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.

All patients were alive and free of permanent ventilation in the ongoing trial2

As of Dec 2019, patients with 2 copies of SMN2 (n=14) were a mean of 11.2 months of age (range 6.0-18.6) and patients with 3 copies of SMN2 were a mean of 9.7 months of age (range 3.3-15.1).2

aEvent is defined as death or the need for permanent ventilatory support consisting of ≥16 hours of respiratory assistance per day continuously for ≥14 days.2

bEvent-free survival at 14 months of age is a secondary endpoint for patients with 2 copies of SMN2.1

aEvent is defined as death or the need for permanent ventilatory support consisting of ≥16 hours of respiratory assistance per day continuously for ≥14 days.2

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

57% (8/14) of patients with 2 copies of SMN2 achieved the primary endpoint of sitting without support for ≥30 seconds as of the Dec 2019 data cut2,a
  • 88% (7/8) of patients who sat did so within an age-appropriate time period2
  • The 6 remaining patients were still within their age-appropriate WHO developmental window for sitting without support, 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 26. As of the data cut (Dec 2019) the age range was 5.7-11.8 months for patients who achieved sitting without support ≥30 seconds up to 18 months of age. WHO MGRS established windows of achievement (1%-99%): 3.8-9.2 months for sitting without support.2,3

bThe age range was 12.2-18.3 months for patients who achieved independent standing alone ≥10 seconds assessed by WHO MGRS. One additional patient achieved stands alone based on Bayley-III, gross motor subtest 40 (child stands alone for ≥3 seconds after you release his or her hands). WHO MGRS established window of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3

cThe age range was 12.2-18.3 months for patients who achieved independent 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

7 of 8 achieved sitting without support within and age-appropriate time period

  • The 6 remaining patients were still within their age-appropriate WHO developmental window for sitting without support

Exploratory endpoint:

Achieved standing alone for ≥10 seconds (WHO)2,b

2 of 3 patients achieved this milestone within an age-appropriate time period

  • 10 patients were still within their age-appropriate WHO developmental window for this milestone

Exploratory endpoint:

Achieved walking alone (WHO)2,c

3 of 4 patients achieved this milestone within an age-appropriate time period

  • 10 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. As of the data cut (Dec 2019) the age range was 5.7-11.8 months for patients who achieved sitting without support ≥30 seconds up to 18 months of age. WHO MGRS established windows of achievement (1%-99%): 3.8-9.2 months for sitting without support.2,3

bThe age range was 12.2-18.3 months for patients who achieved independent standing alone ≥10 seconds assessed by WHO MGRS. One additional patient achieved stands alone based on Bayley-III, gross motor subtest 40 (child stands alone for ≥3 seconds after you release his or her hands). WHO MGRS established window of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3

cThe age range was 12.2-18.3 months for patients who achieved independent walking assessed by WHO MGRS. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3

27% (4/15) of patients with 3 copies of SMN2 achieved the primary endpoint of standing without support by the Dec 2019 data cut2,a
  • 100% (4/4) of the patients who stood without support did so within an age-appropriate time period2
  • The 11 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.

aAs of the Dec 2019 data cut, the age range was 8.9-12.0 months for patients who achieved stands 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

bBayley-III, gross motor subtest item 40. The age range was 9.5-12.4 for patients who achieved standing without support for ≥3 seconds up to 24 months of age. WHO MGRS established windows of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3

cBayley-III, gross motor subtest item 43. The age range was 12.2-15.1 months for patients who achieved the ability to walk alone at any visit up to 24 months of age. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3

Exploratory endpoint:

Achieved stands with assistance (WHO)2,a

8 of 9 achieved this milestone within and age-appropriate time period

  • The remaining 6 patients were still within their age-appropriate WHO developmental window for standing with assistance

Primary endpoint:

Achieved standing alone for ≥3 seconds (Bayley)2,b

4 of 4 patients achieved this milestone within an age-appropriate time period

  • The 11 remaining patients were still within their age-appropriate WHO developmental window for this milestone

Secondary endpoint:

Achieved walking alone (Bayley)2,c

2 of 2 patients achieved this milestone within an age-appropriate time period

  • The 13 remaining 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.

aAs of the Dec 2019 data cut, the age range was 8.9-12.0 months for patients who achieved stands 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

bBayley-III, gross motor subtest item 40. The age range was 9.5-12.4 for patients who achieved standing without support for ≥3 seconds up to 24 months of age. WHO MGRS established windows of achievement (1%-99%): 6.9-16.9 months for standing alone.2,3

cBayley-III, gross motor subtest item 43. The age range was 12.2-15.1 months for patients who achieved the ability to walk alone at any visit up to 24 months of age. WHO MGRS established windows of achievement (1%-99%): 8.2-17.6 months for walking alone.2,3

ZOLGENSMA enabled continued independence from nutritional support in presymptomatic patients with 2 and 3 copies of SMN22

Nearly all patients, 97% (28/29), remained within the normal weight range (3rd-97th percentile) and were free of oral feeding support as of the Dec 2019 data cut2,a,b

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

bNormal weight ranges defined as 3rd though 97th percentile of weight-for-age values for female and male patients, respectively, based on child growth standards from the World Health Organization.2

As of the Dec 2019 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

bNormal weight ranges defined as 3rd though 97th percentile of weight-for-age values for female and male patients, respectively, based on child growth standards from the World Health Organization.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 Dec 2019 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

50% (7/14) of patients with 2 copies of SMN2 and 100% (15/15) of patients with 3 copies of SMN2 achieved gross motor scores similar to same-age peers without SMA, as of the Dec 2019 data cut2,a

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 compares these to a standardized norm.5

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 compares these to a standardized norm.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 Dec 2019 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 ≥60

SD=standard deviation

aScores on the CHOP INTEND scale of motor function range from 0 to 64, with higher scores indicating better function.6

bThe dark gray line at 40 represents the highest possible CHOP INTEND score that children with the most sever 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

bThe dark gray line at 40 represents the highest possible CHOP INTEND score that children with the most sever form of SMA would achieve or maintain, according to natural history.7

Long-Term Follow-Up

A long-term follow-up of the START trial