Nusinersen
Nusinersen, marketed as Spinraza, is a synthetic antisense oligonucleotide administered intrathecally for the treatment of spinal muscular atrophy (SMA), a genetic disorder characterized by motor neuron degeneration due to mutations in the SMN1 gene.[1][2] By binding to a specific site in the SMN2 pre-mRNA, it promotes inclusion of exon 7 during splicing, thereby increasing production of full-length SMN protein essential for motor neuron survival.[3][4] Approved by the U.S. Food and Drug Administration in December 2016, nusinersen became the first therapy specifically indicated for SMA across pediatric and adult patients, regardless of disease severity.[5][1] Pivotal clinical trials, including ENDEAR for infantile-onset SMA and CHERISH for later-onset, demonstrated significant improvements in motor milestones, event-free survival, and Hammersmith Functional Motor Scale scores compared to sham controls or natural history data.[6][7] Long-term follow-up and real-world studies confirm sustained functional benefits, particularly in early-treated patients, with reductions in mortality and ventilation requirements in severe cases.[8][9][10] Treatment involves loading doses followed by maintenance infusions every four months, though repeated lumbar punctures pose procedural challenges and risks such as headache and back pain.[11][12] The safety profile indicates common adverse events including lower respiratory infections, constipation, and procedure-related issues, with rare serious events like thrombocytopenia or aseptic meningitis, but no new long-term concerns identified over multiple years of use.[13][6][14]Medical Indications and Administration
Approved Uses and Patient Populations
Nusinersen, marketed as Spinraza, is indicated for the treatment of spinal muscular atrophy (SMA), a genetic neuromuscular disorder primarily caused by mutations in the SMN1 gene on chromosome 5q, in pediatric and adult patients.[15] The U.S. Food and Drug Administration (FDA) granted accelerated approval on December 23, 2016, based on increased neuronal survival motor neuron-2 (SMN) protein levels as a surrogate endpoint likely to predict clinical benefit, with full approval confirmed in 2018 following confirmatory trials.[15][2] This approval applies to patients with genetically confirmed 5q SMA across all disease severities and ages at onset, including infantile-onset (type 1), later-onset (types 2 and 3), and adult-onset (type 4) forms.[16][17] The European Medicines Agency (EMA) authorized nusinersen in May 2017 for the treatment of 5q SMA in pediatric patients up to 18 years with types 1, 2, or 3, with subsequent expansions to include adults and broader populations.[18] Approvals in over 70 countries worldwide similarly target SMA patients without age or type restrictions in most jurisdictions, though real-world use often prioritizes earlier intervention in symptomatic infants and children due to disease progression dynamics.[19] Prescribing guidelines emphasize initiation prior to irreversible motor neuron loss, but the label permits treatment in presymptomatic infants identified via newborn screening and in adults with established disease.[15][20] Patient populations eligible for nusinersen include those with biallelic SMN1 deletions or mutations, relying on SMN2 copy number for residual protein production, which correlates with phenotype severity (e.g., 2 SMN2 copies typical in type 1, 3-4 in types 2-3).[16] It is not indicated for non-5q SMA variants or other motor neuron diseases lacking SMN1 involvement.[15] Eligibility requires multidisciplinary evaluation, including genetic confirmation via testing for SMN1 exon 7 deletion, and intrathecal administration feasibility, often necessitating fluoroscopy-guided lumbar puncture in non-ambulatory patients.[20]Dosing Regimens and Delivery Methods
Nusinersen is administered at a recommended dose of 12 mg (5 mL) per intrathecal injection for all approved indications in spinal muscular atrophy (SMA).[21] Treatment initiation requires four loading doses: the first three doses spaced at 14-day intervals (typically on days 1, 15, and 29), followed by the fourth dose administered 30 days after the third (approximately day 59).[21] [22] Subsequent maintenance doses of 12 mg are given every 4 months thereafter.[21] This regimen applies across pediatric and adult patients, with no weight- or age-based adjustments specified in the labeling, though dosing remains fixed at 12 mg regardless of body size.[21]| Phase | Dose | Timing |
