We aim to redefine how fibrosis is treated. Our deep understanding of the molecular drivers of fibrotic disease allows us to target these drivers in the specific tissues where they are causing fibrosis. This approach has the potential to provide both a more potent antifibrotic effect, as well as better safety and tolerability than treatments available today.
Fibrosis is a feature of many diseases. It results when normal tissue repair pathways become dysregulated, causing excessive deposition of collagen, otherwise known as scar tissue, in the affected organs. As collagen builds up, it causes thickening and stiffening of organ tissues, potentially leading to irreparable damage and eventual organ failure.
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 is gradually replaced by scar tissue. As lung fibrosis progresses, it becomes more difficult for the lungs to transfer oxygen into the bloodstream causing severe breathing difficulty for people. Currently, there are no therapies that effectively stop the disease progression. Our lead program, PLN-74809, targets the activation of TGF- β, a key driver of the fibrosis process in IPF, with the goal of halting disease progression. In Phase 1 trials, PLN-74809 was shown to be well tolerated, with pharmacokinetics supporting potential once-daily dosing, 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 live explanted human IPF tissue have also shown a strong antifibrotic effect of PLN-74809. We are currently recruiting two Phase 2a trials of PLN-74809 in IPF.
Primary sclerosing cholangitis (PSC) is a progressive liver disorder characterized by inflammation and fibrosis of the bile ducts, which transport bile from the liver to the intestines. This fibrosis can block bile flow and ultimately result 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. Our lead program, PLN-74809, targets the activation of TGF-β in bile ducts and liver cells in PSC, potentially slowing or halting the disease progression. Studies in animal models and explanted fibrotic liver tissue from PSC patients show a strong antifibrotic effect of PLN-74809. We are currently enrolling a Phase 2a trial of PLN-74809 in PSC.
Nonalcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) that is associated with the development of liver fibrosis and potentially life-threatening liver dysfunction. NASH is rapidly becoming the most common cause of liver transplant, affecting 16.5 million adults in the U.S. Many patients with 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, we are targeting the integrin that is the master regulator of hepatic fibrosis. PLN-1474, an oral αVβ1 inhibitor, significantly reduces established fibrosis in human tissue models. PLN-1474 is partnered with Novartis.
Muscular Dystrophy comprises a group of inherited diseases, all characterized by inborn errors in dystrophin, a protein that is crucial to muscle function. Lack of proper dystrophin function results in damage to muscle cells, which over time leads to muscle degeneration, and replacement of muscle tissue with fat and fibrotic tissue. Pliant has identified a target integrin receptor that appears to act as a natural compensatory mechanism in Duchenne muscular dystrophy, as well as other types of muscular dystrophy. By activating this receptor, it may be possible to maximize the compensatory effect of the target mechanism, stabilizing the muscle cells and reducing muscle damage. This program is currently in preclinical development.
As TGF-β biology has become better understood, it has become increasingly evident that TGF-β plays an important anti-inflammatory role in the tumor microenvironment. In the tumor microenvironment, certain integrins, such as αVβ8, can be overexpressed on different cell types, resulting in increased activation and signaling of TGF-β. This over activation of TGF-β can lead to a strong anti-inflammatory effect in the tumor microenvironment. This mechanism is becoming increasingly recognized as a potential cause of resistance to checkpoint inhibitors such as anti-PD-1 therapies encountered in many tumors. We are targeting integrins such as αVβ8 with the goal of removing the anti-inflammatory effect and, ultimately, sensitizing tumors to checkpoint inhibitors.
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. We are dissecting the underlying biology of GI fibrosis as a key first step in developing novel treatment options. We are collaborating with the Cleveland Clinic to accelerate the discovery of novel drug targets for GI 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 CKDs often result 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. We are developing integrin-based therapies to prevent kidney fibrosis and improve renal function.
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, the underlying fibrotic disease has no approved therapies. Our approach to targeting the fibrosis process is currently being studied in animal models of systemic sclerosis.
Our approach to drug development in fibrosis combines our deep knowledge of the biology of fibrosis with various cellular, tissue, and in vivo assays we have developed to interrogate the biology of fibrosis and uncover pathways and potential targets.
In the first step of our process, we examine healthy and fibrotic human tissue to develop an expanding quantitative atlas of gene and protein expression across a host of fibrotic diseases. This database informs target selection and provides biological evidence for the indications we choose to pursue.
Once we identify a target through the atlas, we screen our library of over 7,000 integrin binding molecules for activity against the target. This library is fully annotated and serves as a source of potential development candidates. In addition to screening against targets discovered through the target atlas, this library offers the potential to select “off-the-shelf” candidates for potential partnering opportunities.
As part of our preclinical testing of identified development candidates, we use live human fibrotic disease tissue to test our compounds for antifibrotic activity. This differentiated approach bridges from animal models to human patients, reducing risk in 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).
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. Approximately 60 to 80 percent of patients die within five years of diagnosis. Few treatments exist, and no existing treatment thus far has proven to have a significant effect on long-term patient survival.
PSC is a progressive liver disorder of unknown origin characterized by inflammation and fibrosis of the bile ducts in the liver. While PSC affects approximately 30,000 to 45,000 people in the U.S., the exact cause of PSC is unknown and there are currently no approved therapies to treat the disease.
Unlike the few current FDA-approved therapies that treat symptoms of fibrotic disorders, we are targeting the key mechanism at the root of fibrosis: pathological activation of transforming growth factor beta (TGF-β). TGF-β is a key regulator of physiological healing and pathologic fibrosis.
Past attempts to target TGF-β systemically have yielded undesirable systemic toxicities due to TGF-β’s many physiological roles. We focus on the inhibition of tissue-specific TGF-β signaling through the inhibition of integrins αvβ1 and αvβ6, known to activate TGF-β in fibrotic tissue. These integrins are absent or expressed at very low levels in healthy tissue, but are upregulated in multiple fibrotic tissue types. By taking a tissue-specific approach through integrin inhibition, we believe we can modulate the fibrotic cascade and maximize therapeutic effects, while avoiding adverse effects.
Our lead program, PLN-74809, is an oral small-molecule, dual-selective inhibitor of αvβ1 and 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.
PLN-74809 has completed Phase 1a SAD/MAD trial in healthy volunteers in which it was shown to be orally bioavailable and generally well tolerated. Additionally, PLN-74809 has completed a Phase 1b proof-of-mechanism trial in healthy volunteers in which it was shown to inhibit TGF-β activation by up to 70% in lung tissue in a dose- and exposure-dependent manner. We are currently enrolling two phase 2a trials of PLN-74809 in IPF patients, as well as two additional phase 2a trials in PSC and COVID-19 associated ARDS, respectively.
Pliant Therapeutics, Inc.
260 Littlefield Avenue,
South San Francisco, CA 94080
info@pliantrx.com
650.481.6770