SPINRAZA Solution for injection Ref.[9367] Active ingredients: Nusinersen

Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system
ATC code: M09AX07

Mechanism of action

Nusinersen is an antisense oligonucleotide (ASO) which increases the proportion of exon 7 inclusion in survival motor neuron 2 (SMN2) messenger ribonucleic acid (mRNA) transcripts by binding to an intronic splice silencing site (ISS-N1) found in intron 7 of the SMN2 pre-messenger ribonucleic acid (pre-mRNA). By binding, the ASO displaces splicing factors, which normally suppress splicing. Displacement of these factors leads to retention of exon 7 in the SMN2 mRNA and hence when SMN2 mRNA is produced, it can be translated into the functional full length SMN protein.

SMA is a progressive neuromuscular disease resulting from mutations in chromosome 5q in the SMN1 gene. A second gene SMN2, located near SMN1, is responsible for a small amount of SMN protein production. SMA is a clinical spectrum of disease with disease severity linked to fewer numbers of SMN2 gene copies and younger age of symptom onset.

Clinical efficacy and safety

Symptomatic patients

Infantile onset

Study CS3B (ENDEAR) was a Phase 3, randomized, double-blind, sham-procedure controlled study conducted in 121 symptomatic infants ≤7 months of age, diagnosed with SMA (symptom onset before 6 months of age). CS3B was designed to assess the effect of Spinraza on motor function and survival. Patients were randomized 2:1 to either Spinraza (as per the approved dosing regimen) or sham-control, with a length of treatment ranging from 6 to 442 days.

The median age of onset of clinical signs and symptoms of SMA was 6.5 weeks and 8 weeks for Spinraza treated versus sham-control patients respectively, with 99% of patients having 2 copies of the SMN2 gene and therefore deemed most likely to develop Type I SMA. The median age when patients received their first dose was 164.5 days for treated patients, and 205 days for sham-control. Baseline disease characteristics were largely similar in the Spinraza treated patients and sham-control patients except that Spinraza treated patients at baseline had a higher percentage compared to sham-control patients of paradoxical breathing (89% vs 66%), pneumonia or respiratory symptoms (35% vs 22%), swallowing or feeding difficulties (51% vs 29%) and requirement for respiratory support (26% vs 15%).

At the final analysis, a statistically significant greater percentage of patients achieved the definition of a motor milestone responder in the Spinraza group (51%) compared to the sham-control group (0%) (p<0.0001). Time to death or permanent ventilation (≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event or tracheostomy) was assessed as the primary endpoint. Statistically significant effects on event-free survival, overall survival, the proportion of patients achieving the definition of a motor milestone responder, and the percentage of patients with at least a 4-point improvement from baseline in Children’s Hospital of Philadelphia Infant Test for Neuromuscular Disease (CHOP INTEND) score were observed in patients in the Spinraza group compared to those in the sham-control group (Table 2).

In the efficacy set, 18 patients (25%) in the Spinraza group and 12 patients (32%) in the sham-control group required permanent ventilation. Of these patients, 6 (33%) in the Spinraza group and 0 (0%) in the sham-control group met the protocol-defined criteria for a motor-milestone responder.

Table 2. Primary and secondary endpoints at final analysis – Study CS3B:

¹ CS3B was stopped following positive statistical analysis on the primary endpoint at interim analysis (statistically significantly greater percentage of patients achieved the definition of a motor milestone responder in the Spinraza group (41%) compared to the sham-control group (0%), p<0.0001)
² At the final analysis, event-free survival and overall survival were assessed using the Intent to Treat population (ITT Spinraza n=80; Sham-control n=41).
³ At the final analysis, CHOP INTEND and motor milestone analyses were conducted using the Efficacy Set (Spinraza n=73; Sham-control n=37).
⁴ Assessed at the later of Day 183, Day 302, and Day 394 Study Visit
⁵ According to Hammersmith Infant Neurological Examination (HINE) section 2: ≥2 point increase [or maximal score] in ability to kick, OR ≥1 point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking, AND improvement in more categories of motor milestones than worsening, defined as a responder for this primary analysis.
⁶ Based on log-rank test stratified by disease duration

The extent of improvement in CHOP INTEND is shown in Figure 1 (change from baseline score for each subject).

