiplam for oral solution (Evrysdi) concomitantly (see Pharmacy CPB for Evrysdi criteria); and
   5. If member has already received a loading dose, the maintenance dose will not exceed 12 mg (5 mL) every 4 months.

4. Other

   Aetna considers intrathecal administration with ultrasound or other imaging guidance medically necessary for nusinersen.

   Aetna considers the following procedures medically necessary for administration of nusinersen in members with scoliosis or spinal fusion with instrumentation that interferes with lumbar access:

   1. Cervical puncture with ultrasound guidance
   2. Subcutaneous intrathecal catheter system for repeated dosing of nusinersen
   3. Transforaminal lumbar puncture with cone-beam computed tomography.

   Aetna considers nusinersen experimental, investigational, or unproven for all other indications. See Experimental, Investigational, or Unproven section for additional information. 

Dosage and Administration

Nusinersen is available as Spinraza for injection as 12 mg/5 mL (2.4 mg/mL) in a single-dose vial. Spinraza is administered intrathecally by, or under the direction of, healthcare professionals experienced in performing lumbar punctures.

The recommended dosage is 12 mg (5 mL) per administration. Initiate Spinraza treatment with 4 loading doses. The first three loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter.

Source: Biogen, 2023

Experimental, Investigational, or Unproven

1. Aetna considers the use of biomarkers (including cerebrospinal fluid (CSF) levels of Αβ42, glial fibrillary acidic protein concentration, neurofilament light chain (NfL), S100B, total tau concentration; and ulnar compound motor action potential amplitude and single motor unit potential amplitude changes) is considered experimental, investigational, or unproven for monitoring therapeutic effectiveness in SMA in persons with 5q spinal muscular atrophy.

2. Aetna considers the following biomarkers for monitoring disease progression and response to nusinersen therapy as experimental, investigational, or unproven (not an all-inclusive list):

   1. Cerebrospinal fluid (CSF) neurofilament light chain (NfL)
   2. Circulating muscle-specific miRNAs (myomiRs)
   3. Serum NfL.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes not covered for indications listed in the CPB:
Cerebrospinal fluid (CSF) neurofilament light chain (NfL), circulating muscle-specific miRNAs (myomiRs), serum (NfL), cerebrospinal fluid (CSF) levels of Αβ42, glial fibrillary acidic protein concentration, total tau concentration, ulnar compound motor action potential amplitude and single motor unit potential amplitude changes - no specific code
0361U	Neurofilament light chain, digital immunoassay, plasma, quantitative
86316	Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each [S100B]
Other CPT codes related to the CPB:
00635	Anesthesia for procedures in lumbar region; diagnostic or therapeutic lumbar puncture
62270	Spinal puncture, lumbar, diagnostic
62272	Spinal puncture, therapeutic, for drainage of cerebrospinal fluid (by needle or catheter)
62320	Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, cervical or thoracic; without imaging guidance
62321	Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, cervical or thoracic; with imaging guidance (ie, fluoroscopy or CT)
62322	Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, lumbar or sacral (caudal); without imaging guidance
62323	Injection(s), of diagnostic or therapeutic substance(s) (eg, anesthetic, antispasmodic, opioid, steroid, other solution), not including neurolytic substances, including needle or catheter placement, interlaminar epidural or subarachnoid, lumbar or sacral (caudal); with imaging guidance (ie, fluoroscopy or CT)
62328	Spinal puncture, lumbar, diagnostic; with fluoroscopic or CT guidance
62329	Spinal puncture, therapeutic, for drainage of cerebrospinal fluid (by needle or catheter); with fluoroscopic or CT guidance
62360	Implantation or replacement of device for intrathecal or epidural drug infusion; subcutaneous reservoir
72131	Computed tomography, lumbar spine; without contrast material
76942	Ultrasonic guidance for needle placement (eg, biopsy, aspiration, injection, localization device), imaging supervision and interpretation
77003	Fluoroscopic guidance and localization of needle or catheter tip for spine or paraspinous diagnostic or therapeutic injection procedures (epidural or subarachnoid) (List separately in addition to code for primary procedure)
77012	Computed tomography guidance for needle placement (eg, biopsy, aspiration, injection, localization device), radiological supervision and interpretation
95990	Refilling and maintenance of implantable pump or reservoir for drug delivery, spinal (intrathecal, epidural) or brain (intraventricular), includes electronic analysis of pump, when performed;
95991	requiring skill of a physician or other qualified health care professional
96365 - 96368	Intravenous infusion administration
96450	Chemotherapy administration, into CNS (eg, intrathecal), requiring and including spinal puncture
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
99100	Anesthesia for patient of extreme age, younger than 1 year and older than 70 (List separately in addition to code for primary anesthesia procedure)
99217	Observation care discharge day management (This code is to be utilized to report all services provided to a patient on discharge from outpatient hospital "observation status" if the discharge is on other than the initial date of "observation status." To report services to a patient designated as "observation status" or "inpatient status" and discharged on the same date, use the codes for Observation or Inpatient Care Services [including Admission and Discharge Services, 99234-99236 as appropriate.])
99218 - 99220	Initial observation care
99234 - 99236	Observation or Inpatient Care Services (Including Admission and Discharge Services)
96379	Unlisted therapeutic, prophylactic, or diagnostic intravenous or intra-arterial injection or infusion
HCPCS codes covered if selection criteria are met:
J2326	Injection, nusinersen, 0.1 mg
Other HCPCS codes related to the CPB:
Risdiplam – no specific code
A4221	Supplies for maintenance of drug infusion catheter, per week (list drug separately)
A4301	Implantable access total catheter, port/reservoir (e.g., venous, arterial, epidural, subarachnoid, peritoneal, etc.)
ICD-10 codes covered if selection criteria are met (not all-inclusive):
G12.0	Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]
G12.1	Other inherited spinal muscular atrophy
G12.8	Other spinal muscular atrophies and related syndromes
G12.9	Spinal muscular atrophy, unspecified
ICD-10 codes not covered for indications listed in the CPB:
Z93.0	Tracheostomy status
Z94.84	Stem cells transplant status [gene therapy]
Z99.11	Dependence on respirator [ventilator] status

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Spinraza is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.

