Benefits of prolonged-release pirfenidone plus standard of care treatment in patients with advanced liver fibrosis: PROMETEO study

Abstract

Background and aims Pirfenidone (PFD), an oral antifibrotic drug, has been authorized by the EMA and FDA for treatment of idiopathic pulmonary fibrosis. Few studies have addressed its use in advanced liver fibrosis (ALF). We evaluated a prolonged-release formulation (PR-PFD) plus standard of care on disease progression in ALF. Methods 281 ALF patients from 12 centers receiving PR-PFD (600 mg bid) were screened; 122 completed 1 year of treatment. Additionally, 74 patients received only standard of care regimen. Average age was 64 ± 12 years, 58% female. 43.5% had fatty liver disease (NAFLD), 22.5% viral hepatitis C (VHC), 17% autoimmune hepatitis (AIH), and 17% alcoholic liver disease (ALD). Baseline fibrosis was F4 in 74% and F3 in 26%. Antifibrotic effects were assessed by transient elastography (Fibroscan®) and Fibro Test® (FT); Cytokines and PFD plasma levels were tracked and quality of life evaluated. Results We found a significant reduction in fibrosis in 35% of PR-PFD patients and only in 4.1% in non PR-PFD patients. Child–Pugh score improved in 29.7%. Biochemical values remained stable; 40.6% and 43.3% decreased ALT or AST, respectively. TGFβ1 (pg/mL) levels were lower in PFD-treated patients. PFD serum concentration (µg/mL) was higher (8.2 ± 1.7) in fibrosis regression profile (FRP) patients compared to fibrosis progression profile (FPP) patients (4.7 ± 0.3 µg/mL, p < 0.01). 12% reported transient burning or nausea and 7% photosensitivity. Quality of life (Euro-Qol scale) improved from 62 ± 5 to 84 ± 3 (p < 0.001) and from 32 ± 3 to 42 ± 2 (p < 0.008) (FACIT scale). Conclusions PR-PFD is efficacious and safe in ALF and associated with promising antifibrotic effects. Trial registration Clinical trial number: NCT04099407.

Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment

“…However, this type of biomarkers, requiring more sophisticated techniques and all kinds of omics approaches, might show the way ahead to increase the accuracy over the currently available tools. To support biomarker development for the detection of liver fibrosis, two large projects, one in the United States of Amerika called Non-Invasive Biomarkers of Metabolic Liver Disease (NIMBLE), and one in Europe called the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS), have been set-up (196).…”

“…Several non-invasive markers of fibrosis have been used in several trials and mostly serve to support the data on histology. For example, in the pirfenidone (PFD) study, they evaluated the antifibrotic effects with, similarly, for the cenicriviroc (CVC) study where they used the NFS, FIB-4, APRI, and ELF scores (196,202).…”

“…In 35% of the patients, a significant reduction of fibrosis was seen, leading to the conclusion that PR-PFD is efficacious and safe in patients with advanced liver disease. Moreover, it showed promising antifibrotic effects (196). CVC, a drug that targets macrophages in the liver by inhibiting the C-C chemokine receptors CCR2 and CCR5 (232), met this endpoint as a key secondary endpoint in phase II after 1 year of treatment with an effect size of 9.6% (p = 0.023) but was not significant at 2 years and showed no efficacy on NASH resolution (202,233).…”

Obacunone Attenuates Liver Fibrosis with Enhancing Anti-Oxidant Effects of GPx-4 and Inhibition of EMT

“…Pirfenidone (PFD) is a pyridinone drug for idiopathic pulmonary fibrosis (IPF), while it also manifests a good therapeutic effect on liver fibrosis in multiple studies [ 22 , 23 ]. Thus, PFD is selected as a positive control medicine in this study.…”

Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

“…It is widely used in clinical practice for idiopathic pulmonary fibrosis [ 10 , 11 ]. Its anti-fibrotic properties have been evaluated in animal models of lung injury [ 12 , 13 ], kidney injury [ 14 ], and liver fibrosis [ 15 ], etc . Previous studies have established that PFD significantly suppresses TGF-β1-induced fibrosis [ 16 , 17 ] and decreases the expression of inflammatory factors including TNF-α and IL-6 [ 18 ].…”