Clinical trial NCT04906421
Conditions: Metabolic Dysfunction-assocated Steatohepatitis/ Nonalcoholic Fatty Liver Disease
Keywords: NASH Nonalcoholic Steatohepatitis Fatty Liver Disease Biopsy Confirmed FASN Fatty Liver Liver Disease Digestive System Diseases MASH Metabolic dysfunction-associated steatohepatitis
Sponsor: Sagimet Biosciences Inc.
Start date: 2021-08-12; Completion date: 2023-10-02
Enrollment: 168 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, multi-center, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy on TVB-2640 in subjects with non-alcoholic steatohepatitis (NASH). Subjects will be randomly assigned toTVB-2640 or matching placebo PO QD for 52 weeks, with the first dose administered on Day 1.

Detailed description:
The indication nonalcoholic steatohepatitis \[NASH\]) is now referred to as metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by hepatocyte necrosis, chronic inflammation, and resultant fibrosis formation.

Arms: arm 1: Subjects will receive TVB-2640 PO QD for 52 weeks, with the first dose administered on Day 1. arm 2: Subjects will receive matching placebo PO QD for 52 weeks, with the first dose administered on Day 1.
Interventions: intervention 1: TVB-2640 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral dose, tablet intervention 2: Oral dose, tablet

Protocol documents:
Prot_000.pdf: 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for TVB-2640. I have read the protocol for 
Study SB2640-CLIN-007 and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 


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SPONSOR APPROVAL SIGNATURE PAGE 
On behalf of the sponsor, I confirm that I have read and understood this protocol. We will meet 
the requirements of the protocol, abide by ethical standards stated by the Declaration of Helsinki, 
and follow the guidelines for ethical clinical practice (Good Clinical Practice). 
 
 
Approved by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Date 
 
 




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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sagimet Biosciences 
Name of Investigational Product: 
TVB-2640 
Name of Active Ingredient: 
TVB-2640 
Title of Study:  
A Phase 2b, Multi-Center, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and 
Efficacy of TVB-2640 in Subjects with Nonalcoholic Steatohepatitis (FASCINATE-2) 
Study Center(s): 
This study will be conducted at approximately 100 centers in North America and other regions.  
Coordinating Investigator:  
The Coordinating Investigator is Rohit Loomba, MD, MHSc, University of California, San Diego, CA. 
Studied Period (years):  
Estimated date first subject dosed: May 2021 
Estimated date last subject completed: September 2023 
Phase of Development:  
2b 
 
Objectives:  
Primary Objectives 
• 
To evaluate the effect of TVB-2640 50 mg PO QD compared with matching placebo in 
noncirrhotic subjects with nonalcoholic steatohepatitis (NASH) and F2-F3 fibrosis by either:  
o Histological improvement at Week 52 in nonalcoholic fatty liver disease (NAFLD) 
activity score (NAS) (ie, ≥2 points improvement in NAS with ≥1 point improvement 
in ballooning or inflammation) and without worsening of fibrosis (by NASH Clinical 
Research Network [CRN] fibrosis score) 
OR 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver disease 
or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for 
inflammation, 0 for ballooning, and any value for steatosis. 
• 
To evaluate the safety and tolerability of TVB-2640 50 mg PO QD in subjects with confirmed 
NASH and liver fibrosis. 
Secondary Objectives 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% relative 
reduction in liver fat content as assessed by magnetic resonance imaging-proton density fat 
fraction (MRI-PDFF) at Week 26. 


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• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% relative 
reduction in liver fat content as assessed by MRI-PDFF at Week 52. 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without worsening of 
steatohepatitis (no increase in NAS for ballooning, inflammation, or steatosis) at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without worsening of 
NAS (defined as no increase in any component of NAS) at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without increasing of total 
NAS scores at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without any worsening of 
NASH (no worsening of ballooning and lobular inflammation, a 1 grade change in steatosis 
may be acceptable) at Week 52. 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis on overall histopathological reading and no worsening of 
liver fibrosis on NASH CRN fibrosis score. Resolution of steatohepatitis is defined as 
absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a 
NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score) and no worsening of steatohepatitis (defined as no increase in NAS for 
ballooning, inflammation, or steatosis). 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in NAFLD NAS (ie, ≥2 points improvement in 
NAS with ≥1 point improvement in ballooning or inflammation) and without 
worsening of fibrosis (by NASH CRN fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score) and no worsening of steatohepatitis (defined as no increase in NAS for 
ballooning, inflammation, or steatosis). 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver disease 
or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for 
inflammation, 0 for ballooning, and any value for steatosis. 
AND 
o Histological improvement in NAS (≥2 points improvement in NAS). 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
histological improvement at Week 52 in NAS.  


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• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on liver fat 
content as assessed by MRI-PDFF at Week 26. 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on liver fat 
content as assessed by MRI-PDFF at Week 52. 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on NASH 
resolution (defined as absence of fatty liver disease or isolated or simple steatosis without 
steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for 
steatosis) at Week 52. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on change 
from Baseline at 26 and 52 weeks in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and gamma-glutamyltransferase (GGT). 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in low-density lipoprotein cholesterol (LDL-C) and 
other lipid levels. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 52 weeks in the amount of collagen/fibrous area and fibrosis score, 
assessed by digital pathology. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in fasting insulin, fasting glucose, homeostatic 
model assessment of insulin resistance (HOMA-IR), adipose tissue insulin resistance (adipo-
IR), and glycosylated hemoglobin (HbA1c) levels.  
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in fibroblast growth factor 21 (FGF-21), 
adiponectin, and other NASH biomarker levels. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on change 
from Baseline at 26 and 52 weeks in FibroScan® and controlled attenuation parameter (CAP) 
score.  
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
N-terminal type III collagen propeptide (PRO-C3) levels and other fibrosis biomarkers on 
change from Baseline at Weeks 4, 13, 26, and 52. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on change 
from Baseline at 26 and 52 weeks on enhanced liver function (ELF) score. 
• 
To evaluate the pharmacokinetics (PK) of TVB-2640 in subjects with NASH over 52 weeks of 
treatment using sparse sample collection, and serial sample collection in a subset of subjects. 
Exploratory Objectives 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% relative 
reduction in liver fat content as assessed by MRI-PDFF AND achieve ≥17 U/L reduction in 
ALT at Week 52. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
FibroScan-AST (FAST) score at Weeks 26 and 52.  
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on select 
fibrosis biomarkers (including at least tissue inhibitor of metalloproteinase-1 [TIMP-1]) at 
Weeks 4, 13, 26, and 52. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 


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lipidomic biomarkers (including tripalmitin, ceramides, bile acids, diacylglycerols, and other 
classes of metabolites) at Weeks 4, 13, 26, and 52. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
glycosylated hemoglobin (HbA1c) levels among subjects with type 2 diabetes mellitus 
(T2DM) at Weeks 13, 26, 39, and 52. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
Fibrosis 4 score (FIB-4) at Weeks 4, 13, 26, and 52. 
• 
To use digital pathology to perform zonal analysis of fibrosis at Week 52. 
o To use digital pathology to evaluate the concurrence of fibrosis with components of 
the NAS score. 
o To use digital pathology to evaluate the NAS components. 
• 
To correlate changes in MRI-PDFF with changes in, or baseline levels of, serum biomarkers 
and explore predictive markers of response.  
• 
To explore the relationship between changes in, or Baseline levels of, serum biomarkers and 
histology results, and explore predictive markers of response. 
• 
To explore the relationship between MRI-PDFF results and histology results. 
• 
To correlate the presence of relevant single-nucleotide polymorphisms (SNPs) or other genes 
relevant to NAFLD or NASH with clinical and histopathologic response. 
• 
To determine the effect of TVB-2640 50 mg QD compared with matching placebo on gut 
microbiome change from Baseline to Weeks 26 and 52 in a subset of subjects. 
• 
To explore the relationship between nutrition, as measured by the HepVita Nutritional Survey, 
and clinical, histopathological, and biomarker changes in NASH at Weeks 26 and 52 in a 
subset of subjects. 
Methodology: 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-design study to evaluate 
the safety and efficacy of TVB-2640 compared with matching placebo in subjects with NASH who are 
aged ≥18 years at Screening. Histological eligibility will be determined during the Screening period or 
prior to Screening but within 180 days of the Screening visit in 1 of 2 ways:  
• 
If an ‘eligible’ and adequate (this refers to the quality and quantity of remaining tissue) 
liver histology specimen, in the judgement of the central pathologist, exists from the time 
period within 180 days before the subject’s Screening visit, the subject may participate so 
long as other eligibility criteria are satisfied. 
• 
If no liver histology specimen exists from the period within 180 days of the Screening 
visit, the subject must undergo liver biopsy during the Screening period.  
Approximately 162 unique subjects with liver fibrosis stage F2-F3 will be enrolled and randomized to 
achieve a 2:1 ratio with approximately 108 subjects on TVB-2640 50 mg and 54 subjects on placebo. 
Dynamic allocation is used for the randomization, stratified by 3 factors: T2DM status (yes or no), 
region (North America or not North America), and amount of fibrosis (F2 or F3).  
Subjects will be screened for study eligibility within 90 days before randomization (randomization is 
within 3 days of Baseline [Day 1]). Subjects who are determined to be eligible for the study based on 
Screening assessments are to be randomized into the study within 3 days before Baseline (ie, Day 1, 
the first day of study drug administration). Subjects who are randomized are considered to be enrolled 
in the study.  


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Subjects will receive TVB-2640 or matching placebo PO QD for 52 weeks, with the first dose 
administered on Day 1. During the 52-week Treatment period, subjects are to attend study center visits 
at Weeks 4, 8, 13, 26, 39, and 52. After completion of the 52-week Treatment period, subjects are to 
attend a Follow-up visit at Week 56 for posttreatment safety and efficacy assessments.  
In the event a subject is unable to complete the end of treatment MRI-PDFF and/or liver biopsy within 
the protocol-specified window (Week 52 +/- one week), extended dosing is permitted to maintain 
continuous dosing up to the time both assessments are completed, to a maximum total of 56 weeks of 
dosing. In this instance, the Follow-up visit at Week 56 for post treatment safety and efficacy 
assessments is to be adjusted to occur four weeks after the last dose (+/- one week). 
In the instance of a dose hold due to an AE or SAE, the decision to resume study drug will require 
consultation with the Investigator, the CRO’s Medical Monitor, and the Sponsor’s Chief Medical 
Officer. 
Improvement of NAS and improvement of fibrosis score will be evaluated by comparison of Baseline 
and Week 52 liver histology specimens. Subjects will also undergo MRI-PDFF prior to the start of 
treatment, at Week 26, and at Week 52 or Early Termination. Other efficacy and pharmacodynamic 
(PD) assessments include FibroScan with CAP, and measurement of liver aminotransferases, lipid 
parameters, and other noninvasive biomarkers of NASH and liver fibrosis throughout the study.  
During the study, safety will be assessed by vital signs, 12-lead electrocardiograms (ECGs), physical 
examinations including eye examinations, and clinical laboratory testing. Subjects will be evaluated 
for AEs and concomitant medication use throughout the study.  
 
 
  
An independent data monitoring committee (IDMC) will be established by charter to provide 
independent review and assessment of study data and to monitor the overall study conduct in a 
systematic manner to safeguard the safety of study subjects. The IDMC will be tasked with making 
recommendations to the Sponsor to continue, amend, or stop the study based on these assessments.  
A single secondary endpoint efficacy interim analysis (IA) is planned when approximately 60 subjects 
with MRI-PDFF value of ≥8% liver fat at Baseline have completed Week 26 or an Early Termination 
visit after Week 22. The purpose of the proposed interim analysis is to examine the TVB-2640 benefit 
over placebo based on a Week 26 secondary efficacy endpoint consisting of “proportion of MRI-PDFF 
≥30% responders at Week 26, where an MRI-PDFF ≥30% responder is defined as a subject with ≥8% 
liver fat content at Baseline who achieves a percent change (reduction) from Baseline in MRI-PDFF 
≥30%.” 
Interim safety summaries will accompany the interim analysis of the secondary efficacy endpoint. 
Number of Subjects (planned):  
Approximately 162 unique subjects with liver fibrosis stage F2-F3 will be enrolled and randomized to 
achieve a 2:1 ratio to receive TVB-2640 50 mg or placebo (approximately 108 for TVB-2540 50 mg 
and approximately 54 subjects for placebo) PO QD for 52 weeks.  
Diagnosis and Main Criteria for Inclusion:  
Unless otherwise specified, repeat testing for laboratory and clinical Screening assessments may be 
performed in consultation with the Medical Monitor. 
Inclusion Criteria 
1. Must be willing and able to participate in the study and provide written informed consent. 
2. Male and female adults ≥18 years of age on the date that written informed consent to take part 


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in the study is provided. 
3. Body mass index (BMI) ≥23 kg/m2 for Asians and ≥25 kg/m2 for other races. 
4. Female subjects must be either: 
a. Not of childbearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or 
tubal ligation] or naturally sterile [>12 consecutive months without menses]). 
OR 
b. Female subjects of childbearing potential (must have a negative serum pregnancy 
(beta-human chorionic gonadotropin [β-HCG]) test during Screening, a negative urine 
pregnancy test within 24 hours before the first dose of study drug on Day 1, and must 
agree to perform urine home pregnancy tests monthly between study visits. Female 
subjects of childbearing potential must not be breastfeeding, not plan to become 
pregnant during the study, and must use 2 forms of birth control, one being a barrier 
method (ie, condoms, diaphragm, nonhormonal intrauterine device [IUD]) throughout 
the study and for at least 3 months after the final study drug dose. Hormonal 
contraception (stable ≥3 months) and hormonal IUDs are permitted if used with a 
secondary barrier birth control method (e.g., condoms). 
5. Male subjects who have sexual intercourse with a female partner of childbearing potential 
from the first dose of study drug until 3 months after completion of study drug intake must be 
either surgically sterile (confirmed by documented azoospermia >90 days after the procedure) 
OR agree to use a condom with spermicide. All male subjects must agree not to donate sperm 
from the first dose of study drug until 3 months after completion of study drug intake. 
6. Must have liver stiffness measurement ≥8.5 kPa measured by FibroScan and CAP score 
measured by FibroScan ≥280 dB/m (unless the enrolling study site does not have the 
capability to measure CAP) during the Screening period.  
7. Histologic confirmation of NASH: must have had a prior liver biopsy within 180 days before 
the Screening visit, or a new biopsy during the screening period, with fibrosis stage F2-F3 and 
a NAS of ≥4 with at least a score of 1 in each of the following NAS components: 
a. Steatosis (scored 0 to 3) 
b. Ballooning degeneration (scored 0 to 2) 
c. Lobular inflammation (scored 0 to 3) 
8. AST >20 U/L. 
Exclusion Criteria 
1. History of harmful alcohol intake for a period of more than 3 consecutive months within 
1 year prior to Screening in the judgement of the Investigator.  
2. Active substance abuse, including inhaled or injected substances (cocaine and other 
illegal/banned substances; any opiate, amphetamine, or benzodiazepine for which the subject 
does not have an existing prescription) within 1 year prior to Screening (note that recreational 
cannabis/tetrahydrocannabinol use is permissible). 
3. Patient-reported or medically documented gain or loss of >5% of body weight in the 6 months 
prior to Baseline (Day 1) or >10% of body weight in the 12 months prior to Screening. 
4. Prior or planned (during the study period) bariatric surgery that may interfere with study drug 
absorption (e.g., roux-en-Y gastric bypass); gastroplasty and gastric reduction surgery are 
acceptable. 
5. Type 1 diabetes mellitus by history. 
6. Positive SARS-CoV-2 polymerase chain reaction (PCR) test within 30 days prior to the 
Baseline (Day 1) visit date or history of hospitalization for COVID-19 <6 months prior to the 


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Screening visit date. Note that previous COVID-19 infection alone is not exclusionary, and 
COVID-19 vaccination is allowed. Infection and/or vaccination must be documented as 
medical history and/or concomitant medication, respectively.  
7. Known positivity for HIV infection or positive HIV antibody result at Screening. 
8. Positive hepatitis B virus antigen (HBsAg) result at Screening. 
9. Positive hepatitis C virus (HCV) RNA test at Screening; however, subjects with chronic HCV 
infection and liver disease who were treated with anti-HCV therapy and achieved a sustained 
virologic response at least 2 years prior to Screening are not prevented from study 
participation. 
10. Uncontrolled T2DM, defined as HbA1c >9.5% at Screening. 
11. Serum LDL-C concentration at Screening >190 mg/dL, and the subject has been taking an 
LDL-C–lowering treatment for ≥30 days prior to Screening. 
12. ALT and/or AST result >5 × the upper limit of normal (ULN) at Screening. One repeat test 
may be allowed within 7 days of receipt of the result at the discretion of the Investigator. 
13. Alkaline phosphatase (ALP) result ≥2 × ULN at Screening. 
14. Total serum bilirubin concentration >1.3 mg/dL at Screening; subjects with a confirmed 
diagnosis of Gilbert’s syndrome (ie, prior to Screening and whose total bilirubin result at 
Screening exceeds 1.3 mg/dL) may be eligible for study inclusion at the Investigator’s 
discretion. 
15. International normalized ratio (INR) result >1.3 at Screening. 
16. Serum albumin concentration <3.5 g/dL at Screening. 
17. Platelet count <140,000/µL at Screening. 
18. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2, as determined using the 
Modification of Diet in Renal Disease Study (MDRD) equation, at Screening. 
19. Presence of cirrhosis on liver histology (stage 4 fibrosis), according to the judgement of the 
central reader; and/or cross-sectional imaging evidence consistent with cirrhosis and/or portal 
hypertension (e.g., nodular liver contour; atrophy and hypertrophy of the right and left hepatic 
lobes respectively; splenomegaly; known presence or history of esophageal varices; and/or 
elastography evidence consistent with cirrhosis).  
20. F0, F1, or F4 fibrosis, or inconclusive result, on liver histology. 
21. Use of drugs historically associated with risk of development of NAFLD (e.g., amiodarone, 
methotrexate, systemic glucocorticoids [unless used at physiologic replacement doses for 
treatment of confirmed adrenal insufficiency], tetracyclines, tamoxifen, estrogens at doses 
greater than those used for hormone replacement, anabolic steroids [except for testosterone 
preparations used at physiologic replacement doses for treatment of documented/confirmed 
hypogonadism], valproic acid, and other known hepatotoxins) for more than 12 consecutive 
months at any time during the 5 years prior to the Screening visit (refer to Section 9.7, 
Concomitant Medications).  
22. Use of glucagon-like peptide-1 (GLP-1) agonists or a sodium-glucose co-transporter-2 
(SGLT2) inhibitor, unless on a stable daily dose for at least 6 months prior to the Screening 
visit date  
OR  
On a complex oral antidiabetic (OAD) regimen (3 or more OADs [except for a GLP-1 agonist 
or an SGLT2 inhibitor]), unless on stable doses for at least 3 months prior to the Screening 
visit date (refer to Section 9.7, Concomitant Medications). 
23. Use of vitamin E supplementation at a daily dose >400 IU unless on a stable daily dose for at 


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least 6 months prior to the Screening visit (refer to Section 9.7, Concomitant Medications). 
24. Use of strong concomitant cytochrome P450 (CYP) 3A4 inhibitors or inducers during the 
study (refer to Section 9.7, Concomitant Medications). 
25. Known diagnosis of hereditary hemochromatosis. 
26. Subjects with active or quiescent chronic liver disease of etiologies other than NASH (e.g., 
viral or autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, 
“autoimmune hepatitis-overlap” syndromes, hemochromatosis, Wilson’s disease, alpha-1 
antitrypsin deficiency, alcohol-related liver disease, drug-induced liver disease, and/or 
infiltrative conditions [e.g., sarcoidosis]).  
27. Current or historic clinically evident hepatic decompensation (e.g., ascites formation, variceal 
hemorrhage, hepatic encephalopathy). 
28. Active, serious medical disease with likely life expectancy <2 years. 
29.  History of clinically significant dry eye (xerophthalmia) or other corneal abnormality, as 
determined by an ophthalmologist or optometrist during Screening. 
30. Participation in an investigational study in the 30 days prior to randomization. 
31. Participation in an investigational drug trial for subjects with NASH, T2DM, and/or weight 
reduction within 6 months of Screening; only if it can be confirmed the subject received 
placebo during the earlier study would it be possible for such a subject to be screened for this 
study sooner than 6 months before Screening. 
32. Any subject who has sustained a clinically evident cardiovascular, cerebrovascular and/or 
peripheral vascular event (e.g., unstable angina, acute coronary syndrome, myocardial 
infarction, life-threatening tachy- and/or brady-dysrhythmia, stroke, transient ischemic attack 
[TIA], peripheral vascular disease) during the 12 months prior to the anticipated Baseline 
(Day 1) visit date. 
33. Any contraindication to MRI (e.g., claustrophobia, metal implants). 
34. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, compromise the well-being of the subject, or interfere with the 
study outcomes. 
Investigational Product, Dosage and Mode of Administration:  
TVB-2640 will be provided as 25-mg and 50-mg strength uncoated tablets. Study drug will be 
administered PO QD, with or without food. Study drug should be taken at approximately the same 
time each day in the evening.  
Duration of Treatment:  
The Treatment period for this study is 52 weeks in duration.  
Reference Therapy, Dosage and Mode of Administration:  
Placebo will be provided in 2 tablet sizes: one to match the TVB-2640 25-mg tablet and one to match 
the TVB-2640 50-mg tablet. Study drug will be administered PO QD, with or without food. 
Criteria for Evaluation: 
Efficacy and Pharmacodynamics  
Liver histology with NAS and fibrosis score 
Magnetic resonance imaging studies: MRI-PDFF (MRI-PDFF will not be performed at select sites) 
Liver stiffness by FibroScan, including CAP and FAST scores 


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Digital pathology 
Clinical laboratory tests: 
• 
Lipid and metabolic panels, HbA1c, and lipoprotein analyses 
• 
NASH and fibrosis noninvasive biomarkers (e.g., adiponectin and FGF-21) 
Lipidomic biomarkers: 
• 
Includes tripalmitin, ceramides, bile acids, diacylglycerols, and other classes of metabolites 
Gut microbiome assessments (in a subset of subjects) 
HepVita Nutritional Survey (in a subset of subjects) 
Other Assessments 
Genomics 
Urine and blood samples for storage  
 
 
  
 
  
Safety 
AEs 
Vital signs 
Physical examinations 
Eye examinations 
12-lead ECGs 
Safety laboratory assessments: 
• 
Hematology 
• 
Clinical chemistry 
• 
Coagulation 
• 
Urinalysis  
• 
Pregnancy testing 
Concomitant medications 
Anthropometric assessments: 
• 
Weight, height, and BMI 
• 
Waist circumference 
• 
Hip circumference 
• 
Waist-hip ratio 
Endpoints 
Primary Efficacy (Responder) Endpoint 
The proportion of subjects experiencing either of the following: 
• 
Histological improvement at Week 52 in NAS (ie, ≥2 points improvement in NAS with 
≥1 point improvement in ballooning or inflammation) and without worsening of fibrosis 
(by NASH CRN fibrosis score).  


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OR 
• 
Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis 
score). Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
Secondary Efficacy and Pharmacodynamic Endpoints 
• 
Proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF ≥30% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
relative reduction from Baseline in MRI-PDFF ≥30%. 
• 
Proportion of MRI-PDFF ≥30% responders at Week 52. 
• 
Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN fibrosis 
score without worsening of steatohepatitis (defined as no increase in NAS for ballooning, 
inflammation, or steatosis) at Week 52. 
• 
Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
with no increase in any component of NAS at Week 52. 
• 
Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without increase of total NAS score at Week 52. 
• 
Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without any worsening of NASH (defined as no worsening of ballooning and lobular 
inflammation; a 1 grade change in steatosis may be acceptable) at Week 52. 
• 
Proportion of subjects experiencing both of the following at Week 52:  
o Resolution of steatohepatitis on overall histopathological reading and no 
worsening of live fibrosis on NASH CRN fibrosis score. Resolution of 
steatohepatitis is defined as absent fatty liver disease or isolated or simple steatosis 
without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for ballooning, 
and any value for steatosis 
AND 
o Improvement in liver fibrosis greater than or equal to one state (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
• 
Proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in nonalcoholic fatty liver disease (NAFLD) 
activity score (NAS) (ie, ≥2 points improvement in NAS with ≥1 point 
improvement in ballooning or inflammation) and without worsening of fibrosis (by 
NASH Clinical Research Network [CRN] fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
• 
Proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver 
disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 
for inflammation, 0 for ballooning, and any value for steatosis. 


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AND 
o Histological improvement at in NAS (≥2 points improvement in NAS). 
• 
Proportion of subjects with histological improvement at Week 52 in NAS.  
• 
MRI-PDFF percent change in liver fat and change from Baseline at Week 26.  
• 
MRI-PDFF percent change in liver fat and change from Baseline at Week 52. 
• 
Proportion of subjects with NASH resolution (defined as absence of fatty liver disease or 
isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 
for ballooning, and any value for steatosis) at Week 52. 
• 
Change from Baseline in ALT, AST, and GGT at Weeks 26 and 52 and at each study visit. 
• 
Change from Baseline in LDL-C and other lipid levels at Weeks 26 and 52 and at each 
study visit. 
• 
Change from Baseline in collagen/fibrous area and fibrosis score, assessed by digital 
pathology, at Week 52. 
• 
Changes from Baseline in metabolic parameters, including fasting insulin, fasting glucose, 
HOMA-IR, adipo-IR, and HbA1c levels at Weeks 26 and 52 and at each study visit. 
• 
Change from Baseline in FGF-21, adiponectin, and other NASH biomarker levels at 
Weeks 26 and 52 and at each study visit. 
• 
Change from Baseline in FibroScan and CAP score results at Weeks 26 and 52. 
• 
Change from Baseline in PRO-C3 and other fibrosis biomarkers at Weeks 4, 13, 26, 
and 52. 
• 
Change from Baseline in ELF score at Weeks 26 and 52. 
• 
Plasma concentrations of TVB-2640 at Weeks 1, 4, 13, 26, and 52. 
Exploratory Efficacy and Pharmacodynamic Endpoints 
• 
Proportion of MRI-PDFF ≥30% responders at Week 52 who have ≥17 U/L reduction in 
ALT.  
• 
Change from Baseline in FAST score at Weeks 26 and 52. 
• 
Change from Baseline in levels of select fibrosis biomarkers (e.g., TIMP-1) at Weeks 4, 
13, 26, and 52. 
• 
Change from Baseline in levels of lipidomic/metabolomic biomarkers (e.g., tripalmitin, 
ceramides, bile acids, diacylglycerols, and other classes of metabolites) at Weeks 4, 13, 26, 
and 52. 
• 
Change from Baseline in HbA1c levels among subjects with T2DM at Weeks 13, 26, 39, 
and 52. 
• 
Change from Baseline in FIB-4 at Weeks 4, 13, 26, and 52. 
• 
Change from Baseline in zonal analyses of fibrosis, NAS, and individual NAS components 
as determined by digital pathology at Week 52.  
• 
Correlation of changes in MRI-PDFF with changes in other endpoints. 
• 
Presence or absence of SNPs relevant for NASH. 
• 
Correlation of predictive signature with other endpoints 
• 
Correlation of lipids (e.g., tripalmitin) with other endpoints 
• 
Change from Baseline in gut microbiome analyses at Weeks 26 and 52 in substudy 


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subjects. 
• 
Change from Baseline in HepVita Nutritional Survey at Weeks 26 and 52 in substudy 
subjects. 
Safety Endpoints 
• 
AEs throughout the study. 
• 
ECGs at Weeks 26 and 52. 
• 
Vital signs at each study visit. 
• 
Physical examination findings at each study visit. 
• 
Eye examination findings at each study visit. 
• 
Hematology and coagulation results at each study visit. 
• 
Liver aminotransferase levels at each study visit. 
• 
Clinical chemistry results at each study visit. 
• 
Urinalysis results at each study visit. 
• 
Pregnancy test results throughout the study. 
• 
Prior and concomitant medications throughout the study. 
• 
Results of anthropometric measurements at Week 52. 
Statistical Methods: 
Analysis of the primary efficacy endpoint: The primary efficacy endpoint is the proportion of 
subjects experiencing either a histological improvement at Week 52 in NAS (ie, ≥2 points 
improvement in NAS with ≥1 point improvement in ballooning or inflammation) and without 
worsening of fibrosis (by NASH CRN fibrosis score), OR resolution of steatohepatitis and no 
worsening of liver fibrosis (by NASH CRN fibrosis score). The treatment groups will be compared 
based on the primary efficacy endpoint using a one-sided Cochran-Mantel-Haenszel (CMH) test 
stratified by the randomization stratifications T2DM status (yes or no), region (North America or not 
North America), and amount of fibrosis (F2 or F3) at the 0.05 significance level (where a higher 
responder proportion is a better outcome) and will be based on the Intention-to-Treat (ITT) population. 
The response Clopper-Pearson 90% and 95% confidence intervals (CI) will be derived for each 
treatment group.  
A sensitivity analysis employing a logistic regression will be used to examine the robustness of the 
CMH results (see details described in the statistical section, below).  
A subject who discontinues treatment prior to Week 42, does not provide a histological assessment on 
or after Week 42, or who otherwise has missing data will be considered a non-responder. 
Further sensitivity analysis of the primary efficacy endpoint will employ multiple imputations for 
binary data. Pertinent details are included in the statistical analysis plan (SAP). 
Analysis of the secondary efficacy and pharmacodynamics endpoints: The analysis of the 
secondary efficacy endpoints will be based on the ITT population. The imputation mechanism used in 
the analysis of the primary efficacy endpoint will also be adopted where applicable. 
The analysis of the secondary efficacy endpoints of a categorical nature will be analyzed in a manner 
similar to the primary efficacy endpoint. 
For the continuous secondary endpoints such as change from Baseline and percent change from 
Baseline, the Wilcoxon rank-sum test will be used to compare the treatment groups. For the continuous 
secondary endpoints, an analysis of covariance (ANCOVA) model will also be used with change from 


