Combined strategies for the treatment of NAFLD

The etiopathogenesis of NAFLD is quite complex. Many mechanisms seem to overlap with each other, making the development of the pathology a long, multifactorial process and, for this reason, still partly not fully understood. This concept also underlies the current failure to discover a treatment for this pathology. Many trials are in fact underway in different phases in an attempt to find an agent that can reduce the degree of fibrosis in patients with NAFLD and improve their clinical outcomes, in particular mortality. At the moment none of them have reached a level of safety and efficacy such that they can be effectively considered for large-scale therapy, which at the moment continues to be linked to the modification of the patient’s lifestyle. We know for sure that NAFLD development correlated with insulin resistance, lipotoxicity, systemic inflammation, and fibrogenesis [Ref 1].

The typical multifactoriality of this clinical condition is one of the concepts that keep pushing researchers to experiment integrated approaches for the cure of NAFLD, combining different agents that interact with the many mechanisms responsible for the development of NAFLD. The most recent of these attempts was recently published in the Journal of Hepatology. In this study by Alkhouri N et al. the safety and efficacy of the combined therapy with semaglutide, cilofexor and firsocostat were tested [Ref 2].

Semaglutide is a glucagon-like peptide 1 (GLP-1) analog that promotes glycemic control via several different mechanisms, including insulin secretion, slowing gastric emptying, and reducing postprandial glucagon secretion. The drug was approved in 2021 by the FDA and EMA for chronic weight management in diabetic adults with general obesity or overweight who have at least one weight-related condition [Ref 3].

Cilofexor (GS-9674) is a selective non-steroidal FXR receptor agonist that was tested in patients with primary sclerosing cholangitis and led to significant improvements in markers of cholestasis in these patients [Ref 4] which has also demonstrated anti-inflammatory and antifibrotic effects in experimental preclinical models. Its use in NAFLD was evaluated in a Phase II trial that showed that oral assumption of Cilofexor led to a significant reduction in serum ALP, GGT, AST/ALT compared to placebo [Ref 5].

Firsocostat is an allosteric inhibitor of the enzyme acetyl-CoA carboxylase. Pre-clinical data showed that Firsocostat inhibits fatty acid synthesis in cultured human hepatic cells, while in obese rats the use of this compound decreased hepatic steatosis and improved insulin sensitivity [Ref 6].

In this combination trial, 108 patients were randomized to either 24 weeks of treatment with semaglutide only (21 patients), semaglutide + cilofexor (22 patients at the dosage of 30 mg and 22 at the dosage of 100 mg), semaglutide + firsocostat (22 patients) or all three drugs combined (21 patients). The most common adverse events that were experienced were nausea, diarrhea, and pruritus, with similar rates across all groups. Semaglutide resulted in improvements in triglycerides, and total, LDL and VLDL cholesterol, while triglycerides levels increased in patients taking firsocostat. Moreover, all combinations were associated with improvements in liver biochemistry (in terms of ALT and inflammation levels) that were similar or greater than those observed with semaglutide monotherapy. As far as hepatic steatosis, assessed by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) is concerned, all combinations including cilofexor or firsocostat resulted in decreased levels in comparison with semaglutide monotherapy. Considering hepatic fibrosis, improvements in liver stiffness by transient elastography were observed in all groups, with greater reductions in firsocostat-treated patients [2]. These results seem promising, and a 72-week, phase IIb, randomised controlled trial is already planned to confirm the efficacy and safety of combination treatments including semaglutide, cilofexor and firsocostat in patients with NASH.

REFERENCES

1. Cariou B, Byrne CD, Loomba R, Sanyal AJ. Nonalcoholic fatty liver disease as a metabolic disease in humans: a literature review. Diabetes Obes Metab 2021;23(5):1069–1083.
2. Alkhouri N, Herring R, Kabler H, Kayali Z, Hassanein T, Kohli A et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: A randomised, open-label phase II trial. J Hepatol. 2022 Apr 16:S0168-8278(22)00235-5.
3. Ahren B, Atkin SL, Charpentier G, Warren ML, Wilding JPH, Birch S et al. Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials. Diabetes Obes Metab. 2018 Sep;20(9):2210-2219.
4. Trauner M, Gulamhusein A, Hameed B, Caldwell S, Shiffman ML, Landis C et al. The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology. 2019 Sep;70(3):788-801.
5. Schwabl P, Hambruch E, Budas GR, Supper P, Burnet M, Liles JT et al. The Non-Steroidal FXR Agonist Cilofexor Improves Portal Hypertension and Reduces Hepatic Fibrosis in a Rat NASH Model. Biomedicines. 2021 Jan 9;9(1):60.
6. Alkhouri N, Lawitz E, Noureddin M, DeFronzo R, Shulman GI. GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH). Expert Opin Investig Drugs. 2020 Feb;29(2):135-141.