Xencor NASDAQ: XNCR used a webcast during Digestive Disease Week 2026 to highlight Phase I results for its TL1A-targeting monoclonal antibody XmAb942 and to outline preclinical data supporting XmAb412, a bispecific antibody designed to inhibit both TL1A and IL-23p19.
Charles Liles, Xencor’s head of corporate communications and investor relations, said the company issued a press release the prior day outlining the webcast topics, including Phase I data for XmAb942 and preclinical characterization of XmAb412.
Company frames TL1A as a next-generation IBD opportunity
President and CEO Bassil Dahiyat described Xencor as a clinical-stage biotechnology company leveraging its XmAb protein engineering platform to develop differentiated antibodies, including a six-program wholly owned clinical pipeline. He said the company’s current focus in inflammatory bowel disease is a “TL1A portfolio” that includes XmAb942 and XmAb412.
Dahiyat said XmAb942 is being evaluated in XENITH-UC, a global Phase IIb trial in moderately to severely active ulcerative colitis. He added that XmAb412 is expected to start a Phase I study in the third quarter of 2026. Xencor expects to provide a progress update on XENITH-UC around year-end and said it expects results from the 12-week induction period during 2027.
For XmAb942, Dahiyat said the company engineered a stable antibody with “class-leading potency,” using its Xtend Fc domain to achieve a 74-day half-life in humans, with a high-concentration formulation and every-12-week dosing. For XmAb412, he said Xencor designed a “novel bispecific 1+1 format” intended to minimize immune complex formation and support formulation, also incorporating an Xtend Fc domain for long half-life and “ultra-high potency,” including sub-picomolar binding.
Xencor details XenLock Fab platform and XmAb412 preclinical profile
Chief Scientific Officer John Desjarlais introduced Xencor’s “XenLock Fab” format, which he said enables assembly of stable multispecific antibodies in a native-like IgG format. Desjarlais said the approach allows optimization of affinity and stability without constraints seen in some other multispecific approaches.
Desjarlais said XmAb412 demonstrates “femtomolar affinity” (sub-picomolar) for IL-23 and “single-digit picomolar” affinity for TL1A. In cell-based assays, he said XmAb412 showed the “same or better potency” in suppressing TL1A and IL-23 pathways compared with “leading clinical TL1A and marketed IL-23 antibodies.”
He emphasized a design rationale for trimeric targets such as TL1A, stating that antibodies with two TL1A binding domains can drive large immune complex formation, which he described as an “important driver” of immunogenicity. Desjarlais said Xencor’s 1+1 format reduces the propensity for such complexes, which the company assessed using size exclusion chromatography.
Desjarlais also reported non-human primate pharmacokinetics for XmAb412 showing a half-life greater than 20 days, which he said extrapolates to an expected 60–70 days in humans and could potentially support every-12-week dosing. He added that pharmacodynamic data in primates showed suppression of free TL1A below detection limit for more than two months after a single dose. Xencor said a high-concentration formulation is ready for the planned Phase I study.
XmAb942 Phase I: safety, half-life, target engagement, and immunogenicity
Mark Osterman, senior vice president and head of clinical development for Xencor’s autoimmune programs, reviewed results from a randomized, double-blind, placebo-controlled Phase I healthy participant trial of XmAb942. Osterman said the study assessed four dose levels across single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, including both subcutaneous and intravenous dosing in the SAD portion.
Osterman said XmAb942 was “safe and well-tolerated,” with similar rates of treatment-emergent adverse events (TEAEs) versus placebo. He noted all TEAEs were mild or moderate, with no serious or severe TEAEs and no discontinuations due to adverse events. Headache was the most common event, occurring in 33% of XmAb942 participants versus 38% of placebo participants. He said there were two definite treatment-related adverse events, both mild, occurring at the highest subcutaneous dose: an injection site reaction and an administration site bruise.
Osterman said XmAb942 showed high and extended exposure after 20 weeks of follow-up and that the estimated terminal half-life of 74 days supports drug levels for the 12-week dosing interval being used in XENITH-UC. He also described “dose-dependent and durable target engagement” with complex soluble TL1A and said reductions in free soluble TL1A were “dramatic, rapid, and durable,” remaining below the lower limit of quantification through 20 weeks.
