Semaglutide (SEMA), FXR agonists and ACC inhibitors are under active clinical investigation for the treatment of NASH. Here, we explored whether the effects of SEMA (0.12 mg/kg, s.c., q.d.) on NASH endpoints could be enhanced by addition of an FXR agonist (cilofexor, CILO; 30 mg/kg) and/or an acetyl-CoA carboxylase inhibitor (firsocostat analogue, ACCi; 5 mg/kg, both p.o., q.d.) in the AMLN diet-induced and biopsy-confirmed DIO-NASH mouse (n=15-16/group). After 12 weeks of treatment, SEMA and triple therapy reduced body weight 18%, being slightly enhanced in the double combination of SEMA+CILO (21%). Liver triglyceride concentration was reduced by SEMA (by 38% vs. vehicle, p<0.001). Addition of CILO or ACCi or both to SEMA further reduced liver lipid by 64%, 73% and 81%, respectively (all p<0.001 vs. SEMA). Histopathological pre-to-post NAFLD activity score (NAS) was reduced in 3/16 (19%) of vehicle controls and in all mice (100%) treated with SEMA or triple therapy. Further, the number of mice that exhibited a 3+ point improvement in NAS was improved with the triple combination (12/16; 75%) vs. SEMA alone (2/16, 13%). Likewise, the triple combination caused the greatest improvements in fibrosis stage pre-to-post (7/16, 44%, improved; 1/16 worsened), followed by the SEMA-treated group (6/16, 38% improved; 0/16 worsened) relative to vehicle (2/16, 13% improved; 7/16, 44% worsened). Collagen-1a and a-SMA immunoreactivity (% area) tended to be or were significantly improved with SEMA (4.2%; n.s., and 1.4%; p<0.001) and triple therapy (3.9%; p<0.045 and 0.9% p<0.001) vs. vehicle (6.3% and 4.6%). SEMA significantly improved NAS and fibrosis endpoints. While addition of either single agent improved liver fat reduction, triple therapy improved pre-to-post NAS and fibrosis stage relative to SEMA alone in DIO-NASH mice. These data support development of combination approaches for NASH.


J. Norlin: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. D.A. Miranda: None. J.G. Bates: Employee; Self; Gilead Sciences, Inc. N.E. Zois: Employee; Self; Gubra. S. Veidal: None. M. Feigh: None. J.L. Trevaskis: Employee; Self; Gilead Sciences, Inc. M. Latta: Employee; Self; Novo Nordisk A/S.

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