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

Jorge Luis Poo, Aldo Torre, Juan Ramón Aguilar-Ramírez, Mauricio Cruz, Luis Mejía-Cuán, Eira Cerda, Alfredo Velázquez, Angélica Patiño, Carlos Ramírez-Castillo, Laura Cisneros, Francisco Bosques-Padilla, Larissa Hernández, Frida Gasca, Francisco Flores-Murrieta, Samuel Treviño, Graciela Tapia, Juan Armendariz-Borunda, Linda E Muñoz-Espinosa, Jorge Luis Poo, Aldo Torre, Juan Ramón Aguilar-Ramírez, Mauricio Cruz, Luis Mejía-Cuán, Eira Cerda, Alfredo Velázquez, Angélica Patiño, Carlos Ramírez-Castillo, Laura Cisneros, Francisco Bosques-Padilla, Larissa Hernández, Frida Gasca, Francisco Flores-Murrieta, Samuel Treviño, Graciela Tapia, Juan Armendariz-Borunda, Linda E Muñoz-Espinosa

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.

Keywords: Antifibrotic; Cirrhosis; Elastography; Fibrosis; Fibrosis-progression; Fibrosis-regression; Fibrotest; Liver; Pirfenidone; Prolonged-release pirfenidone.

Conflict of interest statement

The study was conducted in compliance with the International Standard GCP procedures and the principles of the Declaration of Helsinki. The protocol and informed consent form were approved by a local IRBs and registered in clinical trials.gov (NCT04099407).

Figures

Fig. 1
Fig. 1
Inclusion and exclusion criteria
Fig. 2
Fig. 2
a Statistical significance was analyzed by Student’s t test, p = 0.023, compared to baseline values. b Statistical significance was analyzed by Student’s t test, p = 0.0001, compared to baseline values

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