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BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand–conjugated antisense oligonucleotide targeting hepatocyte TTR messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I–III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu ; Unique identifier: EudraCT number 2019-002835-27.

Background and Aims: Accumulating data related to prevention, surveillance and treatment of chronic hepatitis B (CHB) provided the impetus for this updated guideline, using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Methods: The guideline was developed in compliance with the National Academy of Medicine standards. The guideline panel developed structured questions following the Population, Intervention Comparison, Outcomes (PICO) framework. The panel addressed 6 PICO questions covering prevention (maternal to infant transmission and horizontal transmission), surveillance for liver cancer (among hepatitis B surface antigen positive (HBsAg) persons co-infected with hepatitis C virus, hepatitis D virus and/or human immunodeficiency viruses and after HBsAg loss) and treatment (HBsAg positive persons in immune-tolerant or indeterminate phases as well as withdrawal of antiviral therapy), providing evidence-based recommendations on these topics. Four systematic reviews of the literature were conducted, and two existing systematic reviews were utilized to support the recommendations in this practice guideline. Conclusions: This evidence-based guideline provides updated recommendations to optimize the care of persons with CHB.

ABSTRACTIntroduction/AimsThe degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo.MethodsData from the NEURO‐TTRansform trial on patients with ATTRv‐PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor‐based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL‐Diabetic Neuropathy (Norfolk QoL‐DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed.ResultsMeaningful improvement in mNIS+7 was estimated as −4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL‐DN were −12.8 to −4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were −2.4 to −1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m2 × g/L and deterioration was −40.9 kg/m2 × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences.DiscussionEplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials.

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

e13559 Background: Recent advances in targeted therapies have increased the survival and quality of life for non-small cell lung cancer (NSCLC) patients. Understanding clinical characteristics and predicting HER2 status may facilitate efficient use of next-generation sequencing (NGS) testing and promote precision medicine/targeted therapies. Methods: NSCLC patients ≤65 years old, diagnosed between 01/2011 and 06/2021 who have NGS test results were identified in from two National Cancer Institute designated cancer centers in the Northeastern region of the United States. Demographics, behavioral, and clinical characteristics were extracted from electronic health record (EHR) data and EHR-linked cancer registry. Prevalence prediction modelling of HER2/ERBB2 mutation was performed using machine learning (ML) methods including logistic regression (LR), random forest (RF), naïve Bayes (NB), extreme gradient boosting (XGBoost) and multi-layer perceptron (MLP). 10- fold cross validation and k-nearest neighbor method were used to impute missing values. Under-sampling, oversampling and feature selection methods were tried. Results: Among 761 NSCLC patients with NGS reports available, 353 (46%) were ≤65 years old. Among 353 (mean age 57, 58% female, 88% non-Hispanic, 69% white, 57% had metastasis, 58% prescribed chemotherapy) 25 (7%) had a HER2 mutation. Based on univariate significance tests with LR on the complete data: cerebrovascular disease, BMI between 27.5-29.9, KRAS, EGFR and MET were significant with odds ratios (ORs) ranging from 0.2-3.9. In our prediction models, BMI, cerebrovascular disease, weight loss, hepatic metastases, diabetes, congestive heart failure, and KRAS, EGFR, MET and RET alteration status were significant predictors in multivariate analyses, suggesting the potential usefulness of these features in predicting HER2 mutation among patients with NSCLC. Area under the ROC curve (AUC) varied across different models from 70.9% (RF), 70% (XGB and MLP), 69.5% (LR) to 68.2% (Naïve Bayes). The best performing model with RF yielding an AUC ~71% can provide relative high specificity and acceptable sensitivity depending on the cut off. Conclusions: Our prediction models yielded AUC around 70% with the best performing model’s AUC being 71% in a subgroup aged ≤65. After further validation, our prediction model may be used to identify patients appropriate for repeat NGS testing who did not have HER2 testing in first molecular profiling. Future work is needed to predict status in repeat testing with previously test negative patients who relapse or have progression of disease. Random forest (RF) Model performance across different cutoff for the predicted probability. [Table: see text]

AbstractIntroductionThere are concerns regarding the effectiveness and safety of SARS‐CoV‐2 vaccine in inflammatory Bowel Disease (IBD) patients. This systematic review and meta‐analysis comprehensively summarises the available literature regarding the safety and effectiveness of SARS‐CoV‐2 vaccine in IBD.MethodsThree independent reviewers performed a comprehensive review of all original articles describing the response of SARS‐CoV‐2 vaccines in patients with IBD. Primary outcomes were (1) pooled seroconversion rate SARS‐CoV‐2 vaccination in IBD patients (2) comparison of breakthrough COVID‐19 infection rate SARS‐CoV‐2 vaccination in IBD patients with control cohort and (3) pooled adverse event rate of SARS‐CoV‐2 vaccine. All outcomes were evaluated for one and two doses of SARS‐CoV‐2 vaccine. Meta‐regression was performed. Probability of publication bias was assessed using funnel plots and with Egger’s test.ResultsTwenty‐one studies yielded a pooled seroconversion rate of 73.7% and 96.8% in IBD patients after one and two doses of SARS‐CoV‐2 vaccine respectively. Sub‐group analysis revealed non‐statistically significant differences between different immunosuppressive regimens for seroconversion. Meta‐regression revealed that the vaccine type and study location independently influenced seroconversion rates. There was no statistically significant difference in breakthrough infection in IBD patients as compared to control after vaccination.ConclusionIn summary, the systematic review and meta‐analysis suggest that SARS‐CoV‐2 vaccine is safe and effective in IBD patients.