A PHASE 2, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, PARALLEL GROUP, MULTIPLE CENTER STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND EFFICACY OF NGM282 ADMINISTERED FOR 12 WEEKS IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC)

INTERVENTION: Product Name: NGM282 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: engineered recombinant human FGF19 CAS Number: 1616639‐03‐2 Current Sponsor code: NGM282 Other descriptive name: rec‐h‐FGF19 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 1‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Product Name: NGM282 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: engineered recombinant human FGF19 CAS Number: 1616639‐03‐2 Current Sponsor code: NGM282 Other descriptive name: rec‐h‐FGF19 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 3‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: PRIMARY SCLEROSING CHOLANGITIS (PSC) ; MedDRA version: 19.0 Level: LLT Classification code 10036732 Term: Primary sclerosing cholangitis System Organ Class: 10019805 ‐ Hepatobiliary disorders ; MedDRA version: 19.0 Level: HLT Classification code 10004607 Term: Bile duct infections and inflammations System Organ Class: 10019805 ‐ Hepatobiliary disorders ; MedDRA version: 19.0 Level: SOC Classification code 10019805 Term: Hepatobiliary disorders System Organ Class: 10019805 ‐ Hepatobiliary disorders ; MedDRA version: 19.0 Level: PT Classification code 10008609 Term: Cholangitis sclerosing System Organ Class: 10019805 ‐ Hepatobiliary disorders ; MedDRA version: 19.0 Level: HLGT Classification code 10004606 Term: Bile duct disorders System Organ Class: 10019805 ‐ Hepatobiliary disorders Therapeutic area: Diseases [C] ‐ Digestive System Diseases [C06] PRIMARY OUTCOME: Main Objective: • Evaluate the treatment effect of NGM282 as measured by the mean change in alkaline phosphatase (ALP) from Baseline to Week 12 in patients with PSC. Primary end point(s): The primary efficacy endpoint is the mean change in ALP from Baseline at Week 12. Secondary Objective: • Assess the safety and tolerability of NGM282 in patients with PSC with 12 weeks of treatment.; • Evaluate the percentage change from Baseline at Week 12 in ALP.; • Evaluate the absolute and percentage changes from Baseline at Week 12 of the following:; o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin (total, direct), and GGT; o Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides; o 7 alpha hydroxy 4 cholesten 3 one (C4) and serum bile acids; o Bile mediated absorption as measured by fat soluble vitamins and fecal fat content; • Evaluate changes in pruritus and fatigue; • Compare NM282 versus placebo with respect to the incidence and severity of:; o IBD associated intestinal symptoms during the study period; o Acute cholangitis during the study period; • Evaluate the exposure of 1 mg and 3 mg of NGM282 in patients with PSC; • Compare the dose related changes in safety, tolerability, and pharmacodynamic (PD) parameters Timepoint(s) of evaluation of this end point: 12 weeks compared to baseline SECONDARY OUTCOME: Secondary end point(s): The secondary efficacy and PD endpoints are the following: ; ? Percent change from Baseline at Week 12 in ALP ; ? Absolute and percent changes from Baseline at Week 12 in the following: ; o ALT, AST, bilirubin (total, direct), and GGT ; o C4 and serum bile acids ; o Total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides ; ? Bile‐mediated absorption as measured by fat‐soluble vitamins and fecal fat content ; ? Changes in pruritus and fatigue, as measured by the weekly mean of the daily pruritusand fatigue NRS assessments ; ? Incidence and severity of IBD‐associated intestinal symptoms ; ? Incidence and severity of acute cholangitis Timepoint(s) of evaluation of this end point: For each NGM282 treatment group, the LS mean rate of change in ALP during Weeks 1–4 will be compared to that during Weeks 5–12; the changes in slopes will be estimated. This estimation will be performed using a MMRM similar to that of the primary efficacy analysis. It will also be repeated using percent change in ALP. ; Categorical secondary efficacy endpoints (reflecting incidence and severity of ; IBD‐associated symptoms and acute cholangitis) will be analyzed using confidence intervals of differences of population treatment proportions. INCLUSION CRITERIA: Patients who meet the following criteria may be included in the study: 1. Males and females between 18 and 75 years of age inclusive who are able to comprehend instructions and follow the study procedures, and are willing to sign an Informed Consent Form (ICF). 2. Confirmed diagnosis of PSC based any two of the following three criteria: a. Historical evidence of an elevated ALP > ULN from any laboratory b. Liver biopsy consistent with PSC Patients with small‐duct PSC on liver biopsy must also have a concurrent diagnosis of IBD c. Abnormal cholangiography consistent with PSC as measured by MRCP, ERCP, or percutaneous transhepatic cholangiography 3. Subjects must have certain additional laboratory parameters in specified ranges at Screening, as follows: a. ALP > 1.5 × ULN b. Total bilirubin = 2.5 mg/dL c. ALT and AST < 5 × ULN d. Serum creatinine < 2 mg/dL or creatinine clearance > 60 mL/min by Cockroft‐Gau