Prolonged Release Pirfenidone Versus Placebo in Compensated Cirrhosis.

Liver cirrhosis represents a clear public health problem all over the world. In Mexico it ranks sixth as a cause of general mortality (third place in men and seventh in women) with 28,000 to 30,000 deaths per year, according to the latest National Institute of Statistics and Geography report. and the National Population Council.

Hepatic stellate cells are, to date, the main fibrogenic cells in the liver, thus becoming one of the most important therapeutic targets for treatment. Advances in the understanding of the molecular biology of the liver have allowed us to devise therapeutic strategies in order to avoid fibrosis and the consequent loss of liver function.

In 1994, a preliminary report was released publishing the antifibrotic properties of Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone, here and after PFD), a drug initially known for its analgesic and anti-inflammatory capabilities.

In 1995, its antifibrotic properties were described when administered in a hamster model with pulmonary fibrosis induced by bleomycin. Its mechanism of action was not completely well established at that time. It was known to be at the transcriptional level and was shown to modulate the deposition of extracellular matrix, the production of cytokines, growth factors and fibroblast proliferation. It is associated with the inhibition of the production and activity of tumor necrosis factor (TNF-α), transforming growth factor (TGF-ß), interferon-gamma and interleukin (IL) -6 and increases the production of anti-inflammatory cytokines such as IL-10.

The PFD molecule has shown promising effects both in vitro and in vivo in the prevention and treatment of idiopathic pulmonary fibrosis (IPF), in the prevention of capsular contracture after breast implants, renal interstitial fibrosis, in particular focal and segmental glomerulosclerosis or diabetic nephropathy and a wide range of conditions that share the phenomenon of abnormal scarring including hypertrophic and keloid scars, peritoneal adherences, neurofibromatosis and uterine fibromyomas. More recently it has also been evaluated in secondary and progressive variety multiple sclerosis, with promising results. In IPF, PFD has been positioned as the standard of care because it improves the outcomes, slowing down or blocking the decline of respiratory function and improving survival.

In models of liver fibrosis, PFD has also been shown to have antifibrotic activity. In experimental cirrhosis models in rats, it has been found that PFD decreases the levels of aminotransferases and bilirubins and stimulates cell regeneration. At the molecular level, a considerable decrease was also observed in the expression of pro-fibrogenic genes such as collagen I, III and IV, TGF ß-1, Smad-7, tissue inhibitor of metalloproteinases (TIMP-1) and plasminogen inhibitor 1 (PAI-1). In this way, it is known that PFD has various anti-inflammatory and antifibrotic properties, which have molecular support for its application as a potential treatment for liver cirrhosis.

Since 2000, the Mexican company Grupo Medifarma has manufactured the molecule 1-phenyl-5-methyl-2- (1H)-pyridone (PFD), hereinafter KitosCell ® LP in its plant located in Jiutepec, Morelos. Formulation details are confidential and protected by patent rights. However, the pharmacological components of the product are balanced and in sufficient concentration to achieve a stable product with homogeneous concentrations in the production batches. The stability of the KitosCell ® LP formula has been tested from a biochemical, biological and physical point of view. Additionally, the in vitro dissolution tests resulted within the expected physiological concentrations, as well as the sterility tests required by the Mexican Pharmacopeia. From a production point of view, Grupo Medifarma has the experience to demonstrate adherence to good manufacturing practices of the product under study in accordance with the requirements of the Ministry of Health.

Molecular biology studies have established that the mechanism of action of PFD is carried out at the transcriptional level, in the place where an interface occurs between the signals of specific genes or group of genes, which are being transmitted to the process by the following factors:

NF = transcriptional factor regulating the expression of proinflammatory genes. AP1 = a transcriptional factor that regulates expression of collagen proteins.

For all these reasons, PFD is considered a therapeutic resource for:

• Prevent the formation of fibrotic lesions.
• Reduce pre-existing fibrotic progression.
• Reverse fibrotic lesions.

As preclinical studies, studies were carried out in experimental models of cirrhosis in rats. There were 3 groups of rats: 1 control group and 2 groups with different doses of PFD (200 mg and 500 mg) per day, for 11 weeks. They were subsequently sacrificed and histopathological analysis of the liver showed a significant decrease in liver fibrosis in the groups that received PFD.

The first pilot clinical study to evaluate the effect of pirfenidone in patients with viral C liver fibrosis was carried out by J. Armendáriz-Borunda et al., at the Civil Hospital of Guadalajara in conjunction with the Institute of Molecular Biology in Medicine and Gene Therapy.

In this open pilot study, only 15 patients with liver fibrosis of various etiologies and different liver functional stages were included. Liver biopsies performed after 12 months suggested that in 53.3% of patients there was a reduction of two points or more in the necro-inflammatory index (HAI), 60% of steatosis decreased and 30% of fibrosis improved, while 70% regeneration activity was detected.

Problem Statement.

The present study aims to evaluate the efficacy, safety and pharmacodynamics of a formulation based on prolonged release Pirfenidone ( KitosCell® LP) , prepared by Grupo Medifarma, in two dosages (1200 mg and 1800 mg) vs. placebo plus conventional treatment for patients. with liver cirrhosis in the compensated phase with Child-Pugh functional class A and B (≤8 points) without a history of previous complications, of different causes .

The clinical tests aim to cover the international requirements for the development of a new drug under study (phases 1, 2 and 3) with antifibrotic effect. Therefore, if the safety and then the effectiveness of the product are demonstrated, a new therapeutic strategy can be offered for this complex health problem.

Justification of the Study.

Liver cirrhosis is the fifth cause of general mortality in our country, with around 28,000 deaths each year. To date, there is no proven effective therapy that allows reversing or inhibiting the fibrogenic process. This complex disease impacts the economically active population, causing great losses by causing work incapacity as well as the morbidity and mortality that it entails. The investigators consider that it is desirable to carry out a study, with a controlled and double-blind design that allows us to provide new knowledge of the efficacy and safety of the drug under study, in accordance with the recently published recommendations of the American Association for the Study of Liver Diseases (AASLD). by Natalie J. Torok and collaborators (Jan 27, 2015).