Eplontersen Slows FAP Progression, Improves Quality of Life: Trial Data
The therapy has a similar mechanism of action to Ionis Pharmaceuticals' Tegsedi
Eplontersen reduced transthyretin (TTR) protein levels, eased disease progression, and improved quality of life in adults with familial amyloid polyneuropathy (FAP), according to an eight-month interim analysis of the NEURO-TTRansform study.
Based on these data, the investigational therapy’s co-developers Ionis Pharmaceuticals and AstraZeneca will seek regulatory approval this year.
“The promising results from NEURO-TTRansform show eplontersen had a positive impact on disease progression and improved quality of life in a substantial number of patients,” Eugene Schneider, MD, Ionis’ executive vice president and chief clinical development officer, said in a press release. “We are excited about the potential for delivering a new treatment option to patients living with this relentless and devastating disease.”
ATTR amyloidosis is a group of conditions marked by the formation and buildup of toxic clumps of TTR protein in different organs and tissues, including the heart and nerves.
FAP, a hereditary form of ATTR amyloidosis, is caused by defects in the TTR gene that lead to the production of a misfolded version of the TTR protein, which tends to form clumps in peripheral nerves that extend from the brain and spinal cord. Over time, this leads to nerve damage, also known as polyneuropathy.
Eplontersen, developed with Ionis’ LIgand-Conjugated Antisense (LICA) technology, is a second-generation RNA-targeted therapy designed to reduce TTR protein production and prevent toxic clump formation. The treatment has a similar mechanism of action to Ionis’ approved FAP therapy Tegsedi (inotersen), but has been modified to boost its entry into liver cells where TTR is mainly produced.
The worldwide Phase 3 NEURO-TTRansform trial (NCT04136184) is testing the safety and effectiveness of eplontersen in 168 adults, ages 18–82, diagnosed with stage 1 or 2 FAP with mild to moderate symptoms.
Participants were randomly assigned to receive eplontersen once every four weeks or Tegsedi once a week, both by subcutaneous (under-the-skin) injection. After about eight months, those who received Tegsedi will switch to eplontersen until the end of the study.
Results in this trial will be compared with those of the placebo group from a previously completed Phase 2/3 study (NCT01737398) that assessed the safety and effectiveness of Tegsedi in FAP patients.
NEURO-TTRansform’s final analysis will be completed at 66 weeks (15 months), and all participants will be followed for up to 85 weeks (20 months). Those who complete the trial will have the option to enter in an open-label extension study.
This pre-planned interim analysis conducted after 35 weeks (eight months) of treatment with eplontersen was recently presented at the International Symposium on Amyloidosis (ISA) in Germany by Teresa Coelho, MD, a NEURO-TTRansform investigator.
According to the analysis, eplontersen reduced the levels of TTR protein in patients’ blood by a mean of 81.2% compared with baseline (before the study’s start), meeting one of the trial’s co-primary outcomes.
Eplontersen also slowed neuropathic disease progression, as demonstrated by a statistically significant difference in mean change over baseline in the modified Neuropathy Impairment Score +7 (mNIS+7) compared with the external placebo group, meeting another of the study’s co-primary outcomes.
NEURO-TTRansform also met a key secondary outcome of showing that eplontersen significantly improved patient-reported quality of life from baseline compared with the external placebo, as assessed with the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN).
Eplontersen has demonstrated a favorable safety and tolerability profile, with the treatment-emergent adverse events (TEAEs) rate in those receiving eplontersen being either lower or similar to placebo across all major categories. So far, no TEAEs of special interest leading to treatment discontinuation have been reported.
“Eplontersen showed clinically meaningful improvement in neuropathy impairment and quality of life measures relative to baseline,” Coelho, who is also a neurologist and neurophysiologist at Hospital Santo António, Centro Hospitalar Universitário do Porto, Portugal, said. “The significant efficacy, combined with a favorable safety and tolerability profile, indicate that eplontersen has the potential to be an important therapeutic option for patients living with this debilitating and fatal disease.”
Recently, eplontersen was granted orphan drug status in the U.S. This designation encourages the development of therapies for rare and serious diseases by providing certain benefits and incentives.
The therapy is also being evaluated in CARDIO-TTRansform (NCT04136171), a Phase 3 trial aiming to enroll up to 1,000 adults, ages 18–90, with inherited ATTR amyloidosis with heart muscle disease (cardiomyopathy) as well as wild-type ATTR amyloidosis, an acquired form of the condition not linked to known genetic mutations.