BACKGROUND:Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS:DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI ≥25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS:Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48·4 years (SD 10·6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28·8 [95% CI 7·2-115·2]; adjusted relative risk 6·3 [95% CI 2·5-15·9]; p<0·0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION:In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING:D&D Pharmatech, Neuraly.
BACKGROUND:TACE is the standard treatment for intermediate-stage hepatocellular carcinoma but has limited survival benefits. TALENTACE evaluated adding atezolizumab and bevacizumab to on-demand TACE versus on-demand TACE alone in patients with systemically untreated, intermediate-to-high tumour burden unresectable hepatocellular carcinoma. METHODS:In this randomised, open-label, phase 3 study at 40 centres in China and Japan, patients aged 18 years or older with confirmed, unresectable hepatocellular carcinoma and an anticipated life expectancy of 12 months or more were eligible for inclusion. Eligible patients were required to have an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A liver function, no previous systemic therapy, and a sum of tumour maximum diameter (cm) and lesion number of six or more based on the six-and-twelve score. Patients were randomly assigned (1:1), using a permuted-block method implemented via an interactive voice and web response system, to on-demand TACE plus atezolizumab 1200 mg intravenously and bevacizumab 15 mg/kg intravenously once every 3 weeks (initiated 14 days to 8 weeks after TACE), or on-demand TACE alone, with TACE administered at the investigators' discretion. The randomisation sequence was generated by an independent biostatistician at the system vendor and was concealed from the sponsor study team and investigators until randomisation; allocation was stratified by baseline α-fetoprotein, prior locoregional therapy, and baseline Vp1/2 (and geographic region in earlier protocol versions). Primary endpoints were investigator-assessed TACE progression-free survival (TACE-PFS; time from randomisation to untreatable [unTACEable] progression, TACE failure or refractoriness, or death), and overall survival, both analysed in the intention-to-treat population. Overall survival was assessed under a prespecified adaptive (group sequential) design comprising two interim analyses and one final analysis. Safety was evaluated in the as-treated population, defined as all randomised patients who received any study treatment, analysed according to the treatment received. This study is registered with ClinicalTrials.gov (NCT04712643) and is ongoing. FINDINGS:Between Feb 23, 2021, and August 11, 2023, 342 patients were randomly assigned to TACE plus atezolizumab and bevacizumab (n=171) or on-demand TACE alone (n=171). Median age was 61·0 years (range 21·0-90·0), 66 (19%) of 342 participants were female, 276 (81%) were male, 308 (90%) were Chinese, and 34 (10%) were Japanese. The mean size of the largest target lesion per RECIST 1.1 was 7·7 cm (SD 4·3) in both arms. In the TACE plus atezolizumab and bevacizumab group, 36 (21%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 100 (58%) were stage B, and 35 (20%) were stage C; in the TACE alone group, 42 (25%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 105 (61%) were stage B, and 24 (14%) were stage C. At data cutoff (Feb 28, 2025; median follow-up 26·25 months [IQR 21·16-33·74]), median TACE-PFS was 11·30 months (95% CI 7·52-15·01) with TACE plus atezolizumab and bevacizumab versus 7·03 months (95% CI 5·32-8·41) with TACE alone (hazard ratio [HR] 0·71 [95% CI 0·55-0·92]; two-sided stratified log-rank p=0·0089). Overall survival remains immature and was assessed at the first of the prespecified interim analyses; median overall survival was 34·53 months (99·62% CI 24·80-not evaluable) in the TACE plus atezolizumab and bevacizumab group compared with 35·38 months (99·62% CI 24·74-not evaluable) in the TACE alone group (HR 0·96 [99·62% CI 0·58-1·58]). The most common grade 3-4 adverse events in the TACE plus atezolizumab and bevacizumab group were decreased platelet count (23 [14%] of 166), hypertension (23 [14%]), and post-embolisation syndrome (21 [13%]); in the TACE alone group, the most common were post-embolisation syndrome (23 [13%] of 173), decreased platelet count (12 [7%]), and increased aspartate aminotransferase (12 [7%]). The most common serious adverse event was ascites (eight [5%]) in the TACE plus atezolizumab and bevacizumab group and post-embolisation syndrome (six [3%]) in the TACE alone group. Treatment-related deaths occurred in five patients in the TACE plus atezolizumab and bevacizumab group (gastrointestinal haemorrhage, liver abscess, haemolytic anaemia, hypertension, and unknown death) and three patients in the TACE alone group (post-procedural haemorrhage, ascites, and unknown death). No new safety signals were identified. INTERPRETATION:On-demand TACE plus atezolizumab and bevacizumab significantly improved TACE-PFS versus on-demand TACE alone. Overall survival follow-up is ongoing. FUNDING:Shanghai Roche Pharmaceuticals.
