Eplontersen Continues to Show Clinical Benefit in Long-Term Analysis of hATTR Polyneuropathy


Similar to data reported at 35 weeks, patients on eplontersen continued to see consistent reductions in serum transthyretin concentration for up to 66 weeks of treatment.

Sami Khella, MD, chief, department of neurology, Penn Presbyterian Medical Center, and professor of neurology, University of Pennsylvania School of Medicine

Sami Khella, MD

Recently, Ionis Pharmaceuticals announced positive data from its phase 3 NEURO-TTRansform study (NCT04136184) showing that eplontersen, an agent in development for patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), maintained clinical benefit for up to 66 weeks. The FDA recently accepted the company’s new drug application for the therapy, with a scheduled PDUFA action date of December 22, 2023.1

Relative to those assigned to placebo, eplontersen-treated patients continued to demonstrate statistically significant and clinically meaningful changes on the co-primary end points of modified Neuropathy Impairment Score +7 (mNIS+7) and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) for up to 66 weeks. Data from the 35 and 66-week analyses will be presented at the upcoming American Academy of Neurology Annual Meeting in late April.

"The positive results from the 66-week analysis of the Phase 3 NEURO-TTRansform trial show that eplontersen provided consistent and sustained transthyretin protein reduction and that a substantial number of patients improved in measures of both neuropathy progression and quality of life,” Sami Khella, MD, chief, department of neurology, Penn Presbyterian Medical Center, and professor of neurology, University of Pennsylvania School of Medicine, said in a statement.1 "This builds on the favorable 35-week results, which first demonstrated eplontersen's potential to significantly improve outcomes in this underserved population."

In addition to meeting co-primary end points, the study also met its third co-primary end point demonstrating a statistically significant reduction in serum TTR concentration vs an external placebo group. Similar to what was observed at 35 weeks, eplontersen continued to have consistent reductions in TTR and demonstrated a safe and tolerable profile. The final analysis assessing the agent vs placebo was completed at week 66; however, all patients will be followed on treatment until week 85, when they will have the option to transition into an open-label extension study.

"These latest results from our NEURO-TTRansform study represent an important step towards delivering a potential new therapy for ATTRv-PN patients living with this debilitating and fatal disease. We are encouraged by the sustained benefit demonstrated by eplontersen and what a self-administered treatment could mean for patients and families affected by ATTRv-PN,” Eugene Schneider, MD, executive vice president and chief clinical development officer, Ionis, said in a statement.1 "Together with our partner AstraZeneca, we look forward to sharing detailed results from this study at the upcoming American Academy of Neurology Annual Meeting."

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In NEURO-TTRansform, the efficacy and safety of eplontersen was compared to the external placebo group from the phase 2/3 NEURO-TTR registrational trial completed in 2017, which evaluated inotersen (Tegsedi), Ionis’ approved antisense oligonucleotide-based therapy, in 172 adults with familial amyloid polyneuropathy. The 35-week findings, announced in June 2022, showed statistically significant changes in TTR concentration, as well as change from baseline in mNIS+7, a measure of neuropathic disease progression, compared with an external placebo group.2

In a previous phase 1 trial (NCT03728634) of healthy volunteers, injections of eplontersen at a dose of 90 mg per month showed a mean reduction in TTR levels of 94% after 13 weeks of treatment. Eligible participants were assigned to 1 of 3 multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomly assigned 10:2 (active: placebo) to receive a total of 4 subcutaneous doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 subcutaneous dose in the single-dose cohort.3

All randomized participants completed the treatment period with no serious adverse events (AEs) reported. In the multiple-dose cohorts, those on eplontersen 45, 60, and 90 mg demonstrated reduced TTR levels of –85.7% (SD, 8.0), –90.5% (SD, 7.4), and –93.8% (SD, 3.4), compared with –5.9% (SD, 14.0) for pooled placebo (P <.001). A maximum mean reduction in TTR levels of –86.3% (SD, 6.5) from baseline were achieved after the single-dose 120 mg of eplontersen.

1. Ionis reports positive topline 66-week results of eplontersen phase 3 study for patients with ATTRv-PN. News release. Ionis Pharmaceuticals. March 27, 2023. Accessed March 27, 2023. https://www.prnewswire.com/news-releases/ionis-reports-positive-topline-66-week-results-of-eplontersen-phase-3-study-for-patients-with-attrv-pn-301781634.html
2. Eplontersen met co-primary and secondary end points in interim analysis of the NEURO-TTRansform phase 3 trial for hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). News release. June 21, 2022. Accessed March 30, 2023. https://www.astrazeneca-us.com/content/az-us/media/press-releases/2022/eplontersen-met-co-primary-and-secondary-endpoints-in-interim-analysis-of-the-neuro-ttransform-phase-III-trial-for-hereditary-transthyretin-mediated-amyloid-polyneuropathy.html
3. Viney NJ, Guo S, Tai LJ, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Fail. 2021;8(1):652-661. doi:10.1002/ehf2.13154
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