AstraZeneca and Ionis Report Positive Result for Eplontersen from Phase 3 Trial for ATTRv-PN

AstraZeneca and Ionis reported positive high-level results from the NEURO-TTRansform phase 3 trial in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN), which showed that eplontersen met its co-primary endpoints in a planned interim analysis at 35 weeks.

Photo: Mene Pangalos, executive vice president, BioPharmaceuticals R&D, AstraZeneca.

In the trial, eplontersen reached a statistically significant and clinically meaningful change from baseline for its co-primary endpoint of percent change in serum transthyretin (TTR) concentration, reducing TTR protein production. Eplontersen also reached its co-primary endpoint of change from baseline in the modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression, versus external placebo group.

Results showed the trial also met its secondary endpoint of change from baseline in the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) demonstrating treatment with eplontersen significantly improved patient-reported quality of life versus external placebo group. In the trial, eplontersen demonstrated a favorable safety and tolerability profile with no specific concerns.

ATTR cardiomyopathy and polyneuropathy are progressive systemic diseases caused by aging or genetic mutations, resulting in misfolded TTR protein and accumulation as amyloid fibrils in the cardiac myocardium and peripheral nerves, respectively. In patients with both hereditary and wild type ATTR, TTR protein builds up as fibrils in tissues, such as the peripheral nerves and heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid, and bone marrow. The presence of TTR fibrils interferes with the normal functions of these tissues and as the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death.

Hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) is a debilitating disease that leads to peripheral nerve damage with motor disability within five years of diagnosis and, without treatment, is generally fatal within a decade. Eplontersen, formerly known as IONIS-TTR-LRx, is a ligand-conjugated antisense (LICA) investigational medicine designed to reduce the production of TTR protein at its source to treat both hereditary and non-hereditary forms of ATTR.

“Amyloid transthyretin polyneuropathy is a rare and fatal disease that can affect up to 40,000 people worldwide,” said Mene Pangalos, executive vice president, BioPharmaceuticals R&D, AstraZeneca. “These promising results show eplontersen has the potential to be a new and much needed treatment where limited options exist and significant unmet medical need remains.”

NEURO-TTRansform is a global, open-label, randomized trial evaluating the efficacy and safety of eplontersen in patients with ATTRv-PN. The trial has enrolled adult patients with ATTRv-PN Stage 1 or Stage 2 and will be compared to the external placebo group from the Tegsedi (inotersen) NEURO-TTR registrational trial that Ionis completed in 2017. The final primary endpoint analysis will be completed at week 66 and all patients will be followed until week 85, when they will have the option to transition into the open-label extension trial. The co-primary endpoints in the interim analysis were percent change from baseline in serum TTR concentration and change in the mNIS+7 versus external placebo group at week 35. The mNIS+7 uses highly standardized, quantitative, and referenced assessments to quantify muscle weakness, muscle stretch reflexes, sensory loss, and autonomic impairment. The secondary endpoint was change from baseline in the Norfolk QoL-DN score versus external placebo group at week 35. The Norfolk QoL-DN is a patient-reported questionnaire capturing neuropathy-related QoL.

Based on the 35-week interim trial results, the companies will seek regulatory approval for eplontersen and plan to file a new drug application with the U.S. Food and Drug Administration in 2022. ATTRv-PN is expected to be the first indication for which AstraZeneca and Ionis will seek regulatory approval for eplontersen. The results from the 35-week interim analysis of the trial will be submitted for presentation at a forthcoming medical meeting.

As part of a global development and commercialization agreement with Ionis signed in December 2021, eplontersen will be jointly developed and commercialized by both companies in the United States and will be developed and commercialized in the rest of the world by AstraZeneca (except for Latin America).

Eplontersen was granted Orphan Drug designation in the United States and is also currently being evaluated in the CARDIO-TTRansform phase 3 trial for amyloid transthyretin cardiomyopathy (ATTR-CM), a systemic, progressive, and fatal condition that leads to progressive heart failure and death within four years from diagnosis.

Author: Rare Daily Staff