Figure 1. Change in CHOP INTEND from Baseline to Later of Day 183, Day 302, and Day 394 Study Visit – Endear Study/CS3B (Efficacy Set, ES):

To allow for long term follow up of these patients, at the end of Study CS3B, 89 patients (Spinraza: n=65; sham-control: n=24) enrolled in Study CS11 (SHINE). Study CS11 is an open label extension study for SMA patients who previously participated in the other Spinraza clinical studies. In Study CS11 all patients received Spinraza, with the length of treatment ranging from 65 to 592 days (median 289 days) at the time of interim analysis. Improvements in motor function were observed among patients continuing Spinraza from Study CS3B, as well as those who initiated Spinraza in Study CS11 (Figure 3), with the greatest benefit observed in those with earlier treatment initiation. Among patients without permanent ventilation at the baseline of Study CS11, a majority were alive and without permanent ventilation at the time of interim analysis.

In patients randomized to Spinraza in Study CS3B and including the experience in Study CS11, the median time to death or permanent ventilation was 73 weeks. At the time of a Study CS11 interim analysis, 61 out of 65 patients (94%) were alive. Of the 45 patients who had not met the definition of permanent ventilation in Study CS3B, 38 patients (84%) were alive without permanent ventilation in Study CS11 at the time of interim analysis. Further improvement in mean total motor milestone (HINE-Section 2) (2.1; SD 4.36; n=22) and CHOP INTEND (4.68; SD 3.993, n=22) scores were observed from baseline to Study Day 304 in Study CS11.

Patients who first initiated Spinraza treatment in Study CS11 (n=24; sham control in Study CS3B) were of a median age of 17.8 months (range 10-23 months) and had a mean CHOP INTEND score of 17.25 (range 2.0-46.0) at baseline in Study CS11. At the time of interim analysis, 22 out of 24 patients (92%) were alive. Of the twelve patients (50%) who had not met the definition of permanent ventilation in Study CS3B, 7 patients (58%) were alive without permanent ventilation in Study CS11. The median time to death or permanent ventilation was 50.9 weeks after initiation of Spinraza treatment in Study CS11. Improvement in mean total motor milestone (HINE-Section 2) (1.2; SD 1.8; n=12) and CHOP INTEND (3.58; SD 7.051, n=12) scores were observed from baseline to Study Day 304 in Study CS11.

These results are supported by an open-label Phase 2 study in symptomatic patients diagnosed with SMA (CS3A). Median age of onset of clinical signs and symptoms was 56 days and patients had either 2 SMN2 gene copies (n=17) or 3 SMN2 gene copies (n=2) (SMN2 gene copy number unknown for 1 patient). Patients in this study were deemed most likely to develop Type I SMA. The median age at first dose was 162 days.

The primary endpoint was the proportion of patients who improved in one or more categories in motor milestones (according to HINE section 2: ≥2 point increase [or maximal score] in ability to kick or voluntary grasp OR ≥1 point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking). Twelve out of 20 patients (60%) in the study met the primary endpoint with improvement in mean motor milestone achievement over time. An improvement in mean CHOP INTEND score over time was observed from baseline to day 1072 (mean change 21.30). Overall, 11 out of 20 patients (55%) met the endpoint of an increase in total CHOP INTEND score of ≥4 points as of the last study visit. Of the 20 subjects enrolled, 11 (55%) were alive and free of permanent ventilation at the last visit. Four patients met the criteria for permanent ventilation and five patients died during the study.

Later onset

Study CS4 (CHERISH) was a Phase 3, randomised, double-blind, sham-procedure controlled study conducted in 126 symptomatic patients with later-onset SMA (symptom onset after 6 months of age). Patients were randomized 2:1 to either Spinraza (dosed with 3 loading doses and maintenance doses every 6 months) or sham-control, with a length of treatment ranging from 324 to 482 days. The median age at screening was 3 years, and the median age of onset of clinical signs and symptoms of SMA was 11 months. The majority of patients (88%) have 3 copies of the SMN2 gene (8% have 2 copies, 2% have 4 copies, and 2% have an unknown copy number). At baseline, patients had a mean Hammersmith Functional Motor Scale Expanded (HFMSE) score of 21.6, a mean revised upper limb module (RULM) of 19.1, all had achieved independent sitting, and no patients had achieved independent walking. Patients in this study were deemed most likely to develop Type II or III SMA. Baseline disease characteristics were generally similar with the exception of an imbalance in the proportion of patients who had ever achieved the ability to stand without support (13% of patients in the Spinraza group and 29% in sham-control) or walk with support (24% of patients in the Spinraza group and 33% in sham-control).