Nusinersen is available as Spinraza (Biogen, Inc.). Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Nusinersen alters the splicing of SMN2 pre-mRNA in order to increase production of full-length SMN protein. 

Spinraza carries warnings and precautions for risk of thrombocytopenia and coagulation abnormalities, and renal toxicity. The most common adverse reactions that occurred in a least 20% of Spinraza-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection and constipation in patients with infantile-onset SMA, and pyrexia, headache, vomiting, and back pain in patients with later-onset (Biogen, 2023).

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is characterized by loss of motor neurons in the spinal cord and lower brain stem, resulting in severe and progressive muscular atrophy and weakness (Biogen, 2016). Ultimately, individuals with the most severe type of SMA can become paralyzed and have difficulty performing the basic functions of life, like breathing and swallowing. 

Due to a loss of, or defect in, the SMN1 gene, people with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor neurons (Biogen, 2016). The severity of SMA correlates with the amount of SMN protein. People with Type 1 SMA, the most severe life-threatening form, produce very little SMN protein and do not achieve the ability to sit without support or live beyond two years without respiratory support. People with Type 2 and Type 3 SMA produce greater amounts of SMN protein and have less severe, but still life-altering forms of SMA. 

The U.S. Food and Drug Administration (FDA) approved nusinersen (Spinraza) for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients (Biogen, 2016). 

Infantile-Onset SMA

The FDA approval of nusinersen was based on positive results from multiple clinical studies involving approximately 170 patients (Biogen, 2016). The data package included the interim analysis of ENDEAR, a Phase 3 controlled study evaluating nusinersen in infantile-onset, as well as open-label data in presymptomatic and symptomatic patients with, or likely to develop, Types 1, 2 and 3 SMA. 

The efficacy of nusinersen was demonstrated in a multicenter, randomized, double-blind, sham-procedure controlled (ENDEAR) study in 121 symptomatic infants ≤ 7 months of age at the time of first dose, diagnosed with SMA (symptom onset before 6 months of age) (Biogen, 2016). Patients were randomized 2:1 to receive either 12 mg nusinersen or sham injection as a series of loading doses administered intrathecally followed by maintenance doses administered every 4 months. A planned interim efficacy analysis was conducted based on patients who died, withdrew, or completed at least 183 days of treatment. Of the 82 patients included in the interim analysis, 44% were male and 56% were female. Age at first treatment ranged from 30 to 262 days (median 181). Eighty-seven (87%) of subjects were Caucasian, 2% were Black, and 4% were Asian. Length of treatment ranged from 6 to 442 days (median 261 days). Baseline demographics were balanced between the nusinersen and control groups with the exception of age at first treatment (median age 175 vs. 206 days, respectively). The nusinersen and control groups were balanced with respect to gestational age, birth weight, disease duration, and SMN2 copy number (2 copies in 98% of subjects in both groups). Median disease duration was 14 weeks. There was some imbalance in age at symptom onset with 88% of subjects in the nusinersen group and 77% in the control group experiencing symptoms within the first 12 weeks of life. 

The primary endpoint assessed at the time of interim analysis was the proportion of responders: patients with an improvement in motor milestones according to Section 2 of the Hammersmith Infant Neurologic Exam (HINE) (Biogen, 2016). This endpoint evaluates seven different areas of motor milestone development, with a maximum score between 2-4 points for each, depending on the milestone, and a total maximum score of 26. A treatment responder was defined as any patient with at least a 2-point increase (or maximal score of 4) in ability to kick (consistent with improvement by at least 2 milestones), or at least a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking (consistent with improvement by at least 1 milestone). To be classified as a responder, patients needed to exhibit improvement in more categories of motor milestones than worsening. Of the 82 patients who were eligible for the interim analysis, a statistically significantly greater percentage of patients achieved a motor milestone response in the nusinersen group compared to the sham-control group (40% versus 0%; p<0.0001).  Results from the final analysis were consistent with those from the interim analysis. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; p=0.005). 

The primary endpoint assessed at the final analysis was time to death or permanent ventilation (≥ 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event or tracheostomy). Statistically significant effects on event-free survival and overall survival were observed in patients in the nusinersen group compared to those in the sham-control group. A 47% reduction in the risk of death or permanent ventilation was observed in the nusinersen group (p=0.005). Median time to death or permanent ventilation was not reached in nusinersen group and was 22.6 weeks in the sham-control group. A statistically significant 63% reduction in the risk of death was also observed (p=0.004). At the final analysis, the study also assessed treatment effects on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), which is an evaluation of motor skills in patients with infantile-onset SMA. 

The results of the controlled trial in infantile-onset SMA patients were supported by open-label uncontrolled trials conducted in symptomatic SMA patients who ranged in age from 30 days to 15 years at the time of first dose, and in pre-symptomatic patients, who ranged in age from 8 days to 42 days at the time of first dose (Biogen, 2016). The patients in these studies had or were likely to develop Type 1, 2, or 3 SMA. Some patients achieved milestones such as ability to sit unassisted, stand, or walk when they would otherwise be unexpected to do so, maintained milestones at ages when they would be expected to be lost, and survived to ages unexpected considering the number of SMN2 gene copies of patients enrolled in the studies.  

Later-Onset SMA

Mercuri et al (2018) conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; p<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (p<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). The authors concluded that among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group.

