Vutrisiran: Gastrointestinal Events in HELIOS-B

Vutrisiran: Gastrointestinal Events in HELIOS-B

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 Summary

Index

Study Design – Patient Demographics and Baseline Characteristics – Safety Results – Abbreviations – References

 Study Design

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 period, all remaining eligible patients were allowed to receive vutrisiran in an OLE.1

Post-Hoc Analysis of GI AEs

In a post hoc analysis of the HELIOS-B study, GI AE data were analyzed in the overall population, monotherapy population (patients not receiving tafamidis at baseline), and in the baseline tafamidis subgroup (patients receiving tafamidis at baseline).2

Treatment-emergent AEs classified according to PTs under the GI disorders SOC were assessed during the double-blind period of the study. PTs consisted of distinct descriptors of a sign or symptom to standardize clinical data.2

Adjusted ERs and RRs for GI events were calculated using Poisson regression with treatment arm, age group (<75 years vs. ≥75 years of age), ATTR type (hATTR vs. wtATTR), baseline NYHA Functional Classification (I/II vs. III) and log-transformed baseline NT-proBNP as covariates, and the logarithm of the follow-up time as an offset variable. In the overall population, baseline tafamidis use term and vutrisiran-by-base­line tafamidis use interaction term were included as covariates.2

The mean cumulative number of GI events per patient by treatment arm over time was estimated through the nonparametric Nelson–Aalen estimator for the overall population, monotherapy population, and baseline tafamidis subgroup, and for patients with hATTR and wtATTR.2

 Patient Demographics and Baseline Characteristics

A total of 655 patients were enrolled and randomly assigned to receive vutrisiran (n=326) or placebo (n=329). One patient randomized to placebo withdrew and did not receive study drug. The median age of study participants was 77 years, 93% were male, 88% had wtATTR, and 78% had NYHA Class II heart failure. The patient demographic and clinical characteristics at baseline were similar between the vutrisiran and placebo groups, except that NT-proBNP and troponin I levels were higher in the vutrisiran group than the placebo group in the monotherapy population.1,3

At baseline, concomitant tafamidis use was 40% and 39% in the vutrisiran and placebo groups, respectively. Baseline use of SGLT2 inhibitors was 3% in both treatment groups, and baseline use of diuretics was 80% and 79% in the vutrisiran and placebo groups, respectively.3

A summary of reported GI disorders in medical histories are presented in Table 1.4

Table 1. History of GI Disorders Reported in Patients Enrolled in HELIOS-B.4

 Safety Results

GI Event Rates

In the overall population, 64% of patients in the vutrisiran group and 53% of patients in the placebo group experienced no GI events, with similar results in the monotherapy population (62% vs. 52%) and baseline tafamidis subgroup (67% vs. 55%). The number of GI events experienced in the overall population are shown in Figure 1.2

Figure 1. Number of GI Events Experienced in Patients in the Overall Population.2

Overall GI event rates were lower in the vutrisiran group compared with the placebo group. A total of 529 GI events were reported during the double-blind period of the study, with 195 events in 117 patients (36%) treated with vutrisiran (23.4 events/100 PY) and 334 events in 154 patients (47%) treated with placebo (40.6 events/100 PY; unadjusted RR 0.58). A total of 10 GI events (8 in the placebo group and 2 in the vutrisiran group) were considered to be related to treatment by the investigator. The unadjusted RRs and estimates for adjusted RRs of GI events are shown in Figure 2.2

Figure 2. GI Event Rates and Rate Ratios.2

Mean cumulative GI events per patient were lower in patients treated with vutrisiran compared with placebo across the 3 populations analyzed (Figure 3). GI event rates were generally consistent across predefined subgroups assessed. GI event rates by patients with hATTR and wtATTR are shown in Figure 4.2,5

Figure 3. Mean Cumulative GI Events Per Patient.5,a

Figure 4. Mean Cumulative GI Events Per Patient.5,a

PTs for Individual GI Events

Within the GI disorder SOC, 103 PTs were reported in the overall population. Treatment with vutrisiran compared with placebo resulted in a RR for all GI events of 0.58, 0.63, and 0.51 in the overall population, monotherapy population, and baseline tafamidis subgroup, respectively. Treatment with vutrisiran compared with placebo was associated with lower rates of GI events more commonly associated with a negative impact on quality of life in patients with ATTR-CM (Tables 2 and 3).2

Table 2. Overview of GI AEs in the Overall Population and Monotherapy Population.2

Table 3. Overview of GI AEs in the Baseline Tafamidis Subgroup.2

 Abbreviations

AE = adverse event; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; CV = cardiovascular; DB = double-blind; ER = event rate; GERD = gastroesophageal reflux disease; GI = gastrointestinal; hATTR = hereditary transthyretin amyloidosis; hATTR-CM = hereditary transthyretin amyloidosis with cardiomyopathy; HR = hazard ratio; MedDRA = Medical Dictionary for Regulatory Activities; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; NYHA = New York Heart Association; OLE = open-label extension; PT = preferred term; PY = patient-years; RR = rate ratio; SGLT2 = sodium-glucose cotransporter 2; SOC = system organ class; wtATTR = wild-type transthyretin amyloidosis; wtATTR-CM = wild-type transthyretin amyloidosis with cardiomyopathy.

Updated 22 July 2026

References

1.  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

2.  Urey MA, Bui QM, Obici L, et al. Fewer gastrointestinal events with vutrisiran versus placebo in patients with transthyretin amyloidosis with cardiomyopathy: analysis from the phase 3 HELIOS-B study. Amyloid. 2026:1-12. doi:10.1080/13506129.2026.2695367

3.  Supplement to: 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

4.  Supplement to: Urey MA, Bui QM, Obici L, et al. Fewer gastrointestinal events with vutrisiran versus placebo in patients with transthyretin amyloidosis with cardiomyopathy: analysis from the phase 3 HELIOS-B study. Amyloid. 2026:1-12. doi:10.1080/13506129.2026.2695367

5.  Urey MA, Bui QM, Obici L, et al. Evidence of fewer gastrointestinal events in ATTR-CM patients treated with vutrisiran compared with placebo: Analysis from HELIOS-B. Presented at: Heart Failure Society of America (HFSA) Annual Scientific Meeting; September 26-29, 2025; Minneapolis, MN, USA.