Once-monthly efimosfermin for non-cirrhotic MASH.

# Once-monthly efimosfermin for non-cirrhotic MASH *The Lancet 2026* Comment Once-monthly efimosfermin for non-cirrhotic MASH Metabolic dysfunction-associated steatotic liver and MASH resolution without worsening of fibrosis. disease (MASLD) has become the leading cause of liver 84 participants were randomised, although only disease worldwide, affecting one in three people.1,2 65 (77%) underwent week 24 follow-up liver biopsy.11 The inflammatory form of MASLD, namely metabolic The mean age of participants was 53·7 years (SD 10·9), steatohepatitis (MASH), can progress to liver fibrosis BMI was 37·3 kg/m2 (5·8), 44 (52%) were female and and is the most rapidly rising cause of cirrhosis and 40 (48%) were male, 62 (74%) were Hispanic or Latino, hepatocellular carcinoma, especially in women.1 In 48 (57%) had type 2 diabetes, and 36 (43%) had fibrosis the past 2 years, the THR-β agonist resmetirom and stage F3. the GLP-1 receptor agonist semaglutide were the first Efimosfermin achieved higher rates of fibrosis drugs to receive conditional approval for treating non- improvement—defined as at least one stage cirrhotic MASH.3,4 However, additional therapies capable regression without worsening of MASH— Published Online February 5, 2026 of halting or reverting MASH progression in at-risk compared with placebo (14 [45%] of 31 participants https://doi.org/10.1016/ individuals with diverse MASLD subtypes remain an vs seven [21%] of 34; p=0·038), and higher rates of MASH S0140-6736(25)02431-6 urgent unmet medical need.1,5 resolution (21 [68%] vs ten [29%]; p=0·002). Results See Articles page 794 Fibroblast growth factor 21 (FGF21) analogues are in the intention-to-treat population were generally a novel drug class with potent effects on hepatic fat consistent. Notably, 17 (50%) of 34 efimosfermin- accumulation that showed encouraging results on MASH treated participants achieved a ≥50% reduction in HFF resolution and fibrosis improvement,1 even in advanced compared with two (6%) of 31 in the placebo group stages of the disease,6–8 and a favourable effect on the (p<0·001), and 11 (32%) versus one (3%) reached liver fat metabolic profile.9 Efimosfermin alfa (efimosfermin; normalisation (≤5% hepatic fat content; p=0·003). Results formerly BOS-580) is a long-acting FGF21 analogue of non-invasive biomarkers of fibrosis were aligned with administered every 4 weeks by subcutaneous injection. histological outcomes, with efimosfermin inducing larger Engineered through fusion with an IgG1 Fc fragment and reductions in the Enhanced Liver Fibrosis score, Pro-C3, stabilising mutations, efimosfermin overcomes the short and liver enzymes, although the modification in liver half-life of endogenous FGF21. stiffness measurement was not significant. Improvements Previously, in a 12-week phase 2a randomised in lipids and glycaemic control were in line with a broader controlled trial (RCT), escalating doses of efimosfermin cardiometabolic benefit of efimosfermin.11 decreased hepatic fat fraction (HFF) in people with Efimosfermin had a generally well tolerated safety obesity and MASH, aligning with the efficacy of other profile.11 Most treatment-emergent adverse events FGF21 analogues.10 Specifically, all participants randomly were mild to moderate and gastrointestinal in nature, assigned to efimosfermin 300 mg every 4 weeks had consistent with previous FGF21 analogues studies. Bone a ≥30% HFF decline, which is associated with a higher biomarkers did not significantly differ between groups, likelihood of fibrosis regression than a <30% HFF decline.10 no fractures occurred, and CTX (a bone resorption In The Lancet, Mazen Noureddin and colleagues report biomarker) remained within the reference range in the results of a phase 2a RCT investigating the safety and postmenopausal female participants. Although FGF21 efficacy of efimosfermin in people with severe overweight, promotes bone reabsorption,12 longer-term data will metabolic dysfunction, and biopsy-confirmed MASH with be needed to fully assess efimosfermin’s safety on bone F2 or F3 fibrosis.11 The study design included a 24-week health. Only one (2%) of 41 evaluable participants in the blinded, placebo-controlled randomised phase (1:1 ratio efimosfermin group developed anti-drug antibodies, of efimosfermin 300 mg every 4 weeks to placebo), but their presence did not affect pharmacokinetics, followed by an open-label extension (not reported in the pharmacodynamics, or safety in this participant.11 Article), and was conducted in 34 sites in the USA. The Together, these findings support continued develop- primary endpoint was safety and tolerability, and key ment of efimosfermin for MASH-related fibrosis. Indeed, exploratory endpoints included fibrosis improvement achieving fibrosis improvement by one stage or more by one or more stage without worsening of MASH without worsening of MASH in 45% of patients after yrarbiL otohP ecneicS aiv ygolohtapbeW Comment just 24 weeks of efimosfermin is a remarkable result Department of Pathophysiology and Transplantation, Università degli Studi di and a notable strength of the study. The once-monthly Milano, Milan, Italy (LV); Precision Medicine-Biological Resource Center, Transfusion Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore regimen could enhance treatment adherence and reduce Policlinico, Milan 20122, Italy (LV, GP) burden for patients, an important consideration in 1 Targher G, Valenti L, Byrne CD. Metabolic dysfunction-associated steatotic liver disease. N Engl J Med 2025; 393: 683–98. chronic metabolic liver disease. 