A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study in Healthy Participants Followed by a Randomized, Double-Blind, Placebo-Controlled Phase 2 Study in Participants with Moderate-to-Severe Active Ulcerative Colitis.

The primary objective is to evaluate the efficacy of XmAb942 in inducing clinical remission in participants with moderately to severely active ulcerative colitis. This endpoint is clinically relevant as achieving clinical remission represents a key therapeutic goal in the management of ulcerative colitis, reflecting both symptom resolution and disease control.

The secondary objectives include:

• To characterize the safety and tolerability of XmAb942

• To evaluate the efficacy of XmAb942 on inducing endoscopic improvement

• To evaluate the efficacy of XmAb942 on Modified Mayo Score (MMS)

• To evaluate the efficacy of XmAb942 on inducing clinical response

• To evaluate the efficacy of XmAb942 on inducing histologic improvement

This clinical trial enrolled a total of **166 participants** diagnosed with **ulcerative colitis**, a chronic inflammatory bowel disease characterized by relapsing and remitting inflammation of the colonic and rectal mucosa. The study population included both **male and female subjects** aged **18 to 75 years** who were in good general health with no significant medical history. Eligible participants were required to have a confirmed diagnosis of ulcerative colitis for at least 3 months prior to screening and present with moderately to severely active disease, as defined by a **modified Mayo score** of 5 or greater, a **Mayo endoscopic subscore** of 2 or greater, and a rectal bleeding subscore of 1 or greater. Additionally, participants demonstrated evidence of ulcerative colitis extending at least 15 cm from the anal verge, confirmed by screening colonoscopy. The trial specifically recruited individuals who had experienced inadequate response to, loss of response to, or intolerance to at least one conventional or advanced therapy for ulcerative colitis. All participants were required to be able and willing to provide written informed consent.

This is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of **XmAb942** in participants with moderately to severely active **ulcerative colitis**. Ulcerative colitis is a type of **inflammatory bowel disease**, a chronic relapsing and remitting gastrointestinal disorder causing inflammation of the colonic and rectal mucosa. The study follows a multi-stage design, with Phase 2 being conducted to assess the investigational medicinal product in the target patient population. The trial is classified as Phase 2 in the European Union, although it represents an integrated Phase 1-Phase 2 clinical trial design overall.

The primary objective is to evaluate the efficacy of XmAb942 in inducing **clinical remission** in participants with moderately to severely active ulcerative colitis. The **primary endpoint** is clinical remission at Week 12, defined as a **modified Mayo score** of 2 or less, with an **endoscopic subscore** of 1 or less (excluding friability), a **rectal bleeding subscore** of 0, and a **stool frequency subscore** of 1 or less with at least a 1-point decrease from baseline. Secondary endpoints include assessment of **treatment-emergent adverse events** (TEAEs), treatment-related TEAEs, **serious adverse events** (SAEs), and discontinuations due to treatment-related TEAEs. Additional secondary endpoints evaluate endoscopic remission defined as an endoscopic subscore of 1 or less at Week 12, modified Mayo score at baseline and Week 12, clinical response at Week 12, and histologic improvement at Week 12 as defined in the Statistical Analysis Plan.

Participants eligible for enrollment must meet specific inclusion criteria. Key inclusion criteria include age between 18 and 75 years, diagnosis of ulcerative colitis for at least 3 months prior to screening, and moderately to severely active ulcerative colitis as defined by a modified Mayo score of 5 or greater, with a Mayo endoscopic subscore of 2 or greater and rectal bleeding subscore of 1 or greater. Evidence of ulcerative colitis extending at least 15 cm from the anal verge as determined by screening **colonoscopy** is required. Participants must have inadequate response to, loss of response to, or intolerance to at least one of the conventional or advanced therapies for ulcerative colitis. All participants must be able and willing to provide written **informed consent**.

The investigational medicinal product **XmAb942** is administered as a **solution for infusion** via **intravenous**, subcutaneous, or intramuscular routes. The maximum daily dose is 960 mg, with a maximum total dose of 5136 mg over a maximum treatment period of 48 weeks. The **placebo** is a solution of the same formulation excipients at the same concentration and pH as the XmAb942 drug product, except that it contains no active ingredient. The placebo consists of 20 mM histidine buffer, 7% (w/v) sucrose, and 0.04% polysorbate 80 at pH 6.0.

The estimated recruitment start date for the trial is December 2, 2025, with an estimated end date of April 30, 2028. The overall trial duration encompasses the recruitment period, treatment phase, and follow-up assessments. Participant involvement includes a **screening visit** to assess eligibility through clinical evaluation and colonoscopy, followed by randomization to receive either XmAb942 or placebo. Study visits are scheduled at regular intervals throughout the treatment period to monitor efficacy and safety parameters. The primary assessment occurs at Week 12, with continued monitoring through the maximum treatment period of 48 weeks. An **end-of-study visit** is conducted to complete final safety and efficacy evaluations.

Conditions that may lead to early termination from the study include the occurrence of serious adverse events, treatment-related adverse events requiring discontinuation, withdrawal of informed consent by the participant, protocol violations, or investigator discretion based on safety concerns. Participants who discontinue treatment prematurely may be asked to complete end-of-study assessments to ensure comprehensive safety monitoring and data collection.

**XmAb942** is administered as a **solution for infusion** containing the active substance XmAb942, a protein-based therapeutic agent. The investigational medicinal product is manufactured by Xencor and is delivered via **intravenous, subcutaneous, or intramuscular routes**. The maximum daily dose is **960 mg**, with a maximum total dose of **5136 mg** administered over a treatment period of up to **48 weeks**. XmAb942 serves as the experimental intervention in this randomized, double-blind, placebo-controlled study evaluating its efficacy in inducing clinical remission in participants with moderately to severely active **ulcerative colitis**.

The **placebo** comparator is formulated as a solution containing the same excipients at identical concentrations and pH as the XmAb942 drug product, but without any active ingredient. The placebo formulation consists of **20 mM histidine buffer**, **7% (w/v) sucrose**, and **0.04% polysorbate 80** at **pH 6.0**. This matching placebo composition ensures blinding integrity throughout the study by maintaining identical physical and chemical properties to the active treatment, with the exception of the absence of the therapeutic agent.

Efficacy will be assessed using the primary endpoint of **clinical remission** at Week 12, defined as a modified Mayo score of 2 or less, with an endoscopic subscore of 1 or less (excluding friability), a **rectal bleeding** subscore of 0, and a **stool frequency** subscore of 1 or less (with at least a 1-point decrease from baseline). Secondary efficacy endpoints include **endoscopic remission** defined as an endoscopic subscore of 1 or less (excluding friability) at Week 12. The modified Mayo score will be evaluated at baseline and Week 12. **Clinical response** at Week 12 will be assessed, defined as a decrease from baseline in the modified Mayo score of 2 points or more and at least a 30% reduction from baseline, along with a decrease of 1 point or more in rectal bleeding from baseline or rectal bleeding of 1 or less. **Histologic improvement** at Week 12 will be evaluated as defined in the Statistical Analysis Plan.