Randomized, Double‑Blind, Placebo‑Controlled Trial of LY4268989 (Adipic Acid) in Adults with Moderately to Severely Active Ulcerative Colitis

The primary objective is to determine whether oral LY4268989 demonstrates superiority to placebo in inducing clinical remission after a 10‑week induction period in adults with moderately to severely active ulcerative colitis, and to assess whether the same treatment maintains remission through week 52 among participants who achieved a clinical response at week 10. This evaluation addresses both short‑term disease control and long‑term durability of therapeutic effect, directly informing the potential role of LY4268989 in the management algorithm for active ulcerative colitis.

Approximately 270 individuals were enrolled, comprising both male and female adults across a broad age spectrum (approximately 18 to 75 years). All participants had a confirmed diagnosis of Ulcerative Colitis for at least three months and exhibited moderately to severely active disease, defined by a Modified Mayo Score of 5–9 with endoscopic involvement. Selection required endoscopic confirmation, disease extending proximal to the rectum, recent surveillance colonoscopy when indicated, and an inadequate response, loss of response, or intolerance to at least one conventional or advanced therapy, excluding those with prior inadequate response to vedolizumab. Participants were required to meet standard contraception requirements. General health status was otherwise stable, and no specific dietary, physical activity, or habit restrictions were stipulated as part of eligibility.

The study is a multicenter, randomized, double‑blind, placebo‑controlled Phase 4 trial evaluating the efficacy and safety of LY4268989 (MORF‑057) in adults with moderately to severely active ulcerative colitis. After an eligibility screening visit, participants meeting the inclusion criteria are randomized 1:1 to receive either oral LY4268989 tablets or matching placebo for a 10‑week induction period, followed by a maintenance phase through Week 52 for those who achieve clinical response at Week 10. The primary efficacy endpoints are the proportion of subjects attaining clinical remission, defined by a Modified Mayo Score of ≤2 with no individual subscore >1, at Week 10 and, among responders, at Week 52. Study visits are scheduled as follows: screening, baseline/randomization (Day 0), Week 2, Week 4, Week 8, Week 10 (end of induction assessment), then monthly visits through Week 52 (Visit 208), and an end‑of‑study visit. Participant involvement therefore spans approximately 12 months from randomization. Early termination may occur if a participant experiences a serious adverse event, fails to meet predefined response criteria, withdraws consent, or deviates substantially from the protocol.

The investigational product, LY4268989 (MORF‑057), is supplied as an oral tablet containing LY4268989 adipic acid. Each tablet is designated for oral use, with a nominal dose of 0 mg as specified in the study documentation. The medication is administered according to the protocol‑defined schedule: a 10‑week induction phase followed by a maintenance phase extending to week 52 for participants who achieve a clinical response at week 10.

The control arm utilizes a matching placebo tablet formulated to be indistinguishable from the active tablet in appearance and administration route. The placebo is taken orally in accordance with the same dosing schedule applied to the investigational product.

Drug administration is recorded in the study log, and participant adherence is monitored through pill count at each study visit and review of patient‑reported dosing diaries. Any deviations from the prescribed schedule are documented and reported per protocol requirements.

The primary efficacy parameter is the proportion of participants who achieve clinical remission, defined by the Modified Mayo Score, at Week 10. A secondary remission assessment is performed at Week 52 (Visit 208) among participants who demonstrated a clinical response at Week 10.

Efficacy is evaluated using the Modified Mayo Score, a validated composite instrument that incorporates stool frequency, rectal bleeding, endoscopic appearance, and physician’s global assessment. Assessments are conducted at baseline, Week 10, and Week 52, with data collected during scheduled study visits and analyzed to determine remission rates at the specified time points.