Efficacy and Safety Evaluation of GS-1427 in Adults with Moderately to Severely Active Ulcerative Colitis: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to assess the **efficacy** of GS-1427, compared with placebo control, in achieving clinical response at Week 12 in adult participants with moderately to severely active **Ulcerative Colitis** (UC). This is clinically relevant as achieving a clinical response can significantly improve patient outcomes and quality of life in those suffering from UC.

Secondary objectives include:

• Evaluating the safety and tolerability of GS-1427 up to Week 76.
• Assessing the efficacy of GS-1427 in achieving clinical remission at Weeks 12 and 52.
• Comparing the efficacy of GS-1427 with placebo in achieving histologic-endoscopic mucosal improvement, mucosal healing, and endoscopic improvement at Week 12.
• Assessing the efficacy of GS-1427 in achieving partial mMCS remission at Week 76.

The clinical trial involves a total of **144 participants** diagnosed with **Ulcerative Colitis (UC)**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on their confirmed diagnosis of UC, with symptoms persisting for at least 90 days prior to randomization. The trial includes individuals with a minimum disease extent of 15 cm from the anal verge and those with moderately to severely active UC, as determined by endoscopy during screening. Participants have shown an inadequate response, loss of response, or intolerance to at least one UC treatment, including corticosteroids, immunomodulators, or advanced therapies such as TNF-alpha inhibitors, interleukin-12/23 inhibitors, sphingosine 1-phosphate receptor modulators, or Janus Kinase inhibitors. The trial population is inclusive of vulnerable groups, ensuring a comprehensive assessment of the treatment's efficacy across diverse demographics. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of GS-1427 in adult participants with moderately to severely active **ulcerative colitis**. The primary objective is to assess the efficacy of GS-1427 compared to placebo in achieving a clinical response at Week 12. The trial is expected to commence recruitment on August 2, 2024, and conclude by March 15, 2028. Participants will be randomly assigned to receive either GS-1427 or a placebo, with the study drug administered orally in the form of film-coated tablets.

The trial will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to have a confirmed diagnosis of ulcerative colitis with symptoms persisting for at least 90 days prior to randomization. Participants must also demonstrate an inadequate response or intolerance to previous treatments. The primary endpoint is a clinical response at Week 12, defined as a significant reduction in the modified Mayo Clinic Score (mMCS) and rectal bleeding subscore.

Participant involvement is expected to last up to 52 weeks, with the possibility of early termination if adverse events occur or if the participant withdraws consent. Secondary endpoints include the incidence of treatment-emergent adverse events, clinical remission at Weeks 12 and 52, and various measures of mucosal improvement. The study is not classified as low intervention and adheres to the regulatory requirements for a Category Two trial under EU regulations. The trial will ensure rigorous monitoring to maintain the integrity of the double-blind design and the safety of all participants.

The clinical trial involves the evaluation of **GS-1427**, a small molecule investigational drug, in adult participants with moderately to severely active **ulcerative colitis**. GS-1427 is administered in the form of film-coated tablets and is available in three different dosages: 25 mg, 75 mg, and 100 mg. The tablets are taken orally, with a maximum daily dose of 25 mg, 75 mg, or 100 mg, depending on the assigned treatment group. The maximum total dose for the 25 mg, 75 mg, and 100 mg tablets is 1300 mg, 3900 mg, and 6500 mg, respectively, over a treatment period of up to 52 weeks. The active substance, GS-1427, is of chemical origin and is manufactured by Gilead Sciences Inc.

In addition to the experimental treatment, the study includes a placebo group to serve as a comparator. The placebo is designed to match the GS-1427 film-coated tablets in appearance and is administered orally at the same frequency as the active treatment. The placebo tablets are labeled as PTM 25 mg, PTM 75 mg, and PTM 100 mg, corresponding to the dosages of the active treatment groups. The placebo does not contain any active pharmaceutical ingredients.

Participant compliance with the dosing regimen is monitored throughout the study. The trial is conducted in a double-blind manner, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This design helps to maintain the integrity of the study results by minimizing bias. The primary objective of the trial is to assess the efficacy of GS-1427 in achieving a clinical response at Week 12, compared to the placebo control.

The efficacy of GS-1427 in the treatment of moderately to severely active **Ulcerative Colitis** will be assessed through a series of predefined endpoints. The primary endpoint is the clinical response at Week 12, defined as a decrease from baseline in the modified Mayo Clinic Score (mMCS) of ≥ 2 points and at least a 30% reduction from baseline, along with a decrease in rectal bleeding subscore of ≥ 1 from baseline or an absolute rectal bleeding subscore of 0 or 1.

Secondary endpoints include the incidence of treatment-emergent adverse events, serious adverse events, or deaths, and treatment-emergent laboratory abnormalities. Additional secondary endpoints are clinical remission at Week 12 and Week 52, histologic-endoscopic mucosal improvement at Week 12, mucosal healing at Week 12, endoscopic improvement at Week 12, and partial mMCS remission at Week 76. Clinical remission is defined as an mMCS of ≤ 2 points, including a stool frequency subscore (SFS) ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and centrally-read endoscopic subscore ≤ 1 (score of 1 modified to exclude friability). Histologic-endoscopic mucosal improvement is defined as a Geboes score ≤ 3.1 and endoscopic subscore of ≤ 1, while mucosal healing is defined as a Geboes score ≤ 2B.1 and endoscopic subscore ≤ 1. Endoscopic improvement is defined as an endoscopic subscore ≤ 1.