Transition between Patisiran and Vutrisiran

Transition between Patisiran and Vutrisiran

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 Summary

Index

Transition from Patisiran to Vutrisiran – Transition from Vutrisiran to Patisiran – Abbreviations – References

 Transition from Patisiran to Vutrisiran

HELIOS-A Study

HELIOS-A was a phase 3, global, randomized, open-label study designed to evaluate 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. This study used the placebo arm of the APOLLO study as an external control arm (n=77) for the primary endpoint and most other efficacy endpoints. The primary endpoint was the change from baseline in mNIS+7 at 9 months.1,4

Exclusion Criteria

Patients were excluded from the study if they had received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR.5

HELIOS-A RTE Study

After the 18-month treatment period of HELIOS-A was completed, eligible patients (N=149), including those on patisiran as a reference group, entered the RTE and were randomized 1:1 to receive either vutrisiran 25 mg every 3 months (n=76) or vutrisiran 50 mg every 6 months (n=73) by subcutaneous injection for up to 42 months (Figure 1).1 Patients in the patisiran reference arm were administered the last dose of patisiran in Week 81 and received the first dose of vutrisiran on Day 1 of the RTE period, which was 3 weeks after Week 81.5

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 due to the pharmacodynamics of serum TTR recovery seen at the end of the 6-month dosing interval for patients on vutrisiran 50 mg every 6 months.1

Figure 1. HELIOS-A RTE Study Design.1

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 group). The TTR reduction observed in patients in the patisiran/vutrisiran group was comparable with the TTR reduction observed in patients who received vutrisiran during both the 18-month treatment period and the RTE (vutrisiran/vutrisiran group) (Figure 2).1

Figure 2. Mean (±SE) Percent Change from Baseline in Serum TTR During the RTE.1

Clinical Efficacy Endpoints

At Month 18 of the RTE period, a consistent clinical effect was observed across key endpoints compared to the HELIOS-A study baseline following the transition from patisiran to vutrisiran (Table 1).1

Table 1. Change from Baseline for Select Clinical Efficacy Endpoints in Patients Who Switched From Patisiran to Vutrisiran During the RTE.1

Safety Results

The mean treatment duration in the vutrisiran total group (N=149, PY=308.3) was 24.4 months (range: 0.7-33.0 months). The majority of AEs reported were mild or moderate in severity (Table 2). 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.1

Table 2. Safety of Vutrisiran During the RTE.1

Transition from Vutrisiran to Patisiran

Studies evaluating the transition of patients from vutrisiran to patisiran have not been conducted to date.

APOLLO Study

APOLLO was a multicenter, international, randomized (2:1), double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of IV patisiran 0.3 mg/kg every 3 weeks (n=148) versus placebo (n=77) in patients with hATTR-PN. The primary endpoint was the change from baseline in the mNIS+7 at 18 months.2

Exclusion Criteria

Patients were excluded from the study if they had received an investigational agent or device within 30 days of anticipated study drug administration or within 5 half-lives of the investigational drug(s), whichever was longer.6

APOLLO-B Study

APOLLO-B was a multicenter, randomized (1:1), double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of IV patisiran 0.3 mg/kg every 3 weeks (n=181) versus placebo (n=179) in patients with ATTR-CM, including both hATTR and wtATTR. The primary endpoint was the change from baseline in the 6-MWT at 12 months. After the 12-month double-blind treatment period, all patients received patisiran in an OLE period.3

Exclusion Criteria

Patients were excluded from the study if they had received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR.7

 Abbreviations

6-MWT = 6-minute walk test; 10-MWT = 10-meter walk test; AE = adverse event; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; BL = baseline; D = day; FAP = familial amyloid polyneuropathy; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IV = intravenous; KPS = Karnofsky Performance Status; 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; OLE = open-label extension; PND = polyneuropathy disability; PY = patient-years; Q3M = every 3 months; Q6M = every 6 months; Q3W = every 3 weeks; R‑ODS = Rasch-built Overall Disability Scale; RTE = randomized treatment extension; SAE = serious adverse event; SC = subcutaneous; SD = standard deviation; SE = standard error; TTR = transthyretin; wtATTR = wild-type transthyretin amyloidosis. 

Updated 05 March 2025

 References

1.  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.

2.  Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153

3.  Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553-1565. doi:10.1056/NEJMoa2300757

4.  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

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

6.  Protocol for: Adams D, González-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153

7.  Protocol for: Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553-1565. doi:10.1056/NEJMoa2300757