Hereditary Transthyretin Amyloidosis (hATTR)

Developed by Alnylam Pharmaceuticals, Amvuttra® (vutrisiran) is an RNA interference (RNAi)-based drug indicated for the treatment of polyneuropathy in adults with hereditary transthyretin-mediated (hATTR) amyloidosis.1,2 Amvuttra contains vutrisiran, which is a transthyretin-directed small interfering ribonucleic acid (siRNA).3 One of Alnylam’s delivery systems, the Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, is used to administer Amvuttra subcutaneously (under the skin).2

Amvuttra is available as a clear, colorless-to-yellow solution in a single-dose prefilled syringe containing 25 mg/0.5 mL. The recommended dosage is 25 mg once every 3 months, administered subcutaneously.4 

Amvuttra is a double-stranded siRNA that targets mutant and wild‑type transthyretin (TTR) messenger RNA (mRNA) to block the production of TTR protein. In the HELIOS-A phase 3 study, Amvuttra relieved neuropathy relative to baseline in more than 50% of the treated patients. This finding was the basis for the approval of Amvuttra by the US Food and Drug Administration (FDA).1 

So that Amvuttra injection could be used to treat adults with polyneuropathy secondary to hATTR amyloidosis, Alnylam submitted a New Drug Application to the FDA in April 2021, and the FDA approved Amvuttra for this indication on June 13, 2022. Additionally, regulatory agencies in Europe, Brazil, and Japan are evaluating Amvuttra for approval.5 

Read more about hATTR therapies

Mechanism of Action

Vutrisiran is a double-stranded siRNA-GalNAc conjugate that promotes the degradation of mutant and wild-type TTR mRNA through RNA interference, thereby decreasing serum levels of TTR protein and TTR protein deposits in tissues.3 To transport the siRNA to hepatocytes, vutrisiran is covalently attached to a ligand with 3 N-acetyl galactosamine (GalNAc) residues. The Alnylan ESC-GalNAc-conjugate delivery platform enhances the metabolic stability and potency of the drug, allowing subcutaneous administration once every 3 months.5 

Efficacy in Trials and Trial Results

Phase 1 clinical research was conducted in 80 volunteers (60 received vutrisiran and 20 received placebo). Vutrisiran demonstrated a tolerable safety profile, and a single dose decreased serum TTR concentrations for a minimum of 90 days.6

FDA approval of Amvuttra was granted on the basis of positive results from HELIOS-A (NCT03759379), a global, multicenter, randomized, open-label phase 3 clinical study.5 The primary endpoint of HELIOS-A was change in the modified Neuropathy Impairment Score +7 (mNIS+7) between baseline and month 9 of treatment. Secondary endpoints at 9 months included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score and the 10-Meter Walk Test (10MWT) score. The efficacy and safety of Amvuttra were evaluated in 164 patients who had hATTR amyloidosis with polyneuropathy. The patients were assigned randomly in a 3:1 ratio to receive either 25 mg of vutrisiran administered subcutaneously every 3 months or 0.3 mg of Onpattro® (patisiran) per kilogram administered intravenously every 3 months for 18 months. The effectiveness of Amvuttra was assessed by comparing the Amvuttra group in HELIOS-A with an external placebo group comprising 77 patients from APOLLO, a controlled, randomized global phase 3 clinical study of patisiran (Onpattro) conducted in a group of patients similar to those in HELIOS-A. Treatment with Amvuttra in the HELIOS-A study resulted in statistically significant improvements in the mNIS+7, the Norfolk QoL-DN total score, and the 10MWT score at 9 months in comparison with placebo.2,3,5

Amvuttra (vutrisiran) is also being studied for the treatment of cardiomyopathy secondary to ATTR amyloidosis, including both hATTR amyloidosis and wild-type ATTR (wtATTR) amyloidosis, in HELIOS-B (NCT04153149), a randomized, double-blind, placebo-controlled phase 3 study.2,5

Warnings, Precautions, and Adverse Reactions

The most common adverse reactions (≥5%) noted included arthralgia, dyspnea, and reduced levels of vitamin A. Serious adverse reactions of atrioventricular (AV) heart block occurred in 2 of the patients (1.6%) who received Amvuttra, one of which was a complete AV block. Injection site reactions occurred in 5 of the patients who received Amvuttra (4%), including warmth, erythema, pain, bruising, and pruritus. The injection site reactions were transient and minor.3

Get full prescribing information for Amvuttra at MPR

An important precaution is to inform patients that Amvuttra can cause a decrease in serum levels of vitamin A. Supplementation to meet the recommended daily allowance of vitamin A is essential. In case ocular symptoms arise that suggest a vitamin A deficiency (eg, night blindness), the patient should consult an ophthalmologist.3


  1. Stewart J. Amvuttra. Updated July 1, 2022. Accessed July 15, 2022.
  2. Vutrisiran. An investigational RNAi therapeutic for ATTR amyloidosis. Alnylam Pharmaceuticals. Updated November 2021. Accessed July 15, 2022.b
  3. AMVUTTRA (vutrisiran) injection. Alnylam Pharmaceuticals. Revised June 2022. Accessed July 15, 2022. 
  4. AMVUTTRA (vutrisiran) injection. NIH National Library of Medicine. DailyMed. Updated June 21, 2022. Accessed July 15, 2022.
  5. AMVUTTRA (vutrisiran) for the treatment of polyneuropathy of hATTR amyloidosis, USA. Clinical Trials Arena. Updated July 6, 2022. Accessed July 15, 2022.
  6. ​​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

Reviewed by Kyle Habet, MD, on 7/19/2022.