Phase 2a to Evaluate PL-8177 in Subjects with Active Ulcerative Colitis (UC)

Inclusion Criteria:

• Age ≥18 to ≤75 years of age at Screening.

• Has a history of UC diagnosis prior to screening; confirmed by endoscopic andhistologic evidence in the subject chart. If the historical evidence is notavailable, then endoscopic and histologic evidence can be confirmed during thescreening period.

Note: If no complete colonoscopy (adequate in quality to assess for dysplasia and colorectal polyps) has been performed and documented (with reports) within the past 1 year as recommended by local and national guidelines depending on Colorectal cancer risk factors in the specified subject, a full colonoscopy should be performed at screening. If such results are available within one year, a flexible sigmoidoscopy with examination up to the splenic flexure will be used for screening.

• Has active UC defined as a MES ≥2 during screening sigmoidoscopy.

• Has evidence of endoscopic disease extending to at least 5 cm proximal to the analverge.

• If currently receiving 5-ASA, the duration and dose prior to the screening endoscopymust be as specified below, and a stable dose must be maintained throughout thedouble-blind trial: 5-aminosalicylates (5-ASA) (e.g., mesalamine, sulfasalazine,olsalazine, balsalazide) for ≥4 weeks with the dose stable for ≥3 weeks prior to thescreening endoscopy.

• If recently has received any of the following treatments, they must havediscontinued as specified below:

• If 5-ASA has been recently discontinued, it must have been stopped for ≥3 weeksprior to the screening endoscopy.

• If a thiopurine has recently been discontinued, it must have been stopped for ≥4 weeks prior to the screening endoscopy.

• Oral corticosteroids must have been stopped for ≥4 weeks prior to the screeningendoscopy.

• Women of childbearing potential must have a negative serum pregnancy test atscreening and a negative urine pregnancy test at Day 1 prior to first dose of studydrug.

• Male and female subjects of childbearing potential must agree to use 1 highlyeffective form of birth control during study participation and for 30 days after thelast dose of study drug, unless the subject or his/her partner is surgicallysterilized, or the subject agrees to abstain from sexual intercourse.

• Highly effective methods of birth control in this study include intrauterine device,hormonal contraceptives (oral, patch, long acting injectable, implant). Note: Oralhormonal contraceptives should be combined estrogen and progesterone. If aprogesterone-only oral contraceptive is used, then a second method of birth controlshould be used as well.

• Postmenopausal is defined as lack of menses for ≥12 months prior to screening,confirmed by serum FSH >25 IU at Screening.

• Has provided informed consent prior to initiation of any study specificactivities/procedures.

• Understands and is willing and able to comply with study requirements, including theschedule of events and follow-up visits.

Exclusion Criteria:

Subjects will be excluded from the study if they meet any of the following criteria at the Screening visit unless otherwise stated:

• Any condition, physical finding, laboratory or ECG abnormality, which, in theopinion of the Investigator, poses a safety risk, will prevent the subject fromcompleting the study, will interfere with the interpretation of the study results,or might cause the study to be detrimental to the subject.

• Has fulminant colitis, toxic megacolon, microscopic colitis, history ofcolitis-associated colonic dysplasia, active peptic ulcer disease, cervicaldysplasia, or primary sclerosing cholangitis.

• History of Crohn's disease or indeterminate colitis, or the presence or history of afistula consistent with Crohn's disease.

• Presence of ileostomy or colostomy, or history of prior colon resection.

• Presence of adenomatous colonic polyps that have not been removed.

• Stools positive for C. difficile, enteric pathogens (Salmonella, Shigella,Campylobacter), or ova and parasites within 28 days of screening. Screen failuresdue to positive C. difficile or other enteric infection can be re-screened afterappropriate treatment.

• History of mitochondrial disorder.

• History of primary or secondary immunodeficiency.

• History of cancer within the 5 years prior to screening including solid tumors andhematological malignancies (exception: no approval needed for basal cell and in situsquamous cell carcinomas of the skin that have been adequately treated with nore-occurrence for at least 1 year prior to screening).

History of one or more clinically relevant neurologic, psychologic, ophthalmologic, pulmonary, cardiovascular, gastrointestinal (other than the UC), hepatic, renal, endocrine, or other major systemic disease of moderate (or worse) severity, making implementation of the protocol or interpretation of the study difficult. Examples of (but not limited to) conditions to be excluded, are the following:

• Uncontrolled hypertension, with systolic blood pressure (SBP) ≥160 mmHg, diastolicblood pressure (DBP) ≥90 mmHg.

• Uncontrolled hyperlipidemia (even if therapy is ongoing, LDL>200 mg/dl ortriglycerides >500 mg/dL).

