SPR1NT: An open-label, single-arm clinical trial of presymptomatic patients with SMA1
SPR1NT is an ongoing clinical trial of patients with SMA who have 2 or 3 copies of SMN2 (N=30)1,a
All patients enrolled in the study were less than 6 weeks of age and did not display any symptoms of SMA at the time of infusion1
aOne enrolled patient had 4 copies of SMN2 and is not included in the efficacy analysis. This patient will be included in the safety population only.
EXPAND ENDPOINTS AND ENROLLMENT CRITERIA
Endpoints1
2 copies of SMN2 (n=14)
Primary endpoint:
- Functional, independent sitting for ≥30 seconds (Bayley item 26) up to 18 months of age
Secondary endpoints:
- Event-free survival at 14 months of ageb
- Ability to maintain weight at or above the 3rd percentile, based on WHO Child Growth Standards, without nutritional support up to 18 months of age
Exploratory endpoints:
- Other motor milestones (WHO)c
- Gross and fine motor subtests (Bayley)
- Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores
3 copies of SMN2 (n=15)
Primary endpoint:
- Ability to stand without support for ≥3 seconds (Bayley item 40) up to 24 months of age
Secondary endpoint:
- Ability to walk alone (Bayleyd) up to 24 months of age
Exploratory endpoints:
- Other motor milestones (WHO)
- Gross and fine motor subtests (Bayley)
bSurvival is defined as no death or need for permanent ventilatory support (tracheostomy or ≥16 hours respiratory assistance per day continuously for ≥14 days in the absence of an acute reversible illness, excluding perioperative ventilation).
cWHO-Multicenter Growth Study criteria.
dBayley-III, gross motor subtest 43, defined by the ability to take ≥5 steps independently displaying coordination and balance.
Key inclusion and exclusion criteria1
Key inclusion criteria:
- Bi-allelic SMN1 mutations (deletion or point mutations) and 2 or 3 copies of SMN2 (inclusive of SMN2 gene modifier [c.859G>C])
- ≤6 weeks of age at the time of infusion
- Ability to tolerate thin liquids at screening
- Compound muscle action potential (CMAP) ≥2 mV at baseline
Key exclusion criteria:
- Anti-AAV9 antibody titers >1:50
- Any clinical signs or symptoms that are strongly suggestive of SMA
- Treatment with an investigational or commercial product given for the treatment of SMA
All patients were alive and free of permanent ventilation in the ongoing trial2
As of the last follow-up visit prior to June 2020, patients with 2 copies of SMN2 (n=14) were a mean of 14.8 months of age (range 8.8-18.8) and patients with 3 copies of SMN2 (n=15) were a mean of 14.0 months of age (3.3.-21.1).2
aSurvival is defined as no death or need for permanent ventilatory support (tracheostomy or ≥16 hours respiratory assistance per day continuously for ≥14 days in the absence of an acute reversible illness, excluding perioperative ventilation).
bEvent-free survival at 14 months of age is a secondary endpoint for patients with 2 copies of SMN2.1
aSurvival is defined as no death or the need for permanent ventilatory support (tracheostomy or ≥16 hours respiratory assistance per day continuously for ≥14 days in the absence of an acute reversible illness, excluding perioperative ventilation).
bEvent-free survival at 14 months of age is a secondary endpoint for patients with 2 copies of SMN2.1
Presymptomatic patients treated with ZOLGENSMA achieved age-appropriate motor milestones2
Patients with 2 copies of SMN2
79% (11/14) of patients with 2 copies of SMN2 achieved the primary endpoint of sitting without support for ≥30 seconds as of the last visit prior to the June 2020 data cut2,a
- 91% (10/11) of patients who sat did so within an age-appropriate time period2
- The 3 remaining patients were older than the age-appropriate window, but are still younger than 18 months of age, the end-of-study visit2
Age-appropriate time periods were defined according to the WHO Multicenter Growth Reference Study (MGRS) established windows of achievements for the development of motor milestones.
