SPINRAZA 12mg 2.4mg / ml injectible solution medication leaflet

Spinraza 12 mg solution for injection

Each 5 ml vial contains nusinersen sodium equivalent to 12 mg nusinersen.

Each ml contains 2.4 mg of nusinersen.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear and colourless solution with pH of approximately 7.2.

Spinraza is indicated for the treatment of 5q Spinal Muscular Atrophy.

Treatment with Spinraza should only be initiated by a physician with experience in the management ofspinal muscular atrophy (SMA).

The decision to treat should be based on an individualised expert evaluation of the expected benefits oftreatment for that individual, balanced against the potential risk of treatment with Spinraza. Patientswith profound hypotonia and respiratory failure at birth, where Spinraza has not been studied, may notexperience a clinically meaningful benefit due to severe survival motor neuron (SMN) proteindeficiency.

The recommended dosage is 12 mg (5 ml) per administration.

Spinraza treatment should be initiated as early as possible after diagnosis with 4 loading doses on

Days 0, 14, 28 and 63. A maintenance dose should be administered once every 4 months thereafter.

Information on long term efficacy of this medicinal product is not available. The need for continuationof therapy should be reviewed regularly and considered on an individual basis depending on thepatient’s clinical presentation and response to the therapy.

Missed or delayed doses

If a loading or a maintenance dose is delayed or missed, Spinraza should be administered according tothe schedule in Table 1 below.

Table 1: Recommendations for delayed or missed dose

Delayed or missed dose Timing of Dosing Administration

Loading dose

* Administer the delayed or missed loading dose as soon as possible with at least 14 daysbetween doses; continue with subsequent doses on the prescribed intervals from the last dose.

e.g. if the third loading dose is administered 30 days late at Day 58 (instead of the original scheduleat Day 28), then the fourth loading dose should be administered 35 days later at Day 93 (instead ofthe original schedule at Day 63) with a maintenance dose 4 months thereafter.

Maintenance dose Timing of Dosing Administration> 4 to < 8 months from last * Administer the delayed maintenance dose as soon asdose possible; then

* The next maintenance dose per the original scheduled date, aslong as these two doses are administered at least 14 days apart*;≥ 8 to < 16 months from * Administer the missed dose as soon as possible and then the nextlast dose dose 14 days later*;≥ 16 to < 40 months from * Administer the missed dose as soon as possible and then the nextlast dose dose 14 days later, followed by a third dose 14 days later*;≥ 40 months from last dose * Administer the entire loading regimen on the prescribed intervals(Days 0, 14, 28 and 63)*;

*then subsequently to the above recommendations, a maintenance dose 4 months after the last doseshould be administered and repeated every 4 months.

Nusinersen has not been studied in patients with renal impairment. The safety and efficacy in patientswith renal impairment has not been established and they should be closely observed.

Nusinersen has not been studied in patients with hepatic impairment. Nusinersen is not metabolisedvia the cytochrome P450 enzyme system in the liver, therefore dose adjustment is unlikely to berequired in patients with hepatic impairment (see sections 4.5 and 5.2).

Spinraza is for intrathecal use by lumbar puncture.

Treatment should be administered by health care professionals experienced in performing lumbarpunctures.

Spinraza is administered as an intrathecal bolus injection over 1 to 3 minutes, using a spinalanaesthesia needle. The injection must not be administered in areas of the skin where there are signs ofinfection or inflammation. It is recommended that the volume of cerebral spinal fluid (CSF),equivalent to the volume of Spinraza to be injected, is removed prior to administration of Spinraza.

Sedation may be required to administer Spinraza, as indicated by the clinical condition of the patient.

