A Study to Evaluate the Safety, Tolerability, PK and Preliminary Efficacy of HX15001 Combined With Etrasimod in Moderate-severe Ulcerative Colitis

Evaluation of the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HX15001 Injection Combined With Etrasimod Tablets in the Treatment of Moderate-severe Ulcerative Colitis: an Open-label, Exploratory Clinical Trial

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of HX15001 injection combined with Etrasimod tablets in participants with moderately to severely active ulcerative colitis (UC).

Inclusion Criteria:

• Patient able to read and understand, and willing to sign the informed consent form;
• Weight≥40kg;
• Clinical diagnosis of Ulcerative colitis (UC) that has been present for at least 3 years before the screening visit;
• Mayo score of 5-9 at the baseline visits, including Mayo Endoscopic Score ≥2 and Rectal Bleeding Subscore ≥1, and disease extent from the anal verge ≥ 15 cm at screening.
• Participants with a history of extensive colitis of ≥8 years' duration, or left-sided colitis of ≥10 years' duration, must have had a complete coloscopy within the past 1 year to exclude the presence fo dysplastic lesions.
• Participants who have had an inadequate response to prior treatment with biologic agents or JAK inhibitors.
• Willing and able to comply with clinic visits and study-related procedures.
• Willing to use adequate birth control, if of reproductive potential and sexually active

Exclusion Criteria:

• Evidence or history (within 6 months) of fulminant colitis, toxic megacolon, or intestinal perforation.

• Prior colectomy (partial or total), or anticipated need for surgical intervention for UC during the study.

• Prior or current diagnosis of Crohn's disease, fistulas/abscesses, indeterminate colitis, unclassified IBD, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, active diverticulitis, or other colitis/enteritis that may confound efficacy assessment.

• Current unresolved colonic dysplasia, adenoma, adenomatous polyps, or neoplastic lesions. Patients with history of adenomatous polyps are eligible if polyps were completely removed (documented) and screening colonoscopy/histology shows no residual polyps or dysplasia.

• Concomitant primary sclerosing cholangitis or autoimmune hepatitis.

• Malignancy within 5 years prior to screening, except fully resected non-metastatic basal cell carcinoma, squamous cell carcinoma, cervical carcinoma in situ, breast ductal carcinoma in situ, or papillary thyroid carcinoma with no recurrence.

• Major surgery within 6 weeks prior to screening, or planned surgery during the study, unless judged not to increase patient risk or affect study compliance.

• Any condition precluding endoscopic evaluation.

• Unstable or poorly controlled cardiovascular (including atrial fibrillation requiring Class IA/III antiarrhythmics or QT-prolonging agents; unstable ischemic heart disease; Class I/II heart failure; cardiac arrest; cerebrovascular disease; uncontrolled hypertension; symptomatic bradycardia; recurrent cardiogenic syncope; untreated severe sleep apnea; history of second-degree AV block without a functional pacemaker), respiratory, gastrointestinal (excluding UC), hepatic, renal, endocrine, hematologic, neurologic, or psychiatric disease that may compromise patient safety or confound efficacy assessment. - Patients requiring systemic corticosteroids for non-UC conditions (e.g., asthma, adrenal insufficiency, post-transplant) or with peripheral venous access issues are excluded.

• Diabetes mellitus, uveitis, history of ocular surgery/laser, history of maculopathy, or active/uncontrolled macular edema at screening.

• Clinically significant 12-lead ECG abnormalities that may affect safety or interpretation, including QTcF >450 msec (males) or >470 msec (females), QRS >120 msec, or resting heart rate <50 bpm (average of 3 measurements used for qualification).

• Any of the following laboratory abnormalities:

  1. Hemoglobin <8.0 g/dL
  2. WBC <2,500/mm³
  3. Neutrophils <1,000/mm³
  4. Platelets <100,000/mm³
  5. Absolute lymphocyte count <500/mm³
  6. Serum creatinine >2× ULN
  7. ALT or AST >2× ULN
  8. Total bilirubin >1.5× ULN
  9. Any other laboratory abnormality considered by the investigator to pose unacceptable risk.

• History of alcohol, drug, or chemical abuse within 1 year prior to screening.

• Receipt of live or live-attenuated vaccine within 3 months prior to Day 1, or planned during the study or within 5 weeks post-treatment. VZV antibody testing required for patients without documented history or complete vaccination; antibody-positive patients are eligible; antibody-negative patients may rescreen after complete VZV vaccination (≥4 weeks before etrasimod initiation).

• Severe bacterial infection within 3 months (unless resolved with antibiotics), or chronic bacterial infection (e.g., pyelonephritis, osteomyelitis, bronchiectasis).

• C. difficile infection within 30 days prior to Day 1 (may be retested once after 2 weeks of antibiotic therapy; persistent infection excludes enrollment).

• Active invasive fungal infection (e.g., histoplasmosis) or parasitic infection.

• Diagnosis of CMV colitis within 60 days (including screening period). CMV testing on colonic biopsy is required during screening only if clinically suspected.

• Herpes zoster reactivation or CMV infection resolved within 2 months prior to screening.

• Positive for HBsAg, or HBcAb positive with detectable HBV DNA; positive HCV antibody with detectable HCV RNA; positive Treponema pallidum antibody; or positive HIV antibody at screening.

• Positive QuantiFERON-TB Gold or T-SPOT.TB test at screening.

• Use of JAK inhibitors (e.g., tofacitinib, upadacitinib, filgotinib) within 4 weeks (or 5 half-lives, whichever is longer), or anti-TNF agents (e.g., adalimumab, infliximab), vedolizumab, or anti-IL-12/23 agents (e.g., ustekinumab) within 8 weeks (or 5 half-lives, whichever is longer) prior to Day 1.

• Prior S1P receptor modulator therapy without a 3-month washout.

• Use of investigational chemical drugs within 30 days, or investigational biologics within 8 weeks (or 5 half-lives, whichever is longer) prior to Day 1.

• IV corticosteroids within 2 weeks prior to Day 1 or planned during the study.

• Corticosteroid enemas within 4 weeks, or corticosteroid suppositories and/or topical rectal 5-ASA within 2 weeks prior to Day 1, or planned during the study.

• Topical (rectal) herbal enemas or suppositories within 1 week prior to Day 1 or planned during the study.

• Immunosuppressants (e.g., tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil, leflunomide, thalidomide) within 4 weeks (or 5 half-lives, whichever is longer) prior to Day 1 or planned during the study.

• Immunoadsorption or fecal microbiota transplantation within 2 weeks prior to Day 1 or planned during the study.

• NSAIDs (e.g., aspirin >100 mg/day) within 2 weeks prior to Day 1.

• Immunoglobulin or blood products within 1 month prior to Day 1, or any condition likely to require such therapy during the study.