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START (Zolgensma Phase 1)

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

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Year of Publication: 2017

Authors: Mendell JR, Al-Zaidy S, Shell R, ..., Alfano L

Journal: New England Journal of Medicine

Citation: N Engl J Med. 2017 Nov 2;377(18):1713-1722

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1706198

Clinical Question

Is a single IV dose of AAV9-SMN gene replacement therapy safe and effective in infants with SMA Type 1?

Bottom Line

A single IV infusion resulted in 100% survival at 20 months (vs 8% historical). High-dose: 11/12 sat unassisted, 2 walked independently. First-in-human gene therapy for SMA.

        Major Points
        First-in-human gene replacement therapy for any neuromuscular disease -- landmark proof-of-concept for AAV9-mediated gene delivery to motor neurons
All 15 patients alive and event-free at 20 months compared to 8% survival in historical natural history cohorts (NeuroNext SMA cohort)
High-dose cohort (2.0x10^14 vg/kg): 11/12 (92%) sat unassisted, 9/12 (75%) rolled over, 11/12 (92%) fed orally and spoke, 2/12 (17%) walked independently
Rapid CHOP INTEND improvement: +9.8 points at 1 month and +15.4 points at 3 months in high-dose (vs expected decline in historical cohort)
Elevated aminotransferases in 4/15 (27%) patients, all managed with oral prednisolone (1 mg/kg/day) -- establishing need for hepatic monitoring protocol
Single one-time IV infusion over ~60 minutes represents fundamentally different treatment paradigm vs repeated intrathecal nusinersen
Low-dose cohort (3 patients) maintained baseline function without milestone achievement, confirming dose-response relationship

      

Design

Study Type: Phase 1, open-label, dose-escalation, single-center trial

Randomization:

Blinding: Open-label

Enrollment Period: May 2014 to August 2017

Follow-up Duration: Minimum 20 months post-infusion (data cutoff August 7, 2017); 2-year follow-up published separately

Centers: 1

Countries: United States

Sample Size: 15

Analysis: Exploratory; Kaplan-Meier for event-free survival compared with historical NeuroNext SMA cohort; descriptive statistics for motor outcomes

Inclusion Criteria

Age 6-9 months at infusion (cohort-dependent)
SMA Type 1 with biallelic SMN1 mutations and 2 SMN2 copies
Disease onset between birth and 6 months of age
Clinical hypotonia with motor skill delays and poor head control

Exclusion Criteria

Active viral infections (HIV or hepatitis B/C seropositivity)
Invasive ventilation via tracheotomy or oxygen saturation <95%
Concomitant illness creating unnecessary risk for gene transfer
Concomitant myopathy/neuropathy drugs, diabetes agents, or immunosuppressive therapy (corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IVIG, rituximab)
Anti-AAV9 antibody titers >1:50
Abnormal laboratory values: GGT >3x ULN, bilirubin >=3.0 mg/dL, creatinine >=1.8 mg/dL, hemoglobin <8 or >18 g/dL, WBC >20,000
Recent SMA treatment trial participation
Signs of aspiration without commitment to alternative feeding methods
Presence of SMN2 c.859G>C modifier mutation
Unwillingness to disclose study participation to primary care physician

Arms

Field	Cohort 1 (Low-dose)	Cohort 2 (High-dose)
Intervention	Single IV infusion of AVXS-101 (onasemnogene abeparvovec) at 6.7x10^13 vg/kg over ~60 minutes	Single IV infusion of AVXS-101 (onasemnogene abeparvovec) at 2.0x10^14 vg/kg (3x higher than Cohort 1) over ~60 minutes
Duration	One-time infusion; follow-up >=20 months	One-time infusion; follow-up >=20 months

Outcomes

Outcome	Type	Control	Intervention	P-value
Safety: survival and adverse events at 20 months post-infusion	Primary	Historical NeuroNext SMA cohort: 8% alive and event-free at 20 months	15/15 (100%) alive and event-free at 20 months (no deaths, no permanent ventilation)	p<0.001 vs historical
Motor milestones achieved (high-dose cohort, n=12)	Secondary	0% in historical cohort achieve sitting	Sat unassisted: 11/12 (92%); Rolled over: 9/12 (75%); Fed orally/spoke: 11/12 (92%); Walked independently: 2/12 (17%)
CHOP INTEND score change (high-dose cohort)	Secondary	Steady decline in historical cohort	+9.8 points at 1 month; +15.4 points at 3 months; continued improvement through follow-up
Motor milestones (low-dose cohort, n=3)	Secondary		Maintained baseline function; no independent sitting or walking achieved
Elevated aminotransferases	Adverse		4/15 (27%); ALT elevated to >2x ULN; all managed with oral prednisolone (1 mg/kg/day)
Upper respiratory infection	Adverse		Common AE across both cohorts
Bronchiolitis	Adverse		Reported in several patients
Constipation	Adverse		Common AE
Deaths	Adverse		0/15 (0%) deaths during study period

Subgroup Analysis

High-dose cohort (2.0x10^14 vg/kg) showed dramatically superior milestone achievement vs low-dose (6.7x10^13 vg/kg), confirming dose-response relationship. Younger age at infusion trended toward better motor outcomes.