Ultrasound (or other imaging techniques) may be considered to guide intrathecal administration of

Spinraza, particularly in younger patients and in patients with scoliosis; see instructions for use insection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Lumbar puncture procedure

There is a risk of adverse reactions occurring as part of the lumbar puncture procedure (e.g.arachnoiditis, headache, back pain, vomiting; see section 4.8). Potential difficulties with this route ofadministration may be seen in very young patients and those with scoliosis. The use of ultrasound orother imaging techniques to assist with intrathecal administration of Spinraza, can be considered at thephysician’s discretion. Should arachnoiditis be suspected, an MRI should be performed to confirmarachnoiditis and the extent of the inflammation. Identification of arachnoiditis precludes the use ofthe injection site until local inflammation has been ruled out.

Thrombocytopenia and coagulation abnormalities

Thrombocytopenia and coagulation abnormalities, including acute severe thrombocytopenia, havebeen observed after administration of other subcutaneously or intravenously administered antisenseoligonucleotides. If clinically indicated, platelet and coagulation laboratory testing is recommendedprior to administration of Spinraza.

Renal toxicity

Renal toxicity has been observed after administration of other subcutaneously and intravenouslyadministered antisense oligonucleotides. If clinically indicated, urine protein testing (preferably usinga first morning urine specimen) is recommended. For persistent elevated urinary protein, furtherevaluation should be considered.

Hydrocephalus

There have been reports of communicating hydrocephalus not related to meningitis or bleeding inpatients treated with nusinersen in the post-marketing setting. Some patients were implanted with aventriculo-peritoneal shunt. In patients with decreased consciousness, an evaluation for hydrocephalusshould be considered. The benefits-and risks of nusinersen treatment in patients with a ventriculo-peritoneal shunt are unknown at present and the maintenance of treatment needs to be carefullyconsidered.

This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml vial, that is to sayessentially ‘sodium-free’.

This medicinal product contains potassium, less than 1 mmol (39 mg) per 5 ml vial, i.e. essentially‘potassium-free’.

No interaction studies have been performed. In vitro studies indicated that nusinersen is not an induceror inhibitor of CYP450 mediated metabolism. In vitro studies indicate that the likelihood forinteractions with nusinersen due to competition for plasma protein binding, or competition with orinhibition of transporters is low.

There are no or limited amount of data from the use of nusinersen in pregnant women. Animal studiesdo not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of nusinersen during pregnancy.

It is unknown whether nusinersen/metabolites are excreted in human milk.

A risk to the newborn/infants cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from nusinersen therapy taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

In toxicity studies in animals no effects on male or female fertility were observed (see section 5.3).

There are no data available on the potential effects on fertility in humans.

Nusinersen has no or negligible influence on the ability to drive and use machines.

The most common adverse reactions (ADRs) associated with the administration of Spinraza by lumbarpuncture were headache, vomiting and back pain.

The safety of Spinraza was assessed in clinical trials based on two Phase 3 clinical studies in infants(CS3B) and children (CS4) with SMA, together with one Phase 2 study in infants and children with

SMA (CS7) and open-label studies including presymptomatic infants (CS5) genetically diagnosedwith SMA and infants and children with SMA. Study CS11 enrolled infantile and later-onset patientsincluding those who had completed studies CS3B, CS4 and CS12. Of the 352 patients who received

Spinraza up to a maximum of 10.8 years, 256 patients received treatment for at least 5 years.

The safety assessment of Spinraza is based on data from patients from clinical trials and from post-marketing surveillance. The ADRs associated with Spinraza administration are summarised in Table 2.

The assessment of undesirable effects is based on the following frequency data:

Very common (≥ 1/10)

Not known (cannot be estimated from the available data)

Table 2: Adverse reactions related to Spinraza administration

MedDRA System Organ Class Adverse reaction Frequency category

Infections and infestations Meningitis Not known

Immune system disorders Hypersensitivity** Not known

Nervous system disorders Headache* Very common

Aseptic meningitis Not known

Arachnoiditis Not known

Gastrointestinal disorders Vomiting* Very common

Musculoskeletal and connective Back pain* Very commontissue disorders

*Adverse reactions considered related to the lumbar puncture procedure. These reactions can be considered manifestations ofpost-lumbar puncture syndrome. These adverse reactions were reported in CS4 (later onset SMA) with an incidence at least5% higher in patients treated with Spinraza (n=84) compared to Sham control.

