Results From Fully Enrolled NEURO-TTRansform Trial Due Mid-2022

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by Marta Figueiredo PhD |

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NEURO-TTRansform trial testing Ionis’ eplontersen / fully enrolled


Patient enrollment is complete for the Phase 3 NEURO-TTRansform trial testing Ionis Pharmaceuticals’ eplontersen in adults with familial amyloid polyneuropathy (FAP).

The trial exceeded its enrollment target of 140 participants, with Ionis now expecting to register more than 160 patients in the study.

“The speed of enrollment in our pivotal NEURO-TTRansform study speaks to the urgent need for new treatment options for people living with [hereditary transthyretin (ATTR) amyloidosis],” Brett P. Monia, PhD, Ionis’ CEO, said in a press release.

“We remain dedicated to advancing eplontersen as rapidly as possible and look forward to announcing results from a formal interim analysis by mid-year 2022,” Monia said, adding that, if the data are positive, a regulatory application seeking the eplontersen’s approval in the U.S. may be filed by the end of 2022.

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ATTR amyloidosis comprises a group of conditions in which the TTR protein forms toxic aggregates or clumps, called amyloid deposits, that build up in different tissues and organs, including the heart and nerves. These deposits cause damage and disrupt the tissues and organs’ normal function.

FAP, a form of hereditary ATTR amyloidosis, is caused by mutations in the TTR gene, which provides instructions for making the TTR protein. Wild-type ATTR, an acquired, age-related, and more common form of the disease, is not associated with any known genetic mutations.

Formerly known as AKCEA-TTR-L, eplontersen is a second-generation antisense oligonucleotide (ASO)-based therapy designed with Ionis’ Ligand Conjugated Antisense (LICA) technology platform to suppress TTR production.

ASOs are molecules designed to target a specific gene’s messenger RNA — the intermediate molecule derived from DNA that guides protein production — potentially changing, blocking, or boosting the generation of the resulting protein.

The therapy has a similar mechanism of action to Tegsedi (inotersen), Ionis’ approved ASO-based therapy for FAP. But its ASO is attached to a molecule that boosts entry into liver cells, the main producers of TTR. Both therapies are delivered through under-the-skin injections.

“Because eplontersen utilizes Ionis’ LICA technology, it offers the advantages of high potency, convenient, infrequent dosing and an attractive safety and tolerability profile,” Monia said.

The experimental treatment, being co-developed by Ionis and its affiliate, Akcea Therapeutics, is designed to treat all forms of ATTR amyloidosis, including the hereditary and wild-type forms of the disease. 

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In a previous Phase 1 clinical trial (NCT03728634), completed in 2020, eplontersen was found to be generally well-tolerated and able to reduce TTR levels by up to 94% in healthy volunteers.

The global Phase 3 NEURO-TTRansform trial (NCT04136184) is evaluating the safety and effectiveness of eplontersen in adults, ages 18–82, diagnosed with stage 1 or 2 FAP, with mild to moderate symptoms.

Recruited at sites across 16 countries, participants are being randomly assigned to receive either eplontersen once every four weeks or Tegsedi once a week for 65 weeks (more than year). Notably, after 34 weeks of treatment (approximately eight months), patients assigned to Tegsedi will switch to eplontersen until the end of the study.

All participants also will receive daily supplemental doses of the recommended daily allowance of vitamin A.

NEURO-TTRansform’s main goals, which will be assessed at 66 weeks, include analyzing changes in blood TTR levels, nerve damage progression — as assessed by the modified Neuropathy Impairment Score +7 — and quality of life, using the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy.

A planned interim analysis of changes in TTR levels and nerve damage progression will be conducted at 35 weeks.

Patients will be followed for 85 weeks (more than 1.5 years), after which they will have the option to enroll in an open-label extension study.

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Tegsedi (Inotersen)

Results of the trial will be compared with those from the historical placebo group of a previous Phase 2/3 clinical trial (NCT01737398) that evaluated the safety and effectiveness of 65 weeks of treatment with Tegsedi against a placebo in 172 adults with FAP.

NEURO-TTRansform is expected to be completed in January 2024.

Eplontersen also is being tested in up to 750 adults with cardiomyopathy due to hereditary and wild-type AATR amyloidosis in the placebo-controlled Phase 3 CARDIO-TTRansform trial (NCT04136171).

Cardiomyopathy is a disease of the heart muscle that makes it harder for the heart to pump blood to the rest of the body. It can lead to heart failure, a leading cause of death among people with ATTR amyloidosis.

The trial is likely still recruiting participants at sites across 16 countries. Following enrollment, participants will be randomly assigned to receive either eplontersen or a placebo once every four weeks for 120 weeks (more than two years). The study is anticipated to finish in June 2024.