Shattuck Labs (STTK) 43rd Annual J.P. Morgan Healthcare Conference 2025 summary

Key scientific insights and clinical context

• TL1A-DR3 axis is validated as a therapeutic target in inflammatory bowel diseases, with multiple phase II trials showing 20–27% remission rates using TL1A blocking antibodies.

• DR3 is more abundantly and stably expressed than TL1A in both inflamed and uninflamed GI tissue, suggesting broader therapeutic potential for DR3 targeting.

• Preclinical models show DR3 inhibition provides stronger protection from inflammation than TL1A inhibition, with DR3 knockout mice fully protected from Crohn's-like disease.

• TL1A is tissue-restricted and inducible, while DR3 is constitutively expressed by lymphocytes, making DR3 a more consistent target.

• Targeting DR3 avoids immune complex formation seen with TL1A antibodies, potentially reducing anti-drug antibody (ADA) rates.

Program updates and development plans

• Lead DR3 antibody, SL-325, has completed GLP toxicology studies and is set to enter clinical trials in mid-2024.

• First-in-human study will be a single and multi-ascending dose trial, expected to complete by Q2 2026.

• An oral presentation at the European Crohn's and Colitis Congress in February will share non-human primate data and toxicology results.

• Plans include subsequent randomized, placebo-controlled studies in Crohn's disease and ulcerative colitis.

• The program aims to improve remission rates beyond current TL1A inhibitors by more broadly suppressing TL1A signaling.

Competitive landscape and strategic rationale

• All current clinical efforts target TL1A; no other company has a DR3-targeted antibody in development.

• Developing a DR3 antagonist is more challenging than targeting TL1A, but offers potential for superior efficacy and safety.

• The field has been underexplored academically, with few labs studying the TL1A-DR3 axis since its discovery in 2002.

• Early focus on TL1A was influenced by antibody availability and easier development path.

• Recent clinical validation of the axis has increased industry interest and follow-on development.