Criticisms

Small sample size (n=15 total; high-dose n=12) limits generalizability
No concurrent control arm -- all comparisons to historical natural history cohorts which may differ in disease severity and supportive care standards
Open-label design introduces potential for assessment bias in motor milestone evaluation
Hepatotoxicity in 27% requiring immunosuppression with prednisolone raises safety concerns for broader population
Single-center study (Nationwide Children's Hospital, Columbus, Ohio) -- results may reflect center-of-excellence expertise
Limited follow-up at time of publication (20 months); durability of gene expression unknown
Anti-AAV9 antibody exclusion criterion (>1:50) eliminates ~5% of potential patients and precludes re-dosing
One-time treatment: no option for dose adjustment or re-treatment if response is suboptimal

Funding

AveXis (now Novartis Gene Therapies)

Based on: START (Zolgensma Phase 1) (New England Journal of Medicine, 2017)

Authors: Mendell JR, Al-Zaidy S, Shell R, ..., Alfano L

Citation: N Engl J Med. 2017 Nov 2;377(18):1713-1722

Content summarized and formatted by NeuroTrials.ai.

START (Zolgensma Phase 1)

(2017)

Objective

To evaluate the safety and efficacy of a single intravenous dose of AAV9-SMN gene replacement therapy in infants with SMA Type 1

Study Summary

• All 15 patients alive and event-free at 20 months vs 8% survival in historical cohorts; high-dose: 11/12 sat unassisted, 9/12 rolled over, 2/12 walked independently
• CHOP INTEND rapidly improved (+9.8 points at 1 month, +15.4 at 3 months); elevated aminotransferases in 4/15 (27%) managed with prednisolone; single one-time IV infusion vs repeated intrathecal injections for nusinersen

Intervention

Single IV infusion of AVXS-101 (onasemnogene abeparvovec): low dose 6.7x10^13 vg/kg or high dose 2.0x10^14 vg/kg

Inclusion Criteria

Infants with SMA Type 1, biallelic SMN1 mutations

Study Design

Arms: Cohort 1 (low-dose 6.7x10^13 vg/kg) and Cohort 2 (high-dose 2.0x10^14 vg/kg); open-label, no control

Patients per Arm: Cohort 1 (low-dose): 3, Cohort 2 (high-dose): 12

Outcome

• All 15 alive and event-free at 20 months (vs 8% historical survival); no deaths, no permanent ventilation
• High-dose milestones: sat unassisted 11/12 (92%), rolled over 9/12 (75%), walked independently 2/12 (17%), fed orally 11/12 (92%)
• CHOP INTEND: +9.8 points at 1 month, +15.4 at 3 months; elevated aminotransferases in 4/15 (27%) managed with prednisolone

Bottom Line

A single IV infusion resulted in 100% survival at 20 months (vs 8% historical). High-dose: 11/12 sat unassisted, 2 walked independently. First-in-human gene therapy for SMA.

Major Points

First-in-human gene replacement therapy for any neuromuscular disease -- landmark proof-of-concept for AAV9-mediated gene delivery to motor neurons
All 15 patients alive and event-free at 20 months compared to 8% survival in historical natural history cohorts (NeuroNext SMA cohort)
High-dose cohort (2.0x10^14 vg/kg): 11/12 (92%) sat unassisted, 9/12 (75%) rolled over, 11/12 (92%) fed orally and spoke, 2/12 (17%) walked independently
Rapid CHOP INTEND improvement: +9.8 points at 1 month and +15.4 points at 3 months in high-dose (vs expected decline in historical cohort)
Elevated aminotransferases in 4/15 (27%) patients, all managed with oral prednisolone (1 mg/kg/day) -- establishing need for hepatic monitoring protocol
Single one-time IV infusion over ~60 minutes represents fundamentally different treatment paradigm vs repeated intrathecal nusinersen
Low-dose cohort (3 patients) maintained baseline function without milestone achievement, confirming dose-response relationship

Study Design

Study Type: Phase 1, open-label, dose-escalation, single-center trial
Randomization: No
Blinding: Open-label
Sample Size: 15
Follow-up: Minimum 20 months post-infusion (data cutoff August 7, 2017); 2-year follow-up published separately
Centers: 1
Countries: United States

Primary Outcome

Definition: Safety: survival and adverse events at 20 months post-infusion

Control	Intervention	HR/OR	P-value
Historical NeuroNext SMA cohort: 8% alive and event-free at 20 months	15/15 (100%) alive and event-free at 20 months (no deaths, no permanent ventilation)	-	p<0.001 vs historical

Limitations & Criticisms

Small sample size (n=15 total; high-dose n=12) limits generalizability
No concurrent control arm -- all comparisons to historical natural history cohorts which may differ in disease severity and supportive care standards
Open-label design introduces potential for assessment bias in motor milestone evaluation
Hepatotoxicity in 27% requiring immunosuppression with prednisolone raises safety concerns for broader population
Single-center study (Nationwide Children's Hospital, Columbus, Ohio) -- results may reflect center-of-excellence expertise
Limited follow-up at time of publication (20 months); durability of gene expression unknown
Anti-AAV9 antibody exclusion criterion (>1:50) eliminates ~5% of potential patients and precludes re-dosing
One-time treatment: no option for dose adjustment or re-treatment if response is suboptimal

Citation

N Engl J Med. 2017 Nov 2;377(18):1713-1722

View Original Publication →

START (Zolgensma Phase 1)

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about START (Zolgensma Phase 1)