Presymptomatic SMA

The results of the sham-controlled trial in infantile-onset and later-onset SMA patients were supported by an open-label uncontrolled trial conducted in presymptomatic SMA patients, who ranged in age from 3 days to 42 days at the time of first dose. Patients received 12 mg nusinersen as a series of loading doses administered intrathecally followed by maintenance doses administered every 4 months. Some patients receiving nusinersen before the onset of SMA symptoms survived without requiring permanent ventilation beyond what would be expected based on their SMN2 copy number, and some patients also achieved age-appropriate growth and developmental motor milestones such as the ability to sit unassisted, stand, or walk.

Nusinersen is supplied as a 12 mg/5 mL (2.4 mg/mL) solution in a single-dose vial. Nusinersen is administered via intrathecal injection. The recommended dosage is 12 mg (5 mL) per administration. 

Initiate nusinersen treatment with 4 loading doses. The first three loading doses should be administered at 14-day intervals. The 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter. 

If a loading dose is delayed or missed, administer nusinersen as soon as possible, with at least 14-days between doses and continue dosing as prescribed. If a maintenance dose is delayed or missed, administer nusinersen as soon as possible and continue dosing every 4 months.

The most common adverse reactions reported for nusinersen were upper respiratory infection, lower respiratory infection and constipation (Biogen, 2016). Serious adverse reactions of atelectasis were more frequent in nusinersen-treated patients. Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

Biomarkers for Monitoring Disease Progression and Response to Nusinersen

Olsson and associates (2019) stated that nusinersen was approved for SMA and these researchers attempted to find a response marker for this treatment.  In a consecutive, single-center study, a total of 12 children with SMA type 1 and 2 copies of the SMN2 gene were included.  The children were sampled for CSF at baseline and every time nusinersen was given intrathecally.  The neuronal biomarkers neurofilament light chain (NfL) and tau and the glial biomarker GFAP were measured.  Motor function was assessed using CHOP INTEND; 11 similarly aged children, who were examined to rule out neurological or infectious disease, were used as controls.  Baseline levels of NfL (4,598 ± 981 versus 148 ± 39, p = 0.001), tau (939 ± 159 versus 404 ± 86, p = 0.02), and GFAP (236 ± 44 versus 108 ± 26, p = 0.02) were significantly higher in SMA children than controls.  Motor function improved by nusinersen treatment in median 13 points corresponding to 5.4 points per month of treatment (p = 0.001).  NfL levels typically normalized (less than 380 pg/ml) between the 4th and 5th doses [- 879.5 pg/ml/dose, 95 % CI: - 1243.4 to - 415.6), p = 0.0001], tau levels decreased [- 112.6 pg/ml/dose, 95 % CI: - 206-7 to - 18.6), p = 0.01], and minor decreases in GFAP were observed [- 16.9 pg/ml/dose, 95 % CI: - 22.8 to - 11.2), p = 0.02] by nusinersen treatment.  Improvement in motor function correlated with reduced concentrations of NfL (rho = - 0.64, p = 0.03) and tau (rho = - 0.85, p = 0.0008); but not GFAP.  The authors concluded that CSF levels of NfL normalized and correlated with motor improvement in children with SMA type 1 treated with nusinersen.  These researchers stated that NfL may be a novel biomarker to monitor treatment response to nusinersen early in the disease course.

The authors stated that the drawbacks of this study included a small study population (n = 12), which could have influenced some of the results such as the non-significant result for change in motor function in relation to age at start of treatment.  These investigators have included all available children with SMA type 1 in Sweden, since the drug was approved in late 2016.

Faravelli and co-workers (2020) stated that nusinersen has been recently licensed to SMA.  Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed.  These investigators examined CSF concentration of neurofilaments in SMA type 3 patients treated with nusinersen as a potential biomarker of treatment efficacy.  The concentration of phosphorylated neurofilaments heavy chain (pNfH) and NfL in the CSF of SMA type 3 patients (n = 12) was examined before and after 6 months since the 1st nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits.  Clinical evaluation of SMA patients was performed with standardized motor function scales.  Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after 6 months of treatment, while motor functions were only marginally ameliorated.  No significant correlation was observed between the change in motor functions and that of neurofilaments over time.  The authors concluded that the reduction of neurofilament levels suggested a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance.  These researchers stated that the findings of this study mandated further investigations to evaluate neurofilaments as a marker of treatment response. The authors stated that the drawbacks of this study included the small number of patients (n = 12) and the relatively short duration of follow‐up (6 months).  In addition, analytical limitations need to be discussed: the baseline concentration of neurofilaments in this study was below the lower limit of quantification in a significant proportion of patients (4/12 and 2/12 for pNfH and NfL, respectively), thus hindering data interpretation.  However, the remarkable consistency of measurable data and the significant differences observed despite such limitation, inferred against a casual effect.  These concerns may be addressed in future by the use of more sensitive methods designed to detect lower analyte concentrations, such as the single‐molecule array immunoassay that has been recently developed for NfL detection.

Wurster and colleagues (2020) determined the diagnostic and monitoring value of serum NfL in SMA.  These researchers measured serum NfL in 46 SMA patients at baseline and over 14 months of treatment with nusinersen using the ultra-sensitive single molecule array (Simoa) technology.  Serum NfL levels of SMA patients were compared to controls and related to CSF NfL, blood-CSF barrier function quantified by the albumin blood/CSF ratio (Qalb) and motor scores (HFMSE; Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, ALSFRS-R).  Serum NfL levels of SMA patients were in the range of controls (p = 0.316) and did not correlate with CSF NfL (ρ = 0.302, p = 0.142) or Qalb (ρ = - 0.160, p = 0.293).  During therapy, serum NfL levels were relatively stable with notable concentration changes in single SMA patients, however, within the control range.  Higher NfL levels were associated with worse motor performance in SMA (baseline: HFMSE ρ = - 0.330, p = 0.025, ALSFRS-R ρ = - 0.403, p = 0.005; after 10 months: HFMSE ρ = - 0.525, p = 0.008, ALSFRS-R ρ = - 0.537, p = 0.007), but changes in motor scores did not correlate with changes in serum NfL. The authors concluded that diagnostic and monitoring performance of serum NfL measurement appeared to differ between SMA subtypes.  Unlike to SMA type 1, in adolescent and adult SMA type 2 and 3 patients, neurodegeneration was not reflected by increased NfL levels and short-term therapeutic effects could not be observed. These researchers stated that long-term follow-up studies need to be carried out to examine if even low levels of NfL might be good prognostic markers.