**e.g. angiodema, urticaria and rash.

Events of communicating hydrocephalus have been observed in the post-marketing setting (see section4.4).

Adverse reactions associated with the administration of Spinraza by lumbar puncture have beenobserved. The majority of these are reported within 72 hours of the procedure. The incidence andseverity of these events were consistent with events expected to occur with lumbar puncture. Noserious complications of lumbar puncture, such as serious infections, have been observed in theclinical trials of Spinraza.

Some adverse reactions commonly associated with lumbar puncture (e.g. headache and back pain)could not be assessed in the infant population exposed to Spinraza due to the limited communicationappropriate for that age group.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose associated with adverse reactions were reported in clinical studies.

In the event of an overdose, supportive medical care should be provided including consulting with ahealthcare professional and close observation of the clinical status of the patient.

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

M09AX07

Nusinersen is an antisense oligonucleotide (ASO) which increases the proportion of exon 7 inclusionin survival motor neuron 2 (SMN2) messenger ribonucleic acid (mRNA) transcripts by binding to anintronic splice silencing site (ISS-N1) found in intron 7 of the SMN2 pre-messenger ribonucleicacid (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 SMN2mRNA 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 SMN1gene. A second gene SMN2, located near SMN1, is responsible for a small amount of SMN proteinproduction. SMA is a clinical spectrum of disease with disease severity linked to fewer numbers of

SMN2 gene copies and younger age of symptom onset.

The immunogenic response to nusinersen was evaluated in 342 patients with post-baseline plasmasamples for ADAs. Overall, 36 Spinraza-treated patients (11%) developed treatment-emergent ADAs,of which 14 (4%) were transient and 22 (6%) were persistent. No discernible effects of ADAs onefficacy or safety have been observed as measured by incidence of AEs including hypersensitivity,anaphylactic reaction, and angio-oedema.

Symptomatic patients

Infantile onset

Study CS3B (ENDEAR) was a Phase 3, randomized, double-blind, sham-procedure controlled studyconducted in 121 symptomatic infants ≤ 7 months of age, diagnosed with SMA (symptom onset before6 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 patientsreceived their first dose was 164.5 days for treated patients, and 205 days for sham-control. Baselinedisease characteristics were largely similar in the Spinraza treated patients and sham-control patientsexcept that Spinraza treated patients at baseline had a higher percentage compared to sham-controlpatients 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 ofa motor milestone responder in the Spinraza group (51%) compared to the sham-controlgroup (0%) (p< 0.0001). Time to death or permanent ventilation (≥ 16 hours ventilation/daycontinuously for > 21 days in the absence of an acute reversible event or tracheostomy) was assessedas the primary endpoint. Statistically significant effects on event-free survival, overall survival, theproportion of patients achieving the definition of a motor milestone responder, and the percentage ofpatients 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 3).

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

Table 3: Primary and secondary endpoints at final analysis - Study CS3B

Efficacy Parameter Spinraza treated Patients Sham-control Patients

Survival

Event-free survival2

Number of patients who died or 31 (39%) 28 (68%)received permanent ventilation

Hazard ratio (95% CI) 0.53 (0.32 -0.89)p-value6 p = 0.0046

Overall survival2

Number of patients who died 13 (16%) 16 (39%)

Hazard Ratio (95% CI) 0.37 (0.18 - 0.77)p-value6 p=0.0041

Motor function

Motor milestones3

Proportion achieving pre-defined 37 (51%)1 0 (0%)motor milestone responder criteria p<0.0001(HINE section 2)4,5

Proportion at Day 183 41% 5%

Proportion at Day 302 45% 0%

Proportion at Day 394 54% 0%

Proportion with improvement in total 49 (67%) 5 (14%)motor milestone score

Proportion with worsening in total 1 (1%) 8 (22%)motor milestone score

CHOP INTEND3

Proportion achieving a 4-point 52 (71%) 1 (3%)improvement p<0.0001

Proportion achieving a 4-point 2 (3%) 17 (46%)worsening

Proportion with any improvement 53 (73%) 1 (3%)