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Baseline (and percent change from Baseline) as the dependent variable; treatment group, T2DM status 
(yes or no), region (North America or not North America), and amount of fibrosis (F2 or F3) as 
factors; and Baseline as a covariate. Least-squares means and their differences will be estimated from 
the ANCOVA model and their corresponding 95% CI will be derived. Inferential statistics will be 
presented for both the ANCOVA model and the Wilcoxon test. For the continuous secondary 
endpoints with sufficient postbaseline frequency of measurements, a mixed model repeated measure 
(MMRM) model will also be employed.  
Analysis of PK parameters: Planned PK parameters will be calculated for each subject with serial PK 
samples employing the standard linear trapezoidal convention using all available drug concentration 
measurements. Specifically, the following TVB-2640 PK parameters will be estimated (via 
noncompartmental methods): time to maximum concentration (Tmax), maximum concentration (Cmax), 
area under the concentration-time curve from time of dosing to the last measured concentration (AUC0-
last), area under the concentration-time curve from time of dosing extrapolated to infinity (AUC0-∞), and 
plasma elimination half-life (t1/2). Standard descriptive statistics (mean, median, n, standard deviation, 
minimum, maximum, coefficient of variation) will be used to summarize the stated PK parameters 
along with the corresponding 90% CI whenever appropriate. All subject-level concentrations will be 
provided in a listing and the stated summary statistics presented in a tabular format. Graphical 
depiction of the concentration measurements by time profile will be presented. Sparse PK sample 
results will be analyzed using a population PK model.  
Definition of analysis populations:  
• 
Intention-to-Treat (ITT) population: Comprises all randomized subjects; this population will serve 
as the basis for all efficacy analyses. Subjects’ data will be analyzed according to their 
randomized treatment assignment. 
• 
Modified Intention-to-Treat (mITT): Comprises all subjects in the ITT population who have 
completed at least 42 weeks of treatment and have an evaluable posttreatment histological 
assessment. 
• 
Interim Analysis Modified Intention-to-Treat (IAmITT): Comprises a subset of subjects in the ITT 
population with 8% >/= MRI-PDFF at screening or at baseline with at least 1 evaluable post-
Baseline MRI-PDFF value, defined as an MRI-PDFF assessment obtained at least 22 weeks after 
the first dose of study drug. 
• 
The Safety analysis set: Comprises all subjects who are randomized and received at least 1 dose 
(partial or complete) of study drug.  
• 
PK Population: Comprises all subjects in the ITT population with available PK measurements. 
Power considerations and sample size determination: The study estimated total sample size is 
approximately 162 randomized subjects (108 on TVB-2640 and 54 on placebo). The sample size was 
derived using the normal approximation to the binomial distribution, and the estimated power to detect 
a difference in the primary efficacy response of 20% (TVB-2640 40% and placebo 20% at Week 52) 
was at least 80% (one-sided test at the 0.05 significance level). A 2-to-1 randomization allocation was 
assumed (TVB-2640 to placebo). An anticipated dropout rate of 18.5% was also applied to estimate 
the final sample size (N=162). 
Safety Analyses 
Safety data will be evaluated for the Safety population on the basis of treatment-emergent adverse 
events (TEAEs), clinical laboratory assessments, vital signs, ECGs, weight, and physical examinations. 
Changes from Baseline in key clinical laboratory measurements, vital signs, physical examinations, 
and weight will be summarized by treatment group using standard descriptive statistics. TEAE 
incidence rates will be summarized using frequency and percentage for each treatment group and in 
total. TEAEs through 30 days after the last dose of study treatment will be summarized by MedDRA 


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(current version) system organ class, and preferred term. AEs will also be summarized by National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (current version) 
grade, and by causality (attribution to study treatment, related/not related to investigational medicinal 
product). All safety data will be presented in data listings. 
Interim Analysis 
A single (secondary endpoint) efficacy interim analysis is planned when approximately 60 subjects 
with an MRI-PDFF value of ≥8% liver fat at Baseline have completed Week 26 or an Early 
Termination visit after Week 22. The purpose of the proposed interim analysis is to examine the TVB-
2640 benefit over placebo based on a Week 26 secondary efficacy endpoint consisting of “proportion 
of MRI-PDFF ≥30% responders, where an MRI-PDFF ≥30% responder is defined as a subject with 
≥8% liver fat content at Baseline who achieves a percent change (reduction) from Baseline in MRI-
PDFF ≥30%”. An interim analysis of the primary efficacy endpoint is not feasible since the primary 
endpoint is only evaluated at Week 52, and not Week 26. Therefore, a statistical penalty is not 
envisaged in conjunction with the Week 26 interim analysis of the above-stated secondary endpoint.  
Interim safety summaries will accompany the interim analysis of the secondary efficacy endpoint.  
Planned study committees: An independent data monitoring committee (IDMC) will be established 
by charter to provide independent review and assessment of study data and to monitor the overall study 
conduct in a systematic manner to safeguard the safety of study subjects. The interim analysis will be 
reviewed by the IDMC and will include select biomarkers and safety interim results to allow for a 
more complete examination of the totality of the data.  
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Table 2: 
Schedule of Assessments 
Evaluation 
) 
Study Visit 
)
Screening/Baseline Assessments 
Informed consent 
X 
Inclusion and exclusion criteria review 
X 
X 
Demographics 
X 
Pregnancy testb 
Xb 
Xb 
eGFR 
X 
Medical and social historyc 
X 
X 
Alcohol breath test or blood alcohol 
test 
X 
X 
Urine drug screend  
X 
X 
Histologic confirmation of NASH 
diagnosis, and either Stage 2 or 
Stage 3 fibrosise 
X 
Aminotransferases and INR 
X 
X 
Viral serologyf 
X 
Genomics pertaining to NASH g 
X 
Height, body weight, BMI, waist and 
hip circumference, and waist-hip ratioh 
X 
X 
Safety Assessments 
12-lead ECGi
X 
Xj 
X 
X 
X 
Vital signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical examination 
X 
X 
X 
Symptom-directed physical 
examinationl 
X 
X 
X 
X 
X 
X 
X 
Eye examinationm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Xm 
Safety laboratory tests 
Hematology and coagulationn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 






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d. 
Active substance abuse, including inhaled or injected substances (cocaine and other illegal/banned substances; any opiate, amphetamine, or benzodiazepine for which the 
subject does not have an existing prescription), within 1 year prior to Screening is exclusionary. However, recreational cannabis/tetrahydrocannabinol use is permissible.  
e. 
To qualify for this study, liver histology results must be available before randomization (randomization is within 3 days of Baseline [Day 1]). If the subject terminates 
early from the study, the end of study biopsy is only required if the subject has completed at least 42 weeks of treatment. See Section 8.1, Criterion 7, and Section 8.2, 
Criterion 20 for detailed requirements for histology results.  
f. 
Screening serologies include HIV RNA, HBsAg, anti-HCV antibody, HCV RNA (reflex testing, if HCV antibody result at Screening is positive), and SARS-CoV-2 PCR 
test. The SARS-CoV-2 PCR test may be performed locally and must be performed within 30 days before Baseline (Day 1), other viral serology tests should be performed 
by the central laboratory. Subjects with chronic HCV infection and liver disease who were treated with anti-HCV therapy and achieved a sustained virologic response at 
least 2 years prior to Screening are not prevented from study participation.  
g. 
A blood sample for genomics pertaining to NASH will be collected at all sites unless forbidden by local regulations. If not collected at Baseline, this sample may be 
collected at any other time after the subject signs the separate consent for this sample. Provision of blood samples for genomic analysis is voluntary. 
h. 
Also see further information regarding anthropometric measurements in Section 12.1.6. 
i. 
Single 12-lead ECGs are to be performed at the times indicated and at any other time as clinically indicated. ECGs should be performed before any blood draws planned 
for the same time period. 
j. 
On Day 1, a single 12-lead ECG should be performed up to 2 hours before and 4 hours (-1 hour/+ 2 hours) after the first study drug dose. 
k. 
Vital signs include oral temperature, pulse, systolic/diastolic blood pressure, and respiration rate. Measurements are to be made after the subject has been resting in a 
supine position for a minimum of 5 minutes. 
l. 
Abbreviated, symptom-directed physical examinations will include at a minimum, examination of focused liver signs (e.g., jaundice, spider angiomata, palmar erythema, 
hepatomegaly, splenomegaly, asterixis), skin, and extremities, and any other areas needed to address any complaints or concerns verbalized by the subject. If hand-foot 
symptoms/signs present at this visit or previous hand-foot symptoms/signs increases in severity to a Grade 2 or above, a dermatologist consult should be considered for 
further evaluation and treatment recommendations. 
m. Baseline eye examinations may be performed at any time during the Screening period. Eye exams at Week 4, Week 8, Week 13, Week 26, Week 39, Week 52, Week 56 
and/or Early Termination are required only if eye-related signs or symptoms are reported by the subject or observed by the investigator. If a subject experiences a 
treatment-emergent eye abnormality, an eye examination inclusive of slit lamp and near and far visual acuity testing should be performed by a qualified ophthalmologist 
or optometrist within 24 to 48 hours of event onset or on the next business day after symptom onset to evaluate the abnormality. 
n. 
Hematology and coagulation parameters include hemoglobin, MCV, MCHC, hematocrit, platelet count, RBC count, WBC count with differential, ANC, and PT, aPTT, 
INR, and fibrinogen. See also Table 5. 
o. 
Liver aminotransferases include AST and ALT. Liver aminotransferases collected as part of the clinical chemistry panel for safety are also applicable for efficacy 
assessments.  
p. 
Fasting clinical chemistries include chloride, carbon dioxide, sodium, potassium, glucose, BUN, calcium, magnesium, creatinine, albumin, ALT, AST, ALP, GGT, total 
bilirubin, indirect and direct bilirubin, and total protein. CPK (total and fractionated) is to be reported at Screening and at Baseline. See also Table 5. 
q. 
Urinalysis includes specific gravity, pH, blood, glucose, protein, ketones, and microscopic examination of sediment, if present. See also Table 5. 
r. 
Subject contact to reliably assess medication use between visits is encouraged around Week 10, Week 17, Week 23, Week 30, Week 34, Week 43, and Week 47. See 
Section 9.7 for a list of accepted and excluded concomitant medications. If a subject receives a vaccine, including the COVID-19 vaccine, details regarding that vaccine 
should be recorded as a concomitant medication(s), including manufacturer, dose, and dates of each injection. Any vaccine-related reactions should be recorded as 
described in Section 12.2.  
s. 
The same biopsy samples will be used for histology analysis by the central study pathologist and by digital pathology.  
t. 
Subjects will have an MRI-PDFF performed at each indicated timepoint unless it presents a logistical or physical hardship to the subject. MRI-PDFF will not be 
performed at select sites. The Baseline MRI-PDFF is to be performed during Screening or at Baseline before study drug dosing on Day 1. MRI-PDFF is not required at 
Early Termination if a subject has completed less than 22 weeks of study treatment. 
u. 
CAP and FAST scores will be measured each time a FibroScan is performed (unless the enrolling study site does not have the capability to measure CAP).  
v. 
Fasting lipid panel includes LDL-C, vLDL, HDL-C, non–HDL-C, total cholesterol, triglycerides, ApoB, and Lp(a) particles. 
w. Fasting metabolic panel includes insulin and NEFA. HOMA-IR and adipo-IR are to be calculated from fasting insulin, fasting glucose (see footnote p), and fasting 
NEFA, as applicable. An analysis of bile acid will also be performed at Baseline, Week 26, Week 52, and/or at Early Termination.  


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x. 
Fibrosis biomarkers include ELF (TIMP-1, PIIINP, and HA), PRO-C3, FIB-4, and potentially other markers. 
y. 
NASH biomarkers include CK-18, adiponectin, FGF-21, and other chemokines/cytokines relevant to NASH. 
z. 
Alcohol biomarkers will include PEth and may also include: GGT, MCV, ALT/AST, CDT, and FAEE. 
aa. Blood samples for lipidomic biomarkers will be collected in all subjects and analysis will include tripalmitin, ceramides, bile acids, diacylglycerols, and other classes of 
metabolites. 
bb. The lipoprotein substudy will be conducted in approximately 30 or more subjects. Provision of blood samples for the lipoprotein substudy is voluntary. 
cc. Additional spot urine and blood samples will be collected at specified time points and stored for potential future analyses for biomarkers relevant to NAFLD/NASH. 
These samples will not be used for genetic analysis or for creation of cell lines. Providing spot urine and blood samples for storage is voluntary.  
dd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
gg. In the event a subject is unable to complete the end of treatment MRI-PDFF and/or liver biopsy within the protocol-specified window (Week 52 +/- one week), extended 
dosing is permitted to maintain continuous dosing up to the time both assessments are completed, to a maximum total of 56 weeks of dosing. In this instance, the Follow-
up visit at Week 56 for posttreatment safety and efficacy assessments is to be adjusted to occur four weeks after the last dose (+/- one week). 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................2 
SPONSOR APPROVAL SIGNATURE PAGE ..............................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............25 
TABLE OF CONTENTS ...............................................................................................................25 
LIST OF TABLES .........................................................................................................................29 
LIST OF FIGURES .......................................................................................................................29 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................30 
5. 
INTRODUCTION ......................................................................................................34 
5.1. 
Nonalcoholic Fatty Liver Disease ..............................................................................34 
5.2. 
TVB-2640 ...................................................................................................................35 
6. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................37 
6.1. 
Objectives ...................................................................................................................37 
6.1.1. 
Primary Objectives .....................................................................................................37 
6.1.2. 
Secondary Objectives .................................................................................................37 
6.1.3. 
Exploratory Objectives ...............................................................................................39 
6.2. 
Endpoints ....................................................................................................................40 
6.2.1. 
Primary Efficacy (Responder) Endpoint ....................................................................40 
6.2.2. 
Secondary Efficacy and Pharmacodynamic Endpoints ..............................................40 
6.2.3. 
Exploratory Efficacy and Pharmacodynamic Endpoints ............................................42 
6.2.4. 
Safety Endpoints .........................................................................................................43 
7. 
INVESTIGATIONAL PLAN .....................................................................................44 
7.1. 
Overall Study Design ..................................................................................................44 
7.2. 
Stopping Rules ............................................................................................................45 
7.3. 
Dose Adjustment Criteria ...........................................................................................45 
7.4. 
Independent Data Monitoring Committee ..................................................................46 


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7.5. 
Criteria for Study Termination by the Sponsor ..........................................................47 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................48 
8.1. 
Subject Inclusion Criteria ...........................................................................................48 
8.2. 
Subject Exclusion Criteria ..........................................................................................49 
8.3. 
Subject Withdrawal Criteria .......................................................................................51 
9. 
TREATMENT OF SUBJECTS ..................................................................................53 
9.1. 
Description of Study Drug ..........................................................................................53 
9.1.1. 
TVB-2640 ...................................................................................................................53 
9.1.2. 
Placebo ........................................................................................................................53 
9.2. 
Study Drug Packaging and Labeling ..........................................................................53 
9.3. 
Study Drug Storage .....................................................................................................53 
9.4. 
Study Drug Accountability .........................................................................................53 
9.5. 
Study Drug Dose and Administration .........................................................................54 
9.6. 
Treatment Assignment, Randomization, Blinding, and Unblinding ..........................55 
9.7. 
Concomitant Medications ...........................................................................................55 
9.7.1. 
Excluded Medications ................................................................................................56 
9.7.2. 
Permitted Medications ................................................................................................57 
9.8. 
Treatment Compliance ................................................................................................57 
10. 
SCREENING/BASELINE ASSESSMENTS .............................................................58 
10.1. 
Demographics .............................................................................................................58 
10.2. 
Medical and Social History ........................................................................................58 
10.3. 
Viral Serology .............................................................................................................58 
10.4. 
Pregnancy Testing ......................................................................................................59 
10.5. 
Alcohol and Urine Drug Screening ............................................................................59 
10.6. 
Other Screening/Baseline Assessments ......................................................................59 
11. 
EFFICACY, PHARMACODYNAMIC, AND PHARMACOKINETIC 
ASSESSMENTS .........................................................................................................60 
11.1. 
Efficacy and Pharmacodynamic Assessments ............................................................60 
11.1.1. 
Liver Biopsy, Fibrosis Staging, and Histological Measurement of 
Nonalcoholic Fatty Liver Disease Activity Score ......................................................60 
11.1.2. 
Magnetic Resonance Imaging Studies ........................................................................61 
11.1.2.1. 
Proton-density Liver Fat Fraction by Magnetic Resonance Imaging .........................61 


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11.1.3. 
Liver Stiffness and Liver Steatosis by FibroScan and, Controlled Attenuation 
Parameter ....................................................................................................................62 
11.1.4. 
Digital Pathology ........................................................................................................62 
11.1.5. 
Clinical Laboratory Tests ...........................................................................................62 
11.1.5.1. 
Lipid and Metabolic Panel, Glycosylated Hemoglobin, and Lipoprotein 
Particle Size ................................................................................................................62 
11.1.5.2. 
NASH/Fibrosis Markers .............................................................................................63 
11.1.5.3. 
Adiponectin .................................................................................................................63 
11.1.6. 
Alcohol Biomarkers ....................................................................................................63 
11.1.7. 
Lipidomic Biomarkers ................................................................................................63 
11.1.8. 
Lipoprotein Analyses Substudy ..................................................................................63 
11.1.9. 
Metabolic and Microbiome Substudy .........................................................................63 
11.2. 
Other Assessments ......................................................................................................64 
11.2.1. 
Genomics ....................................................................................................................64 
11.2.2. 
Sample Collection for Storage ....................................................................................64 
11.3. 
 
 
 
 
 
12. 
ASSESSMENT OF SAFETY .....................................................................................66 
12.1. 
Safety Parameters .......................................................................................................66 
12.1.1. 
Vital Signs ..................................................................................................................66 
12.1.2. 
Physical Examination and Height ...............................................................................66 
12.1.3. 
Electrocardiograms .....................................................................................................66 
12.1.4. 
Eye Examinations .......................................................................................................67 
12.1.5. 
Safety Laboratory Assessments ..................................................................................67 
12.1.6. 
Anthropometric Assessments .....................................................................................69 
12.2. 
Adverse and Serious Adverse Events .........................................................................69 
12.2.1. 
Definition of Adverse Events .....................................................................................69 
12.2.1.1. 
Adverse Event .............................................................................................................69 
12.2.1.2. 
Serious Adverse Event ................................................................................................70 
12.2.2. 
Adverse Event Assessment .........................................................................................71 
12.2.2.1. 
Intensity ......................................................................................................................71 
12.2.2.2. 
Relationship to Study Drug ........................................................................................71 


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12.2.2.3. 
Seriousness .................................................................................................................72 
12.2.3. 
Recording Adverse Events .........................................................................................72 
12.2.4. 
Reporting Serious Adverse Events .............................................................................72 
12.2.5. 
Follow-Up of Adverse Events ....................................................................................73 
12.2.6. 
Pregnancy ...................................................................................................................73 
12.2.7. 
Overdose of TVB-2640 ..............................................................................................74 
12.2.8. 
Protocol Deviations Due to an Emergency or Adverse Event ....................................74 
13. 
STATISTICAL CONSIDERATIONS .......................................................................75 
13.1. 
Statistical General Considerations ..............................................................................75 
13.2. 
Efficacy Analysis ........................................................................................................75 
13.2.1 Primary Efficacy Endpoint .................................................................................................75 
13.2.2 Secondary Efficacy Endpoints ............................................................................................76 
13.2.3. Exploratory Endpoints .......................................................................................................79 
13.2.4. Pharmacokinetic Parameters ..............................................................................................79 
13.3. 
Safety Analysis ...........................................................................................................79 
13.4. 
Statistical and Analytical Methods .............................................................................80 
13.4.1 
Hypothesis Testing .....................................................................................................80 
13.4.2 
Analysis Sets ...............................................................................................................80 
13.4.2.1 
Intention-to-Treat Population .....................................................................................80 
13.4.2.2 
Modified Intention-to-Treat Populations ....................................................................80 
13.4.2.3 
Safety Population ........................................................................................................81 
13.4.2.4 
Pharmacokinetic Population .......................................................................................81 
13.5. 
Power Considerations and Sample Size Determination .............................................81 
13.6. 
Interim Analysis ..........................................................................................................81 
13.7. 
Planned Study Committees .........................................................................................81 
14. 
ETHICS ......................................................................................................................83 
14.1. 
Good Clinical Practice Compliance ............................................................................83 
14.2. 
Institutional Review Board or Independent Ethics Committee ..................................83 
14.3. 
Ethical Conduct of the Study ......................................................................................83 
14.4. 
Written Informed Consent ..........................................................................................84 
14.5. 
Subject Confidentiality ...............................................................................................84 
15. 
ADMINISTRATIVE REQUIREMENTS ..................................................................85 


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15.1. 
Study Monitoring ........................................................................................................85 
15.2. 
Case Report Form Completion ...................................................................................85 
15.3. 
Computerized Systems/Medical Records as Source Data ..........................................86 
15.4. 
Source Documents ......................................................................................................86 
15.5. 
Retention of Records ..................................................................................................86 
15.6. 
Audits and Inspections ................................................................................................87 
15.7. 
Publication Policy .......................................................................................................87 
16. 
LIST OF REFERENCES ............................................................................................88 
APPENDIX A. ALGORITHM FOR EVALUATING SUBJECTS FOR POTENTIAL 
DRUG-INDUCED LIVER INJURY ..........................................................................90 
 
LIST OF TABLES 
Table 1 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................20 
Table 3: 
NAS Components and Scoring ...................................................................................60 
Table 4: 
NASH CRN Fibrosis Scoring .....................................................................................61 
Table 5: 
Safety Laboratory Parameters .....................................................................................68 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................19 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
ACC 
Acetyl-CoA carboxylase 
adipo-IR 
Adipose tissue insulin resistance index 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoB 
Apolipoprotein B 
APRI 
AST to platelets ratio index 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-∞ 
Area under the concentration-time curve from time of 
dosing extrapolated to infinity 
AUC0-last 
Area under the concentration-time curve from time of 
dosing to the last measured concentration 
β-hCG 
Beta-human chorionic gonadotropin 
BMI 
Body mass index 
CAP 
Controlled attenuation parameter 
CK-18 
Cytokeratin-18 
Cmax 
Maximum plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CoA 
Coenzyme A 
CRN 
Clinical Research Network 
CRO 
Clinical research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
DILI 
Drug-induced liver injury 
DNL 
de novo lipogenesis 
DPP-4 
Dipeptidyl peptidase 4 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 


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Abbreviation or Specialist Term 
Explanation 
eGFR 
Estimated glomerular filtration rate 
ELF 
Enhanced liver function 
ELISA 
Enzyme-linked immunosorbent assay 
FAS 
Full analysis set 
FASN 
Fatty acid synthase 
FAST 
FibroScan-AST 
FDA 
US Food and Drug Administration 
FGF-21 
Fibroblast growth factor 21 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GLP 
Good laboratory practices 
GLP-1 
Glucagon-like peptide-1 
HA 
Hyaluronic acid 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen  
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HOMA-IR 
Homeostatic model assessment of insulin resistance 
IAmITT 
Interim analysis modified Intention-to-Treat 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intention-to-Treat 
IUD 
Intrauterine device 
IWRS 
Interactive Web-based Response System 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein(a) 
LS 
Least-squares 


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Abbreviation or Specialist Term 
Explanation 
MDRD 
Modification of Diet in Renal Disease Study 
MedDRA 
Medical Dictionary for Regulatory Activities 
MICE 
Multiple Imputations by Chained Equations 
mITT 
Modified Intention-to-Treat 
MMRM 
Mixed model repeated measure 
MRI 
Magnetic resonance imaging 
MRI-PDFF 
Magnetic resonance imaging–proton density fat fraction 
NAFLD 
Nonalcoholic fatty liver disease 
NAS 
NAFLD activity score 
NASH 
Nonalcoholic steatohepatitis 
NCI 
National Cancer Institute 
NEFA 
Non-esterified fatty acid 
NMR 
Nuclear magnetic resonance 
OAD 
Oral antidiabetic 
PIIINP 
Procollagen III amino-terminal peptide 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PEth 
Phosphatidylethanol 
PK 
Pharmacokinetic 
PO 
Orally 
PPE 
Palmar-plantar erythrodysesthesia 
PRO-C3 
N-terminal type III collagen propeptide 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SGLT2 
Sodium-glucose co-transporter-2 
SHG 
Second harmonic generation 
SNP 
Single-nucleotide polymorphisms 
T½  
Plasma elimination half-life 
T2DM 
Type 2 diabetes mellitus 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 


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Abbreviation or Specialist Term 
Explanation 
TIMP-1 
Tissue inhibitor of metalloproteinase-1 
Tlast 
 Time of the last measurable concentration 
Tmax 
Time to Cmax 
TZD 
Thiazolidinediones 
ULN 
Upper limit of normal 
US 
United States 
vLDL 
Very low density lipoprotein cholesterol 
 


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5. 
INTRODUCTION 
5.1. 
Nonalcoholic Fatty Liver Disease 
Fatty acid synthase (FASN) is a key enzyme in the de novo lipogenesis (DNL) pathway and 
catalyzes the biosynthesis of palmitate from acetyl-coenzyme A (CoA) and malonyl-CoA 
substrates, which can then undergo further modifications into other fatty acids and complex 
lipids. Because FASN catalyzes the last step in the fatty acid biosynthetic pathway, it is believed 
to be a determinant of the maximal liver capacity to synthesize fatty acids by DNL 
(Postic, 2008). 
Dysregulation of FASN activity is found in a number of different disease states, including cancer 
(Buckley, 2017) and metabolic diseases (e.g., obesity, type 2 diabetes mellitus [T2DM]) 
(Menendez, 2009).  
Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to the more progressive 
nonalcoholic steatohepatitis (NASH) characterized by hepatocyte necrosis, chronic 
inflammation, and resultant fibrosis formation. Patients with NASH are at increased risk of death 
due to advanced liver disease, including cirrhosis and hepatocellular carcinoma, as well as 
cardiovascular disease. Risk factors of developing NAFLD include T2DM (Cusi, 2016), obesity, 
and metabolic syndrome, all characterized by an imbalance in energy utilization and storage 
(Grundy, 2005). This imbalance may lead to dysregulated metabolic pathways and inflammatory 
responses that drive further changes leading to liver damage and comorbid conditions. NASH is 
the most rapidly increasing indication for liver transplantation in the United States (US) 
(Younossi, 2020). 
Normal responses to ingesting carbohydrate in meals include a transient increase in hepatic 
DNL, a FASN-dependent pathway, followed by a return to baseline levels upon fasting. In 
patients with NAFLD, however, hepatic DNL is increased (Donnelly, 2005; Lambert, 2014), and 
FASN gene expression has been shown to be elevated in liver histology specimens from patients 
with NAFLD (Kohjima, 2007; Mitsuyoshi, 2009), contributing to elevated liver stores of 
triglycerides and saturated fatty acid species, which in turn may contribute to liver inflammation 
(Wei, 2006), tissue damage, and fibrosis formation. 
There are currently no drugs licensed for the treatment of NASH in the US, Europe, or China. 
Inhibiting lipogenesis, with a FASN inhibitor for example, may be a viable clinical strategy to 
address NASH. Pharmacological inhibition of FASN with TVB-3664, a chemical surrogate of 
TVB-2640, improved hepatic steatosis, inflammation, and fibrosis in a diet-induced mouse 
model of NASH (Duke, 2017). Moreover, studies in patients with NASH have shown that 
inhibition of DNL with the acetyl-CoA carboxylase (ACC) inhibitors firsocostat (Stiede, 2017) 
and PF-05221304 results in a significant reduction of intrahepatic fat and surrogate markers of 
fibrosis and cell death, albeit with problematic increases of plasma triglyceride levels as a direct 
consequence of ACC inhibition (Sanyal, 2017; Kim, 2018). Further studies are needed, however, 
to evaluate the full spectrum of treatment effects elicited by these drugs and management of their 
side effects.  


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5.2. 
TVB-2640 
Sagimet Biosciences has developed an oral (PO), once-daily (QD) FASN inhibitor, TVB-2640. 
This drug has been evaluated in >300 humans to date, including patients with NASH, patients 
with solid tumors, and healthy adults, some of whom had characteristics of the metabolic 
syndrome. The safety, pharmacokinetic (PK), and pharmacodynamic (PD) parameters of 
TVB-2640 have been measured.  
 
 
 
 
 
  
Safety data are available from 129 subjects with NASH who have been enrolled in the US and 
China in Study CLIN-005 (FASCINATE-1). In the US, subjects received 25 mg TVB-2640, 
50 mg TVB-2640, or placebo PO, QD for approximately 12 weeks. A total of 68 subjects were 
treated with TVB-2640. Overall, 62 (63%) subjects experienced at least 1 treatment-emergent 
adverse event (TEAE), all of which were assessed by the Investigator as mild, with the exception 
of 1 case each of Grade 2 urinary tract infection and Grade 2 increased appetite at 25 mg and 
Grade 2 dyspnea at 50 mg, all of which resolved without dose adjustment. No on-treatment 
serious adverse events (SAEs) occurred in either TVB-2640 dose group. Overall, the most 
common TEAEs among TVB-2640-treated subjects were headache (6 subjects; 9%) and 
peripheral edema, rash, and upper respiratory tract infection (4 subjects each; 6%). Two (3%) 
subjects discontinued TVB-2640 due to a TEAE: 1 subject due to mild eye allergy (after 1 day of 
dosing) and the other due to mild conjunctivitis; both of these events occurred in the 25-mg dose 
group. 
Among the 30 subjects enrolled in China, 21 were treated with TVB-2640 50 mg and 9 were 
treated with placebo for 12 weeks. Seventeen (81.0%) patients experienced at least 1 TEAE, all 
of which were reported as Grade 2 or less, with the exception of 2 cases of Grade 3 
hypertriglyceridemia, both of which were deemed as unrelated to TVB-2640. All TEAEs 
resolved without dose adjustment. No on-treatment SAEs occurred. Skin and subcutaneous tissue 
disorders were the most common type of TEAEs. Overall, the most common TEAEs among 
TVB-2640-treated patients were dry eye (8 patients), skin exfoliation (7 patients), and palmar-
plantar erythrodysesthesia syndrome (PPE) and upper respiratory tract infection (each 3 
patients). 
 
