Eplontersen Meets Primary, Secondary End Points in Phase 3 Trial for hATTR Polyneuropathy


Based on the 35-week interim trial results, AstraZeneca and Ionis will seek regulatory approval for eplontersen and plan to file a new drug application with the FDA in 2022.

Mene Pangalos, executive vice president, BioPharmaceuticals R&D, AstraZeneca

Mene Pangalos

In a planned interim analysis of the phase 3 NEURO-TTRansform study (NCT04136184), AstraZeneca and Ionis’ investigational agent eplontersen reached statistically significant changes in coprimary end points for patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN). Based on this data, the companies will file a new drug application (NDA) to the FDA for eplontersen to treat ATTRv-PN.1

Eplontersen, formerly known as IONIS-TTR-LRX,is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of transthyretin, or TTR protein. After 35 weeks of treatment, patients demonstrated statistically significant changes in TTR concentration, as well as change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression, compared with an external placebo group.

"These encouraging data reinforce the safety profile of eplontersen and demonstrate clear evidence of its potential to provide much needed therapeutic benefit to patients living with hereditary transthyretin-mediated amyloid polyneuropathy," study investigator Teresa Coelho, MD, neurologist and neurophysiologist, Hospital Santo Antonio, Centro Hospitalar Universitario do Porto, said in a statement.1 The trial also met its secondary end point of change from baseline in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), with eplontersen-treated patients showing significantly improved patient-reported quality of life relative to those on placebo. Additionally, the study drug showed a safe and tolerable profile with no specific safety concerns.

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 final primary end point analysis will be completed at week 66 and all patients will be followed until week 85, when they will become eligible to transition to the open-label extension.

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"Amyloid transthyretin polyneuropathy is a rare and fatal disease that can affect up to 40,000 people worldwide,” Mene Pangalos, executive vice president, BioPharmaceuticals R&D, AstraZeneca, said in a statement.1 "These promising results show eplontersen has the potential to be a new and much needed treatment where limited options exist, and significant unmet medical need remains."

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.2

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. 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 June 23, 2022. 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
2. 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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