Primary Biliary Cholangitis (PBC) is a cholestatic autoimmune liver disease of small bile ducts. Ursodeoxycholic acid (UDCA) was approved as a first line therapeutic option for PBC in 1997. It was later noted that 40
BACKGROUND:The growing prevalence of metabolic dysfunction-associated steatohepatitis (MASH) underscores the unmet need for effective and safe liver-targeted therapies to prevent fibrosis and disease progression. The aim of this study was to evaluate the efficacy and safety of efimosfermin alfa (henceforth referred to as efimosfermin, formerly BOS-580), an FGF21 analogue taken once per month, in patients with MASH and moderate or advanced fibrosis. METHODS:This 24-week, randomised, double-blind, placebo-controlled, phase 2 trial evaluated the safety and efficacy of efimosfermin in participants aged 18-75 years with a BMI of at least 27 kg/m2 and MASH and F2 or F3 fibrosis present on a diagnostic liver biopsy done either during screening or within 6 months before the first day of dosing, and total activity Nonalcoholic Fatty Liver Disease Activity Score (NAS) of at least 4 with a minimum score of 1 point for all three NAS components (steatosis, hepatocyte ballooning, and lobular inflammation). The trial was conducted at 34 clinical research study sites in the USA. Participants were randomly assigned 1:1 to efimosfermin 300 mg or placebo administered by subcutaneous injection every 4 weeks (Q4W) over 24 weeks, stratified by MASH fibrosis stage (F2 vs F3 stage). Participants, investigators, and those assessing outcomes were masked to group assignment. The primary endpoint was safety and tolerability (ie, treatment-emergent adverse events, changes from baseline to week 24 in blood pressure and heart rate, and the incidence of grade 3 and grade 4 laboratory abnormalities at week 24), analysed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov (NCT04880031) and was completed on Sept 18, 2024. FINDINGS:Between May 4, 2023, and March 22, 2024, of 1171 participants screened, 84 participants were randomly assigned to efimosfermin 300 mg Q4W (n=43) or placebo (n=41); 44 (52%) were female and 40 (48%) were male. 48 (57%) had F2 fibrosis and 36 (43%) had F3 fibrosis; 65 had evaluable week-24 biopsy results. All 43 in the efimosfermin group and 40 of 41 participants in the placebo group received at least one dose. Adverse events were reported in 29 (67%) of 43 participants receiving efimosfermin and 22 (55%) of 40 receiving placebo. The majority of treatment-emergent adverse events were mild (24 [56%] of 43 in the efimosfermin group vs 15 [38%] of 40 in the placebo group) or moderate (18 [42%] vs 14 [35%]) in severity. Most frequent adverse events were gastrointestinal events, which were transient and occurred within the first few weeks of treatment. There were no clinically meaningful changes in vital signs between treatment and placebo groups, and no clinically significant grade 3 or higher laboratory abnormalities observed for either group. No deaths or adverse events greater than grade 3 were observed during the study. INTERPRETATION:In this phase 2 trial, treatment with efimosfermin once per month was generally well tolerated in participants with biopsy-confirmed MASH and F2 or F3 fibrosis. These results support the further development of efimosfermin for treatment of MASH-related fibrosis. FUNDING:Boston Pharmaceuticals and GSK.
HFE -related hemochromatosis (HC) is caused by hepcidin dysregulation and is characterized by excessive iron absorption and accumulation in the liver, heart, and endocrine glands, which leads to complications including arthropathy, cirrhosis, and hepatocellular carcinoma. Standard of care (SoC) typically involves phlebotomy, with iron chelators used less frequently. However, these therapies may cause side effects and negatively impact quality of life, making them troublesome for some patients. Using the Delphi methodology, a survey was developed to identify unmet needs and clinical challenges within the current therapeutic landscape of HC, and to establish consensus statements for its management. Consensus was defined as ≥75% agreement. Thirty-two HC specialists from Europe, Australia and the USA responded to the survey. After three rounds of survey refinement, final consensus statements were compiled. The Delphi process identified key unmet needs in HC, including lack of alternatives to phlebotomy, persistent symptoms, and burden related to the use of current SoC. The consensus process helped establish definitions for high phlebotomy treatment burden, intolerance, and suboptimal response to phlebotomy. The process also identified the subgroup of patients overly burdened by phlebotomy. Patient-reported outcomes were considered key to assessing phlebotomy’s impact, although they are rarely measured in clinical practice. The Delphi study highlighted the limitations of phlebotomy, with respondents identifying a high unmet need for patients who cannot be managed with or do not tolerate this approach. The study suggested exploring alternative therapy options for patients who experience high treatment burden or intolerance to phlebotomy.
