Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Abstract

ImportanceTransthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.ObjectiveTo evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and ParticipantsNEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013–November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo (“placebo”) group.InterventionsSubcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and MeasuresPrimary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, –22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, –4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.ResultsAmong 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was −81.7% with eplontersen and −11.2% with placebo (difference, −70.4% [95% CI, −75.2% to −65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, −24.8 [95% CI, −31.0 to −18.6; P < .001) and for Norfolk QoL-DN (−5.5 vs 14.2; difference, −19.7 [95% CI, −25.6 to −13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and RelevanceIn patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10

Eplontersen: First Approval

“…It has a similar design and identical nucleobase sequence to inotersen, an antisense oligonucleotide that has been previously approved for polyneuropathy of ATTRv (ATTRv-PN) [ 4 ]; however, eplontersen has unique chemistry and is conjugated to a ligand containing three N -acetyl galactosamine (GalNAc) residues to target the drug to hepatocytes, the primary source of TTR in the body [ 3 ]. This results in a less frequent and lower dosage of eplontersen needed for efficacy [ 5 ] and is expected to lead to an improved safety profile compared with inotersen [ 3 ]. Eplontersen is the first approved drug for ATTRv-PN that can be self-administered by patients via an auto-injector [ 1 ].…”

Earlier diagnosis of peripheral neuropathy in primary care: A call to action

“…The DN4 questionnaire has been more widely used but is subject to misunderstanding when self‐administered. Validated questionnaires assessing the impact of PN on quality of life such as NeuroQoL 55 and Norfolk QOL‐DN 56 have proven to be useful, but are time‐consuming and not readily available in multiple languages.…”

Cardiac Amyloidosis Due to Transthyretin Protein

“…Treatment of ATTR cardiomyopathy includes medications that bind to and kinetically stabilize the TTR protein to inhibit tetramer dissociation, thereby slowing amyloid formation (tafamidis, acoramidis, and diflunisal), and agents that suppress hepatic TTR protein synthesis with small interfering mRNAs (patisiran, vutrisiran) or antisense oligonucleotides (inotersen, eplontersen) (Table 4). Therapies that suppress hepatic synthesis of TTR (patisiran, vutrisiran, inotersen, and eplontersen) were evaluated in clinical trials for patients with ATTR polyneuropathy resulting in regulatory approval for patients with ATTR polyneuropathy (with or without cardiomyopathy; Table 4). Subsequently, certain of these therapies have been evaluated in those with ATTR cardiomyopathy specifically, but none of these agents are currently approved for ATTR cardiomyopathy without polyneuropathy .…”

“… Therapies that suppress hepatic synthesis of TTR (patisiran, vutrisiran, inotersen, and eplontersen) were evaluated in clinical trials for patients with ATTR polyneuropathy resulting in regulatory approval for patients with ATTR polyneuropathy (with or without cardiomyopathy; Table 4). Subsequently, certain of these therapies have been evaluated in those with ATTR cardiomyopathy specifically, but none of these agents are currently approved for ATTR cardiomyopathy without polyneuropathy . Another promising strategy is amyloid depletion or removal of deposits with antibody-driven phagocytic degradation …”