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Pivotal trial design

ENDEAR: phase 3 (N=121, 13 months)2

  • Patients with infantile-onset (Type 1) SMA
  • Multicenter, double-blind, randomized, sham procedure–controlled study
  • Patients were randomized 2:1 to receive either SPINRAZA or sham injection
  • Planned interim efficacy analysis: was conducted based on 82 patients who completed at least 183 days of treatment, died, or withdrew from the study
  • Endpoints:
    • Primary endpoint: proportion of patients meeting the criteria for responder using Hammersmith Infant Neurological Examination (HINE) Section 2
    • Additional assessments:
      • Change in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
      • Safety (includes data from all 121 patients)

Interim efficacy set (IES)1,2

A planned interim efficacy analysis was conducted based on 82 patients who completed at least 183 days of treatment, withdrew from the study, or died.

Bar chart showing the interim efficacy set

SPINRAZA (n=52)

75% Alive and ongoing (39/52)

23% Died (12/52)

2% Withdrew (1/52)

Untreated (n=30)

54% Alive and ongoing (16/30)

43% Died (13/30)

3% Withdrew (1/30)

For subjects who were alive and ongoing in the study, the efficacy data were calculated at the later of days 183, 302, or 394.

Flag artwork highlighting the criteria for being a motor milestone responderPRIMARY ENDPOINT AT INTERIM ANALYSIS: proportion of motor milestone responders2

Responders are patients achieving an improvement of more categories of motor milestones than worsening according to HINE Section 21,2*:

*Excludes voluntary grasp.
For subjects who were alive and ongoing in the study, the efficacy data were calculated at the later of days 183, 302, or 394.

Baseline characteristics in ENDEAR1,2

Disease characteristics SPINRAZA
n=80
Untreated
n=41
Disease duration (median) 14 weeks
Disease onset ≤12 weeks 88% 77%
Age at first treatment (median, all ≤7 months) 175 days 206 days
Length of treatment (median) 261 days (range 6-442 days)
Paradoxical breathing 89% 66%
Pneumonia or respiratory symptoms 35% 22%
Swallowing or feeding difficulties 51% 29%
Requirement for respiratory support 26% 15%
Mean CHOP INTEND score 26.63 28.43
Key Icon

Patients in the SPINRAZA arm had earlier onset of spinal muscular atrophy (SMA), more respiratory issues, and more difficulties swallowing or feeding at baseline.2

Supportive open-label trials1

CS3A: phase 2 (N=20, 45 months)1

  • Patients with infantile-onset (Type 1) spinal muscular atrophy (SMA)
  • Primary endpoint: proportion of patients achieving a level of improvement in motor milestones as assessed by HINE Section 2§
  • Other endpoints: CHOP INTEND, event-free survival, safety and tolerability

CS2/CS12: phase 2, longitudinal analysis across 2 studies (N=28, 35 months)1

  • Patients with later-onset (Type 2 and Type 3) SMA
  • Primary endpoint: safety and tolerability of SPINRAZA administered intrathecally
  • Other endpoints: Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT)

NURTURE/CS5: phase 2 (N=17, 28 months)1

  • Presymptomatic infants (genetically diagnosed with SMA)
  • Primary endpoint: time to death or respiratory intervention
  • Other endpoints: HINE, CHOP INTEND, World Health Organization (WHO) motor milestones, safety and tolerability

§Endpoint included voluntary grasp.

Key Icon

Clinical trials with SPINRAZA included a broad range of patients with spinal muscular atrophy.2

Photo of Emma aged 7 years old with Type 3 SMA swimming in pool
Emma
age 7

Later-onset (Type 3) SMA treated with SPINRAZA

Individual results may vary based on several factors, including severity of disease and duration of therapy.

INDICATION

SPINRAZA is indicated for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients.

IMPORTANT SAFETY INFORMATION

Coagulation abnormalities and thrombocytopenia, including acute severe thrombocytopenia, have been observed after administration of some antisense oligonucleotides. Patients may be at increased risk of bleeding complications. Perform a platelet count and coagulation laboratory testing at baseline and prior to each administration of SPINRAZA and as clinically needed.

In a clinical study, 11% of SPINRAZA-treated patients with normal or above normal platelet levels at baseline developed a platelet level below the lower limit of normal compared to zero sham-procedure control patients. No patient had a platelet count <50,000 cells per mcL and no patient developed a sustained low platelet count despite continued drug exposure.

Renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides.

SPINRAZA is present in and excreted by the kidney. In a clinical study (mean treatment exposure 7 months), 33% of SPINRAZA-treated patients had elevated urine protein, compared to 20% of sham-control patients. In a group of later-onset SMA patients (mean treatment exposure 34 months), 69% had elevated urine protein.

No elevations in serum creatinine or cystatin C were observed in studies with SPINRAZA. Conduct quantitative spot urine protein testing (preferably using a first morning urine specimen) at baseline and prior to each dose of SPINRAZA. For urinary protein concentration >0.2 g/L, consider repeat testing and further evaluation.

Severe hyponatremia was reported in an infant treated with SPINRAZA requiring salt supplementation for 14 months.

Cases of rash were reported in patients treated with SPINRAZA.

SPINRAZA may cause a reduction in growth as measured by height when administered to infants, as suggested by observations from the controlled study. It is unknown whether any effect of SPINRAZA on growth would be reversible with cessation of treatment.

The most common adverse reactions that occurred in the controlled study in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were upper respiratory infection (39% vs 34%), lower respiratory infection (43% vs 29%), and constipation (30% vs 22%). Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (14%) than in control patients (5%). Because patients in the controlled study were infants, adverse reactions that are verbally reported could not be assessed in this study. In the open-label studies, the most common adverse events in later onset patients were headache (50%), back pain (41%) and post lumbar puncture syndrome (41%).

Please see full Prescribing Information for additional Important Safety Information.

As a courtesy, our full Prescribing Information is also available en Español. For prescribing decisions, please refer to official approved labeling.

REFERENCES