Vutrisiran: Immunogenicity

Vutrisiran: Immunogenicity

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 Summary

Index

Relevant Information – Clinical Data – Global Safety Database – Label Information – Abbreviations – References

 Relevant Information

Vutrisiran Formulation

Vutrisiran utilizes GalNAc conjugate technology as the method of drug delivery which allows for subcutaneous injection.3 GalNAc conjugation facilitates siRNA delivery into the liver via the ASGPR expressed on hepatocytes. Vutrisiran uses second generation ESC, which includes a combination of additional phosphorothioate linkages, as well as 2′-O-methyl and 2′-fluoro nucleotide modifications, that provide improved molecular and metabolic stability.9

ADA Testing Availability

ADA testing for vutrisiran is not commercially available.

 Clinical Data

HELIOS-A Study

HELIOS-A was a phase 3, global, randomized, open-label study designed to evaluate the efficacy and safety of vutrisiran in patients with hATTR-PN. Patients were randomized (3:1) to receive either vutrisiran 25 mg every 3 months by subcutaneous injection (n=122) or patisiran 0.3 mg/kg every 3 weeks by IV infusion (as a reference group, n=42) for 18 months. This study used the placebo arm of the APOLLO study as an external control arm (n=77) for the primary endpoint and most other efficacy endpoints. The primary endpoint was the change from baseline in mNIS+7 at 9 months.3

ADAs

The presence of ADAs to vutrisiran was assessed as an exploratory endpoint of the HELIOS-A study. Blood samples for ADA testing were collected at specified time points (Day 1 pre-dose; Week 3, 12, 24, 36, 48, 72, 79-80) during the study and assessed using a validated ELISA method.10

In the HELIOS-A study, 3 (2.5%) vutrisiran-treated patients developed ADAs by Month 9, with a total of 4 (3.3%) patients by Month 18. ADA titers were low and transient with no evidence of an effect on clinical efficacy, safety, or PD parameters of vutrisiran.3–5

HELIOS-B Study

HELIOS-B was a phase 3, global, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of vutrisiran in patients with ATTR-CM, including both hATTR and wtATTR. Patients were randomized (1:1) to receive either vutrisiran 25 mg (n=326) or placebo (n=329) every 3 months by subcutaneous injection for up to 36 months. The primary endpoint was the composite endpoint of all-cause mortality and recurrent CV events (CV hospitalizations and urgent heart failure visits) at the end of the double-blind period in the overall population and in the monotherapy population (patients not receiving tafamidis at baseline). After the double-blind treatment period, all eligible patients remaining on the study were allowed to receive vutrisiran in an OLE.11

ADAs

The presence of ADAs to vutrisiran was assessed as a PD endpoint of the HELIOS-B study. Blood samples for ADA testing were collected at specified time points (Week 1, 12, 24, 36, 48, and 108 during the double-blind treatment period; the pre-tafamidis drop-in visit; and every 12 weeks during the follow-up period) and assessed using a validated ELISA method.12

In the HELIOS-B study, 1 (0.3%) vutrisiran-treated patient developed transient, low-titer ADAs. The available data are limited to make definitive conclusions regarding the effect of ADAs on PK or PD of vutrisiran.6

Pooled Safety Analysis of HELIOS-A and HELIOS-B

A pooled safety analysis including data from 707 patients who received at least one dose of vutrisiran at any time during the HELIOS-A and HELIOS-B studies was conducted to evaluate the safety of vutrisiran in patients with ATTR who received treatment for up to 58 months.7

The HELIOS-A vutrisiran group consisted of 160 patients who received at least one dose of vutrisiran in the initial 18-month treatment period (n=122) or initially received patisiran in the treatment period and were re-randomized to receive vutrisiran during the RTE (n=38). The HELIOS-B vutrisiran group consisted of 547 patients who received at least one dose of vutrisiran during the double-blind treatment period (n=326) or initially received placebo during the double-blind period and transitioned to vutrisiran in the OLE (n=221).7

ADAs

Incidence of ADAs was low with vutrisiran treatment up to 58 months. In the combined vutrisiran group, 64.9% of patients had baseline and postbaseline ADA results. Treatment emergent ADAs developed in 1.5% of these patients. ADA titers were low and transient, with no pattern of AEs in patients with ADAs to suggest an impact of ADAs on the safety profile of vutrisiran.7

 Global Safety Database

A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify safety concerns regarding ADAs.8

 AMVUTTRA Prescribing Information – Relevant Content

For relevant labeling information, please refer to the following section(s) of the AMVUTTRA Prescribing Information6:

      CLINICAL PHARMACOLOGY Section 12.2 Pharmacodynamics: Cardiomyopathy of Wild-type (wt) or Hereditary Transthyretin-mediated Amyloidosis (hATTR)

      CLINICAL PHARMACOLOGY Section 12.6 Immunogenicity

 Abbreviations

ADA = antidrug antibody; AE = adverse event; ASGPR = asialoglycoprotein receptor; ATTR = transthyretin amyloidosis; ATTR‑CM = transthyretin amyloidosis with cardiomyopathy; CV = cardiovascular; ELISA = enzyme-linked immunosorbent assay; ESC = enhanced stabilization chemistry; GalNAc = N‑acetyl galactosamine; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IV = intravenous; mNIS+7 = modified Neuropathy Impairment Score +7; OLE = open-label extension; PD = pharmacodynamics; PK = pharmacokinetics; RTE = randomized treatment extension; siRNA = small interfering ribonucleic acid; wtATTR = wild-type transthyretin amyloidosis.

Updated 23 October  2025

 References

1.  Supplement to: Habtemariam BA, Karsten V, Attarwala H, et al. Single‐dose pharmacokinetics and pharmacodynamics of transthyretin targeting N‐acetylgalactosamine–small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects. Clin Pharmacol Ther. 2021;109(2):372-382. doi:10.1002/cpt.1974

2.  Habtemariam BA, Karsten V, Attarwala H, et al. Single‐dose pharmacokinetics and pharmacodynamics of transthyretin targeting N‐acetylgalactosamine–small interfering ribonucleic acid conjugate, vutrisiran, in healthy subjects. Clin Pharmacol Ther. 2021;109(2):372-382. doi:10.1002/cpt.1974

3.  Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023;30(1):18-26. doi:10.1080/13506129.2022.2091985

4.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2200007.

5.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2200046.

6.  AMVUTTRA (vutrisiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.

7.  Witteles RM, Garcia-Pavia P, Morbach C, et al. Vutrisiran in transthyretin amyloidosis: a pooled safety analysis of HELIOS-A and HELIOS-B. JACC Adv. 2025;4(9). doi:10.1016/j.jacadv.2025.102066

8.  Alnylam Pharmaceuticals. Data on file. MED-ALL-VUTRI-2500021.

9.  Janas MM, Zlatev I, Liu J, et al. Safety evaluation of 2’-deoxy-2’-fluoro nucleotides in GalNAc-siRNA conjugates. Nucleic Acids Res. 2019;47(7):3306-3320. doi:10.1093/nar/gkz140

10.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2300015.

11.  Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

12.  Protocol for: Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134