Vutrisiran: Randomized Treatment Extension Period of the HELIOS-A Study

Vutrisiran: Randomized Treatment Extension Period of the HELIOS-A Study

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INDEX

Study Design – Patient Demographics & Baseline Characteristics – Efficacy Results – Safety Results – Abbreviations – References

Study Design

HELIOS-A was a phase 3, global, randomized, open-label study designed to assess 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. After the 18-month treatment period was completed, all eligible patients, including those on patisiran, entered the RTE and were randomized 1:1 to receive either vutrisiran 25 mg every months or vutrisiran 50 mg every 6 months by subcutaneous injection (Figure 1).1,2

During the RTE period, a protocol amendment was enacted to transition patients on vutrisiran 50 mg every 6 months to vutrisiran 25 mg every 3 months.2

Figure 1. HELIOS-A RTE Study Design.2

At data cutoff (February 23, 2024), 64 patients (43%) continued with vutrisiran treatment; 67 patients (45%) completed vutrisiran treatment; and 18 patients (12%) discontinued vutrisiran treatment due to: death (n=12), physician decision (n=3), lost to follow-up (n=2), or an AE (n=1).2

Patient Demographics & Baseline Characteristics

The baseline demographics and disease characteristics of the total vutrisiran group at HELIOS-A RTE enrollment is summarized in Table 1.2

Table 1. HELIOS-A RTE Baseline Demographics and Disease Characteristics.2

Efficacy Results

Vutrisiran 25 mg Q3M vs. Vutrisiran 50 mg Q6M

Serum TTR Level

At Month 9, the H-L median TTR reduction was 89.73% in the vutrisiran 25 mg every 3 months arm (n=76) and 90.37% in the vutrisiran 50 mg every 6 months arm (n=73). Non-inferiority of vutrisiran 50 mg every 6 months versus vutrisiran 25 mg every 3 months was established at Month 9 based on mean serum TTR percent reduction. The H-L median difference between the two arms was 0.58 (95% CI: -1.28, 2.92), in which the lower 95% CI limit was >-10%, the prespecified non-inferiority margin.2

Recovery of serum TTR was noted at the end of the vutrisiran 50 mg every 6 months dosing interval; thus, a protocol amendment was initiated to transition all patients on vutrisiran 50 mg every 6 months to vutrisiran 25 mg every 3 months. The mean percent change in serum TTR from baseline during the RTE period is shown in Figure 2.2  

Figure 2. Mean (±SE) Percent Change from Baseline in Serum TTR During the RTE.2

Total Vutrisiran Group

Clinical Efficacy Endpoints

The clinical efficacy endpoint results at Months 9 and 18 of the RTE period among the total vutrisiran group are presented in Table 2.2

Table 2. Mean Change from RTE Baseline in Clinical Efficacy Endpoints at Months 9 and 18.2,a

Switch from Patisiran to Vutrisiran

Serum TTR Level

A sustained TTR reduction was observed in patients who received patisiran during the 18-month treatment period and were transitioned to vutrisiran during the RTE (patisiran/vutrisiran). The TTR reduction observed in patients in the patisiran/vutrisiran group was comparable to the TTR reduction observed in patients who received vutrisiran during both the 18-month treatment period and the RTE (vutrisiran/vutrisiran) (Figure 3).2

Figure 3. Mean (±SE) Percent Change from Baseline in Serum TTR During the RTE.2

Clinical Efficacy Endpoints

At Month 18 of the RTE period, a consistent clinical effect was observed across key endpoints compared with the HELIOS-A study baseline following switch from patisiran to vutrisiran (Table 3).2

Table 3. Change from Baseline for Select Clinical Efficacy Endpoints for Patients Who Switched From Patisiran to Vutrisiran During the RTE.2

Safety Results

The mean treatment duration in the total vutrisiran group was 24.4 months (range: 0.7-33.0 months). The majority of AEs reported were mild or moderate in severity (Table 4). The most common AEs reported in ≥10% of patients in the total vutrisiran group were COVID-19 (28.9%), urinary tract infection (15.4%), and fall (12.8%). None of the deaths were considered related to study drug by investigators. The safety profile of vutrisiran was consistent with that observed previously in the treatment period of the HELIOS-A study.2

Table 4. Safety of Vutrisiran During the RTE.2

Abbreviations

10-MWT = 10-meter walk test; AE = adverse event; BL = baseline; CI = confidence interval; D = day; FAP = familial amyloid polyneuropathy; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; H-L = Hodges-Lehmann; IV = intravenous; M = month; mBMI = modified body mass index; mNIS+7 = modified Neuropathy Impairment Score +7; NIS = Neuropathy Impairment Score; Norfolk QOL-DN = Norfolk Quality of Life-Diabetic Neuropathy; NT-proBNP = N-terminal prohormone of brain-type natriuretic peptide; NYHA = New York Heart Association;
PND = polyneuropathy disability; PY = patient-years; Q3M = every 3 months; Q6M = every 6 months; RTE = randomized treatment extension; R‑ODS = Rasch-built Overall Disability Scale; SAE = serious adverse event; SD = standard deviation; SE = standard error; TTR = transthyretin.

Updated 20 February 2025  

References

1.  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

2.  Cauquil C, Adams D, Polydefkis M, et al. HELIOS-A: 18-month randomised treatment extension analysis of vutrisiran in patients with hereditary transthyretin amyloidosis with polyneuropathy. Presented at: Société Francophone du Nerf Périphérique (SFNP); January 31-February 1, 2025; Paris, France.