Shattuck Labs (STTK) Study Update summary

Interim results and discontinuation of SL-172154

• Interim phase Ib data for SL-172154 in high-risk MDS and TP53 mutant AML showed improved complete response rates but only marginal improvements in overall survival compared to azacitidine alone.

• Median overall survival for TP53 mutant high-risk MDS was reported as 15.6 months (benchmark: 9-12 months), and for TP53 mutant AML, 10.5 months (benchmark: 5-8 months), with no survival benefit exceeding 13.1 and 11.7 months in other reports.

• The overall survival benefit was deemed insufficient for further development, leading to the discontinuation of SL-172154.

• SL-172154 demonstrated a manageable safety profile, with no new safety concerns and infusion-related reactions as the most common adverse events.

Introduction and rationale for SL-325 (DR3 antagonist antibody)

• SL-325 is a first-in-class DR3 antagonist antibody targeting the TL1A/DR3 axis, implicated in inflammatory and autoimmune diseases, especially IBD.

• Preclinical data show DR3 blockade may offer superior efficacy over TL1A blockade due to stable DR3 expression and broader anti-inflammatory potential.

• SL-325 binds human DR3 with high affinity (KD 1.3pM), does not bind other TNF receptor family members, and demonstrates ~10-fold greater potency than benchmark anti-TL1A antibodies.

• Effectively blocks TL1A-induced IFNy secretion from healthy donor and IBD patient PBMCs, and is engineered to remove Fc gamma receptor binding.

• The approach avoids immune complex formation and supports future bispecific antibody development.

Development plans and milestones for SL-325

• IND-enabling work for SL-325 is ongoing, with IND filing expected in Q3 2025 and initial clinical data anticipated in 2026.

• The phase I trial will enroll healthy volunteers to assess safety, receptor occupancy, and PK profile, setting the stage for IBD patient studies.

• Key pharmacodynamic biomarker will be receptor occupancy on circulating lymphocytes.

• The company is also developing bispecific antibodies and exploring additional autoimmune indications beyond IBD.

• Cash runway supports operations and development into 2027.