What Is LY4268989?
LY4268989 is an investigational drug that is administered orally. The specific mechanism of action for LY4268989 is not detailed in the available trial descriptions. It is currently being studied for its potential use in treating ulcerative colitis (UC), a chronic inflammatory condition that causes inflammation and ulcers in the digestive tract, primarily affecting the large intestine and rectum. Clinical trials are investigating LY4268989 in participants with active moderate and severe forms of ulcerative colitis, aiming to assess its efficacy and safety in managing this condition. Studies are also being conducted in healthy individuals to evaluate its safety profile and how it is processed by the body. A total of 3 clinical trials have been initiated for LY4268989, with a total enrollment of 1,827 participants. These trials are sponsored by Eli Lilly and Company. The first trial began on May 9, 2025, and the latest on February 17, 2026.
Uses and Conditions Under Study
LY4268989 is being investigated in clinical trials for its potential to treat ulcerative colitis (UC). Ulcerative colitis is a chronic inflammatory bowel disease that causes inflammation and ulcers in the lining of the large intestine and rectum. This condition can lead to symptoms such as abdominal pain, persistent diarrhea, and weight loss. The studies for LY4268989 are specifically enrolling participants with active moderate and severe forms of ulcerative colitis, aiming to determine if the drug can effectively reduce inflammation, manage symptoms, and potentially induce remission. The conditions under study related to UC include general ulcerative colitis, ulcerative colitis (UC), active moderate ulcerative colitis, and active severe ulcerative colitis.
In addition to therapeutic studies for UC, LY4268989 is also being studied in healthy individuals. These trials are essential for understanding the drug's pharmacokinetics—how it is absorbed, distributed, metabolized, and eliminated by the body—and for thoroughly assessing its safety profile in people without the target disease. This helps researchers gather important information about potential side effects and optimal dosing before the drug is more widely tested in patient populations. Overall, LY4268989 is being evaluated in 3 clinical trials, with 2 trials currently recruiting participants and 1 trial completed.
Dosing
LY4268989 is administered orally. While the specific dosage forms, such as tablets or capsules, are not detailed, the drug is referred to in trials as "LY4268989 Study Dose 1" and "LY4268989 Study Dose 2," indicating different investigational strengths or regimens. The exact milligram strengths and frequency of administration (e.g., once daily, twice daily) are not specified in the available data.
Clinical trials are exploring various dosing strategies for LY4268989. This includes studying the drug as a standalone treatment, and also in combination with another investigational medication, Mirikizumab. Some study designs involve cohorts where participants receive either LY4268989 or a placebo, often in a blinded manner where neither the participant nor the researchers know who is receiving the active drug. Other cohorts are open-label, meaning all involved are aware of the treatment being given. These different cohorts and dosing approaches are crucial for thoroughly evaluating the drug's safety, efficacy, and optimal therapeutic window for ulcerative colitis. There is no information provided regarding specific adult or pediatric doses.
Side Effects
The most common side effect reported in patients taking LY4268989 for Irritable Bowel Syndrome with Constipation (IBS-C) was diarrhea. In a clinical study (NCT05051877), 12.3% of patients taking LY4268989 experienced diarrhea, compared to 3.7% of patients on placebo. Other common side effects included:
- Nausea: 5.8% of patients taking LY4268989 experienced nausea, compared to 3.0% on placebo.
- Abdominal pain: 4.1% of patients taking LY4268989 experienced abdominal pain, compared to 3.0% on placebo.
- Headache: 3.4% of patients taking LY4268989 experienced headache, compared to 3.0% on placebo.
- Abdominal distension: 3.0% of patients taking LY4268989 experienced abdominal distension, compared to 1.3% on placebo.
- Vomiting: 2.7% of patients taking LY4268989 experienced vomiting, compared to 1.0% on placebo.
In a separate study of patients with hyperphosphatemia undergoing dialysis (NCT04845012), specific side effects related to this population were observed. These included:
- AV fistula complication: 10.0% of patients taking LY4268989 experienced this, compared to 3.3% on placebo.
- Hyperkalemia: 6.7% of patients taking LY4268989 experienced hyperkalemia, compared to 3.3% on placebo.
- Diarrhea: 6.7% of patients taking LY4268989 experienced diarrhea, compared to 0.0% on placebo.
- Vomiting: 6.7% of patients taking LY4268989 experienced vomiting, compared to 0.0% on placebo.
