TL1A

The promise of PRA023: taking on inflammation and fibrosis by inhibiting TL1A activity

Fibrosis is a key factor in IBD progression—constituting the biggest unmet need.

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

rendering of intestines and other internal organs.

rendering of intestines and other internal organs.

rendering of intestines and other internal organs.

normal intestine vs. intestine with stricture.

diagram showing association of TL1A with fibrosis and inflammation.

 

TL1A has a strong mechanistic rationale in tackling IBD

Since its discovery in 1999 by Prometheus Biosciences founder Dr. Stephan Targan at Cedars-Sinai, TL1A (TNFSF15) has been established as a key immune factor.

In particular, TL1A has been associated with both intestinal inflammation and fibrosis in IBD.

  • 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

TL1A is linked to multiple immune and fibrotic diseases

Discovered in 1999, 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.

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