Phase 2 Platform Trial to Assess the Efficacy and Safety of Long-acting Antibodies as Single Agents and in Combinations for Moderately to Severely Active Ulcerative Colitis

The primary objective is divided into two parts. Part A evaluates the effects of intervention on histologic disease activity following 12 weeks of treatment in patients with moderately to severely active ulcerative colitis. Part B assesses the efficacy of intervention in inducing clinical remission following 12 weeks of treatment. These objectives are clinically relevant as histologic assessment and clinical remission represent key treatment outcomes in ulcerative colitis management, reflecting both mucosal healing and symptomatic control.

The secondary objectives include multiple endpoints across both study parts. Part A secondary objectives are: • To assess the efficacy of intervention in inducing clinical remission following 12 weeks of treatment. • To assess the efficacy of intervention in inducing endoscopic improvement following 12 weeks of treatment. • To assess the efficacy of intervention in improving clinical disease activity following 12 weeks of treatment. • To evaluate pharmacokinetics of intervention during the Induction Treatment Period (ITP). • To evaluate the presence of anti-drug antibodies (ADA) during the ITP. Part B secondary objectives are: • To assess the efficacy of intervention in inducing endoscopic improvement following 12 weeks of treatment. • To assess the efficacy of intervention in inducing clinical response following 12 weeks of treatment. • To assess the efficacy of intervention in inducing histologic improvement following 12 weeks of treatment. • To assess the efficacy of intervention in inducing histologic endoscopic mucosal improvement (HEMI) following 12 weeks of treatment. • To assess the efficacy of intervention in achieving clinical remission at the end of the Maintenance Treatment Period (MTP). • To evaluate pharmacokinetics of study drug(s) during the ITP. • To evaluate the presence of anti-drug antibodies (ADA) during the ITP.

This clinical trial enrolled a total of **407 participants** diagnosed with **moderately to severely active ulcerative colitis**. The study population consisted of both **male and female adults** aged **18 years and older**. Participants were required to have a confirmed diagnosis of ulcerative colitis for at least 3 months prior to enrollment, with active disease extending at least 15 cm from the anal verge, although up to approximately 15% of the total population could have only **proctitis** (less than 15 cm from the anal verge). Disease activity was defined by a modified Mayo score of 5 to 9, a rectal bleeding subscore of at least 1, and a Mayo endoscopic subscore of at least 2. The trial population was selected based on a history of **corticosteroid dependence**, inadequate response, loss of response, or intolerance to either conventional therapy (including oral corticosteroids or **immunosuppressants**) or approved advanced therapies (such as **anti-TNF agents**, **anti-α4β7**, **anti-IL-12/IL-23**, **anti-IL-23**, **JAK inhibitors**, or **S1P receptor antagonists**). Participants receiving oral corticosteroids at enrollment were required to maintain a stable dose for at least 2 weeks prior to study initiation. The study did not include vulnerable populations.

This is a Phase 2 platform trial designed to evaluate the efficacy and safety of long-acting antibodies administered as single agents and in combinations in participants with moderately to severely active ulcerative colitis. The trial employs a platform design consisting of two parts: Part A and Part B. The investigational products include SPY001-001 and SPY002, administered via intravenous and subcutaneous routes. SPY001-001 is available as a solution for infusion and solution for injection, while SPY002 is similarly formulated in both solution for infusion and solution for injection. The trial also includes placebo products designated as SPYPBO-101 and SPYPBO-102. The maximum treatment period is 36 months for subcutaneous formulations and 12 months for intravenous formulations.

The trial is designed to enroll male and female participants aged 18 years or older who have a confirmed diagnosis of ulcerative colitis for at least 3 months prior to Day 1, verified by endoscopy and histology. Eligible participants must present with active disease extending at least 15 cm from the anal verge, with the exception of up to approximately 15% of participants who may have proctitis with disease extent less than 15 cm. Disease activity must be moderately to severely active, defined by a modified Mayo score of 5 to 9, a rectal bleeding subscore of at least 1, and a Mayo endoscopic subscore of at least 2. Participants must have a history of corticosteroid dependence, inadequate response, loss of response, or intolerance to either conventional therapy (including oral corticosteroids or immunosuppressants) or approved advanced therapies (including anti-TNF, anti-α4β7, anti-IL-12/IL-23, anti-IL-23, JAK inhibitors, or S1P receptor antagonists). Participants receiving oral corticosteroids at doses up to 20 mg/day prednisone or equivalent, 9 mg/day budesonide, or 5 mg/day beclomethasone must maintain a stable dose for at least 2 weeks prior to Day 1.

