Efficacy and Safety of Vutrisiran and Patisiran

Efficacy and Safety of Vutrisiran and Patisiran

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 Summary

Index

Efficacy Results – Safety Results – Abbreviations – References

Efficacy Results

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 the 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

Baseline Characteristics

Baseline characteristics were similar across treatment groups and clinically comparable (Table 1).2

Table 1. HELIOS-A Baseline Demographic and Disease Characteristics.2

Pharmacodynamics

In the HELIOS-A study, vutrisiran achieved a mean steady-state serum TTR reduction from baseline of 88%, which was non‑inferior to that observed in the within-study patisiran reference arm (86%) over 18 months (Figure 1).1,5

Figure 1. HELIOS-A: Secondary Endpoint of Percent Change from Baseline in Serum TTR Levels at Month 18 for Vutrisiran and Patisiran.1

HELIOS-A Post-Hoc Analysis

A post-hoc analysis evaluated the LS mean change from baseline of the primary and secondary endpoints at months 9 and 18 in the vutrisiran and patisiran groups in the HELIOS-A study. Results from the vutrisiran and patisiran arms were comparable across clinical endpoints (mNIS+7, Norfolk QOL-DN, 10-MWT, mBMI, and R-ODS) (Table 2).2

Table 2. Post-Hoc Analysis of Primary and Secondary Endpoints from HELIOS-A.2

NT-proBNP

Change in NT-proBNP from baseline was assessed as part of the post-hoc analysis. The change in NT-proBNP was comparable between vutrisiran and patisiran at 18 months. The fold change ratio between vutrisiran and patisiran at 18 months was 0.931 (95% CI: 0.718, 1.207), nominal p=0.5873.2

Cross Study Comparative Assessment of the HELIOS-A and APOLLO Study Results

HELIOS-A and APOLLO Comparative Results

APOLLO was a randomized, double-blind, placebo-controlled, phase 3 study to assess 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 to Month 18 in the mNIS+7 at 18 months.4

In a comparative assessment of the overall results from the HELIOS-A and APOLLO studies, efficacy endpoints in HELIOS-A were similar to those observed  in APOLLO (Figure 2, Table 3).3,6

Figure 2. Clinical and Cardiac Endpoints at Month 18 for Vutrisiran (HELIOS-A) and Patisiran (APOLLO) vs. Placebo (APOLLO).6

Table 3. Post-Hoc Cross-Study Assessment of LS Mean Change from Baseline to Month 18 from HELIOS-A and APOLLO.3

 Safety Results

The majority of AEs from both the HELIOS-A and APOLLO studies were mild or moderate in severity at month 18 (Table 4).1,4 

Table 4. HELIOS-A and APOLLO Summary of AEs at Month 18.1,4

In the vutrisiran arm of HELIOS-A, there were no treatment discontinuations or deaths that were deemed to be related to vutrisiran. Three patients (2.5%) in the vutrisiran arm discontinued the study due to AEs (2 due to death, 1 due to a non-fatal heart failure event). One death was due to COVID‑19 pneumonia, and the other was due to iliac artery occlusion. Two SAEs (dyslipidemia and urinary tract infection) were deemed related to vutrisiran by the Investigators. AEs occurring in ≥10% of patients in the vutrisiran arm included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia, and dizziness. All AEs, apart from pain in extremity and arthralgia, were reported at a similar or lower frequency than in the external placebo arm. ISRs were reported in 5 patients (4.1%) receiving vutrisiran, all of which were mild and transient. Overall, there were no safety signals regarding liver function tests, hematology, or renal function related to vutrisiran.1

In the patisiran arm of HELIOS-A, there were no treatment discontinuations or deaths that were deemed to be related to patisiran. Three patients (7.1%) in the patisiran arm discontinued the study due to death. One death was due to COVID-19 pneumonia, one was due to cardiac arrhythmia, and one was due to triple-vessel coronary artery disease.1,5

 Abbreviations

10-MWT = 10-meter walk test; AE = adverse event; CI = confidence interval; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; IQR = interquartile range; ISR = injection site reaction; IV = intravenous; LS = least squares; LSMD = least squares mean difference; LV = left ventricular; mITT = modified intent-to-treat; mNIS+7 = modified Neuropathy Impairment Score +7; NIS = Neuropathy Impairment Score; Norfolk QOL-DN = Norfolk Quality of Life-Diabetic Neuropathy; NT‑proBNP = N‑terminal pro-brain natriuretic peptide; PND = polyneuropathy disability; R-ODS = Rasch-built Overall Disability Scale; SAE = serious adverse event; SE = standard error; TTR = transthyretin.

Updated 6 April 2026

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.  Polydefkis M, Birklein F, Sekijima Y, et al. Comparison of efficacy outcomes with vutrisiran vs. patisiran in hATTR amyloidosis with polyneuropathy: Post-hoc analysis of the HELIOS-A study. Presented at: American Academy of Neurology (AAN) Annual Meeting; April 22-27, 2023; Boston, MA, USA.

3.  Adams D, Tournev IL, Taylor MS, et al. HELIOS-A: Results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at: American Academy of Neurology (AAN) Annual Meeting; April 2-7, 2022; Seattle, WA, USA.

4.  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

5.  Supplement to: 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

6.  Adams D, Tournev IL, Taylor MS, et al. HELIOS A: Study of vutrisiran in patients with hATTR amyloidosis. Presented at: Société Francophone du Nerf Périphérique (SFNP) Annual Meeting; January 21-22, 2022; Paris, France.