• Known uncontrolled hyperthyroidism or hypothyroidism.

• Impaired hepatic function (Aspartate aminotransferase [AST] or Alanineaminotransferase [ALT] values >2.0 times the upper limit of the reference rangeand/or serum bilirubin >1.5 times the upper limit of the reference range at thescreening visit).

• Cardiac or pulmonary disease, such as unstable angina or myocardial infarctionwithin the past 12 months, congestive heart failure (CHF) Grade 2, 3, or 4 accordingto New York Heart Association criteria, valvular heart disease, cardiac arrhythmiarequiring treatment, pulmonary hypertension, or chronic pulmonary disease requiringoxygen, venous thrombosis.

• Stroke or transient ischemic attack (TIA) in the 12 months before screening.

• Major depressive illness in the last 3 years; any history of severe psychiatricillness (eg, schizophrenia).

• Multiple sclerosis or any other demyelinating disease.

• Any of the following laboratory abnormalities:

• Hemoglobin <8.5 g/dl (international system units [SI]: <85 g/L).

• Neutrophils <1500/mm3 (SI: < 1.5 x 109/L).

• White blood cell (WBC) count <3,000/mm3 (SI: < 3.0 x 109/L).

• Platelets <80,000 mm3 (SI: 80 x 109/L).

• International normalized ratio (INR) >1.5.

• Serum creatinine >1.5 x the upper limit of normal.

• Has a current bacterial, parasitic, fungal, viral, or mycobacterial infection, orany major episode of infection requiring hospitalization or treatment withintravenous (IV) antibiotics within 4 weeks prior to the screening visit, and/ororal antibiotics within 2 weeks prior to screening visit and at any time during thescreening period.

• Serological evidence of human immunodeficiency virus (HIV), hepatitis B surfaceantigen (HbsAg), or hepatitis C (HCVAb) at Screening (note: HCV subjects withundetectable viral load will be eligible).

• Clinically significant findings on 12-lead ECG such as, but not limited to, 2nd or 3rd degree AV block, prolongation of QRS complex over 120 msec, or QTcF interval ≥450 msec for males and ≥470 msec for females.

Medications of exclusion:

• Non-steroidal anti-inflammatory drugs (NSAIDs) daily.

• Subjects on anti-coagulation therapy within 28 days prior to screening and throughDay 56.

Note: (A daily dose of ASA 81mg, taken for cardio prophylaxis, is considered acceptable to be continued during the study.)

• Topical (i.e., enema or suppository) mesalamine or steroid within 14 days prior toscreening endoscopy.

• Azathioprine, 6-mercaptopurine, or methotrexate within the 28 days prior toscreening.

• Any prior use of mycohphenolic acid, tacrolimus, sirolimus, cyclosporine,thalidomide

• Any prior use of biologics: rituximab, efalizumab, anti-integrines (natalizumab,vedolizumab, etrolizumab), TNF antagonists (infliximab, , golimumab, certolizumabpegol), anti-IL-12/23 (ustekinumab, guselkumab, risankizumab, or mirikizumab) ≤ 3months prior to first dosing or ≤ 5 elimination half-lives prior to first dosing (whichever is shorter).

• Any prior use of small molecules: JAK inhibitors (tofacitinib, baricitinib,upadacitinib, or other) or S1P receptor modulator (fingolimod, ozanimod, etrasimod) ≤ 3 months prior to first dosing or ≤ 5 elimination half-lives prior to first dosing (whichever is shorter).

• Use of PPI (proton pump inhibitor) during the study (Should be discontinued 72 hoursprior to Day 1).

• Use of prescription medications started or with a dose adjustment within 4 weeksprior to study screening, or over-the-counter medications or supplements started orwith a dose adjustment within 2 weeks prior to study screening. Medications underInclusion Criterion #5 are not included. Short-term administration of drugs foracute conditions are acceptable.

• Anti-diarrheal medications are not allowed within 48 hours of screening andthroughout the study.

• Participated in another clinical trial of an investigational drug (or medicaldevice) within 30 days prior to screening or is currently participating in anothertrial of an investigational drug (or medical device).

• Subjects with planned hospitalization or surgery during the study.

• Subject has known sensitivity to any of the products or components to beadministered during dosing.

• Has previously received PL8177.

• History of alcohol or drug abuse and/or positive drug test at screening (withexception of marijuana if legal within the state and no drug abuse is noted in thePI's assessment)

• Positive TB or COVID 19 test. Note: Patients with positive TB results who had activeor latent TB in the two years preceding the screening visit and who were treated forTB can participate in study