Fibrosis is a silent killer in more ways than one.

There is the typical way in which diseases can sneak up on their victims. The scarring that is the hallmark of fibrosis can go undetected for years before patients show any symptoms.

But the other side of the coin is that fibrosis' scope tends to be under-appreciated, even by those working on the issue.

According to one analysis of death certificates, fibrosis is a contributing factor in nearly half of all deaths. That figure, however, surprised even fibrosis researchers when it came out. The Mount Sinai School of Medicine's Scott Friedman recounted calling the author to satisfy himself that the paper's methods had been rigorous. (See BioWorld Insight, Jan. 14, 2013.)

One reason that the true magnitude of fibrosis remains under-appreciated, Thomas Wynn of the National Institute of Allergy and Infectious Diseases told BioWorld Insight, is that fibrosis "is a pathology – it's not a disease."

In that way, fibrosis has parallels to inflammation – and it is part of chronic inflammatory diseases and results from inflammation, but the fibrosis mechanism is "very distinct" from inflammation itself.

Not that industry is ignoring fibrosis – Wynn said that at the most recent Keystone Symposia on Molecular and Cellular Biology on fibrosis, there were dozens of companies in attendance. And Friedman said that "what is coalescing now is a broad and durable interest" from industry.

As an organ-centric view is being replaced, or maybe complemented, by a molecular view that cuts across organs, it is also becoming more obvious how frequently fibrosis contributes to disease. "That's been an important change," Wynn said, pointing to another Keystone meeting in 2005, as the first scientific gathering that crossed organ boundaries, rather than "the lung people getting together, and the kidney people getting together, and so forth."

Organ Site Makes a Difference

Wynn noted that fibrosis still differs according to its organ site, partly because the immune system plays such a large role in the disease. "Certainly, the lung" – where the immune system is the first responder to all sorts of airborne pathogens – "is very different from the liver." Epithelial and endothelial cells, whose damage is the first event in fibrosis, also differ from organ to organ.

Additionally, fibrosis "has many different causes, so it's going to be context dependent." Fibrosis can be set off by everything from injury to obesity, aided sometimes, but not always, by underlying genetic conditions.

Fibrosis has several parallels to cancer, both in its being a condition marked by unchecked tissue growth – in this case, of scar tissue – and in having organ-specific aspects, but also underlying molecular universals. Indeed, a number of the drugs in development for fibrosis are also being tested in different cancers, and some approved cancer drugs, such as Velcade (bortezomib, Millennium: The Takeda Oncology Co.) and Gleevec (imatinib, Novartis AG) are in trials for fibrotic diseases.

Wynn said that molecular profiling, which is used in cancer to understand the activated pathways via gene expression, would yield useful insights for patient stratification in clinical trials.

To some degree, the molecular events in fibrosis can be broken down into an early inflammatory response, with non-inflammatory mechanisms in the fibrotic tissue itself, kicking in later. Wynn stressed that the delineation is anything but clear-cut; for example, "even in late idiopathic pulmonary fibrosis, a lot of the immune mediators are still activated."

Therapies in Development

The fibrosis therapy that is furthest along in clinical development targets that inflammatory response. InterMune Inc.'s Esbriet (pirfenidone) is approved in a number of European Union countries as well as Canada. Data from its Phase III ASCEND trial is expected to be out in about a year. That trial was requested by the FDA in its complete response letter the first time the drug went up for approval in the U.S., in 2010. (See BioWorld Today, March 8, 2010, and May 5, 2010.)

Genzyme Inc.'s fresolimumab and Eli Lilly and Co.'s LY2382770, which are both in early phases of development, also go after TGF-beta, which is a key driver of fibrosis. Immune-cell produced TGF-beta can nudge fibroblasts into becoming activated myofibroblasts after an injury.

Those myofibroblasts can also be targeted directly. Examples include Biogen Idec's STX-100, Gilead Science's GS-6624, and FibroGen Inc.'s FG-3019, which target connective tissue growth factor (CTGF). CTGF plays a role in epithelial to mesenchymal transition (EMT). EMT is necessary for wound healing, but in fibrosis, the process does not stop when it is supposed to. The permanent state of EMT is driven by CTGF. FibroGen is testing FG-3019 in a number of different organs including the kidney, the liver, and the lung.

FibroGen hopes that targeting EMT cannot only stop fibrosis, but reverse it. According to the company's information material, "It is now appreciated that permanent scar takes a very long time to develop and the process is dynamic. There is an increasing acceptance that fibrosis, as a derivative of this process, is also dynamic and therefore amenable to reversal."

Thus, targeting a key participant such as CTGF to achieve a state favoring regenerative repair should provide opportunity to not only beneficially influence outcome in repair, but also to affect reversal of fibrosis."