Proportion with any worsening 5 (7%) 18 (49%)1CS3B was stopped following positive statistical analysis on the primary endpoint at interim analysis (statisticallysignificantly greater percentage of patients achieved the definition of a motor milestone responder in the Spinrazagroup (41%) compared to the sham-control group (0%), p<0.0001)2At 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).3At the final analysis, CHOP INTEND and motor milestone analyses were conducted using the Efficacy Set (Spinraza n=73;

Sham-control n=37).4Assessed at the later of Day 183, Day 302, and Day 394 Study Visit5According to Hammersmith Infant Neurological Examination (HINE) section 2: ≥2 point increase [or maximal score] inability 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.6Based on log-rank test stratified by disease duration

The extent of improvement in CHOP INTEND is shown in Figure 1 (change from baseline score foreach 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-labelextension study for SMA patients who previously participated in the other Spinraza clinical studies. Inpatients randomised to Spinraza in Study CS3B and including the extension of treatment with Spinrazain Study CS11, patients received the medication for 6 to 3043 days (median 2443 days). In patientsrandomised to sham in Study CS3B and initiating Spinraza in Study CS11, patients received themedication for 65 to 2520 days (median 2090 days).

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 benefitobserved in those with earlier treatment initiation. The majority of patients were alive at their last visitafter initiating treatment with Spinraza in either Study CS3B or Study CS11.

Patients initiating Spinraza in Study CS3B were of median age 5.5 months (range 1.7 to 14.9 months).

From Spinraza initiation and including extension of treatment in Study CS11, the median time to deathor permanent ventilation was 1.4 years. At the end of Study CS11, 60 out of 81 patients (74%) werealive and 41 out of 81 patients (51%) were alive and had not met the Study CS11 definition ofpermanent ventilation. Mean HINE-2 total motor milestonescore increased by 5.3 (SD 4.6; n=52) and

CHOP INTEND score increased by 18.4 (SD 14.7; n=38) points from initiation of Spinraza to followup visit day 394 and 2198 respectively.

Patients randomised to sham in Study CS3B and initiating Spinraza in Study CS11 were of a medianage of 17.8 months (range 10.1 to 23.0 months). Prior to Spinraza initiation 12 out of 24 patients(50%) had met the Study CS11 definition of permanent ventilation. The median time to death orpermanent ventilation was 2.76 years after initiation of Spinraza in Study CS11. At the end of Study

CS11, 19 out of 24 patients (79%) were alive and 6 out of 12 patients (50%) were alive withoutpermanent ventilation. Improvement in mean total motor milestone score of 1.4 (SD 1.8; n=12) and

CHOP INTEND score of 11.5 (SD 12.2, n=10) scores were observed from Study CS11 baseline tofollow up visit day 394 or 2198 respectively.

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 either2 SMN2 gene copies (n=17) or 3 SMN2 gene copies (n=2) (SMN2 gene copy number unknown for1 patient). Patients in this study were deemed most likely to develop Type I SMA. The median age atfirst dose was 162 days.

The primary endpoint was the proportion of patients who improved in one or more categories in motormilestones (according to HINE section 2: ≥2 point increase [or maximal score] in ability to kick orvoluntary 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 withimprovement 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, 11out of 20 patients (55%) met the endpoint of an increase in total CHOP INTEND score of ≥4 points asof the last study visit. Of the 20 subjects enrolled, 11 (55%) were alive and free of permanentventilation at the last visit. Four patients met the criteria for permanent ventilation and five patientsdied during the study.

