NURTURE
(2019)Objective
To evaluate the long-term safety and efficacy of intrathecal nusinersen initiated in infancy during the presymptomatic stage of spinal muscular atrophy (SMA) in infants with 2 or 3 SMN2 copies.
Study Summary
• All 25 participants (100%) achieved independent sitting and 88% achieved independent walking, milestones largely absent in untreated siblings with identical SMN2 copy numbers.
• pNF-H levels were elevated at baseline even before symptom onset, declined rapidly with nusinersen loading, and predicted future motor function -- supporting the importance of newborn screening and immediate presymptomatic treatment.
Intervention
Intrathecal nusinersen 12 mg administered as 4 loading doses (Days 1, 15, 29, 64), then maintenance every 119 days over 5 years.
Inclusion Criteria
Age <=6 weeks at first dose; genetic documentation of 5q SMA (biallelic SMN1 deletion or mutation); 2 or 3 SMN2 copies; baseline ulnar CMAP >=1 mV; no hypoxemia; no clinical signs or symptoms of SMA.
Study Design
Arms: Single arm: nusinersen (no control group; internal ethical justification given expected fatal natural history).
Patients per Arm: 25 (15 with 2 SMN2 copies; 10 with 3 SMN2 copies)
Outcome
• Motor milestones: 25/25 (100%) achieved sitting without support; 23/25 (92%) achieved walking with assistance; 22/25 (88%) achieved independent walking -- all exceeding the expected SMA Type I/II phenotype and markedly better than untreated siblings.
• CHOP INTEND scores rose from a mean of 49.0 at baseline to near-maximum (62-63/64) at last visit; pNF-H declined rapidly with nusinersen loading and stabilized; no new safety concerns identified.
Bottom Line
Presymptomatic nusinersen in SMA infants with 2 or 3 SMN2 copies resulted in 100% survival without permanent ventilation and near-normal motor milestone achievement at median 2.9 years of follow-up, dramatically exceeding the expected natural history of SMA Types I and II and the outcomes of their untreated siblings, supporting immediate treatment after genetic diagnosis via newborn screening.
Major Points
- NURTURE is a Phase 2, open-label, single-arm study; no control group was included given the expected fatal or severely disabling natural history of untreated 2- and 3-copy SMN2 SMA.
- 25 infants enrolled (15 with 2 SMN2 copies, 10 with 3 SMN2 copies); median age at first dose 22 days (range 3-42 days).
- Interim analysis data cutoff: March 29, 2019; median age at last visit 34.8 months (range 25.7-45.4 months); median follow-up 2.9 years.
- Primary endpoint: all 25 participants alive; 0 required tracheostomy or permanent ventilation. Only 4/25 (16%, all 2-copy) used temporary respiratory support during acute reversible illness.
- Motor milestones (WHO criteria): 25/25 (100%) achieved sitting without support; 23/25 (92%) achieved walking with assistance; 22/25 (88%) achieved independent walking -- outcomes inconsistent with expected SMA Type I or II natural history.
- Most milestones achieved within the WHO normative developmental window: 84% sat without support, 65% walked with assistance, and 73% walked independently by the WHO 99th percentile age.
- 3-copy participants performed better than 2-copy participants: all 10 (100%) with 3 SMN2 copies achieved independent walking vs. 12/15 (80%) with 2 SMN2 copies.
- CHOP INTEND scores rose from a mean of 49.0 at baseline to approximately 62-63/64 at last visit for both subgroups. 10/15 (67%) 2-copy and 10/10 (100%) 3-copy participants achieved the maximum score of 64.
- HINE-2 motor milestone total scores increased from a mean of 2.7-3.2 at baseline to 23.9-26.0 at last observed visit, approaching scale maximum.
- Sibling comparison: NURTURE participants dramatically exceeded motor outcomes of untreated siblings with identical SMN2 copy numbers; 5/6 siblings (2-copy) with SMA required tracheostomy and/or died by 16 months -- vs. 0 NURTURE participants.
- pNF-H levels were elevated at baseline in presymptomatic infants (even before symptom onset), significantly higher in 2-copy vs. 3-copy participants (plasma P=0.0050; CSF P=0.0020), declined rapidly with nusinersen loading, and lower Day 64 pNF-H levels predicted earlier achievement of independent walking (rs=0.64, P=0.0025).
- CMAP amplitudes remained stable over time in both subgroups, contrasting with rapid deterioration in historical untreated SMA cohorts.
- 8/25 (32%) infants had AEs considered possibly related to nusinersen; no AEs definitively related to study drug; no SAEs related to study drug; no new safety signals identified.
- Key limitations: open-label, no sham control, small sample size, interim analysis of ongoing study, caregiver-reported milestone timing, variable baseline presentation, CHOP INTEND ceiling effect at 60-64 points.
Study Design
- Study Type
- Phase 2, open-label, single-arm, multinational, interventional trial (interim analysis)
- Randomization
- No
- Blinding
- None (open-label)
- Sample Size
- 25
- Follow-up
- Median 33.9 months (range 25.3-45.1 months) at interim data cutoff; ongoing 5-year treatment period
- Centers
- 15
- Countries
- USA, Italy, Taiwan, Germany, Australia, Turkey, Qatar
Primary Outcome
Definition: Time to death or respiratory intervention (invasive or non-invasive ventilation for >=6 h/day continuously for >=7 days, or tracheostomy)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | 0/25 deaths; 0/25 required tracheostomy or permanent ventilation. 4/25 (16%, all 2-copy) required temporary respiratory support >=6 h/day for >=7 days during acute reversible illness. | - |
Limitations & Criticisms
- Open-label design with no sham or placebo control group
- Small sample size (n=25); interim analysis of ongoing study
- Caregiver-reported milestone timing may introduce variability
- No formal prospective assessments of siblings with SMA
- CHOP INTEND ceiling effect at ~60/64
- HINE-2 only assessed until Day 778
- Variable baseline clinical presentation despite all meeting presymptomatic criteria
- Cross-study comparisons with ENDEAR/CHERISH limited by population differences
- Funded by Biogen; several co-authors are Biogen employees
- Long-term durability through childhood/adolescence remains to be determined
Citation
De Vivo DC, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11):842-856.