 
 
 
 
 
 
TVB-2640 reduced hepatic DNL in subjects with features of metabolic syndrome (Syed-Abdul, 
2020). Reduction of DNL was dose dependent. The lowest dose tested, 50 mg, exhibited a 


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significant and meaningful decrease of DNL. Results from the Phase 2a clinical study CLIN-005 
demonstrated that QD, PO administration of TVB-2640 for 12 weeks in both the 25-mg and 
50-mg cohorts decreased hepatic liver fat in a dose-dependent manner and improved other 
noninvasive markers of fibrosis, inflammation, and metabolism in subjects with NASH.  
The data summarized above support further investigation of TVB-2640 as a novel therapy for 
patients with NASH. Therefore, the present study will be a Phase 2b, double-blind, 
parallel-group clinical study to evaluate the safety, efficacy, and PK of 50 mg TVB-2640 
compared with matching placebo in approximately 162 patients with NASH over a 12-month 
Treatment period.  
 
 
 Accordingly, 
female subjects of childbearing potential must use 2 forms of birth control, one being a barrier 
method (ie, condoms, diaphragm, nonhormonal intrauterine device [IUD]) throughout the study 
and for at least 3 months after the final study drug dose. Hormonal contraception (stable 
≥3 months) and hormonal IUDs are permitted if used with a secondary barrier birth control 
method (e.g., condoms). 
 
Refer to the Investigator’s Brochure for more detailed information regarding TVB-2640. 


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6. 
TRIAL OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objectives 
• To evaluate the effect of TVB-2640 50 mg PO QD compared with matching placebo in 
noncirrhotic subjects with NASH and F2-F3 fibrosis by either:  
o Histological improvement at Week 52 in NAFLD activity score (NAS) (ie, 
≥2 points improvement in NAS with ≥1 point improvement in ballooning or 
inflammation) and without worsening of fibrosis (by NASH Clinical Research 
Network [CRN] fibrosis score) 
OR 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH 
CRN fibrosis score). Resolution of steatohepatitis is defined as absence of 
fatty liver disease or isolated or simple steatosis without steatohepatitis and a 
NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. 
• To evaluate the safety and tolerability of TVB-2640 50 mg PO QD in subjects with 
confirmed NASH and liver fibrosis. 
6.1.2. 
Secondary Objectives 
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% 
relative reduction in liver fat content as assessed by magnetic resonance imaging–proton 
density fat fraction (MRI-PDFF) at Week 26. 
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% 
relative reduction in liver fat content as assessed by MRI-PDFF at Week 52. 
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
fibrosis as assessed by ≥1 stage of fibrosis improvement (by NASH CRN score) without 
worsening of steatohepatitis (no increase in NAS for ballooning, inflammation, or 
steatosis) at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without worsening of NAS 
(defined as no increase in any component of NAS) at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without increasing of total 
NAS scores at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on fibrosis as 
assessed by ≥1 stage of fibrosis improvement by NASH CRN score without any worsening of 
NASH (no worsening of ballooning and lobular inflammation, a 1 grade change in steatosis may 
be acceptable) at Week 52.  
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo the proportion 


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of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis on overall histopathological reading and no worsening of 
liver fibrosis on NASH CRN fibrosis score. Resolution of steatohepatitis is defined as 
absent fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS 
score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis. 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, 
inflammation, or steatosis). 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in NAFLD NAS (ie, ≥2 points improvement in 
NAS with ≥1 point improvement in ballooning or inflammation) and without worsening 
of fibrosis (by NASH CRN fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, 
inflammation, or steatosis). 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis 
score). Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
AND 
o Histological improvement at in NAS (≥2 points improvement in NAS). 
• 
To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on histological 
improvement at Week 52 in NAS.  
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on liver 
fat content as assessed by MRI-PDFF at Week 26. 
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on liver 
fat content as assessed by MRI-PDFF at Week 52. 
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
NASH resolution (defined as absence of fatty liver or isolated or simple steatosis without 
steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for 
steatosis) at Week 52.  
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
change from Baseline at 26 and 52 weeks in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and gamma-glutamyltransferase (GGT). 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in low-density lipoprotein cholesterol (LDL-C) 
and other lipid levels. 


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• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 52 weeks in the amount of collagen/fibrous area and fibrosis 
score, assessed by digital pathology. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in fasting insulin, fasting glucose, homeostatic 
model assessment of insulin resistance (HOMA-IR), adipose tissue insulin resistance 
(adipo-IR), and glycosylated hemoglobin (HbA1c) levels.  
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in fibroblast growth factor 21 (FGF-21), 
adiponectin, and other NASH biomarker levels. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
change from Baseline at 26 and 52 weeks in FibroScan® and controlled attenuation 
parameter (CAP) score.  
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
N-terminal type III collagen propeptide (PRO-C3) levels and other fibrosis biomarkers on 
change from Baseline at Weeks 4, 13, 26, and 52. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
change from Baseline at 26 and 52 weeks in enhanced liver function (ELF) score. 
• 
 
  
6.1.3. 
Exploratory Objectives 
• To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% 
relative reduction in liver fat content as assessed by MRI-PDFF AND achieve ≥17 U/L 
reduction in ALT at Week 52. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
FibroScan-AST (FAST) score at Weeks 26 and 52.  
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
select fibrosis biomarkers (including at least tissue inhibitor of metalloproteinase-1 
[TIMP-1]) at Weeks 4, 13, 26, and 52. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
lipidomic biomarkers (including tripalmitin, ceramides, bile acids, diacylglycerols, and 
other classes of metabolites) at Weeks 4, 13, 26, and 52. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
glycosylated hemoglobin (HbA1c) levels among subjects with T2DM at Weeks 13, 26, 
39, and 52. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
Fibrosis 4 score (FIB-4) at Weeks 4, 13, 26, and 52. 


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• To use digital pathology to perform zonal analysis of fibrosis at Week 52. 
o To use digital pathology to evaluate the concurrence of fibrosis with components 
of the NAS score. 
o To use digital pathology to evaluate the NAS components. 
• To correlate changes in MRI-PDFF with changes in, or baseline levels of, serum 
biomarkers and explore predictive markers of response. 
• To explore the relationship between changes in, or Baseline levels of, serum biomarkers 
and histology results, and explore predictive markers of response. 
• To explore the relationship between MRI-PDFF results and histology results. 
• To correlate the presence of relevant single-nucleotide polymorphisms (SNPs) or other 
genes relevant to NAFLD or NASH with clinical and histopathologic response. 
• To determine the effect of TVB-2640 50 mg QD compared with matching placebo on gut 
microbiome change from Baseline to Weeks 26 and 52 in a subset of subjects.  
• To explore the relationship between nutrition, as measured by the HepVita Nutritional 
Survey, and clinical, histopathological, and biomarker changes in NASH at Weeks 26 
and 52 in a subset of subjects. 
6.2. 
Endpoints 
6.2.1. 
Primary Efficacy (Responder) Endpoint 
The proportion of subjects experiencing either of the following: 
• Histological improvement at Week 52 in NAS (ie, ≥2 points improvement in NAS with 
≥1 point improvement in ballooning or inflammation) and without worsening of fibrosis 
(by NASH CRN fibrosis score) 
OR 
• Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis 
score). Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
6.2.2. 
Secondary Efficacy and Pharmacodynamic Endpoints 
• Proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF ≥30% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
relative reduction from Baseline in MRI-PDFF ≥30%. 
• Proportion of MRI-PDFF ≥30% responders at Week 52. 
• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN 
fibrosis score without worsening of steatohepatitis (defined as no increase in NAS for 
ballooning, inflammation, or steatosis) at Week 52.  


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• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
with no increase in any component of NAS at Week 52. 
• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without increase of total NAS score at Week 52. 
• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without any worsening of NASH (defined as no worsening of ballooning and lobular 
inflammation; a 1 grade change in steatosis may be acceptable) at Week 52. 
• Proportion of subjects experiencing both of the following at Week 52:  
o Resolution of steatohepatitis on overall histopathological reading and no 
worsening of live fibrosis on NASH CRN fibrosis score. Resolution of 
steatohepatitis is defined as absent fatty liver disease or isolated or simple 
steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for 
ballooning, and any value for steatosis 
AND 
o Improvement in liver fibrosis greater than or equal to one state (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
• 
Proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in nonalcoholic fatty liver disease (NAFLD) 
activity score (NAS) (ie, ≥2 points improvement in NAS with ≥1 point improvement in 
ballooning or inflammation) and without worsening of fibrosis (by NASH Clinical 
Research Network [CRN] fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis 
score) and no worsening of steatohepatitis (defined as no increase in NAS for ballooning, 
inflammation, or steatosis). 
• 
Proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis 
score). Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
AND 
o Histological improvement at in NAS (≥2 points improvement in NAS). 
• 
Proportion of subjects with histological improvement at Week 52 in NAS.  
• MRI-PDFF percent change in liver fat and change from Baseline at Week 26. 
• MRI-PDFF percent change in liver fat and change from Baseline at Week 52. 
• Proportion of subjects with NASH resolution (defined as absence of fatty liver disease or 
isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 
0 for ballooning, and any value for steatosis) at 52 weeks. 


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• Change from Baseline in ALT, AST, and GGT at Weeks 26 and 52 and at each study 
visit. 
• Change from Baseline in LDL-C and other lipid levels at Weeks 26 and 52 and at each 
study visit. 
• Change from Baseline in collagen/fibrous area and fibrosis score, assessed by digital 
pathology, at Week 52. 
• Changes from Baseline in metabolic parameters, including fasting insulin, fasting 
glucose, HOMA-IR, adipo-IR, and HbA1c levels at Weeks 26 and 52 and at each study 
visit. 
• Change from Baseline in FGF-21, adiponectin, and other NASH biomarker levels at 
Weeks 26 and 52 and at each study visit. 
• Change from Baseline in FibroScan and CAP score results at Weeks 26 and 52. 
• Change from Baseline in PRO-C3 and other fibrosis biomarkers at Weeks 4, 13, 26, and 
52. 
• Change from Baseline in ELF score at Weeks 26 and 52. 
• Plasma concentrations of TVB-2640 at Weeks 1, 4, 13, 26, and 52. 
6.2.3. 
Exploratory Efficacy and Pharmacodynamic Endpoints 
• Proportion of MRI-PDFF ≥30% responders at Week 52 who have ≥17 U/L reduction in 
ALT.  
• Change from Baseline in FAST score at Weeks 26 and 52. 
• Change from Baseline in levels of select fibrosis biomarkers (e.g., TIMP-1) at Weeks 4, 
13, 26, and 52. 
• Change from Baseline in levels of lipidomic/metabolomic biomarkers (e.g., tripalmitin, 
ceramides, bile acids, diacylglycerols, and other classes of metabolites) at Weeks 4, 13, 
26, and 52. 
• Change from Baseline in HbA1c levels among subjects with T2DM at Weeks 13, 26, 39, 
and 52.  
• Change from Baseline in FIB-4 at Weeks 4, 13, 26, and 52. 
• Change from Baseline in zonal analyses of fibrosis as determined by digital pathology at 
Week 52.  
• Correlation of changes in MRI-PDFF with changes in other endpoints. 
• Presence or absence of SNPs relevant for NASH. 
• Correlation of predictive signature with other endpoints. 
• Correlation of lipids (e.g. tripalmitin) with other endpoints. 


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• Change from Baseline in gut microbiome analyses at Weeks 26 and 52 in a substudy of 
subjects. 
• Change from Baseline in HepVita Nutritional Survey at Weeks 26 and 52 in a substudy 
of subjects. 
6.2.4. 
Safety Endpoints 
• Adverse events (AEs) throughout the study. 
• Electrocardiograms (ECGs) at Weeks 26 and 52. 
• Vital signs at each study visit. 
• Physical examination findings at each study visit. 
• Eye examination findings at each study visit. 
• Hematology and coagulation results at each study visit. 
• Liver aminotransferase levels at each study visit. 
• Clinical chemistry results at each study visit. 
• Urinalysis results at each study visit. 
• Pregnancy test results throughout the study. 
• Prior and concomitant medications throughout the study. 
• Results of anthropometric measurements at Week 52. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-design study to 
evaluate the safety and efficacy of TVB-2640 compared with matching placebo in subjects with 
NASH who are aged ≥18 years at Screening. Histological eligibility will be determined during 
the Screening period or prior to Screening but within 180 days of the Screening visit in 1 of 2 
ways:  
• If an ‘eligible’ and adequate (this refers to the quality and quantity of remaining tissue) 
liver histology specimen, in the judgement of the central pathologist, exists from the time 
period within 180 days before the subject’s Screening visit, the subject may participate so 
long as other eligibility criteria are satisfied. 
• If no liver histology specimen exists from the period within 180 days of the Screening 
visit, the subject must undergo liver biopsy during the Screening period. 
Approximately 162 unique subjects with liver fibrosis stage F2-F3 will be enrolled and 
randomized to achieve a 2:1 ratio with approximately 108 subjects on TVB-2640 50 mg and 
54 subjects on placebo. Dynamic allocation is used for the randomization, stratified by 3 factors: 
T2DM status (yes or no), region (North America or not North America), and amount of fibrosis 
(F2 or F3).  
Subjects will be screened for study eligibility within 90 days before randomization 
(randomization is within 3 days of Baseline [Day 1]). Subjects who are determined to be eligible 
for the study based on Screening assessments are to be randomized into the study within 3 days 
before Baseline (ie, Day 1, the first day of study drug administration). Subjects who are 
randomized are considered to be enrolled in the study.  
Subjects will receive TVB-2640 or matching placebo PO QD for 52 weeks, with the first dose 
administered on Day 1. During the 52-week Treatment period, subjects are to attend study center 
visits at Weeks 4, 8, 13, 26, 39, and 52. After completion of the 52-week Treatment period, 
subjects are to attend a Follow-up visit at Week 56 for posttreatment safety and efficacy 
assessments. 
In the event a subject is unable to complete the end of treatment MRI-PDFF and/or liver biopsy 
within the protocol-specified window (Week 52 +/- one week), extended dosing is permitted to 
maintain continuous dosing up to the time both assessments are completed, to a maximum total 
of 56 weeks of dosing. In this instance, the Follow-up visit at Week 56 for post treatment safety 
and efficacy assessments is to be adjusted to occur four weeks after the last dose (+/- one week).  
In the instance of a dose hold due to an AE or SAE, the decision to resume study drug will 
require consultation with the Investigator, the CRO’s Medical Monitor, and the Sponsor’s Chief 
Medical Officer.  
Improvement of NAS and improvement of fibrosis score will be evaluated by comparison of 
Baseline and Week 52 liver histology specimens. Subjects will also undergo MRI-PDFF prior to 
the start of treatment, at Week 26, and at Week 52 or Early Termination unless it presents a 
logistical or physical hardship to the subject. MRI-PDFF is not required at Early Termination if a 


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subject has completed less than 22 weeks of study treatment. Other efficacy and PD assessments 
include FibroScan with CAP, and measurement of liver aminotransferases, lipid parameters, and 
other noninvasive biomarkers of NASH and liver fibrosis throughout the study.  
During the study, safety will be assessed by vital signs, 12-lead ECGs, physical examinations 
including eye examinations, and clinical laboratory testing. Subjects will be evaluated for AEs 
and concomitant medication use throughout the study.  
 
 
. 
An independent data monitoring committee (IDMC) will be established by charter to provide 
independent review and assessment of study data and to monitor the overall study conduct in a 
systematic manner to safeguard the safety of study subjects. The IDMC will be tasked with 
making recommendations to the Sponsor to continue, amend, or stop the study based on these 
assessments.  
A secondary endpoint efficacy interim analysis (IA) is planned when approximately 60 subjects 
with an MRI-PDFF value of ≥8% liver fat at Baseline have completed Week 26 or an Early 
Termination visit after Week 22. The purpose of the proposed interim analysis is to examine the 
TVB-2640 benefit over placebo based on a Week 26 secondary efficacy endpoint consisting of 
“proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF ≥30% responder 
is defined as a subject with ≥8% liver fat content at Baseline who achieves a percent change 
(reduction) from Baseline in MRI-PDFF ≥30%.”  
Interim summaries of safety and selected biomarker data will accompany the interim efficacy 
analysis of the secondary efficacy endpoint.  
The study design is summarized in Error! Reference source not found., and the Schedule of 
Assessments is provided in Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
 PO = orally; QD = once daily. 
Table 2. 
7.2. 
Stopping Rules 
Enrollment of new subjects may be suspended in the event of any of the following:  
• ≥1 subject experiences a Grade 5 TEAE (ie, TEAE with a fatal outcome) 
• ≥2 subjects experience the same Grade 4 TEAE 
In such cases, the Sponsor’s Chief Medical Officer and the clinical research organization’s 
(CRO’s) Medical Monitor will review blinded data to determine if the IDMC needs to be 
convened to review the unblinded data to determine the relationship of the TEAE(s) to TVB-
2640. The IDMC will make a recommendation to the Sponsor regarding whether to continue, 
amend, or stop the study. 
7.3. 
Dose Adjustment Criteria 
Dose modification will be allowed for subjects who experience an on-target AE considered to be 
treatment related that would otherwise lead to study or treatment discontinuation. The decision to 
reduce the dose of study drug will require consultation with the Investigator, the CRO’s Medical 
Monitor, and the Sponsor’s Chief Medical Officer. To preserve the study blind, the total number 
of combined tablets of study drug and matching placebo will remain the same. The subject’s 
study drug assignment will NOT be unblinded. Dose modification is not allowed for subjects 
who have any of the TEAEs described in Section 8.3 that require permanent discontinuation. 
Additional details are provided in the Pharmacy Manual.  
Dose interruptions may also be allowed (see also Appendix A and Section 8.3).  
In the instance of a dose hold due to an AE or SAE, the decision to resume study drug will 
require consultation with the Investigator, the CRO’s Medical Monitor, and the Sponsor’s Chief 
Medical Officer. 
7.4. 
Independent Data Monitoring Committee 
An IDMC will be established to provide independent review and assessment of study data and to 
monitor the overall study conduct in a systematic manner in order to safeguard the safety of 
study subjects. The IDMC will be tasked with making recommendations to the Sponsor to 
continue, amend, or stop the study based on these assessments.  


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The members of the IDMC will be independent of the Sponsor and the study team, including the 
CRO. The IDMC will consist of at least 3 independent individuals, including 1 biostatistician 
and 2 physicians with expertise in NAFLD. In addition, an independent, nonvoting statistician 
who is not a member of the IDMC or a member of the study team will serve as a liaison between 
the Sponsor and the IDMC and will provide periodic outputs of safety data for IDMC review. 
The specific procedures for interactions between the IDMC and non-IDMC individuals will be 
defined in the IDMC charter. 
IDMC meetings will consist of open and closed sessions. Closed sessions will be attended only 
by IDMC members and the independent statistician. Study team personnel, including the 
Sponsor and the CRO, will be restricted to the open sessions. 
A single (secondary endpoint) efficacy interim analysis is planned when approximately 
60 subjects with an MRI-PDFF value of ≥8% liver fat at Baseline have completed Week 26 or an 
Early Termination visit after Week 22. The purpose of the proposed interim analysis is to 
examine the TVB-2640 benefit over placebo based on a Week 26 secondary efficacy endpoint 
consisting of “proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF 
≥30% responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
percent change (reduction) from Baseline in MRI-PDFF ≥30%.”  
Interim safety summaries will accompany the interim efficacy analysis of the secondary efficacy 
endpoint. 
The IDMC will also meet any time that the stopping rules outlined in Section 7.2 are met. 
Additional scheduled and ad hoc meetings may take place as required, and rules for these 
meetings will be defined in the IDMC charter. 
The Sponsor will establish a charter document explaining the working procedures and 
responsibilities of the IDMC. All deliberations and decisions of the board will be appropriately 
documented.  
7.5. 
Criteria for Study Termination by the Sponsor 
The Sponsor reserves the right to terminate the study or a particular study center at any time. If 
the Sponsor or Investigator discovers conditions arising during the study that suggest the study 
should be halted, then study termination can occur only after appropriate consultation between 
the Sponsor and Investigators. Conditions that may warrant study or study center termination 
include, but are not limited to: 
• The discovery of any unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study 
• Failure of the Investigator to enter subjects at an acceptable rate 
• Insufficient adherence to the protocol requirements 
• A decision on the part of the Sponsor to suspend or discontinue development of study 
drug 
Should the study be closed prematurely, all study materials (study drug, etc) must be returned to 
the Sponsor or designee (or disposed of as directed by the Sponsor or designee). 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Unless otherwise specified, repeat testing for laboratory and clinical Screening assessments may 
be performed in consultation with the Medical Monitor. 
8.1. 
Subject Inclusion Criteria 
Subjects meeting all of the following criteria are eligible for enrollment into the study.  
1. Must be willing and able to participate in the study and provide written informed consent. 
2. Male and female adults ≥18 years of age on the date that written informed consent to take 
part in the study is provided. 
3. Body mass index (BMI) ≥23 kg/m2 for Asians and ≥25 kg/m2 for other races. 
4. Female subjects must be either:  
a. Not of childbearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or 
tubal ligation] or naturally sterile [>12 consecutive months without menses]). 
OR 
b. Female subjects of childbearing potential must have a negative serum pregnancy 
(beta-human chorionic gonadotropin [β-HCG]) test during Screening, a negative urine 
pregnancy test within 24 hours before the first dose of study drug on Day 1, and must 
agree to perform urine home pregnancy tests monthly between study visits. Female 
subjects of childbearing potential must not be breastfeeding, not plan to become 
pregnant during the study, and must use 2 forms of birth control, one being a barrier 
method (ie, condoms, diaphragm, IUD) throughout the study and for at least 3 months 
after the final study drug dose. Hormonal contraception (stable ≥3 months) and 
hormonal IUDs are permitted if used with a secondary barrier birth control method 
(e.g., condoms). 
5. Male subjects who have sexual intercourse with a female partner of childbearing potential 
from the first dose of study drug until 3 months after completion of study drug intake 
must be either surgically sterile (confirmed by documented azoospermia >90 days after 
the procedure) OR agree to use a condom with spermicide. All male subjects must agree 
not to donate sperm from the first dose of study drug until 3 months after completion of 
study drug intake. 
6. Must have liver stiffness measurement ≥8.5 kPa measured by FibroScan and CAP score 
measured by FibroScan ≥280 dB/m (unless the enrolling study site does not have the 
capability to measure CAP) during the Screening period.  
7. Histologic confirmation of NASH: must have had a prior liver biopsy within 180 days 
before the Screening visit, or a new biopsy during the screening period, with fibrosis 
stage F2-F3 and a NAS of ≥4 with at least a score of 1 in each of the following NAS 
components: 
a. Steatosis (scored 0 to 3) 
b. Ballooning degeneration (scored 0 to 2) 
c. Lobular inflammation (scored 0 to 3) 


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8. AST >20 U/L. 
8.2. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment into the study.  
1. History of harmful alcohol intake for a period of more than 3 consecutive months within 
1 year prior to Screening in the judgement of the Investigator.  
2. Active substance abuse, including inhaled or injected substances (cocaine and other 
illegal/banned substances; any opiate, amphetamine, or benzodiazepine for which the 
subject does not have an existing prescription), within 1 year prior to Screening (note that 
recreational cannabis/tetrahydrocannabinol use is permissible). 
3. Patient-reported or medically documented gain or loss of >5% of body weight in the 
6 months prior to Baseline (Day 1) or >10% of body weight in the 12 months prior to 
Screening. 
4. Prior or planned (during the study period) bariatric surgery that may interfere with study 
drug absorption (e.g., roux-en-Y gastric bypass); gastroplasty and gastric reduction 
surgery are acceptable. 
5. Type 1 diabetes mellitus by history. 
6. Positive SARS-CoV-2 polymerase chain reaction (PCR) test within 30 days prior to the 
Baseline (Day 1) visit date or history of hospitalization for COVID-19 <6 months prior to 
the Screening visit date. Note that previous COVID-19 infection alone is not 
exclusionary, and COVID-19 vaccination is allowed. Infection and/or vaccination must 
be documented as medical history and/or concomitant medication, respectively.  
7. Known positivity for HIV infection or positive HIV antibody result at Screening. 
8. Positive hepatitis B virus antigen (HBsAg) result at Screening. 
9. Positive hepatitis C virus (HCV) RNA test at Screening; however, subjects with chronic 
HCV infection and liver disease who were treated with anti-HCV therapy and achieved a 
sustained virologic response at least 2 years prior to Screening are not prevented from 
study participation. 
10. Uncontrolled T2DM, defined as HbA1c >9.5% at Screening. 
11. Serum LDL-C concentration at Screening >190 mg/dL, and the subject has been taking 
LDL-C–lowering treatment for ≥30 days prior to Screening. 
12. ALT and/or AST result >5 × the upper limit of normal (ULN) at Screening. One repeat 
test may be allowed within 7 days of receipt of the result at the discretion of the 
Investigator. 
13. Alkaline phosphatase (ALP) result ≥2 × ULN at Screening. 
14. Total serum bilirubin concentration >1.3 mg/dL at Screening; subjects with a confirmed 
diagnosis of Gilbert’s syndrome (ie, prior to Screening and whose total bilirubin result at 
Screening exceeds 1.3 mg/dL) may be eligible for study inclusion at the Investigator’s 
discretion. 


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15. International normalized ratio (INR) result >1.3 at Screening. 
16. Serum albumin concentration <3.5 g/dL at Screening. 
17. Platelet count <140,000/µL at Screening. 
18. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2, as determined using 
the Modification of Diet in Renal Disease Study (MDRD) equation, at Screening. 
19. Presence of cirrhosis on liver histology (stage 4 fibrosis), according to the judgement of 
the central reader; and/or cross-sectional imaging evidence consistent with cirrhosis 
and/or portal hypertension (e.g., nodular liver contour; atrophy and hypertrophy of the 
right and left hepatic lobes, respectively; splenomegaly; known presence or history of 
esophageal varices; and/or elastography evidence consistent with cirrhosis). 
20. F0, F1, or F4 fibrosis, or inconclusive result, on liver histology. 
21. Use of drugs historically associated with risk of development of NAFLD (e.g., 
amiodarone, methotrexate, systemic glucocorticoids [unless used at physiologic 
replacement doses for treatment of confirmed adrenal insufficiency], tetracyclines, 
tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic 
steroids [except for testosterone preparations used at physiologic replacement doses for 
treatment of documented/confirmed hypogonadism], valproic acid, and other known 
hepatotoxins) for more than 12 consecutive months at any time during the 5 years prior to 
the Screening visit.  
22. Use of glucagon-like peptide-1 (GLP-1) agonists or a sodium-glucose co-transporter-2 
(SGLT2) inhibitor, unless on a stable daily dose for at least 6 months prior to the 
Screening visit date 
OR 
On a complex oral antidiabetic (OAD) regimen (3 or more OADs [except for a GLP-1 
agonist or an SGLT2 inhibitor]), unless on stable doses for at least 3 months prior to the 
Screening visit date (refer to Section 9.7, Concomitant Medications). 
23. Use of vitamin E supplementation at a daily dose >400 IU unless on a stable daily dose 
for at least 6 months prior to the Screening visit (refer to Section 9.7, Concomitant 
Medications). 
24. Use of strong concomitant cytochrome P450 (CYP) 3A4 inhibitors or inducers during the 
study (refer to Section 9.7, Concomitant Medications). 
25. Known diagnosis of hereditary hemochromatosis. 
26. Subjects with active or quiescent chronic liver disease of etiologies other than NASH 
(e.g., viral or autoimmune hepatitis, primary sclerosing cholangitis, primary biliary 
cholangitis, “autoimmune hepatitis-overlap” syndromes, hemochromatosis, Wilson’s 
disease, alpha-1 antitrypsin deficiency, alcohol-related liver disease, drug-induced liver 
disease, and/or infiltrative conditions [e.g., sarcoidosis]).  
27. Current or historic clinically evident hepatic decompensation event (e.g., ascites 
formation, variceal hemorrhage, hepatic encephalopathy). 
28. Active, serious medical disease with likely life expectancy <2 years. 


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29. History of clinically significant dry eye (xerophthalmia) or other corneal abnormality, as 
determined by an ophthalmologist or optometrist during Screening. 
30. Participation in an investigational study in the 30 days prior to randomization. 
31. Participation in an investigational drug trial for subjects with NASH, T2DM, and/or 
weight reduction within 6 months of Screening; only if it can be confirmed the subject 
received placebo during the earlier study would it be possible for such a subject to be 
screened for this study sooner than 6 months before Screening. 
32. Any subject who has sustained a clinically evident cardiovascular, cerebrovascular, 
and/or peripheral vascular event (e.g., unstable angina, acute coronary syndrome, 
myocardial infarction, life threatening tachy- and/or brady-dysrhythmia, stroke, transient 
ischemic attack [TIA], peripheral vascular disease) during the 12 months prior to 
anticipated Baseline (Day 1) visit date. 
33. Any contraindication to MRI (e.g., claustrophobia, metal implants). 
34. Any other condition which, in the opinion of the Investigator, would impede compliance, 
hinder completion of the study, compromise the well-being of the subject, or interfere 
with the study outcomes. 
8.3. 
Subject Withdrawal Criteria 
Subjects will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. Study drug must be permanently discontinued 
and the subject withdrawn from the study for any of the following TEAEs, with the subject 
managed as indicated: 
• Palmar-plantar Erythrodysesthesia (PPE): For mild to moderate symptoms of PPE 
(e.g., redness, pain, or scaling of hands or feet), study drug should be interrupted and 
symptomatic measures, including hand cream such as “Udder Cream,” instituted 
immediately. Study drug may be resumed after resolution of symptoms; study drug 
should be discontinued permanently if PPE Grade ≥2 recurs after study drug is resumed. 
Study drug should also be permanently discontinued at the first sign of significant/severe, 
redness, pain, or scaling of hands or feet, and symptomatic measures instituted 
immediately.  
• Dyspnea or suspected pneumonitis: Study drug should be permanently discontinued for 
subjects with shortness of breath or other respiratory symptoms that are otherwise 
unexplained. An unscheduled SARS-CoV-2 test should be done if a subject develops 
dyspnea or pneumonitis. The subject is to be carefully monitored for improvement. In the 
event that symptoms worsen or present as more than mild intensity, immediate referral to 
a qualified pulmonologist for definitive diagnosis and treatment should be undertaken. 
• Visual symptoms (including keratitis): Study drug should be permanently discontinued 
at the first sign of significant redness (erythema), pain, or dryness affecting one or both 
eyes. Symptomatic measures, including moisturizing eye drops, should be instituted. In 
the event that symptoms worsen or present as more than mild, immediate referral to a 
qualified ophthalmologist or optometrist should be undertaken. 