Later onset

Study CS4 (CHERISH) was a Phase 3, randomised, double-blind, sham-procedure controlled studyconducted 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 dosesevery 6 months) or sham-control, with a length of treatment ranging from 324 to 482 days. Themedian 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% have2 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 limbmodule (RULM) of 19.1, all had achieved independent sitting, and no patients had achievedindependent 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 theproportion of patients who had ever achieved the ability to stand without support (13% of patients inthe Spinraza group and 29% in sham-control) or walk with support (24% of patients in the Spinrazagroup 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 4 , Figure 2).

The analysis was conducted in the ITT population (Spinraza: n=84; sham-control: n=42), andpost-baseline HFMSE data for patients without a Month 15 visit were imputed using the multipleimputation method. An analysis of the subset of patients in the ITT population who had observedvalues at Month 15 demonstrated consistent, statistically significant results. Of those with observedvalues 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 includingfunctional measures and WHO motor milestone achievement were formally statistically tested and aredescribed in Table 4.

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

Table 4: Primary and secondary endpoints at final analysis - Study CS41

Spinraza treated Patients Sham-control Patients

HFMSE score

Change from baseline in total 3.9 (95% CI: 3.0, 4.9) -1.0 (95% CI: -2.5, 0.5)

HFMSE score at 15 months1,2,3 p=0.0000001

Proportion of patients who achieved 56.8% (95% CI:45.6, 68.1) 26.3% (95% CI: 12.4,40.2)at least a 3 point improvement from P=0.00065baseline to month 152

RULM

Mean change from baseline to month 4.2(95% CI: 3.4, 5.0) 0.5 (95% CI: -0.6, 1.6)15 in total RULM score2,3 p=0.00000016

WHO motor milestones

Proportion of patients who achieved 19.7% (95% CI: 10.9, 5.9% (95% CI: 0.7,new motor milestones at 15 months4 31.3) 19.7)p=0.08111CS4 was stopped following positive statistical analysis on the primary endpoint at interim analysis (statistically significantimprovement 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 15visit were imputed using the multiple imputation method3Least squares mean4 Assessed using the Month 15 Efficacy Set (Spinraza n=66; Sham control n=34); analyses are based onimputed 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 atbaseline6Nominal 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 (83 Spinraza and 42 sham) patients enrolled in

Study CS11 (SHINE) where all patients received Spinraza. The majority of Spinraza treated patientsexperienced stabilization or improvement in motor function, with the greatest benefit observed inthose with earlier treatment initiation.

Patients initiating Spinraza in Study CS4 were of a median age 4.1 years (range 2.1 to 9.2 years). From

Spinraza initiation and including extension of treatment in Study CS11, patients received themedication for a median time of 7.2 years (range 1.3 to 8.4 years). HFMSE mean score increased 1.3(SD 9.4 n=54) and RULM mean score increased by 6.4 (SD 6.5 n=54) at follow up visit day 2070.

Patients randomised to sham in Study CS4, initiated treatment with Spinraza in Study CS11 at amedian age of 4.9 years (range 3.3 to 9.0 years). From Spinraza initation in Study CS11, patientsreceived the medication for a median time of 5.8 years (range 2.7 to 6.7 years). HFMSE mean scoredecreased by 1.3 (SD 9.3 n=22) and RULM, score increased by 4.2 (SD 4.4 n=23) points at follow upvisit day 2070.

In contrast, the natural disease course of untreated patients of similar age and clinical characteristicsshows a progressive loss of motor function over time, with an estimated mean decline in HFMSE of6.6 points over a similar period of 5 years.

These results are supported by 2 open label studies (study CS2 and study CS12). The analysis included28 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 the28 patients, 3 were at least 18 years of age at their last study visit. 1 out of 28 patients had 2 SMN2gene 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 patientswith 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 of1.9 (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, amean 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) achievedindependent walking, and one non-ambulatory patient (Type II) achieved independent walking.

An additional clinical study, CS7 (EMBRACE) was opened for patients not eligible for participationin 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 werefollowed for a median of 302 days.

