The promise of PRA023: taking on inflammation and fibrosis by inhibiting TL1A activity
Inflammation and fibrosis are key factors in numerous immune-mediated diseases. Since its discovery in 1999 by Prometheus Biosciences founder Dr. Stephan Targan at Cedars-Sinai, TNF family member TL1A (TNFSF15) has been established as a key immune factor mediating both fibrosis and inflammation throughout the body. By inhibiting TL1A, we believe our therapeutic PRA023 is uniquely positioned to improve outcomes for immune-mediated disease patients.
TL1A has a strong mechanistic rationale in tackling IBD
TL1A was first discovered and characterized in the setting of inflammatory bowel disease (IBD), where it is strongly associated with disease activity and inflammatory/fibrotic processes.
- Basal levels of TL1A are low, but are rapidly elevated on immune activation
- Through its receptor DR3, TL1A potently drives inflammatory processes, including Th1 and Th17 responses
- TL1A also directly activates fibroblasts, leading to collagen disposition and fibrosis, in part independently of inflammation
Fibrosis is a key factor in IBD progression
Crohn’s Disease (CD)
- 70% of patients develop stricturing/perforating disease
- Stricturing disease is the leading indication for surgery in CD
- The use of anti-inflammatory agents over the past 20 years has not significantly changed the rate of stricturing disease or the need for surgery
- No approved therapies targeting fibrosis and inflammation are available
Ulcerative Colitis (UC)
- While observed at lower rates than in CD, subclinical fibrosis could have significant impact on patient quality of life
- Subclinical fibrosis could contribute to symptoms of diarrhea, abdominal pain, urgency, and incontinence
- Potential explanation for persistent symptoms after the inflammation is resolved
TL1A is linked to multiple immune-mediated and fibrotic diseases beyond IBD
TL1A has long been linked to intestinal inflammation and fibrosis. In the past decade, a large body of literature has emerged implicating TL1A in a host of other fibrotic conditions affecting nearly every organ system.
Systemic Sclerosis is an immune-mediated disease that causes fibrosis and has significant unmet clinical need
Systemic Sclerosis (SSc) is an orphan disease characterized by inflammation-driven fibrosis of the skin and internal organs. TL1A has been shown to play an important role in the disease and its progression. More than half of SSc patients develop Interstitial Lung Disease (SSc-ILD), which leads to progressive fibrosis of the lungs and is the leading cause of death in SSc patients.
TL1A is mechanistically implicated in Systemic Sclerosis-associated Interstitial Lung Disease pathogenesis
Ample evidence supports the role of TL1A and its receptor DR3 in driving the Systemic Sclerosis disease process:
- Intratracheal administration of TL1A in normal mice promotes lung fibrosis and remodeling through an immune-inflammation independent pathway
- Knocking down TL1A’s only cognate receptor, DR3, or blocking TL1A prevents fibrosis in mouse models of fibrosing lung disease
- Circulating levels of TL1A are elevated in SSc patients, and patients with higher disease activity have higher TL1A levels
- Pulmonary fibroblasts of human SSc patients express a higher level of DR3 mRNA than those of healthy subjects
- TL1A can directly drive remodeling-relevant activity in human lung fibroblasts (proliferation and expression of periostin and collagen)
There remains great opportunity for PRA023 in other immune-mediated diseases
We will continue to investigate further opportunities to employ our lead therapeutic candidate PRA023 in additional inflammatory and fibrosis disease areas with remaining unmet need and compelling commercial potential.