PDF: NEURO-TTR
(2018)Objective
To evaluate the efficacy and safety of inotersen, an antisense oligonucleotide inhibitor of hepatic transthyretin production, in patients with hereditary transthyretin amyloidosis with polyneuropathy
Study Summary
• mNIS+7 change: −19.7 points favoring inotersen (95% CI −26.4 to −13.0; P<0.001)
• Norfolk QOL-DN change: −11.7 points favoring inotersen (95% CI −18.3 to −5.1; P<0.001)
• 36% of inotersen patients had no mNIS+7 worsening; 50% improved on Norfolk QOL-DN
• Benefits independent of mutation type, disease stage, or cardiomyopathy presence
• Serious AEs: glomerulonephritis (3%) and thrombocytopenia (3%) in inotersen group; 5 deaths in inotersen vs 0 placebo
• Enhanced monitoring for platelets and renal function mandated after safety signal
Intervention
Inotersen 300 mg subcutaneous weekly (3 loading doses in week 1, then weekly) for 15 months vs placebo subcutaneous weekly; all patients received vitamin A supplementation
Inclusion Criteria
• Age 18–82 years
• Stage 1 (ambulatory) or stage 2 (ambulatory with assistance) hATTR polyneuropathy
• NIS 10–130
• TTR mutation determined by genotyping
• Documented amyloid deposits on biopsy
• No tafamidis or diflunisal during intervention
• No previous liver transplant
• No NYHA class III or higher
Study Design
Arms: Array
Patients per Arm: Inotersen: 112; Placebo: 60
Outcome
• Co-primary: Norfolk QOL-DN LS mean change at wk 66: −11.7 (95% CI −18.3 to −5.1); P<0.001
• mNIS+7: inotersen +5.8 vs placebo +25.5
• Norfolk QOL-DN: inotersen +1.0 vs placebo +12.7
• 36% inotersen improved (no increase in mNIS+7); 50% improved on Norfolk QOL-DN
• Glomerulonephritis: 3/112 (3%) inotersen; thrombocytopenia: 3/112 (3%)
• Deaths: 5 inotersen vs 0 placebo (1 thrombocytopenia-related)
• 81% inotersen vs 87% placebo completed trial
Bottom Line
Inotersen significantly improved both co-primary endpoints at 66 weeks: mNIS+7 (difference −19.7; P<0.001) and Norfolk QOL-DN (difference −11.7; P<0.001) vs placebo. Benefits were consistent across mutation type, disease stage, and cardiomyopathy status. However, serious safety signals — glomerulonephritis (3%) and severe thrombocytopenia (3%, with 1 fatal case) — necessitated enhanced monitoring programs. Published simultaneously with the APOLLO patisiran trial, providing two distinct therapeutic approaches for hATTR.
Major Points
- NEURO-TTR was a randomized, double-blind, placebo-controlled, phase 3 trial of 172 patients (112 inotersen, 60 placebo) at 24 centers in 10 countries, conducted from March 2013 to November 2017.
- Patients had stage 1 or 2 hATTR polyneuropathy with NIS 10–130 and documented TTR mutation with amyloid deposits. Approximately half had Val30Met mutation; 63% had cardiomyopathy.
- Both co-primary endpoints were met: mNIS+7 LS mean difference of −19.7 (95% CI −26.4 to −13.0; P<0.001) and Norfolk QOL-DN difference of −11.7 (95% CI −18.3 to −5.1; P<0.001).
- 36% of inotersen patients showed no worsening on mNIS+7, and 50% improved on Norfolk QOL-DN, demonstrating meaningful clinical benefit beyond just slowing progression.
- Efficacy was consistent across all 16 prespecified subgroups: Val30Met vs non-Val30Met, stage 1 vs stage 2, with vs without cardiomyopathy, and with vs without prior stabilizer therapy.
- Serious safety concerns emerged: glomerulonephritis in 3 patients (3%), severe thrombocytopenia in 3 patients (3%) with one fatal intracranial hemorrhage, necessitating an FDA-mandated REMS program with enhanced platelet monitoring.
- Five deaths occurred in the inotersen group vs 0 in placebo, though most were attributed to disease progression. The thrombocytopenia-related death led to enhanced monitoring requirements.
- 81% of inotersen patients completed the trial (22% discontinued for adverse events) vs 87% placebo (5% discontinued for progression), reflecting the safety challenges of this antisense approach.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, phase 3 trial; 2:1 randomization; 15-month intervention with 6-month post-intervention follow-up; stratified by Val30Met status, disease stage, and prior stabilizer use
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 172
Primary Outcome
Definition: mNIS+7 LS mean change from baseline to week 66 (inotersen minus placebo): −19.7 (95% CI −26.4 to −13.0); P<0.001 | Norfolk QOL-DN LS mean change from baseline to week 66: −11.7 (95% CI −18.3 to −5.1); P<0.001
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | P<0.001 |
Citation
N Engl J Med 2018;379:22-31