aBayley-III, gross motor subtest item 26. WHO MGRS established windows of achievement (1%-99%): 3.8-9.2 months for sitting without support.2,3
bIndependent standing ≥10 seconds assessed by WHO MGRS. WHO MGRS established window of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3
cIndependent walking assessed by WHO MGRS. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3
Primary endpoint:
Achieved sitting without support for ≥30 seconds (Bayley)2,a
10 of 11 patients achieved sitting without support within and age-appropriate time period
- The 3 remaining patients were older than the age-appropriate window, but are still younger than 18 months of age, the end-of-study visit2
Exploratory endpoint:
Achieved standing alone for ≥10 seconds (WHO)2,b
2 of 4 patients achieved this milestone within an age-appropriate time period
- 7 patients were still within their age-appropriate WHO developmental window for this milestone
Exploratory endpoint:
Achieved walking alone (WHO)2,c
4 of 5 patients achieved this milestone within an age-appropriate time period
- 7 patients were still within their age-appropriate WHO developmental window for this milestone
Age-appropriate time periods were defined according to the WHO Multicenter Growth Reference Study (MGRS) established windows of achievements for the development of motor milestones.
aBayley-III, gross motor subtest item 26. WHO MGRS established windows of achievement (1%-99%): 3.8-9.2 months for sitting without support.2,3
bIndependent standing ≥10 seconds assessed by WHO MGRS. WHO MGRS established window of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3
cIndependent walking assessed by WHO MGRS. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3
Patients with 3 copies of SMN2
53% (8/15) of patients with 3 copies of SMN2 achieved the primary endpoint of standing without support by the last visit prior to the June 2020 data cut2,a
- 100% (8/8) of the patients who stood without support did so within an age-appropriate time period2
- The 7 remaining patients were still within their age-appropriate WHO developmental window for this milestone, at the time of the data cut2
Age-appropriate time periods were defined according to the WHO Multicenter Growth Reference Study (MGRS) established windows of achievements for the development of motor milestones.
aBayley-III, gross motor subtest item 40. WHO MGRS established windows of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3
bBayley-III, gross motor subtest item 43. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3
cStands with assistance as assessed by WHO MGRS. WHO MGRS established windows of achievement (1%-99%): 4.8-11.4 months for standing with assistance.2,3
Primary endpoint:
Achieved standing alone for ≥3 seconds (Bayley)2,a
8 of 8 patients achieved this milestone within an age-appropriate time period
- The 7 remaining patients were still within their age-appropriate WHO developmental window for this milestone
Secondary endpoint:
Achieved walking alone (Bayley)2,b
6 of 6 patients achieved this milestone within an age-appropriate time period
- The 9 remaining patients were still within their age-appropriate WHO developmental window for this milestone
Exploratory endpoint:
Achieved stands with assistance (WHO)2,c
10 of 12 patients achieved this milestone within an age-appropriate time period
- The remaining 3 patients were still within their age-appropriate WHO developmental window for standing with assistance
Age-appropriate time periods were defined according to the WHO Multicenter Growth Reference Study (MGRS) established windows of achievements for the development of motor milestones.
aBayley-III, gross motor subtest item 40. WHO MGRS established windows of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3
bBayley-III, gross motor subtest item 43. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3
cStands with assistance as assessed by WHO MGRS. WHO MGRS established windows of achievement (1%-99%): 4.8-11.4 months for standing with assistance.2,3
ZOLGENSMA enabled continued independence from nutritional support in presymptomatic patients with 2 and 3 copies of SMN22
aZOLGENSMA-treated patients in SPR1NT were separated into 2 cohorts by SMN2 copy number. 14 patients had 2 copies of SMN2. 15 patients had 3 copies of SMN2. All patients were required to be able to swallow thin liquids and be free from ventilatory support at baseline.2
As of the last visit prior to the June 2020 data cut2,a:
Feeding support status
100% (29/29) of patients
were free of feeding support
aZOLGENSMA-treated patients in SPR1NT were separated into 2 cohorts by SMN2 copy number. 14 patients had 2 copies of SMN2. 15 patients had 3 copies of SMN2. All patients were required to be able to swallow thin liquids and be free from ventilatory support at baseline.2
ZOLGENSMA enabled continued independence from respiratory support in all patients treated presymptomatically2
In natural history, most patients with SMA Type 1 required respiratory support by 12 months of age4
aZOLGENSMA-treated patients in SPR1NT were separated into 2 cohorts by SMN2 copy number. 14 patients had 2 copies of SMN2. 15 patients had 3 copies of SMN2. All patients were required to be able to swallow thin liquids and be free from ventilatory support at baseline. Ventilatory support included noninvasive ventilatory support, invasive ventilatory support, cough assist, or BiPAP.
