Long-term adherence, safety and effectiveness of nusinersen in spinal muscular atrophy patients: a population-based study

This population-based study demonstrates that while nusinersen treatment is highly effective and well-adhered to in children with spinal muscular atrophy, its long-term persistence significantly declines in adolescents and adults due to treatment burden and limited efficacy, though a subset of older patients with higher baseline function still experience sustained motor benefits.

The Gist

Imagine Spinal Muscular Atrophy (SMA) as a car engine that is slowly losing its spark plugs. Without treatment, the engine (the muscles) gets weaker and weaker until the car can no longer move. Nusinersen is like a special fuel additive designed to fix the spark plugs and keep the engine running.

This study is a long-term report card on how well that "fuel additive" works for people living in the Valencia region of Spain. The researchers looked at 72 patients, splitting them into two main groups: Kids (under 12) and Teens & Adults (12 and older). They followed them for about 7 years to see who kept taking the medicine, who stopped, and how their "engines" performed.

Here is the story of what they found, told in simple terms:

1. The Kids: A Resounding Success Story

For the children under 12, the results were like a perfectly tuned race car.

• Adherence: Almost every single child (100%) started the treatment, and almost all of them kept taking it.
• Effectiveness: Every child who stayed on the treatment showed improvement or at least held their ground. They didn't just stop getting worse; many actually got stronger.
• The Verdict: For kids, this medicine is a game-changer. It's highly effective, and the families are happy to keep giving it to them.

2. The Teens and Adults: A Rocky Road

For the older group (12+), the story is more complicated, like a hiking trip up a steep mountain.

• The Drop-off: While about half of the adults started the treatment, 75% of them eventually stopped. That's a huge drop-off compared to the kids.
• Why did they quit? It wasn't usually because the medicine was dangerous. It was because the journey was too hard:
  • The Burden: The treatment requires a needle injection into the spine (a lumbar puncture) every four months for the rest of your life. Imagine having to go to the hospital for a painful back injection four times a year, forever. For many adults, especially those with scoliosis (curved spines), this became too much of a hassle.
  • The "So What?" Factor: Some adults didn't feel like they were getting better. If you are climbing a mountain and you stop moving forward, you might decide the hike isn't worth the effort.
  • The New Option: Once an oral pill (Risdiplam) became available, many adults switched to that because it's much easier than the spinal injections.

3. Who Stays on the Hike?

The researchers found a pattern for the adults who did stick with the spinal injections for the long haul. They were like the fittest, most prepared hikers:

• Younger: Those under 40 were more likely to stay.
• Stronger Start: Those who started with better muscle function were more likely to see a benefit worth the pain.
• Gender: Interestingly, men were more likely to stay on the treatment than women (perhaps because women are statistically more prone to headaches after spinal taps).

4. The "Stability" Illusion

Here is a crucial finding: The study compared adults who stopped the medicine to those who never took it at all.

• The Surprise: The adults who stopped the medicine didn't get much worse than the ones who never took it. Their scores stayed flat.
• The Meaning: This suggests that for some adults, the disease naturally slows down and becomes "stable" on its own. So, if the medicine isn't making them better, but just keeping them stable, and the treatment is painful and burdensome, it makes sense why they would quit.

The Big Picture Takeaway

Think of Nusinersen as a powerful tool, but not a magic wand that works the same for everyone.

• For Children: It is a miracle. It stops the engine from dying and helps it roar back to life. Everyone should use it.
• For Adults: It is a high-maintenance tool. It works beautifully for a specific group (younger, stronger adults), but for many others, the cost (pain, time, hassle) outweighs the benefit.

The Lesson: Doctors need to be honest with adult patients. They shouldn't promise a miracle. Instead, they should say: "If you are young and strong, this might help you climb higher. If you are older or weaker, the climb might be too steep for the reward, and you might want to consider easier options."

This study helps doctors and families make smarter choices, ensuring that the right people get the right treatment without suffering unnecessary burdens.

Technical Summary

1. Problem Statement

Nusinersen was the first disease-modifying therapy approved for 5q spinal muscular atrophy (SMA). While clinical trials and open-label extensions have demonstrated significant benefits in infants and young children (up to 12 years), data regarding long-term safety, effectiveness, and persistence in adolescents and adults remains limited and conflicting.

• The Gap: Existing real-world studies often suffer from selection bias (focusing only on treated patients in referral centers), short follow-up periods (<3 years), and a lack of untreated control groups.
• The Challenge: It is unclear whether nusinersen provides sustained functional improvement in older populations or if the invasive nature of intrathecal administration (lumbar punctures) outweighs the benefits, leading to high discontinuation rates.

2. Methodology

The study employed a single-center, ambispective, population-based observational design covering the entire Valencian Community in Spain (approx. 5 million inhabitants).

