Eplontersen promising for hereditary ATTRv-PN

Eplontersen, a ligand-conjugated antisense (LICA) investigational agent designed to reduce transthyretin (TTR) production or TTR protein, ably halts neuropathy progression and improves quality of life (QoL) in patients with hereditary transthyretin-mediated amyloid polyneuropathy (ATTRv-PN) in the phase III NEURO-TTRansform trial.

ATTRv-PN is a progressive and fatal disease that leads to debilitating peripheral nerve damage, resulting in loss of motor function within 5 years of diagnosis. Left untreated, death can occur within 5–15 years of disease onset.

“The earlier the diagnosis is made, the better patients do,” said principal investigator Dr Sami Khella, chief of the Department of Neurology at Penn Presbyterian Medical Center in Philadelphia, Pennsylvania, US at AAN 2023. [Abstract 1150]

“In our study, eplontersen led to clinically and statistically significant benefits at week 66,” she added. “There was an early and rapid, sustained reduction in TTR concentration, a halting of neuropathy impairment, and a trend to improvement in QoL.”

The results are further backed by the secondary endpoints, which all met statistical significance.

A big win for patients

Patients (n=168) included in the study had stage 1 or 2 ATTRv-PN and were treated with subcutaneous eplontersen vs placebo.

At 66 weeks, patients had improvements in all three coprimary endpoints of change from baseline in serum TTR concentration, neuropathy impairment, and QoL.

There was a mean reduction of 82 percent in TTR serum concentration from baseline with eplontersen vs only 11 percent with placebo (p<0.0001). The modified Neuropathy Impairment Score +7 (mNIS+7)* increased by 0.28 points with eplontersen vs 25 points with placebo (p<0.0001). Overall, 47 percent of patients treated with eplontersen had improvements from baseline in neuropathy at 66 weeks vs 17 percent with placebo.

Patient-reported QoL also improved significantly (p<0.0001) as assessed by the Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN**). Overall, 58 percent of patients treated with eplontersen had improvements in QoL at 66 weeks vs 20 percent of those on placebo.

Benefits extend to 66 weeks

The benefits extended from 35 weeks to 66 weeks. Eplontersen was well tolerated in this cohort, Khella reported.

Treatment-emergent adverse events were comparable between groups across all major categories and no adverse events of special interest led to eplontersen discontinuation.

There were two deaths prior to the interim analysis that were related to ATTR-amyloidosis sequelae. Patients will be followed on treatment until week 85, with the option to to transition into an open-label extension study.

Eplontersen was granted orphan drug designation in the US by the FDA for the treatment of transthyretin-mediated amyloidosis (ATTR-CM) in January this year. A new drug application for ATTRv-PN has been accepted by the agency. Decision is expected by December.

“In the past, patients with ATTRv-PN usually deteriorated given the limited available treatments. Our results demonstrate that eplontersen has a consistent and sustained treatment effect and reinforces its potential as an important therapeutic for patients living with this debilitating and fatal disease,” Khella said.