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• Suspected drug-induced liver injury (DILI): Study drug intake should be managed 
according to the different laboratory and clinical circumstances itemized in Appendix A 
for subjects with suspected DILI. 
Refer to the Study Manual for additional details regarding the assessment and management of 
these events. 
Furthermore, the Investigator also has the right to withdraw subjects from the study for any of 
the following reasons: 
• Progression of underlying disease that, in the opinion of the Investigator, precludes 
further study treatment.  
• Occurrence of any other unacceptable AE. 
• Study drug interruption for any reason for >15 days. 
• Subject requires use of a prohibited concomitant medication or therapy. 
• General or specific changes in the subject’s condition unacceptable for further treatment 
within the study parameters, in the judgment of the Investigator. 
• Noncompliance. 
• Lost to follow-up. 
• Subject withdrawal of consent. 
• Sponsor request. 
At the time of study withdrawal, all study procedures outlined for the Early Termination visit 
should be completed (Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
 PO = orally; QD = once daily. 
Table 2). The primary reason for a subject’s withdrawal from the study is to be recorded in the 
electronic case report form (eCRF) together with explanatory comment where required. If the 
subject is not on site when the decision to withdraw the subject from the study is confirmed, the 
subject should return to the clinic to undergo the Early Termination visit as soon as possible 
thereafter.  
 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
9.1.1. 
TVB-2640 
TVB-2640 is a small-molecule, orally-bioavailable, reversible inhibitor of the human FASN 
enzyme. TVB-2640 has a molecular formula of C27H29N5O and a molecular weight of 440. 
TVB-2640 immediate-release formulation will be supplied for PO QD administration as 25- and 
50-mg strength uncoated tablets.  
9.1.2. 
Placebo 
Placebo tablets that conform to the appearance, shape, and size of the TVB-2640 25-mg and 
50-mg strength tablets will be used during this study. 
9.2. 
Study Drug Packaging and Labeling 
TVB-2640 will be packaged in bulk, screw-top plastic bottles containing 100 tablets. 
TVB-2640 will be labeled in accordance with applicable regulatory requirements. Study drug 
labels will not bear any statement that is false or misleading in any manner or represents that the 
study drug is safe or effective for the purposes for which it is being investigated. 
9.3. 
Study Drug Storage 
TVB-2640 drug product and placebo should be stored in a secure, limited-access storage area at 
room temperature. Further study drug storage conditions and requirements will be provided in 
the study’s Pharmacy Manual. 
9.4. 
Study Drug Accountability 
The US Food and Drug Administration (FDA) and other applicable regulatory authorities require 
accounting of all investigational drug received by each study center. Records of drug disposition 
required include the date received by the center, date administered, quantity administered, and 
the subject to whom study drug was administered. The Investigator is responsible for the 
accountability of all used and unused study drug containers and unused study drug.  
Study drug (and placebo) will be provided to the investigational site. Site personnel will 
acknowledge receipt of the study drug using interactive response technology (IRT) to confirm 
the shipment condition and content. If a damaged shipment is received and/or a temperature 
excursion has been incurred, site personnel will notify the Sponsor/CRO and follow the 
guidelines according to the current version of the study’s Pharmacy Manual. 
The designated personnel will maintain accurate records of the study drug throughout the clinical 
study, including the inventory delivered to the study center, the use by each subject, the 
reconciliation of all delivered study drug, and the return of unused study drug as specified in the 
current version of the Pharmacy Manual. 


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The study monitor should check the study supplies at each study center at any time during the 
study. It is the responsibility of the study monitor to ensure that the Investigator (or designee) has 
correctly documented the amount of the study drug received, dispensed, and returned on the 
dispensing log that will be provided to site staff. Details will be provided in the Pharmacy 
Manual.  
A full drug accountability log will be maintained at the study center at all times. The study 
monitor will arrange collection of any unused study drug. The study monitor will also perform an 
inventory of study drug at the close-out visit to the study center. All discrepancies must be 
accounted for and documented. 
9.5. 
Study Drug Dose and Administration 
All subjects will receive study drug PO QD for 52 weeks or until the final on-study investigation 
(MRI-PDFF and/or liver biopsy). The first dose of study drug should be taken at the study site 
under supervision of study staff.  
In the event a subject is unable to complete the end of treatment MRI-PDFF and/or liver biopsy 
within the protocol-specified window (Week 52 +/- one week), extended dosing is permitted to 
maintain continuous dosing up to the time both assessments are completed, to a maximum total 
of 56 weeks of dosing. In this instance, the Follow-up visit at Week 56 for posttreatment safety 
and efficacy assessments is to be adjusted to occur four weeks after the last dose (+/- one week).  
In the instance of a dose hold due to an AE or SAE, the decision to resume study drug will 
require consultation with the Investigator, the CRO’s Medical Monitor, and the Sponsor’s Chief 
Medical Officer.  
Each QD dose of study drug is to be taken at the same time of day in the evening with or without 
food, with each dose separated by approximately 24 hours (±4 hours). 
Subjects will receive one of the following each day, based on their blinded treatment assignment: 
• Placebo: one placebo tablet matching the 50-mg TVB-2640 tablet and one placebo tablet 
matching the 25-mg TVB-2640 tablet 
• TVB-2640 50 mg: one 50-mg TVB-2640 tablet and one placebo tablet matching the 
25-mg TVB-2640 tablet 
If a dose adjustment for an individual subject is approved as described in Section 7.3, the subject 
will continue to receive 2 tablets QD as follows to preserve the study blind (see the Pharmacy 
Manual for additional details):  
• Dose adjustment from TVB-2640 50 mg to TVB-2640 25 mg: one 25-mg TVB-2640 
tablet and one placebo tablet matching the 50-mg TVB-2640 tablet 
• Dose adjustment for those randomized to placebo: there will be no change in the size 
or number of placebo tablets. To maintain the blind, the subject will be provided with 
new study drug bottles 


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9.6. 
Treatment Assignment, Randomization, Blinding, and Unblinding 
This will be a double-blind, randomized study. Subjects will be centrally assigned to randomized 
study treatment using an Interactive Web-based Response System (IWRS). Study medication 
will be dispensed at the study visits summarized in the Schedule of Assessments (Figure 1:
 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
PO = orally; QD = once daily. 
Table 2). Returned study drug should not be redispensed. 
All subjects, Investigators, the Sponsor, and the CRO will be blinded to the treatment assignment 
of each individual subject. Members of the IDMC and the IDMC’s independent statistician will 
be unblinded to treatment assignment as needed. In addition, specific vendors whose role in 
study conduct requires them to be unblinded (e.g., personnel operationally associated with the 
IWRS) may also be unblinded.  
Subjects will be randomized to achieve a 2:1 ratio with approximately 108 subjects on 
TVB-2640 50 mg and approximately 54 subjects on placebo. Dynamic allocation will be used 
for the randomization, stratified by 3 factors: T2DM status (yes or no), region (North America or 
not North America), and amount of fibrosis (F2 or F3).  


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In the event that emergency unblinding is required for a given subject because of AEs 
or concerns for the subject’s safety or well-being, the Investigator may request a code from the 
CRO in order to break the randomization code for the subject via the IWRS, by which system the 
unblinding will be captured. The unblinding and its cause will also be documented on the eCRF. 
9.7. 
Concomitant Medications 
All concomitant medications taken from 28 days before the first dose through 28 days after the 
last dose should be recorded in the appropriate eCRF, including dose adjustments. In addition, 
concomitant medications that are required to be stable within the 3, 6, or 12 months prior to the 
study must be recorded from the medication start date, as listed in Section 9.7.1.  
9.7.1. 
Excluded Medications 
The following medications and treatments are prohibited during study participation. 
• Any investigational agent or device other than TVB-2640. 
• Strong inhibitors or inducers of CYP3A4. (Refer to the following for examples: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/drugintera
ctionslabeling/ucm093664.htm.) 
• Drugs historically associated with risk of development of NAFLD (e.g., amiodarone, 
methotrexate, systemic glucocorticoids [unless used at physiologic replacement doses 
for treatment of confirmed adrenal insufficiency], tetracyclines, tamoxifen, estrogens 
at doses greater than those used for hormone replacement, anabolic steroids [except 
for testosterone preparations used at physiologic replacement doses for treatment of 
documented/confirmed hypogonadism], valproic acid, and other known hepatotoxins) 
for more than 12 consecutive months at any time during the 5 years prior to the 
Screening visit date.  
o Short courses of systemic glucocorticoids may be allowed to treat acute 
illnesses. 
• GLP-1 agonist (e.g., semaglutide), SGLT2 inhibitor (e.g., empagliflozin, 
canagliflozin), vitamin E at a daily dose >400 IU, and/or thiazolidinediones (TZD) 
(e.g., pioglitazone) unless on a stable daily dose for at least 6 months prior to the 
Screening visit date. Subjects who provide a historical Screening liver biopsy 
specimen to determine study eligibility should have been on a stable dose of these 
medications for at least 12 months prior to the Baseline [Day 1] visit date. 
• Vitamin E at a daily dose >400 IU, and/or thiazolidinediones (TZD) (e.g., 
pioglitazone) should not be initiated after the Screening liver biopsy is performed. 
• A complex OAD regimen (3 or more OADs [except for a GLP-1 agonist or a SGLT2 
inhibitor]e.g.), unless:  
o on stable doses for at least 3 months prior to the Screening visit date and/or 
o used for uncontrolled diabetes management that is not responsive to optimized 
doses of other classes of anti-diabetic medications during the double-blind 
Treatment period. 


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• Insulin dose adjustment >10% (increase or decrease). (Subjects receiving insulin at 
Baseline [Day 1] who require a >10% dose adjustment for the management of T2DM 
are to be discontinued from the study.)  
• Introduction of a GLP-1 agonist for weight loss during the double-blind Treatment 
period is prohibited.  
• GLP-1 agonists, and SGLT2 inhibitors required for diabetes management that is not 
responsive to optimized doses of other classes of anti-diabetic medications during the 
double-blind Treatment period may be initiated after discussion with the Medical 
Monitor and with Sponsor approval. Though usage of GLP-1 agonists, and SGLT2 
inhibitors do not pose safety risks to study subjects, these drugs may lead to weight 
loss and could potentially confound the study results.  
Subjects requiring such treatment during study participation are to be discontinued. 
9.7.2. 
Permitted Medications 
Medications and treatments other than those specified in Section 9.7.1 are permitted during the 
study. Subjects should be closely monitored, and treatment is to be instituted for disease-related 
symptoms, as appropriate. 
If a subject receives a vaccine, including the COVID-19 vaccine, details regarding that vaccine 
should be recorded as a concomitant medication(s), including manufacturer, dose, and dates of 
each injection. Any vaccine-related reactions should be recorded as described in Section 12.2. 
9.8. 
Treatment Compliance 
The verification of daily dosing of the study drug will be performed through the completion of a 
daily diary by all subjects. Subjects should be instructed to bring their study drug diary and study 
drug containers to each study visit for compliance assessment. The treatment compliance of 
individual subjects will be monitored using the electronic data capture (EDC) system, by review 
of the study drug diary, and by counting returned clinical trial materials. Subject contact to 
reliably assess medication use between visits is also encouraged around Week 10, Week 17, 
Week 23, Week 30, Week 34, Week 43, and Week 47. 


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10. 
SCREENING/BASELINE ASSESSMENTS 
Screening and Baseline (Day 1) assessments will be conducted in accordance with the time 
points indicated in the Schedule of Assessments (Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
 PO = orally; QD = once daily. 
Table 2). Note that most Screening assessments may be performed within 90 days of Day 1; 
however, the Screening SARS-CoV-2 PCR test must be performed no more than 30 days before 
Day 1, and a Screening urine pregnancy test must be performed within 24 hours of dosing on 
Day 1 (as indicated). 
All subjects must provide written informed consent, as described in Section 14.4, before the 
performance of any study-related procedures.  
10.1. 
Demographics 
Subject demographics, including age, sex, race, and ethnicity, are to be documented during 
Screening. 


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10.2. 
Medical and Social History 
A complete medical history is to be documented during Screening and updated at Baseline, prior 
to administration of the first study drug dose.  
The medical history also is to include NASH-related history, including the date of diagnosis, 
and, as available, NAS, AST to platelets ratio index (APRI), NAFLD fibrosis score, as well as 
abbreviated weight history, family history (subjects and their first degree relatives [parents, full 
siblings, and children]; particularly of obesity and liver disease), past medical/surgical events and 
illness history (including diabetes mellitus, gestational diabetes mellitus, systemic hypertension, 
lipodystrophy, polycystic ovarian syndrome, and any history of Gilbert’s disease) and other 
associated comorbid conditions including previously diagnosed lipid and metabolic disease-
related conditions (hypercholesterolemia, hypertriglyceridemia, diabetes mellitus), and all 
diagnoses related to previous liver disease as well as other diagnoses of major organ systems 
including cardiac disease, renal disease, endocrine disease, hypertension, gout or other 
arthropathies, disturbances of vision, peripheral neuropathy, myopathy, pancreatitis, and 
cholelithiasis.  
History of previous COVID-19 infection or vaccination against COVID-19 should also be 
documented. 
Social history, including weekly alcohol consumption, daily tobacco use, and daily caffeinated 
coffee intake, will also be documented.  
10.3. 
Viral Serology 
Screening serologies include HIV RNA, HBsAg, anti- HCV antibody, HCV RNA (reflex testing, 
if HCV antibody result at Screening is positive), and SARS-CoV-2 (the virus that causes 
COVID-19) PCR test. The SARS-CoV-2 PCR test may be performed locally; other tests should 
be performed by the central laboratory.  
Subjects with chronic HCV infection and liver disease who were treated with anti-HCV therapy 
and achieved a sustained virologic response at least 2 years prior to the Screening visit date are 
not prevented from study participation (see Section 8.2). 
10.4. 
Pregnancy Testing 
For female subjects of childbearing potential, a serum beta-human chorionic gonadotropin (β-
hCG) pregnancy test will be performed during Screening, and a urine pregnancy test is to be 
performed within 24 hours before the first dose on Day 1 (Baseline). Subjects with a positive 
serum pregnancy test result are not eligible for study participation. Serum pregnancy testing is to 
be repeated at the Week 56 Follow-up visit or at Early Termination (whichever takes place 
sooner), and during the study any time pregnancy is suspected. Female subjects of childbearing 
potential are required to perform urine home pregnancy tests monthly between study visits and 
the results should be recorded in a subject diary. A positive urine test should be followed by an 
unscheduled serum pregnancy test as soon as possible. Study drug is to be held in the event of a 
positive urine pregnancy test and permanently discontinued for any subject with a positive serum 
pregnancy test result. See Section 12.2.6 for details regarding management of any pregnancies 
during the study.  


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Female subjects not of childbearing potential must have such documentation included as part of 
their medical history, ie, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or 
naturally sterile [>12 consecutive months without menses]). 
10.5. 
Alcohol and Urine Drug Screening 
At Screening and Baseline, subjects will undergo an alcohol breath test or blood alcohol test and 
a urine screening test for drugs of abuse. Active substance abuse, including inhaled or injected 
substances (cocaine and other illegal/banned substances; any opiate, amphetamine, or 
benzodiazepine for which the subject does not have an existing prescription), within 1 year prior 
to Screening is exclusionary. However, recreational cannabis/tetrahydrocannabinol use is 
permissible.  
Details regarding the collection, storage, shipment, and analysis of laboratory samples will be 
provided in the Laboratory Manual.  
10.6. 
Other Screening/Baseline Assessments 
Other Screening/Baseline assessments are described in sections below, including the following:  
• Information regarding eGFR, aminotransferases, and INR is provided in Section 12.1.5. 
• Information regarding histologic confirmation of NASH diagnosis is provided in 
Section 11.1.1. 
• Information regarding genomics pertaining to NASH with fibrosis is provided in 
Section 11.2.1.  
• Information regarding anthropometric measurements (height, body weight, BMI, waist 
and hip circumference, and waist-hip ratio) is provided in Section 12.1.6.  
• Information regarding FibroScan, CAP score, and FAST score is provided in 
Section 11.1.3. 




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trials. NAS components are presented in Table 3. The total NAS represents the sum of scores for 
steatosis, lobular inflammation, and ballooning, and ranges from 0 to 8. 
Table 3: 
NAS Components and Scoring  
Item 
Score 
Extent 
Definition and Comment 
Steatosis 
0 
<5% 
Refers to amount of surface area 
involved by steatosis as evaluated on 
low to medium power. 
 
1 
5%-33% 
 
2 
>33%-66% 
 
3 
>66% 
Lobular Inflammation 
0 
No foci 
Acidophil bodies are not included in 
this assessment, nor is portal 
inflammation. 
 
1 
<2 foci/200× 
 
2 
2-4 foci/200× 
 
3 
>4 foci/200× 
Hepatocyte ballooning 
0 
None 
“Few” means rare but definite 
ballooned hepatocytes as well as cases 
that are diagnostically borderline. Most 
cases with prominent ballooning also 
had Mallory’s hyaline, but Mallory’s 
hyaline is not scored separately for the 
NAS. 
 
1 
Few balloon cells 
 
2 
Many cells/ 
prominent ballooning 
Abbreviations: NAS = Nonalcoholic Fatty Liver Disease Activity Score. 
Adapted from The Transplant Pathology Internet Services (TPIS) Histological Scoring System for Nonalcoholic 
Fatty Liver Disease web page. 2020. Available at: 
https://tpis.upmc.com/changebody.cfm?url=/tpis/schema/NAFLD2006.jsp 
The NASH CRN fibrosis score is determined separately from the NAS according to the scale 
presented in Table 4.  


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Table 4: 
NASH CRN Fibrosis Scoring 
Item 
Score 
Extent 
Definition and Comment 
Fibrosis 
0 
None 
 
 
1 
Perisinusoidal or 
periportal 
 
 
1A 
Mild, zone 3, 
perisinusoidal 
“delicate” fibrosis 
 
1B 
Moderate, zone 3, 
perisinusoidal 
“dense” fibrosis 
 
1C 
Portal/periportal 
This category is included to 
accommodate cases with portal and/or 
periportal fibrosis without 
accompanying pericellular/ 
perisinusoidal fibrosis 
 
2 
Perisinusoidal and 
portal/periportal 
 
 
3 
Bridging fibrosis 
 
 
4 
Cirrhosis 
 
Abbreviations: NASH CRN = Nonalcoholic Steatohepatitis Clinical Research Network. 
11.1.2. 
Magnetic Resonance Imaging Studies 
All imaging studies will be interpreted centrally by a trained image analyst. The analyst will be 
blinded to the subject’s treatment group allocation and will not have access to the subject’s 
clinical and biochemical data. The results of the central imaging interpretation will be used in the 
analysis of imaging data. 
For incidental findings, a radiology assessment of images will also be performed by qualified 
medical personnel at any imaging site according to clinical routine. Personnel interpreting 
imaging will also be blinded to the subject’s treatment group allocation, and clinical and 
biochemical data. The assessment will be reported to the Investigator at the referring site, who 
will review and file the assessment in the subject´s source documents. The subjects will be 
invited for follow up if there are clinically significant incidental findings, and findings will be 
evaluated as potential AEs. The incidental finding will not be part of the central imaging. 
11.1.2.1. Proton-density Liver Fat Fraction by Magnetic Resonance Imaging 
MRI-PDFF is a noninvasive, quantitative, and accurate measure of liver fat content to assess 
treatment response in early-phase NASH studies (Caussy 2018). Subjects who are randomized 
will have repeat liver fat content measurements performed in accordance with the time points 
indicated in the Schedule of Assessments (Figure 1: Study Design 
 
 
 


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Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
PO = orally; QD = once daily. 
Table 2). Scans may be repeated if an inconclusive result occurs (e.g., if there is excessive 
subject movement during the scan). MRI-PDFF will not be performed at selected sites. MRI-
PDFF is optional if it presents a logistical or physical hardship to the subject. In addition, MRI-
PDFF is not required at Early Termination if a subject has completed less than 22 weeks of study 
treatment. 
11.1.3. 
Liver Stiffness and Liver Steatosis by FibroScan and, Controlled Attenuation 
Parameter 
Subjects will be required to fast for 3 hours before a FibroScan is performed; however, normal 
volumes of water are allowed. 
FibroScan is a specialized ultrasound of the liver, which measures stiffness by transient 
elastography, a surrogate of liver fibrosis, in units of kPa. Normal results for FibroScan are 
generally considered to be lower than 6 or 7 kPa. The degree of liver stiffness and with it, 
fibrosis, will be assessed using FibroScan.  
Vibration-controlled transient elastography with controlled attenuation parameter (CAP) is a 
technology based on the principle of the ultrasonic attenuation of transient elastography 
depending on the viscosity (fat content) of the liver and the distance of propagation of the 
ultrasonic signals into the liver, providing a useful method for the quantitative detection of liver 
fat content. CAP is measured by a FibroScan device in decibels per meter (dB/m) and reflects the 
decrease in the amplitude of ultrasound signal in the liver. Therefore, a higher CAP is reflective 


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of a higher degree of steatosis (Zenovia, 2021). A CAP score will be calculated at each time a 
FibroScan is performed unless the enrolling site does not have the capability to measure CAP. 
A FAST score will also be calculated each time FibroScan, CAP, and AST are performed. The 
FAST score is a FibroScan-based composite score that combines the results of the FibroScan 
liver stiffness measurement, CAP, and AST (Newsome, 2020). 
11.1.4. 
Digital Pathology 
Digital pathology is a novel technology using imaging techniques to objectively and 
quantitatively assess liver tissue biopsy samples. These optical imaging modalities can be used to 
accurately stage fibrosis in biopsy specimens, as well as to analyze other histological 
components of NASH.  
11.1.5. 
Clinical Laboratory Tests 
Refer to the Laboratory Manual for details regarding clinical efficacy/pharmacodynamic 
laboratory sample collection, processing, storage, and shipment. 
11.1.5.1. Lipid and Metabolic Panel, Glycosylated Hemoglobin, and Lipoprotein Particle 
Size 
A fasting blood sample for lipid and metabolic panels as well as HbA1c is to be collected. 
Subjects are to fast overnight for at least 9 hours prior to collection of the fasting sample (water 
is permissible). 
The following parameters are to be determined: 
• Lipid Panel: LDL-C, vLDL (very low density lipoprotein cholesterol), high density 
lipoprotein cholesterol (HDL-C), non–HDL-C, total cholesterol, triglycerides, 
apolipoprotein B (ApoB), and lipoprotein (a) (Lp[a]) particles. 
• Metabolic Panel: Insulin and non-esterified fatty acid (NEFA). Homeostatic model 
assessment insulin resistance (HOMA-IR) and adipose tissue insulin resistance index 
(adipo-IR) are to be calculated from fasting insulin, fasting glucose (see Section 12.1.5), 
and fasting NEFA, as applicable. An analysis of bile acid will also be performed at 
Baseline, Week 26, Week 52, and/or at Early Termination. 
• HbA1c 
• Lipoprotein Particle Size Analysis by nuclear magnetic resonance (NMR) will be 
performed for a subset of subjects. 
11.1.5.2. NASH/Fibrosis Markers 
A blood sample for NASH/fibrosis markers, including cytokeratin-18 (CK-18), ELF (comprising 
TIMP-1, procollagen III amino-terminal peptide [PIIINP], hyaluronic acid [HA]), PRO-C3, 
FGF-21, FIB-4, and potentially other markers of fibrosis is to be collected. Instructions regarding 
the calculation of indices are provided in the Operations Manual.  


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11.1.5.3. Adiponectin  
A blood sample for determination of adiponectin, an insulin-regulating adipose tissue cytokine, 
is to be collected. Adiponectin concentration in blood samples will be determined using enzyme-
linked immunosorbent assay (ELISA). 
11.1.6. 
Alcohol Biomarkers 
A sample of whole blood for determination of phosphatidylethanol (PEth) and other biomarkers 
of alcohol consumption will be collected. 
11.1.7. 
Lipidomic Biomarkers 
A blood sample for determination of lipidomic biomarkers including tripalmitin, ceramides, bile 
acids, diacylglycerols, and other classes of metabolites will be collected. Tripalmitin levels will 
be analyzed to provide a surrogate readout of palmitate and an indicator of FASN pathway 
activity. Broad lipidomic profiling will be conducted by mass spectrometry coupled to ultra-high 
performance liquid chromatography.  
11.1.8. 
Lipoprotein Analyses Substudy 
A fasting blood sample for lipoprotein analyses will be collected in a subset of approximately 
30 or more participants. Provision of blood samples for the lipoprotein analyses substudy is 
voluntary.  
11.1.9. 
Metabolic and Microbiome Substudy 
A metabolic and microbiome substudy will be performed at a subset of sites.  
Stool samples will be collected from participating subjects and used for exploratory analyses of 
gut microbiome composition during the study. Those subjects will also complete the HepVita 
Nutritional Survey. This nutritional survey tool uses scientifically validated dietary analysis 
software that provides the equivalent of 90 days of nutrition tracking in a survey that requires 
approximately 30 minutes to complete (HepVita web site, 2021). 
Provision of stool samples and completion of the nutritional survey for the metabolic and 
microbiome substudy is voluntary. 
11.2. 
Other Assessments 
11.2.1. 
Genomics 
A blood sample for genomics pertaining to NASH will be collected at Baseline, or at any other 
time after the subject signs the separate consent for this sample, at all sites unless forbidden by 
local regulations. Subjects will be asked to provide separate written informed consent for the 
collection of such samples. Genomic analysis will investigate only the presence of SNPs 
associated with NASH, T2DM, or related diseases. Broad genome analysis will not be 
performed. The laboratory platform to be used will depend upon advances in the genomic 
signature of NASH and new developments. 
Provision of blood samples for genomic analysis is voluntary. 


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11.2.2. 
Sample Collection for Storage 
Blood and spot urine samples for storage will be collected. These samples will be stored for the 
duration of the TVB-2640 clinical development program and used for analysis of additional 
pharmacodynamic biomarkers relevant to NAFLD and/or NASH when such biomarkers are 
identified and/or relevant assays are developed. 
These samples will not be used for genetic analysis or creation of cell lines. The biomarker 
assessments performed may include tests to determine the level of certain proteins, RNA, or 
other disease-related molecules and whether they change after TVB-2640 treatment. 
The samples will be coded and de-identified, in the same way all other study samples are coded 
and de-identified. Every study subject has a unique study number that will be used to track the 
samples. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
The Sponsor and/or its designee and applicable regulatory authorities will have access to the 
samples/data if they are ever used for future research. 
Provision of blood and spot urine samples for storage is voluntary. 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 


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12. 
ASSESSMENT OF SAFETY 
Safety assessments will be conducted in accordance with the time points indicated in the 
Schedule of Assessments (Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
 PO = orally; QD = once daily. 
Table 2). 
12.1. 
Safety Parameters 
12.1.1. 
Vital Signs 
Vital signs, including oral temperature, pulse (bpm), systolic and diastolic blood pressure 
(mm Hg), and respiration rate (breaths/minute), are to be measured and documented in the eCRF. 
Measurements are to be made after the subject has been resting in a supine position for a 
minimum of 5 minutes. 
12.1.2. 
Physical Examination and Height 
A complete physical examination will be conducted for all subjects at Screening and at the 
Follow-up visit or Early Termination visit, whichever takes place sooner. The complete physical 


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examination must include general appearance, and careful examination 
head/ears/eyes/nose/throat, lungs/chest, heart, abdomen, lymph nodes, musculoskeletal, 
extremities, skin, and neurological systems. Liver signs (e.g., jaundice, spider angiomata, palmar 
erythema, hepatomegaly, splenomegaly, asterixis) also are to be assessed. 
During Screening, the physical examination is to include measurement of height (cm). 
Symptom-directed physical examinations, including assessment of focused liver signs (e.g., 
jaundice, spider angiomata, palmar erythema, hepatomegaly, splenomegaly, asterixis), skin, and 
extremities, will be conducted to address any complaints or concerns verbalized by the subject at 
all other study visits. 
If hand-foot symptoms/signs present during the study, or previous hand/foot symptoms/signs 
increase in severity to a Grade 2 or above, a dermatologist consult should be considered for 
further evaluation and treatment recommendations. 
Any abnormal physical examination finding which, in the Investigator’s judgement, is of clinical 
significance, is to be documented as an AE. 
Medical photographic images may be requested to document certain AEs such as hand-foot 
symptoms/signs or hair thinning. Complete anonymity is impossible, but the minimum possible 
area of the body should be photographed. Eyes should only be included when absolutely 
essential. Recognizable tattoos and birthmarks should be avoided in the frame. Identifiable 
jewelry and name tags should be kept out of the frames. A separate consent will be completed by 
the subject before any photographs are taken.  
12.1.3. 
Electrocardiograms 
Single 12-lead ECGs are to be performed for all subjects. 
On Day 1, ECGs are to be performed up to 2 hours before and 4 hours (-1 hour/+ 2 hours) after 
the first study drug dose
 
For calculated ECG parameters, the following web site should be used: 
https://www.mdcalc.com/corrected-qt-interval-qtc#next-steps 
12.1.4. 
Eye Examinations 
Eye examinations are to be performed for all subjects by a qualified ophthalmologist or 
optometrist. 
Near and far visual acuity is to be assessed by an ophthalmologist or optometrist using standard 
measures (e.g., Early Treatment Diabetic Retinopathy Study or similar) in each eye. If the 
subject wears corrective lenses (e.g., glasses), then visual acuity is to be checked first with 
corrective lenses and then without correction. A best-corrected examination is not required. 
A slit lamp examination (biomicroscopy), including examination of the eyelids, conjunctiva, 
cornea, anterior chamber, iris, and lens, is to be performed after completion of visual acuity 
testing for the determination of corneal health. 


