Spinraza - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Spinraza 12 mg solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear and colourless solution with pH of approximately 7.2.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

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

Posology

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.

Duration of treatment

Information on long term efficacy of this medicinal product is not available. The need for continuation of therapy should be reviewed regularly and considered on an individual basis depending on the patient’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 to the 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 maintenance dose as soon as possible; then
• • The next maintenance dose per the original scheduled date, as long as these two doses are administered at least 14 days apart*;

> 8 to < 16 months from last dose

• • Administer the missed dose as soon as possible and then the next dose 14 days later*;

> 16 to < 40 months from last dose

• • Administer the missed dose as soon as possible and then the next 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 dose should be administered and repeated every 4 months.

Special populations

Renal impairment

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

Hepatic impairment

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

Method of administration

Spinraza is for intrathecal use by lumbar puncture.

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

Spinraza is administered as an intrathecal bolus injection over 1 to 3 minutes, using a spinal anaesthesia needle. The injection must not be administered in areas of the skin where there are signs of infection 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 in section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Lumbar puncture procedure

There is a risk of adverse reactions occurring as part of the lumbar puncture procedure (e.g. headache, back pain, vomiting; see section 4.8). Potential difficulties with this route of administration may be seen in very young patients and those with scoliosis. The use of ultrasound or other imaging techniques to assist with intrathecal administration of Spinraza, can be considered at the physician’s dis­cretion.

Thrombocytopenia and coagulation abnormalities

Thrombocytopenia and coagulation abnormalities, including acute severe thrombocytopenia, have been observed after administration of other subcutaneously or intravenously administered antisense oligonucleotides. If clinically indicated, platelet and coagulation laboratory testing is recommended prior to administration of Spinraza.

Renal toxicity

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

Hydrocephalus

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

Excipients

Sodium

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

Potassium

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

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of nusinersen in pregnant women. Animal studies do 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.

Breast-feeding

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 discontinue breast-feeding or to discontinue/abstain from nusinersen therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

The most common adverse reactions (ADRs) associated with the administration of Spinraza 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 pre-symptomatic infants (CS5) genetically diagnosed with SMA and infants and children with SMA. Study CS11 enrolled infantile and later-onset patients including those who had completed studies CS3B, CS4 and CS12. Of the 352 patients who received Spinraza up to a maximum of 5 years, 271 patients received treatment for at least 1 year.

Tabulated list of adverse reactions

The safety assessment of Spinraza is based on data from patients from clinical trials and from postmarketing 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* Aseptic meningitis	Very common Not known
Gastrointestinal disorders	Vomiting*	Very common
Musculoskeletal and connective tissue disorders	Back pain*	Very common

*Adverse reactions considered related to the lumbar puncture procedure. These reactions can be considered manifestations of post-lumbar puncture syndrome. These adverse reactions were reported in CS4 (later onset SMA) with an incidence at least 5% 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 section 4.4).

Description of selected adverse reactions

Adverse reactions associated with the administration of Spinraza by lumbar puncture have been observed. The majority of these are reported within 72 hours of the procedure. The incidence and severity of these events were consistent with events expected to occur with lumbar puncture. No serious complications of lumbar puncture, such as serious infections, have been observed in the clinical 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 communication appropriate for that age group.

Immunogenicity

The immunogenic response to nusinersen was determined in 346 patients with baseline and post-baseline plasma samples evaluated for anti-drug antibodies (ADA). Overall, the incidence of ADAs was low, with 15 (4%) patients classified as ADA positive overall, of which 4 had a transient response, 5 had a persistent response, and 6 patients had responses which could not be classified as transient or persistent at the time of data cut off. The impact of immunogenicity on safety was not formally analysed as the number of patients with ADAs was low. However, individual safety data for the treatment-emergent ADA-positive cases were reviewed, and no adverse events (AEs) of interest were identified.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

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 a healthcare professional and close observation of the clinical status of the patient.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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 3).

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 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 received permanent ventilation Hazard ratio (95% CI) p-value6	31 (39%)	28 (68%)
	0.53 (0.32 –0.89) p = 0.0046
Overall survival2 Number of patients who died Hazard Ratio (95% CI) p-value6	13 (16%)	16 (39%)
	0.37 (0.18 – 0.77) p=0.0041
Motor function
Motor milestones3 Proportion achieving pre-defined motor milestone responder criteria (HINE section 2)4,5	37 (51%)1 p<0.0001	0 (0%)

Efficacy Parameter	Spinraza treated Patients	Sham-control Patients
Proportion at Day 183	41%	5%
Proportion at Day 302	45%	0%
Proportion at Day 394	54%	0%
Proportion with improvement in total motor milestone score	49 (67%)	5 (14%)
Proportion with worsening in total motor milestone score	1 (1%)	8 (22%)
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 (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)

• 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 Visit

5According 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. 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 for each subject).

