Nusinersen (1) – Spinraza®

• Clinical trials
  • The ENDEAR trial is a randomised, double-blind, multicentre Phase III trial, which included approximately equal numbers of boys and girls with infantile, genetically confirmed 5q-SMA.
  • The CHERISH registration trial is also a randomised, double-blind, sham-controlled, multicentre Phase III trial.
  • The open-label, multicentre, single-arm Phase II NURTURE trial enrolled 25 presymptomatic patients aged ≤ 6 weeks whose condition was confirmed by genetic testing.

a) For patients with 5q-associated spinal muscular atrophy (5q-SMA) type 1

• The G-BA classifies the extent of the additional benefit of nusinersen as ‘major’ for patients with type 1 5q-SMA, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in the treatment of the condition.
• This represents a significant improvement in treatment-related benefit that has not been achieved to date, in particular due to a major prolongation of survival, an alleviation of disease-defining symptoms and a reduction in serious side effects, taking into account the uncertainties outlined.
• mortality
  • The time from administration of the first dose of the study medication or randomisation until the occurrence of death was recorded over the entire study period.
  • Thirteen (16%) patients died in the nusinersen group compared with 16 patients (39%) receiving best-supportive care (BSC), meaning that the risk of death was statistically significantly reduced by 63.3% with nusinersen treatment (hazard ratio (HR): 0.367; 95% confidence interval (CI): [0.18; 0.76]; p=0.0074).
  • Median survival was not reached in either study arm.
• Morbidity – time to death or to the need for permanent ventilation
  • For the combined endpoint ‘time to death or to permanent ventilation’, only the first event to occur was counted in each case.
  • Overall, the risk of death or the need for permanent ventilation was statistically significantly reduced by 53% in the nusinersen arm compared with the control arm (HR: 0.47; 95% CI: [0.28; 0.78]; p=0.0037).
  • The median time to death or permanent ventilation in the placebo group was 22.6 weeks (95% CI: [13.6; 31.3]); with nusinersen, the median time to the event could not be determined (n.a.; 95% CI: [36.3; n.a.]).
  • In the separate analysis of the composite endpoint relating to ventilation of ≥ 16 hours/day continuously for more than 21 days in the absence of an acute, reversible event or tracheotomy, no statistically significant difference was observed.
• Morbidity – Hammersmith Infant Neurological Examination – HINE (subscale 2)
  • A statistically significant improvement was observed in the achievement of motor milestones for treatment with nusinersen (difference in mean values (MV): 3.60; 95% CI: [2.29; 4.90]; p<0.0001).
  • The effect can be classified as clinically relevant, as the 95% confidence interval of the standardised mean difference lies above the irrelevance threshold of 0.2 (Hedges’ g: 1.05 (95% CI: [0.64; 1.44]; p < 0.0001).
• Morbidity – Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disease – CHOP INTEND
  • The change in total scores from baseline shows a statistically significant increase in the nusinersen arm compared with the control arm (difference in mean: 18.66; 95% CI: [15.42; 21.90]; p<0.0001).
  • The effect can be classified as clinically relevant, as the 95% confidence interval of the standardised mean difference lies above the irrelevance threshold of 0.2 (Hedges’ g: 2.19; 95% CI: [1.72; 2.66]; p<0.0001).
• Morbidity – Incidence of serious respiratory events
  • In the post-hoc analysis of serious AEs classified under the System Organ Class (SOC) ‘Diseases of the respiratory tract, thoracic cavity and mediastinum’, no statistically significant difference was observed between the intervention and control arms.
• Morbidity – incidence of hospitalisations
  • The total duration of hospital stays per study participant per study day was presented as an adjusted rate. No statistically significant difference was observed between the treatment arms.
• quality of life
  • The ENDEAR study did not assess health-related quality of life.
• Side effects
  • Over 95% of patients experienced an adverse event (AE) in the ENDEAR study.
  • A statistically significant difference in favour of nusinersen was observed in the ENDEAR study with regard to the reduction in the relative risk (RR) of severe AEs (RR=0.70; 95% CI: [0.55; 0.89]; p=0.004), serious AEs (RR=0.80; 95% CI: [0.70; 0.92]; p=0.002) and therapy discontinuations due to AEs (RR=0.42; 95% CI [0.22; 0.78]; p=0.006).
  • All AEs that led to therapy discontinuation were fatal AEs.
  • The advantages of nusinersen with regard to AEs should be interpreted in light of the fact that symptoms were likely also recorded as AEs, and therefore the probability of double-counting exists.
  • As it is not to be expected that more adverse events would occur with the administration of a sham intervention than with the administration of a placebo, and as, furthermore, no information is available on the avoidance of double-counting, the interpretability of these results is subject to uncertainty.
• Overall conclusion
  • Results from the ENDEAR study on mortality, morbidity and side effects are available for assessing the additional benefit of nusinersen in patients with 5q-SMA type 1.
  • Specifically, there are major advantages in terms of mortality (time to death); the median survival was not reached in the study.
  • Further advantages are emerging in the category of morbidity. The risk of death or the need for long-term ventilator support decreased statistically significantly.
  • The results of the HINE and CHOP INTEND studies (achievement of motor milestones) are interpreted as a significant, clinically relevant improvement in morbidity following treatment with nusinersen, although the validity of the assessment tools is downgraded due to the lack of final validation.
  • With regard to side effects, it should be noted that, despite a longer duration of treatment in the nusinersen arm, patients experienced statistically significantly fewer serious or severe AEs.

b) For patients with 5q-SMA type 2

• The G-BA classifies the extent of the additional benefit of nusinersen, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in the treatment of the condition for patients with Type 2 5q-SMA as considerable.
• This involves a previously unattained reduction in serious symptoms and a noticeable alleviation of the condition.
• mortality
  • Fatalities were recorded as part of the safety assessment. No patients died during the study.
• Morbidity – Hammersmith Functional Motor Scale Expanded (HFMSE)
  • The change in motor function from baseline to month 15 shows a statistically significant result in favour of nusinersen (Least Squares (LS) mean difference: 4.42; 95% CI: [2.46; 6.38]; p<0.0001).
  • The 95% confidence interval for Hedges’ g lies entirely above the irrelevance threshold of 0.2, suggesting a clearly clinically relevant effect (Hedges’ g: 0.99; 95% CI: [0.55; 1.42]; p<0.0001).
• Morbidity – Revised Upper Limb Module (RULM)
  • The changes from baseline to month 15 show statistically significant advantages for nusinersen (difference LS MW: 3.34; 95% CI: [1.87; 4.82]; p<0.0001); however, the clinical relevance cannot be conclusively assessed, as the lower end of the 95% confidence interval ([0.15; 1.0]; p=0.008) of Hedges’ g (0.57) does not lie entirely above the irrelevance threshold of 0.2.
• Morbidity – Incidence of serious respiratory events
  • In line with the analysis in the ENDEAR study, serious AEs classified under the SOC ‘Diseases of the respiratory tract, thoracic cavity and mediastinum’ were analysed post hoc.
  • The results show no statistically significant difference for this endpoint between nusinersen and the sham intervention.
• Morbidity – incidence of disease-related hospitalisations
  • Here, a statistically significant difference was observed between the treatment arms in favour of nusinersen (rate ratio: 0.35; 95% CI: [0.14; 0.87]; p=0.02), although it remains unclear whether there was any double-counting of hospitalisations during the recording of adverse events.
• Quality of life – Paediatric Quality of Life Inventory (PedsQL)
  • The quality of life data are therefore not usable for evaluation due to the low questionnaire response rate throughout the entire study duration.
• Side effects
  • Every patient in the control group and 93% of those in the intervention group experienced an AE, none of which led to therapy discontinuation.
  • There is no advantage or disadvantage associated with treatment with nusinersen.
• Overall conclusion
  • The results of the CHERISH study on mortality, morbidity, quality of life and side effects are available for assessing the additional benefit of nusinersen in patients with 5q-SMA type 2.
  • In the overall assessment of the results for nusinersen, the potential for bias at both the study and endpoint levels is classified as low.
  • The available data do not allow an assessment of the extent of the additional benefit of nusinersen, either in terms of mortality or quality of life.
  • With regard to morbidity, statistically significant, clinically relevant advantages were observed for treated patients in terms of motor function, as measured by the change in the HFMSE score from baseline to the end of the study.
  • Patients in the nusinersen arm were hospitalised for disease-related reasons less frequently, although this finding is subject to uncertainty.
  • With regard to general side effects, treatment with nusinersen shows neither advantages nor disadvantages in the AE or SAE presented.

c) For patients with 5q-SMA type 3

• Consequently, the G-BA classifies the extent of the non-quantifiable additional benefit of nusinersen on the basis of the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition.
• An additional benefit exists, but is non-quantifiable because the scientific evidence does not permit this.
• As the pharmaceutical manufacturer did not submit any separate analyses for patients with 5q-SMA type 3 from the CHERISH study, there are no evaluable data available for this patient population.

d) For patients with 5q-SMA type 4

• The pharmaceutical manufacturer has not provided any data for these patient groups.
• There is an additional benefit in accordance with Section 35a(1), sentence 11, first half-sentence of SGB V, but it is non-quantifiable because the scientific data available does not permit this.

Courtesy translation only, please refer to the German original.