Vutrisiran: Immunogenicity
Download PDF
The following information is provided in response to your unsolicited inquiry. It is intended to provide you with a review of the available scientific literature and to assist you in forming your own conclusions in order to make healthcare decisions. This document is not for further dissemination or publication without authorization.
The full Prescribing Information for AMVUTTRA® (vutrisiran) is provided here. Alnylam Pharmaceuticals does not recommend the use of its products in any manner that is inconsistent with the approved Prescribing Information. This resource may contain information that is not in the approved Prescribing Information.
If you are seeking additional scientific information related to Alnylam medicines, you may visit the Alnylam US Medical Affairs website at RNAiScience.com.
Summary
A pooled analysis of adverse events from the HELIOS-A and HELIOS-B studies was conducted to evaluate the safety of vutrisiran in patients with ATTR (n=707) who received treatment for up to 58 months.4 o Of the patients with baseline and postbaseline ADA results, 1.5% developed treatment emergent, transient, low-titer ADAs with no pattern of AEs to suggest an impact on the safety profile of vutrisiran.4 In a post-hoc analysis assessing serum TTR levels in patients in HELIOS-A (n=5) and HELIOS-B (n=4), all cases of positive ADA titers were low (50-100), transient, and did not impact serum TTR knockdown.5 A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify safety concerns regarding ADAs.6 ADA testing for vutrisiran is not commercially available. |
Relevant Information – Clinical Data – Global Safety Database – Label Information – Abbreviations – References
Vutrisiran Formulation
Vutrisiran utilizes GalNAc conjugate technology as the method of drug delivery which allows for subcutaneous injection.1 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.7
ADA Testing Availability
ADA testing for vutrisiran is not commercially available.
HELIOS-A Study
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.8
In the HELIOS-A study, 3 (2.5%) vutrisiran-treated patients developed treatment-emergent 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.1,2,9
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.10
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.11
In the HELIOS-B study, 1 (0.3%) vutrisiran-treated patient developed treatment-emergent ADAs, which were transient and low-titer. The available data are limited to make definitive conclusions regarding the effect of ADAs on PK or PD of vutrisiran.3,5
Pooled Analysis of HELIOS-A and HELIOS-B
A pooled analysis including adverse event 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.4
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).4
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.4
Serum TTR Post-Hoc Analysis
A post-hoc analysis was conducted to assess serum TTR knockdown with vutrisiran in patients with hATTR-PN in HELIOS-A and ATTR-CM in HELIOS-B. In HELIOS-A, 5 out of 121 patients (4.1%) tested positive for ADA titers to vutrisiran; 4 had treatment-emergent ADAs, and 1 was ADA-positive at baseline and at ≥1 post-baseline assessment. In HELIOS-B, 4 out of 321 patients (1.2%) tested positive for ADA titers to vutrisiran; 1 patient with treatment-emergent ADAs and 3 who tested positive at baseline and ≥ 1 post-baseline assessment. In all cases, ADA titers were low (50-100), transient, and did not impact TTR knockdown. In HELIOS-A, maximum median serum TTR knockdown through Month 18 was 93.4% for the 5 patients who tested positive for ADA compared to the maximum median serum TTR knockdown of 91.6% in patients who tested negative for ADA (n = 116). In HELIOS-B, maximum median serum TTR knockdown through Month 30 was 81.3% for the 4 patients who tested positive for ADA compared to the maximum median serum TTR knockdown of 90.4% in patients who tested negative for ADA (n = 313).5
A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify safety concerns regarding ADAs.6
AMVUTTRA Prescribing Information – Relevant Content
For relevant labeling information, please refer to the following section(s) of the AMVUTTRA Prescribing Information3:
CLINICAL PHARMACOLOGY Section 12.2 Pharmacodynamics: Cardiomyopathy of Wild-type (wt) or Hereditary Transthyretin-mediated Amyloidosis (hATTR)
CLINICAL PHARMACOLOGY Section 12.6 Immunogenicity
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; TTR = transthyretin; wtATTR = wild-type transthyretin amyloidosis.
Updated 9 June 2026
2. Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2200007.
3. AMVUTTRA (vutrisiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.
6. Alnylam Pharmaceuticals. Data on file. MED-ALL-VUTRI-2600002.
8. Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2300015.
9. Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2200046.
|
|
|
MED-ALL-TTRSC02-2300035 8.0 Approved through Jun 2028 |
