Xencor Reports Positive Interim Data From First-in-Human Study of XmAb942, Plans Phase 2b Trial for Inflammatory Bowel Disease
Xencor, Inc. (NASDAQ: XNCR), a clinical-stage biopharmaceutical company specializing in the development of engineered monoclonal antibodies and cytokines to treat cancer and autoimmune diseases, today announced encouraging interim results from its first-in-human clinical trial of XmAb942. This investigational anti-TL1A antibody—engineered for high potency and extended half-life—is being developed as a potential treatment for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD).
The interim data come from a Phase 1 dose-escalation study involving healthy volunteers and suggest that XmAb942 is well tolerated across a range of doses and administration routes. Importantly, the trial demonstrated a notably extended half-life of more than 71 days, supporting a potential 12-week dosing interval during the maintenance phase of treatment. This finding aligns with preclinical models and underlines the therapeutic promise of XmAb942 as a less frequently dosed yet highly effective IBD therapy.
As a result of these promising outcomes, Xencor is preparing to advance XmAb942 into a Phase 2b trial for patients with moderate-to-severely active UC. Dubbed XENITH-UC, this trial is slated to begin in the second half of 2025.
A Strategic Advancement in Anti-TL1A Therapeutics
TL1A (Tumor necrosis factor-like cytokine 1A) is a member of the TNF superfamily of cytokines and is believed to play a key role in the pathogenesis of IBD by promoting inflammation in the gastrointestinal tract. Inhibiting TL1A has emerged as a novel therapeutic strategy for IBD, with several pharmaceutical companies—including Xencor—pursuing this target.
XmAb942 was designed to improve upon current anti-TL1A approaches by combining a high degree of potency with a significantly prolonged half-life. This would allow for reduced dosing frequency, which could not only enhance patient adherence and convenience but may also lead to improved long-term disease control.
“Our Phase 1 data for XmAb942 validate our design goals for a best-in-class anti-TL1A therapy, combining high potency with less frequent dosing to potentially improve clinical outcomes and convenience for patients living with inflammatory bowel disease,” said Dr. Bassil Dahiyat, President and Chief Executive Officer at Xencor. “We are excited to begin our Phase 2b XENITH-UC trial later this year. It is strategically designed to support efficient dose selection for our anticipated pivotal studies.”
Dr. Dahiyat added that the company’s progress is underpinned by a strong financial position, allowing it to pursue multiple development programs in parallel, including another investigational antibody targeting both TL1A and IL-23.
Interim Results: Safety, Pharmacokinetics, and Pharmacodynamics
The Phase 1 clinical trial of XmAb942 is a randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity in healthy adult volunteers. The study includes both intravenous (IV) and subcutaneous (SC) administration routes across escalating dose levels.
The interim analysis includes data from 64 participants, broken down as follows:
- Single dose IV cohort: 24 subjects
- Single dose SC cohort: 24 subjects
- Multiple dose IV cohort: 16 subjects
Safety
Safety is a critical endpoint for first-in-human studies, and XmAb942 demonstrated a favorable safety profile at all tested dose levels. According to the blinded interim safety review, there were no serious adverse events (SAEs) reported in any of the cohorts. Furthermore, no adverse events led to participant withdrawal from the study. The safety profile was consistent across IV and SC routes of administration.
Pharmacokinetics (PK)
One of the standout findings from the interim analysis is the estimated half-life of XmAb942, which exceeds 71 days. This result is consistent with preclinical data obtained from non-human primate studies, which showed a half-life of approximately 23 days. The extended half-life supports a potential dosing schedule of once every 12 weeks during the maintenance phase—a major advantage in managing chronic conditions like UC and CD.
Pharmacodynamics (PD)
XmAb942’s PD profile further supports its therapeutic potential. In both IV and SC cohorts, researchers observed dose-dependent increases in total TL1A in circulation, a sign that the drug is effectively binding its target. At the same time, levels of circulating free TL1A were significantly reduced compared to placebo. These findings are consistent with XmAb942’s mechanism of action and its high binding affinity for TL1A.
Immunogenicity
Immunogenicity—referring to the body’s immune response against a therapeutic protein—can complicate antibody therapy development. Encouragingly, early PK data from both single and multiple dose cohorts show no evidence of anti-drug antibodies (ADAs) against XmAb942. This suggests a low risk of immunogenicity, enhancing the molecule’s potential for long-term clinical use.
XENITH-UC: Preparing for Phase 2b in Ulcerative Colitis
Following these favorable interim results, Xencor is preparing to initiate its Phase 2b study, XENITH-UC, in patients with moderate-to-severely active ulcerative colitis. This double-blind, placebo-controlled trial will evaluate the safety and efficacy of XmAb942 in patients who have experienced inadequate response, loss of response, or intolerance to at least one conventional or advanced therapy.
The study will include:
- A 12-week induction period, during which XmAb942 will be administered intravenously
- A maintenance period, in which responders will receive subcutaneous injections every 12 weeks
- An estimated enrollment of 220 participants across multiple global sites
- Three induction dose levels, to inform dose selection for potential Phase 3 trials
- Primary endpoint: Clinical remission at week 12, based on the modified Mayo scoring system
By using both IV and SC routes and incorporating different induction dosing strategies, Xencor aims to determine the optimal balance of efficacy, safety, and patient convenience before progressing to late-stage development.
Expanding the Pipeline: TL1A x IL-23p19 Bispecific
In parallel with the XmAb942 program, Xencor continues to advance its next-generation bispecific antibody targeting TL1A and IL-23p19—two critical cytokines implicated in the inflammatory pathways of IBD. The bispecific antibody is designed in a simple IgG format and is currently undergoing final lead selection.
Recent in vitro studies indicate that several lead candidates possess inhibition potencies comparable to leading commercial monospecific antibodies, potentially offering enhanced efficacy through dual pathway inhibition. Manufacturing preparations are already underway to support a planned first-in-human study in 2026.
Xencor’s latest results reinforce its position as a frontrunner in the development of next-generation therapies for autoimmune diseases. The favorable safety, pharmacokinetic, and pharmacodynamic profile of XmAb942 provides a strong foundation for further clinical development. With the upcoming launch of the Phase 2b XENITH-UC study and continued progress on its bispecific antibody program, Xencor is strategically positioned to transform the treatment landscape for inflammatory bowel disease.
For patients living with UC and CD—chronic conditions that can severely impact quality of life—XmAb942 represents a potential new therapeutic option that combines infrequent dosing with powerful anti-inflammatory action.
As the biopharmaceutical industry continues to shift toward targeted, long-acting biologics, Xencor’s XmAb platform and its clinical pipeline stand out as key contributors to the future of autoimmune disease treatment.
