Eplontersen Continues to Show Long-Term Effectiveness in hATTR Polyneuropathy


At 19 weeks, eplontersen-treated patients showed substantial and sustained reductions in serum TTR concentration compared with baseline.

Eugene Schneider, MD, executive vice president and chief clinical development officer at Ionis

Eugene Schneider, MD

Newly announced phase 3 findings from the NEURO-TTRansform study (NCT04136184) showed that treatment with eplontersen (Ionis Pharmaceuticals) resulted in halted neuropathy progression and improved quality of life at 85 weeks in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). Currently under review with the FDA, a decision on eplontersen as a potential therapy for ATTRv-PN is expected by December 22, 2023.1,2

NEURO-TTRansform was an open-label study where patients were randomly assigned 6:1 to eplontersen (n = 144) or inotersen (Tegsedi), AstraZeneca’s previously approved therapy for hATTR, for a 66-week double-blind period, followed by an open-label extension. The study also included a 60-patient external placebo control group.

At week 85, investigators observed a mean reduction of 81.8% in serum TTR concentration relative to baseline for eplontersen-treated patients. In comparison with placebo at the 65-week period, there was a 70.4% (95% CI, –75.2 to –65.7%; P <.0001) least-square means difference (LSMD) in serum TTR concentration reduction. Patients on eplontersen showed improvement in neuropathy impairment through 19 months of treatment, indicated by mean reductions of –2.9 in modified Neuropathy Impairment Score +7 (mNIS+7) composite score.

"These positive findings further strengthen eplontersen's efficacy and safety profile, underscoring its potential to be an important, differentiated advancement for patients with this progressive, debilitating and fatal disease," Eugene Schneider, MD, executive vice president and chief clinical development officer at Ionis, said in a statement. “ATTRv-PN continues to be an underserved patient population and we look forward to working with regulatory authorities to bring this important new, self-administered treatment to patients."

Quality of life, assessed through the Norfolk Quality of Life-Diabetic Neuropathy total score, was substantially improved in treated patients, with mean changes of –6.2 from baseline at week 85. In comparison, at week 66, there was a LSMD of –19.7 (95% CI, –25.6 to –13.8; P <.0001) when comparing with placebo. At week 66, 57.6% of treated patients showed improvements on Norfolk QoL-DN compared with only 20.0% of those on placebo.

READ MORE: Patient Dosing Complete for Part 1 of Gene Therapy Trial in Friedreich Ataxia Cardiomyopathy

Among the newly released findings, eplontersen continued to show a favorable safety and tolerability profile at 85 weeks. Specifically, treatment-emergent adverse event (TEAE) incidence remained consistent with previous observations at week 66, and no TEAEs of special interest led to study drug discontinuation. In total, 18.8% of treated patients experienced a serious TEAE, although none were considered related to the study drug. In comparison, 21.7% of those on placebo reported serious TEAEs as well.

Investigators continued to report no imbalance of ocular events excluding vitamin A decrease or deficiency. Of note, 3 non-drug related deaths were reported in the eplontersen group, all related to the sequalae of ATTR amyloidosis.

These data were consistent with positive 66-week findings presented at the 2023 American Academy of Neurology Annual Meeting, held earlier this year. In that data, 47.2% of patients treated with the agent showed improvements on mNIS+7 compared with 16.7% of those on placebo. 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; <.0001). Additionally, more patients on eptlontersen demonstrated improvement or no change in polyneuropathy disability.3

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; <.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.

1. Eplontersen continued to show improvement in ATTRv-PN through 85 weeks. News release. Ionis Pharmaceuticals. July 10, 2023. Accessed July 24, 2023. https://www.prnewswire.com/news-releases/eplontersen-continued-to-show-improvement-in-attrv-pn-through-85-weeks-301872558
2. Eplontersen: NEURO-TTRansform week 85 topline results. News release. Ionis Pharmaceuticals. July 10, 2023. Accessed July 24, 2023. https://www.ionispharma.com/wp-content/uploads/2023/07/Week85.pdf
3. 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
Related Videos
Ro'ee Gilron, PhD
Monica Verduzco-Gutierrez, MD
Shahid Nimjee, MD, PhD
Peter J. McAllister, MD, FAAN
Video 6 - "Utilization of Neuroimaging in Alzheimer’s Disease"
Video 5 - "Contribution of Multiple Pathways to the Development of Alzheimer’s Disease"
Michael Levy, MD, PhD
Michael Levy, MD, PhD
© 2024 MJH Life Sciences

All rights reserved.