Vutrisiran (AMVUTTRA)
Details
Vutrisiran (brand name AMVUTTRA; Alnylam Pharmaceuticals) is a subcutaneously administered RNA interference (RNAi) therapeutic — a GalNAc-conjugated small interfering RNA (siRNA) — that silences both wild-type and mutant TTR mRNA in hepatocytes, preventing synthesis of the amyloidogenic transthyretin protein before monomers can form and aggregate. It is administered as a 25 mg subcutaneous injection every 12 weeks (once every 3 months). Approved for hereditary ATTR amyloidosis with polyneuropathy (based on HELIOS-A); approved for ATTR-CM based on HELIOS-B results.
Key Facts
Mechanism of Action
- GalNAc ligand (triantennary N-acetylgalactosamine) binds asialoglycoprotein receptor on hepatocyte surface → receptor-mediated endocytosis → siRNA loaded into RISC complex → cleavage of complementary TTR mRNA → suppression of hepatic TTR protein synthesis. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
- Phosphonothioate linkages at 5' end and increased 2'-O-methyl nucleotide content enhance potency and allow quarterly dosing. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
- Silences both wild-type and variant TTR mRNA — active in both ATTRwt and ATTRv. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
- Achieves rapid and sustained mean trough TTR reduction of 81.0% (95% CI 79.0–83.0) at 30 months. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Clinical Trials
HELIOS-B (ATTR-CM; NEJM 2025)
- Phase 3 double-blind RCT; n=655; vutrisiran 25 mg SC Q12W vs placebo for up to 36 months; 87 sites, 26 countries.
- Primary endpoint (all-cause death + recurrent CV events): HR 0.72 (95% CI 0.56–0.93; P=0.01) overall; HR 0.67 (95% CI 0.49–0.93; P=0.02) in monotherapy population (no baseline tafamidis).
- All-cause mortality through 42 months: HR 0.65 (95% CI 0.46–0.90; P=0.01) overall — 60 (18%) vs 85 (26%) deaths.
- 6-minute walk test at 30 months: LS mean difference +26.5 m (95% CI 13.4–39.6; P<0.001).
- KCCQ-OS at 30 months: LS mean difference +5.8 points (95% CI 2.4–9.2; P<0.001) — exceeds 5-point MCID.
- NYHA improvement/stability at 30 months: 68% vs 61% (LS mean difference 8.7 pp; P=0.02).
- Benefits consistent in patients on and off background tafamidis and across all prespecified subgroups.
- Safety: adverse events in 99% vs 98%; serious AEs in 62% vs 67%; no new safety signals. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
HELIOS-A (hereditary ATTR polyneuropathy)
- Phase 3 RCT showing significant improvement in modified Neuropathy Impairment Score+7 at 9 months vs external placebo; basis for initial approval in ATTRv-PN.
- Exploratory cardiac endpoints suggested TTR lowering may benefit cardiac manifestations (NT-proBNP, echo, scintigraphy). (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Dosing and Administration
- 25 mg subcutaneous injection every 12 weeks (every 3 months).
- All patients instructed to take recommended daily allowance of vitamin A (TTR is a retinol carrier — TTR suppression may reduce retinol transport). (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Approved Indications
- Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN).
- Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) — both wild-type and variant — based on HELIOS-B.
Contradictions / Open Questions
- No head-to-head comparison vs tafamidis: HELIOS-B allowed background tafamidis (40% of patients) but was not designed to compare vutrisiran monotherapy directly against tafamidis monotherapy. The relative efficacy of these two classes (TTR silencer vs TTR stabilizer) as first-line monotherapy remains unknown. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
- Delayed mortality benefit pattern: Kaplan-Meier curves diverged at ~6 months — consistent with tafamidis data from ATTR-ACT — suggesting early treatment initiation may be critical for maximal mortality benefit. Optimal timing of treatment initiation relative to disease stage is not established. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
- Additive benefit on top of tafamidis not formally tested: While overall population (40% on tafamidis) showed similar HR to monotherapy population, the subgroup of tafamidis-on patients was not independently powered (HR 0.79; 95% CI 0.51–1.21) — it is not statistically confirmed that adding vutrisiran to tafamidis provides incremental mortality reduction. (sources/vutrisiran-attrcm-heliosb-nejm-2025 — very high)
Connections
- Related to entities/ATTR-Amyloidosis — primary disease target
- Related to concepts/Gene-Silencing-Therapy — class mechanism (GalNAc-siRNA, RNAi)
- Related to entities/Heart-Failure — primary clinical outcome domain
- Related to entities/HFpEF — ATTR-CM typically presents with preserved EF