Eplontersen Improves Disease State and QoL in People with Hereditary ATTRv-PN

In the phase 3 clinical trial NEURO-TTRansform (NCT04136184), treatment with eplontersen (AstraZeneca; Cambridge, UK; Ionis Pharmaceuticals, Carslbad, CA), an investigational ligand-conjugated antisense (LICA) medication that inhibits production of the transthyretin (TTR) protein, was associated with improved disease state and quality of life (QoL) for people with hereditary amyloid transthyretin amyloidosis polyneuropathy (ATTRv-PN). The study results were published in the Journal of the American Medical Association (JAMA).

NEURO-TTRansform was a global, open-label, phase 3 trial that included 168 adult participants with a diagnosis of ATTRv-PN. Participants were randomly assigned 6:1 to receive either subcutaneous eplontersen at 45 mg every 4 weeks or subcutaneous Tegsedi (inotersen; Sobi, Waltham, MA) at 300 mg every week, the latter transitioning to eplontersen at week 37. Results were compared to the historical placebo group from the earlier phase 3 NEURO-TTR clinical trial (NCT01737398). Treatment with eplontersen was associated with improved disease state vs historical placebo in all primary outcomes, including the following results:

• A difference of -70.4% in adjusted mean percentage reduction in serum TTR concentration (95% CI, -75.2% to -65.7%; P<.001)
• A difference of -24.8 in adjusted mean change improvement in Neuropathy Impairment Score (mNIS+7) (95% CI, -31.0 to -18.6; P<.001)
• A difference of -19.7 in adjusted mean change in Norfolk Quality of Life Diabetic Neuropathy (QoL-DN) total score (95% CI, -25.6 to -13.8; P<.001)

Results were consistent, suggesting that treatment with eplontersen is associated with lowered serum TTR concentration, less impairment from neuropathy, and better QoL for people with ATTRv-PN. Common treatment emergent adverse events (TEAEs) were COVID-19, diarrhea, urinary tract infection, vitamin A deficiency, and nausea. 

"The totality of positive, consistent eplontersen data position this therapy, which can be self-administered, to be an important and empowering potential new medicine for treating hereditary transthyretin-mediated amyloid polyneuropathy," said Sami Kheila, MD, Principal Investigator on the NEURO-TTRansform trial. "Without treatment, hereditary transthyretin-mediated amyloid polyneuropathy is a debilitating and devasting disease that can ultimately result in death."

Globally, there are an estimated 40,000 people living with ATTRv-PN, a condition which, without treatment, is generally fatal within 10 years. In March 2023, the Food and Drug Administration (FDA) accepted the new drug application for eplontersen, which was granted orphan drug designation in the United States.