Shattuck Labs (STTK) TD Cowen 46th Annual Health Care Conference summary

Program overview and scientific rationale

• Focus on developing DR3 blocking antibodies for IBD, targeting the TL1A-DR3 axis, which has shown strong efficacy and safety in ulcerative colitis with existing TL1A blockers.

• DR3 is a more stable and specific target than TL1A, with the expectation of lower immunogenicity and potentially superior efficacy.

• SL-325 is a human DR3 blocking antibody with Fc silencing to avoid off-target effects and receptor-mediated endocytosis.

• SL-425 is a variant with a YTE mutation for half-life extension; both are supported by a pipeline of DR3-targeting bispecifics.

• Over 64% of patients develop ADA to TL1A blockers due to immune complex formation, a problem DR3 blockers aim to avoid.

Clinical development and trial plans

• Phase I trial for SL-325 is nearly complete, with data expected in Q2; single and multiple ascending dose cohorts are fully enrolled.

• Phase IIb randomized controlled trial in Crohn's disease will start in Q3, comparing high dose, low dose, and placebo in 170–180 patients.

• The trial will cover both induction and maintenance phases, leveraging recent completion of chronic tox studies for both SL-325 and SL-425.

• The study is powered for a 20% improvement in endoscopic response, aiming for at least 25% to ensure clinical relevance.

• Dose selection for phase III is expected from this trial, with SL-425 as a backup for life cycle management or indication splitting.

Immunogenicity, efficacy, and safety considerations

• TL1A blockers consistently induce high ADA rates, reducing efficacy by up to 50% at induction; DR3 blockers are expected to have much lower ADA rates, as shown in non-human primate studies.

• 100% blockade of TL1A signaling is the goal for optimal efficacy.

• Non-human primate studies showed no evidence of T cell proliferation or cytokine changes, supporting a favorable safety profile.

• Receptor occupancy assays are used to confirm pathway inhibition, with efficacy proxies drawn from peer TL1A datasets.

• No new toxicities are expected due to the monogamous ligand-receptor relationship and antibody engineering.