AstraZeneca/Ionis Announce Detailed Phase III Results of Eplontersen in ATTRv-PN

On April 24, AstraZeneca/Ionis presented the 66-week analysis data from the Phase III NEURO-TTRansform study of the antisense oligonucleotide (ASO) drug eplontersen for the treatment of hereditary transthyretin (TTR)-mediated amyloidosis with polyneuropathy (ATTRv-PN) at the American Academy of Neurology (AAN) Annual Meeting.

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 impairment within five years of diagnosis and is usually fatal within a decade if left untreated. Worldwide, there are approximately 40,000 patients with ATTRv-PN.

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

The 66-week analysis results showed that, compared with the external placebo group, the eplontersen group demonstrated sustained benefits across all three co-primary endpoints: modified Neuropathy Impairment Score +7 (mNIS+7, an indicator measuring neuropathy progression), Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), and serum TTR concentration.

Among them, the serum TTR concentration of treated patients decreased by an average of 82% from baseline, compared to 11% in the placebo group (p<0.0001). At 66 weeks, the mNIS+7 score of the treatment group increased by only 0.28 points from baseline, while the placebo group increased by 25.06 points (p<0.0001). Overall, 47% of patients experienced relief from neuropathy, compared to 17% in the external placebo group. Additionally, the quality of life score of the treatment group decreased by 5.5 points from baseline, while the placebo group increased by 14.2 points (p<0.0001). In general, after 66 weeks of treatment with eplontersen, 58% of patients showed improvement in quality of life, compared to 20% in the external placebo group.

Eplontersen also achieved significant improvements in all secondary endpoints, demonstrating good safety and tolerability.

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 approvals in Europe and other regions worldwide. The FDA accepted the new drug application for eplontersen in treating ATTRv-PN this March, with a PDUFA date 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 commonly leads to progressive heart failure, with patients typically succumbing within 3-5 years after symptom onset.

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