Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Keywords: Clinical trial; Neurofilament; Newborn screening; Nusinersen; Presymptomatic; Spinal muscular atrophy.

Fig. 1

NURTURE study design. Intention-to-treat population is all infants who received ≥1 dose of study drug (n = 25). ^aInfants who attended or had the opportunity to attend the visit. ^bInfants treated with nusinersen 12 mg; some infants received a 12-mg scaled equivalent dose before the protocol was revised in March 2017.

Fig. 2

Kaplan–Meier plot for age at death or respiratory intervention.^a SMN2, survival motor neuron 2. No participants have died or required tracheostomy or permanent ventilation (defined as ≥16 h/day continuously for >21 days in the absence of an acute reversible event or tracheostomy). ^aRespiratory intervention was defined as ventilator use for ≥6 h per day for ≥7 days or tracheostomy.

Fig. 3

Site- or caregiver-reported^a age at first WHO motor milestone achievement. SMN2, survival motor neuron 2; WHO, World Health Organization. ^aIf caregiver-reported, achievement was confirmed by the study site at the next study visit with a yes or no response. ^bWHO motor milestone windows of achievement were determined based on the WHO Multicenter Growth Reference Study windows of achievement in healthy children .

Fig. 4

Mean HINE-2 motor milestone scores over time. HINE-2, Hammersmith Infant Neurologic Examination, Section 2; SE, standard error; SMN2, survival motor neuron 2. Time points with n ≥ 5 included. HINE-2 score was assessed in NURTURE participants up until the Day 778 study visit.

Fig. 5

(A) Mean CHOP INTEND score over time, (B) Kaplan–Meier plot for time to first achievement of maximum CHOP INTEND score of 64 points.^a CHOP INTEND, Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders; SE, standard error; SMN2, survival motor neuron 2. For Fig. 5(A), time points with n ≥ 5 included. ^aIn the original protocol, CHOP INTEND was to be assessed in participants at each visit up to Day 778; however, this was amended to be until they had a maximum score of 64. Once a score of 64 was achieved, CHOP INTEND was no longer assessed.

Fig. 6

(A) Plasma pNF-H levels at baseline in NURTURE infants and infants <1 year of age without SMA, (B) plasma pNF-H levels in NURTURE infants by study visit.^a CI, confidence interval; ELLA, enzyme-linked lectin assay; pNF-H, phosphorylated neurofilament heavy chain; SMA, spinal muscular atrophy; SMN2, survival motor neuron 2. pNF-H levels were evaluated using a pNF-H ELLA from ProteinSimple. 7.46 pg/mL was used as the imputed value if the pNF-H concentration was below the limit of quantification. Baseline pNF-H values in NURTURE infants were obtained on Study Visit Day 1, either prior to nusinersen administration or four h post-dose. Samples from infants without SMA were provided by Boston Children's Hospital. ^aTime points with n ≥ 5 included. The number of decimal places reported in summary statistics is not indicative of biomarker assay precision or sensitivity. In Panel A, some data points have an x-value offset of +/−0.2 months for better visualization.

Fig. 7

Plasma pNF-H levels at Day 64 and achievement of WHO motor milestone of walking alone pNF-H, phosphorylated neurofilament heavy chain; SMN2, survival motor neuron 2; WHO, World Health Organization. ¹WHO 99th percentile for age of achievement for development in healthy children .