Shattuck’s SL-325 Delivers >10-Week TL1A Blockade and 3.7% ADA Rate
STTK•SL-325 achieved complete DR3 occupancy and durable TL1A blockade beyond 10 weeks at doses ≥1 mg/kg with only 3.7% of subjects developing low-titer ADAs in a 72-participant Phase 1 study. A 174-patient Phase 2b Crohn’s disease trial begins Q3 2026, and bispecific SL-846 advances to IND toxicology ahead of H1 2027 Phase 1.
1. Phase 1 Trial Design and Pharmacokinetic Outcomes
Shattuck Labs conducted a randomized, placebo-controlled Phase 1 trial enrolling 72 healthy volunteers across six single-ascending dose cohorts (0.1–30 mg/kg) and three multiple-ascending dose cohorts (1–10 mg/kg). Complete DR3 receptor occupancy was achieved at doses ≥0.1 mg/kg, with TL1A blockade durable for over 10 weeks; PK modeling predicts sustained inhibition beyond three months at doses ≥1 mg/kg, supporting potential quarterly dosing.
2. Low Immunogenicity Profile
Antidrug antibodies (ADAs) emerged in only 3.7% of participants (2 of 54 dosed subjects), both with low titers (≤16) and no detectable impact on pharmacokinetics or receptor occupancy. The ADA assay demonstrated sensitivity down to 5 ng/ml with tolerance up to 160 µg/ml drug concentration, underscoring SL-325’s favorable immunogenicity compared to existing TL1A inhibitors and its potential to improve long-term efficacy.
3. Safety and Tolerability Findings
SL-325 was well tolerated at all dose levels, with no serious or severe treatment-emergent adverse events reported. All 12 treatment-related adverse events were Grade 1, and no signs of DR3 agonism, lymphocyte proliferation, cytokine alterations, or increased serum TL1A were observed. A subcutaneous formulation compatible with autoinjector delivery was also developed, reinforcing the candidate’s suitability for outpatient administration.
4. Next-Stage Trials and Pipeline Progress
The RECEPTIVE-CD1 Phase 2b trial in moderate-to-severe Crohn’s disease is scheduled to initiate in Q3 2026, enrolling approximately 174 patients in a 1:1:1 low-dose SL-325, high-dose SL-325, or placebo design, with primary endoscopic response at Week 12 and clinical remission as a key secondary endpoint. Meanwhile, bispecific candidate SL-846, targeting both DR3 and IL-23R, is in IND-enabling toxicology studies ahead of a planned Phase 1 in H1 2027.
