Xencor Reports Positive Early Data for Anti-TL1A Antibody in Bowel Disease
Xencor, Inc. a leading clinical-stage biopharmaceutical company specializing in the development of engineered antibodies for the treatment of cancer and autoimmune diseases, has announced positive interim results from the first-in-human study of XmAb942, an investigational high-potency, extended half-life anti-TL1A antibody. This novel therapeutic candidate is being explored for its potential in treating inflammatory bowel disease (IBD), including both ulcerative colitis (UC) and Crohn’s disease (CD).
The initial findings from the healthy volunteer dose-escalation study are promising, suggesting that XmAb942 is well tolerated across both single and multiple doses. Pharmacokinetic analysis of the single-dose cohorts estimated a human half-life for XmAb942 of more than 71 days, a finding that aligns with preclinical data and supports the potential for a 12-week dosing interval during the maintenance phase of treatment.
This progress has paved the way for the next phase in XmAb942’s clinical development. Based on the encouraging interim data, Xencor is advancing XmAb942 into the XENITH clinical program. The first step in this program will be a Phase 2b study specifically targeting patients with moderate-to-severely active UC, dubbed XENITH-UC. This pivotal study is set to begin in the latter half of 2025.
In addition to XmAb942, Xencor continues to make significant strides in the development of its other promising pipeline candidate, the XmAb TL1A x IL23p19 bispecific antibody. This bispecific antibody is designed to target two key proteins implicated in autoimmune diseases, and recent in vitro studies have shown that lead candidates in this program exhibit comparable target inhibition potency to commercial monospecific antibodies, albeit in a simple bispecific immunoglobulin G (IgG) format. These candidates are currently in the final stages of lead selection and manufacturing, with the goal of initiating a first-in-human study in 2026.
“Positive Phase 1 Results for XmAb942 Reinforce Our Goal of Delivering Best-in-Class Therapy for IBD Patients”
Bassil Dahiyat, Ph.D., president and CEO of Xencor, expressed his enthusiasm about the early data for XmAb942, stating, “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.” He further added, “We are excited to start our Phase 2b XENITH-UC trial later this year to efficiently support dose selection for pivotal studies, and we are poised to select our TL1A x IL23p19 bispecific lead candidate for an anticipated Phase 1 start in 2026. These and other milestones across our clinical portfolio are supported by our strong cash position.”
The announcement comes at a significant time for Xencor, as the company’s portfolio continues to expand and its financial position remains robust. The clinical and preclinical advancements outlined by Xencor underscore the company’s commitment to developing novel therapies with the potential to make a profound impact on the lives of patients suffering from autoimmune diseases such as IBD.
Key Highlights from the Phase 1 Study Interim Results
The Phase 1 study of XmAb942 is a randomized, double-blind, placebo-controlled, dose-escalation trial that explores both intravenous (IV) and subcutaneous (SC) dosing routes. The study involved three escalating dose levels, and the interim results reflect analyses of subjects in single-dose cohorts (IV, n=24; SC, n=24) as well as in multiple-dose cohorts (IV, n=16).
- Safety: The blinded interim safety analysis revealed that all dose levels and administration routes were well tolerated. Importantly, no serious adverse events were observed, and there were no adverse events leading to discontinuation of the study. The study remains blinded until the completion of the follow-up for the multiple-dose portion.
- Pharmacokinetics: The pharmacokinetic analysis of the single-dose cohorts indicated that XmAb942 has a human half-life of greater than 71 days. This result is consistent with previous data observed in non-human primates and with scaling metrics for antibodies that have extended half-lives. This extended half-life suggests that XmAb942 could be administered less frequently, a significant advantage for patients who require long-term treatment.
- Pharmacodynamics: The interim results demonstrated that XmAb942 produces large and durable dose-dependent increases in total TL1A in circulation, in both IV and SC cohorts. These increases were observed to persist over time, suggesting that XmAb942’s design provides robust therapeutic exposure. Furthermore, circulating free TL1A levels were significantly reduced compared to placebo in all cohorts, further validating the efficacy of XmAb942 in modulating its target.
- Immunogenicity: Early pharmacokinetic analyses of both single and multiple-dose cohorts did not show any evidence of anti-drug antibodies (ADAs) against XmAb942, which is an encouraging sign regarding the potential immunogenicity profile of the antibody.
XENITH-UC: The Phase 2b Study in Ulcerative Colitis (UC)
The next step for XmAb942 in clinical development is the Phase 2b XENITH-UC trial, which will evaluate its efficacy and safety in patients with moderate-to-severely active UC, a chronic form of inflammatory bowel disease. UC often results in long-term inflammation and ulceration of the colon and rectum, leading to debilitating symptoms. Many patients with UC do not achieve satisfactory results with conventional treatments, highlighting the need for new therapeutic options.
The XENITH-UC trial will be a randomized, double-blind, placebo-controlled study, involving approximately 220 patients. These patients will have active UC that has not adequately responded to at least one conventional or advanced therapy. The study will investigate XmAb942 administered intravenously during the 12-week induction period, followed by subcutaneous dosing every 12 weeks during the maintenance phase.
The primary endpoint of the trial will be clinical remission, assessed by the modified Mayo score at week 12. The study is designed to power dose selection for subsequent Phase 3 trials, ensuring that the appropriate dosing regimen is established. The XENITH-UC study is expected to commence in the second half of 2025, with the goal of advancing XmAb942 as a potential treatment option for patients suffering from UC who have limited treatment options.
Strong Pipeline and Strategic Vision
In addition to XmAb942, Xencor is also advancing its next-generation antibody therapies, including the XmAb TL1A x IL23p19 bispecific antibody, which targets both TL1A and IL23p19, proteins involved in immune system regulation and inflammation. Recent in vitro studies of the bispecific antibody candidates have shown promise, with the ability to effectively inhibit both targets at potency levels comparable to existing commercial therapies, but within the simpler bispecific IgG format.
Xencor’s focus on delivering effective therapies for autoimmune diseases aligns with the company’s broader strategy of leveraging its proprietary XmAb technology platform to design antibodies with improved properties, such as extended half-lives, potent activity, and reduced dosing frequency. These efforts position Xencor well for continued success as it works toward improving patient outcomes in autoimmune and oncology indications.
Xencor’s recent progress with XmAb942 in IBD and its strategic plans for upcoming clinical trials reflect a significant step forward in the company’s mission to develop breakthrough therapies for patients in need. With strong interim data supporting the safety and pharmacokinetics of XmAb942, the upcoming Phase 2b study in UC is poised to be a critical milestone. Coupled with the promising development of its bispecific antibody program, Xencor is well-positioned to make meaningful advancements in the treatment of inflammatory diseases and beyond.
Xencor’s robust pipeline, strong leadership, and healthy financial position provide the foundation for its continued growth and success in the biopharmaceutical industry. As the company moves forward with its clinical programs, patients, clinicians, and stakeholders will be closely watching the impact of these novel therapies in addressing some of the most pressing medical challenges in autoimmune and cancer care.
