Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy

Abstract

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.

Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.

Design, setting, and participants: NEURO-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.

Interventions: Subcutaneous 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 measures: Primary 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.

Results: Among 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 relevance: In 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 registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

Figure 1.. Recruitment, Randomization, and Patient Flow in the NEURO-TTRansform Trial

^aSpecific reasons for not meeting eligibility criteria (patients could have had >1 reason) included not meeting minimum criteria for signs and symptoms of hereditary transthyretin (ATTRv) amyloidosis (n = 13); urinalysis positive for blood (n = 5); serum vitamin A/retinol level less than lower limit of normal (n = 5); no documented genetic mutation in TTR gene (n = 5); platelet count less than 125 × 10⁹/L (n = 3); known history of or positive test result for HIV, hepatitis C, or chronic hepatitis B (n = 2); urine protein to creatinine ratio 1000 mg/g or greater (n = 2); monoclonal gammopathy of unknown significance and/or immunoglobulin free light chain ratio less than 0.26 and greater than 1.65 (n = 2); history of bleeding, diathesis, or coagulopathy (n = 2); consent not given (n = 2); clinically significant abnormalities in medical history (n = 1); renal insufficiency (difference between cystatin C and creatinine estimated glomerular filtration rate <60 mL/min/1.73 m²) (n = 2); bilirubin level greater than or equal to 1.5 times upper limit of normal (n = 1); active infection requiring systemic antiviral or antimicrobial therapy that would not be completed prior to study day 1 (n = 1); Karnofsky performance status 50% or less (n = 1); presence of known type 1 or type 2 diabetes mellitus (n = 1); no reason recorded (n = 1). ^bEligible patients were randomized 6:1 to receive eplontersen or inotersen, respectively, using an Interactive Voice/Web-Response system (IxRS, Almac). ^cThe inotersen reference group was included to confirm sufficiently comparable disease progression and treatment response patterns between NEURO-TTRansform and NEURO-TTR, the source of the historical placebo. A diagram showing recruitment, randomization, and patient flow for the NEURO-TTR inotersen and placebo groups has been published. ^dOne additional patient discontinued study drug after week 66 due to a treatment-emergent adverse event that started before week 66. ^eSee eFigure 1 in Supplement 2 for study design relative to the inotersen reference group in NEURO-TTRansform.

Figure 2.. Change From Baseline in Primary End Points (Serum Transthyretin Concentration, mNIS+7 Composite Score, Norfolk QoL-DN Total Score)

A, Means (filled circles), medians (open diamonds), and first and third quartiles (lower and upper ends of whiskers) for percentage changes from baseline in serum transthyretin concentration at each study visit. The adjusted mean difference between eplontersen and historical placebo at week 65 was −70.4% (95% CI, −75.2% to −65.7%; P < .001). B, Changes from baseline (adjusted means [filled circles] and 95% CIs [lower and upper ends of whiskers]) in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, which range from −22.3 to 346.3, with higher scores indicating poorer function. The adjusted mean difference between eplontersen and historical placebo at week 66 was −24.8 (95% CI, –31.0 to −18.6; P < .001). C, Changes from baseline (adjusted means [filled circles] and 95% CIs [lower and upper ends of whiskers]) in Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QoL-DN) total score, which range from −4 to 136, with higher scores indicative of poorer quality of life. The adjusted mean difference between eplontersen and historical placebo at week 66 was –19.7 (95% CI, –25.6 to –13.8; P < .001). For the mNIS+7 composite score and Norfolk QoL-DN total score, a decrease in score indicates improvement. Data point values can be found in eTable 6 in Supplement 2.

Figure 3.. Change From Baseline in Secondary End Points (NSC Total Score, SF-36 PCS Score, Distribution of Polyneuropathy Disability Scores at Baseline and Week 65, mBMI)

The difference between eplontersen and historical placebo in Neuropathy Symptom and Change (NSC) score at week 66 was –8.2 (95% CI, –10.7 to –5.8; P < .001). The difference between eplontersen and historical placebo in SF-36 score at week 65 was 5.3 (95% CI, 3.2-7.4; P < .001). The proportion of patients who could walk without assistance (polyneuropathy disability [PND] 1) remained at 39.6% in the eplontersen group and decreased from 37.3% to 29.4% in the historical placebo group. The difference between eplontersen and historical placebo in modified body mass index (mBMI) at week 65 was 82.7 kg/m² × g/L (95% CI, 54.6-110.8; P < .001). See eFigure 12 in Supplement 2 for individual contributions of changes in body mass index (BMI) and albumin to changes in mBMI. Data point values for panels A, B, and D are reported in eTable 7 in Supplement 2. SF-36 PCS indicates 36-Item Short Form Survey physical component summary. ^aChange from baseline in NSC total score at week 35 was also assessed in the final analysis (difference between eplontersen and historical placebo at week 35: −3.9 [95% CI, −6.1 to −1.8; P < .001]). ^bPercentages for patients with both baseline and week 65 values. The prespecified analysis of change from baseline in PND score vs historical placebo at week 65 was statistically significant (P < .05).