Shattuck Labs (STTK) Study result summary

Study background and rationale

• SL-325 is a fully human, Fc-silenced IgG1 monoclonal antibody that selectively binds DR3, blocking its interaction with TL1A, aiming for superior efficacy and reduced immunogenicity compared to TL1A antibodies.

• DR3 blockade avoids immune complex formation, which can trigger a feedback loop increasing TL1A expression and ADA risk seen with TL1A antibodies.

Phase I clinical trial results for SL-325

• SL-325 was well tolerated in healthy volunteers across all dose levels, with only mild, transient or Grade 1 adverse events and no serious adverse events observed.

• No evidence of DR3 agonism, lymphocyte proliferation, or cytokine changes was detected, confirming SL-325 as a pure DR3 blocker.

• Only 3.7% of participants developed anti-drug antibodies, with no impact on pharmacokinetics or receptor occupancy, indicating a best-in-mechanism immunogenicity profile.

• Complete DR3 occupancy and TL1A blockade were achieved at low doses, with durable inhibition for over three months at 1 mg/kg, supporting extended or quarterly dosing intervals.

• Pharmacokinetics showed dose-proportional increases and a terminal half-life of approximately 16 days.

Mechanistic and commercial implications

• DR3 is a more stable and membrane-restricted target than TL1A, reducing immune complex formation and immunogenicity.

• Immune complexes from TL1A-blocking antibodies can drive increased TL1A expression and higher ADA rates, potentially limiting long-term efficacy.

• Non-immunogenic therapies like SL-325 may enable sustained clinical remission and long-term use in inflammatory diseases.

• The TL1A/DR3 axis is implicated in multiple inflammatory diseases beyond IBD, expanding the potential market.