BACKGROUND:Colorectal cancer is the third most common and second deadliest cancer in the USA, but cases and deaths are preventable through appropriate screening. Blood-based screening tests hold promise for increasing participation in colorectal cancer screening; however, their preventive effect remains limited if premalignant lesions are missed. Detection of advanced adenomas is essential to reduce both colorectal cancer incidence and mortality. The DENEB study aimed to develop and evaluate a novel blood-based assay for this purpose. METHODS:The DENEB study was an outcome-enriched case-controlled multicentre biomarker study, conducted according to the Early Detection Research Network phase I-III framework to discover circulating biomarkers associated with colorectal cancer and advanced adenomas (phase I) and then train (phase II) and test a blood-based assay (phase III) in non-overlapping cohorts. Discovery cohort 1 (n=274; March 16, 2010 to Dec 20, 2017; Barcelona, Spain) and discovery cohort 2 (n=307; Sept 9, 2013 to Dec 26, 2017; Tsu, Japan) and in silico cohorts (n=99, GSE39833, Japan; n=61, GSE25609, Spain; and n=107, GSE41655, China) were used for biomarker discovery; clinical cohort 1 (n=535; July 2, 2018, to Sept 27, 2023; Barcelona, Spain and Tsu, Japan) was used for training and clinical cohort 2 (n=230; July 2, 2018, to Sept 27, 2023; Barcelona, Spain and Tsu, Japan) for testing. In each cohort, data from average-risk individuals (aged 18-100 years) with colonoscopy findings from screening or diagnostic colonoscopy were included in the analyses, including data from treatment-naive patients with colorectal cancer recruited before surgery to enrich for this outcome. Individuals were classified according to their colonoscopy findings and histopathology as having colorectal cancers, advanced adenomas, low-risk adenomas, or as non-disease controls (negative colonoscopy findings). To develop the test, candidate miRNAs overexpressed in the blood of patients with colorectal cancer and adenomas were identified via small RNA sequencing in discovery cohorts 1 and 2. The in-silico cohorts were used as a biological validation and reproducibility filter. Only those biomarkers with significant overexpression in at least two of the discovery and in-silico cohorts were retained. The identified biomarkers were measured with reverse transcription quantitative PCR (RT-qPCR) in clinical cohorts 1 and 2. In clinical cohort 1, using an XGBoost machine-learning model, we built and locked two separate models (one for colorectal cancer and one for advanced adenomas) and established their diagnostic thresholds. These thresholds were then tested in clinical cohort 2. The primary outcome measures were sensitivity for colorectal cancer and advanced adenomas, and specificity for advanced neoplasia assessed in all eligible participants aged 45 years or older. This study is registered with ClinicalTrial.gov, NCT06342440. FINDINGS:The blood-based test developed through discovery and training interrogated the transcriptional expression of 19 cell-free and 20 exosomal miRNAs using RT-qPCR. In the testing cohort (clinical cohort 2), the test showed an area under the receiver operating characteristic curve of 95% (95% CI 92-98) for distinguishing colorectal cancers and advanced adenomas from non-disease controls. Sensitivity for colorectal cancer of any stage was 91% (95% CI 80-96; 89% [75-96] for males and 95% [75-99] for females), while sensitivity for stage I, II, or III colorectal cancers was 92% (80-97). Sensitivity for advanced adenomas was 81% (69-89; 82% [67-91] for males and 79% [57-92] for females). The specificity for advanced neoplasia was 85% (95% CI 77-90). Specificity for a negative colonoscopy was 83% (95% CI 72-91). INTERPRETATION:These findings provide the rationale for advancing this assay into large-scale prospective studies to determine its performance, clinical utility, and potential role within population-based screening strategies. FUNDING:National Institutes of Health and AIRC Foundation.
