Phase 3 NEURO-TTRansform Findings Signify Eplontersen as Promising Agent for hATTR Polyneuropathy


After 66 weeks of treatment, patients on eplontersen showed sustained reduction in TTR concentration, halted progression of neuropathy impairment, and improved quality of life.

Sami Khella, MD, chief, Department of Neurology, University of Pennsylvania School of Medicine

Sami Khella, MD

About a month after Ionis Pharmaceuticals announced positive results from its phase 3 NEURO-TTRansform study (NCT04136184) assessing its investigational agent eplontersen in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), further details of the study were presented at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts.1

All told, treatment with eplontersen resulted in clinically and statistically significant benefits seen through week 66 compared with placebo. Overall, 47.2% and 57.6% of patients treated with the agent showed improvements on modified Neuropathy Impairment Score +7 (mNIS +7) composite score and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, whereas 16.7% and 20.0% of those on placebo improved on these respective measures.

"In the past, patients with hereditary transthyretin amyloid polyneuropathy usually deteriorated given the limited available treatments. This new study shows eplontersen can halt progression of neuropathy and improve quality of life at 66 weeks when compared to placebo,” principal investigator Sami Khella, MD, chief, Department of Neurology, University of Pennsylvania School of Medicine, said in a statement.2 "Today’s important results demonstrate that eplontersen has a consistent and sustained treatment effect and reinforces its potential as an important medicine for the thousands of patients living with this debilitating and fatal disease."

The multicenter, global trial enrolled 168 patients across 15 countries, with 144 who received eplontersen and 24 who received inotersen (Tegsedi), AstraZeneca’s previously approved therapy for hATTR. Patients in the study were between 18 and 82 years old and had ATTRv-PN defined by Coutinho Stage 1 or 2, documented genetic mutation in the TTR gene, and had signs/symptoms consistent with polyneuropathy. Patients on inotersen crossed over at 35 weeks, while those originally assigned to eplontersen remained on the drug through the final analysis at 66 weeks. The study also includes an open-label extension of up to 3 years or 20-week post-treatment evaluation.

In total, 136 of the 144 individuals on eplontersen completed 66 weeks of treatment, with reasons for discontinuation that included adverse events (AEs; n = 5), voluntary withdrawal (n = 1), investigator decision (n = 1), and ineligibility (n = 1). At week 65, eplontersen-treated individuals showed significant and sustained reductions in serum TTR concentration relative to placebo. Specifically, those on the active drug showed least square mean changes of –81.7% compared with placebo, which showed –11.2% (difference, ­–70.4%; 95% CI, –75.2 to –65.7; P <.0001).

Consistent improvement across all secondary end points compared with placebo was also observed in the eplontersen group. Neuropathy Symptom and Change (NSC) scores, used to assess symptom severity, showed least square mean differences of 0.3 for eplontersen and 8.2 for placebo (difference, –8.2; 95% CI, –10.7 to –5.8; P <.0001). Additionally, more patients on eptlontersen demonstrated improvement or no change in polyneuropathy disability. On 36-item Short Form Survey, patient physical health-related quality of life improved by scores of 0.9, compared with the placebo group, which worsened by –4.5 over the 65 weeks (least square mean difference, 5.3; 95% CI, 3.2-7.4; P <.0001). Furthermore, nutritional status, assessed through modified body mass index, showed least square mean changes of –8.1 and –90.8, for eplontersen- and placebo-treated patients, respectively.

In terms of safety, treatment-emergent adverse events (TEAEs) were found in 97.2% of patients in the eplontersen group vs 100% of those on placebo. No TEAEs of special interest led to study drug discontinuation, and no serious AEs were related to study drug. Two deaths occurred in the eplontersen group prior to the interim analysis, both related to known sequalae of ATTR amyloidosis, and neither assessed as drug related.

"Without treatment, hereditary transthyretin-mediated amyloid polyneuropathy is a relentlessly progressive disease. These results show that eplontersen sustains reduced transthyretin levels and improves neuropathy progression and quality of life consistently across a substantial number of patients,” Mene Pangalos, executive vice president, BioPharmaceuticals R&D, AstraZeneca, said in a statement.2 "We are confident in eplontersen’s potential to be a much needed and differentiated treatment option for patients living with all types of this devastating disease, which can also lead to heart failure."

Click here for more coverage of AAN 2023.

1. Khella S, Marques W, Dasgupta NR, et al. Eplontersen in hereditary ATTR-polyneuropathy: week 66 final analysis of the phase 3 NEURO-TTRansform study. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. LB
2. NEURO-TTRansform phase 3 resulted presented at AAN showed eplontersen demonstrated consistent and sustained improvement in all measures of disease and quality of life through 66 weeks. News release. AstraZeneca. April 24, 2023. Accessed April 26, 2023.
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