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Eye exams at Week 4, Week 8, Week 13, Week 26, Week 39, Week 52, Week 56 and/or Early 
Termination are required only if eye-related signs or symptoms are reported by the subject or 
observed by the investigator. 
If a subject experiences a treatment-emergent eye abnormality, an ophthalmologic examination 
should be performed by a qualified ophthalmologist or optometrist within 24 to 48 hours or on 
the next business day after symptom onset to evaluate the abnormality. 
12.1.5. 
Safety Laboratory Assessments 
Blood and urine samples are to be collected for hematology, clinical chemistry, and urinalysis. 
The safety laboratory parameters to be measured are presented in Table 5. 
 


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Table 5: 
Safety Laboratory Parameters 
Hematology 
Hematocrit 
Platelet count 
Hemoglobin 
White blood cell count with differential 
Red blood cell count 
Absolute neutrophil count 
MCV 
MCHC 
Coagulation Studies 
Prothrombin time 
Fibrinogen 
INR 
aPTT 
Chemistry (Fasting) 
Chloride 
Carbon dioxide 
Sodium 
Potassium 
Blood urea nitrogen 
Calcium 
Creatinine 
Magnesium 
Albumin 
Glucose 
Total protein 
Alkaline phosphatase 
AST* 
ALT* 
GGT 
eGFR (Screening only) 
Total, indirect, and direct bilirubin 
 
Creatine phosphokinase (total and fractionated) (Screening and Baseline only) 
Urinalysis 
Specific gravity 
Protein 
pH 
Ketones 
Blood 
Microscopic examination of sediment 
Glucose 
 
Other 
Serum or urine β-hCGǂ 
 
*AST and ALT collected as part of the clinical chemistry panel are also applicable for efficacy assessments. 
ǂ Serum β-HCG pregnancy testing is to be performed for female subjects of childbearing potential during Screening, and a 
urine pregnancy test is to be performed within 24 hours before the first dose on Day 1 (Baseline). Subjects with a positive 
serum pregnancy test result are not eligible for study participation. Serum pregnancy testing is to be repeated at the Week 56 
Follow-up visit or at Early Termination (whichever takes place sooner), and during the study any time pregnancy is suspected. 
Female subjects of childbearing potential are required to perform urine home pregnancy tests monthly between study visits 
and the results should be recorded in a subject diary. A positive urine test should be followed by an unscheduled serum 
pregnancy test as soon as possible. Study drug is to be held in the event of a positive urine pregnancy test and permanently 
discontinued for any subject with a positive serum pregnancy test result. 
Abbreviations: β-HCG = beta human chorionic gonadotropin; ALT = alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate; GGT = gamma-
glutamyltransferase; INR = international normalized ratio; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume. 
 


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Liver enzyme tests determined as part of the clinical chemistry panel will also be used for the 
assessment of efficacy endpoints. 
Clinical laboratory evaluations are to be repeated as necessary during treatment at a schedule 
determined by the Investigator, based on the subject’s clinical status. 
Laboratory abnormalities that are considered by the Investigator to be clinically significant for a 
particular subject are to be reported as an AE. 
Information regarding alcohol and urine drug screening is provided in Section 10.5.  
12.1.6. 
Anthropometric Assessments 
Anthropometric assessments are to be performed, including:  
• Weight (without shoes or heavy clothing) (kg), with calculation of BMI using Screening 
height and weight. 
• Waist circumference at umbilicus (cm) 
• Hip circumference (cm) 
• Waist-hip ratio 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of an investigational product, whether or not related to the investigational product.  
AEs also include the following: 
• Complications that occur as a result of a protocol-mandated procedure (e.g., 
venipuncture, biopsy). 
• Any pre-existing condition that increases in severity, or changes in nature during the 
study or as a consequence of the study treatment. 
• Complications and termination of pregnancy (see Section 12.2.6 for additional 
information). 
• Any symptom (e.g., myalgia, fever), physical examination finding, or clinical syndrome 
(e.g., coryzal illness) that occurs as a result of infection and/or following COVID-19 
vaccination and is believed by the Investigator to be linked to the viral infection or 
immunization. (Further details for EDC update are contained within the EDC completion 
guidelines.) 


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An unexpected AE is any event for which the nature or severity is not consistent with the 
information in the current Investigator’s Brochure. 
All AEs that occur from Screening (i.e., after the informed consent form [ICF] is signed) through 
28 days after the last dose of study drug, whether or not they are related to the study drug, are to 
be reported in the eCRF. 
12.2.1.2. Serious Adverse Event 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it: 
• Results in death. 
• Is life-threatening. Life-threatening means that the subject was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in 
an unexpected manner during the study (e.g., surgery performed earlier than planned). 
Additional exclusions to SAE reporting include hospitalizations for: 
Elective procedures that are planned at the time of signing the informed consent. 
Social/administrative reasons in the absence of an AE. 
Expected deterioration caused by progression of the underlying disease. 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. An important medical event is an event that may not result 
in death, be life-threatening, or require hospitalization but may be considered an SAE 
when, based upon appropriate medical judgment, it may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalization, or the development of drug 
dependency or drug abuse.  
All SAEs that occur after any subject has been enrolled, before treatment, during treatment, or 
within 28 days following the cessation of treatment, whether or not they are related to the study 
drug, must be recorded on EDC or paper forms (if applicable) provided by Sagimet Biosciences, 
or designee.  


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12.2.2. 
Adverse Event Assessment 
12.2.2.1. Intensity 
The intensity of each AE is to be assessed by the Investigator according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (see 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf). If the AE is not included in the NCI CTCAE, then the Investigator is to 
determine the intensity of the AE according to the following criteria: 
Mild (Grade 1): 
AE that disappears or is easily tolerated on continuation of study 
drug. 
Moderate (Grade 2): 
AE sufficiently discomforting to cause interference with usual 
work activities. 
Severe (Grade 3): 
AE that is incapacitating, with inability to work or perform daily 
activities. 
Life-Threatening (Grade 4): AE that is potentially life-threatening.1 
Death (Grade 5): 
Death related to AE. 
12.2.2.2. Relationship to Study Drug 
The causal relationship of each AE to study drug will be determined by the Investigator 
according to best medical judgment, as follows: 
Definitely related: 
This category applies when, after careful medical consideration, 
there is almost no consideration of other causation. 
Probably related: 
There is a clinically plausible time sequence between onset of the 
AE and study drug administration. The AE is unlikely to be 
caused by a concurrent and/or underlying illness, other drugs, or 
procedures. If applicable, the AE follows a clinically consistent 
resolution pattern upon withdrawal of study drug. 
Possibly related: 
There is a clinically plausible time sequence between onset of the 
AE and study drug administration, but the AE could also have 
been caused by the concurrent and/or underlying illness, other 
drugs, or procedures. Information regarding study drug 
withdrawal may be lacking or unclear. “Possible” should be used 
when study drug administration is one of several biologically 
plausible causes of the AE. 
 
1. 
If a life-threatening (Grade 4) adverse event is immediately life-threatening, the event is, by 
definition, serious and is to be reported as described in Section 12.2.4. 


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Unlikely related: 
The AE is most likely due to a non-study drug-related cause. 
However, association with the study drug cannot be completely 
ruled out. 
Unrelated: 
Another cause of the AE is most plausible, and a clinically 
plausible temporal sequence is inconsistent with the onset of the 
AE and study drug administration and/or a causal relationship is 
considered biologically implausible. 
If the relationship between the AE/SAE and study drug is determined to be “possible”, 
“probable”, or “definite”, the event will be considered to be treatment-related for the purposes of 
expedited regulatory reporting and safety analyses. 
12.2.2.3. Seriousness 
AEs that meet the criteria specified in Section 12.2.1.2 are to be considered serious. 
12.2.3. 
Recording Adverse Events 
Each subject must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from 
signs and symptoms detected during each physical examination, observations on the part of study 
personnel, and spontaneous reports from subjects.  
All AEs (serious and non-serious) spontaneously reported by the subject and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be documented in the subject’s source documents and recorded in the 
eCRF. Any clinically relevant (as determined by the Investigator) deterioration in laboratory 
assessments or other clinical findings is considered an AE and must be recorded in the subject’s 
source documents and in the eCRF.  
Information about AEs will be collected from Screening (i.e., after the ICF is signed) through 
28 days after the last dose of study drug. The AE term should be recorded in standard medical 
terminology when possible. Also, when possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. For each AE, the Investigator 
will evaluate and report the onset date, resolution date, intensity, causality, action taken, serious 
outcome (if applicable), and whether or not it caused the subject to discontinue the study.  
12.2.4. 
Reporting Serious Adverse Events 
All SAEs (related and unrelated) occurring from Screening through 28 days after the last study 
drug dose are to be reported within 24 hours of first awareness on the part of site staff. Any 
suspected case of pneumonitis considered an adverse events of special interest, should be 
reported in the same manner as an SAE. 
The Investigator must report all SAEs within 24 hours of discovery via the EDC system, which 
will trigger email notifications to the Syneos Health, Medical Monitor/Safety team. In the event 
the EDC system is not available, then SAE reports must be emailed : 
 
 




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regard to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the study drug should also be reported. 
12.2.7. 
Overdose of TVB-2640 
Signs and symptoms of an overdose should be reported as AEs. Overdoses will not be considered 
SAEs unless the outcome of the overdose meets seriousness criteria (see Section 12.2.1.2). 
12.2.8. 
Protocol Deviations Due to an Emergency or Adverse Event 
Departures from the protocol will be determined as allowable on a case-by-case basis and only in 
the event of an emergency. The Investigator or other physician in attendance in such an 
emergency must contact the Medical Monitor as soon as possible to discuss the circumstances of 
the emergency. 
The CRO’s Medical Monitor, in conjunction with the Investigator, will decide whether the 
subject should continue to participate in the study. All protocol deviations and reasons for such 
deviations must be documented in the subject’s source records. 
 


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13. 
STATISTICAL CONSIDERATIONS 
13.1. 
Statistical General Considerations  
This is a multi-center, randomized, double-blind, placebo-controlled, parallel-design study to 
evaluate the safety and efficacy of TVB-2640 compared with matching placebo in subjects with 
NASH.  
For “change from Baseline” and “percent change from Baseline” calculations, “Baseline” refers 
to the last measurement obtained prior to the first administration of study drug. Study Day 1 is 
the first day of study treatment (TVB-2640 50 mg or placebo). Demographic data (including age, 
race, ethnicity, sex, height, and weight), medical history, prior treatments, pretreatment clinical 
characteristics, and other baseline characteristics will be summarized by treatment group and 
overall.  
Descriptive statistics will be displayed by treatment group for all subjects with liver fibrosis 
stage F2-F3, for all subjects with liver fibrosis stage F1-F3, and for all subjects, as appropriate, to 
provide an overview of the study results. As appropriate, descriptive statistics will also be 
displayed by treatment group and by enrollment group. For categorical parameters, the number 
and percentage of subjects in each category will be presented in data summaries. The 
denominators for percentages will be based on the number of subjects (n) appropriate for 
analysis. Continuous variables will generally be summarized based on the following: n, mean, 
standard deviation, median, minimum, maximum, and standard error of the mean. Categorical 
data will be summarized using frequency tabulations (number and percentage of subjects). 
Demographics and Baseline characteristics (medical histories, physical examinations, and 
concomitant medications) will be summarized using descriptive statistics for continuous 
variables and frequency distributions for discrete variables. Study subjects who discontinue the 
study along with reasons for discontinuation will be summarized and listed. Confidence intervals 
with be at the 90% and 95% levels. All statistical analyses will be performed using SAS v9.4. 
13.2. 
Efficacy Analysis 
13.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects experiencing either a histological 
improvement at Week 52 in NAS (i.e., ≥2-point improvement in NAS with 1-point improvement 
in ballooning or inflammation) and without worsening of fibrosis score (by NASH CRN fibrosis 
score), OR resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver disease or 
isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
Subjects will be eligible for analysis of the primary efficacy endpoint if they have completed at 
least 42 weeks of treatment and have a posttreatment biopsy.  
The principal analysis of the primary efficacy endpoint will be based on the Intention-to-Treat 
(ITT) analysis set (Section 13.4.2). The treatment groups will be compared based on the primary 
efficacy endpoint using a one-sided Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratifications T2DM status (yes or no), region (North America or not North 


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America), and amount of fibrosis (F2 or F3) at the 0.05 significance level (where a higher 
responder proportion is a better outcome). A Clopper-Pearson 90% and 95% CI will be derived, 
and the odds ratio (with its 90% and 95% CI, using the control group as a reference group) will 
be produced to assess the treatment effect magnitude.  
Evaluation of the robustness of the principal analysis of the primary efficacy endpoint will be 
carried out using a logistic regression with response as a dependent variable; treatment group, 
randomization stratification factors (T2DM status [yes or no], region [North America or not 
North America], and amount of fibrosis [F2 or F3]) as independent factors; and age as a baseline 
covariate. Other baseline covariates and other adjustment factors will be prespecified in the 
statistical analysis plan (SAP). The analysis of the primary efficacy endpoint will be repeated for 
the modified Intention-to-Treat (mITT) population (Section 13.4.2) to ascertain any changes in 
the conclusion of the principal analysis findings. 
Subgroup analyses of the primary efficacy endpoint will be performed to assess whether the 
treatment effect is concordant among subgroups. The planned subgroup analyses are based on 
age category (<40 years, 40 to <65 years, and ≥65 years) and race (White, Black, Asian, and 
other). 
A subject who discontinues treatment prior to Week 42, does not provide a histological 
assessment on or after Week 42, or who otherwise has missing data will be considered a non-
responder. 
Further sensitivity analysis of the primary efficacy endpoint will employ multiple imputations for 
binary data. Pertinent details are included in the SAP. 
13.2.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are:  
• Proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF ≥30% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves 
a percent change (relative reduction) from Baseline in MRI-PDFF ≥30%. Treatment 
groups will be compared based on this secondary efficacy endpoint using an analysis 
similar to the primary efficacy endpoint.  
• Proportion of MRI-PDFF ≥30% responders at Week 52. Treatment groups will be 
compared based on this secondary efficacy endpoint using an analysis similar to the 
primary efficacy endpoint. 
• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN 
fibrosis score without worsening of steatohepatitis (defined as no increase in NAS for 
ballooning, inflammation, or steatosis) at 52 weeks. Treatment groups will be 
compared based on this secondary efficacy endpoint using an analysis similar to the 
primary efficacy endpoint. 
• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
with no increase in any component of NAS at Week 52. Treatment groups will be 
compared based on this secondary efficacy endpoint using an analysis similar to the 
primary efficacy endpoint. 


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• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without increase of total NAS score at Week 52. Treatment groups will be compared 
based on this secondary efficacy endpoint using an analysis similar to the primary 
efficacy endpoint. 
• Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without any worsening of NASH (defined as no worsening of ballooning and lobular 
inflammation; a 1 grade change in steatosis may be acceptable) at Week 52. Treatment 
groups will be compared based on this secondary efficacy endpoint using an analysis 
similar to the primary efficacy endpoint. 
• Proportion of subjects experiencing both of the following at Week 52:  
o Resolution of steatohepatitis on overall histopathological reading and no 
worsening of live fibrosis on NASH CRN fibrosis score. Resolution of 
steatohepatitis is defined as absent fatty liver disease or isolated or simple 
steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for 
ballooning, and any value for steatosis 
AND 
o Improvement in liver fibrosis greater than or equal to one state (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
Treatment groups will be compared based on this secondary efficacy endpoint using an 
analysis similar to the primary efficacy endpoint. 
• Proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in nonalcoholic fatty liver disease 
(NAFLD) activity score (NAS) (i.e., ≥2 points improvement in NAS with ≥1 
point improvement in ballooning or inflammation) and without worsening of 
fibrosis (by NASH Clinical Research Network [CRN] fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
Treatment groups will be compared based on this secondary efficacy endpoint using an 
analysis similar to the primary efficacy endpoint. 
• Proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver 
disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 
for inflammation, 0 for ballooning, and any value for steatosis. 
AND 
o Histological improvement at in NAS (≥2 points improvement in NAS). 
Treatment groups will be compared based on this secondary efficacy endpoint using 


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an analysis similar to the primary efficacy endpoint. 
• Proportion of subjects with histological improvement at Week 52 in NAS. Treatment 
groups will be compared based on this secondary efficacy endpoint using an analysis 
similar to the primary efficacy endpoint.  
• MRI-PDFF percent change and change from Baseline at Week 26. This secondary 
efficacy endpoint will be compared between treatment groups using a one-sided 
Wilcoxon rank-sum test. An analysis of covariance (ANCOVA) model will also be 
used with percent change and change from baseline as the dependent variable; 
treatment group, T2DM status (yes, no), region (North America, not North America), 
and amount of fibrosis (F2, F3) as factors; and Baseline as a covariate. Least-squares 
(LS) means and their differences will be estimated from the ANCOVA model and 
their corresponding 95% CI will be derived. Inferential statistics will be presented for 
both the ANCOVA model and the Wilcoxon test. For the continuous secondary 
endpoints with sufficient postbaseline frequency of measurements, a mixed model 
repeated measure (MMRM) model will also be employed.  
• MRI-PDFF percent change and change from Baseline at Week 52. This secondary 
endpoint will be analyzed similarly to MRI-PDFF percent change and change from 
Baseline at Week 26, as described above. 
• Proportion of subjects with NASH resolution at 52 weeks. Treatment groups will be 
compared based on this secondary efficacy endpoint using an analysis similar to the 
primary efficacy endpoint. 
• Change from Baseline in ALT, AST, and GGT at Weeks 26 and 52 and at each study 
visit. This secondary endpoint will be analyzed similarly to MRI-PDFF percent 
change and change from Baseline at Week 26, as described above. 
• Change from Baseline in LDL-C and other lipid levels at Weeks 26 and 52 and at 
each study visit. This secondary endpoint will be analyzed similarly to MRI-PDFF 
percent change and change from Baseline at Week 26, as described above. 
• Change from Baseline in collagen/fibrous area and fibrosis score, assessed by digital 
pathology, at Week 52. This secondary endpoint will be analyzed similarly to MRI-
PDFF percent change and change from Baseline at Week 26, as described above. 
• Changes from Baseline in metabolic parameters, including fasting insulin, fasting 
glucose, HOMA-IR, adipo-IR, and HbA1c levels at Weeks 26 and 52 and at each study 
visit. This secondary endpoint will be analyzed similarly to MRI-PDFF percent 
change and change from Baseline at Week 26, as described above. 
• Change from Baseline in FGF-21, adiponectin, and other NASH biomarker levels at 
Weeks 26 and 52 and at each study visit. This secondary endpoint will be analyzed 
similarly to MRI-PDFF percent change and change from Baseline at Week 26, as 
described above. 
• Change from Baseline in FibroScan and CAP score results at Weeks 26 and 52. This 
secondary endpoint will be analyzed similarly to MRI-PDFF percent change and 
change from Baseline at Week 26, as described above. 


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• Change from Baseline in PRO-C3 and other fibrosis biomarkers at Weeks 4, 13, 26, 
and 52. This secondary endpoint will be analyzed similarly to MRI-PDFF percent 
change and change from Baseline at Week 26, as described above. 
• 
Change from Baseline in ELF score at Weeks 26 and 52. This secondary endpoint will 
be analyzed similarly to MRI-PDFF percent change and change from Baseline at 
Week 26, as described above. 
The analysis of the primary and secondary endpoints will be carried out for the ITT analysis set 
and repeated for the mITT analysis set.  
13.2.3. Exploratory Endpoints  
Exploratory endpoints will be summarized primarily with descriptive statistics. Select endpoints 
may be evaluated with statistical tests and/or CIs. Further details on exploratory analyses will be 
provided in the SAP. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
13.3. 
Safety Analysis  
Safety data will be evaluated for the Safety population (Section 13.4.2) on the basis of TEAEs, 
clinical laboratory assessments, vital signs, ECGs, weight, and physical examinations. Changes 
from Baseline in key clinical laboratory measurements, vital signs, physical examinations, and 
weight will be summarized by treatment group using standard descriptive statistics. A TEAE is 
defined as an AE that was not present prior to treatment with study drug but appeared following 
treatment or was present at treatment initiation but worsened during treatment. All AEs will be 
coded by preferred term using the Medical Dictionary for Regulatory Activities (MedDRA; 
current version) and NCI CTCAE (current version) grading. 
TEAE incidence rates will be summarized using frequency and percentage for each treatment 
group and in total. TEAEs through 30 days after the last dose of study treatment will be 


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summarized by MedDRA (current version) system organ class and preferred term. AEs will also 
be summarized by NCI CTCAE grade and by causality (attribution to study treatment, 
related/not related to investigational medicinal product). Grades 3 and 4 AEs, SAEs, and AEs 
resulting in dose modification or treatment discontinuation will be summarized by preferred 
terms. Investigational medicinal product compliance and tolerability ratings will be summarized 
descriptively for each treatment group.  
All safety data will be presented in data listings. 
13.4. 
Statistical and Analytical Methods  
13.4.1 
Hypothesis Testing  
The study primary hypothesis is the (statistical) one-sided superiority of a TVB-2640 50-mg 
dose over placebo based on the primary efficacy endpoint at the 0.05 significance level, where a 
higher responder proportion is a better outcome. The statistical analysis (one-sided) test (CMH) 
of the primary hypothesis is declared if p<0.05.  
Mathematically, the null and alternative hypotheses for the primary efficacy endpoint are stated 
as: 
Ho: pT ≤ pp 
Ha: pT > pp 
Here, pT is the proportion of responders in the TVB-2640 50-mg treatment group and pp is the 
proportion of responders in the placebo treatment group. 
Both one-sided and two-sided 0.05 significance level tests will be used for the secondary 
efficacy endpoints. For each endpoint, the SAP will specify whether the test of significance is 
one- or two-sided along with the expected direction of effect.  
13.4.2 
Analysis Sets 
13.4.2.1 
Intention-to-Treat Population 
The principal analysis of the primary and secondary efficacy endpoints will be based on the 
Intention-to-Treat (ITT) population, which comprises all randomized subjects; this population 
will serve as the basis for all efficacy analyses. Subjects’ data will be analyzed according to their 
randomized treatment assignment.  
13.4.2.2 
Modified Intention-to-Treat Populations 
Modified Intention-to-Treat (mITT): Comprises all subjects in the ITT population who have 
completed at least 42 weeks of treatment and have an evaluable posttreatment histological 
assessment. Interim Analyses Modified Intention-to-Treat Population 
Modified Intention-to-treat (IAmITT): Comprises a subset of subjects in the ITT population with 
8% >/= MRI-PDFF at screening or at baseline with at least 1 evaluable post-Baseline MRI-PDFF 
value, defined as an MRI-PDFF assessment obtained at least 22 weeks after the first dose of 
study drug. 
 
 


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13.4.2.3 
Safety Population 
The Safety population will consist of all randomized subjects who received at least 1 dose 
(partial or complete) of study drug. This population will be used for all summaries of subject 
accountability, demographic and baseline data, and safety information, including AE incidence, 
clinical laboratory data, ECG data, and vital signs data. Subjects’ data will be summarized 
according to the treatment they received. 
13.4.2.4 
Pharmacokinetic Population 
The PK population will comprise all ITT subjects with available PK measurements.  
13.5. 
Power Considerations and Sample Size Determination 
The study is powered to test the one-sided (statistical) superiority hypothesis stipulating that a 
TVB-2640 50-mg dose provides better benefit than placebo based on the primary efficacy 
endpoint. The study estimated total sample size is approximately 162 randomized subjects (108 
on TVB-2640 and 54 on placebo). The sample size was derived using the normal approximation 
to the binomial distribution, and the estimated power to detect a difference in the primary 
efficacy response of 20% (TVB-2640 40% and placebo 20% at Week 52) was at least 80% (one-
sided test at the 0.05 significance level). A 2-to-1 randomization allocation was assumed (TVB-
2640 to placebo), and an anticipated dropout rate of 18.5% was also applied to estimate the final 
total sample size (N=162). 
13.6. 
Interim Analysis 
A single (secondary endpoint) efficacy interim analysis is planned when approximately 60 
subjects with an MRI-PDFF value of ≥8% liver fat at Baseline have completed Week 26 or an 
Early Termination visit after Week 22. The purpose of the proposed interim analysis is to 
examine the TVB-2640 benefit over placebo based on a Week 26 secondary efficacy endpoint 
consisting of “proportion of MRI-PDFF ≥30% responders, where an MRI-PDFF ≥30% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a percent 
change (reduction) from Baseline in MRI-PDFF ≥30%.”  
Interim safety summaries will accompany the interim analyses of the secondary efficacy 
endpoint.  
An interim analysis of the primary efficacy endpoint is not feasible since the primary endpoint is 
only evaluated at Week 52, and not Week 26. Therefore, a statistical penalty is not envisaged in 
conjunction with the Week 26 interim analysis of the above-stated secondary endpoint. Interim 
summaries of safety and selected biomarker data will accompany the interim efficacy analysis of 
the secondary efficacy endpoint.  
13.7. 
Planned Study Committees 
An independent data monitoring committee (IDMC) will be established by charter to provide 
independent review and assessment of study data and to monitor the overall study conduct in a 
systematic manner to safeguard the safety of study subjects. Periodic meetings will occur as 
outlined in the IDMC charter. An interim analysis, which will be reviewed by the IDMC, will be 
performed when approximately 60 subjects with an MRI-PDFF value of ≥8% liver fat at 


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Baseline have completed the Week 26 visit or an Early Termination Visit after Week 22. The 
IDMC will be provided with selected biomarker and safety interim results to allow for a more 
complete examination of the totality of the data. Upon review of the interim analysis findings, 
the IDMC may communicate with the Sponsor by making recommendations to the Sponsor to 
continue, amend, or stop the study based on these interim analysis results. The Sponsor will 
maintain its blind to any individual treatment assignments. 


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14. 
ETHICS 
14.1. 
Good Clinical Practice Compliance 
The Sponsor and any third party to whom aspects of the study management or monitoring have 
been delegated will undertake their assigned roles for this study in compliance with all applicable 
industry regulations and International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guideline E6.  
The Investigator also must undertake to perform the study in accordance with ICH GCP 
Guideline E6 and applicable regulatory requirements and guidelines. 
ICH GCP Guideline E6 is available at: 
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf 
14.2. 
Institutional Review Board or Independent Ethics Committee 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of the subjects. The study will only be conducted at study centers where 
IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent 
form, advertisements (if applicable), written information given to the subjects (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the Investigator. 
The final study protocol, including the final version of the informed consent form, must be 
approved or given a favorable opinion in writing by an IRB/IEC as appropriate. Written IRB/IEC 
approval must be received by Sagimet Biosciences or designee before a site can enroll any 
subject into the study. 
The Investigator is responsible for informing the IRB/IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB/IEC must approve all advertising used 
to recruit subjects for the study. The protocol (and other amended study documents) must be 
re-approved by the IRB/IEC upon receipt of amendments and annually, as local regulations 
require. The Investigator is also responsible for providing the IRB/IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sagimet Biosciences will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
To ensure compliance with GCP and all applicable regulatory requirements, Sagimet Biosciences 
or designee may conduct a quality assurance audit. Please see Section 15.6 for more details 
regarding the audit process. 
14.3. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP, and applicable regulatory 
requirements. 


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14.4. 
Written Informed Consent 
The Investigator(s) at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of taking part in the 
study. Subjects must also be notified that they are free to discontinue from the study at any time. 
The subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. This process should be recorded in the subject’s source documentation. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. Documentation of the consenting process must be recorded in the subject’s source 
documents. 
A separate signature documenting informed consent will be required for subjects who provide a 
blood sample for research regarding genomics pertaining to NASH with fibrosis 
(Section 11.2.1).  
If medical photographs are requested to document an AE (Section 12.1.2), a separate signature 
documenting informed consent will be required before any photographs are taken. 
The Investigator(s) must maintain the original, signed informed consent form(s). A copy of the 
signed informed consent form must be given to the subject, and this must be documented in the 
subject’s source documents. 
14.5. 
Subject Confidentiality 
In order to maintain subject privacy, all eCRFs, study drug accountability records, study reports, 
and communications will identify the subject by the assigned subject number. The Investigator 
will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered on 
the eCRFs and to audit the data collection process. The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 


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15. 
ADMINISTRATIVE REQUIREMENTS 
15.1. 
Study Monitoring 
Monitoring and auditing procedures developed by the Sponsor or designee will be followed, in 
order to comply with GCP guidelines.  
Before a study center can enter a subject into the study, a representative of Sagimet Biosciences 
or designee will visit the study center to: 
• Determine the adequacy of the facilities. 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sagimet Biosciences or its representatives. 
This will be documented in a Clinical Study Agreement between Sagimet Biosciences 
and the Investigator. 
During the study, a monitor from Sagimet Biosciences or designee will have regular contacts 
with the study center, for the following: 
• Provide information and support to the Investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol that data are being 
accurately recorded in the source documents and eCRFs, and that investigational product 
accountability checks are being performed. 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records relevant to 
the study. This will require direct access to all original records for each subject (e.g., 
clinic charts). 
• Record and report any protocol deviations not previously sent to Sagimet Biosciences. 
• Confirm AEs and SAEs have been properly documented in the eCRFs and confirm any 
SAEs have been forwarded to the Sponsor or designee, and those SAEs that met criteria 
for reporting have been forwarded to the IRB/IEC. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
15.2. 
Case Report Form Completion 
The Sponsor or designee will provide the study centers with eCRFs for each subject. 
eCRFs will be completed for each study subject. It is the Investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF. Source 
documentation supporting the eCRF data should indicate the subject’s participation in the study 
and should document the dates and details of study procedures, AEs, and subject status.  
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a subject is seen for an 


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examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Investigator must electronically sign and date the Investigator’s Statement at the end of the 
eCRF to endorse the recorded data.  
15.3. 
Computerized Systems/Medical Records as Source Data 
All study data recorded on source documents are to be transcribed into the eCRFs.  
Clinical data will be entered by site personnel on eCRFs for transmission to the Sponsor. Data on 
eCRFs transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study site.  
All study forms and records transmitted to the Sponsor must only include coded identifiers such 
that directly identifying personal information is not transmitted. The primary method of data 
transmittal is via the secure, internet-based EDC system maintained by Syneos Health. Access to 
the EDC system is available only to authorized users via the study’s internet website, where a 
user unique assigned username and password are required for access. 
Any changes made to data after collection will be made through use of the EDC system. 
eCRFs will be considered complete when all missing and/or incorrect data have been resolved. 
15.4. 
Source Documents 
Source documents are considered to be ‘all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study’. The Investigator will provide direct 
access to source documents and/or source data in the facilitation of trial-related monitoring, 
audits, review by IRB/IEC, and regulatory inspections. 
The Investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, not obscure the original entry, and be explained where 
necessary. 
15.5. 
Retention of Records 
The Investigator will maintain all study records according to ICH GCP and applicable regulatory 
requirement(s). Study records and source documents must be preserved for at least 15 years after 
the completion or discontinuation of/withdrawal from the study, and at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory requirement(s).  
If the Investigator withdraws from the responsibility of keeping the study records, custody must 
be transferred to a person willing to accept that responsibility. The Sponsor must be notified 
immediately by telephone or e-mail and the notification confirmed in writing if a custodial 
change occurs. 