All patients who received Spinraza were alive as of the early termination of Part 1, however, onepatient 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: ≥2point increase [or maximal score] in ability to kick OR ≥1 point increase in the motor milestones ofhead control, rolling, sitting, crawling, standing or walking and improvement in more categories ofmotor 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 groupmet this definition of response.

Adult

Real world clinical findings support the effectiveness of nusinersen to stabilize or improve motorfunction in some SMA adult Type II and III patients.

By month 14 of nusinersen treatment, the number of patients with a clinically meaningfulimprovement from baseline on HFMSE (≥ 3 points) was 53 out of 129 patients, the number of patientswith clinically meaningful improvement on the RULM (≥ 2 points) was 28 out of 70 and amongwalkers 25 out of 49 for the 6MWT (≥ 30 meters).

The safety data in the adult population are consistent with the known safety profile of nusinersen andwith co-morbidities associated with the underlying disease of SMA.

Presymptomatic infants

Study CS5 (NURTURE) is an open-label study in presymptomatic infants genetically diagnosed with

SMA, who were enrolled at 6 weeks of age or younger. Patients in this study were deemed most likelyto 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 a median of 48.3 months (36.6to 57.1 months) and were of a median age at last visit of 46.0 months (34.0 to 57.1 months). At theinterim analysis, all 25 patients (2 SMN2 gene copies, n=15; 3 SMN2 gene copies, n=10) were alivewithout 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 daysor 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 initiatedventilatory support during an acute reversible illness.

Patients achieved milestones unexpected in Type I or II SMA and more consistent with normaldevelopment. At the interim analysis, all 25 (100%) patients had achieved the WHO motor milestoneof sitting without support, 23 (92%) patients were walking with assistance and 22 (88%) had achievedwalking alone. Twentyone (84%) patients achieved the maximum attainable CHOP INTEND score of64. All patients had the ability to suck and swallow at last visit (Day 788), with 22 (88%) infantsachieving a maximal score on the HINE Section 1.

Patients developing clinically manifested SMA was assessed at Day 700 visit. The protocol-definedcriteria for clinically manifested SMA included age-adjusted weight below the fifth WHO percentile, adecrease of 2 or more major weight growth curve percentiles, the placement of a percutaneous gastrictube, and/or the inability to achieve expected age-appropriate WHO milestones (sitting withoutsupport, standing with assistance, hands-and-knees crawling, walking with assistance, standing aloneand walking alone). At day 700, 7 out of 15 patients (47%) with 2 SMN2 gene copies and 0 out of 5patients (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 symptomaticinfantile-onset SMA and presymptomatic SMA is shown in Figure 3.

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

Single- and multiple-dose pharmacokinetics (PK) of nusinersen, administered via intrathecal injection,were determined in paediatric patients diagnosed with SMA.

Intrathecal injection of nusinersen into the CSF allows nusinersen to be fully available for distributionfrom the CSF to the target central nervous system (CNS) tissues. The average increase in trough CSFlevels from the start of the maintenance phase through to the last observation timepoint across allpatients was approximately 3.2-fold and 2.3-fold in the later-onset and infantile-onset populationsrespectively. Overall, cumulative CSF PK data collected through to the end of CS11 indicated that ininfantile and later onset SMA patients, the standard dosing regimen (12 mg every 4 months) leads to asteady state CSF concentration by 7 to 8 years of treatment. Following intrathecal administrationtrough plasma concentrations of nusinersen were relatively low compared to the trough CSFconcentration. Median plasma Tmax values ranged from 1.7 to 6.0 hours. Mean plasma Cmax and AUCvalues increased approximately dose proportionally over the evaluated dose range. There is noaccumulation in plasma exposure measures (Cmax and AUC) after multiple doses.

Autopsy data from patients (n=3) show that nusinersen administered intrathecally is broadlydistributed within the CNS achieving therapeutic levels in the target spinal cord tissues. Presence ofnusinersen was also demonstrated in neurons and other cell types in the spinal cord and brain, andperipheral tissues such as skeletal muscle, liver, and kidney.