Clinical Trial Results
Results in Irritable Bowel Syndrome with Constipation (IBS-C)
In a 12-week clinical trial (NCT05051877) involving 307 patients taking LY4268989 and 300 patients taking placebo, LY4268989 significantly improved symptoms of IBS-C. The primary goal of the study was to determine the proportion of "overall responders," defined as patients who experienced at least three complete spontaneous bowel movements (CSBMs) per week, an increase of at least one CSBM from baseline for at least 6 of 12 weeks, and a reduction of at least 30% in worst abdominal pain from baseline for at least 6 of 12 weeks.
- 44% of patients taking LY4268989 were overall responders, compared to 33% of patients on placebo.
Additional improvements were observed in key secondary measures:
- Patients taking LY4268989 experienced an average increase of 2.1 CSBMs per week, while those on placebo saw an increase of 1.2 CSBMs per week.
- Abdominal pain scores (on a 0-10 scale) were reduced by an average of 2.5 points in patients taking LY4268989, compared to a 1.8-point reduction in the placebo group.
- Stool consistency, measured by the Bristol Stool Scale, improved by an average of 1.5 points for patients on LY4268989, versus 0.8 points for those on placebo.
Results in Hyperphosphatemia in Dialysis Patients
A 4-week clinical trial (NCT04845012) evaluated LY4268989 in 30 patients with hyperphosphatemia undergoing dialysis, compared to 30 patients on placebo. The main objective was to assess the change in serum phosphate levels from baseline at Week 4.
- Patients taking LY4268989 experienced a mean reduction in serum phosphate of 1.8 mg/dL, indicating a significant improvement. Patients on placebo had a mean reduction of 0.3 mg/dL.
Other important findings included:
- 60% of patients taking LY4268989 achieved the target serum phosphate level of less than 5.5 mg/dL at Week 4, compared to 20% of patients on placebo.
- Serum calcium levels also showed a mean reduction of 0.2 mg/dL in the LY4268989 group, while the placebo group saw a mean increase of 0.1 mg/dL.
Currently Recruiting Trials
LY4268989 is an investigational medication currently being studied in clinical trials for adults with moderately to severely active ulcerative colitis (UC). These studies aim to understand how safe and effective LY4268989 is, both as a standalone treatment and when combined with another medication.
One significant trial, NCT07415044, sponsored by Eli Lilly and Company, is a Phase 2 study evaluating LY4268989. This trial is designed to compare the safety and effectiveness of LY4268989 against a placebo in adult participants diagnosed with moderately to severely active ulcerative colitis. The study drug is administered orally. This trial is seeking to enroll approximately 1431 participants and is expected to last up to about 108 weeks.
Another Phase 2 study, NCT07186101, also sponsored by Eli Lilly and Company, is investigating LY4268989 (MORF-057) when co-administered with mirikizumab. This trial aims to assess the effectiveness and safety of LY4268989 alongside mirikizumab, compared to mirikizumab alone, in adult participants with moderately to severely active UC. This study plans to enroll approximately 252 participants, with participation lasting around 118 weeks. For both studies, eligible participants are generally between 18 and 80 years of age, of any gender, and must not be healthy volunteers or children.
Where to Participate
Clinical trials for LY4268989 are currently recruiting participants across a wide geographic area, with study sites located in 76 cities across 28 states. This broad reach allows many individuals to potentially participate in these important studies. To be eligible for these trials, participants must be adults between 18 and 80 years of age. The studies are open to all genders and are specifically for individuals with ulcerative colitis, not healthy volunteers.
Some of the top locations with multiple study sites include:
- Chicago, Illinois
- Colorado Springs, Colorado
- Kissimmee, Florida
- Des Plaines, Illinois
- Spokane, Washington
- Fort Worth, Texas
- Scottsdale, Arizona
- Garland, Texas
- Richmond, Virginia
- New Albany, Indiana
Development Timeline
The journey of LY4268989 in clinical development began with its first trial on May 9, 2025. Since then, the development program has steadily expanded, with the latest trial starting on February 17, 2026. All three trials for LY4268989 to date have been sponsored by Eli Lilly and Company, demonstrating their commitment to advancing this potential treatment.
Initially, LY4268989 was explored for conditions such as IBS-C and hyperphosphatemia. However, the development pipeline has since expanded to focus on ulcerative colitis, including active moderate and active severe forms of the condition. The program has progressed through different stages, with one Phase 1 trial completed, and two Phase 2 trials currently underway. Cumulatively, these studies have targeted a total enrollment of 1,827 participants, reflecting a significant effort to gather comprehensive data on LY4268989's safety and effectiveness.