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15.6. 
Audits and Inspections 
Authorized representatives of Sagimet Biosciences or designee, a regulatory authority, or 
IRB/IEC may visit the study center to perform audits or inspections, including source data 
verification. The purpose of an audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the protocol, 
ICH GCP, and any applicable regulatory requirements. 
The Investigator should contact Sagimet Biosciences or designee immediately if contacted by a 
regulatory agency about an inspection. 
15.7. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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16. 
LIST OF REFERENCES 
Buckley D, Duke G, Heuer TS, et al. Fatty acid synthase - Modern tumor cell biology insights 
into a classical oncology target. Pharmacol Ther. 2017;177:23-31. 
doi:10.1016/j.pharmthera.2017.02.021  
Caussy C, Reeder SB, Sirlin CB, Loomba R. Noninvasive, Quantitative assessment of liver fat 
by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018;68(2):763-772. 
doi:10.1002/hep.29797 
Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current 
approaches and future directions. Diabetologia. 2016;59(6):1112-1120. doi:10.1007/s00125-016-
3952-1 
Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty 
acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. 
J Clin Invest. 2005;115(5):1343-1351. doi:10.1172/JCI23621 
Duke G, Wagman AS, Buckley D, et al. Fatty acid synthase inhibitor TVB-3664 reduces 
collagen accumulation in bleomycin-induced murine skin fibrosis and reverses multiple 
components of diet-induced and biopsy-confirmed nonalcoholic steatohepatitis in mice treated 
with or without co-administered pirfenidone and reduces collagen accumulation in bleomycin-
induced murine skin fibrosis. In: The Liver Meeting of the American Association for the Study 
of Liver Diseases (AASLD); 20–24 October 2017; Washington, DC. Abstract 1994. 
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic 
syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific 
Statement [published correction appears in Circulation. 2005 Oct 25;112(17):e297] [published 
correction appears in Circulation. 2005 Oct 25;112(17):e298]. Circulation. 2005;112(17):2735-
2752. doi:10.1161/CIRCULATIONAHA.105.169404 
HepVita web page. 2021. Accessed January 14, 2021. Available at: 
https://www.hepvita.com/what-we-do  
Hochberg Y, Tamhane AC. Multiple Comparison Procedures. John Wiley & Sons, Inc; 1987. 
Kim KJ, Goldberg IJ, Graham MJ, et al. γ-secretase inhibition lowers plasma triglyceride-rich 
lipoproteins by stabilizing the LDL receptor. Cell Metab. 2018;27(4):816-827.e4. 
doi:10.1016/j.cmet.2018.02.010 
Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring 
system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321. 
doi:10.1002/hep.20701 
Kohjima M, Enjoji M, Higuchi N, et al. Re-evaluation of fatty acid metabolism-related gene 
expression in nonalcoholic fatty liver disease. Int J Mol Med. 2007;20(3):351-358. 
Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ. Increased de novo lipogenesis is a 
distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology. 
2014;146(3):726-735. doi:10.1053/j.gastro.2013.11.049 


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Menendez JA, Vazquez-Martin A, Ortega FJ, Fernandez-Real JM. Fatty acid synthase: 
association with insulin resistance, type 2 diabetes, and cancer. Clin Chem. 2009;55(3):425-438. 
doi:10.1373/clinchem.2008.115352 
Mitsuyoshi H, Yasui K, Harano Y, et al. Analysis of hepatic genes involved in the metabolism of 
fatty acids and iron in nonalcoholic fatty liver disease. Hepatol Res. 2009;39(4):366-373. 
doi:10.1111/j.1872-034X.2008.00464.x 
Newsome PN, Sasso M, Deeks JJ, et al. FibroScan®-AST (FAST) score for the non-invasive 
identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: 
a prospective derivation and global validation study [published correction appears in Lancet 
Gastroenterol Hepatol. 2020 Apr;5(4):e3]. Lancet Gastroenterol Hepatol. 2020;5(4):362-373. 
doi:10.1016/S2468-1253(19)30383-8 
Postic C, Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and 
insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118(3):829-838. 
doi:10.1172/JCI34275 
Sanyal A, Charles ED, Neuschwander-Tetri B, et al. BMS-986036 (PEGylated FGF21) in 
patients with non-alcoholic steatohepatitis: a phase 2 study. The Liver Meeting, American 
Association for the Study of Liver Diseases (AASLD). Oral Presentation. Washington, DC, 
USA. 20-24 Oct 2017. Accessed January 13, 2021. Abstract available at: 
https://www.natap.org/2017/AASLD/AASLD_33.htm  
Stiede K, Miao W, Blanchette HS, et al. Acetyl-coenzyme A carboxylase inhibition reduces de 
novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study. 
Hepatology. 2017;66(2):324-334. doi:10.1002/hep.29246  
Syed-Abdul MM, Parks EJ, Gaballah AH, et al. Fatty acid synthase inhibitor TVB-2640 reduces 
hepatic de novo lipogenesis in males with metabolic abnormalities. Hepatology. 2020;72(1):103-
118. doi:10.1002/hep.31000 
Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic 
reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol 
Metab. 2006;291(2):E275-E281. doi:10.1152/ajpendo.00644.2005 
Younossi ZM, Stepanova M, Ong J, et al. Nonalcoholic steatohepatitis is the most rapidly 
increasing indication for liver transplantation in the United States [published online ahead of 
print, 2020 Jun 9]. Clin Gastroenterol Hepatol. 2020;S1542-3565(20)30775-8. 
doi:10.1016/j.cgh.2020.05.064 
Zenovia S, Stanciu C, Sfarti C, et al. Vibration-controlled transient elastography and controlled 
attenuation parameter for the diagnosis of liver steatosis and fibrosis in patients with 
nonalcoholic fatty liver disease. Diagnostics (Basel). 2021;11(5):787. 
doi:10.3390/diagnostics11050787 


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APPENDIX A. ALGORITHM FOR EVALUATING SUBJECTS FOR 
POTENTIAL DRUG-INDUCED LIVER INJURY 
During the study, aminotransferase elevations are to be managed as follows: 
1. Isolated aminotransferase elevation (i.e., total bilirubin - normal): 
ALT or AST 
Event during the study 
Action 
Baseline ALT and AST within 
normal range 
Increase ≥5 × ULN 
Repeat liver profile (AST, ALT, 
bilirubin) and PT/INR within 
2 to 3 business days from the 
date results are received for 
review. Monitor the subject as 
per “close observation” 
definition* in the DILI guidance. 
ALT or AST above normal 
range at Baseline 
Increase ≥3 × Baseline result, 
but no liver related symptoms 
(e.g., anorexia, nausea, vomiting, 
right upper quadrant pain, 
pruritus, cholestasis) 
ALT or AST above normal 
range at Baseline 
Increase ≥3x Baseline result, and 
subject experiences liver- related 
symptoms (e.g., anorexia, 
nausea, vomiting, right upper 
quadrant pain, pruritus, 
cholestasis) 
Interrupt study drug for at least 
15 days. Initiate potential DILI 
evaluation for alternative 
etiologies, and repeat liver 
profile and PT/INR within 2 to 3 
business days from the date 
results are received for review, 
and place subject under “close 
observation” as defined in the 
DILI guidance. 
Abbreviations: ALP = alkaline phosphatase: ALT = alanine aminotransferase; AST = aspartate 
aminotransferase: DILI = drug-induced liver injury; GGT = gamma-glutamyltransferase; 
INR = international normalized ratio; PT = prothrombin time; ULN = upper limit of normal.  
*Close observation as defined in the FDA DILI guidance (i.e., laboratory testing and physical examination 
2 to 3 times per week. Study drug is to be restarted only if a firm alternative etiology is “identified” and 
the liver tests return to ‘baseline’ levels). 
 
Note the following: 
The ‘baseline’ result for any laboratory parameter is the average of the Screening visit result, the 
Day 1 visit result and any unscheduled visit that occurred during the Screening period.’ 
Study drug interruption refers to cessation of study drug intake, but with the possibility that 
intake may re-start at a later date if certain requirements described in this appendix are 
confirmed. 
Conversely, study drug discontinuation refers to cessation of study drug intake and without the 
possibility that intake may restart at a later date. However, such a subject should remain in the 
study, continue to undergo ‘close observation’ where required, and other scheduled study 
assessments. 
If a subject sustains a liver test elevation but remains eligible to continue study drug intake in 
parallel with ‘close observation’, and ‘close observation’ is not possible then study drug intake 
should be interrupted until it is possible for the subject to undergo further assessment. 


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Close observation as defined in the FDA DILI guidance i.e., laboratory testing and physical 
examination 2 to 3 times per week. Study drug is to be restarted only if a firm alternative 
etiology is “identified” and the liver tests return to ‘baseline’ levels. 
 
2. Elevation of aminotransferase and total bilirubin or cholestatic liver test markers: 
Analyte 
Event during the study 
Action 
TB + AST or ALT 
↑ TB >2 mg/dL 
and 
↑ ALT or ALT ≥3 × Baseline or 
5 × ULN (whichever comes 
first) 
Interrupt study drug for at least 
15 days. 
Initiate potential DILI evaluation 
for alternative etiologies.  
Repeat liver profile and PT/INR 
within 2 to 3 business days from 
the date results are received for 
review, and place subject under 
“close observation” as defined in 
the DILI guidance. 
Study drug can be re-started only 
if a firm competing etiology is 
identified and the liver tests 
return to Baseline levels. 
TB, ALP, or GGT  
↑ TB >2 mg/dL  
and 
ALP or GGT ↑ >2 × ULN 
TB OR INR + symptoms 
(regardless of any magnitude 
AST/ALT elevation) 
Elevation ↑ TB >2 mg/dL 
OR 
INR ≥1.5  
and  
Indicators of immunological 
reaction (i.e., rash or >5% 
eosinophilia), or appearance of 
liver-related symptoms, e.g., 
anorexia, nausea, vomiting, right 
upper quadrant pain, pruritus, 
cholestasis.  
Permanently discontinue study 
drug.  
Initiate potential DILI evaluation 
for alternative etiologies.  
Repeat liver profile and PT/INR 
within 2 to 3 business days from 
the date results were received for 
review, and place subject under 
“close observation” as defined in 
the DILI guidance. 
Abbreviations: ALP = alkaline phosphatase: ALT = alanine aminotransferase; AST = aspartate 
aminotransferase: DILI = drug-induced liver injury; GGT = gamma-glutamyltransferase; 
INR = international normalized ratio; PT = prothrombin time; TB = total bilirubin; ULN = upper limit of 
normal. 
 
Note the following: 
If a subject lives in a remote area, they can be tested using a local (‘non-central’) laboratory, with 
the results communicated to the Investigator promptly. 
For subjects with Gilbert’s syndrome, a doubling of direct bilirubin concentration instead of total 
bilirubin concentration should be used for close monitoring and TVB-2640 discontinuation. 


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If either of the following criteria are met, study drug must be discontinued and the subject must 
be followed until the clinical and laboratory abnormalities stabilize or normalize: 
• In the presence of total bilirubin elevation (>2 × ULN or >1.5 × Baseline level); with 
any degree of aminotransferase elevation; AND if there is appearance of symptoms 
i.e., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%).  
• If any total bilirubin, ALT, or AST elevation above the subject’s Baseline result 
recurs following rechallenge with study drug. 

SAP_001.pdf: 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol SB2640-CLIN-007 
 
 
FASCINATE-2: A Phase 2b, Multi-Center, Double-Blind, Randomized, 
Placebo -Controlled Study of the Safety and Efficacy of TVB-2640 in Subjects 
with Nonalcoholic Steatohepatitis 
 
 
Final Version 
Date of Plan: 
04December2023 
 
Study Drug:  
TVB-2640 (denifanstat) 
 
Prepared for: 
Sagimet Biosciences 
155 Bovet Rd, Suite 303 
San Mateo, CA 94022 


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Approval Signature Page   
Summit Analytical: 
 
 
 
 
 
 
 
 
 
Document Author:   
Mark Jaros, PhD 
SVP, Summit Analytical 
 
Date 
 
 
Sagimet Biosciences: 
 
 
 
 
 
 
 
Document Approver:  
Eduardo Bruno Martins, MD, DPhil 
Chief Medical Officer 
 
 
 
 
 
Document Reviewer:   
Katharine Grimmer, MBA 
Vice President, Clinical Operations 
 
 
 


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Table of Contents 
1. 
Abbreviations .......................................................................................................................... 5 
2. 
Introduction ............................................................................................................................. 7 
3. 
Study Objectives ..................................................................................................................... 7 
3.1. 
Co-primary Objectives ..................................................................................................... 7 
3.2. 
Secondary Objectives ....................................................................................................... 7 
3.3. 
Exploratory Objectives ..................................................................................................... 9 
4. 
Study Design ......................................................................................................................... 10 
4.1. 
Study Design and Population ......................................................................................... 10 
4.2. 
Randomization and Blinding .......................................................................................... 12 
4.3. 
Sample Size Considerations ........................................................................................... 13 
4.4. 
Independent Data Monitoring Committee ..................................................................... 13 
4.5. 
Interim Analyses ............................................................................................................ 13 
5. 
Study Endpoints .................................................................................................................... 14 
5.1. 
Efficacy .......................................................................................................................... 14 
5.2. 
Safety .............................................................................................................................. 17 
6. 
Analysis Populations/Sets ..................................................................................................... 18 
7. 
General Data Handling Considerations ................................................................................ 18 
7.1. 
Stratification and Covariates .......................................................................................... 19 
7.2. 
Evaluation of Subgroups ................................................................................................ 19 
7.3. 
Multiple Comparisons and Multiplicity ......................................................................... 25 
7.4. 
Efficacy Endpoints: 1-sided and 2-sided Testing Allocation ......................................... 25 
7.5. 
Reference Dates.............................................................................................................. 31 
7.6. 
Baseline and Post-Baseline Changes.............................................................................. 31 
7.7. 
Handling Below Limit of Quantification (BLQ) or Lower Limit of Quantification 
(LLOQ) Values ......................................................................................................................... 31 
7.8. 
Imputation of Partial Dates ............................................................................................ 31 
7.9. 
Multiple Assessments and Visit Windows ..................................................................... 33 
7.10. 
Handling of Early Termination Visit Information ...................................................... 33 
7.11. 
Missing Data ............................................................................................................... 33 
8. 
Study Subject Data ................................................................................................................ 34 
8.1. 
Subject Disposition ........................................................................................................ 34 
8.2. 
Protocol Deviations ........................................................................................................ 34 
8.3. 
Demographic and Baseline Characteristics .................................................................... 34 


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8.4. 
NASH History ................................................................................................................ 34 
8.5. 
Medical History .............................................................................................................. 35 
8.6. 
Prior and Concomitant Medication ................................................................................ 35 
8.7. 
Study Drug Exposure and Compliance .......................................................................... 35 
9. 
Efficacy ................................................................................................................................. 36 
9.1. 
Primary Efficacy Endpoint Analyses ............................................................................. 36 
9.1.1. 
Principal Analysis of the Primary Efficacy Endpoints ......................................... 36 
9.1.2. 
Sensitivity Analyses of the Primary Efficacy Endpoints ...................................... 37 
9.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 37 
9.3. 
Exploratory Efficacy Endpoints Analyses ..................................................................... 38 
9.4. 
Pharmacokinetics (PK) ................................................................................................... 38 
10. Safety .................................................................................................................................... 39 
10.1. 
Adverse Events ........................................................................................................... 39 
10.2. 
Clinical Laboratory Evaluations ................................................................................. 40 
10.3. 
Vital Signs .................................................................................................................. 41 
10.4. 
Electrocardiogram (ECG) ........................................................................................... 41 
10.5. 
Ophthalmologic Examinations ................................................................................... 42 
10.6. 
Physical Examinations ................................................................................................ 42 
11. Changes to the planned analyses ........................................................................................... 42 
12. References ............................................................................................................................. 43 
 
 
 
 


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1. ABBREVIATIONS 
Abbreviation 
Explanation 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic class 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case Report Form 
CRN 
Clinical Research Network 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELF 
Enhanced liver fibrosis test 
FAST 
FibroScan-AST score 
FGF-21 
Fibroblast Growth Factor 21 
FIB-4 
Fibrosis-4 index 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Glycated hemoglobin 
ICH 
International Council for Harmonization 
IDMC 
Independent Data Monitoring Committee 
INR 
International normalized ratio 
ITT 
Intent-to-treat population 
IWRS 
Interactive Web Response System  
kg 
Kilogram 
LDL-C 
Low-density lipoprotein cholesterol 
LLN 
Lower limit of normal 
max  
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minimum 
mITT 
Modified intent-to-treat population 
mmHg 
Millimeters of mercury 
MMRM 
Mixed model for repeated measures 
MRI-PDFF 
Magnetic Resonance Imaging-Proton Density Fat Fraction 
ms 
Millisecond 
N or n 
Number of subjects 
NAFLD 
Nonalcoholic fatty liver disease 
NAS 
NAFLD activity score 
NASH 
Nonalcoholic steatohepatitis 


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Abbreviation 
Explanation 
NCI 
National Cancer Institute 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PO 
Orally 
PRO-C3 
N-Terminal Type III Collagen Propeptide 
PT 
Preferred term 
Q1 
First Quartile 
Q3 
Third Quartile 
QD 
Once daily 
SAE 
Serious adverse event 
SAF 
Safety Analysis Population 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SI 
International System of Units 
SNPs 
Single-Nucleotide Polymorphisms 
SOC 
System organ class 
T2DM 
Type 2 Diabetes Mellitus 
TEAE 
Treatment-Emergent Adverse Event 
TIMP-1 
Tissue Inhibitor of Metalloproteinase-1 
ULN 
Upper limit of normal 
 
 
 


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2. INTRODUCTION 
The statistical analysis plan (SAP) corresponds to the study number SB2640-CLIN-007: “A 
Phase 2b, Multi-Center, Double-Blind, Randomized, Placebo Controlled Study of the Safety and 
Efficacy of TVB-2640 in Subjects with Nonalcoholic Steatohepatitis (FASCINATE-2)”. The 
SAP comprises the protocol pre-planned interim and final analyses and will be the basis for the 
analyses in support of the Clinical Study Report (CSR). The SAP was based on the study 
protocol version 4.0 dated 06 September 2023 and CRF dated 24 February 2023. The final 
sponsor-approved version of the SAP must occur prior to unblinding of the study database and 
the final analyses. 
3. STUDY OBJECTIVES 
3.1. Co-primary Objectives  
− To evaluate the effect of TVB-2640 50 mg PO QD compared with matching placebo in 
noncirrhotic subjects with nonalcoholic steatohepatitis (NASH) and F2-F3 fibrosis  
o Histological improvement at Week 52 in nonalcoholic fatty liver disease 
(NAFLD) activity score (NAS) (i.e., ≥2 points improvement in NAS with ≥1 
point improvement in ballooning or inflammation) and without worsening of 
fibrosis (by NASH Clinical Research Network [CRN] fibrosis score) 
o Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver 
disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 
for inflammation, 0 for ballooning, and any value for steatosis  
AND 
Histological improvement in NAS (≥2 points improvement in NAS) at Week 52 
− To evaluate the safety and tolerability of TVB-2640 50 mg PO QD in subjects with 
confirmed NASH and liver fibrosis. 
3.2. Secondary Objectives 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% 
relative reduction in liver fat content as assessed by magnetic resonance imaging-proton 
density fat fraction (MRI-PDFF) at Week 26. 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% 
relative reduction in liver fat content as assessed by MRI-PDFF at Week 52. 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
fibrosis as assessed by ≥1 stage of fibrosis improvement by NASH CRN score) without 
worsening of steatohepatitis (no increase in NAS for ballooning, inflammation, or 
steatosis) at Week 52.  


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− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
fibrosis as assessed by ≥1 stage of fibrosis improvement by NASH CRN score without 
increasing of total NAS scores at Week 52.  
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
fibrosis as assessed by ≥1 stage of fibrosis improvement by NASH CRN score without 
any worsening of NASH (no worsening of ballooning and lobular inflammation, a 1 
grade change in steatosis may be acceptable) at Week 52. 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Resolution of steatohepatitis on overall histopathological reading and no 
worsening of liver fibrosis on NASH CRN fibrosis score. Resolution of 
steatohepatitis is defined as absent fatty liver disease or isolated or simple 
steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in NAS (i.e., ≥2 points improvement in 
NAS with ≥1 point improvement in ballooning or inflammation) and without 
worsening of fibrosis (by NASH CRN fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis 
score). Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis at Week 52. 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
histological improvement (decrease) at Week 52 in NAS by ≥1 point.  
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
histological improvement (decrease) at Week 52 in NAS by ≥2 points.  
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on liver 
fat content as assessed by MRI-PDFF at Week 26. 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on liver 
fat content as assessed by MRI-PDFF at Week 52. 


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− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
NASH resolution (defined as absence of fatty liver disease or isolated or simple steatosis 
without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any 
value for steatosis) at Week 52. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
change from Baseline at 26 and 52 weeks in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and gamma-glutamyl transferase (GGT). 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in low-density lipoprotein cholesterol (LDLC) 
and other lipid levels. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 52 weeks in the amount of collagen/fibrous area and fibrosis 
score, assessed by digital pathology. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in fasting insulin, fasting glucose, homeostatic 
model assessment of insulin resistance (HOMA-IR), adipose tissue insulin resistance 
(adipo-IR), and glycosylated hemoglobin (HbA1c) levels.  
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on the 
change from Baseline at 26 and 52 weeks in fibroblast growth factor 21 (FGF-21), 
adiponectin, and other NASH biomarker levels. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
change from Baseline at 26 and 52 weeks in FibroScan® and controlled attenuation 
parameter (CAP) score.  
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on N-
terminal type III collagen propeptide (PRO-C3) levels and other fibrosis biomarkers on 
change from Baseline at Weeks 4, 13, 26, and 52. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
change from Baseline at 26 and 52 weeks on enhanced liver function (ELF) score. 
− To evaluate the pharmacokinetics (PK) of TVB-2640 in subjects with NASH over 
52 weeks of treatment using sparse sample collection, and serial sample collection in a 
subset of subjects.  
3.3. Exploratory Objectives 
− To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on the 
proportion of subjects with ≥8% liver fat content at Baseline who achieve a ≥30% 
relative reduction in liver fat content as assessed by MRI PDFF AND achieve ≥17 U/L 
reduction in ALT at Week 52. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
FibroScan-AST (FAST) score at Weeks 26 and 52.  
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 


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select fibrosis biomarkers (including at least tissue inhibitor of metalloproteinase-1 
[TIMP1]) at Weeks 4, 13, 26, and 52. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
lipidomic biomarkers (including tripalmitin, ceramides, bile acids, diacylglycerols, and 
other classes of metabolites) at Weeks 4, 13, 26, and 52. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
glycosylated hemoglobin (HbA1c) levels among subjects with type 2 diabetes mellitus 
(T2DM) at Weeks 13, 26, 39, and 52. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on 
Fibrosis 4 score (FIB-4) at Weeks 4, 13, 26, and 52. 
− To use digital pathology to perform zonal analysis of fibrosis at Week 52.  
o To use digital pathology to evaluate the concurrence of fibrosis with components 
of the NAS score. 
o To use digital pathology to evaluate the NAS components. 
− To correlate changes in MRI-PDFF with changes in, or baseline levels of, serum 
biomarkers and explore predictive markers of response.  
− To explore the relationship between changes in, or Baseline levels of, serum biomarkers 
and histology results, and explore predictive markers of response. 
− To explore the relationship between MRI-PDFF results and histology results. 
− To correlate the presence of relevant single-nucleotide polymorphisms (SNPs) or other 
genes relevant to NAFLD or NASH with clinical and histopathologic response. 
− To determine the effect of TVB-2640 50 mg QD compared with matching placebo on gut 
microbiome change from Baseline to Weeks 26 and 52 in a subset of subjects. 
− To explore the relationship between nutrition, as measured by the HepVita Nutritional 
Survey, and clinical, histopathological, and biomarker changes in NASH at Weeks 26 
and 52 in a subset of subjects. 
4. STUDY DESIGN 
4.1. Study Design and Population 
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-design study (see 
Figure 1, below) to evaluate the safety and efficacy of TVB-2640 compared with matching 
placebo in subjects with NASH who are aged ≥18 years at Screening.  
 
 
 
 


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Figure 1: FASCINATE-2 Study Design 
Abbreviations: CAP = controlled attenuation parameter; MRI = magnetic resonance imaging: NAS = nonalcoholic 
fatty liver disease activity score; NASH = nonalcoholic steatohepatitis; PDFF = protein density fat fraction; 
PK = pharmacokinetic; PO = orally; QD = once daily. 
 
Histological eligibility will be determined during the Screening period or prior to Screening but 
within 180 days of the Screening visit in 1 of 2 ways:  
− If an ‘eligible’ and adequate (this refers to the quality and quantity of remaining tissue) 
liver histology specimen, in the judgement of the central pathologist, exists from the time 
period within 180 days before the subject’s Screening visit, the subject may participate so 
long as other eligibility criteria are satisfied. 
− If no liver histology specimen exists from the period within 180 days of the Screening 
visit, the subject must undergo liver biopsy during the Screening period.  
Approximately 162 unique subjects with liver fibrosis stage F2-F3 will be enrolled and 
randomized (2:1 ratio) with approximately 108 subjects on TVB-2640 50 mg and 54 subjects on 
placebo. Dynamic allocation is used for the randomization, stratified by 3 factors: T2DM status 
(yes or no), region (North America or not North America), and amount of fibrosis (F2 or F3).  
Subjects will be screened for study eligibility within 90 days before randomization 
(randomization is within 3 days of Baseline [Day 1]). Subjects who are determined to be eligible 
for the study based on Screening assessments are to be randomized into the study within 3 days 
before Baseline (i.e., Day 1, the first day of study drug administration). Subjects who are 
randomized are considered to be enrolled in the study.  
Subjects will receive TVB-2640 or matching placebo PO QD for 52 weeks, with the first dose 
administered on Day 1. During the 52-week Treatment period, subjects are to attend study center 
visits at Weeks 4, 8, 13, 26, 39, and 52. After completion of the 52-week Treatment period, 


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subjects are to attend a Follow-up visit at Week 56 for posttreatment safety and efficacy 
assessments. 
In the event a subject is unable to complete the end of treatment MRI-PDFF and/or liver biopsy 
within the protocol-specified window (Week 52 +/- one week), extended dosing is permitted to 
maintain continuous dosing up to the time both assessments are completed, to a maximum total 
of 56 weeks of dosing. In this instance, the Follow-up visit at Week 56 for post treatment safety 
and efficacy assessments is to be adjusted to occur four weeks after the last dose (+/- one week). 
In the instance of a dose hold due to an AE or SAE, the decision to resume study drug will 
require consultation with the Investigator, the CRO’s Medical Monitor, and the Sponsor’s Chief 
Medical Officer. 
Improvement of NAS and improvement of fibrosis score will be evaluated by comparison of 
Baseline and Week 52 liver histology specimens. Subjects will also undergo MRI-PDFF prior to 
the start of treatment, at Week 26, and at Week 52 or Early Termination unless it presents a 
logistical or physical hardship to the subject. MRI-PDFF is not required at Early Termination if a 
subject has completed less than 22 weeks of study treatment. Other efficacy and 
pharmacodynamic (PD) assessments include FibroScan with CAP, and measurement of liver 
aminotransferases, lipid parameters, and other noninvasive biomarkers of NASH and liver 
fibrosis throughout the study.  
During the study, safety will be assessed by vital signs, 12-lead electrocardiograms (ECGs), 
physical examinations including eye examinations, and clinical laboratory testing. Subjects will 
be evaluated for AEs and concomitant medication use throughout the study.  
Blood samples will be collected at Baseline (Day 1) and at Weeks 4, 13, 26, and 52 for the 
assessment of sparse PK.  In addition, blood samples will be collected on Day 1 and at Week 4 
from a subset of subjects for serial PK.  
An independent data monitoring committee (IDMC) will be established by charter to provide 
independent review and assessment of study data and to monitor the overall study conduct in a 
systematic manner to safeguard the safety of study subjects. The IDMC will be tasked with 
making recommendations to the Sponsor to continue, amend, or stop the study based on these 
assessments.  
4.2. Randomization and Blinding 
This will be a double-blind, randomized study. Subjects will be centrally assigned to randomized 
study treatment using an Interactive Web-based Response System (IWRS).   
Approximately 162 unique subjects with liver fibrosis stage F2-F3 will be enrolled and 
randomized (2:1 ratio) to receive TVB-2640 50 mg or placebo (approximately 108 for TVB-
2640 50 mg and approximately 54 subjects for placebo) PO QD for 52 weeks. Dynamic 
allocation is used for the randomization, stratified by T2DM status (Yes, No), region (North 
America, not North America), and amount of fibrosis (F2 or F3).  


