A Phase 2a active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with nonalcoholic fatty liver disease

Background and aimsThis study assessed the effects of the GLP-1/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with nonalcoholic fatty liver disease (NAFLD).MethodsThis was a Phase 2a, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to open-label efinopegdutide 10 mg subcutaneous (SC) once weekly or semaglutide 1 mg SC once weekly for 24 weeks, stratified according to concurrent diagnosis of type 2 diabetes. Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment.ResultsAmong 145 randomized participants (efinopegdutide N=72, semaglutide N=73), 33.1% had T2DM. At baseline, mean body mass index was 34.3 kg/m2and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p<0.001) greater with efinopegdutide (72.7% [90% CI: 66.8, 78.7]) than with semaglutide (42.3% [90% CI: 36.5, 48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs semaglutide 7.1%; p=0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events.ConclusionsIn patients with NAFLD, treatment with efinopegdutide 10 mg weekly led to a significantly greater reduction in LFC than semaglutide 1 mg weekly. (EudraCT: 2020-005136-30; NCT: 04944992) IMPACT AND IMPLICATIONS: Currently, there are no approved therapies for nonalcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of nonalcoholic fatty liver disease (NAFLD) patients with the GLP-1/glucagon receptor co-agonist efinopegdutide at 10 mg weekly led to a significantly greater reduction in LFC compared with the GLP-1 receptor agonist semaglutide at 1 mg weekly, suggesting that efinopegdutide may be an effective treatment for NASH.Clinical trial numberEudraCT: 2020-005136-30; NCT: 04944992

Next-Generation Sequencing with a 54-Gene Panel Identifies Unique Mutational Profile and Prognostic Markers in Chinese Patients with Myelofibrosis

634. Myeloproliferative Syndromes: Clinical: Poster I: no. 1638Introduction and objectives: Myelofibrosis (MF) has the worst outcome amongst various myeloproliferative neoplasms. Its prognosis is determined by clinicopathologic features and mutations in key driver genes. An increasing number of gene mutations involving various biological pathways in myeloid malignancies has been discovered. The prognostic significance of these mutations have not been clearly defined. In this study, we aim to describe the genomic characteristic in a large cohort of MF patients and identify clinical and molecular predictors of outcome. Methods: We evaluated the genetic profile of 101 patients with MF (primary, N=70; secondary, N=30) using next-generation sequencing with a 54-gene panel comprising: ABL1, ASXL1, ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2. Multivariate cox regression analysis was used to determine prognostic factors for overall survival (OS) and leukemia-free survival (LFS). Results: We identified mutations in 39 genes implicated in myeloid malignancies (Figure 1A). 96 patients (95%) with MF had a mutation in 1 or more genes: 14 patients (13.9%) had 1 mutation, 38 patients (37.6%) had 2 mutations, 18 patients (17.8%) had 3 mutations, 15 patients (14.9%) had 4 mutations, 7 patients (6.9%) had 5 mutations and 4 patients (4%) had 6 or more mutations. TET2/JAK2V617F (16 patients, 15.9%), ASXL1/JAK2V617F (12 patients, 11.9%) and ASXL1/CALR (10 patients, 9.9%) were the most frequently co-mutated genes (Figure 1B). Other JAK2 variants occurred concomitantly with JAK2V617F in 10 patients (9.9%) and CALR mutations in 4 patients (4%) mutations. Other frequently concomitant mutations included CUX1/JAK2V617F (6 patients, 5.9%), EZH2/JAK2V617F (6 patients, 5.9%), RUNX1/JAK2V617F (5 patients, 5%), SF3B1/JAK2V617F (5 patients, 5%), SETBP1/JAK2V617F (4 patients, 4%) and ZRSR2/JAK2V617F (4 patients, 4%). The median follow-up of the cohort was 49 (1-256) months. The 5-year and 10-year OS were 66.3% and 35.4%. The 5-year and 10-year LFS of were 84% and 63.3%. There were no statistically significant differences in OS and LFS between primary and secondary MF. Significant negative prognostic indicators were identified on multivariate analysis, including male gender (P=0.044), age > 65 years (P=0.044), Hb < 10g/dL (P=0.001), mutated CUX1 (P=0.003) and mutated TP53 (P=0.043) for OS, and Hb < 10g/dL (P=0.007), mutated TP53 (P=0.043) and mutated IDH2 (P=0.001) for LFS. In primary MF, inferior prognostic indicators included male gender (P=0.031), Hb < 10g/dL (P=0.002), platelet count < 100 x 109/L (P=0.021), mutated TET2 (P=0.011) and mutated CUX1 (P=0.011) for OS; and Hb < 10g/dL (P=0.027), mutated RUNX1 (P=0.019) and mutated DNMT3A (P=0.004) for LFS. In JAK2V617F positive MF, inferior prognostic indicators included mutated ASXL1 (P=0.006) and mutated SRSF2 (P<0.001) for OS; and mutated U2AF1 (P=0.037) for LFS. Conclusion: Our study demonstrated unique molecular profiles and prognostic predictors of outcome in Chinese patients with MF