Eplontersen feasible gene silencing technique for treating hereditary transthyretin amyloidosis with polyneuropathy: JAMA

144 people received 45 mg subcutaneous eplontersen every 4 weeks, a small reference group of 24 individuals received 300 mg subcutaneous inotersen weekly and 60 received subcutaneous placebo weekly.

Primary efficacy endpoint at week 65/66 were determined as changes from baseline in serum transthyretin concentration, Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores imply poorer quality of life), and modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function).

The study led to the following findings:

• Among 144 eplontersen-treated patients, 94.4% completed week-66 follow-up; among 60 placebo patients, 86.7% completed week-66 follow-up.
• At week 65, the adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo.
• Adjusted mean change from baseline to week 66 was lower (better) with eplontersen versus placebo for mNIS+7 composite score (0.3 versus 25.1) and Norfolk QoL-DN (−5.5 versus 14.2).
• Adverse events by week 66 that led to study drug discontinuation occurred in 4% of patients in the eplontersen group versus 3% in the placebo group.
• Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (intracerebral haemorrhage, cardiac arrhythmia); there were no deaths in the placebo group.

"This study adds to the growing body of evidence related to TTR gene silencing in general, and hepatic-targeted therapies in specific, for ATTRv polyneuropathy patients, and these therapies are suggested as among first-line treatments in ATTRv amyloidosis expert consensus statements," the researchers concluded.

Reference:

Coelho T, Marques W, Dasgupta NR, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. 2023;330(15):1448–1458. doi:10.1001/jama.2023.18688