At the final analysis, a statistically significant improvement in HFMSE score from baseline to Month 15 was seen in the Spinraza group compared to the sham-control group (Table 3, Figure 2). The analysis was conducted in the ITT population (Spinraza: n=84; sham-control: n=42), and post-baseline HFMSE data for patients without a Month 15 visit were imputed using the multiple imputation method. An analysis of the subset of patients in the ITT population who had observed values at Month 15 demonstrated consistent, statistically significant results. Of those with observed values at Month 15, a higher proportion of Spinraza treated subjects had improvement (73% vs 41%, respectively) and a lower proportion of Spinraza treated subjects had worsening (23% vs 44%, respectively) in total HFMSE score compared to sham-control. Secondary endpoints including functional measures and WHO motor milestone achievement were formally statistically tested and are described in Table 3.

Initiation of treatment sooner after symptom onset resulted in earlier and greater improvement in motor function than those with delayed treatment initiation; however, both groups experienced benefit compared to sham-control.

Table 3. Primary and secondary endpoints at final analysis – Study CS4 1:

¹ CS4 was stopped following positive statistical analysis on the primary endpoint at interim analysis (statistically significant improvement from baseline HFMSE score was observed in Spinraza treated patients compared to the sham-control patients (Spinraza vs. sham-control: 4.0 vs. -1.9; p=0.0000002))
² Assessed using the Intent to Treat population (Spinraza n=84; Sham-control n=42); data for patients without a Month 15 visit were imputed using the multiple imputation method
³ Least squares mean
⁴ Assessed using the Month 15 Efficacy Set (Spinraza n=66; Sham control n=34); analyses are based on imputed data when there are missing data.
⁵ Based on logistic regression with treatment effect and adjustment for each subject’s age at screening and HFMSE score at baseline
⁶ Nominal p value

Figure 2. Mean change from baseline in HFMSE score over time at final analysis (ITT) – Study CS4^1,2:

Upon completion of Study CS4 (CHERISH) 125 patients enrolled in Study CS11 (SHINE), where all patients received Spinraza. The length of treatment ranged from 74 to 474 days (median 250 days) at the time of the interim analysis. A majority of Spinraza treated patients experienced stabilization or improvement in motor function, with the greatest benefit observed in those with earlier treatment initiation.

Of patients who initiated Spinraza treatment in Study CS4 (n=39), stabilization or additional improvements in mean HFMSE (0.2; SD 3.06) and RULM (0.7; SD 2.69) scores were observed from baseline to Study Day 265 in Study CS11.

Patients who initiated Spinraza treatment in Study CS11 (n=20) had a median age of 4.0 years (range 3-8 years). Of these patients, stabilization or improvement in mean HFMSE (1.4; SD 4.02) and RULM (2.1; SD 2.56) scores were observed from baseline to Study Day 265 in Study CS11.

These results are supported by 2 open label studies (study CS2 and study CS12). The analysis included 28 patients who received their first dose in study CS2, and then transferred to the extension phase, study CS12. The studies enrolled patients who were between 2 to 15 years of age at first dose. Of the 28 patients, 3 were at least 18 years of age at their last study visit. 1 out of 28 patients had 2 SMN2 gene copies, 21 had 3 copies, and 6 had 4 copies.

Patients were assessed over a 3 year treatment period. A sustained improvement was seen in patients with Type II SMA who experienced a mean improvement from baseline HFMSE score of 5.1 (SD 4.05, n=11) at Day 253, and 9.1(SD 6.61, n=9) at Day 1050. The mean total score was 26.4 (SD 11.91) at Day 253 and 31.3 (SD 13.02) at Day 1050, no plateau was observed. Patients with Type III SMA demonstrated a mean improvement from baseline HFMSE score of 1.3 (SD 1.87, n=16) at Day 253 and 1.2 (SD 4.64, n=11) at Day 1050. The mean total score was 49.8 (SD 12.46) at Day 253 and 52.6 (SD 12.78) at 1050 days.

In patients with Type II SMA the Upper Limb Module test was conducted with mean improvement of 1.9 (SD 2.68, n=11) at Day 253 and 3.5 (SD 3.32, n=9) at Day 1050. The mean total score was13.8 (SD 3.09) at Day 253 and 15.7 (SD 1.92) at Day 1050.

