NURTURE
Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study
Year of Publication: 2019
Authors: Darryl C De Vivo, Enrico Bertini, Kathryn J Swoboda, ..., Wildon Farwell; on behalf of the NURTURE Study Group
Journal: Neuromuscular Disorders
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.
Link: https://doi.org/10.1016/j.nmd.2019.09.007
PDF: http://www.nmd-journal.com/article/S0960896619311277/pdf
PDF: Clinical Question
Can nusinersen, initiated intrathecally in presymptomatic infants with genetically confirmed 5q SMA (2 or 3 SMN2 copies) at age <=6 weeks, prevent or profoundly attenuate the severity of SMA -- including survival, respiratory, and motor outcomes -- compared with the expected natural history?
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.
Design
Study Type: Phase 2, open-label, single-arm, multinational, interventional trial (interim analysis)
Randomization:
Blinding: None (open-label)
Enrollment Period: May 2015 - February 2017
Follow-up Duration: 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
Sample Size: 25
Analysis: Intent-to-treat population (all infants receiving >=1 dose). Kaplan-Meier for time-to-event and milestone achievement. Descriptive statistics for CHOP INTEND, HINE-2, CMAP, pNF-H. Wilson score CI with continuity correction for proportion with clinically manifested SMA. Spearman correlation for predictors of motor function. SAS version 9.4.
Inclusion Criteria
- Age <=6 weeks at first dose
- Genetic documentation of 5q SMA (biallelic deletion or protein-disabling mutation of SMN1 gene)
- 2 or 3 copies of the SMN2 gene
- Baseline ulnar CMAP amplitude >=1 mV
- Absence of hypoxemia
- No clinical signs or symptoms suggestive of SMA at enrollment
- On stable medications for >=1 month prior to baseline visit (if applicable)
- Women of childbearing age required to agree to birth control from consent to 2 months after last dose
Exclusion Criteria
- Prior medical condition that would prevent safe study participation (investigator judgment)
- Participation in another interventional clinical study within 30 days prior to baseline
- Concurrent enrollment in non-interventional research incompatible with NURTURE (investigator judgment)
- Adverse reaction to nusinersen in a prior study contraindicating further treatment
- Creatinine clearance <=30 mL/min
- QTc >450 ms (males) or >480 ms (females)
- Uncontrolled hypertension
- History of active alcoholism or drug addiction in the year prior to screening
- Clinically significant hypersensitivity or allergy to any study drug excipient
- Study center or sponsor personnel or their immediate family
Baseline Characteristics
| Characteristic | 2 SMN2 Copies (n=15) | 3 SMN2 Copies (n=10) |
|---|---|---|
| Age at First Dose - Median (range), days | 19.0 (8-41) | 23.0 (3-42) |
| Age at First Dose - Mean (SD), days | 19.5 (9.29) | 22.3 (12.45) |
| Sex - Male, n (%) | 8 (53%) | 4 (40%) |
| CHOP INTEND Total Score - Median (range) | 45.0 (25.0-60.0) | 53.5 (40.0-60.0) |
| CHOP INTEND Total Score - Mean (SD) | 47.0 (10.04) | 51.9 (6.10) |
| HINE-2 Total Motor Milestone Score - Mean (SD) | 2.7 (1.59) | 3.2 (1.87) |
| Ulnar CMAP Amplitude - Mean (SD), mV | 2.69 (1.516) | 3.11 (1.119) |
| Plasma pNF-H - Geometric Mean (95% CI), pg/mL | 20880.9 (9639.4-45231.9) | 1870.7 (1152.9-3035.5) |
| CSF pNF-H - Geometric Mean (95% CI), pg/mL | 20139.2 (10075.0-40256.7) | 951.5 (366.5-2470.2) |
Arms
| Field | Nusinersen |
|---|---|
| Intervention | Intrathecal nusinersen 12 mg administered by lumbar puncture: 4 loading doses on Days 1, 15, 29, and 64, followed by maintenance doses every 119 days over 5 years. |
| Duration | 5-year treatment period (ongoing at interim analysis; median 33.9 months at data cutoff) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to death or respiratory intervention (invasive or non-invasive ventilation for >=6 h/day continuously for >=7 days, or tracheostomy) | Primary | 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. | |||
| WHO motor milestone - Sitting without support | Secondary | 25/25 (100%); median age 7.9 months (2-copy), 6.4 months (3-copy); 84% within WHO 99th percentile | |||
| WHO motor milestone - Walking with assistance | Secondary | 23/25 (92%); median age 16.1 months (2-copy), 9.6 months (3-copy) | |||
| WHO motor milestone - Walking alone | Secondary | 22/25 (88%); 12/15 (80%) 2-copy, 10/10 (100%) 3-copy; median age 20.4 months (2-copy), 12.3 months (3-copy) | |||
| CHOP INTEND total score at last visit | Secondary | Mean 62.1/64 (2-copy); mean 63.4/64 (3-copy). 67% 2-copy and 100% 3-copy achieved max score of 64. | |||
| HINE-2 total motor milestone score | Secondary | Mean increased from 2.7 to 23.9 (2-copy); from 3.2 to 26.0 (3-copy). Scale max = 26. | |||
| Plasma pNF-H change over time | Secondary | Baseline 20880.9 pg/mL (2-copy) vs 1870.7 pg/mL (3-copy). Declined rapidly during loading. Day 64 pNF-H predicted walking age (rs=0.64, P=0.0025). | |||
| Any AE | Adverse | 25/25 (100%) | |||
| Serious AE | Adverse | 12/25 (48%); no SAEs related to study drug | |||
| AE possibly related to drug | Adverse | 8/25 (32%); none definitively related | |||
| AE related to lumbar puncture | Adverse | 8/25 (32%); hemorrhages near thecal space in 4 | |||
| Treatment discontinuation | Adverse | 0/25 (0%) | |||
| Pyrexia | Adverse | 21/25 (84%) | |||
| Upper respiratory infection | Adverse | 19/25 (76%) | |||
| Pneumonia | Adverse | 6/25 (24%); all 2-copy | |||
| Tremor | Adverse | 7/25 (28%); all 2-copy |
Subgroup Analysis
3 SMN2 copies had uniformly better outcomes than 2 copies. Baseline pNF-H was the strongest predictor of HINE-2 at Day 302 (rs=-0.53, P=0.0120) and walking age (rs=0.55, P=0.0147). In 2-copy, Day 64 weight-for-age (rs=0.72, P=0.0027) and CMAP (rs=0.66, P=0.0098) also correlated with HINE-2.
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
Funding
Biogen (Cambridge, MA, USA); medical writing support funded by Biogen.
Based on: NURTURE (Neuromuscular Disorders, 2019)
Authors: Darryl C De Vivo, Enrico Bertini, Kathryn J Swoboda, ..., Wildon Farwell; on behalf of the NURTURE Study Group
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.
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