Bonanno and associates (2020) noted that SMA is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons.  The paralogous SMN2 gene partially compensates full-length SMN protein production, mitigating the phenotype. Antisense oligonucleotide nusinersen (Spinraza) enhances SMN2 gene expression.  SMN is involved in RNA metabolism and biogenesis of microRNA (miRNA), key gene expression modulators, whose dysregulation contributes to neuromuscular diseases.  They are stable in body fluids and may reflect distinct pathophysiological states, thus acting as promising biomarkers.  Muscle-specific miRNAs (myomiRs) as biomarkers for clinical use in SMA have not been examined yet.  These investigators analyzed the expression of miR-133a, -133b, -206 and -1, in serum of 21 infantile SMA patients at baseline and after 6 months of nusinersen treatment, and correlated molecular data with response to therapy evaluated by the HFMSE.  The authors concluded that these findings showed that myomiR serological levels decreased over disease course upon nusinersen treatment.  Notably, miR-133a reduction predicted patients' response to therapy.  These researchers stated that these findings identified myomiRs as potential biomarkers to monitor disease progression and therapeutic response in SMA patients.

The authors stated that despite serum miR-133b and -206 expression levels decreased in SMA patients who showed an improvement in motor function, there was no significant association between those miRNA changes and clinical outcome.  This might be due to the relatively low number of patients (n = 21) enrolled in the analyses.  Larger cohorts of patients, including also SMA type I and adults, are needed to confirm and further extend these findings.  Another limitation of this study was the lack of pediatric healthy controls, due to difficulty in collecting biological samples for the biobank in healthy children.  This restricted the information these researchers could gather about myomiR baseline expression levels; however, the performed paired statistical analysis in samples from treated patients compared to their own baseline (pre-treatment) allowed the authors to disclose significant variation in the expression of key myomiRs, obtaining novel informative data in SMA patients.

Biomarkers of Therapeutic Efficacy in Patients with 5q Spinal Muscular Atrophy

Simic et al (2024) stated that considering the substantial variability in treatment response across patients with SMA, reliable markers for monitoring response to therapy and predicting treatment responders need to be identified.  These researchers examined if measured concentrations of disease biomarkers (total tau protein, neurofilament light chain, and S100B protein) would correlate with the duration of nusinersen treatment and with scores obtained using functional scales for the assessment of motor abilities.  A total of 30 subjects with SMA treated with nusinersen between 2017 and 2021 at the Department of Pediatrics, University Hospital Centre Zagreb, Croatia, were included in this study.  Cerebrospinal fluid (CSF) samples were collected by lumbar puncture before intrathecal application of nusinersen.  Protein concentrations in CSF samples were determined by ELISA in 26 subjects.  The motor functions were evaluated by means of functional motor scales.  The main finding was significantly decreased total tau correlating with the number of nusinersen doses and motor improvement in the first 18 to 24 months of treatment (in all SMA patients and SMA type 1 patients).  Neurofilament light chain and S100B were not significantly changed following administration of nusinersen.  The authors concluded that the measurement of total tau concentration in CSF is emerging as a reliable biomarker for monitoring the response of SMA patients to nusinersen treatment in the first 2-year period.  Moreover, these researchers stated that a drawback of this study was the lack of a control group of patients/respondents; however, lumbar puncture is considered an invasive procedure and is performed on healthy subjects only in exceptional circumstances.  This study also had a small sample size (n = 26).

Gavriilaki et al (2023) noted that the therapeutic landscape of SMA was dramatically transformed with the introduction of 3 disease-modifying therapies (DMTs).  In a systematic review, these investigators examined available evidence regarding quantitative therapeutic biomarkers used in SMA patients older than 11 years under treatment with DMTs.  They carried out a literature search in Medline, Embase, Cochrane databases and gray literature resources in June 2021.  Studies reporting only motor function or muscle strength scales or pulmonary function tests were excluded.  Primary outcome was the change from baseline score of any serum, cerebrospinal fluid (CSF) or neurophysiologic biomarker examined.  Database and gray literature search yielded a total of 8,050 records.  These researchers identified 14 records published from 2019 until 2021 examining 18 putative serum, CSF or neurophysiologic biomarkers along with routine CSF parameters in 295 SMA nusinersen-treated type 2-4 patients older than 11 years of age.  There is evidence based on real-world observational studies suggesting that serum creatinine, creatine kinase activity levels along with CSF Αβ42, glial fibrillary acidic protein concentration as well as ulnar compound motor action potential (MAP) amplitude and single motor unit potential amplitude changes may depict therapeutic response in this population.  The authors concluded that this systematic review examined for the first-time biomarkers used to monitor therapeutic effectiveness in SMA adolescents and adults treated with DMTs.  Moreover, these investigators stated that research in this area is in its early stages, and this systematic review could facilitate selection of quantitative therapeutic biomarkers that may be used as surrogate measures of treatment efficacy in future trials.

Cervical Puncture with Ultrasound Guidance for Administration of Nusinersen

Veerapandiyan and associates (2018) noted that SMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells.  Nusinersen, the 1st FDA-approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible.  Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections.  In a retrospective chart review, these researchers reported their experience in delivering intrathecal nusinersen through cervical puncture in patients with SMA with no lumbar access.  They used C1/C2 puncture as an alternative to administer nusinersen.  Intrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbo-sacral spinal fusion: a 12-year-old girl with type 1 SMA, and 2 17-year old girls with type 2 SMA.  Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1 to C2 interspace and full dose of nusinersen (12 mg/5 ml) was injected after visualizing free cerebrospinal fluid (CSF) flow. Patients completed their 4 loading doses and 1st maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated.  The authors concluded that the findings of this report suggested that cervical puncture, when done by providers with experience in this technique, is a feasible alternative route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access.  However, they stated that more case studies are needed to determine the safety of cervical puncture in patients with SMA.