|---|---|---|
| Loading Dose 1 | 12 mg | Day 1 |
| Loading Dose 2 | 12 mg | Day 15 (14 days after Dose 1) |
| Loading Dose 3 | 12 mg | Day 29 (14 days after Dose 2) |
| Loading Dose 4 | 12 mg | Day 59 (30 days after Dose 3) |
| Maintenance | 12 mg | Every 4 months starting after Dose 4 |
Clinical Efficacy Evidence
Pivotal Clinical Trials
The pivotal clinical trials for nusinersen, an antisense oligonucleotide approved for spinal muscular atrophy (SMA), were the phase 3 ENDEAR and CHERISH studies, which demonstrated efficacy in infantile- and later-onset SMA, respectively, and supported its accelerated FDA approval on December 23, 2016.[30] These double-blind, sham-procedure-controlled trials evaluated intrathecal administration of 12 mg nusinersen versus sham, focusing on motor function improvements in symptomatic patients untreated prior to enrollment.[31][7] ENDEAR (NCT02193074) enrolled 121 infants aged 3-7 months with symptomatic infantile-onset SMA (type 1), randomized 2:1 to nusinersen (n=80) or sham (n=41).[32] The primary endpoint was the proportion achieving motor-milestone responses at 13 months per the Hammersmith Infant Neurological Exam Section 2 (HINE-2), with secondary endpoints including event-free survival (time to death or permanent ventilation).[31] An interim analysis at day 183 showed 40% of nusinersen-treated infants achieved a motor-milestone response versus 0% in sham (P<0.001), prompting early termination and open-label extension; overall, 51% versus 0% responded by study end, with median event-free survival of 374 versus 110 days.[31][33] CHERISH (NCT02292537) included 126 children aged 2-9 years with later-onset SMA (symptom onset after 6 months, never achieved independent walking), randomized 2:1 to nusinersen (n=84) or sham (n=42).[34] The primary endpoint was change from baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) score at 15 months, assessing gross motor function.[7] Nusinersen yielded a least-squares mean HFMSE change of +3.9 points versus -1.0 for sham (difference 4.9 points, P<0.001), with sustained benefits in upper limb milestones and subgroup consistency across ages and disease duration.[7]| Trial | Population | Primary Endpoint | Key Result |
|---|---|---|---|
| ENDEAR | Infants (3-7 months), infantile-onset SMA | HINE-2 motor-milestone response rate | 51% response (nusinersen) vs. 0% (sham); P<0.001[31] |
| CHERISH | Children (2-9 years), later-onset SMA | HFMSE score change at 15 months | +3.9 points (nusinersen) vs. -1.0 (sham); P<0.001[7] |
Long-Term and Real-World Outcomes
Long-term follow-up data from extension studies of pivotal trials, such as the SHINE study (NCT02594124), have demonstrated sustained motor function improvements and high survival rates in patients with spinal muscular atrophy (SMA) treated with nusinersen. In the NURTURE study, a phase 2 trial for presymptomatic infants, all 25 participants remained alive at the conclusion with ongoing clinical benefits, including achievement of developmental milestones like sitting and standing, after up to several years of treatment.[35] For later-onset SMA, the CHERISH trial extension showed stabilization or gains in Hammersmith Functional Motor Scale-Expanded (HFMSE) scores over 3 years, with reversal of prior motor losses in some type II and III patients.[36] Real-world evidence from observational cohorts corroborates these findings, particularly emphasizing the importance of early initiation. A 2024 multicenter study of adults with 5q SMA reported motor function improvement or stabilization in the majority of patients for up to 38 months, assessed via tools like the Expanded Hammersmith Functional Motor Scale (HFMSE) and Revised Upper Limb Module (RULM), with treatment well-tolerated despite advanced disease stages.[37] In a diverse pediatric and adult cohort, nusinersen led to continuous functional gains over 30 months, including better respiratory support independence and reduced scoliosis progression, though outcomes varied by SMA type and treatment start age.