Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis. METHODS: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing. FINDINGS: Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred. INTERPRETATION: Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials. FUNDING: Akero Therapeutics.

Treating hepatocellular carcinoma without liver transplantation.

Hepatocellular carcinoma, a significant health problem throughout the world, generally occurs in the setting of cirrhosis. Choice of treatment depends on the size and location of the tumor and hepatic reserve. Liver transplantation provides the best chance for long-term survival and can be performed regardless of hepatic reserve, but it requires small tumor sizes and is available to only a few patients. All other treatments require adequate hepatic reserve. Surgical resection, percutaneous ethanol injection, and radiofrequency ablation are effective treatments for patients with good hepatic reserve and small tumors isolated to the liver. For larger and multinodular tumors, chemoembolization is the best choice. With metastasis, portal vein invasion, or large bilobar disease and intact hepatic function, modest improvements in survival have occurred with the use of sorafenib, a recently approved targeted chemotherapy agent. Patients with poor hepatic function or low performance status should receive only supportive care.

Malignant mediastinal lymphadenopathy detected by staging EUS in patients with pancreaticobiliary cancer.

BACKGROUND: In patients with pancreatic cancer, the presence of malignant mediastinal lymphadenopathy (MML) would preclude definitive resection. A recent study suggested routine evaluation for mediastinal lymph-node metastases in all patients being evaluated for pancreaticobiliary masses. In our practice, we routinely assess for mediastinal lymph-node metastases in all patients undergoing EUS for pancreaticobiliary cancer. METHODS: We retrospectively evaluated the presence of MML by EUS-guided FNA (EUS-FNA) in 160 consecutive patients with a definite diagnosis of pancreaticobiliary cancer (pancreatic and periampullary cancers) who underwent EUS-FNA by a single operator from 2000 to 2004. Lymph nodes that were round and hypoechoic with sharp margins were considered suspicious and were sampled by FNA. RESULTS: Of the 160 patients included in this study, 78 had peripancreatic lymph nodes (49%: 95% CI[41%, 58%]), 25 had celiac lymph nodes (16%: 95% CI[10%, 22%]), and 14 patients had mediastinal lymph nodes (9%: 95% CI[4%, 13%]) that were suspicious for malignancy by morphologic criteria. In 8 of 14 patients with suspicious mediastinal lymph nodes, FNA documented MML in 5%: 95% CI[2%, 8%]. Only one of these 8 patients with MML had other sites of documented distant metastases by CT and/or positron emission tomography scans. However, 7 of 8 patients had locally advanced cancers. CONCLUSIONS: MML is detected by staging EUS-FNA in 5% of patients with pancreaticobiliary cancer. Because of its important implications, endosonographers should routinely assess for MML in patients who undergo staging EUS for pancreaticobiliary malignancy.