Shattuck Labs (STTK) Wells Fargo 21st Annual Healthcare Conference summary

SL-325, the lead DR3 antibody, demonstrated no agonist activity in preclinical and human studies. Developing a DR3-blocking antibody is technically challenging due to the need to avoid residual agonism, which could worsen inflammation. DR3 is a stable receptor expressed on lymphocytes and endothelial cells, making it a more consistent therapeutic target than the transiently expressed TL1A. Current pipeline centers on DR3 blockade, offering advantages over TL1A targeting due to greater target stability and reduced immunogenicity. Phase II RECEPTIVE-CD1 trial in Crohn's disease is underway, with induction data expected in H1 2028 and maintenance data later that year. Quarterly dosing is projected to be feasible with SL-325 due to durable DR3 occupancy, as shown in phase I. SL-325's low ADA rate (3.7%) is attributed to the absence of immune complex formation, unlike TL1A antibodies. Data from the ARTEMIS-UC trial suggest that high-dose maintenance can double remission rates, but ADA limits this benefit. TL1A class shows higher induction remission rates than IL-23s, but lacks improvement from induction to maintenance due to anti-drug antibodies (ADA). DR3 blockade is expected to outperform TL1A and potentially IL-23s, especially in maintenance efficacy due to lower immunogenicity. The company is developing a bispecific antibody (SL-846) targeting DR3 and IL-23R, with clinical entry planned for early next year. Combination therapies are anticipated to be the future standard in IBD, with DR3 blockade positioned as a desirable backbone. The pipeline may expand into other indications such as hidradenitis suppurativa and primary biliary cirrhosis, leveraging the anti-fibrotic potential of TL1A/DR3 inhibition.