Eplontersen for 1 year found to safely ease symptoms in FAP adults

All goals met in Phase 3 NEURO-TTRansform trial, top-line data show

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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More than one year of treatment with eplontersen safely reduced symptoms of nerve damage and improved quality of life for adults with familial amyloid polyneuropathy (FAP), according to top-line data from the Phase 3 NEURO-TTRansform trial.

The experimental therapy from Ionis Pharmaceuticals and AstraZeneca also significantly lowered blood levels of transthyretin — the protein that toxically accumulates in FAP, also known as hereditary transthyretin-mediated amyloid polyneuropathy, or ATTRv-PN — after approximately 16 months.

These benefits, overall, were similar to those reported in a previous interim analysis, conducted after 35 weeks or about eight months of treatment. Data from both the interim and top-line analyses will be presented at the upcoming American Academy of Neurology Annual Meeting, to be held in Boston April 22-27.

“These latest results from our NEURO-TTRansform study represent an important step towards delivering a potential new therapy for ATTRv-PN patients living with this debilitating and fatal disease,” Eugene Schneider, MD, executive vice president and chief clinical development officer at Ionis, said in a company press release.

“We are encouraged by the sustained benefit demonstrated by eplontersen and what a self-administered treatment could mean for patients and families affected by ATTRv-PN,” Schneider added.

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Eplontersen Granted Orphan Drug Status in US for ATTR Amyloidosis

Therapy now under regulatory review in US

The U.S. Food and Drug Administration last month agreed to review an application from Ionis seeking eplontersen’s approval for treating FAP. A final decision from the regulatory agency is expected by Dec. 22. The companies also plan to seek a similar approval in the European Union and in other parts of the world.

In FAP, transthyretin buildup in the body’s tissues is caused by mutations in the TTR gene.  The peripheral nerves — those found outside the brain and spinal cord — are particularly susceptible to this buildup, leading to progressive nerve damage.

Self-administered through under-the-skin (subcutaneous) injections, eplontersen is designed to reduce transthyretin production, thereby preventing its toxic accumulation. It does so by targeting TTR’s messenger RNA, an intermediate template molecule that’s used to make the transthyretin protein.

That’s a similar mechanism to Ionis’ approved FAP therapy Tegsedi (inotersen), but eplontersen is expected to be more efficient at reaching liver cells, where most transthyretin is produced.

Eplontersen holds orphan drug status in the U.S., which is intended to help speed its development toward regulatory approval.

Ionis’ application to the FDA was backed by data from the ongoing Phase 3 NEURO-TTRansform trial (NCT04136184), which enrolled 168 adults, ages 18-82, at 47 sites worldwide. Each of the participants had been diagnosed with stage 1 or 2 FAP.

Participants were randomly assigned to receive either eplontersen once every four weeks or Tegsedi once per week for 34 weeks, or about eight months. After that, patients on Tegsedi were switched to eplontersen for the remaining 31 weeks of the trial.

The trial’s main goals were to assess changes in blood transthyretin levels, nerve damage (neuropathy) progression, and quality of life. Data were compared with those of an external placebo group from a previous Phase 2/3 trial (NCT01737398) of Tegsedi, completed in 2017.

The previous interim analysis at 35 weeks showed that eplontersen led to a significant, 81.2% drop in blood transthyretin levels.

Moreover, compared with the external placebo group, eplontersen significantly slowed the rate of neuropathy progression — as assessed by the Neuropathy Impairment Score +7 — and improved life quality, which was measured with the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy.

Top-line data now indicate that these gains were maintained up to week 66, with eplontersen continuing to result in a statistically significant and clinically meaningful reduction in neuropathy compared with the external placebo group. The patients in this trial also had significant and meaningful life quality gains.

Blood transthyretin levels were significantly reduced relative to the placebo comparator and were consistent with findings from week 35.

The therapy continued to be safe and well-tolerated with longer treatment, with a safety profile similar to that observed at 35 weeks.

“This builds on the favorable 35-week results, which first demonstrated eplontersen’s potential to significantly improve outcomes in this underserved population,” said Sami Khella, MD, neurology chief at Penn Presbyterian Medical Center and a professor of clinical neurology at the University of Pennsylvania School of Medicine.

These results further underscore eplontersen’s potential to be a best-in-class treatment across all forms of transthyretin-mediated amyloidosis.

Meanwhile, all participants are being followed until week 85 — about 21 months — after which they will have the option of continuing treatment for about 3.5 years in an open-label extension study (NCT05071300).

Eplontersen also is being evaluated in the Phase 3 CARDIO-TTRansform trial  (NCT04136171), which is examining its effectiveness in people with transthyretin-mediated amyloid cardiomyopathy, wherein transthyretin mainly accumulates in the heart and can cause heart failure. The study is enrolling up to 1,400 participants at more than 100 sites globally.

“These results further underscore eplontersen’s potential to be a best-in-class treatment across all forms of transthyretin-mediated amyloidosis,” said Mene Pangalos, executive vice president of BioPharmaceuticals R&D at AstraZeneca.

“With limited treatment options currently available, there is an urgent unmet medical need for new therapies and earlier, accurate diagnosis across the different types of this systemic, progressive and fatal condition.”