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

Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant disease primarily caused by single-point sequence variants in the TTR gene that codes for transthyretin, vitamin A transporter, and thyroxine. Transthyretin gene silencing is an emerging treatment strategy for ATTRv amyloidosis that specifically targets and degrades TTR messenger RNA in the liver.

Sami Khella, University of Pennsylvania School of Medicine, Philadelphia, and colleagues aimed to evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy in NEURO-TTRansform, an open-label, single-group, phase 3 trial.

The trial was conducted at 40 sites across 15 countries (2019-2023) comprising 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with a placebo from NEURO-TTR, an inotersen trial with similar endpoints and eligibility criteria, served as a historical placebo (“placebo”) group.

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