Shattuck Labs advances SL-325 into Phase 2b Crohn’s disease testing after Phase 1 showed durable DR3 blockade, low immunogenicity and favorable safety.
Written By: Shaik Yasmeen, PharmD
Reviewed By: Pharmacally Editorial Team
Shattuck Labs is preparing to initiate the RECEPTIVE-CD1 Phase 2b trial of SL-325 in patients with moderately to severely active Crohn’s disease in the third quarter of 2026. The move follows Phase 1 (NCT07158437) findings showing that the antibody produced durable target engagement at low doses while maintaining a favorable safety profile.
Only 3.7% of Phase 1 participants developed antidrug antibodies, supporting a low immunogenicity profile. At doses of 1 mg/kg or higher, SL-325 achieved complete blockade of TL1A binding to Death Receptor 3 (DR3) for more than three months, a pharmacodynamic finding that could support quarterly maintenance dosing.
The trial also found no evidence of residual DR3 agonism, an important consideration for an antibody targeting this receptor.
Targeting the TL1A-DR3 Pathway
TL1A and its receptor DR3 form an inflammatory signaling pathway implicated in inflammatory bowel disease and other immune-mediated conditions. While several therapeutic programs target TL1A, Shattuck is pursuing DR3 blockade to inhibit TL1A signaling at the receptor level.
SL-325 is a fully Fc-silenced, fully human IgG monoclonal antibody. Preclinical studies reported high-affinity DR3 binding and activity that the company says support direct targeting of DR3 rather than TL1A.
The clinical development strategy will now test whether durable DR3 blockade translates into meaningful disease control in Crohn’s disease.
RECEPTIVE-CD1 Will Test Three Dose Levels
RECEPTIVE-CD1 will be a randomized, double-blind, placebo-controlled Phase 2b study enrolling approximately 232 patients. Participants will be randomized equally across three SL-325 dose groups and placebo.
The primary endpoint is endoscopic response at week 12. Shattuck expects those data in the first half of 2028.
Patients will continue treatment through week 50 in a treat-through maintenance phase, allowing investigators to assess whether efficacy accumulates with continued DR3 blockade. Participants may subsequently enter a long-term extension study.
Shattuck CEO Taylor Schreiber said the Phase 1 results support advancing SL-325 into Phase 2 and highlighted the planned evaluation of three doses during both induction and maintenance.
SL-846 Expands the DR3 Pipeline
The company is also advancing SL-846, a half-life-extended bispecific antibody that blocks both DR3 and the interleukin-23 receptor (IL-23R).
SL-846 is undergoing an IND-enabling GLP toxicology study in non-human primates. Shattuck expects to present safety, pharmacokinetic, and receptor-occupancy findings at United European Gastroenterology Week in October 2026.
The company plans to begin a Phase 1 healthy-volunteer study of SL-846 and report initial clinical data in 2027. Preclinical studies have shown activity against both targets in assays comparing the molecule with benchmark IL-23 therapies, including sequence-equivalent versions of risankizumab and icotrokinra.
Cash Runway Supports Clinical Development
Shattuck reported approximately $208.3 million in cash, cash equivalents, and short-term investments as of June 30, 2026. The company expects these resources to fund operations into 2029, providing financial support for the planned Phase 2b development of SL-325 and early clinical development of SL-846.
The next major clinical milestone will be initiation of RECEPTIVE-CD1, followed by the Phase 2b endoscopic response readout expected in the first half of 2028.
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About the Writer
Shaik Yasmeen (LinkedIn) is a Pharm.D graduate with interests in clinical pharmacy, pharmacovigilance, and medical writing. She has gained experience through hospital clinical postings, patient case reviews, case presentations, and literature evaluation. Passionate about evidence-based healthcare, she is committed to creating accurate and engaging medical content while continuously expanding her professional knowledge.