On immunogenicity, Osterman said XmAb942 demonstrated “best-in-class immunogenicity” compared with reported rates from first-generation anti-TL1A drugs in healthy volunteer studies. He said that for the induction and maintenance regimens being used in XENITH-UC, no healthy volunteers had neutralizing antibodies and 25% had anti-drug antibody (ADA) positivity at any time point.
External IBD expert discusses exposure-response and trial design
Xencor also featured a discussion with Dr. Vipul Jairath, professor of medicine in gastroenterology at Western University and chief medical officer at Alimentiv. Osterman and Jairath discussed ongoing unmet need in ulcerative colitis, including that “more than half” of patients do not adequately respond to advanced therapies, and the potential for TL1A as a more “pleiotropic” mechanism.
Jairath said he expects exposure-response relationships across the TL1A class and emphasized that optimizing drug exposure can help both efficacy and durability, while potentially reducing immunogenicity risk seen with low drug concentrations.
Osterman described Xencor’s quantitative systems pharmacology (QSP) model integrating clinical and published data and said model-based projections suggest enhanced target inhibition for XmAb942 versus first-generation TL1A antibodies during induction and maintenance. Jairath said he was “impressed” by the modeling, adding that higher exposures could translate into higher response and remission rates and durable benefit, and he said the predicted differences in inhibition compared with first-generation competitors were “substantial.”
They also reviewed key features of the XENITH-UC Phase IIb trial, including three active arms versus placebo, asymmetric randomization with 77% of induction patients receiving active drug, and a 12-week placebo period. Osterman said all patients would receive active drug at week 12 for up to two years through an open-label extension. Jairath called it a “state-of-the-art trial,” citing the dose-ranging design, recruitment features, and convenient every-12-week maintenance dosing.
On XmAb412, Osterman said the bispecific targets IL-23p19 rather than p40 and is designed to robustly suppress both TL1A and IL-23 pathways. Jairath said TL1A plus IL-23 inhibition is “probably the most exciting prospect” in the field and noted potential regulatory and development advantages of a bispecific compared with combination or co-formulation approaches.
Development timeline and investor Q&A: 2027 as decision point
Chief Strategy Officer Dane Leone said Xencor expects 2027 to be “data-driven,” with the primary analysis of XENITH-UC’s 12-week induction period expected during 2027 and interim results from the XmAb412 first-in-human study expected in the first half of 2027. Leone said those data sets are expected to help the company “optimize our investment across our TL1A pipeline.”
During Q&A, management said it views ulcerative colitis as a first proof-of-concept setting for XmAb942 and indicated that further expansion into Crohn’s disease would be triggered by data from XENITH-UC in the “back half of 2027.” Responding to questions about immunogenicity in the Phase I XmAb942 study, Dahiyat said ADA incidence decreased with higher dosing across cohorts, and he attributed the overall pattern to a common phenomenon in monoclonal antibody therapeutics where higher exposure can reduce the magnitude and frequency of ADA positivity.
Management also discussed how XmAb942 and XmAb412 could coexist, with Dahiyat and Leone pointing to a role for TL1A monotherapy across indications and the bispecific as a targeted approach for settings where both TL1A and IL-23 are implicated. Osterman and Jairath said they see room for both approaches within IBD, depending on patient needs and where bispecifics fit into evolving treatment paradigms.
In closing remarks, Dahiyat said Xencor plans to advance XmAb412 into first-in-human testing later in 2026 and looks ahead to XmAb942 data readouts during 2027, while also aiming to initiate Phase II studies for XmAb412 in 2027.
About Xencor NASDAQ: XNCR
Xencor, Inc is a clinical-stage biopharmaceutical company focused on the design and development of engineered protein therapeutics for the treatment of autoimmune diseases, cancer and neurological disorders. The company applies its proprietary XmAb® platform to manipulate antibody structure and function, creating molecules with enhanced immune engagement and extended half-life. Xencor's research programs span a range of therapeutic modalities, including monoclonal antibodies, bispecific antibodies and cytokine-based fusion proteins.
The XmAb® platform enables precise modification of the Fc region to augment key properties such as receptor binding, effector function and pharmacokinetics.
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