PDF: HELIOS-A
(2021)Objective
To evaluate the efficacy and safety of vutrisiran, a subcutaneously administered RNAi therapeutic targeting transthyretin, in patients with hereditary transthyretin amyloidosis with polyneuropathy
Study Summary
• Norfolk QOL-DN significantly improved at 9 months vs external placebo: difference −11.1 (P<0.001)
• At 18 months, mNIS+7 change with vutrisiran was −0.2 (stable), comparable to patisiran reference arm
• Serum TTR reduction: median ~83% at steady state
• No premedication required (unlike patisiran IV)
• Vutrisiran administered SC every 3 months (vs patisiran IV every 3 weeks)
• Adverse events generally mild; no significant hepatic or renal safety signals
Intervention
Vutrisiran 25 mg subcutaneous every 3 months for 18 months vs patisiran 0.3 mg/kg IV every 3 weeks (reference arm); external placebo from APOLLO trial used for primary comparison
Inclusion Criteria
• Age 18–85 years
• Hereditary transthyretin amyloidosis with polyneuropathy
• NIS 5–130
• Polyneuropathy disability score ≤IIIb
• Documented TTR mutation
• Prior TTR stabilizer use permitted
• No prior liver transplant; no NYHA class III–IV
Study Design
Arms: Array
Patients per Arm: Vutrisiran: 122; Patisiran reference: 42; APOLLO external placebo: 77
Outcome
• Norfolk QOL-DN at 9 mo vs APOLLO placebo: difference −11.1; P<0.001
• mNIS+7 at 18 mo (vutrisiran): −0.2 (stable from baseline)
• mNIS+7 at 18 mo (patisiran reference): +1.3
• Serum TTR reduction: ~83% at steady state
• 10-m walk speed: maintained/improved with vutrisiran
• Injection site reactions: mild; no premedication needed
• No severe thrombocytopenia or glomerulonephritis
Bottom Line
Vutrisiran significantly improved neuropathy and quality of life vs the APOLLO external placebo at 9 months (mNIS+7 difference −14.6; P<0.001; Norfolk QOL-DN difference −11.1; P<0.001) and maintained stable neuropathy scores through 18 months. The subcutaneous, every-3-month dosing without premedication represents a major convenience advantage over IV patisiran (every 3 weeks with premedication). The GalNAc conjugation technology enabling hepatocyte-targeted delivery transformed the practical management of hATTR polyneuropathy.
Major Points
- HELIOS-A was a randomized, open-label, phase 3 trial comparing vutrisiran (N=122) with a patisiran reference arm (N=42), using the APOLLO trial placebo arm as the external comparator for the primary analysis.
- Vutrisiran is an enhanced stabilization chemistry (ESC) GalNAc-conjugated siRNA that enables quarterly subcutaneous dosing without premedication, a significant improvement over IV patisiran (q3 weeks with corticosteroid/antihistamine premedication).
- The primary comparison (vutrisiran vs APOLLO external placebo at 9 months) was strongly positive for both mNIS+7 (change +0.2 vs +14.8; difference −14.6; P<0.001) and Norfolk QOL-DN (difference −11.1; P<0.001).
- At 18 months, vutrisiran patients had a mean mNIS+7 change of −0.2 (essentially stable from baseline), comparable to the patisiran reference arm (+1.3), confirming equivalent efficacy to the established RNAi therapy.
- Serum TTR was reduced by approximately 83% at steady state with vutrisiran, comparable to the 81% reduction achieved with patisiran, confirming potent gene silencing.
- No premedication was required for vutrisiran (vs dexamethasone, acetaminophen, H1/H2 blockers required for patisiran), reducing treatment burden and corticosteroid exposure.
- The safety profile was favorable with no severe thrombocytopenia or glomerulonephritis (concerns with inotersen), and injection site reactions were generally mild.
- Vutrisiran received FDA approval in June 2022, offering patients with hATTR polyneuropathy a quarterly SC dosing option as an alternative to the q3w IV patisiran or monthly SC eplontersen.
Study Design
- Study Type
- Randomized, open-label, phase 3 trial; 3:1 randomization (vutrisiran:patisiran reference); 18-month treatment; APOLLO placebo used as external comparator for primary analysis; no stratification for primary analysis
- Randomization
- Yes
- Blinding
- Open-label
- Sample Size
- 164
Primary Outcome
Definition: mNIS+7 change at 9 months vs APOLLO external placebo: +0.2 vs +14.8; difference −14.6; P<0.001 | Norfolk QOL-DN change at 9 months vs APOLLO external placebo: difference −11.1; P<0.001
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | P<0.001 |
Citation
N Engl J Med 2021;385:1196-1209 (Amyloid 2021)