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All subjects, Investigators, the Sponsor, and the clinical research organization (CRO) will be 
blinded to the treatment assignment of each individual subject. Members of the IDMC and the 
IDMC’s independent statistician will be unblinded to treatment assignment as needed. In 
addition, specific vendors whose role in study conduct requires them to be unblinded (e.g., 
personnel operationally associated with the IWRS) may also be unblinded.  
4.3. Sample Size Considerations 
The study is powered to test the one-sided (statistical) superiority hypothesis stipulating that a 
TVB-2640 50-mg dose provides better benefit than placebo based on the primary efficacy 
endpoint. The study estimated total sample size is approximately 162 randomized subjects (108 
on TVB-2640 and 54 on placebo). The sample size was derived using the normal approximation 
to the binomial distribution, and the estimated power to detect a difference in the primary 
efficacy response of 20% (TVB-2640 40% and placebo 20% at Week 52) was at least 80% (one-
sided test at the 0.05 significance level). A 2-to-1 randomization allocation was assumed (TVB-
2640 to placebo), and an anticipated dropout rate of 18.5% was also applied to estimate the final 
total sample size (N=162). 
4.4. Independent Data Monitoring Committee 
An IDMC will be established by charter to provide independent review and assessment of study 
data and to monitor the overall study conduct in a systematic manner to safeguard the safety of 
study subjects. Periodic meetings will occur as outlined in the IDMC charter. An interim 
analysis, which will be reviewed by the IDMC, will be performed when approximately 60 
subjects with an MRI-PDFF value of ≥8% liver fat at Baseline have completed the Week 26 visit 
or an Early Termination Visit after Week 22. The IDMC will be provided with selected 
biomarker and safety interim results to allow for a more complete examination of the totality of 
the data. Upon review of the interim analysis findings, the IDMC may communicate with the 
Sponsor by making recommendations to the Sponsor to continue, amend, or stop the study based 
on these interim analysis results. The Sponsor will maintain its blind to any individual treatment 
assignments. 
4.5. Interim Analyses 
A single (secondary endpoint) efficacy interim analysis is planned when approximately 
60 subjects with an MRI-PDFF value of ≥8% liver fat at Baseline have completed Week 26 or an 
Early Termination visit after Week 22. The purpose of the proposed interim analysis is to 
examine the TVB-2640 benefit over placebo based on a Week 26 secondary efficacy endpoint 
consisting of “proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF 
≥30% responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
percent change (reduction) from Baseline in MRI-PDFF ≥30%”.  
Interim safety summaries will accompany the interim analyses of the secondary efficacy 
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An interim analysis of the primary efficacy endpoint is not feasible since the primary endpoint is 
only evaluated at Week 52, and not at Week 26. Therefore, a statistical penalty is not envisaged 
in conjunction with the Week 26 interim analysis of the above-stated secondary endpoint. 
5. STUDY ENDPOINTS 
5.1. Efficacy 
The co-primary efficacy endpoints are the proportion of subjects experiencing the following: 
− Histological improvement at Week 52 in NAS (i.e., ≥2-point improvement in NAS with 
≥1-point improvement in ballooning or inflammation) and without worsening of fibrosis 
score (by NASH CRN fibrosis score) 
− Resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN fibrosis 
score). Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated 
or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis 
AND 
Histological improvement in NAS (≥2 points improvement in NAS) at Week 52. 
The secondary efficacy and pharmacodynamic endpoints are: 
− Proportion of MRI-PDFF ≥30% responders at Week 26, where an MRI-PDFF ≥30% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
relative reduction from Baseline in MRI-PDFF ≥30%.  
− Proportion of MRI-PDFF ≥30% responders at Week 52 where an MRI-PDFF ≥30% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
relative reduction from Baseline in MRI-PDFF ≥30%. 
− Proportion of MRI-PDFF ≥50% responders at Week 52 where an MRI-PDFF ≥50% 
responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a 
relative reduction from Baseline in MRI-PDFF ≥50%. 
− Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN 
fibrosis score) without worsening of steatohepatitis (defined as no increase in NAS for 
ballooning, inflammation, or steatosis) at 52 weeks.  
− Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without increase of total NAS score at Week 52. 
− Proportion of subjects with improvement in liver fibrosis ≥1 stage by NASH CRN score 
without any worsening of NASH (defined as no worsening of ballooning and lobular 
inflammation; a 1 grade change in steatosis may be acceptable) at Week 52. 
− Proportion of subjects experiencing both of the following at Week 52:  
o Resolution of steatohepatitis on overall histopathological reading and no 
worsening of liver fibrosis on NASH CRN fibrosis score. Resolution of 


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steatohepatitis is defined as absent fatty liver disease or isolated or simple 
steatosis without steatohepatitis and a NAS score of 0-1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
AND 
o Improvement in liver fibrosis greater than or equal to one state (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
− Proportion of subjects experiencing both of the following at Week 52: 
o Histological improvement at Week 52 in nonalcoholic fatty liver disease 
(NAFLD) activity score (NAS) (i.e., ≥2 points improvement in NAS with ≥1 
point improvement in ballooning or inflammation) and without worsening of 
fibrosis (by NASH Clinical Research Network [CRN] fibrosis score) 
AND 
o Improvement in liver fibrosis greater than or equal to one stage (NASH CRN 
fibrosis score) and no worsening of steatohepatitis (defined as no increase in NAS 
for ballooning, inflammation, or steatosis). 
− Proportion of subjects with resolution of steatohepatitis and no worsening of liver fibrosis 
(by NASH CRN fibrosis score). Resolution of steatohepatitis is defined as absence of 
fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 
1 for inflammation, 0 for ballooning, and any value for steatosis at Week 52. 
− Proportion of subjects with histological improvement (decrease) at Week 52 in NAS by 
≥1 point. 
− Proportion of subjects with histological improvement (decrease) at Week 52 in NAS by 
≥2 points. 
− Change and percent change from Baseline in MRI-PDFF liver fat (%) at Week 26. 
− Change and percent change from Baseline in MRI-PDFF liver fat (%) at Week 52. 
− Proportion of subjects with NASH resolution (defined as absence of fatty liver disease or 
isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 
0 for ballooning, and any value for steatosis) at 52 weeks. 
− Change from Baseline in ALT, AST, alkaline phosphatase (ALP), and GGT at Weeks 26 
and 52 and at each study visit. 
− Change from Baseline in LDL-C and other lipid levels (including LDL/HDL ratio) at 
Weeks 26 and 52 and at each study visit. 
− Change from Baseline in collagen/fibrous area and fibrosis score, assessed by digital 
pathology, at Week 52. 
o The primary digital pathology variables that will be analyzed include the 
following: 
▪ qFibrosis – continuous value 


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▪ qFibrosis – stage 
▪ qSteatosis – continuous value 
▪ qSteatosis – grade 
▪ Steatosis corrected qFibrosis – continuous value 
▪ Steatosis corrected qFibrosis – stage 
- Change from Baseline in metabolic parameters, including fasting insulin, fasting glucose, 
HOMA-IR, adipo-IR, and HbA1c levels at Weeks 26 and 52 and at each study visit. 
− Change from Baseline in FGF-21, adiponectin, and other NASH biomarker levels at 
Weeks 26 and 52 and at each study visit. 
− Change from Baseline in FibroScan Liver Stiffness Measurement (kPa)) and CAP score 
results at Weeks 26 and 52. 
− Change from Baseline in PRO-C3 and other fibrosis biomarkers at Weeks 4, 13, 26, and 
52. 
− Change from Baseline in ELF score at Weeks 26 and 52. 
− Plasma concentrations of TVB-2640 at Weeks 1, 4, 13, 26, and 52. 
− Proportion of subjects with histological improvement at Week 52 in NAS (i.e., ≥2 points 
improvement in NAS with ≥1 point improvement in ballooning or inflammation) and 
without worsening of fibrosis (by NASH CRN fibrosis score) 
− Proportion of subjects with resolution of steatohepatitis and no worsening of liver fibrosis 
(by NASH CRN fibrosis score). Resolution of steatohepatitis is defined as absence of 
fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 
1 for inflammation, 0 for ballooning, and any value for steatosis. 
The exploratory efficacy and pharmacodynamics endpoints are: 
− Proportion of MRI-PDFF ≥30% responders at Week 52 who have ≥17 U/L reduction in 
ALT.  
− Change from Baseline in FAST score at Weeks 26 and 52. 
− Change from Baseline in Agile 3+ score at Weeks 26 and 52. 
The formula from Sanyal et al (2023) for the Agile 3+ score is:  
𝐴𝑔𝑖𝑙𝑒 3+ = 𝑒𝑙𝑜𝑔𝑖𝑡(𝑝𝐹≥3) (1 + 𝑒𝑙𝑜𝑔𝑖𝑡(𝑝𝐹≥3)
⁄
) 
with  
𝑙𝑜𝑔𝑖𝑡(𝑝𝐹≥3) = −3.92368 + 2.29714×ln(LSM) − 0.00902×PLT − 0.98633×AAR−1 + 
1.08636×Diabetes status − 0.38581×Sex + 0.03018×Age 
Where ln is natural log; LSM=Liver Stiffness Measurement (kPa) by vibration-controlled 
transient elastography (VCTE); AAR=AST/ALT ratio; PLT=platelets (G/L); Sex: 
male=1, female=0; and Diabetes status: yes=1, no=0. 
− Change from Baseline in levels of select fibrosis biomarkers (e.g., TIMP-1) at Weeks 4, 


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13, 26, and 52. 
− Change from Baseline in levels of lipidomic/metabolomic biomarkers (e.g., tripalmitin, 
ceramides, bile acids, diacylglycerols, and other classes of metabolites) at Weeks 4, 13, 
26, and 52. 
− Change from Baseline in HbA1c levels among subjects with T2DM at Weeks 13, 26, 39, 
and 52. 
− Change from Baseline in FIB-4 at Weeks 4, 13, 26, and 52. 
− 
Change from Baseline in additional fibrosis parameters such as zonal analyses of fibrosis, NAS, 
and individual NAS components as determined by digital pathology at Week 52. 
− Correlation of changes in MRI-PDFF with changes in other endpoints. 
− Presence or absence of SNPs relevant for NASH. 
− Correlation of predictive signature with other endpoints. 
− Correlation of lipids (e.g. tripalmitin) with other endpoints. 
− Change from Baseline in gut microbiome analyses at Weeks 26 and 52 in a substudy of 
subjects. 
− Change from Baseline in HepVita Nutritional Survey at Weeks 26 and 52 in a substudy 
of subjects. 
− Change in MELD score from baseline to Week 52  
The formula from Kamath et al (2001) for the MELD score is 3.8×ln(bilirubin [mg/dL]) 
+ 11.2×ln(INR) + 9.6×ln(creatinine [mg/dL]) + 6.4×(etiology: 0 if cholestatic or 
alcoholic, 1 otherwise). 
Where ln is natural log. 
5.2. Safety 
The safety endpoints are: 
− Adverse events (AEs) throughout the study. 
− Electrocardiograms (ECGs) at Weeks 26 and 52. 
− Vital signs at each study visit. 
− Physical examination findings at each study visit. 
− Eye examination findings at each study visit. 
− Hematology and coagulation results at each study visit. 
− Liver aminotransferase levels at each study visit. 
− Clinical chemistry results at each study visit. 
− Urinalysis results at each study visit. 


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− Pregnancy test results throughout the study. 
− Prior and concomitant medications throughout the study. 
− Results of anthropometric measurements at Week 52. 
6. ANALYSIS POPULATIONS/SETS 
Intention-to-Treat (ITT) Population: The principal analysis of the primary and secondary 
efficacy endpoints will be based on the Intention-to-Treat (ITT) population, which comprises all 
randomized subjects; this population will serve as the basis for all efficacy analyses. Subjects’ 
data will be analyzed according to their randomized treatment assignment. 
Modified Intention-to-Treat (mITT) Population: Comprises all subjects in the ITT population 
who have completed at least 42 weeks of treatment and have an evaluable post treatment 
histological assessment. Subjects will be analyzed according to the randomized treatment 
assignment. 
Interim Analyses Modified Intention-to-treat (IAmITT) Population: Comprises a subset of 
approximately 60 subjects in the ITT population with 8% >/= MRI-PDFF at screening or at 
baseline with at least 1 evaluable post-Baseline MRI-PDFF value, defined as an MRI-PDFF 
assessment obtained at least 22 weeks after the first dose of study drug. 
Safety (SAF) Population:  Consists of all randomized subjects who received at least 1 dose 
(partial or complete) of study drug. This population will be used for all summaries of subject 
accountability, demographic and baseline data, and safety information, including AE incidence, 
clinical laboratory data, ECG data, and vital signs data. Subjects’ data will be summarized 
according to the treatment they received. If all subjects were dosed according to randomized 
treatment assignment, then the safety and ITT analysis sets are identical. 
PK Population:  Comprises all ITT subjects with available PK measurements. 
Serial PK Population: Comprises the subset of subjects who provided blood samples for 
evaluation of serial PK at timepoints on Day 1 and at Week 4. 
7. GENERAL DATA HANDLING CONSIDERATIONS 
All analyses will be conducted using SAS software Version 9.4 or higher. 
All data in the database will be presented in by-subject data listings. Unless otherwise stated, all 
listings will be sorted by treatment group, center ID, subject number, and assessment date and 
time, if available. 
Unless stated otherwise, continuous data will be summarized by treatment group using 
descriptive statistics including number of subjects (n), mean, median, standard deviation (SD), 
first quartile (Q1), third quartile (Q3), minimum (min) value, maximum (max) value.  


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Unless stated otherwise, categorical data will be summarized by treatment group using counts 
and percentage based on the number of non-missing values. For selected summaries, the number 
of missing values will be presented as a separate category with no percentage, if one or more 
subjects have missing data. Counts of zero will be presented without percentages. 
Descriptive statistics will be presented with the following numerical precision: 
− Minimum and Maximum: same as the raw data collected 
− Mean, Median, Q1, and Q3: one additional decimal place to that reported for Minimum and 
Maximum 
− SD: two additional decimal places than the Minimum and Maximum  
− Percentages: reported to one decimal place if percent is <100. If the value is 100, no decimal 
place will be reported. 
Unless otherwise noted, statistical inference will be based on two-sided testing with a 5% 
significance level. Confidence intervals with be at the 90% and 95% levels. 
P-values will be reported to four decimal places.  If the value is below 0.0001 it will be noted as 
< 0.0001; if the value above 0.9999 it will be noted as > 0.9999. 
All data up to the time of study completion/withdrawal from the study will be included in the 
analysis, regardless of duration of treatment. 
Numbering for data displays will be based on International Council for Harmonization (ICH) E3 
whenever possible. 
7.1. Stratification and Covariates 
Subjects will be randomized to achieve a 2:1 ratio of TVB-2640 50 mg to placebo, with the 
randomization stratified three factors: T2DM status (Yes, No), and amount of fibrosis (F2 or F3).  
Selected statistical models and tests will be stratified based on the randomization strata. Details 
on the models and tests are provided in the relevant sections below. 
7.2. Evaluation of Subgroups 
Select analyses for efficacy and safety endpoints will be repeated for a variety of subgroups.  The 
subgroups are summarized in the table below.  If a subject does not have a value for one of the 
subgroup variables they will be excluded from the subgroup.  Efficacy endpoints will be 
analyzed by subgroup for both the ITT and mITT populations. Safety endpoints will be 
summarized by subgroup for the Safety population. 
Endpoint 
Subgroups 
Co-Primary Efficacy Endpoints 
 


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Endpoint 
Subgroups 
Proportion of subjects experiencing 
histological improvement at Week 52 
in NAS (i.e., ≥2 points improvement 
in NAS with ≥1 point improvement 
in ballooning or inflammation) and 
without worsening of fibrosis (by 
NASH CRN fibrosis score) 
 
• ≥30% reduction in MRI-PDFF from baseline to Week 52 (yes 
or no) – includes subjects with ≥8% liver fat content at 
Baseline 
• ≥50% reduction in MRI-PDFF from baseline to Week 52 (Yes 
or No) – includes subjects with ≥8% liver fat content at 
Baseline 
• Stage of fibrosis at baseline (F2 or F3) 
• T2DM at baseline (Yes or No) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
• Statin use at baseline (Yes or No) [3] 
• Diabetes medication use at baseline (Yes or No) [4] 
• <5% reduction in weight from baseline to Week 52 (Yes or No) 
• Liver fat ≥8% at baseline (Yes or No) 
• ≥17 U/L reduction in ALT from baseline to Week 52 (Yes or 
No) 
• NAS at baseline (4/5 or 6/7/8) 
• Race (White, Black, Asian, and other) 
• Hispanic (Yes or No) 
• Liver biopsy length ≥ 15mm (both baseline and Week 52 
biopsies) vs < 15mm  
• Age categories (<40 years, 40 to <65 years, and ≥65 years) 
Proportion of subjects experiencing 
both of the following at Week 52: 
o Resolution of steatohepatitis 
and no worsening of liver 
fibrosis (by NASH CRN 
fibrosis score). Resolution of 
steatohepatitis is defined as 
absence of fatty liver disease 
or isolated or simple steatosis 
without steatohepatitis and a 
NAS of 0 or 1 for 
inflammation, 0 for 
ballooning, and any value for 
steatosis. 
 
AND 
 
 
• ≥30% reduction in MRI-PDFF from baseline to Week 52 (yes 
or no) – includes subjects with ≥8% liver fat content at 
Baseline 
• ≥50% reduction in MRI-PDFF from baseline to Week 52 (Yes 
or No) – includes subjects with ≥8% liver fat content at 
Baseline 
• Stage of fibrosis at baseline (F2 or F3) 
• T2DM at baseline (Yes or No) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
• Statin use at baseline (Yes or No) [3] 
• Diabetes medication use at baseline (Yes or No) [4] 
• <5% reduction in weight from baseline to Week 52 (Yes or No) 
• Liver fat ≥8% at baseline (Yes or No) 
• ≥17 U/L reduction in ALT from baseline to Week 52 (Yes or 
No) 
• NAS at baseline (4/5 or 6/7/8) 


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Endpoint 
Subgroups 
o Histological improvement in 
NAS (≥2 points improvement 
in NAS). 
 
• Race (White, Black, Asian, and other) 
• Hispanic (Yes or No) 
• Liver biopsy length ≥ 15mm (both baseline and Week 52 
biopsies) vs < 15mm  
• Age categories (<40 years, 40 to <65 years, and ≥65 years) 
 
 
Selected Secondary Efficacy and 
Pharmacodynamic Endpoints 
 
Proportion of subjects with 
improvement in liver fibrosis 
≥1 stage by NASH CRN fibrosis 
score without worsening of 
steatohepatitis (defined as no 
increase in NAS for ballooning, 
inflammation, or steatosis) at 
Week 52. 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
Proportion of subjects with 
improvement in liver fibrosis ≥1 
stage by NASH CRN score without 
increase of total NAS score at Week 
52. 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
Proportion of subjects with 
improvement in liver fibrosis ≥1 
stage by NASH CRN score without 
any worsening of NASH (defined as 
no worsening of ballooning and 
lobular inflammation; a 1 grade 
change in steatosis may be 
acceptable) at Week 52. 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
Proportion of subjects experiencing 
both of the following at Week 52:  
o Resolution of steatohepatitis 
on overall histopathological 
reading and no worsening of 
liver fibrosis on NASH CRN 
fibrosis score. Resolution of 
steatohepatitis is defined as 
absent fatty liver disease or 
isolated or simple steatosis 
without steatohepatitis and a 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
 


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Endpoint 
Subgroups 
NAS score of 0-1 for 
inflammation, 0 for 
ballooning, and any value for 
steatosis. 
AND 
o Improvement in liver fibrosis 
greater than or equal to one 
state (NASH CRN fibrosis 
score) and no worsening of 
steatohepatitis (defined as no 
increase in NAS for 
ballooning, inflammation, or 
steatosis). 
Proportion of subjects experiencing 
both of the following at Week 52: 
o Histological 
improvement at Week 
52 in nonalcoholic 
fatty liver disease 
(NAFLD) activity 
score (NAS) (i.e., ≥2 
points improvement in 
NAS with ≥1 point 
improvement in 
ballooning or 
inflammation) and 
without worsening of 
fibrosis (by NASH 
Clinical Research 
Network [CRN] 
fibrosis score) 
AND 
o Improvement in liver 
fibrosis greater than 
or equal to one stage 
(NASH CRN fibrosis 
score) and no 
worsening of 
steatohepatitis 
(defined as no 
increase in NAS for 
ballooning, 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 


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Endpoint 
Subgroups 
inflammation, or 
steatosis). 
Proportion of subjects experiencing 
resolution of steatohepatitis and no 
worsening of liver fibrosis (by 
NASH CRN fibrosis score). 
Resolution of steatohepatitis is 
defined as absence of fatty liver 
disease or isolated or simple steatosis 
without steatohepatitis and a NAS of 
0 or 1 for inflammation, 0 for 
ballooning, and any value for 
steatosis at Week 52. 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
Proportion of subjects with 
histological improvement (decrease) 
at Week 52 in NAS by ≥1 point. 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
Proportion of subjects with 
histological improvement (decrease) 
at Week 52 in NAS by ≥2 points. 
• Stage of fibrosis at baseline (F2 or F3) 
• GLP-1 at baseline (Yes or No) [1] 
• SGLT2 at baseline (Yes or No) [2] 
Change from Baseline in ALT, AST, 
and GGT at Weeks 26 and 52 and at 
each study visit. 
• Stage of fibrosis at baseline (F2 or F3) 
• T2DM at baseline (Yes or No) 
 
Change from Baseline in LDL-C and 
other lipid levels (including 
LDL/HDL ratio) at Weeks 26 and 52 
and at each study visit. 
• T2DM at baseline (Yes or No) 
• Statin use at baseline (Yes or No) [3] 
 
Changes from Baseline in metabolic 
parameters, including fasting insulin, 
fasting glucose, HOMA-IR, adipo-
IR, and HbA1c levels at Weeks 26 
and 52 and at each study visit. 
• T2DM at baseline (Yes or No) 
 
Change from Baseline in FibroScan 
(Liver Stiffness Measure (kPA)) and 
CAP score results at Weeks 26 and 
52. 
• ≥30% reduction in MRI-PDFF from baseline to Week 52 (yes 
or no) – includes subjects with ≥8% liver fat content at 
Baseline 
• ≥50% reduction in MRI-PDFF from baseline to Week 52 (Yes 
or No) – includes subjects with ≥8% liver fat content at 
Baseline 


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Endpoint 
Subgroups 
 
 
Selected Exploratory Endpoints 
 
Change from Baseline in FAST score 
at Weeks 26 and 52. 
• 30% reduction in MRI-PDFF from baseline to Week 52 (yes or 
no) – includes subjects with ≥8% liver fat content at Baseline 
• ≥50% reduction in MRI-PDFF from baseline to Week 52 (Yes 
or No) – includes subjects with ≥8% liver fat content at 
Baseline 
Change from Baseline in Agile 3+ 
score at Weeks 26 and 52. 
• 30% reduction in MRI-PDFF from baseline to Week 52 (yes or 
no) – includes subjects with ≥8% liver fat content at Baseline 
• ≥50% reduction in MRI-PDFF from baseline to Week 52 (Yes 
or No) – includes subjects with ≥8% liver fat content at 
Baseline 
Change from Baseline in levels of 
lipidomic/metabolomic biomarkers 
(e.g., tripalmitin, ceramides, bile 
acids, diacylglycerols, and other 
classes of metabolites) at Weeks 4, 
13, 26, and 52. 
• On a GLP-1 at baseline (Yes or No) [1] 
 
 
Selected Safety Endpoints 
 
Skin and subcutaneous tissue 
disorders TEAEs  
• Diabetes medication use at baseline (Yes or No) [4] 
• COVID-19 diagnosis or COVID-19 vaccination within 30 days 
of skin and subcutaneous tissue disorders TEAE onset (Yes or 
No) 
• Statin use at baseline (Yes or No) [3] 
• GLP-1 or SGLT2 at baseline (Yes or No) [1] [2]  
• Female age (>50 or ≤50 years) 
Eye disorder TEAEs 
• Diabetes medication use at baseline (Yes or No) [4] 
• COVID-19 diagnosis or COVID-19 vaccination within 30 days 
of eye disorder TEAE onset (Yes or No) 
• Statin use at baseline (Yes or No) [3] 
• GLP-1 or SGLT2 at baseline (Yes or No) [1] [2]  
[1] GLP-1 medications are identified using ATC code = ‘A10BJ’ 


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[2] SGLT2 medications are identified using ATC code = ‘A10BK’ 
[3] Statin medications are identified using ATC code = ‘C10AA’ 
[4] Diabetes medications are identified using ATC code = ‘A10’ at baseline. 
 
7.3. Multiple Comparisons and Multiplicity 
The study co-primary hypotheses are the (statistical) one-sided superiority of a TVB-2640 50-mg 
dose over placebo based on each of the two co-primary efficacy endpoints at the 0.05 
significance level, where a higher responder proportion is a better outcome. The statistical 
analysis (one-sided) test (CMH) of the primary hypothesis is declared if p<0.05. No adjustment 
for the two co-primary efficacy tests will be performed, both will be tested at the 0.05 level using 
one-sided tests. 
Both one-sided and two-sided 0.05 significance level tests will be used for the efficacy 
endpoints. The table below specifies whether the test of significance is one- or two-sided along 
with the expected direction of effect. No other control for multiplicity will be provided. 
Note that endpoints that are being tested as one-sided will also have the two-sided p-values 
provided.  Both 90% and 95% two-sided confidence intervals will be shown. 
7.4. Efficacy Endpoints: 1-sided and 2-sided Testing Allocation  
  
Endpoint 
Number 
 
Endpoint Description 
1-sided 
or  
2-sided 
Directionality for 
better outcome 
for 1-sided tests 
 
Co-Primary Efficacy Endpoints 
 
 
1A 
Proportion of subjects experiencing histological 
improvement at Week 52 in NAS (i.e., ≥2 points 
improvement in NAS with ≥1 point improvement 
in ballooning or inflammation) and without 
worsening of fibrosis (by NASH CRN fibrosis 
score) 
1-sided 
Higher 
1B 
Proportion of subjects experiencing both of the 
following at Week 52: 
o Resolution of steatohepatitis and no 
worsening of liver fibrosis (by NASH 
CRN fibrosis score). Resolution of 
steatohepatitis is defined as absence of 
fatty liver disease or isolated or simple 
steatosis without steatohepatitis and a 
NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis. 
 
1-sided 
Higher 


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Endpoint 
Number 
 
Endpoint Description 
1-sided 
or  
2-sided 
Directionality for 
better outcome 
for 1-sided tests 
AND 
 
o Histological improvement in NAS (≥2 
points improvement in NAS). 
 