• Cohort: 72 genetically confirmed SMA patients living in the region were included (18 children <12 years; 54 adolescents/adults ≥12 years).
  • Follow-up: Median of 7 years (IQR 5.5–7.4), extending from September 2017 to December 2025.
  • Groups: Patients were categorized into:
    1. Children (<12) treated with nusinersen.
    2. Adolescents/Adults (≥12) treated with nusinersen (sustained vs. discontinued).
    3. Adolescents/Adults (≥12) who remained untreated (serving as an external comparator).
• Intervention: Nusinersen administered via lumbar puncture (4 loading doses, then every 4 months). Radiological guidance was used for patients with complex spines.
• Outcome Measures:
  • Primary Metric: SMA-FCR (Spinal Muscular Atrophy Functional Composite Score Revised), a composite score merging HFMSE, RULM, and 6MWT to minimize floor/ceiling effects across different phenotypes.
  • Classification: Patients were classified as sustained responders, partial responders, or non-responders.
  • Discontinuation Analysis: Reasons for stopping treatment were recorded (burden, loss of benefit, lack of benefit).
• Statistical Analysis:
  • Bayesian Modeling: Used to assess independent predictors (age, sex, baseline SMA-FCR) for nusinersen discontinuation in the ≥12 cohort.
  • Mixed Linear Regression: Used to model SMA-FCR trajectories over time across the three subgroups (untreated, discontinued, sustained treatment), adjusting for age and sex.

3. Key Contributions

• Population-Based Design: Unlike center-based studies prone to selection bias, this study captured the entire regional SMA population, including untreated patients and those who discontinued therapy, providing a more realistic "real-world" efficacy profile.
• Long-Term Data: With a median follow-up of 7 years, it offers one of the longest longitudinal assessments of nusinersen in adults.
• Comparative Trajectory Analysis: It directly compares the natural history of untreated adults against treated groups, distinguishing between disease stabilization (natural history) and true therapeutic improvement.
• Predictive Modeling: Identification of specific demographic and clinical predictors for treatment discontinuation.

4. Key Results

A. Pediatric Cohort (<12 years)

• Adherence: 100% of children were treated.
• Efficacy: 100% were classified as responders (15 sustained, 3 partial).
• Trajectory: SMA-FCR scores improved significantly during the first two years of treatment and then stabilized.
• Discontinuation: Very low (11%); reasons included death (unrelated to SMA) or switching to a clinical trial.

B. Adolescent/Adult Cohort (≥12 years)

• Treatment Initiation: Only 54% (28/52 eligible) initiated nusinersen; 46% remained untreated initially (mostly due to patient preference for oral options or lack of perceived need).
• Efficacy & Response:
  • Non-responders: 32% (9/28).
  • Partial Responders: 43% (12/28).
  • Sustained Responders: 25% (7/28).
• Discontinuation Rates: Extremely high at 75% (21/28).
  • Median time to discontinuation: 35 months.
  • Primary Reasons: Treatment burden (71%), loss of initial benefit (53%), and lack of perceived benefit (43%).
• Predictors of Discontinuation (Bayesian Model):
  • Older age: Independent risk factor (ExpEstimate = 1.028).
  • Lower baseline SMA-FCR: Independent risk factor (ExpEstimate = 0.84).
  • Female sex: Associated with higher risk (likely due to post-lumbar puncture headache susceptibility and procedural burden).
• Trajectory Analysis:
  • Sustained Treatment Group: Showed a mild increase in SMA-FCR (+0.97 points/year) followed by stabilization.
  • Discontinued Group: Trajectory mirrored the untreated group, showing stability or slight deterioration, suggesting that stopping treatment reverted patients to their natural disease course.
  • Untreated Group: Showed stability over time, indicating that long-term stability can be part of the natural history in adult SMA, not necessarily a treatment effect.

C. Safety

• Adverse events were generally mild and related to the administration procedure.
• Two adult patients developed moderate neurogenic bladder attributed to nusinersen; symptoms partially resolved upon discontinuation.

5. Significance and Conclusion

• Age-Dependent Efficacy: The study confirms that nusinersen is highly effective and persistent in children but faces significant challenges in adolescents and adults.
• Risk-Benefit Ratio: In adults, the invasive nature of intrathecal administration often outweighs the benefits for those with lower baseline function or older age. The "burden of treatment" is a primary driver for discontinuation.
• Patient Selection: The study identifies a specific subset of adults who benefit long-term: younger (<40), male, ambulatory patients with higher baseline SMA-FCR scores.
• Clinical Implications:
  • Clinicians should set realistic expectations for older adults and those with severe baseline impairment.
  • The availability of oral alternatives (e.g., risdiplam) is crucial for improving persistence in populations where intrathecal burden is a barrier.
  • Future research must focus on identifying biomarkers to predict response before initiating invasive therapy in adult populations.

Summary: While nusinersen remains a cornerstone of SMA care, this population-based study highlights a stark divergence in outcomes between children and adults. Long-term success in adults is limited to a specific phenotype, with the majority discontinuing due to procedural burden and diminishing returns, underscoring the urgent need for less invasive therapeutic options and better predictive biomarkers.