Vutrisiran: Use in Patients with Renal Impairment

Vutrisiran: Use in Patients with Renal Impairment

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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.

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 Summary

Index

Clinical Pharmacology – HELIOS-B Study – Global Safety Database – Label Information – Abbreviations – References

 Clinical Pharmacology

Vutrisiran clinical pharmacology studies conducted in both healthy subjects and patients with hATTR‑PN showed the mean serum t1/2 ranged from 4 to 7.5 hours following subcutaneous administration After reaching the Cmax, vutrisiran concentration declined rapidly to the LLOQ by 24 to 48 hours. Renal clearance is not a major route of elimination of vutrisiran.1,8

Pooled Safety Population

In a pooled PK/PD population (n=202) including data from the Phase 1 and HELIOS-A studies, patients with mild to moderate renal impairment showed similar TTR reductions to those with no renal impairment. No significant impact of impaired renal function was observed, with a less than 25% increase in Cmax and AUC0-24 predicted in patients with mild or moderate renal impairment compared with patients with normal renal function.8

 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 treatment 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.9

Per the HELIOS-B study protocol, patients with an eGFR <30 mL/min/1.73 m2 (using the MDRD formula) were excluded from the study; however, the development of CKD stage ≥4 (eGFR <30mL/min/1.73 m2) during the study period was not a protocol-defined reason to interrupt or discontinue treatment, and these patients remained in the study until completion or withdrawal for other reasons.5

eGFR was calculated using the Chronic Kidney Disease Epidemiology formula and was assessed at baseline, weeks 1 and 6, and months 6, 12, 18,24, 30, and 36.5

Post-Hoc Analysis of All HELIOS-B Patients

Change in eGFR Over Time

The change from baseline in eGFR over time was evaluated in the overall population of the HELIOS-B study by patients with a baseline eGFR <60 mL/min/1.73 m2 or ≥60 mL/min/1.73 m2 (Figure 1).5

Figure 1. Change from Baseline in eGFR Over 30 Months in HELIOS-B.5,a

Efficacy Results in the Overall Population by Baseline eGFR

In the overall population of the HELIOS-B study, treatment with vutrisiran reduced the risk of the primary composite endpoint of all-cause mortality and recurrent CV events when compared with placebo (HR 0.72; 95% CI 0.56, 0.93; P=0.01).9

In the subgroup of patients with a baseline eGFR <60 mL/min/1.73 m2 (n=264), treatment with vutrisiran compared with placebo resulted in a HR of 0.697 (95% CI 0.478, 1.016) in all-cause mortality and recurrent CV events. In the subgroup of patients with a baseline eGFR ≥60 mL/min/1.73 m2 (n=390), treatment with vutrisiran compared with placebo resulted in a HR of 0.719 (95% CI 0.505, 1.024) in all‑cause mortality and recurrent CV events.5

In the overall population, treatment with vutrisiran reduced the risk of the secondary endpoint of all‑cause mortality through 42 months when compared with placebo (HR of 0.65; 95% CI 0.46, 0.90; P=0.01).9

In the subgroup of patients with a baseline eGFR <60 mL/min/1.73 m2 (n=264), treatment with vutrisiran compared with placebo resulted in a HR of 0.638 (95% CI 0.394, 1.033) in all-cause mortality through 42 months. In the subgroup of patients with a baseline eGFR ≥60 mL/min/1.73 m2 (n=390), treatment with vutrisiran compared with placebo resulted in a HR of 0.664 (95% CI 0.421, 1.048) in all‑cause mortality through 42 months.5

The number of all-cause mortality and recurrent CV events that occurred in the overall population during the double-blind period by baseline KDIGO categories are summarized in Tables 1 and 2.5

Table 1. Composite of All-Cause Mortality and Recurrent CV Events by eGFR Category G1 and 2.5

Table 2. Composite of All-Cause Mortality and Recurrent CV Events by eGFR Category G3 and ≥4.5

Post-Hoc Analysis of Patients Advancing to CKD Stage ≥4 During the Double-Blind Period