Nusinersen is metabolized slowly and predominantly via exonuclease (3’- and 5’) -mediatedhydrolysis and is not a substrate for, or inhibitor or inducer of CYP450 enzymes.

The mean terminal elimination half-life in CSF is estimated at 135 to 177 days. The primary route ofelimination is expected via urinary excretion of nusinersen and its metabolites.

In vitro studies indicated that nusinersen is not an inducer or inhibitor of CYP450-mediated oxidativemetabolism and therefore should not interfere with other medicinal products for these metabolicpathways. Nusinersen is not a substrate or inhibitor of human BCRP, P-gp, OAT1, OAT3, OCT1,

OCT2, OATP1B1, OATP1B3, or BSEP transporters.

Characteristics in specific patient populations

The pharmacokinetics of nusinersen in patients with renal or hepatic impairment has not been studied.

The effect of hepatic or renal insufficiency as covariates could not be thoroughly evaluated in thepopulation PK model given the rarity of patients displaying clinically relevant liver or kidneyinsufficiencies. Population PK analyses revealed no apparent correlation between hepatic and renalclinical chemistry markers and inter-subject variability.

The majority of patients studied were Caucasian. The population PK analysis suggests that race isunlikely to affect the PK of nusinersen.

Genotoxicity/Carcinogenity

Nusinersen demonstrated no evidence of genotoxicity. Nusinersen was not carcinogenic in a 2-yearstudy in mice at plasma exposure levels 104-fold higher than in patients receiving 12 mg ofmaintenance nusinersen.

Reproductive toxicology studies were conducted using subcutaneous administration of nusinersen inmice and rabbits. No impact on male or female fertility, or embryo-foetal development, orpre/post-natal development was observed.

In repeat-dose toxicity studies (14-weeks and 53-weeks) of intrathecal administration to juvenilecynomolgus monkeys, nusinersen was well tolerated. The exception was an acute, transient deficit inlower spinal reflexes which occurred at the highest dose levels in each study (3 or 4 mg per dose;equivalent to 30 or 40 mg per intrathecal dose in patients). These effects were observed within severalhours post-dose and generally resolved within 48 hours.

In the 53-week intrathecal dosing study in cynomolgus monkeys no toxicity effects were seen at levelsup to 14-fold the recommended annual clinical maintenance dose.

Sodium dihydrogen phosphate dihydrate

Disodium phosphate

Sodium chloride

Potassium chloride

Calcium chloride dihydrate

Magnesium chloride hexahydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

Not applicable.

5 years

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

If no refrigeration is available, Spinraza may be stored in its original carton, protected from light at orbelow 30°C for up to 14 days.

Prior to administration, unopened vials of Spinraza can be removed from and returned to therefrigerator if necessary. If removed from the original carton, the total combined time out ofrefrigeration should not exceed 30 hours, at a temperature that does not exceed 25°C.

5 ml in a Type I glass vial with bromobutyl rubber stopper and an aluminium over-seal and plasticcap.

Pack size of one vial per carton.

For single use only.

Instructions for preparation of the medicinal product before administration1. The Spinraza vial should be inspected for particles prior to administration. If particles are observedand/or the liquid in the vial is not clear and colourless, the vial must not be used.2. Aseptic technique should be used when preparing Spinraza solution for intrathecal administration.3. The vial should be taken out of the refrigerator and allowed to warm to room temperature (25°C)without using external heat sources, prior to administration.4. If the vial remains unopened and the solution is not used, it should be returned back to therefrigerator (see section 6.4).5. Just prior to administration, remove the plastic cap and insert the syringe needle into the vialthrough the centre of the over-seal to remove the appropriate volume. Spinraza must not be diluted.

The use of external filters is not required.6. Once drawn into the syringe, if the solution is not used within 6 hours, it must be discarded.

7. Any unused product or waste material must be disposed of in accordance with local requirements.

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/17/1188/001

Date of first authorisation: 30 May 2017

Date of latest renewal: 31 January 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.