In a retrospective study, Ortiz and co-workers (2019) examined the technical feasibility and complications of ultrasound (US)-guided cervical puncture for nusinersen administration.  These investigators reviewed 14 consecutive US-guided cervical punctures for nusinersen administration with local anesthesia; they reviewed technical success and complications.  All procedures were technically successful.  There were no major complications; however, there were 2 minor complications (including headaches) that resolved within 24 hours after the procedure. The authors concluded that this case-series study described a successful novel method of US-guided cervical spine access for intrathecal administration of nusinersen, adding to the armamentarium of procedures for delivering nusinersen to adolescents with challenging lumbar spine access caused by scoliosis and spinal instrumentation. They stated that this technique has the advantages of real-time US guidance and potential avoidance of general anesthesia in children.

Nusinersen in Adults With Spinal Muscular Atrophy

Walter and associates (2019) noted that based on randomized clinical trials in children with SMA type 1 and 2, nusinersen has been approved as the 1st treatment for all types of SMA, including adults with SMA type 3.  In a prospective, observational study, these researchers examined the safety and treatment effects of nusinersen in long-standing adult 5q-SMA type 3.  Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every 4 months up to 300 days.  These investigators monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including Medical Research Council (MRC) sum score, vital capacity in sitting position (VC, VC % pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and HFMSE.  They also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, ß-Amyloid 1-40, ß-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK).  Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6).  For statistical analysis, these researchers compared baseline to V4, V5 and V6, using the paired sample t-test.  When there were significant differences, They added Cohen's d and effect size r for evaluation of clinical meaningfulness.  A total of 19 patients were included, 17 of them have completed the observation period of 10 months (day 300, V6).  Patients were aged 18 to 59 years with disease duration ranging from 6 to 53 years.  Except for the 6MWT, the RULM and the peak cough flow, there were no relevant significant changes in all functional outcome assessments at V4, V5 or V6, compared to baseline.  For the 6MWT, there was a statistically significant improvement at visit 5 and at visit 6.  RULM-score increased significantly at V6, and peak cough flow at visit 5.  In biomarker studies, there was a significant decline in NSE and pTAU as well as a slight increase in proteins.  In safety analysis, overall, nusinersen applications were well-tolerated; 11 patients reported AEs that were related to the study procedures, comprising back pain in 7 patients and post-lumbar-puncture headache following intrathecal administration in 4 patients.  Post-lumbar-puncture headache was reported in 3 females and 1 male, in total 11 times of 108 punctures (10% ).  No serious AEs occurred.  The authors concluded that the findings of this study indicated a mild treatment effect in adults with long-standing SMA3 after 10 months of treatment with nusinersen, which had never occurred in the natural history of the disease.  In this cohort, the most significant outcome measures were the 6MWT with statistically significant changes after day 180 and day 300, RULM after day 300 and peak cough flow after day 180.

The authors stated that this study had several drawbacks; treatment duration was still too short (maximum of 300 days) to examine long-term treatment efficacy and sustainability of improvement.  While this small cohort (n = 19) with heterogeneous phenotypes (ambulant and non-ambulant SMA3 patients with a wide range of disease duration) may impede the interpretation of these data; nevertheless, even in SMA3 patients with a long-standing disease course up to 53 years and a median disease duration of 24 years, improvement of motor function exceeded the expectations of mere disease stabilization, justifying treatment beyond childhood and early adolescence.  The optimal time for a meaningful intervention is not yet fully elucidated, particularly at which point irreversibility of decline precludes any meaningful therapeutic response.  More importantly, treatment response should not be based on the improvement of motor function alone, but focus on preventing all aspects of disease progression.  This may include additional objective measurements of disease progression, like quantitative high-resolution muscle US or magnetic resonance imaging (MRI) of muscle and peripheral nerve to indicate early nerve tissue changes and to detect and measure the progression of muscular atrophy and nerve tissue changes in response to the treatment.  Furthermore, suitable questionnaires for patient-related outcomes have to be developed to evaluate the efficacy of future treatments.  These researchers stated that the clinical benefit in patients with the long-standing disease will have to be further evaluated regarding efficacy and side effects in the years to come.

Hagenacker and colleagues (2020) stated that nusinersen is approved for the treatment of 5q SMA of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce.  These researchers examined the safety and efficacy of nusinersen in adults with 5q SMA.  They carried out an observational cohort study at 10 academic clinical sites in Germany.  Patients with genetically confirmed 5q SMA (age of 16 to 65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total HFMSE score, examined at months 6, 10, and 14, and based on pre-post comparisons.  Between July 13, 2017, and May 1, 2019, a total of 173 patients were screened, of whom 139 (80 %) were eligible for data analysis.  Of these, 124 (89 %) were included in the 6-month analysis, 92 (66 %) in the 10-month analysis, and 57 (41 %) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses.  Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference [MD] 1.73 [95 % confidence interval [CI]: 1.05 to 2.41], p < 0.0001), 10 months (2.58 [1.76 to 3.39], p < 0.0001), and 14 months (3.12 [2.06 to 4.19], p < 0.0001).  Clinically meaningful improvements (greater than or equal to 3 points increase) in HFMSE scores were observed in 35 (28 %) of 124 patients at 6 months, 33 (35 %) of 92 at 10 months, and 23 (40 %) of 57 at 14 months.  To 14-month follow-up, the most frequent AEs among 173 patients were headache (61 [35 %] patients), back pain (38 [22 %]), and nausea (19 [11 %]). No serious AEs were reported.  The authors concluded that despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, these findings provided evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q SMA, with clinically meaningful improvements in motor function in a real-world cohort.

Jochmann and co-workers (2020) stated that nusinersen recently became the 1st drug approved for the treatment of SMA. It was approved for all ages, albeit the clinical trials were conducted exclusively on children.  Hence, clinical data on adults being treated with nusinersen is scarce.  In a case-series study, these investigators reported on drug application, organizational demands, and preliminary effects during the first 10 months of treatment with nusinersen in 7 adult patients.  All patients received intrathecal injections with nusinersen. In cases with severe spinal deformities, these investigators performed CT-guided applications.  They carried out a total of 40 administrations of nusinersen; and evaluated the patients with motor, pulmonary, and laboratory assessments, and tracked patient-reported outcome.  Intrathecal administration of nusinersen was successful in most patients, even though access to the lumbar intrathecal space in adults with SMA is often challenging.  No severe AEs occurred; 6 of the 7 patients reported stabilization of motor function or reduction in symptom severity.  The changes in the assessed scores did not reach a significant level within this short time period.  The authors concluded that treating adult SMA patients with nusinersen was feasible and most patients considered it beneficial.  It demanded a complex organizational and inter-disciplinary effort. These researchers stated that due to the slowly decreasing motor functions in adult SMA patients, time, and increasing numbers of treated adults will show whether the currently established motor assessments are able to sufficiently depict clinical status in this group of patients, and if nusinersen could stabilize, or even improve, the situation for adult patients to a similar degree as is the case for children.

The authors stated that an inevitable limitation of the data presented was that a placebo effect leading to increasing scores could not be excluded since the data was deduced from clinical data from an approved treatment and not from a controlled clinical trial.

Yeo, et al (2020) reported on a single-center prospective cohort study of 6 adults with SMA type 3, with inclusion/exclusion criteria intended to optimize the ability to demonstrate change using established outcome measures. Primary outcomes were the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Measure (RULM). Secondary outcomes were the PedsQL Fatigue scale, the SMA Functional Rating Scale (SMAFRS), and the 6-minute and 10-meter walk tests (6 MWT and 10 MWT). Estimates of change in HFMSE and RULM mean scores across visits were calculated using a linear mixed effects model. Change from baseline was used for other outcome measures. HFMSE and RULM scores over 12 months were stable or improved in all participants, with a mean increase of 2 points in each. Other measures showed high intra-individual variability. Adverse events related to the primary diagnosis, including injury and infection, significantly impacted the ability to reliably perform walk tests in the four ambulatory participants. The investigators concluded that HFMSE and RULM show potential as responsive outcome measures of motor function in ambulatory and non-ambulatory adults with SMA type 3. A time-dependent accrual of benefit of nusinersen on motor function was apparent in this cohort. More sensitive alternative measures of quality of life, fatigue, exercise tolerance, stability and ADLs are clearly needed for adults with SMA.

Osmanovic, et al (2020) reported on a longitudinal single-center study in 24 adult patients with SMA types 2-4, The Stanford Expectations of Treatment Scale (SETS) was assessed prior to and during nusinersen treatment. Treatment outcome was evaluated using patient-reported outcomes (PROs) as well as objectively quantifiable motor outcome measures. The investigators reported that adult SMA patients had high expectations of nusinersen treatment effectiveness regarding increase in muscle strength and disease stabilization. Via PROs, 75% stated improvements in muscle strength, endurance and independence under therapy which was in line with slight improvements in quantifiable motor scores during a ten-month observation period. In contrast, patients only expressed few negative expectations which further decreased during therapy.

Elsheikh and colleagues (2021) examined the safety, tolerability, and treatment effect of nusinersen in non-ambulatory adults with SMA.  Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled in this study.  In subjects with spinal fusion, fluoroscopy-guided cervical C1 to C2 lateral approach was used.  Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment.  Forced vital capacity (FVC) was the primary outcome, and secondary outcomes included RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology (compound muscle action potential [CMAP], single motor unit size, and motor unit number); AEs and SAEs as well as clinically significant vital sign or laboratory abnormalities were recorded.  Results from 12 women and 7 men (mean age of 39.7 ± 13.9 years, range of 21 to 64) were analyzed.  No clinically significant changes of vital signs or laboratory parameters were observed; 5 subjects were hospitalized for pneumonia.  Other AEs included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections (UTIs).  High baseline protein/creatinine ratio without significant change on treatment were noted in 4 subjects.  While FVC was feasible in all subjects, HFMSE and RULM were not feasible in the majority of them; FVC and functional outcomes were stable without improvement.  CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable. The authors concluded that nusinersen, including C1/C2 delivery, was safe and well-tolerated.  Several outcome measures were limited by floor effect.  Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.  Moreover, these researchers stated that the generalizability of the findings should be considered in the context of this study's small sample size (n = 19), open-label design, and limited longitudinal data. They stated that future studies should focus on improvement of outcome measures for this population and understanding of the impact of different routes of intrathecal delivery. 

Osmanovic and associates (2021) stated that nusinersen was the 1st drug available for all types of 5q- SMA.  The dosing regime has been derived from pivotal clinical trials in infants and children.  The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been carried out.  These researchers systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach.  They found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration.  Symptoms and functions affected were primarily general strength as well as arm and leg muscle function next to endurance and independence in daily routine.  Lack of walking ability and higher body mass index (BMI) were characteristic phenotypic features in patients with consistent wearing-off effects.  The authors concluded that this study identified clinically observed wearing-off phenomena in adult 5q-SMA patients under nusinersen treatment.  Efforts towards treatment optimization in specific adult SMA patient phenotypes might improve the therapeutic efficacy. 

The authors stated that this study had several drawbacks.  SMA is a rare disease and nusinersen is an expensive treatment, which is only available at specialized neuromuscular centers in a multi-disciplinary setting.  Thus, only a small number of patients were included and analyzed in this study.  Furthermore, the mono-centric study design led to small patient numbers; however, the main drawback of this study was the patient self-reported approach used to examine wearing-off phenomena.  Patients might have expected the treatment to be highly effective immediately after treatment and to lose efficacy over time until the next dose.  A potential bias towards positive answers according to patients’ individual expectations could not be excluded.  Validation of these findings, preferably by means of more objective outcome measures in a larger cohort, is needed, especially regarding the further characterization of specific SMA phenotypes that might benefit from treatment modifications such as higher doses, shorter treatment intervals or a combination of two splice-modifying mechanisms.

Duong et al (2021) conducted a prospective observational study to determine changes in motor and respiratory function after treatment with nusinersen of adults with SMA in the real-world setting. The authors collected data on participants that were in the Pediatric Neuromuscular Clinical Research Network. "Baseline assessments of SMA outcomes including the Expanded Hammersmith Functional Rating Scale (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) occurred <5 months before treatment, and post-treatment assessments were made up to 24 months after nusinersen initation." Of the 42 adult SMA participants (age range 17 to 66 years) who received nusinersen for a mean of 12.5 months, the authors found that several motor and respiratory measures showed improvement distinct from the progressive decline typically seen in untreated adults. The authors also noted that qualitative improvements including muscle strength, stamina, breathing and bulbar related outcomes were reported by the participants, and did not have significant adverse events. The authors concluded that their study outcomes suggests nusinersen may be efficacious in adults wth SME; however, larger well-controlled studies are needed to confirm efficacy of nusinersen in adults with SMA (LOE: IV).

Vázquez-Costa and colleagues (2022) conducted a prospective multicenter observational study aimed to assess the safety and efficacy of nusinersen in patients older than 15 years with 5q spinal muscular atrophy (SMA). Of the 79 SMA patients included in their study, 39 were treated with nusinersen and compared to 40 non-treated patients. Treated patients were injected with 12 mg loading doses of nusinersen (at days 0, 14, 28 and 65) and maintenance doses every 4 months, as per label, and received conventional and imaging‐guided lumbar punctures. One treated patient was excluded from efficacy analysis after the second dose of nusinersen due to the lack of lumbar access. All patients were followed for at least 6 months with one motor scale (i.e., Hammersmith Functional Motor Scale Expanded [HFMSE]; Revised Upper Limb Module [RULM]) and received the same multidisciplinary care in one of the five referral centers, regardless of whether they were treated or not. The clinical and patients' global impression of change (CGI‐C and PGI‐C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS‐R) and the percentage predicted forced vital capacity were collected when available. The authors found that "compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p < 0.001) after 6 months. After a mean follow‐up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR] 1.15, p = 0.006), the 6‐min walk test (OR = 1.07, p < 0.001) and the EK2 (OR = 0.81, p = 0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p = 0.033), ALSFRS‐R (p = 0.005) and EK2 (p < 0.001). According to the CGI‐C and PGI‐C, 64.1% and 61.5% of treated patients improved with treatment. Being a non‐sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild". The authors concluded that their multicenter real‐world study provides class III evidence that nusinersen treatment is associated with mild motor and functional improvements in up to 60% of adult SMA patients, which includes frequent mild adverse events noted. The authors acknowledge limitations to their study, such as their small sample size and some "methodological heterogeneity amongst centers" regarding retrospective data and baseline patient characteristics between groups. The authors report that 16 months of follow-up may be insufficient to detect changes in both patient groups. Thus, collaborative long‐term studies are warranted to confirm their analysis, which would help to personalize therapeutic decisions in adult SMA patients.

Arslan et al (2023) present their clinical experience in adult SMA patients treated with nusinersen according to the CHERISH study. Thirty-two SMA patients treated with nusinersen were included in the study. Median age at initiation was 33.5 (20.0-60.0) years, of which 23 were male. Six (18.8%) patients had SMA type 2, and 26 (81.2%) had SMA type 3. Median follow-up period was 17 months (9-21). The authors found that 23 patients improved by at least 3 HFMSE points after loading doses. There was significant HFMSE score increase in type 3 patients at each time point, whereas type 2 patients seem to benefit from nusinersen loading doses, subsequently stayed stable. Motor improvement was positively correlated with baseline HFMSE scores in patients whose baseline HFMSE scores were less than or equal to 47. There was a correlation between the changes in Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score and HFMSE scores. Ambulatory patients who could not show clinically meaningful increase in HFMSE scores improved at least 30 m by 6-min walk test (6MWT). The authors concluded that overall, 78% of patients have responded to treatment according to HFMSE or 6MWT.  Furthermore, ALSFRS-R and 6MWT may be alternative tools to monitor nusinersen effect.

Subcutaneous Intrathecal Catheter System for Repeated Dosing of Nusinersen

Strauss and associates (2018) stated that many patients with SMA who might benefit from intrathecal nusinersen therapy have scoliosis or spinal fusion that precludes safe drug delivery.  To circumvent spinal pathology, these researchers designed a novel subcutaneous intrathecal catheter (SIC) system by connecting an intrathecal catheter to an implantable infusion port.  Device safety and tolerability were tested in 10 SMA patients (age of 5.4 to 30.5 years; 80 % with 3 copies of SMN2); each received 3 sequential doses of nusinersen (n = 30 doses).  Pre-treatment disease burden was evaluated using the revised Hammersmith Scale, dynamometry, National Institutes of Health (NIH) pegboard, pulmonary function testing, electromyography (EMG), and 2 health-related quality of life (QOL) tools.  Device implantation took less than or equal to 2 hours and was well-tolerated.  All outpatient nusinersen doses were successfully administered via SIC within 20 minutes on the first attempt, and required no regional or systemic analgesia, cognitive distraction, US guidance, respiratory precautions, or sedation.  Cerebrospinal fluid withdrawn from the SIC had normal levels of glucose and protein; CSF white blood cells were slightly elevated in 2 (22 %) of 9 specimens (median of 1 cell/µL; range of 0 to 12 cells/µL) and red blood cells were detected in 7 (78 %) specimens (median of 4; range of 0 to 2,930 cells/µL).  The authors concluded that preliminary observations revealed the SIC to be relatively safe and well-tolerated in SMA patients with advanced disease and spinal fusion.  They stated that the SIC warrants further study and, if proven effective in larger trials of longer duration, could double the number of patients able to receive nusinersen worldwide while reducing administration costs 5- to 10-fold.

Transforaminal Lumbar Puncture with Cone-Beam Computed Tomography for Administration of Nusinersen

Weaver and colleagues (2018) stated that nusinersen, the only treatment approved by the FDA for SMA, is delivered intrathecally.  Many children with SMA have extensive spinal instrumentation and deformities, often precluding the use of standard approaches for gaining intrathecal access.  Furthermore the anatomical distortion that often occurs with roto-scoliosis could complicate the use of fluoroscopic guidance.  Compared to fluoroscopy, computed tomography (CT) affords superior guidance for complex needle placements.  This opens up alternatives to the posterior (interlaminar) technique, including transforaminal and caudal approaches.  In a retrospective review, these investigators described the early results of technical success, complications and radiation dose of intrathecal delivery of nusinersen using cone-beam CT guidance with 2-axis fluoroscopic navigational overlay.  A total of 15 consecutive nusinersen injections performed in 4 children with SMA and extensive spinal hardware precluding standard posterior lumbar puncture techniques.  These children were treated using transforaminal thecal access employing cone-beam CT with navigational overlay.  These researchers analyzed results including technical success, complications and total fluoroscopy time.  All procedures were technically successful.  No major complications and 1 minor complication were reported; the minor complication was a post-procedural neuropathic headache that was attributed to procedural positioning and was treated successfully with gabapentin.  The average procedural fluoroscopy time and air kerma were 1.9 mins and 55.8 mGy, respectively.  The authors concluded that cone-beam CT guidance with 2-axis navigational overlay is a safe, effective method for gaining transforaminal intrathecal access in children with spinal abnormalities and hardware precluding the use of standard techniques.  These preliminary findings need to be further investigated.

Nascene and associates (2018) noted that they had recently used a transforaminal approach in selected situations.  Between May 2016 and December 2017, a total of 26 transforaminal lumbar punctures were performed in 9 patients (25 CT-guided, 1 fluoroscopy-guided); 7 had SMA and were referred for intrathecal nusinersen administration.  In 2, CT myelography was performed via transforaminal lumbar puncture.  The lumbar posterior elements were completely fused in 8, and there was an overlying abscess in 1.  The L1 to L2 level was used in 2; the L2 to L3 level, in 10; the L3 to L4 level, in 12; and the L4 to L5 level, in 2 procedures.  Post-lumbar puncture headache was observed on 4 occasions, which resolved without blood patching; 1 patient felt heat and pain at the injection site that resolved spontaneously within hours; 1 patient had radicular pain that resolved with conservative treatment.  The authors concluded that transforaminal lumbar puncture may become an effective alternative to classic interlaminar lumbar puncture or cervical puncture.

In a retrospective, single-center study, Spiliopoulos and co-workers (2020) examined the safety and feasibility of CT-guided, trans-foraminal, lumbar puncture for the intrathecal administration of nusinersen in a cohort of adult subjects with SMA type 2, severe neuromuscular scoliosis and previous spinal surgery.  Between January 2019 and October 2019, a total of 5 men with SMA type 2 were eligible to be treated in the authors’ Center with Nusinersen.  The mean age of the patients was 31 ± 9 years (range of 19 to 43).  Study's outcome measures were technical success, adverse events (AEs) and radiation exposure.  A total of 4 patients completed the 4 loading doses, while the 5th subject received only 1 loading dose; 2 subjects also received their 1st maintenance dose.  Overall, 20 consecutive trans-foraminal, intrathecal, treatments were analyzed.  Technical success was 100 % (20/20 intrathecal infusions).  No AEs were documented following the procedures.  Mean dose length product (DLP) value per injection was 665.4 ±715.5 mGy*cm.  Estimated mean effective dose per injection was 12.7± 12.9 mSv.  Subgroup analysis between the chronologically first 10 versus subsequent 10 procedures demonstrated a clear trend towards less radiation exposure in the latter, although this difference did not reach statistical significance (DLP: 984.7 ± 903.3 versus 436.7 ± 321.5 mGy*cm, p = 0.165; respectively).  The authors concluded that CT-guided trans-foraminal access for intrathecal injection of nusinersen was proven safe and feasible; a decrease in radiation dose over time was noted.

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Appendix

Types of Spinal Muscular Atrophy

• SMA Type 1 (also called infantile onset SMA or Werdnig-Hoffmann disease): SMA symptoms are present at birth or by the age of 6 months. Babies typically have generalized muscle weakness, a weak cry, and breathing distress. They often have difficulty swallowing and sucking and don't reach the developmental milestone of being able to sit up unassisted. These babies have increased risk of aspiration and failure to thrive.
• SMA Type 2: (or intermediate SMA or Dubowitz disease): Onset of SMA symptoms between the ages of 3 and 15 months and before the child can stand or walk independently.
• SMA Type 3: (also known as juvenile-onset SMA or Kugelberg-Welander disease): Onset of SMA symptoms usually appear between age 18 months and adulthood, and affected individuals can achieve independent mobility, although assisted mobility devices may be required.
• SMA Type 4 (also known as late-onset or adult-onset form of proximal spinal muscular atrophy): Age of onset is not defined but is usually after age 30. Type 4 is a mild form of SMA and therefore lifespan remains normal. Patients are able to achieve motor milestones and maintain their mobility throughout life.

Source: Muscular Dystrophy Association, 2021

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References