WHERE ARE DRUGS FOR TREATMENT OF IPF (IDIOPATHIC PULMONARY FIBROSIS)?_

During the last decade extensive research has been conducted on IPF and therapeutic approaches to treat this condition. New targets for drug development, as well as new leads, were identified. However, there are still no FDA-approved drugs for the treatment of this condition

There have been several barriers to the development of effective therapeutics for IPF. One is the fact that IPF is considered an orphan disease because of its prevalence, lessening the urgency for finding a cure. Moreover, the pharmaceutical industry underestimates the medical need and the potential profitability of antifibrotic drugs. Because the population in developed countries is rapidly aging, IPF is becoming a more common disorder. It is anticipated that companies will begin to look more favorably on drug development in this area as it is becoming apparent that fibrotic diseases as a group may share the same therapeutic targets. In this case, drugs developed for the treatment of pulmonary fibrosis may be useful in the therapy of renal, myocardial, hepatic and other fibrotic diseases as well, broadening the use of such agents.

The complexity of fibrogenesis and the multiplicity of profibrotic and antifibrotic factors, are other reasons for the failure to develop effective drugs. With the advancement of basic research in fibrosis many new targets for drug development have been discovered. However, these discoveries have yet to be translated through to drug discovery and clinical testing. In addition, the consolidation of the pharmaceutical industry has resulted in more focused research programs and less enthusiasm for undertaking higher risk projects that lack “proof of concept”.

There is also a justifiable skepticism about the relevance of the in vitro or animal research methodology that is currently used in drug discovery. The findings of cell culture experiments are not always applicable to the whole organism, and results obtained in mice or rats may not be relevant to humans. Although the bleomycin-induced fibrosis in rodents test tends to identify false positive leads, it might be most relevant in the “therapeutic” rather than the “preventive” protocol. Animal models are often more sensitive than patients in clinical trials, as experimental animals are homogenous in genetic background, sex, age, weight, general health and diet. Compounds which are safe and effective at reasonable doses in a “therapeutic” protocol of bleomycin-induced fibrosis should be considered for optimization and eventual clinical evaluation.

Lack of patentability, toxicity, ignorance of the molecular target or questionable “drugability” of potential antifibrotic drugs are common barriers to their development. In today’s highly competitive environment, few companies are willing to pay for the development of a generic agent like N-acetyl cysteine for the treatment of IPF without proprietary protection. Also, some of the drugs identified as antifibrotics belong to chemical classes known for their toxicity, extensive metabolism, or poor bioavailability and, therefore, are not considered good candidates for development.

It is conceivable that a blockade of only one profibrotic factor cannot stop or reverse fibrogenesis. A drug combination product designed to affect multiple fibrogenic pathways may be required for the effective therapy of IPF.
Another strategy is to search for drugs to enhance resolution of fibrosis. It has been shown that experimental hepatic fibrosis in rodents can be resolved by drugs. The reversibility of pulmonary fibrosis is a controversial subject. It has been suggested that in pulmonary fibrosis the loss of basement membrane, and consequently of normal lung architecture, establishes the point of no return.. Perhaps at earlier stages of the disease pulmonary fibrosis is reversible. Unfortunately, the mechanism of resolution of fibrosis is poorly understood and only a few approaches for the development of fibrolytic targets have been identified.
A better understanding of fibrogenesis and fibrolysis will greatly facilitate discovery and development of new antifibrotic drugs. Based on past experience, many more years are needed to advance the knowledge base of this field to a level adequate for successful design and development of drugs capable to selectively modifying fibrosis in humans. In the interim, available leads should be optimized on the basis of their activity in mice with bleomycin-induced fibrosis or a similar model. If the endpoint of a clinical trial is mortality, the same endpoint should be used in an animal model.
There is also an urgent need for better biomarkers for use in clinical trials. The duration of trials of drugs for treating IPF can be substantially reduced in time and cost if mortality is replaced by an endpoint based on a meaningful biomarker.

The histories of pirfenidone in pulmonary fibrosis reveal several important issues with drug development. The antifibrotic effectiveness of pirfenidone in animals has been known for 14 years and in humans for 10 years. However, resounding proof of its efficacy in human IPF is still not available. This illustrates the imperfect nature of the drug development process and a lack of focus on fibrotic diseases in the pharmaceutical industry.