2 Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global Current limitations are mainly related to the small epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 2023; 77: 1335–47. sample size and short follow-up. In future studies, it 3 Petta S, Targher G, Romeo S, et al. The first MASH drug therapy on the will be important to examine the relative benefit of horizon: current perspectives of resmetirom. Liver Int 2024; 44: 1526–36. 4 Petta S, Kim K, Targher G, et al. Focus on semaglutide 2.4 mg/week for the efimosfermin in clinically relevant MASLD subtypes— treatment of metabolic dysfunction-associated steatohepatitis. Liver Int for example, those based on type 2 diabetes, the use 2025; 45: e70407. 5 Mancina RM, Valenti L, Romeo S. Human genetics of steatotic liver disease: of other medications that effect MASH (eg, incretin insights into insulin resistance and lipid metabolism. Nat Metab 2025; 7: 2199–211. receptors agonists and SGLT2 inhibitors1), fibrosis 6 Noureddin M, Rinella ME, Chalasani NP, et al. Efruxifermin in compensated stage, sex, and genetic background.5 Results of larger liver cirrhosis caused by MASH. N Engl J Med 2025; 392: 2413–24. 7 Noureddin M, Frias JP, Neff GW, et al. Safety and efficacy of once-weekly phase 3 studies (ZENITH-1 [NCT07221227] and efruxifermin versus placebo in metabolic dysfunction-associated ZENITH-2 [NCT07221188] in patients with non-cirrhotic steatohepatitis (HARMONY): 96-week results from a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet 2025; MASH) are therefore awaited to substantiate these 406: 719–30. initial promising findings and the long-term safety 8 Loomba R, Sanyal AJ, Kowdley KV, et al. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH. N Engl J Med 2023; 389: 998–1008. of efimosfermin, including in people with cirrhosis. 9 Lin RT, Sun QM, Xin X, et al. Comparative efficacy of THR-β agonists, FGF-21 Efimosfermin could soon expand therapeutic options analogues, GLP-1R agonists, GLP-1-based polyagonists, and pan-PPAR agonists for MASLD: a systematic review and network meta-analysis. for people with MASH-related fibrosis, but supporting Metabolism 2024; 161: 156043. 10 Loomba R, Kowdley KV, Rodriguez J, et al. Efimosfermin alfa (BOS-580), evidence of its efficacy and long-term safety in larger a long-acting FGF21 analogue, in participants with phenotypic metabolic phase 3 trials will be crucial before its integration into dysfunction-associated steatohepatitis: a multicentre, randomised, double- blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol 2025; clinical practice. 10: 734–45. 11 Noureddin M, Kowdley KV, Odrljin T, et al. Efimosfermin alfa (BOS-580) LV declares speaker fees from Viatris, Novo Nordisk, and GSK; consulting fees once per month in people with metabolic dysfunction-associated from Novo Nordisk, Pfizer, Boehringer Ingelheim, Resalis, GSK, Almac, and AIRNA; steatohepatitis with F2 or F3 fibrosis: results from a 24-week, randomised, and travel support from Novo Nordisk. GP declares no competing interests. double-blind, placebo-controlled, phase 2 trial. Lancet 2026; published online Feb 5. https://doi.org/10.1016/S0140-6736(25)02276-7. *Luca Valenti, Giulia Periti 12 Tang Y, Zhang M. Fibroblast growth factor 21 and bone homeostasis. luca.valenti@unimi.it Biomed J 2023; 46: 100548. Venezuela’s health system: when force meets fragility Published Online The US military strikes on Venezuela on Jan 3, 2026 were never fully consolidated, and chronic underfunding, February 5, 2026 and seizure of the country’s President Nicolás Maduro political instability, and economic mismanagement https://doi.org/10.1016/ S0140-6736(26)00203-5 represent a profound shock to a health system already in have left it barely operational. The country has faced See Editorial Lancet 2026; collapse. With US President Donald Trump asserting that severe health and humanitarian challenges (panel).3–12 407: 547 the US Government will run Venezuela for an unspecified In Venezuela, public expenditure on health fell to about period,1 the question is stark: will this claimed stabilisation 1·7% of gross domestic product (GDP) by 2018,3 well help restore essential health services or will it deepen under the Latin American average of approximately disruption and affect the most vulnerable populations? 4%, and far short of the 6% of GDP recommended by Venezuela’s health system was historically built on a the Pan American Health Organization and WHO as mixed public–private model with aspirations towards a benchmark for effective health systems.4 By March, universal health coverage. The flagship Barrio Adentro 2020, more than half of public hospital beds were programme, launched in 2003 with Cuban medical already inoperable due to health system and supply personnel, initially expanded primary care access for chain limitations.5 A reversal of decades of public underserved communities and reduced barriers to health gains has driven malaria cases to nearly 1 million essential services.2 However, the system’s foundations annually,6 alongside the re-emergence of measles and 740 --- [PDF原文](https://sci-net.xyz/storage/7286337/c8a8aa588d381560595b3e1da32aea7303d75e496885d6239fb4fe01b1c6f6ee/Once-monthly-efimosfermin-for-non-cirrhotic-MASH.pdf) DOI: 10.1016/S0140-6736(25)02431-6