Eplontersen Exceeds Established Thresholds for Symptom and Disability Improvement in ATTRv-PN

Investigators from an international collaboration have recently identified of thresholds for clinically meaningful differences in autonomic symptoms and overall disability in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) from the phase 3 NEURO-TTRansform study (NCT04136184). In the study, findings showed that treatment with eplontersen (Wainua; AstraZeneca), an FDA-approved medication for ATTRv-PN, exceeded those thresholds in unadjusted comparisons with an external placebo group.¹

At baseline, for participants (n = 141), mean scores for the Composite Autonomic Symptoms Score (COMPASS-31) were 19.4 (SD, 11.3) and 35.8 (SD, 10.3) for the Rasch-built Overall Disability Scale (R-ODS), with score ranging from 0.0–51.0 and 1.0–48.0, respectively. Estimated meaningful improvement in COMPASS-31 ranged from 0.5 to 3.2 points, and from 0.1 to 2.3 points for R-ODS. When compared indirectly to a placebo group from an external study (APOLLO; NCT01960348), the difference observed with eplontersen in NEURO-TTRansform exceeded the established thresholds, showing 4.8 points for COMPASS-31 and 9.4 points for R-ODS.

Led by Márcia Waddington-Cruz, MD, PhD, academic researcher at Federal University of Rio de Janeiro in Brazil, the study aimed to define what constitutes a meaningful change in scores on the 31-question COMPASS-31 and the R-ODS for patients with ATTRv-PN, using anchor-based approaches. Only patients who received eplontersen in the NEURO-TTRansform study were assessed, as these measures were not collected in a control group. Thresholds for meaningful change were estimated by comparing patient-reported outcomes, such as the Patient Global Impression of Change (PGIC), to score differences.

Presented at the 2025 Peripheral Nerve Society (PNS) Annual Meeting, held May 17-20, in Edinburgh, Scotland, researchers noted that the study is the first to establish thresholds for clinically meaningful changes in autonomic symptoms and overall disability in ATTRv-PN using COMPASS-31 and R-ODS. Based on these thresholds, investigators reported that the findings suggest treatment with eplontersen was associated with improvements in both measures when compared indirectly with external placebo data.

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Additional data presented at PNS 2025 from a prespecified exploratory analysis of NEURO-TTRansform revealed that eplontersen may prevent disability progression and deterioration of gait speed in patients with ATTRv-PN.² In the exploratory analysis, change in R-ODS was used to test overall disability while 10-Meter Walk Test (10MWT) was used to assess gait speed. In the eplontersen group, R-ODS and 10MWT were measured at baseline, week 37, and week 81, while in the placebo group, R-ODS was assessed at baseline, week 39, and week 78, and 10MWT only at baseline and week 78.

Results of the study showed stable R-ODS scores among eplontersen-treated patients (n = 144) at both weeks 37 (mean change, 0.6 [SEM, 0.41]) and 81 (mean change, –0.5 [SEM, 0.45]) in comparison with baseline. In comparison, those on placebo demonstrated deterioration in R-ODS at weeks 39 and 78, with adjusted least square mean (LSM) change from baseline of –4.0 (SEM, 0.69) and –8.9 (SEM, 0.88), respectively.

In addition to demonstrating stabilization in R-ODS scores, those on eplontersen demonstrated enhancements in 10MWT speeds for both fast (week 37: 0.098 [SEM, 0.57]; week 81: 0.047 [SEM, 0.50]) and comfortable walking speeds (week 37: 0.036 [SEM, 0.43]; week 81: 0.013 [SEM, 0.36]). In contrast, those assigned to placebo declined in walking speed after 78 weeks of observation (LSM, –0.24 [SE, 0.04]).

Eplontersen, a ligand-conjugated antisense oligonucleotide, is a once-monthly RNA-targeted medicine that provides upstream suppression of transthyretin (TTR) production and is designed to target and reduce the production of TTR protein at its source in the liver. Originally approved in the U.S. and marketed under the name Wainua, eplontersen more recently gained European Union approval in March under the market name Wainzua. To date, it remains the only approved medicine in the EU for the treatment of ATTRv-PN that can be self-administered monthly via an auto-injector.

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REFERENCES
1. Waddington-Cruz M, Berk J, Coelho T, et al. Estimating Meaningful Differences in Measures of Autonomic Symptom Impairment and Overall Disability in Patients with ATTRv-Polyneuropathy. Presented at: 2025 Peripheral Nerve Society (PNS) Annual Meeting; May 17-20; Edinburgh, Scotland. P461.
2. Polydefkis M, Berk J, Coelho T, et al. Eplontersen Slows Disability Progression and Deterioration of Gait Speed in Patients with ATTRv Polyneuropathy. Presented at: 2025 PNS Annual Meeting; May 17-20. Edinburgh, Scotland. P495.