Eplontersen Slows Disability Progression and Deterioration of Gait Speed in ATTRv Polyneuropathy

Michael Polydefkis, MD

Data from a prespecified exploratory analysis of the phase 3 NEURO-TTRansform study (NCT04136184) revealed that eplontersen (Wainua; AstraZeneca), an FDA-approved therapy for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), may prevent disability progression and deterioration of gait speed in patients with ATTRv-PN.¹

In the exploratory analysis, change in Rasch-built Overall Disability Scale (R-ODS) was used to test overall disability while 10-Meter Walk Test (10MWT) was used to assess gait speed. Led by Michael Polydefkis, MD, professor of neurology at Johns Hopkins University School of Medicine, patients from NEURO-TTRansform–the study that led to eplontersen’s 2023 approval–were compared with an external placebo arm from the APOLLO A study (NCT01960348). 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.

Presented at the 2025 Peripheral Nerve Society (PNS) Annual Meeting, held May 17-20, in Edinburgh, Scotland, results 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.

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.

READ MORE: CRISPR Gene Therapy Nexiguran Ziclumeran Shows Promise in Early-Stage Study of ATTR Amyloidosis With Polyneuropathy

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]).

Findings from NEURO-TTRansform, published in JAMA Neurology, represented the main body of evidence for the FDA’s approval of eplontersen in 2023. In the placebo-controlled study, the adjusted mean percentage reduction in serum TTR was –81.7% with eplontersen and –11.2% with placebo, representing a statistically significant –70.4% difference (P <.001). In addition, adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for modified Neuropathy Impairment Score +7 (mNIS+7) composite score (0.3 vs 25.1; difference, –24.8; 95% CI, –31.0 to –18.6; P <.001) and for Norfolk QoL-DN (–5.5 vs 14.2; difference, –19.7; 95% CI, –25.6 to –13.8; P <.001).²

Additional post-hoc data from the study showed that 47% and 58% of patients treated with eplontersen had score reductions from baseline to week 66 in mNIS+7 composite score and Norfolk QoL-DN total score, respectively. In comparison, 17% and 20% of those on placebo had score reductions at week 66. At week 66, among study completers, 53% and 65% of eplontersen-treated patients showed reductions in mNIS+7 and Norfolk QoL-DN scores, respectively, compared with 19% and 23% of placebo patients.

Eplontersen is also currently being studied in patients with amyloid transthyretin cardiomyopathy (ATTR-CM) through the phase 3 CARDIO-TTRansform study (NCT04136171), a 1400-patient cohort trial that’s considered the largest of ATTR-CM to date. This double-blind study randomizes patients to either subcutaneous eplontersen or placebo once every 4 weeks for up to 140 weeks. Investigators will use the composite outcome of cardiovascular (CV), mortality, and recurrent CV events up to 140 weeks as the primary outcome, while secondary outcomes include 6-minute walk test distance and change in Kansas City Cardiomyopathy Questionnaire scores at week 121.³

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REFERENCES
1. 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. Abstract P495.
2. Coelho T, Marques W, Dasgupta NR, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA Network. 2023;330(15):1448-1458. doi:10.1001/jama.2023.18688
3. Eplontersen granted US fast track designation for patients with transthyretin-mediated amyloid cardiomyopathy. News release. Ionis. February 8, 2024. Accessed May 19, 2025. https://ir.ionispharma.com/news-releases/news-release-details/eplontersen-granted-us-fda-fast-track-designation-patients