AstraZeneca/Ionis Antisense Oligonucleotide Therapy Eplontersen Shows Positive Phase III Results in ATTRv-PN, FDA Accepts NDA

On March 27, Ionis Pharmaceuticals announced positive 66-week analysis results from the Phase III NEURO-TTRansform study of the antisense oligonucleotide (ASO) drug eplontersen for the treatment of hereditary transthyretin (TTR)-mediated amyloidosis polyneuropathy (ATTRv-PN).

TTR cardiomyopathy and polyneuropathy are progressive systemic diseases caused by aging or genetic mutations, resulting from the misfolding of TTR protein and its accumulation as amyloid fibrils in the myocardium and peripheral nerves. The presence of TTR fibrils disrupts the normal function of these tissues. ATTRv-PN can lead to peripheral nerve damage accompanied by motor dysfunction within five years of diagnosis, and if untreated, it is typically fatal within a decade. Worldwide, there are approximately 40,000 patients with ATTRv-PN.

Eplontersen, a ligand-conjugated antisense (LICA) drug designed to reduce the production of serum transthyretin (TTR) for the treatment of hereditary and non-hereditary ATTR, was granted orphan drug designation by the FDA in January 2022. In December 2021, AstraZeneca entered into a collaboration agreement with Ionis Pharmaceuticals to jointly develop and commercialize eplontersen in a deal worth up to $3.585 billion.

The 66-week analysis results showed that, compared with the external placebo group, patients in the eplontersen group continued to demonstrate statistically significant and clinically meaningful improvements in the co-primary endpoints: the modified Neuropathy Impairment Score +7 (mNIS+7, an indicator measuring neuropathy progression) and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN). The study also met the third co-primary endpoint, showing a statistically significant reduction in serum TTR concentration in the eplontersen group compared with the external placebo group, consistent with the TTR reduction reported at Week 35. Eplontersen continued to show safety and tolerability consistent with what was observed at Week 35.

Data from the 35-week and 66-week analyses will be presented as an Emerging Science report at the American Academy of Neurology (AAN) Annual Meeting in April. Preliminary results from the 35-week analysis of the study were previously presented in September 2022 at the International Symposium on Amyloidosis.

As part of a global development and commercialization agreement, Ionis and AstraZeneca are seeking regulatory approval in the United States for eplontersen to treat ATTRv-PN, with plans to pursue regulatory approval in Europe and other regions worldwide. Earlier this month, the PDUFA date was set for December 22, 2023.

Eplontersen is currently undergoing a Phase III CARDIO-TTRansform study aimed at evaluating its efficacy in treating transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is a systemic, progressive, and fatal disease that typically leads to progressive heart failure, with patients usually succumbing within 3-5 years after symptom onset.

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