Fibrosis is a category of diseases that covers a lot of bases, striking everything from the lungs, to the heart, to the skin and more. And its causes are just as diverse, ranging from diabetes, to environmental factors, to genetics and even certain medications.
At its most basic level, fibrosis is the thickening and scarring of connective tissue, usually is a result of chronic disease or injury, including surgical scarring, chemotherapy drug complications, radiation treatment, accidental injury and burns. Fibrotic changes can also occur as the result of various vascular disorders, including cardiac disease, cerebral disease and peripheral vascular disease, as well as in all the main tissues and organ systems, including the skin, kidney, lung and liver.
If left unchecked, it can have devastating consequences.
Fibrosis is associated with significant morbidity and mortality and, in fact, more than 40% of deaths in the developed world can be attributed to fibrotic disorders. It is considered the “common endpoint” of many different chronic diseases.
These related diseases include interstitial lung disease, in which inflammation and fibrosis prevent regular lung function; cirrhosis of the liver; kidney disease, in which scarring and other damage leads to a progressive loss of kidney function; heart disease, in which scar tissue impairs the ability of the heart to pump; and macular degeneration of the eyes, which causes vision loss.
Fibrosis Treatments are scarce
Of these, three—nonalcoholic fatty liver disease (NASH), diabetic nephropathy and idiopathic pulmonary fibrosis (IPF)—afflict some 15 million Americans, costing the healthcare system billions and leading to a long list of potential complications. Idiopathic pulmonary fibrosis, for example, has a median survival of 3-5 years from diagnosis and is often fatal without lung transplant.
The market for IPF treatment is expected to rise from just over $900 million in 2015 to $3.2 billion by 2025, while the market for NASH treatments is expected to reach $1.6 billion worldwide by 2020. The global diabetic nephropathy market is expected to grow more than 5% annually to reach $3.1 billion in the next three years.
Still, there are very few approved therapies for the vast majority of fibrotic conditions, despite the millions of patients who are suffering from chronic, progressive and often life-threatening related diseases. Due to the fact that symptoms and disorders vary widely—including prevalence, causes, severity and more—treating these conditions is not easy, and drug development has been, to date, challenging.
But some commonalities do exist, representing an opportunity for novel treatments.
Most fibrotic cases are based on a persistent inflammatory stimulus that causes the damage, as well as enzymes and proteins that sustain it, constantly working together to remodel and destroy healthy tissue in the body. One of these commonalities is TGF-β, a protein that has been found to be a base cause of several different fibrotic diseases. As a result, researchers have tagged the molecular pathways that control TGF-β as a potential target for new fibrosis treatments with the potential to prevent scarring and, depending upon the condition, allow for the re-growth of normal tissue.
The founders of Indalo Therapeutics, a biotech startup based in St. Louis, are working to develop novel therapies around this concept, targeting the role that a specific class of proteins, called RGD-binding integrins, plays in activating TGF-β. According to their research, RGD-binding integrins, which are prevalent in fibrotic lesions, are key contributors to the progression of fibrotic disease, showing up in greater numbers in fibrotic lesions than in healthy tissue and displaying unique characteristics based on different cell types. The “pro-fibrotic” role played by multiple RGD-binding integrins stands up to testing and has been proven can be reversed (to become “anti-fibrotic) through genetic depletion and pharmacologic modulation in preclinical models.
Collectively, these results suggest that specifically targeting appropriate subsets of RGD-binding integrins may represent an attractive therapeutic strategy.
Indalo an unmet need
Indalo’s treatment technology is based on disrupting the integrin-mediated activation of TGF-β. Using a rational drug-design approach, the company has developed a robust portfolio of novel small molecules that bind to targeted integrins with high potency and selectivity, targeting specific proteins individually based on their fibrosis-causing result.
These compounds have demonstrated strong activity in preclinical models of renal, hepatic, pulmonary, pancreatic, cardiac, muscular and surgical implant fibrosis when delivered orally. Indalo intends to exploit this broad portfolio of chemical triggers to develop new treatments that address unmet needs in fibrosis.
This includes orally bioavailable compounds that broadly target RGD-binding integrins central to fibrotic responses, as well as compounds that target more restricted subsets of RGD-binding integrins.
Indalo Therapeutics was formed in October 2016 as the result of a merger between biotech firms Antegrin and Cascadia bringing small-molecule integrin technology together with strong drug-development expertise, courtesy of three key Cascadia executives who were a part of the last major fibrosis drug exit.