Full eplontersen Phase 3 trial results support efficacy in FAP

More than year of treatment shows reductions in transthyretin blood levels

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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More than a year of treatment with the experimental therapy eplontersen significantly reduces blood levels of transthyretin — the protein that accumulates to toxic levels in familial amyloid polyneuropathy (FAP) — eases nerve damage-related disability, and improves quality of life for patients.

That’s according to the full results of the Phase 3 NEURO-TTRansform clinical trial (NCT04136184), which indicated that all co-primary and secondary goals were met after about 15 months and that its benefits were maintained up to 19 months (about 1.5 years).

The full data were recently published in JAMA in “Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.” The work was funded by Ionis Pharmaceuticals, which is developing eplontersen with AstraZeneca.

“These data reinforce the ability of eplontersen to halt disease progression and improve quality of life throughout the 19-month treatment period,” Eugene Schneider, MD, executive vice president and chief clinical development and operations officer at Ionis, said in a company press release.

“The JAMA publication reinforces the growing body of evidence showing that eplontersen significantly reduces [blood] transthyretin concentration, may halt progression of neuropathy [nerve damage] impairment, and improves overall patient quality of life, providing hope to this community,” said Sami Khella, MD, the trial’s principal investigator at the Penn Presbyterian Medical Center site and a professor at the University of Pennsylvania School of Medicine. “The totality of positive, consistent eplontersen data position this therapy, which can be self-administered, to be an important and empowering potential new medicine for treating [FAP].”

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FDA set to consider eplontersen for FAP

The NEURO-TTRansform findings supported Ionis’ application to the U.S. Food and Drug Administration (FDA) to approve eplontersen for treating FAP. A decision is expected in December.

“We look forward to the upcoming FDA action date in December and bringing eplontersen to this underserved patient community in the U.S. and around the world,” Schneider said.

The companies also plan to seek eplontersen’s approval in Europe and other regions outside the U.S., where AstraZeneca holds exclusive commercialization rights.

FAP, also known as hereditary transthyretin-mediated amyloid polyneuropathy, is a genetic disorder wherein transthyretin forms toxic clumps that cause damage to nerve cells.

Eplontersen is designed to reduce the protein’s production. It works similarly to Tegsedi (inotersen) — an approved FAP treatment sold by Ionis — but is engineered to be better at getting into the liver, where most transthyretin is made. It’s injected subcutaneously (under the skin) once monthly, which can be done by patients at home with appropriate training.

In the trial, 144 adults with FAP were given eplontersen, with more than 94.4% of them completing about 66 weeks, or about 15 months, of treatment. The results were compared with data from FAP patients given a placebo in an earlier Tegsedi Phase 2/3 trial (NCT01737398).

By week 66, eplontersen-treated patients showed a significantly greater reduction in transthyretin than those in the external placebo group (81.7% vs. 11.2%).

Changes in the modified Neuropathy Impairment Score +7 (mNIS+7) — which assesses nerve damage-related disability — and the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN), which measures quality of life, also significantly favored eplontersen over a placebo.

Specifically, mNIS+7 scores for those given eplontersen were generally stable throughout the trial, with an average change of just 0.3 points by week 66. For those given a placebo, mNIS+7 scores worsened by more than 25.1 points, on average.

Similarly, average scores on the Norfolk QoL-DN improved by 5.5 points in those treated with eplontersen at week 66 and worsened by 14.2 points in the external placebo group.

Compared with those on a placebo, a greater proportion of patients given eplontersen saw a reduction in neuropathy-related disability (47% vs. 17%) and improvements in life quality (58% vs. 20%) after more than a year on treatment.

Average scores on the 36-Item Short Form Survey physical component, a general measure of physical health, also improved by 0.9 points for eplontersen patients and worsened by 4.5 points in the external placebo group at week 66.

Results of eplontersen treatment after a year

Longer-term data indicated these improvements were mostly maintained through 85 weeks (about 1.5 years) on eplontersen. These results are expected to be presented at an upcoming medical meeting, the release stated.

Eplontersen was well tolerated overall. The most common safety issues reported were COVID-19, diarrhea, urinary tract infection, vitamin A deficiency, and nausea.

There were two deaths reported in patients on eplontersen. Both were considered potentially related to FAP, not the medication. Only 4% of patients given eplontersen discontinued it due to side effects.

The findings showed eplontersen-treated FAP patients “demonstrated changes consistent with significantly lowered [blood] transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo,” the researchers wrote.