Eplontersen may stabilize, slow heart damage in FAP patients
FDA decision expected this week on potential approval of eplontersen
A little more than a year of treatment with eplontersen was found to stabilize or even improve the heart’s structure and function in people with familial amyloid polyneuropathy (FAP) who also were experiencing symptoms of heart disease, known as cardiomyopathy.
That’s according to an exploratory analysis of data from the Phase 3 NEURO-TTRansform clinical trial (NCT04136184) against results of patients given a placebo in an earlier Phase 2/3 trial (NCT01737398) of the now-approved FAP therapy Tegsedi (inotersen).
“Collectively, these findings suggest that eplontersen may attenuate [reduce the effect of] the progression of the cardiac manifestations of [FAP],” the researchers wrote.
The analysis, “Effect of Eplontersen on Cardiac Structure and Function in Patients with Hereditary Transthyretin Amyloidosis,” was published in the Journal of Cardiac Failure. It was funded by AstraZeneca, which is codeveloping eplontersen with Ionis Pharmaceuticals.
New analysis compares results of 2 Phase 3 clinical trials
NEURO-TTRansform’s top-line data previously showed that the therapy can reduce nerve damage-related disability and improve quality of life in people with FAP, also known as hereditary transthyretin amyloidosis with polyneuropathy.
Based on these findings, eplontersen is up for approval in the U.S. for treating the neurodegenerative disorder. A decision is expected by the end of this week.
An ongoing, global Phase 3 trial called CARDIO-TTRansform (NCT04136171) is expected to provide further insights into eplontersen’s effects on the heart over more than 2.5 years of treatment.
The study — fully, CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) — enrolled 1,438 people with transthyretin amyloidosis with cardiomyopathy. This is a related condition characterized mainly by heart damage.
FAP is a progressive neurodegenerative disease caused by the buildup of toxic clumps of a protein called transthyretin (TTR) in the body’s tissues due to mutations in the TTR gene.
The disease is characterized by toxic aggregates, or clumps, in the nerves outside the brain and spinal cord, which lead to a range of nerve damage-related symptoms. However, the TTR clumps also can accumulate in the heart, causing the heart muscle to stiffen and thicken, and making it hard to pump blood through the body.
Eplontersen is a second-generation experimental therapy designed to reduce TTR protein production, which is expected to prevent the formation of toxic TTR aggregates. Working in a similar way to Ionis’ first-generation Tegsedi, it was modified to boost its entry into liver cells, the body’s main producers of TTR.
Both therapies are administered through subcutaneous or under-the-skin injections, but eplontersen is given every four weeks, instead of every week like Tegsedi.
The NEURO-TTRansform trial enrolled 168 adults diagnosed with stage 1 or 2 FAP with mild to moderate symptoms. Participants first received either eplontersen or Tegsedi for eight months, after which all were given the experimental therapy for seven months — for a total of up to about 15 months, or more than one year, of treatment.
In addition to completing nerve damage-related measures, all participants underwent heart assessments at the study’s start and at 15 months.
Results show gains on heart measures for patients given eplontersen
This new heart analysis compared data from 144 participants, including 49 (34%) with cardiomyopathy, in NEURO-TTRansform against those of 60 patients, including 30 (50%) with cardiomyopathy, who were on a placebo in an earlier Tegsedi trial. The 49 patients from NEURO-TTRansform had been assigned to receive eplontersen during the trial.
At study’s start, eplontersen-treated patients were an average of 6.5 years younger than those on the placebo (53 vs. 59.5). They also had nearly six times more TTR protein and twice as less NT-proBNP, a marker of heart damage, in the blood than the external placebo group.
These two groups also significantly differed in many heart measures.
For example, stroke volume — the volume of blood pumped out of the left ventricle (one of the heart’s lower chambers) with each heartbeat — was lower in the eplontersen group (44.5 vs. 57.1 mL). The left ventricle’s end-diastolic volume (LVEDV), or the volume of blood remaining in the chamber after the heart has contracted, also was smaller (71.6 vs. 90.5 mL).
Among the patients with cardiomyopathy at the study’s start, those given eplontersen also showed significantly lower stroke volume (41.4 vs. 55.9 mL) and LVEDV (68.5 vs. 88.3 mL).
However, after more than a year of eplontersen treatment, patients with cardiomyopathy showed a significant improvement in stroke volume (by 10.6 mL) and left ventricle’s ejection fraction — stroke volume divided by end-diastolic volume — (by 4.3%) relative to the external placebo group.
Other heart structural and functional measures remained stable in the eplontersen-treated patients with cardiomyopathy.
In the overall patient population, eplontersen was associated with significant improvements over a placebo in stroke volume, LVEDV, and other measures.
“These findings suggest that eplontersen treatment was associated with stable or improved measures of [heart] structure and function,” the researchers wrote.
While the cardiomyopathy subgroup was considerably small, the consistency of the results “provide reassurance of the performance of eplontersen” in FAP patients with cardiomyopathy, “while we await the results of the CARDIO-TTRansform trial,” the researchers concluded.