Molecular basis and clinical endopoints for the development of antifibrogenic drugs

The last two decades have witnessed a considerable progress in the understanding of the mechanisms responsible for the fibrogenic progression of chronic liver diseases. However, no drugs have been approved as antifibrotic agents in humans. Considering the central role attributed to hepatic stellate cells (HSCs) in liver fibrosis, this cell type has represented, and still represents, a major focus of antifibrotic research. Indeed, the well-described pathway of HSC activation, subsequent fibrogenesis, with the potential for apoptosis and reversibility, provides a logical framework to define the sites of intervention. Consequently, the search for effective antifibrogenic strategies is based on the knowledge gained in the area of HSC biology, including the biology of the factors (growth factors, cytokines, etc.) conditioning their pro-fibrogenic attitude. Regardless, it is absolutely clear that the best antifibrogenic treatment would be represented by any strategy able to eliminate the primary cause of parenchymal damage, metabolic overload or excessive oxidative stress. Since the fibrogenic process is essentially a compensatory phenomenon aimed at maintaining a sufficient tissue continuity and cohesion in the presence of a continuous microscopic parenchymal collapse, it would be erroneous to attempt to cure fibrogenic chronic liver diseases (CLDs) only with antifibrogenic drugs, once some effective compounds will become available for clinical use. Once this primary requirement is fulfilled, the association with an antifibrogenic drug would be relevant for stabilising the cure and favour an optimal remodelling. Putative antifibrogenic drugs include:

It should be stressed that most of the evidence indicating a beneficial effect of these drugs derives from the studies performed in vitro or in animal models of fibrogenesis. Therefore, it is still debatable whether or not these agents could be truly effective. Considering the above limitations, it is about time to select some of the most promising agents emerging from preclinical studies and start testing their clinical efficacy. However, testing for clinical efficacy may prove difficult and expensive. Appropriate end-points for studies need to be defined and agreed as the timeframe for regression of fibrosis is likely to be adequately measurable only in years. Consequently, the relative need to set long-term prospective studies represents a major limitation for the enthusiasm of researchers embarking on this task. Since all CLDs are in general characterised by a very slow course to cirrhosis, the above-mentioned limitations contrast with the possibility that any suitable antifibrogenic treatment could effectively render the fibrogenic evolution even slower and eventually reduce the number of patients reaching end-stage disease within a reasonable life timeframe.

Appropriate end-points for studies need to be defined and agreed upon, as the timeframe for regression of fibrosis is likely to be adequately measurable only in years. In addition, considering that the majority of CLDs are consequent to chronic hepatitis B and hepatitis C virus (HBV and HCV, respectively) infection, any ethically correct study involving a potentially antifibrogenic drug would need to introduce the drug in association with the current standard treatment (e.g., IFNα, ribavarin, etc.), whose end-points do not necessarily include reduction of fibrosis. The following groups of patients could be proposed as ‘ideal’ for clinical trials investigating the therapeutic efficacy of antifibrogenic strategies:

(1)Patients with rapidly progressing fibrosis such as those with HCV re-infection after liver transplant or with HCV–HIV co-infection. In these patients the duration of clinical trials could be reduced to 1–2years because of the more rapid progression.

(2)Patients identified as non-responders to the standard treatment who have reached a stage of advanced fibrosis. In these patients, the use of imaging techniques and the measurement of HVPG could be instrumental in demonstrating a down-staging of disease progression.

(3)Patients with non-alcoholic steatohepatitis (NASH), for whom no well-defined standard treatment is available as yet.

For practical purposes, the antifibrogenic compounds proposed thus far can be classified as ‘direct’ and ‘indirect’. We define ‘direct’ antifibrogenic agents as those compounds that are able to directly modulate gene expression and/or the synthesis of fibrillar ECM components (in most cases pro-collagen type I) or those that able to induce their degradation. The term ‘indirect’ antifibrogenic agents defines some compounds affecting the deposition of fibrillar ECM indirectly, that is, through the inhibition of other pro-fibrogenic features of HSCs, such as proliferation and motility, or through the induction of HSC apoptosis.

A distinct class of drugs with a potential multi-task action in patients with CLDs is represented by the so-called ‘antioxidants’. This class includes compounds thought to reduce the pro-fibrogenic effects of reactive oxygen intermediates (ROIs) and/or reactive aldehydes, including acetaldehyde. Although some of these agents are commonly classified as antioxidants and free-radical scavengers, their antifibrogenic activity could rather be ascribed to a direct effect on the expression/synthesis of ECM components. Regardless, the real effectiveness of antioxidant agents is questionable because of their limited bioavailability. Another class of potentially useful agents concerns the so-called ‘herbal drugs’. It is likely that some progress in the treatment of fibrosis in CLDs will derive from a better characterisation and definition of the active moieties present in herbal mixtures according to Western medicine standards. Indeed, with the exception of sylimarine, most herbal agents were and are still proposed as mixtures derived from traditional Chinese medicine. Therefore, in general, it is impossible to ascertain the active moiety responsible for the antifibrogenic effect. However, recent studies have started addressing this issue and some active moieties have been identified and characterised.