As of the last visit prior to the June 2020 data cut2,a:
Respiratory status
100% (29/29) of patients
did not require respiratory support of any kinda
aZOLGENSMA-treated patients in SPR1NT were separated into 2 cohorts by SMN2 copy number. 14 patients had 2 copies of SMN2. 15 patients had 3 copies of SMN2. All patients were required to be able to swallow thin liquids and be free from ventilatory support at baseline. Ventilatory support included noninvasive ventilatory support, invasive ventilatory support, cough assist, or BiPAP.
ZOLGENSMA enabled age-appropriate development of gross motor function2
64% (9/14) of patients with 2 copies of SMN2 and 100% (15/15) of patients with 3 copies of SMN2 had gross motor performance similar to same-aged children2,a,b
SD=standard deviation
aGross motor function was measured by the Bayley Scales of Infant and Toddler Development, a well-accepted, standardized tool to assess the development of children between the ages of 1 and 42 months and compare these to a standardized norm.5
bEach line represents the raw scores of an individual patient on the Bayley-III gross motor subtest. The normal range for raw scores on the Bayley-III Gross Motor Test is based on scaled score equivalents for unaffected patients: mean ± 2 standard deviations (4-16 score [mean = 10, SD = 3, Range of 1-19]).2,5
SD=standard deviation.
aGross motor function was measured by the Bayley Scales of Infant and Toddler Development, a well-accepted, standardized tool to assess the development of children between the ages of 1 and 42 months and compare these to a standardized norm.5
bEach line represents the raw scores of an individual patient on the Bayley-III gross motor subtest. The normal range for raw scores on the Bayley-III Gross Motor Test is based on scaled score equivalents for unaffected patients: mean ± 2 standard deviations (4-16 score [mean = 10, SD = 3, Range of 1-19]).2,5
Presymptomatic patients with 2 copies of SMN2 achieved increased motor function scores from baseline
Motor function was assessed using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
CHOP INTEND was specifically developed to assess motor function in patients with SMA. The CHOP INTEND score is measured in points, which are assigned based on a patient’s ability to perform specific motor skills. The test consists of 16 measures, each scored on a scale of 0-4, with the highest possible score being 64 points.6
Increases from baseline in CHOP INTEND were seen as early as 1 month post infusion in patients with 2 copies of SMN22
Motor function, as assessed by CHOP INTEND score by the June 2020 data cut
100% (14/14) of patients with 2 copies of SMN2 achieved or maintained a CHOP INTEND score ≥502,a
86% (12/14) of patients achieved a score ≥60b
SD=standard deviation
aScores on the CHOP INTEND scale of motor function range from 0 to 64, with higher scores indicating better function.6
bOf the 2 remaining patients, 1 patient achieved a maximum post-baseline score of 55 points, and 1 patient achieved 3 consecutive scores ≥58 and, per protocol, did not undergo additional CHOP INTEND examinations.2
cThe dark gray line at 40 represents the highest possible CHOP INTEND score that children with the most severe form of SMA would achieve or maintain, according to natural history.7
SD=standard deviation
aScores on the CHOP INTEND scale of motor function range from 0 to 64, with higher scores indicating better function.6
bOf the 2 remaining patients, 1 patient achieved a maximum post-baseline score of 55 points, and 1 patient achieved 3 consecutive scores ≥58 and, per protocol, did not undergo additional CHOP INTEND examinations.2
cThe dark gray line at 40 represents the highest possible CHOP INTEND score that children with the most severe form of SMA would achieve or maintain, according to natural history.7
References: 1. Novartis Pharmaceuticals Corporation. Pre-symptomatic study of intravenous onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) for patients with multiple copies of SMN2 (SPR1NT). https://clinicaltrials.gov/ct2/show/NCT03505099. ClinicalTrials.gov identifier: NCT03505099. Updated November 17, 2020. Accessed March 17, 2021. 2. Data on file. Novartis Gene Therapies, Inc. 2021. 3. WHO Multicentre Growth Reference Study Group. WHO Motor Development Study: windows of achievement for six gross motor development milestones. Acta Paediatr Suppl. 2006;450:86-95. 4. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014; 83(9):810-817. 5. Bayley N. Bayley Scales of Infant and Toddler Development: Administration Manual. 3rd ed. The Psychological Corporation; 2006. 6. Glanzman AM, Mazzone E, Main M, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord. 2010;20(3):155-161. 7. Kolb SJ, Coffey CS, Yankey JW, et al; NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol. 2017;82(6):883-891.