The primary objectives of this study are as follows:

• To assess the safety and tolerability of escalating single and multiple doses of GS-5745 (andecaliximab) in participants with moderate to severe ulcerative colitis (UC) as assessed by adverse events (AEs) and laboratory abnormalities
• To assess the pharmacokinetics (PK) of GS-5745 (andecaliximab) in participants with moderate to severe UC.

The study will test the safety of the drug. Participants will be given different concentrations of the drug in Cohorts, starting from a lower dose to a higher dose.

Single-Dose Treatment:

A thorough assessment of safety and tolerability will be performed before escalating to the next higher dose. For example, the first 2 participants will be dosed in a staggered fashion 24 hours apart. Provided that there are no significant safety signals up to 24 hours post-dose for the first 2 participants, the remaining 4 participants will be dosed. A thorough assessment of safety and tolerability (through Day 14 post-dose) will be performed by the safety review committee before escalating to the next higher dose. Participants enrolled in a SAD cohort will be eligible to participate in a MAD or adaptive MAD cohort if eligibility criteria are met.

Multiple-Dose Treatment:

This design follows the same set-up as the Single-Dose Treatment. Dosing will not commence in the first MAD cohort until safety data from the second dose level SAD cohort has been reviewed through Day 15. Successive MAD cohorts will only be dosed after safety data from the previous, lower dose MAD cohort through Day 43 and the next higher dose SAD cohort through Day 15, have been reviewed by the safety review committee. An additional Adaptive MAD cohort will explore a subcutaneous dosing of andecaliximab 150 mg prefilled syringe once a week for 5 weeks.

Key Inclusion Criteria:

• Male or Female, 18 to 65 years of age
• Negative pregnancy test at screening
• Documented diagnosis of UC with a minimum disease extent of 15 centimeters (cm) from the anal verge
• Mayo Score of at least 3 for the SAD cohort and Mayo Score of at least 6 for the MAD cohorts
• Hepatic panel (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, direct bilirubin, alkaline phosphatase, lactate dehydrogenase [LDH] ≤ 2 times the upper limit of the normal range [ULN])
• Serum creatinine ≤ 1.5 times the ULN
• Hemoglobin ≥ 10 grams per deciliter (g/dL) (both males and females)
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1,500 milli meters [mm]^3)
• Platelets ≥ 100 x 10^9/L.

Key Exclusion Criteria:

• Pregnant or lactating females
• Exhibit severe UC/ clinically significant active infection
• Current use of oral corticosteroids at a dose equivalent to > 20 mg/day of prednisone
• Any dose adjustment in oral corticosteroids or oral immunosuppressants (6-MP, Azathioprine), or oral 5-aminosalicylate (5-ASA) compounds within 30 days of Baseline
• Use of rectal formulations of 5-ASA compounds or corticosteroids within 2 weeks prior to randomization
• Crohn's disease or indeterminate colitis
• History of colectomy, partial colectomy, or dysplasia on biopsy
• Stool sample positive for Clostridium difficile (C. difficile) toxin, E. coli, Salmonella, Shigella, Campylobacter or Yersinia
• Treatment with Infliximab, Adalimumab, Natalizumab, Golimumab, Vedolizumab or Certolizumab within 8 weeks of randomization
• Any chronic medical condition (including, but not limited to, cardiac or pulmonary disease) that, in the opinion of the Investigator, would make the individual unsuitable for the study or would prevent compliance with the study protocol.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.