Our Science
Pliant aims to redefine how fibrosis is treated. We’re cultivating a deeper understanding of the molecular drivers of fibrotic disease and then targeting these drivers in specific patient populations.
Fibrosis Is Involved in Multiple Diseases
Fibrosis, a pathologic feature of many diseases, is caused when normal tissue repair pathways become dysregulated, causing excessive collagen deposition in the affected organs and ultimately impairing their physiological function. If left untreated, fibrosis can result in scarring of vital organs, causing irreparable damage and eventual organ failure.
Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, lung disease of unknown cause affecting approximately 140,000 patients in the United States, and an estimated 30,000 to 40,000 new cases are diagnosed each year. In IPF, healthy lung tissue becomes replaced by scar tissue. As lung fibrosis progresses, it becomes more difficult for the lungs to transfer oxygen into the bloodstream. Currently, there are no therapies that effectively stop the disease progression. Pliant’s lead program, PLN-74809, targets the fibrosis process in IPF, potentially halting the disease progression. In the Phase 1b trials, PLN-74809 was shown to be well tolerated and demonstrated human proof-of-mechanism by inhibiting TGF-β activation by up to 70 percent in the lungs of healthy volunteers. Studies in animal models and explanted human IPF tissue also show a strong antifibrotic effect of PLN-74809.
Liver Fibrosis – Primary Sclerosing Cholangitis
Liver fibrosis is the replacement of healthy liver tissue with scar tissue. It occurs as the result of many chronic liver diseases. Untreated, liver fibrosis can progress to cirrhosis and liver failure.
In primary sclerosing cholangitis (PSC), chronic injury to the bile ducts can block bile flow and ultimately results in bile flow obstruction, or cholestasis, causing liver damage and progressive fibrosis of the liver. There are currently no effective treatments for PSC, which affects approximately 30,000 to 45,000 patients in the U.S. Pliant’s lead program, PLN-74809, targets the fibrosis process in bile ducts and liver cells in PSC, potentially slowing and halting the disease progression. Studies in animal models and explanted fibrotic liver tissue from PSC patients show a strong antifibrotic effect of PLN-74809.
Nonalcoholic steatohepatitis (NASH) is rapidly becoming the most common cause of liver transplant in the U.S. Many patients with nonalcoholic fatty liver disease (NAFLD) progress to NASH and then fibrosis. Progressive liver fibrosis can lead to complications, such as cirrhosis and ultimately liver failure. While several investigational agents target mechanisms that impact the earlier stages of the NASH continuum, Pliant is targeting the integrin that is the master regulator of hepatic fibrosis. Its oral αVβ1 inhibitor significantly reduces established fibrosis in human tissue models.
Duchenne Muscular Dystrophy (DMD)
DMD is a progressive form of muscular dystrophy that occurs primarily in young boys. The disease is characterized by progressive limb weakness, respiratory and cardiac failure and premature death. Fibrosis is a prominent pathological feature of muscle biopsies from patients with DMD. Pliant is developing combination therapies that may directly improve muscle function and viability and reduce the reactive fibrosis that results from progressive muscle destruction.
Gastrointestinal Fibrosis
Gastrointestinal (GI) fibrosis is a common complication of Crohn’s disease, which results in stricture formation, the progressive stiffening and narrowing of the small intestine and colon. This can ultimately lead to obstruction of the intestine, requiring surgical intervention. Novel therapeutic approaches are needed to prevent this scarring from reoccurring, leading to a better quality of life for patients without the need for repetitive surgeries. Pliant is dissecting the underlying biology of GI fibrosis as a key first step in developing novel treatment options. Pliant has a research collaboration with Cleveland Clinic to accelerate the discovery of novel drug targets for GI fibrosis.
Renal Fibrosis
Fibrosis in the kidney, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common manifestation of a wide variety of chronic kidney diseases (CKD). Irrespective of the initial causes, progressive CKD often results in widespread tissue scarring that leads to destruction of the kidneys and end-stage renal failure, a devastating condition that requires dialysis or kidney replacement. Pliant is developing integrin-based therapies to prevent kidney fibrosis and improve renal function.
Systemic Sclerosis
Systemic sclerosis is a form of scleroderma that is characterized by skin and internal organ fibrosis. In some patients, fibrosis occurs only in limited areas, but for others, it can affect other major organs resulting in a progressive life-threatening disease. While some features of systemic sclerosis can be managed with medications, currently the underlying fibrotic disease has no therapy. Pliant’s approach to targeting the fibrosis process is currently being studied in animal models of systemic sclerosis.
Product Discovery Engine
Our unique approach combines drug discovery and translational medicine with an exceptional understanding of the disease process. We examine pathological fibrotic human tissue to inform target selection and provide biological evidence for the indications we choose to pursue. We use fresh human fibrotic disease tissue to test our compounds for antifibrotic activity. This differentiated approach de-risks clinical testing and fuels our highly productive discovery engine.
The compounds we discover address fibrosis in a variety of organs and conditions, including the lung (IPF), liver (primary sclerosing cholangitis, NASH and liver fibrosis), kidney (renal fibrosis), skin (systemic sclerosis and keloids), muscle (Duchenne muscular dystrophy) and the gastrointestinal tract (intestinal fibrosis in inflammatory bowel disease).
Pliant’s Lead Program
Targets idiopathic pulmonary fibrosis (IPF) and primary sclerosing cholangitis (PSC).
IPF is a chronic lung disease that affects approximately 140,000 people in the U.S. Patients with IPF experience debilitating symptoms, including shortness of breath and difficulty performing routine functions and, eventually, complete respiratory failure. Median survival is two to three years. Few treatments exist, and no treatment thus far has proven to have an effect on long-term patient survival or symptom management.
PSC is a progressive liver disorder of unknown origin characterized by inflammation and fibrosis of the bile ducts in the liver. While PSC affects nearly 50,000 patients in the U.S., the exact cause of PSC is unknown and there is currently no approved therapy to treat the disease.
Unlike the few current FDA-approved therapies that treat symptoms of fibrotic disorders, Pliant is targeting the key mechanism at the root of fibrosis: exaggerated activation of transforming growth factor beta 1 (TGF-β1). TGF-β1 is a key regulator of physiological healing and pathologic fibrosis.
Pliant focuses on the antagonism of tissue-specific TGF-β1 signaling through the inhibition of integrins (αVβ1 / αVβ6) known to mediate the enhanced release of activated TGF-β1 in fibrotic tissue. Past attempts to target TGF-β1 broadly has yielded undesirable systemic side effects. But by taking a tissue-specific approach through integrin inhibition, Pliant believes it can effectively modulate the fibrotic cascade, maximizing therapeutic effects while avoiding adverse events. In addition to integrin inhibitors, Pliant is building a pipeline of small molecule, cell-specific inhibitors of TGF-β1 signaling in fibrotic tissue.
Our lead program, PLN-74809, is an orally bio-available inhibitor of αVβ1 / αVβ6 integrins. The dual approach of tissue-specific TGF-β1 antagonism provides a novel therapeutic option to treat fibrotic disorders such as IPF and PSC. Dual integrin antagonism provides a more profound antifibrotic effect in preclinical models of fibrosis.
Pliant Therapeutics, Inc.
260 Littlefield Avenue,
South San Francisco, CA 94080
info@pliantrx.com
650.481.6770