Aim: Primary biliary cholangitis (PBC) is a rare liver disease associated with high morbidity. This study assessed the burden of fatigue and/or pruritus among patients with PBC in the US. Materials & methods: This retrospective study used IQVIA PharMetrics® Plus data (2016-2022). Patients with PBC and fatigue and/or pruritus were selected as cases. Controls were patients with PBC (no fatigue nor pruritus), matched 1:1 to cases by key characteristics. The index date for cases was a random symptom diagnosis date post-initial PBC diagnosis and for controls, a random medical visit date matching the time distribution from initial PBC diagnosis to index. Cumulative incidence of PBC comorbidities was described using Kaplan-Meier analysis and compared via Cox Proportional hazard models. Generalized estimating equations compared healthcare resource use (HRU) and costs per-patient-per-year. Results: A total of 1839 fatigue cases/controls (mean age [years]: 56.5; 88.7% female) and 760 pruritus cases/controls were included (mean age [years]: 55.8; 90.8% female). Comorbidities at 1, 3 and 5-years post-index were higher for cases than controls (fatigue: 1.7 vs 0.7, 2.2 vs 0.9 and 2.5 vs 1.0; pruritus: 1.9 vs 0.8, 2.3 vs 1.0 and 2.7 vs 1.0; all p < 0.001). Common comorbidities were anxiety, urinary tract infection, depression and sleep disorders (hazard ratios in cases vs controls: fatigue, 1.3-4.0; pruritus, 1.5-2.8; all p < 0.01). One-year post-index, cases had higher rates of healthcare visits (incidence rate ratios: fatigue, 1.8-5.8; pruritus 1.6-6.1) and total healthcare costs (mean cost difference: fatigue, $42,515; pruritus $40,536). Conclusion: Patients with PBC who experience fatigue and/or pruritus faced a greater clinical and economic burden compared with those without these symptoms, highlighting the need for effective treatments to alleviate PBC symptoms.
Abstract Background: This umbrella review synthesizes evidence from meta-analyses and reviews comparing transarterial chemoembolization (TACE) combined with sorafenib versus monotherapy for unresectable hepatocellular carcinoma. Methods: Following PRIOR guidelines, PubMed, Google Scholar, Web of Science, and Embase were searched from inception to December 2024. Outcomes included overall survival (OS), time to progression (TTP), disease control rate (DCR), and objective response rate (ORR). Corrected covered area (CCA) assessed overlap, and methodological quality was evaluated using AMSTAR-2. Results: Of 13,821 records, 9 meta-analyses were included, with substantial overlap (CCA: 49%). Eight reviews assessed OS; five reported a significant survival benefit (hazard ratio [HR] 0.62–0.74, p < 0.001), while two found no significant effect (HR 0.75–0.97, p > 0.05). Eight evaluated TTP; six showed a significant reduction in risk (HR 0.61–0.75, p < 0.05), while two reported non-significant findings (HR 0.74–0.77, p > 0.05). Four assessed DCR; two reported a significant benefit (odds ratio [OR] 0.52–4.72, p < 0.01), one showed a non-significant trend (OR: 1.57, p = 0.06), and one found no significant effect (relative risk [RR] 1.04, p = 0.57). Six assessed ORR; three reported a significant increase in response (OR 2.19–3.59, p < 0.01), one showed a significant reduction (OR 0.85, p < 0.001), one found no significant effect (RR 1.20, p = 0.26), and one reported a significant protective effect (OR 0.39, p = 0.008). Conclusions: TACE plus sorafenib improves TTP, ORR, and OS in unresectable HCC and highlights the need for personalized treatment and further research.
