PDF: NEURO-TTRansact
(2023)Objective
To evaluate the efficacy and safety of eplontersen, a ligand-conjugated antisense oligonucleotide targeting transthyretin, in patients with hereditary transthyretin amyloidosis with polyneuropathy
Study Summary
• Norfolk QOL-DN significantly improved: LS mean difference −12.3 (P<0.001)
• Median serum TTR reduction of ~82% with eplontersen
• 36% of eplontersen patients had improvement in mNIS+7 from baseline
• No cases of glomerulonephritis or severe thrombocytopenia (unlike inotersen)
• Injection site reactions most common adverse event; generally mild
• Monthly dosing (vs weekly for inotersen) due to GalNAc conjugation improving hepatocyte uptake
Intervention
Eplontersen 45 mg subcutaneous every 4 weeks (after 3 loading doses in first 2 weeks) for 66 weeks vs placebo subcutaneous on same schedule
Inclusion Criteria
• Age 18–82 years
• Stage 1 or stage 2 hereditary ATTR polyneuropathy
• NIS 10–130
• Documented TTR mutation and amyloid deposits
• No prior liver transplant
• No NYHA class III–IV
• Tafamidis or diflunisal use permitted as background therapy (unlike NEURO-TTR)
Study Design
Arms: Array
Patients per Arm: Eplontersen: 144; Placebo: 72
Outcome
• Co-primary: Norfolk QOL-DN LS mean change at wk 66: −12.3; P<0.001
• Serum TTR reduction: median ~82% with eplontersen
• 36% of eplontersen patients improved on mNIS+7
• No severe thrombocytopenia or glomerulonephritis
• Injection site reactions: most common AE (mild)
• Consistent benefit across mutation type, disease stage, and cardiomyopathy subgroups
Bottom Line
Eplontersen significantly improved both co-primary endpoints vs placebo at 66 weeks: mNIS+7 (difference −17.0; P<0.001) and Norfolk QOL-DN (difference −12.3; P<0.001), with efficacy comparable to inotersen but markedly improved safety. Critically, no cases of glomerulonephritis or severe thrombocytopenia occurred, eliminating the major safety concerns that limited inotersen. Monthly subcutaneous dosing (vs weekly for inotersen) further improved convenience due to GalNAc conjugation enhancing hepatocyte-specific uptake.
Major Points
- NEURO-TTRansact was a randomized, double-blind, placebo-controlled, phase 3 trial of approximately 216 patients (2:1 randomization) with stage 1 or 2 hATTR polyneuropathy.
- Eplontersen is a ligand-conjugated (GalNAc) antisense oligonucleotide that delivers the drug directly to hepatocytes via the asialoglycoprotein receptor, allowing monthly dosing with improved safety vs unconjugated inotersen.
- Both co-primary endpoints were met: mNIS+7 LS mean difference of −17.0 (P<0.001) and Norfolk QOL-DN difference of −12.3 (P<0.001), confirming robust neuropathy benefit.
- Serum TTR was reduced by approximately 82% at steady state, comparable to the ~80% reduction achieved with patisiran.
- 36% of eplontersen patients had improvement (decrease) in mNIS+7 from baseline, demonstrating neuropathy reversal beyond just stabilization.
- The critical safety advantage: no cases of glomerulonephritis or severe thrombocytopenia, unlike inotersen (which required REMS). This is attributed to the GalNAc conjugation reducing systemic exposure.
- Monthly subcutaneous dosing (vs weekly for inotersen, vs q3w IV for patisiran) represented the most convenient dosing regimen among hATTR therapies.
- Unlike the NEURO-TTR trial, background tafamidis or diflunisal was permitted, making results applicable to real-world practice where patients may already be on stabilizer therapy.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, phase 3 trial; 2:1 randomization (eplontersen:placebo); 66-week treatment period; stratified by TTR mutation type and disease stage
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 216
Primary Outcome
Definition: mNIS+7 LS mean change from baseline to week 66 (eplontersen minus placebo): −17.0; P<0.001 | Norfolk QOL-DN LS mean change from baseline to week 66: −12.3; P<0.001
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | P<0.001 |
Citation
N Engl J Med 2023;389:55-67