Shattuck Labs (STTK) 7th Annual Evercore ISI HealthCONx Healthcare Conference summary

Mechanistic differentiation and rationale

• DR3 is a unique receptor for TL1A, with no other ligands, offering specificity and safety advantages over targeting TL1A itself.

• TL1A is expressed in a pulsatile manner by antigen-presenting and endothelial cells, while DR3 is more stably and abundantly expressed on migratory lymphocytes.

• Blocking DR3 may provide more durable inhibition across inflamed and non-inflamed tissue compared to TL1A blockade, which is limited by the transient expression of TL1A.

• Targeting DR3 could overcome challenges seen with TL1A antibodies, such as limited efficacy in patients with localized disease.

Clinical development and differentiation

• Preclinical studies show durable receptor occupancy with DR3 antibodies, similar to established drugs like Keytruda, even as serum drug levels decline.

• Both non-half-life extended and half-life extended DR3 antibodies are in development, with chronic toxicology studies for the latter planned for 2025.

• DR3 targeting may close the gap between clinical response and remission rates observed with TL1A inhibitors.

• DR3-directed bispecifics may avoid high immunogenicity issues seen with TL1A bispecifics, as they do not form circulating immune complexes.

Program status and clinical plans

• IND submission is scheduled for mid-2025, with a 70-patient single- and multiple-ascending dose study starting late Q3 2025 and completing enrollment by Q2 2026.

• Primary endpoints include safety, pharmacokinetics, and receptor occupancy, with full data expected by mid-2026.

• Preclinical data confirm no evidence of residual agonism with the DR3 antibody.