Shattuck Labs, Inc. (Shattuck or the Company) (NASDAQ:STTK), a clinical-stage biotechnology company pioneering the development of potential first-in-class monoclonal and bispecific DR3 blocking antibodies for the treatment of patients with inflammatory and immune-mediated diseases, today announced data from its Phase 1 clinical trial of SL-325, Shattuck's lead DR3 blocking antibody candidate.

"SL-325 is now the first antibody that blocks the receptor for TL1A, known as DR3, to generate human clinical data. The profile of SL-325 is highly encouraging, including a potentially best-in-mechanism immunogenicity profile, saturation of DR3 at low doses of SL-325, and durable inhibition of TL1A binding for months after a single dose." said Taylor Schreiber, M.D., Ph.D., Chief Executive Officer of Shattuck. "These data indicate that blocking DR3 with SL-325, or with our DR3 by IL-23 receptor blocking bispecific antibody candidate, SL-846, may substantially improve upon the efficacy shown to date with the TL1A inhibitor class, providing an opportunity to maximize potential efficacy for TL1A blockade in IBD and beyond."

Key Phase 1 Findings

The Phase 1 trial is a first-in-human, randomized, placebo-controlled trial evaluating the safety, tolerability, pharmacokinetics ("PK"), receptor occupancy ("RO"), pharmacodynamics ("PD"), and immunogenicity of SL-325 in healthy volunteers. The study enrolled 72 participants, across six single-ascending dose cohorts, with doses ranging from 0.1 mg/kg to 30.0 mg/kg, and three multiple-ascending dose cohorts, with doses ranging from 1 mg/kg to 10 mg/kg.

  • Immunogenicity: Antidrug antibodies ("ADA") to SL-325 were detected in 3.7% [2/54] of participants who received SL-325.
    • In these two participants, ADA were low titer (≤16), and no impact to PK or receptor occupancy was observed.
    • The ADA assay used to detect ADA to SL-325 has a sensitivity of 5.0 ng/ml and drug tolerance of up to SL-325 concentrations of 160.0 µg/ml in the serum. For each participant in this Phase 1 trial, samples were analyzed over a time course, ensuring that samples from each participant fell within the dynamic range of the assay across the full dose range, and thus limiting the possibility of false negative results.
    • Published and emerging data suggest that ADA to anti-TL1A antibodies impact efficacy. SL-325's potentially best-in-mechanism immunogenicity profile is expected to lead to improved efficacy at both the induction and maintenance timepoints compared to anti-TL1A antibodies.
  • Pharmacokinetics and Receptor Occupancy:
    • Complete DR3 occupancy, as measured by blockade of TL1A binding, was observed at doses of 0.1 mg/kg and higher in all participants.
    • Complete inhibition of TL1A binding was durable for more than 10 weeks, and extended PK modeling suggests that complete inhibition of TL1A binding may be sustained for greater than 3 months at doses of greater than1 mg/kg of SL-325.
    • The PK profile of SL-325 demonstrated proportional increases in Cmax and AUClast across all dose levels.
    • Repeated dosing demonstrated an accumulation ratio of 1.64-1.75.
    • A subcutaneous formulation of SL-325 has been developed. These Phase 1 results indicate the potential for quarterly dosing at a volume compatible with an autoinjector pen.
  • Pharmacodynamics: Clinical data now corroborate our previous preclinical findings that SL-325 is a pure DR3 blocking antibody.
    • No evidence of DR3 agonism was observed.
    • No evidence of SL-325 mediated lymphocyte proliferation or changes in serum cytokines was observed in any participant at any dose level.
    • No increases in serum levels of TL1A from baseline were observed.
  • Safety: SL-325 was well tolerated at all dose levels and upon repeat dosing, with a favorable safety profile consistent with the TL1A inhibitor class.
    • There were no serious treatment-emergent adverse events ("TEAEs") or serious adverse events.
    • All treatment-related adverse events ("TRAEs") were Grade 1. TRAEs were observed in 12 participants.

       

RECEPTIVE-CD1 Phase 2b Trial of SL-325 in Crohn's Disease

The RECEPTIVE-CD1 clinical trial is designed as a randomized, double-blind, placebo-controlled Phase 2b clinical trial to evaluate the safety and efficacy of two dose levels of SL-325 as monotherapy versus placebo in moderate-to-severe Crohn's disease. SL-325 will be administered intravenously, and the trial will include a 12-week induction period, followed by a 40-week maintenance period, for a total of 52 weeks of treatment for each patient enrolled.

  • RECEPTIVE-CD1 is expected to enroll approximately 174 patients, randomized 1:1:1, with patients receiving either low dose SL-325, high dose SL-325, or placebo. RECEPTIVE-CD1 will enroll patients at clinical sites in the United States, Canada, and Europe.
  • RECEPTIVE-CD1 is expected to enroll patients with moderate-to-severe Crohn's disease, as defined with a Crohn's Disease Activity Index ("CDAI") score of between 220 and 450.
  • The primary endpoint is expected to be endoscopic response at Week 12, and the key secondary endpoint will be clinical remission at Week 12.
  • Patients randomized to the placebo arm will be eligible to receive SL-325 after the 12-week induction period.
  • The primary endpoint, endoscopic response at 12 weeks, is expected to be disclosed in the first half of 2028.

     

SL-846: A Dual DR3 and IL-23 Receptor Blocking Antibody

SL-846 is Shattuck's lead bispecific product candidate and is designed to simultaneously bind to DR3 and to IL-23 receptor, blocking the interaction with TL1A and IL-23, respectively, while avoiding the risk of immune complex formation and resulting ADA challenges of the TL1A-based bispecifics.

  • SL-846 is an Fc-silenced, half-life extended, IgG1 bispecific antibody.
  • Preclinical data demonstrated that SL-846 was equipotent, or more potent, than sequence equivalents of risankizumab and icotrokinra controls in multiple in vitro and cell-based potency assays.
  • SL-846 is currently being evaluated in an ongoing IND-enabling GLP toxicology study in non-human primates. Safety and immunogenicity data are expected in the second half of 2026.
  • Shattuck expects to submit an IND for SL-846 in the first half of 2027.