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 4 , 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 4.

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 4: Primary and secondary endpoints at final analysis – Study CS4 1

	Spinraza treated Patients	Sham-control Patients
HFMSE score Change from baseline in total HFMSE score at 15 months1,2,3	3.9 (95% CI: 3.0, 4.9) p=0.0000001	–1.0 (95% CI: –2.5, 0.5)
Proportion of patients who achieved at least a 3 point improvement from baseline to month 152	56.8% (95% CI:45.6, 68.1) P=0.00065	26.3% (95% CI: 12.4,40.2)
RULM Mean change from baseline to month 15 in total RULM score2,3	4.2(95% CI: 3.4, 5.0) p=0.00000016	0.5 (95% CI: –0.6, 1.6)
WHO motor milestones Proportion of patients who achieved new motor milestones at 15 months4	19.7% (95% CI: 10.9, 31.3) p=0.0811	5.9% (95% CI: 0.7, 19.7)

1CS4 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

3Least 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

6Nominal p value

Figure 2: Mean change from baseline in HFMSE score over time at final analysis (ITT) -

Study CS4 1,2

Months

P Spinraza (N=84)   — -+ — Control (N=42)

'Data for patients without a Month 15 visit were imputed using the multiple imputation method 2Error bars denote +/- standard error

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 infantileonset 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 shamcontrol 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.

Adult

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

By month 14 of nusinersen treatment, the number of patients with a clinically meaningful improvement from baseline on HFMSE (> 3 points) was 53 out of 129 patients, the number of patients with clinically meaningful improvement on the RULM (> 2 points) was 28 out of 70 and among walkers 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 and with co-morbidities associated with the underlying disease of SMA.

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 (95th 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

Population used in figure: CS5 subjects in the ITT set with SMN2 copy number denoted in parentheses. CS3A: SMN2 2 copy subjects, CS3B; Subjects with SMN2 2 copy in ITT set.

For CS3B the data were windowed into intervals based on time from baseline.

For each study, visits with n < 5 are not plotted.

CS5 (#3) CS5 (#2) CS3A

CS3B-active + CS11

CS11 (CS3B-sham)

CS3B-sham

5.2 Pharmacokinetic properties

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

Absorption

Intrathecal injection of nusinersen into the CSF allows nusinersen to be fully available for distribution from the CSF to the target central nervous system (CNS) tissues. Mean CSF trough concentrations of nusinersen accumulated approximately 1.4– to 3-fold after multiple loading and maintenance doses, and reached a steady state within approximately 24 months. Following intrathecal administration trough plasma concentrations of nusinersen were relatively low compared to the trough CSF concentration. Median plasma Tmax values ranged from 1.7 to 6.0 hours. Mean plasma Cmax and AUC values increased approximately dose proportionally over the evaluated dose range. There is no accumulation in plasma exposure measures (Cmax and AUC) after multiple doses.

Distribution

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

Biotransformation

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

Elimination

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

Interactions

In vitro studies indicated that nusinersen is not an inducer or inhibitor of CYP450-mediated oxidative metabolism and therefore should not interfere with other medicinal products for these metabolic pathways. 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

Renal and hepatic impairment

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 the population PK model given the rarity of patients displaying clinically relevant liver or kidney insufficiencies. Population PK analyses revealed no apparent correlation between hepatic and renal clinical chemistry markers and inter-subject variability.

Race

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

5.3 Preclinical safety data

Carcinogenesis

Long-term studies in animals to evaluate the carcinogenic potential of nusinersen have not been performed.

Mutagenesis

Nusinersen demonstrated no evidence of genotoxicity.

Reproductive toxicity

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

Toxicology

In repeat-dose toxicity studies (14-weeks and 53-weeks) of intrathecal administration to juvenile cynomolgus monkeys, nusinersen was well tolerated. The exception was an acute, transient deficit in lower 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 several hours post-dose and generally resolved within 48 hours.

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

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

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

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

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 or below 30°C for up to 14 days.

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

6.5 Nature and contents of container

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

Pack size of one vial per carton.

6.6 Special precautions for disposal and other handling

For single use only.

Instructions for preparation of the medicinal product before administration

• 1. The Spinraza vial should be inspected for particles prior to administration. If particles are observed and/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 the refrigerator (see section 6.4).

• 5. Just prior to administration, remove the plastic cap and insert the syringe needle into the vial through 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.

7. MARKETING AUTHORISATION HOLDER

Biogen Netherlands B.V.

Prins Mauritslaan 13

1171 LP Badhoevedorp

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1188/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 May 2017

Date of latest renewal: