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SPINRAZA FOR SYMPTOMATIC PATIENTS1
A supportive study exploring SPINRAZA in symptomatic SMA
Prior to this supportive study, SPINRAZA was studied in a pivotal trial of patients with early-onset SMA.
Pivotal trial: ENDEAR2,3
Treatment duration: 13 months; SPINRAZA (12 mg)2
Participants: 121 symptomatic patients with early-onset SMA aged ≤7 months at time of first dose3
Primary endpoints: Time to death or permanent ventilation and proportion of patients meeting the criteria for motor milestone responder using HINE-23
Safety: The most common adverse reactions that occurred in at least 20% of SPINRAZA-treated patients and occurred at least 5% more frequently than in control patients were lower respiratory infection and constipation. Serious adverse reactions of atelectasis were more frequent in SPINRAZA-treated patients (18%) than in control patients (10%)3
Results:
- Statistically significant effects on event-free survival and overall survival were observed in patients in the SPINRAZA group compared to those in the control group. A 47% reduction in the risk of death or permanent ventilation was observed in the SPINRAZA group (P=0.005)3
- A significantly higher percentage of infants in the SPINRAZA group than in the control group had a motor-milestone response using HINE-2 (interim analysis, N=82, 40% vs 0%). In the final analysis, 51% of the infants in the nusinersen group and no infants in the control group had a motor-milestone response (N=110)3
HINE-2, Hammersmith Infant Neurological Examination Section 2; SMA, spinal muscular atrophy.
Review the Warnings and Precautions, including thrombocytopenia, coagulation abnormalities, and renal toxicity1
Rationale for RESPOND: Evaluating nusinersen after onasemnogene abeparvovec-xioi (OA)
Gene therapy with IV OA is an approved treatment for SMA that has shown clinical benefit1,4; children may experience residual weakness and motor delays despite receiving OA.5-7
The RESPOND study is based on the hypothesis that SPINRAZA may deliver additional clinical benefit after suboptimal clinical status following onasemnogene abeparvovec-xioi as determined by investigator.1
IV, intravenous; SMA, spinal muscular atrophy.
Interim results: Examining SPINRAZA in patients with investigator-determined suboptimal clinical status following onasemnogene abeparvovec-xioi (OA)1
Study: Open-label study spanning multiple international centers (60% of sites in US)1,8
Objective: To provide clinical, biomarker, and safety findings for RESPOND participants at Month 10 post nusinersen initiation9
Study duration: ≤95 weeks on treatment with nusinersen; 4-month follow-up safety period8
Inclusion criteria: Genetic documentation of 5q SMA; SMN2 copy number of ≥1; ≤36 months of age at the time of first nusinersen dose; previously received OA per the approved label or local/regional regulations ≥2 months prior to first nusinersen dose; suboptimal clinical status per the investigator; symptomatic at OA administration; alanine aminotransferase and aspartate aminotransferase levels ≤2 times the upper limit of normal at screening and ≤7 days prior to dosing1
Exclusion criteria: Severe or serious adverse events related to OA treatment that were ongoing during screening1
Primary endpoint: HINE-2 total motor milestone score9
Secondary outcome measures: Safety, additional motor function, and biomarker outcomes, among others1.
Study Limitations1:
- Open-label trial without a comparator group
- Observed improvements cannot be directly attributed to nusinersen as participants received OA prior to enrollment
- Placebo effects or expectation bias may influence investigator- and caregiver-assessed outcomes
- Not statistically powered to detect significant differences
- No clear consensus on what constitutes suboptimal clinical status after OA; definition based on investigators’ assessments may be subjective
- Details of symptoms at the time of OA administration could not be examined as participants received OA prior to study enrollment
- No consensus on clinically meaningful thresholds for many clinical and biomarker outcomes in study, especially among previously treated individuals
- Did not examine correlation or predictive analyses between biomarker and clinical outcomes
Participants: 46 individuals were enrolled. The efficacy set included 37 participants who had received ≥1 dose of nusinersen and had the opportunity to complete the Month 10 assessment. The safety set included all 46 enrolled participants1
CHOP INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2, Hammersmith Infant Neurological Examination Section 2; IT, intrathecal; IV, intravenous; OA, onasemnogene abeparvovec-xioi; SD, standard deviation; SMA, spinal muscular atrophy; SMN2, survival motor neuron 2 gene; WHO, World Health Organization.
Increases in motor function as measured by HINE-21||
The study was not powered to detect significant differences. All outcomes were summarized using descriptive statistics. Due to the open-label nature of the trial, not all observed improvements can be directly attributed to nusinersen treatment.1
Improvements in motor function as measured by CHOP INTEND1¶
The study was not powered to detect significant differences. All outcomes were summarized using descriptive statistics. Due to the open-label nature of the trial, not all observed improvements can be directly attributed to nusinersen treatment.1
CHOP INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2, Hammersmith Infant Neurological Examination Section 2; SD, standard deviation; SMN2, survival motor neuron 2 gene.
Increases in number of patients achieving independent sitting1
The study was not powered to detect significant differences. All outcomes were summarized using descriptive statistics. Due to the open-label nature of the trial, not all observed improvements can be directly attributed to nusinersen treatment.
OA, onasemnogene abeparvovec-xioi; SMN2, survival motor neuron 2 gene; WHO, World Health Organization.
Interim safety profile
The safety set included all 46 enrolled participants.9
- See full Prescribing Information for respective product information
- A full evaluation of safety will be available at the conclusion of the study
AE, adverse event.
Investigator- and caregiver-reported outcomes1
AE, adverse event; SMN2, survival motor neuron 2 gene.
Patients entered the RESPOND study with elevated plasma NfL levels, indicating active neurodegeneration1
Plasma and CSF NfL levels were measured with a single molecular array immunoassay via the Simoa® HD-X Analyzer (Quanterix®).1
This figure demonstrates diversity of plasma NfL concentrations by age. Conclusions cannot be drawn as to individual patient results.
NfL is increasingly recognized as a promising biomarker of SMA disease activity to support clinical observations.1,9,10
Its clinical relevance in SMA is unknown.
The study was not powered to detect significant differences. All outcomes were summarized using descriptive statistics. Due to the open-label nature of the trial, not all observed improvements can be directly attributed to nusinersen treatment.1
CSF, cerebrospinal fluid; NfL, neurofilament light chain; SMA, spinal muscular atrophy; SMN2, survival motor neuron 2 gene.
Decreases in NfL levels after treatment with SPINRAZA1
Results show a reduction in plasma NfL concentrations regardless of age or time since OA administration.1
CSF, cerebrospinal fluid; NfL, neurofilament light chain; OA, onasemnogene abeparvovec-xioi; SD, standard deviation; SMN2, survival motor neuron 2 gene.