[38] Late-treated patients still achieved gains or halted decline, but early starters showed superior motor milestones, with no deaths observed in the cohort.[39] A 2025 systematic review and meta-analysis of long-term nusinersen use across adolescent and adult SMA populations confirmed effectiveness in maintaining or enhancing motor outcomes, drawing from real-world registries and extensions, though benefits were more pronounced in ambulatory patients and less consistent in non-ambulatory advanced cases.[40] Electrophysiological improvements, such as enhanced compound muscle action potentials, paralleled motor gains in treated adolescents and adults after 2-4 years.[41] Dosing adjustments to every 6 months in stable adults preserved these effects without loss of efficacy.[42] Overall, real-world data indicate nusinersen alters disease trajectory across SMA spectrum, with survival exceeding historical untreated rates (e.g., >90% at 4 years vs. <30% in untreated type I), but plateauing benefits highlight need for combination therapies in refractory cases.[43]Comparative Effectiveness with Alternatives
Direct head-to-head randomized controlled trials comparing nusinersen with alternative disease-modifying therapies for spinal muscular atrophy (SMA)—such as onasemnogene abeparvovec (a one-time intravenous gene therapy approved for children under 2 years) and risdiplam (an oral small-molecule SMN2 splicing modifier approved across ages)—are absent, limiting conclusions to indirect comparisons via network meta-analyses, matching-adjusted indirect comparisons (MAIC), and real-world observational data.[44][45] These methods adjust for baseline differences but face challenges including clinical heterogeneity in patient ages, disease severity, and trial designs, as well as potential biases from single-arm studies or historical controls.[46][47] In SMA type 1, onasemnogene abeparvovec demonstrates superior event-free survival (death or permanent ventilation) and motor milestones compared to nusinersen. A 2024 meta-analysis reported 95% overall survival with onasemnogene abeparvovec (95% CI: 88–100), versus 60% with nusinersen (95% CI: 50–70), alongside higher rates of ventilatory independence (relative risk [RR] 0.10, 95% CI: 0.02–0.53) and Hammersmith Infant Neurological Examination section 2 (HINE-2) motor response (86%, 95% CI: 65–97 vs. 58%, 95% CI: 41–73 for nusinersen).[44] Network meta-analysis ranked onasemnogene abeparvovec highest for motor milestone achievement (RR 30.36 vs. control, 95% CI: 1.4–659.82), exceeding nusinersen's RR of 3.79 (95% CI: 1.16–12.39).[46] Risdiplam also outperforms nusinersen in type 1, with MAIC showing 80% lower event-free survival hazard (HR 0.20, 95% CI: 0.06–0.42) and odds ratios favoring risdiplam for motor response (OR 3.97, 95% CI: 2.03–8.38) and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) improvement ≥4 points (OR 7.59, 95% CI: 3.06–35.71); long-term data indicate risdiplam yields 45% higher HINE-2 response (HR 1.45, 95% CI: 1.21–1.80) and 186% higher CHOP-INTEND response (HR 2.86, 95% CI: 2.18–4.48).[45][47] For SMA types 2 and 3, comparative data are sparser, with onasemnogene abeparvovec limited by age restrictions and primarily studied in type 1. Indirect analyses suggest comparable motor function gains between nusinersen and risdiplam, such as similar Hammersmith Functional Motor Scale Expanded (HFMSE) improvements, though population differences preclude firm conclusions; real-world cohorts report stabilization or modest gains with both, without clear superiority.[45][48] Across types, all therapies increase survival and motor scores versus untreated historical controls, but indirect estimates favor onasemnogene abeparvovec and risdiplam over nusinersen for profound early interventions, with caveats for study biases and short follow-up in some analyses (e.g., <36 months).[44][46]| Outcome (SMA Type 1) | Onasemnogene Abeparvovec | Risdiplam | Nusinersen |
|---|---|---|---|
| Overall Survival (%) | 95 (95% CI: 88–100)[44] | 86 (95% CI: 76–94)[44] | 60 (95% CI: 50–70)[44] |
| CHOP-INTEND ≥4 pt Improvement (%) | 92 (95% CI: 62–100)[44] | 90 (95% CI: 77–97)[44] | 74 (95% CI: 66–81)[44] |
| HINE-2 Motor Response (%) | 86 (95% CI: 65–97)[44] | 61 (95% CI: 45–76)[44] | 58 (95% CI: 41–73)[44] |