The 6MWT (six-minute walk test) was conducted for ambulatory patients only. In these patients, a mean improvement of 28.6 meters (SD 47.22, n=12) at Day 253 and 86.5 metres (SD 40.58, n=8) at Day 1050. The mean 6MWT distance was 278.5 meters (SD 206.46) at Day 253 and 333.6 metres (SD 176.47) at Day 1050. Two previously non-independent ambulatory patients (Type III) achieved independent walking, and one non-ambulatory patient (Type II) achieved independent walking.

An additional clinical study, CS7 (EMBRACE) was opened for patients not eligible for participation in Study CS3B or Study CS4 due to screening age or SMN2 copy number. CS7 is a phase 2, randomized, double-blind, sham-procedure study in symptomatic patients diagnosed with infantile-onset SMA (≤6 months) or later-onset SMA (>6 months) and 2 or 3 copies of SMN2 (Part 1), followed by a long-term open label extension phase (Part 2). In Part 1 of the study, patients were followed for a median of 302 days.

All patients who received Spinraza were alive as of the early termination of Part 1, however, one patient in the control arm died at Study Day 289. In addition, no patients in the Spinraza or sham- control group required the use of permanent ventilation. Of the 13 patients with infantile-onset SMA, 7 of out 9 patients (78%; 95%CI: 45, 94) in the Spinraza group and 0 out of 4 patients (0%; 95%CI: 0, 60) in the sham group met the criteria for motor milestone response (according to HINE section 2: ≥2 point increase [or maximal score] in ability to kick OR ≥1 point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking and improvement in more categories of motor milestones than worsening). Of the 8 patients with later-onset SMA, 4 out of 5 patients (80%; 95% CI: 38, 96) in the Spinraza group and 2 out of 3 (67%; 95% CI: 21, 94) in the sham-control group met this definition of response.

Pre-symptomatic infants

Study CS5 (NURTURE) is an open-label study in pre-symptomatic infants genetically diagnosed with SMA, who were enrolled at 6 weeks of age or younger. Patients in this study were deemed most likely to develop Type I or II SMA. Median age at first dose was 22 days.

An interim analysis was conducted when patients had been on study for median of 27.1 months (15.1-35.5 months) and were of a median age at last visit of 26.0 months (14.0-34.3 months). At the interim analysis, all 25 patients (2 SMN2 gene copies, n=15; 3 SMN2 gene copies, n=10) were alive without permanent ventilation. The primary endpoint, time to death or respiratory intervention (defined as invasive or non-invasive ventilation for ≥6 hours/day continuously for ≥7 consecutive days OR tracheostomy), could not be estimated as there were too few events. Four patients (2 SMN2 copies) required respiratory intervention >6 hours/day continuously for ≥7 days, all of whom initiated ventilatory support during an acute reversible illness.

Patients achieved milestones unexpected in Type I or II SMA and more consistent with normal development. At the interim analysis, all 25 (100%) patients had achieved the WHO motor milestone of sitting without support, 22 (88%) patients were walking with assistance. Among patients older than the WHO defined window for expected age of achievement (95 th percentile), 17 of 22 (77%) had achieved walking alone. The mean CHOP INTEND score at last assessment was 61.0 (46-64) amongst patients with 2 SMN2 copies and 62.6 (58-64) amongst those with 3 SMN2 copies. All patients had the ability to suck and swallow at last assessment, with 22 (88%) infants achieving a maximal score on the HINE Section 1.

The proportion of patients developing clinically manifested SMA was assessed amongst patients who reached the Day 700 visit at the interim analysis (n=16). The protocol-defined criteria for clinically manifested SMA included age-adjusted weight below the fifth WHO percentile, a decrease of 2 or more major weight growth curve percentiles, the placement of a percutaneous gastric tube, and/or the inability to achieve expected age-appropriate WHO milestones (sitting without support, standing with assistance, hands-and-knees crawling, walking with assistance, standing alone and walking alone). At day 700, 7 out of 11 patients (64%) with 2 SMN2 gene copies and 0 out of 5 patients (0%) with 3 SMN2 copies, met the protocol-defined criteria of clinically manifested SMA, however, these patients were gaining weight and achieving WHO milestones, inconsistent with Type I SMA. A comparison of motor milestone achievement among the patients with symptomatic infantile-onset SMA and pre-symptomatic SMA is shown in Figure 3.

Figure 3. Change in HINE Motor Milestones versus Study days for Study CS3B (treated and sham-control), CS3A, CS5 and CS11: