Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

Abstract

Introduction: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study.

Methods: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed.

Results: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: -21.0; p = 1.84 × 10^-10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I-II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10^-7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10^-7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10^-15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10^-15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo.

Conclusion: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment.

Trial registration number: ClinicalTrials.gov: NCT03759379.

Keywords: ATTRv amyloidosis; Nutritional status; Physical function; Polyneuropathy; Quality of life; RNA interference; Vutrisiran; hATTR amyloidosis.

Fig. 1

Norfolk QOL-DN assessments in the HELIOS-A study. a Mean Norfolk QOL-DN total and domain scores at baseline in patients receiving vutrisiran or placebo (APOLLO). b LS mean change in Norfolk QOL-DN total score and in individual Norfolk QOL-DN domains from baseline to month 18 in patients receiving vutrisiran or placebo (APOLLO). Score ranges for each domain are shown on the x-axis; a higher score indicates worse quality of life. ADL activities of daily living, LS least squares, Norfolk QOL-DN Norfolk Quality of Life-Diabetic Neuropathy, SE standard error

Fig. 2

Mean Norfolk QOL-DN total score at baseline and at month 18 in HELIOS-A patients receiving vutrisiran or placebo (APOLLO), stratified according to baseline PND score. The Norfolk QOL-DN questionnaire captures QOL components specifically relating to neuropathy. The total score range is –4 to 136, where higher score indicates worse QOL. Norfolk QOL-DN Norfolk Quality of Life-Diabetic Neuropathy, PND polyneuropathy disability, QOL quality of life, SE standard error

Fig. 3

Change from baseline at 18 months in percentage of patients reporting a specific symptom of the Norfolk QOL-DN symptoms domain at each of four specified extremity locations (hands, arms, feet, and legs). Norfolk QOL-DN Norfolk Quality of Life-Diabetic Neuropathy

Fig. 4

LS mean change in EQ-VAS score (range 1–100) from baseline to month 18 in patients receiving vutrisiran or placebo (APOLLO). At baseline, the mean (± SD) EQ-VAS was 64.5 (18.5) in the vutrisiran group and 54.6 (18.0) in the external placebo group. mITT population. Value of n is the number of evaluable patients at each timepoint. Data plotted are MMRM data. EQ-VAS records a respondent’s self-rated health at the time of assessment (range 0–100), with minimum and maximum values ranging from “the worst health you can imagine” (0) to “the best health you can imagine” (100). CI confidence interval, EQ-VAS EuroQoL-Visual Analog Scale, LS least squares, LSMD LS mean difference, mITT modified intent-to-treat, MMRM mixed-effects model for repeated measures, SD standard deviation, SE standard error

Fig. 5

a LS mean change (MMRM analysis) in 10-MWT from baseline to month 18 in patients receiving vutrisiran or placebo (APOLLO). 10-MWT is a measure of gait speed that is calculated based on the mean time (seconds) taken to complete the 10-m walk across two assessments at each visit (imputed as 0 for patients unable to perform the walk), with lower gait speeds indicating worse ambulatory function. At baseline, the mean (± SD) gait speed on 10-MWT was 1.006 (0.393) m/s in the vutrisiran group and 0.790 (0.319) m/s in the external placebo group. b LS mean change (MMRM analysis) in overall R-ODS score from baseline to month 18 in patients receiving vutrisiran or placebo (APOLLO). R-ODS score range is 0–48, with lower scores indicating greater disability. At baseline, the mean (± SD) R-ODS score was 34.1 (11.0) in the vutrisiran group and 29.8 (10.8) in the external placebo group. c Distribution of patients according to level of shift in KPS score scale from HELIOS-A baseline to month 18 in the vutrisiran arm or from APOLLO baseline to Global OLE baseline in the placebo arm. Distribution of KPS scores at baseline in the vutrisiran arm of HELIOS-A and in the external placebo comparator arm is shown in Table 1. KPS is presented on an 11-point functional impairment scale (starting with 0% and increasing up to 100% in 10% increments) in which patients are classified along a range from normal functioning (100%) to dead (0%). Improvement is defined as an increase in KPS score from baseline. Lower scores indicate a lower ability to perform activities and a worse survival prognosis [45]. 10-MWT 10-m walk test, CI confidence interval, KPS Karnofsky Performance Status, LS least squares, LSMD LS mean difference, MMRM mixed-effects model for repeated measures, OLE open-label extension, R-ODS Rasch-built Overall Disability Scale, SD standard deviation, SE standard error

Fig. 6

LS mean change in mBMI from baseline to month 18 in patients receiving vutrisiran or placebo (APOLLO). At baseline, the mean (± SD) mBMI was 1057.4 (233.8) kg/m² × g/L in the vutrisiran group and 989.9 (214.2) kg/m² × g/L in the external placebo group. mITT population. Value of n is the number of evaluable patients at each timepoint. Data plotted are MMRM data. mBMI is calculated as BMI (in kg/m²) × serum albumin (in g/L), with lower scores indicating worse nutritional status. BMI body mass index, CI confidence interval, LS least squares, LSMD LS mean difference, mBMI modified BMI, mITT modified intent-to-treat, MMRM mixed-effects model for repeated measures, SD standard deviation, SE standard error