The primary objective of Part A is to assess the effects of intervention on histologic disease activity following 12 weeks of treatment, with the primary endpoint being the change in Robarts Histopathology Index (RHI) from baseline at Week 12. The primary objective of Part B is to assess the efficacy of intervention in inducing clinical remission following 12 weeks of treatment, with clinical remission at Week 12 serving as the primary endpoint. Secondary endpoints for Part A include clinical remission at Week 12, endoscopic improvement at Week 12, change in modified Mayo score from baseline at Week 12, study drug concentration through Week 12, and the percentage of participants with anti-drug antibodies (ADAs) to study drug(s) through Week 12. Secondary endpoints for Part B include endoscopic improvement at Week 12, clinical response at Week 12, histologic improvement at Week 12, histologic-endoscopic mucosal improvement (HEMI) at Week 12, clinical remission at Week 48, study drug concentration through Week 12, and the percentage of participants with ADAs to study drug(s) through Week 12.

Participants in Part A will undergo an induction treatment period (ITP) during which they will remain on a stable corticosteroid dose through Week 12. Participants in Part B will maintain their baseline corticosteroid dose through Week 6, at which point a corticosteroid taper will be initiated at Week 6. The trial includes a screening visit to assess eligibility criteria, followed by baseline assessments on Day 1 when treatment is initiated. Study visits will occur at regular intervals to monitor efficacy, safety, and pharmacokinetic parameters, including assessments of disease activity, endoscopic evaluations, and collection of blood samples for drug concentration and immunogenicity testing. The estimated recruitment start date is October 30, 2025, with an estimated trial completion date of March 31, 2028. Participant involvement in Part A will extend through Week 12, while participants in Part B will be followed through Week 48 to assess long-term clinical remission. Early termination from the study may occur due to withdrawal of consent, adverse events, protocol violations, loss to follow-up, or at the discretion of the investigator if continued participation is deemed not in the best interest of the participant.

The experimental medication SPY001-001 is administered as a solution for infusion via the intravenous route with a maximum treatment period of 12 months. The active substance SPY001-001 is a protein-based compound. The dosage is expressed in milligrams per milliliter. This formulation serves as a test product in the trial.

The experimental medication SPY001-001 is also administered as a solution for injection via the subcutaneous route with a maximum treatment period of 36 months. The active substance is SPY001-001, a protein-based compound. The dosage is expressed in milligrams per milliliter. This formulation serves as a test product in the trial.

The experimental medication SPY002 is administered as a solution for infusion via the intravenous route with a maximum treatment period of 12 months. The active substance SPY002 is a protein-based compound. The dosage is expressed in milligrams per milliliter. This formulation serves as a test product in the trial.

The experimental medication SPY002 is also administered as a solution for injection via the subcutaneous route with a maximum treatment period of 36 months. The active substance is SPY002, a protein-based compound. The dosage is expressed in milligrams per milliliter. This formulation serves as a test product in the trial.

The placebo products SPYPBO-101 and SPYPBO-102 are utilized as comparator treatments in the trial. These products serve as control interventions to assess the efficacy of the experimental medications.

Efficacy will be assessed through distinct primary endpoints for each part of the trial. In Part A, the primary endpoint is the change in Robarts Histopathology Index (RHI) from baseline at Week 12. In Part B, the primary endpoint is clinical remission at Week 12. Secondary endpoints for Part A include clinical remission at Week 12, endoscopic improvement at Week 12, change in modified Mayo score from baseline at Week 12, study drug concentration through Week 12, and the percentage of participants with anti-drug antibodies (ADAs) to study drug(s) through Week 12. Secondary endpoints for Part B include endoscopic improvement at Week 12, clinical response at Week 12, histologic improvement at Week 12, histologic-endoscopic mucosal improvement (HEMI) at Week 12, clinical remission at Week 48, study drug concentration through Week 12, and the percentage of participants with ADAs to study drug(s) through Week 12. The modified Mayo score is utilized to define moderately to severely active disease at baseline, requiring a score of 5 to 9 with a rectal bleeding subscore of at least 1 and a Mayo endoscopic subscore of at least 2. Active ulcerative colitis with disease extent of at least 15 cm from the anal verge is confirmed by screening endoscopy. Efficacy assessments are conducted at specified timepoints including Week 12 and Week 48.