Eplontersen: New antisense oligonucleotide for a rare disease

Transthyretin-associated amyloidosis (ATTR) is caused by the misfolding of transthyretin (TTR), the liver-derived transport protein of the thyroid hormone thyroxine. This protein accumulates in tissues and disrupts their function, which can lead to, among other things, cardiac or neurological disorders. There are both hereditary (hereditary, hATTR) and non-hereditary (wild-type) forms of ATTR. ATTR with cardiomyopathy (ATTR-CM) primarily affects the heart, while ATTR with polyneuropathy (ATTR-PN) affects the peripheral nervous system. It is estimated that there are up to 40,000 patients with hATTR-PN worldwide.

Several drugs are already approved for the treatment of this serious disease. The new active ingredient eplontersen (Wainzua® 45 mg solution for injection in a pre-filled pen, Astra-Zeneca), like patisiran , vutrisiran , and inotersen, is approved for the treatment of adults with hATTR-PN stages 1 and 2. According to the Wainzua product information, doctors can continue treatment in patients whose disease progresses to stage 3 if the benefits outweigh the risks.

Like inotersen, eplontersen is an antisense oligonucleotide (ASO). The new drug is an N-acetylgalactosamine (GalNAc)-conjugated ASO. The GalNAc conjugate enables targeted delivery of the ASO to hepatocytes, the primary site of TTR production. Eplontersen's selective binding to TTR mRNA leads to its degradation and prevents TTR synthesis.

The approval of eplontersen is based on data from the Phase III NeuroTTRansform study. In this study, 144 patients with hATTR-PN were treated with 45 mg eplontersen subcutaneously every four weeks until week 65. A placebo cohort of patients from the pivotal inotersen study (NEURO-TTR) served as an external control. This cohort received subcutaneous placebo injections once weekly. Both studies had identical inclusion criteria.

The co-primary endpoints in the analysis included the percentage change from baseline in serum TTR concentration at week 65 and the change from baseline in modified neuropathy impairment score +7 (mNIS+7).

After 65 weeks, the mean serum TTR concentration was reduced by approximately 80 percent from baseline in the eplontersen cohort, compared to a reduction of approximately 10 percent in the external placebo arm. The deterioration in neurological function (corresponding to an increase in the mNIS+7 score) was significantly lower in the eplontersen cohort at week 66 compared to the placebo arm: The mean increase in the least squares (LS) mean in the active cohort was 3.2 points from baseline. The increase in the external placebo group was 26.3 points.