Patient Demographics and Baseline Characteristics

A total of 63 patients advanced to CKD Stage 4 or greater during the double-blind period. The baseline characteristics of these patients across treatment groups are summarized in Table 3.5

Table 3. Baseline Characteristics of Patients Advancing to CKD Stage ≥4.5,a

Efficacy Results

Among patients who advanced to CKD Stage ≥4, 19 out of 31 patients (61.3%) in the vutrisiran group and 22 out of 32 patients (68.8%) in the placebo group had a primary composite endpoint event of all-cause mortality or recurrent CV event. Treatment with vutrisiran compared with placebo resulted in a HR of 0.467 (95% CI 0.258, 0.845) in the composite of all-cause mortality and recurrent CV events in the overall population and a HR of 0.532 (95% CI 0.251, 1.126) in the monotherapy population. A summary of the rates of clinical outcomes are shown in Figure 2.5

Figure 2. Clinical Outcomes Among Patients Who Advanced to CKD Stage ≥4.5

Safety Results

A summary of the safety results including events occurring on or after advancement to CKD Stage ≥4 is presented in Table 2. There were no study drug-related AEs that led to interruption, discontinuation, or withdrawal. No new safety concerns were reported.5,6

Table 2. Safety Results in Patients Who Advanced to CKD Stage ≥4 During the Double-Blind Period.6,a,b

 Global Safety Database

A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any safety concerns with the use of vutrisiran in patients with a history of severe renal impairment or ESRD.  The available data from the global safety database do not suggest an increased risk or varying safety profile with use of vutrisiran in this population.2,7

 Amvuttra Prescribing Information – Relevant Content

The USE IN SPECIFIC POPULATIONS section provides the following information10:

Renal Impairment

No dose adjustment is recommended in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m2). AMVUTTRA has not been studied in patients with severe renal impairment or end-stage renal disease.

The CLINICAL PHARMACOLOGY section provides the following information10:

Pharmacokinetics: Specific Populations

No clinically significant differences in the pharmacokinetics of vutrisiran were observed based on age, sex, race, mild and moderate renal impairment (eGFR ≥30 to <90 mL/min/1.73 m2), or mild (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) and moderate (total bilirubin >1.5 to 3 × ULN and any AST) hepatic impairment. Vutrisiran has not been studied in patients with severe renal impairment, end-stage renal disease, severe hepatic impairment, or in patients with prior liver transplant.

 Abbreviations

ACM = all-cause mortality; AE = adverse event; AST = aspartate aminotransferase; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; AUC0-‑24 = area under the concentration time curve from 0 to 24 hours; BMI = body mass index;  Cmax = maximum serum concentration; CKD = chronic kidney disease; CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; hATTR = hereditary transthyretin-mediated amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; HR = hazard ratio; KDIGO = Kidney Disease: Improving Global Outcomes; LLOQ = lower limit of quantification; MDRD = Modification of Diet in Renal Disease; OLE = open-label extension; PD = pharmacodynamic; PK = pharmacokinetic; Q = quartile; SAE = serious adverse event; TTR = transthyretin; ULN = upper limit of normal; wtATTR = wild-type transthyretin-mediated amyloidosis.

Updated 15 May 2026

 References

1.  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.  Alnylam Pharmaceuticals. Data on file. MED-ALL-TTRSC02-2400036.

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

4.  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

5.  Sheikh FH, Dang J, Fontana M, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy and renal impairment: Analyses from HELIOS-B. J Card Fail. 2026;32(5):853-863. doi:10.1016/j.cardfail.2026.02.049

6.  Supplement to: Sheikh FH, Dang J, Fontana M, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy and renal impairment: Analyses from HELIOS-B. J Card Fail. 2026;32(5):853-863. doi:10.1016/j.cardfail.2026.02.049

7.  Alnylam Pharmaceuticals. Data on file. MED-ALL-VUTRI-2600002.

8.  AMVUTTRA : EPAR – Public assessment report. European Medicines Agency. Published July 21, 2022. Accessed May 15, 2026. https://www.ema.europa.eu/en/documents/assessment-report/amvuttra-epar-public-assessment-report_en.pdf.

9.  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

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