Therapeutic: eplontersen for ATTRv-PN

Published: 6-Jun-2023

Hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) is the result of a misfolded mutated protein — transthyretin (TTR) — accumulating in the peripheral nerves

Debilitating nerve damage leads to a progressive loss of motor functions, including the ability to walk. The TTR can also accumulate as amyloid deposits within other major organs where it results in progressive damage.

Disability typically occurs within 5 years of diagnosis and death within a decade. A potential treatment is being developed by Ionis in conjunction with AstraZeneca.

Eplontersen is a ligand-conjugated antisense drug that inhibits the production of the TTR protein by degrading hepatic TTR mRNA.1

It is formulated as a subcutaneous injection that is self-administered once a month. In a Phase III study, 168 patients with ATTRv-PN were treated with 45 mg of subcutaneous eplontersen every 4 weeks or 300 mg of inotersen every week for 25 weeks; all were then given the eplontersen regimen.2

Eplontersen gave a least squares (LS) mean reduction of 82% in serum TTR concentration from baseline compared with a fall of 11% from baseline in the external placebo group — from the company’s registration trial for inotersen, which was completed in 2017.3

It also halted disease progression as measured by the modified neuropathy impairment score +7: there was a 0.28 point mean increase with the drug, whereas there was a 25.06 point increase for the external placebo group.

Overall, 47% of eplontersen-treated patients showed improvements from baseline in neuropathy at 66 weeks, compared with 17% for the placebo group.

Among those who completed the study, the proportions were 53% with treatment and 19% with the placebo. There were also improvements in quality of life, with the drug giving a 5.5 point LS mean decrease — in other words, an improvement — in the Norfolk quality of life questionnaire for diabetic neuropathy.

There was a 14.2 point increase with the placebo, so the condition worsened. In all, 58% of those treated with the drug showed quality of life improvements compared with 20% in the external placebo group. Again, those who completed the study showed even more pronounced improvements, with benefits in 66% compared with 23% in the placebo group.

Its safety and tolerability profiles were also favourable. Treatment-emergent adverse events were comparable between the verum and placebo groups.

A Phase III study is also under way in transthyretin-mediated amyloid cardiomyopathy. This condition causes progressive heart failure and, typically, death within 3–5 years of disease onset.


  1. J.K. Diep, et al., Br. J. Clin. Pharmacol. 88, 5289 (2022).
  2. T. Coelho, et al., Neurol. Ther. 12, 267 (2023).
  3. S. Khella, et al., “Emerging  Science” presentation at the AAN (American Academy of Neurology) Annual Meeting 2023 (22–27 April, Boston, MA, US).

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