Evaluation of SPH3127 in Patients With Mild-to-Moderate Ulcerative Colitis

A Double-Blind, Placebo-Controlled Trial to Investigate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of SPH3127 in Patients With Mild-to-Moderate Ulcerative Colitis

SPH3127-US-01 is a multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and preliminary efficacy of SPH3127 for the treatment of mild-to-moderate ulcerative colitis.

SPH3127-US-01 is a proof-of-concept multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics, and preliminary efficacy of of daily oral administration of SPH3127 or placebo for 8 weeks in patients with mild-to-moderate ulcerative colitis. After meeting all inclusion and exclusion criteria, eligible patients will be randomized to receive SPH3127 (50 mg daily, 50 mg twice daily) or placebo tablets; all patients will take 2 tablets (SPH3127 or placebo) twice a day for 8 weeks. All randomized subjects will have the opportunity to enter an active-treatment extension (50 mg SPH3127 once or twice daily) for an additional 10 months.

Inclusion Criteria:

1. Signed Informed Consent Form (ICF);
2. Adult males and females ≥ 18 to < 70 years of age on the day of signing the ICF.
3. A diagnosis of UC (documented or confirmed at screening) will be eligible provided they have mild-to-moderate active UC extending ≥ 15 cm from the anal verge.
4. At screening/baseline, a Modified Mayo Clinic Score (MMCS) from 4-9, a rectal bleeding subscore ≥ 1, and a Mayo Clinic Endoscopic Subscale (MCES) score ≥ 2 determined by central reading.
5. Patient has a negative urine drug screen (e.g., amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates, methadone) at Screening.
6. Patient has a negative alcohol breath test at Screening.
7. Female patients who have a negative pregnancy test at Screening and who agree to use adequate birth control methods throughout the entire study (and extension, if applicable) or who is post-menopausal (i.e., amenorrhea ≥ 1 year) or who have been surgically sterilized.
8. Male patients with partners of child-bearing potential who agree to use adequate birth control methods throughout the entire study (and extension, if applicable) or who have been surgically sterilized.

Exclusion Criteria:

1. Diagnosis of severe UC, defined as the presence of ≥ 6 bloody stools daily with one or more of the following: (1) oral temperature > 37.8°C or > 100.0°F; (2) pulse > 90 beats/min; (3) hemoglobin concentration < 10.5 g/dL; or erythrocyte sedimentation ratio (ESR) > 30.

2. Patients treated with oral mesalamine >2.4 g/d, systemic steroids or rectal steroids within 4 weeks prior to randomization, rectal mesalamine (within 2 weeks), immunomodulators or immunosuppressant drugs, including, but not limited to, IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents and JAK inhibitors within 5 half-lives prior to randomization, antibiotics, anti-diarrheals (within 2 weeks), drugs blocking the renin-angiotensin system (e.g., direct renin inhibitors, angiotensin converting enzyme inhibitors, or angiotensin II receptor blockers) (within 4 weeks) or administration of any investigational drug (within 4 weeks). Because SPH3127 is a direct renin inhibitor with the potential to reduce blood pressure, other classes of antihypertensives (e.g., calcium channel blockers, beta blockers, diuretics, direct vasodilators, alpha blockers, central α2 antagonists) (within 4 weeks) will also be excluded. Drugs, herbal medicines and substances that inhibit or induce CYP3A4 (e.g., ritonavir, itraconazole, grapefruit juice) (within 2 weeks or 5 half-lives, whichever is longer) will be excluded.

3. History of colectomy or partial colectomy, colorectal dysplasia, Crohn's disease, toxic megacolon, or bleeding disorders.

4. A stool sample positive for enteric pathogens, including Clostridium difficile.

5. Patients with an estimated glomerular filtration rate (eGFR) < 60.

6. Patients with hepatic impairment or history of liver cirrhosis.

7. Serum creatinine > 1.5 times the upper limit of normal, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL) or alkaline phosphatase (ALP) > 2 times the upper limit of normal.

8. Serious underlying disease other than UC.

9. Previous participation in clinical trials with SPH3127

10. Known hypersensitivity to tablet ingredients or history of a significant allergic reaction to any drug as determined by the investigator.

11. Known seropositivity or positive test at screening for an active viral/bacterial infection with:

    • Hepatitis B virus (HBV) (except seropositivity due to HBV vaccination)
    • Hepatitis C virus
    • Human immunodeficiency virus
    • COVID-19 (only active infection excluded)
    • Tuberculosis

12. Known clinically relevant immunological disorders.

13. History of severe allergic or anaphylactic reactions.

14. History of malignancy, unless deemed cured by adequate treatment with no evidence of recurrence for a minimum 3 years before screening; completely eradicated non-melanoma skin cancer (such as basal cell carcinoma or squamous cell carcinoma) is not exclusionary.

15. Clinically relevant abnormalities detected on ECG regarding either rhythm or conduction (e.g., QTcF > 450 ms or a known long QT syndrome). A first-degree heart block or sinus arrhythmia will not be considered a significant abnormality.

16. Low blood pressure at screening (i.e., SBP < 90 mmHg or DBP < 60 mmHg).

17. Clinically relevant abnormalities detected on vital signs prior to dosing.

18. Significant blood loss (including blood donation > 500 mL) or transfusion of any blood product within 12 weeks prior to the IP administration or scheduled transfusion within 4 weeks after the end of the trial.

19. Treatment with any drug known to have a well-defined potential for toxicity to a major organ in the last 3 months preceding the initial investigational product (IP) administration.

20. Concurrent participation, or participation within 30 days prior to the IP administration or 5 half-lives of the investigational drug (whichever is longer), in any drug/device or biologic investigational research trial.

21. Women who are breastfeeding.

22. Vaccination (including influenza and COVID-19) within the last 4 weeks prior to randomization.

23. History of drug or alcohol abuse.

24. Is an investigator, sub-investigator, research assistant, pharmacist, trial coordinator, or other staff of a relative who is directly involved in the conduct of the trial.

25. Any condition or circumstances that in the opinion of the investigator may make a subject unlikely or unable to complete the trial or comply with trial procedures and requirements.