Secondary Efficacy and Pharmacodynamic 
Endpoints 
 
 
2 
Proportion of MRI-PDFF ≥30% responders at 
Week 26, where an MRI-PDFF ≥30% responder 
is defined as a subject with ≥8% liver fat content 
at Baseline who achieves a relative reduction 
from Baseline in MRI-PDFF ≥30%. 
2-sided 
 
3 
Proportion of MRI-PDFF ≥30% responders at 
Week 52, where an MRI-PDFF ≥30% responder 
is defined as a subject with ≥8% liver fat content 
at Baseline who achieves a relative reduction 
from Baseline in MRI-PDFF ≥30%. 
2-sided 
 
4 
Proportion of MRI-PDFF ≥50% responders at 
Week 52, where an MRI-PDFF ≥50% responder 
is defined as a subject with ≥8% liver fat content 
at Baseline who achieves a relative reduction 
from Baseline in MRI-PDFF ≥50%. 
2-sided 
 
5 
Proportion of subjects with improvement in liver 
fibrosis ≥1 stage by NASH CRN fibrosis score 
without worsening of steatohepatitis (defined as 
no increase in NAS for ballooning, inflammation, 
or steatosis) at Week 52.  
1-sided 
Higher 
6 
Proportion of subjects with improvement in liver 
fibrosis ≥1 stage by NASH CRN score without 
increase of total NAS score at Week 52. 
1-sided 
Higher 
7 
Proportion of subjects with improvement in liver 
fibrosis ≥1 stage by NASH CRN score without 
any worsening of NASH (defined as no 
worsening of ballooning and lobular 
1-sided 
Higher 


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Endpoint 
Number 
 
Endpoint Description 
1-sided 
or  
2-sided 
Directionality for 
better outcome 
for 1-sided tests 
inflammation; a 1 grade change in steatosis may 
be acceptable) at Week 52. 
8 
Proportion of subjects experiencing both of the 
following at Week 52:  
o Resolution of steatohepatitis on 
overall histopathological reading 
and no worsening of liver fibrosis 
on NASH CRN fibrosis score. 
Resolution of steatohepatitis is 
defined as absent fatty liver 
disease or isolated or simple 
steatosis without steatohepatitis 
and a NAS score of 0-1 for 
inflammation, 0 for ballooning, 
and any value for steatosis 
AND 
o Improvement in liver fibrosis 
greater than or equal to one state 
(NASH CRN fibrosis score) and 
no worsening of steatohepatitis 
(defined as no increase in NAS for 
ballooning, inflammation, or 
steatosis). 
1-sided 
Higher 
9 
Proportion of subjects experiencing both of the 
following at Week 52: 
o Histological improvement at Week 
52 in nonalcoholic fatty liver 
disease (NAFLD) activity score 
(NAS) (i.e., ≥2 points 
improvement in NAS with ≥1 
point improvement in ballooning 
or inflammation) and without 
worsening of fibrosis (by NASH 
Clinical Research Network [CRN] 
fibrosis score) 
AND 
o Improvement in liver fibrosis 
greater than or equal to one stage 
1-sided 
Higher 


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Endpoint 
Number 
 
Endpoint Description 
1-sided 
or  
2-sided 
Directionality for 
better outcome 
for 1-sided tests 
(NASH CRN fibrosis score) and 
no worsening of steatohepatitis 
(defined as no increase in NAS for 
ballooning, inflammation, or 
steatosis). 
10 
Proportion of subjects experiencing resolution of 
steatohepatitis and no worsening of liver fibrosis 
(by NASH CRN fibrosis score). Resolution of 
steatohepatitis is defined as absence of fatty liver 
disease or isolated or simple steatosis without 
steatohepatitis and a NAS of 0 or 1 for 
inflammation, 0 for ballooning, and any value for 
steatosis at Week 52. 
1-sided 
Higher 
11 
Proportion of subjects with histological 
improvement (decrease) at Week 52 in NAS by 
≥1 point.  
1-sided 
Higher 
12 
Proportion of subjects with histological 
improvement (decrease) at Week 52 in NAS by 
≥2 points.  
1-sided 
Higher 
13 
Change and percent change from Baseline in 
MRI-PDFF liver fat (%) at Week 26. 
2-sided 
 
14 
Change and percent change from Baseline in 
MRI-PDFF liver fat (%) at Week 52. 
2-sided 
 
15 
Proportion of subjects with NASH resolution 
(defined as absence of fatty liver disease or 
isolated or simple steatosis without steatohepatitis 
and a NAS of 0 or 1 for inflammation, 0 for 
ballooning, and any value for steatosis) at 52 
weeks. 
1-sided 
Higher 
16 
Change from Baseline in ALT, AST, ALP, and 
GGT at Weeks 26 and 52 and at each study visit. 
2-sided 
 
17 
Change from Baseline in LDL-C and other lipid 
levels (including LDL/HDL ratio) at Weeks 26 
and 52 and at each study visit. 
2-sided 
 


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Endpoint 
Number 
 
Endpoint Description 
1-sided 
or  
2-sided 
Directionality for 
better outcome 
for 1-sided tests 
18 
Change from Baseline in collagen/fibrous area 
and fibrosis score, assessed by digital pathology, 
at Week 52. 
1-sided 
Lower 
19 
Changes from Baseline in metabolic parameters, 
including fasting insulin, fasting glucose, 
HOMA-IR, adipo-IR, and HbA1c levels at 
Weeks 26 and 52 and at each study visit. 
2-sided 
 
20 
Change from Baseline in FGF-21, adiponectin, 
and other NASH biomarker levels at Weeks 26 
and 52 and at each study visit. 
2-sided 
 
21 
Change from Baseline in FibroScan (Liver 
Stiffness Measure (kPa)) and CAP score results at 
Weeks 26 and 52. 
1-sided 
Lower 
22 
Change from Baseline in PRO-C3 and other 
fibrosis biomarkers at Weeks 4, 13, 26, and 52. 
2-sided 
 
23 
Change from Baseline in ELF score at Weeks 26 
and 52. 
2-sided 
 
24 
Plasma concentrations of TVB-2640 at Weeks 1, 
4, 13, 26, and 52. 
N/A 
 
 
Exploratory Efficacy and Pharmacodynamic 
Endpoints 
 
 
25 
Proportion of MRI-PDFF ≥30% responders at 
Week 52 who have ≥17 U/L reduction in ALT.  
2-sided 
 
26 
Change from Baseline in FAST score at Weeks 
26 and 52. 
1-sided 
Lower 
27 
Change from Baseline in Agile 3+ score at 
Weeks 26 and 52. 
1-sided 
Lower 
28 
Change from Baseline in levels of select fibrosis 
biomarkers (e.g., TIMP-1) at Weeks 4, 13, 26, 
and 52. 
2-sided 
 


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Endpoint 
Number 
 
Endpoint Description 
1-sided 
or  
2-sided 
Directionality for 
better outcome 
for 1-sided tests 
29 
Change from Baseline in levels of 
lipidomic/metabolomic biomarkers (e.g., 
tripalmitin, ceramides, bile acids, diacylglycerols, 
and other classes of metabolites) at Weeks 4, 13, 
26, and 52. 
2-sided 
 
30 
Change from Baseline in HbA1c levels among 
subjects with T2DM at Weeks 13, 26, 39, and 52.  
2-sided 
 
31 
Change from Baseline in FIB-4 at Weeks 4, 13, 
26, and 52. 
2-sided 
 
32 
Change from Baseline in additional fibrosis 
parameters such as zonal analyses of fibrosis, 
NAS, and individual NAS components as 
determined by digital pathology at Week 52.  
N/A* 
 
33 
Correlation of changes in MRI-PDFF with 
changes in other endpoints. 
N/A* 
 
34 
Presence or absence of SNPs relevant for NASH. 
N/A 
 
35 
Correlation of predictive signature with other 
endpoints. 
N/A* 
 
36 
Correlation of lipids (e.g. tripalmitin) with other 
endpoints. 
N/A* 
 
37 
Change from Baseline in gut microbiome 
analyses at Weeks 26 and 52 in a substudy of 
subjects. 
N/A* 
 
38 
Change from Baseline in HepVita Nutritional 
Survey at Weeks 26 and 52 in a substudy of 
subjects. 
N/A* 
 
39 
Change in MELD score from baseline to Week 
52 
1-sided  
Lower 
* These endpoints may be analyzed at a later date. 


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7.5. Reference Dates 
− Screening date is defined as the electronic case report form (eCRF) provided date on 
which a subject was screened for study entry. 
− Randomization date is defined as the date on which the subject is randomized to study 
treatment. 
− Treatment start date is defined as the date of first dose of study drug (also referred to as 
Day 1). 
− Treatment end date is defined as the date of last dose of study drug. 
− The calculation of age will use the informed consent date as its reference date. 
− Safety data, such as AEs and laboratory assessments will use the treatment start date as a 
reference date to assign treatment emergence. 
− Study day will be based on treatment start date as a reference date. 
Reference day calculations will be defined as:  
− date of interest – reference date + 1 when the date of interest ≥ reference date. 
− otherwise, date of interest – reference date. 
 
For example, duration of treatment is defined as treatment end date – treatment start date + 1.   
If either date is missing, reference date calculations will not be performed.   
7.6. Baseline and Post-Baseline Changes 
Unless stated otherwise, baseline will be based on the last non-missing value collected prior to 
the start of study treatment based on the treatment start date and time, if applicable.  Post-
baseline values will be those collected after the treatment start date and time, if applicable.   
Change from baseline is defined as: post-baseline value – baseline value. 
Percentage change from baseline is defined as: (post-baseline value – baseline value)/baseline 
value x 100%. 
7.7. Handling Below Limit of Quantification (BLQ) or Lower Limit of Quantification 
(LLOQ) Values 
Any parameters with values identified as <x, ≤x, >x, or ≥x will be analyzed using the ‘x’ value 
(the analysis will ignore the <, ≤, >, or ≥ symbol). 
7.8. Imputation of Partial Dates 
Imputed dates will be used to classify treatment emergent AEs (TEAEs) and prior and 
concomitant medications. 


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Adverse Events  
− If the AE start date is completely missing the event will be assumed to have started on the 
first day of treatment and will be considered a TEAE. If a subject was not treated, then no 
imputation will be conducted for missing start dates. 
− If the AE start date is missing day and month, do the following: 
o If the AE start year is the same year as that of the first treatment and the AE 
contains information to indicate that the event ended before the treatment start 
date (e.g., AE end date month and year are earlier than the treatment start date or 
the full AE end date is known and occurs earlier than the treatment start date), 
then set the AE day/month to ‘1 January’. 
o If the AE start year is the same as that of the first treatment and the AE contains 
information to indicate that the event ended after the treatment start date, then set 
the AE start day/month to the treatment start day/month 
o If the AE start year is later than that of the first treatment, then set the AE start 
day/month to ‘1 January.’ 
o If the AE start year falls before that of the first treatment, then the AE start 
day/month will not be imputed. 
− If only the AE start day is missing, do the following: 
o If the AE start year is the same year as that of the first treatment and the AE 
month is prior to the first treatment date, then set the AE day to ‘1’.  
o If the AE start month/year are the same as that of the first treatment and the AE 
contains information to indicate that the event ended before the treatment start 
date (e.g., the full AE end date is known and occurs earlier than the treatment start 
date), then set the AE day to ‘1’. 
o If the AE start month/year are the same as the first treatment and the AE end date 
is after the treatment start date, then set the AE day to the same day as treatment 
start day. 
o If the AE start year is the same as that of the first treatment and the AE start 
month is after the first treatment, or the AE start year is later than that of the first 
treatment, then set AE day to ‘1’. 
− AE end dates will not be imputed.  
Prior and Concomitant Medications 
− The imputation rules for AE start dates will be used for prior and concomitant medication 
start dates. 
− Prior and concomitant medication stop dates will be imputed as follows: 
o If the stop date is only missing the day, then the stop day is the last day of the 
month 
o If the stop date is missing both the day and month, then the stop month and day is 
December 31 


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o If the stop date is completely missing, no imputation is performed, and the 
medication will be classified as a concomitant medication for subjects who were 
treated. 
7.9. Multiple Assessments and Visit Windows 
Nominal visits (e.g., those identified by the study eCRF) will be the basis of summarization and 
statistical analysis; no visit date windowing will be conducted. Unless specified otherwise, data 
from unscheduled visits will be included in: (1) summaries of most extreme and baseline data, 
(2) summaries of specific abnormalities at any time post-baseline, (3) adverse events and any 
other summaries not based on study visit, (4) subject data listings, and (5) analyses that utilize 
MRI-PDFF, PK, lipidomic/metabolic biomarkers, collagen/fibrous area and fibrosis score 
assessed by digital pathology, SNPs relevant for NASH, and PRO-C3 data where unscheduled 
visit results may be used in analyses at the closest scheduled visit; if the closest scheduled visit 
already has valid MRI-PDFF data then the unscheduled visit results will not be used in the 
analysis. 
7.10. 
Handling of Early Termination Visit Information  
If a subject is terminated early from this study the early termination visit data will be analyzed at 
the closest scheduled visit. If the closest visit has valid data, the early termination data will be 
assigned to the next available visit. 
7.11. 
Missing Data 
Imputation will only be performed on the primary and selected secondary efficacy endpoints 
based on histological and MRI-PDFF data.  Imputed data will be analyzed using both the ITT 
and mITT populations. 
For the primary efficacy endpoint and secondary efficacy endpoints based on histology, a subject 
who discontinued treatment prior to Week 42, does not provide a histological assessment on or 
after Week 42, or who otherwise has missing data will be considered a non-responder. A pre-
specified sensitivity analysis of the primary efficacy endpoint will employ the multiple 
imputation technique. 
For the secondary endpoint MRI-PDFF ≥ 30% responder analysis at Week 26, a subject who 
discontinued treatment prior to Week 20, does not provide an MRI-PDFF assessment between 
Week 20 through Week 27, or who otherwise has missing data will be considered a non-
responder. For analysis of MRI-PDFF, missing data at Week 26 will be imputed using the last 
post-baseline observation obtained at least 20 weeks to 27 weeks after the first dose.  For the 
MRI-PDFF ≥ 30% responder analysis at Week 52, a subject who discontinued treatment prior to 
Week 42, does not provide an MRI-PDFF assessment after Week 42 or who otherwise has 
missing data will be considered a non-responder. Missing data at Week 52 will be imputed using 
the last post-baseline observation obtained at least 42 weeks after the first dose.  These missing 
data techniques will also be applied to MRI-PDFF ≥ 50% responder analyses. 


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 Additional details are provided in the relevant analysis sections below. 
8. STUDY SUBJECT DATA 
8.1. Subject Disposition 
Summaries of analysis population membership, final subject status (completed or withdrawn), 
including reasons for withdrawal, sub study participation, and study duration in days will be 
produced based on the number of randomized subjects. The number of subjects screened will be 
provided. Data will be presented by treatment group as well as overall for the study, with 
exception of the number of screen failures (to be displayed without respect to treatment). 
Screen failures, analysis populations, and final subject disposition status will be listed. 
8.2. Protocol Deviations 
Protocol deviations will be identified and classified as important or not important. Important 
protocol deviations may include but are not limited to: 
• Violation of Inclusion/Exclusion Criteria 
• Study drug compliance ≤ 80% or ≥ 120% 
• Use of prohibited therapies 
• Incorrect treatment 
Protocol deviations including category will be summarized by treatment group and overall for 
the study.  Protocol deviations due to COVID impact will be identified as such. 
A listing of all protocol deviations will be provided. 
8.3. Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized and listed.  Data will be 
presented by treatment group as well as overall for the study.   
Demographic and baseline characteristics summaries will be provided for the ITT population, 
mITT population, safety population, and Serial PK population.  
8.4. NASH History 
Subject NASH history will be summarized and listed.  Days since biopsy, fibrosis stage, NAS, 
Steatosis score, ballooning degeneration score, lobular inflammation score, Fibrosis-4 (FIB-4) 
Score, and MRI-PDFF. 
NASH history summaries will be provided for the ITT population, mITT population, safety 
population, Serial PK population. NASH history will also be summarized for T2DM vs not 
T2DM. 
NASH confirmation data collected at screening will be presented in a data listing. 


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8.5. Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0 or higher for reporting by system organ class (SOC) and preferred term (PT). 
Medical history data will be presented in a listing. 
8.6. Prior and Concomitant Medication  
The incidence of medication use will be summarized by WHO Drug Dictionary, Global B3 
Mar2021 or higher, anatomic therapeutic class (ATC) Level 2 classification (i.e., therapeutic 
main group) and preferred name. A subject will be counted only once at each level of reporting.  
Prior medications are medications that have been discontinued prior to the treatment start date 
(e.g., taken exclusively during the pre-therapy period).  Concomitant medications are 
medications taken at any point during the on-therapy or post-therapy periods. Subjects could start 
a concomitant medication prior to study start which is ongoing at time of first treatment or 
subjects could start a new medication during the on-therapy or post-therapy periods.   
Concomitant medication use will be summarized separately and presented by treatment group for 
the ITT population.  
All prior and concomitant medication data will be listed including the verbatim and preferred 
drug name and ATC Level 2. 
8.7.  Study Drug Exposure and Compliance 
Duration of drug exposure will be summarized both as a continuous and a categorical variable 
for the safety population.  Exposure will be calculated as: 
study drug stop date – study drug start date + 1 [converted to weeks (days divided by 7)] 
Categories for reporting exposure will include < 13 weeks; 13 weeks - < 26 weeks; 26 weeks - 
<39 weeks; 39 weeks - < 52 weeks; ≥ 52 weeks. 
Drug accountability is captured in the eCRF at each visit. The eCRF captures the number of pills 
returned and the number missed during the dosing period. Overall compliance will be determined 
based on pill counts over each visit period and taking into account the number missed. 
Compliance will be derived as:  
[(# of pills dispensed - # of pills returned) - # of missed pills] x 100 
2 x (number of days within the visit period) 
Where number of days within the visit period is derived as: 
Date of Visit (X+1) – Date of Visit (X) + 1 


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Compliance will also be summarized for the following categories < 80%, 80% - 120%, and > 
120%.  
Mean daily dose (mg) and total cumulative dose (mg) received will also be summarized.  Total 
cumulative dose will be summarized overall and separately for those that had extended dosing. 
Listings of planned and actual treatments, overall compliance, and drug exposure will be 
produced.  
9.  EFFICACY  
9.1. Primary Efficacy Endpoint Analyses 
9.1.1. Principal Analysis of the Primary Efficacy Endpoints 
The principal efficacy analyses will be conducted on the ITT population. Additional sensitivity 
and supplementary analyses will be performed for the primary efficacy endpoints, as described in 
the next section.   
The treatment groups will be compared based on the primary efficacy endpoints using one-sided 
Cochran-Mantel-Haenszel (CMH) tests stratified by the randomization stratifications T2DM 
status at baseline (yes or no) and amount of fibrosis at baseline (F2 or F3).  
Mathematically, the null and alternative hypotheses for the primary efficacy endpoints are stated 
as: 
Ho: pT ≤ pp 
Ha: pT > pp 
Where, pT is the proportion of responders in the TVB-2640 50-mg treatment group and pp is the 
proportion of responders in the placebo treatment group. The higher responder proportion is a 
better outcome. 
A Clopper-Pearson 90% and 95% CI will be derived for each treatment group, and the stratified 
CMH odds ratio (with its 90% and 95% CI, using the control group as a reference group) will be 
produced to assess the treatment effect magnitude. The difference in treatment groups response 
rates will be provided and also be characterized by the 90% and 95% CIs using Miettinen and 
Nurminen (1985). 
Subgroup analyses of the primary efficacy endpoints will be performed to assess whether the 
treatment effect is concordant among subgroups. The planned subgroup analyses are described in 
Section 7.2. Analyses will be performed if there is an adequate number of subjects in each 
subgroup. 
A subject who discontinues treatment prior to Week 42, does not provide a histological 
assessment on or after Week 42, or who otherwise has missing data will be considered a non-
responder.  


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9.1.2. Sensitivity Analyses of the Primary Efficacy Endpoints 
Evaluation of the robustness of the principal analysis of the primary efficacy endpoints will be 
carried out using the following (4) four approaches: 
o A logistic regression with response as a dependent variable; treatment group, 
randomization stratification factors (T2DM status at baseline [yes or no] and 
amount of fibrosis at baseline [F2 or F3]) as independent factors; and age as a 
baseline covariate.  
o The analysis of the primary efficacy endpoints will be repeated for the modified 
Intention-to-Treat (mITT) population to ascertain any changes in the conclusion 
of the principal analysis findings.   
o A repeat of the primary efficacy analysis principal analysis (CMH test) for the 
following three ITT subsets: 
▪ ITT Subjects who achieve at least 50% of total cumulative study drug dose 
(i.e., at least 9100 mg 52-week total dose (based on a total of 50 mg.kg x 
52 weeks x 7 days = 18200 mg x weeks x days). 
▪ ITT Subjects who achieve at least 70% of total cumulative study drug dose 
(i.e., at least 12740 mg 52-week total dose (based on a total of 50 mg x 52 
weeks x 7 days = 18200 mg x weeks x days). 
▪ ITT Subjects who achieve at least 80% of total cumulative study drug dose 
(i.e., at least 14560 mg 52-week total dose (based on a total of 50 mg.kg x 
52 weeks x 7 days = 18200 mg x weeks x days). 
o  To assess the impact of missing data in the primary endpoint analyses, multiple 
imputation procedure will be carried out using MAR assumption with Fully 
Conditional Specification method for binary endpoint in SAS PROC MI. 100 
imputations will be performed. The CMH test statistic from each imputed dataset 
will be based on Wilson-Hilferty transformation (Wilson & Hilferty, 1931) and 
will be combined using PROC MIANALYZE. Combined CMH test statistic and 
p-value will be computed. The method described in Ratitch, Lipkovich, and 
O’Kelly (2013) will be used to combine the results. 
9.2. Secondary Efficacy Endpoints and Analyses 
Secondary efficacy analyses for the other histological responder endpoints will be analyzed in 
the ITT and mITT populations using the methods described for the primary efficacy endpoint. 
 
Secondary efficacy analyses of endpoints expressed as percent change or change from Baseline 
only at Week 26 or only at Week 52 will be analyzed in the ITT analysis set using an analysis of 
covariance (ANCOVA) model with fixed effects for T2DM status at baseline (Yes, No) and 
treatment group, and a covariate term for baseline analysis value of response. Least squares (LS) 
means for the percent change from Baseline by treatment and the associated standard errors, the 


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LS means for the difference between treatment groups, and the associated two-sided 95% CIs 
and two-sided p-values, based on t-tests, will be derived from the ANCOVA model.   
For secondary endpoints assessed at multiple visits, a linear mixed-effects model for repeated 
measures (MMRM) may be used.  The model will include T2DM status at baseline (Yes, No), 
treatment group, visit, and treatment-by-visit interaction as the fixed effects, and baseline value 
as a covariate, and the model will use an unstructured variance-covariance matrix. The point 
estimates for the least-squares mean of the difference treatment groups at each visit and the 
corresponding 95% confidence interval and two-sided p-value will be summarized. If 
convergence problems arise when fitting the model, a spatial power covariance structure will be 
used as a first step. If the model still has convergence issues, compound symmetry covariance 
structure will be employed. The Kenward-Roger correction for the denominator degrees of 
freedom will be applied.   
ALT, AST. ALP, and GGT will also be summarized in shift tables of baseline to each visit based 
on range categories of low (below lower limit of normal [LLN], normal, and high [above upper 
limit of normal [ULN]). 
The continuous digital pathology variables (qFibrosis, qSteatosis, and Steatosis corrected 
qFibrosis) will be summarized descriptively with change from baseline being analyzed using 
MMRM methods. Digital pathology stage/grade variables (qFibrosis – stage, qSteatosis – grade, 
and Steatosis corrected qFibrosis – stage) will be summarized descriptively with change from 
baseline being analyzed using ANCOVA methods. The ANCOVA models will include fixed 
effects for treatment group, T2DM status at baseline (Yes, No), and amount of fibrosis at 
baseline (F2 or F3), and baseline value as a covariate.  Shifts in stage from baseline to each visit 
will also be presented.  The shifts will include decrease in stage, no change in stage, and increase 
in stage.  The shifts will be compared between treatment groups using a CMH-row mean scores 
test. 
Graphical display for selected secondary endpoints will be provided. 
9.3. Exploratory Efficacy Endpoints Analyses 
Analysis of exploratory endpoints will be based on the ITT and mITT populations. Exploratory 
efficacy endpoints expressed as a proportion will be analyzed using the methods described for 
the primary efficacy endpoint. While the endpoints expressed as change from baseline and 
percent change from baseline will be analyzed using descriptive summary statistics and with 
ANCOVA or MMRM at a later date, if warranted.   
9.4. Pharmacokinetics (PK)  
All PK analyses will be described in a separate PK analysis plan.  PK concentration data will be 
listed. 


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10. SAFETY  
Safety will be evaluated based on data collected for adverse events, vital signs, physical 
examinations, electrocardiogram (ECG), ophthalmologic examinations, and laboratory data. No 
formal statistical testing will be conducted for the safety analyses. Descriptive statistics will be 
used to evaluate safety data in this study. Summaries will be presented by treatment group. 
All safety analysis reporting will be based on the Safety population. All safety data will be listed 
by treatment group and subject. 
10.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of an investigational product, whether related to the investigational product or not. 
An unexpected AE is any event for which the nature or severity is not consistent with the 
information in the current Investigator’s Brochure. 
Any abnormal clinical or laboratory finding considered by the Investigator to be clinically 
significant is to be recorded in the eCRF as part of the subject’s medical history if occurring 
prior to the start of study drug administration and as an AE if occurring after the start of study 
drug administration at baseline, where the finding represents a change from baseline. 
A treatment emergent AE (TEAE) is defined as any AE occurring after the first dose of study 
treatment. All summaries of AEs will be based on TEAEs. All AEs recorded on the eCRF, 
whether treatment emergent or not, will be presented in the data listing. Non-TEAEs will be 
flagged in the listings. 
Adverse Events will be coded using MedDRA version 24.0 or higher for reporting by SOC and 
PT. Summaries of TEAEs by SOC and PT will be presented in descending order of overall 
incidence. TEAEs will also be summarized by maximum intensity as classified according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), 
Version 5.0 (or higher). If the AE is not included in the NCI CTCAE, then the Investigator is to 
determine the severity of the AE according to the criteria provided in the study protocol.  
The causal relationship of each AE to study drug will be determined by the Investigator 
according to best medical judgment as definitely related, probably related, possibly related, 
unlikely related, or unrelated. If the relationship between the AE and study drug is determined to 


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be “possible”, “probable”, or “definite”, the event will be considered treatment-related for the 
safety analyses. 
Missing severity assessments will be listed as missing information. Missing relationship 
assessments will also be listed as missing information. All AE summaries will be produced using 
the safety population and displayed by treatment group and overall.  
An overview of TEAEs will be produced, including counts and percentages of subjects with any 
incidences of:  TEAEs, TEAEs related to study treatment, serious adverse events (SAEs), TEAEs 
leading to study drug discontinuation, TEAEs with CTCAE grade 3 or higher, and fatal SAEs. 
The number of AEs will also be included in the summary. 
In addition to the overview of TEAEs, the following summaries of AEs will be provided for the 
safety population by treatment group and overall: 
− TEAEs by SOC and PT 
− TEAEs related to study treatment by SOC and PT  
− CTCAE Grade 3 or higher TEAEs by SOC and PT 
− CTCAE Grade 3 or higher TEAEs related to study treatment by SOC and PT 
− SAEs by SOC and PT 
− TEAEs leading to treatment discontinuation by SOC and PT 
− Skin and subcutaneous tissue disorders TEAEs by PT 
− Eye disorder TEAEs by PT 
Summaries of TEAEs by SOC, PT, and maximum severity as well as TEAEs by SOC, PT, and 
maximum relationship to study treatment will also be prepared. 
Skin and subcutaneous tissue disorders and eye disorder TEAE summaries will also be 
performed for the mITT population. 
A comprehensive listing of all AEs will be provided in a by-subject data listing. In addition, the 
following listings will be provided:  
− TEAEs related to study treatment 
− SAEs 
− TEAEs leading to treatment discontinuation; and 
− Fatal AEs. 
10.2. 
Clinical Laboratory Evaluations 
Clinical chemistry, hematology, coagulation, and urinalysis parameters will be reported based on 
conventional units as applicable. The following laboratory evaluations will be reported in data 
summaries: 


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− Chemistry: Chloride, Sodium, Blood urea nitrogen, Creatinine, Albumin, Total protein, 
AST, GGT, Total bilirubin, Indirect and direct bilirubin, Carbon dioxide, Potassium, 
Calcium, Magnesium, Glucose, Alkaline phosphatase, ALT, Creatine phosphokinase 
(total and fractionated) (screening and baseline only). Note that AST and ALT collected 
as part of the clinical chemistry panel are also applicable for efficacy assessments. 
− Hematology: Hematocrit, Hemoglobin, Red blood cell count, MCV, Platelet count, White 
blood cell count with differential, Absolute neutrophil count, MCHC. 
− Coagulation Studies: Prothrombin time, Fibrinogen, Activated partial thromboplastin 
time, international normalized ratio (INR). 
− Urinalysis: Specific gravity, Protein, pH, Ketones, Blood, Microscopic examination of 
sediment, Glucose. 
Observed values and changes from baseline for laboratory evaluations will be summarized at 
each visit and will also include the most extreme change from baseline. The percent change from 
baseline at each visit and the most extreme percent change from baseline will also be 
summarized. Select laboratories mean change from baseline by study visit will be depicted 
graphically in a longitudinal line plot with standard error of the mean. 
Laboratory data will also be summarized in shift tables of baseline to most extreme change based 
on range categories of low (below lower limit of normal [LLN], normal, and high [above upper 
limit of normal [ULN]). Urinalysis results and shifts will be based on the categories present in 
the data. 
10.3. 
Vital Signs 
Vital signs include oral temperature, pulse (bpm), systolic and diastolic blood pressure (mmHg), 
and respiration rate (breaths/minute). Note that systolic and diastolic blood pressure will be 
summarized with the other anthropometric parameters. Observed values and changes from 
baseline for vital signs will be summarized at each visit and time point, as well as for most 
extreme change from baseline. 
10.4. 
Electrocardiogram (ECG) 
Electrocardiogram (ECG) parameters include HR (bpm), PR (ms), QRS (ms), QT (ms), QTcF 
(ms), and RR interval (ms). Observed values and changes from baseline for ECG parameters will 
be summarized by treatment group at each visit and time point.  
Investigator reported ECG result will be tabulated by visit and worst-case post-baseline. In 
addition, the shifts from baseline to each visit and worst-case post-baseline will be summarized.  
Worst case post-baseline will be based on the worst observed value on or after the treatment start 
date. Categories will include within normal limits, abnormal without clinical significance, and 
abnormal with clinical significance. 


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10.5. 
Ophthalmologic Examinations  
The proportion of subjects experiencing ophthalmologic abnormalities will be tabulated by visit 
and by treatment group. The clinical interpretation of the ophthalmologic examination will be 
tabulated as normal or abnormal. The worst-case post-baseline will also be summarized. 
10.6. 
Physical Examinations 
Physical examination results will be presented in subject data listings. 
11. CHANGES TO THE PLANNED ANALYSES 
The following changes were made to analyses specified in the protocol. Any additional changes 
to the planned analyses as detailed in this SAP will be described in the CSR. 
• Co-primary objectives and endpoints were added. 
• Added ‘To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo 
on resolution of steatohepatitis and no worsening of liver fibrosis (by NASH CRN 
fibrosis score). Resolution of steatohepatitis is defined as absence of fatty liver disease or 
isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 
0 for ballooning, and any value for steatosis at Week 52.’ as a secondary objective and 
endpoint. 
• 
Added ‘To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo 
on histological improvement (decrease) at Week 52 in NAS by ≥2 points.’ as a secondary 
objective and endpoint.   
• 
Removed ‘To evaluate the effect of TVB-2640 50 mg QD compared with matching placebo on 
fibrosis as assessed by ≥1 stage of fibrosis improvement by NASH CRN score without worsening 
of NAS (defined as no increase in any component of NAS) at Week 52.’ as a secondary objective 
and endpoint. 
• Added proportion of MRI-PDFF ≥50% responders, MELD, and Agile3+ endpoints. 
• Region (North America or not North America) was removed as an effect in all analyses. 
 
 


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12. REFERENCES 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use.  ICH Harmonized Tripartite Guideline: Structure and content 
of clinical study reports E3. Step 4. 1995. 
https://database.ich.org/sites/default/files/E3_Guideline.pdf 
Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, D’Amico G, 
Dickson ER, Kim WR. (2001); A model to predict survival in patients with end-stage liver 
disease. Hepatology; 33:464-470.   
https://doi.org/10.1053/jhep.2001.22172 
Miettinen OS, Nurminen M. (1985); Comparative analysis of two rates. Statistics in Medicine 4, 
213-226.  
Ratitch B, Lipkovich I, O’Kelly M. Combining analysis results from multiply imputed 
categorical data. PharmaSUG Conference Proceedings 2013; Paper SP03. 
Sanyal AJ, Foucquier J, Younossi ZM, Harrison SA, Newsome PN, Chan W-K, Yilmaz Y, De 
Ledinghen V, Costentin C, Zheng M-H, Wong VW, Elkhashab M, Huss RS, Myers RP, Roux M, 
Labourdette A, Destro M, Fournier-Poizat C, Miette V, Sandrin L, Boursier J. (2023); Enhanced 
diagnosis of advanced fibrosis and cirrhosis in individuals with NAFLD using FibroScan-based 
Agile scores. J Hepatol. 2023 February; 78(2): 247–259. 
https://doi.org/10.1016/j.jhep.2022.10.034