Conditions: MASLD/MASH (Metabolic Dysfunction-Associated Steatotic Liver Disease / Metabolic Dysfunction-Associated Steatohepatitis)
Keywords: NASH Non-Alcoholic Steatohepatitis Fatty Liver Disease Fatty Liver Liver Diseases FASN Fatty Acid Synthase Inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 142
Healthy volunteers: no

Brief summary:
This is a Phase 2 multi-center, randomized, single-blind, placebo-controlled study to evaluate the safety and efficacy of TVB-2640 in subjects with non-alcoholic steatohepatitis (NASH), a type of fatty liver disease. Subjects will be randomly assigned to 1 of 2 treatment groups (TVB-2640 at one of three doses or placebo). Following randomization, subjects will begin the 12-week treatment period and will receive once daily TVB-2640 or placebo.

Detailed description:

Arms:
arm 1: Subjects randomly assigned to receive the study drug will take TVB-2640 tablet orally every day for 12 week treatment period. The dose is to be taken at the same time of the day, with each dose separated by 24 hours (±4 hours). arm 2: Subjects randomly assigned to receive the study drug will take TVB-2640 tablet orally every day for 12 week treatment period. The dose is to be taken at the same time of the day, with each dose separated by 24 hours (±4 hours). arm 3: Subjects randomly assigned to placebo will receive placebo tablets orally once a day under the same conditions and frequency as described for TVB-2640. arm 4: Subjects randomly assigned to receive the study drug will take TVB-2640 tablet orally every day for 12 week treatment period. The dose is to be taken at the same time of the day, with each dose separated by 24 hours (±4 hours). arm 5: Subjects randomly assigned to placebo will receive placebo tablets orally once a day under the same conditions and frequency as described for TVB-2640. arm 6: After completion of Cohorts 1 and 2, and if no stopping criteria are met upon review by the Independent SRC, an additional TVB-2640 75 mg open-label Cohort 3 will open in the US

Interventions: intervention 1: TVB-2640 25 mg (US) intervention 2: TVB-2640 50 mg (US) intervention 3: Placebo (US) intervention 4: TVB-2640 50 mg (China) intervention 5: Placebo (China) intervention 6: TVB-2640 75 mg (US)
Intervention descriptions: intervention 1: Oral dose, tablet, daily dosing intervention 2: Oral dose, tablet, daily dosing intervention 3: Oral dose, tablet, daily dosing intervention 4: Oral dose, tablet, daily dosing intervention 5: Oral dose, tablet, daily dosing intervention 6: Oral dose, tablet, daily dosing

Protocol document:
Prot_000.pdf: 
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1. 
TITLE PAGE 
 
PROTOCOL 3V2640-CLIN-005 
A PHASE 2, MULTI-CENTER, SINGLE-BLIND, 
RANDOMIZED, PLACEBO CONTROLLED STUDY OF 
TVB-2640 IN SUBJECTS WITH NON-ALCOHOLIC 
STEATOHEPATITIS 
IND Number: 
138506 
Protocol Version: 
7.0 (US Only) 
Date: 
17 March 2021 
Replaces Version: 
6.0 (Amendment 5) (US Only), 29 April 
2020 
Sagimet Biosciences 
 
 
 
 
 


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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 3V2640-CLIN-005 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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Table 1 
Emergency Contact Information 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Serious Adverse Event 
(SAE) Reporting
SAEs are to be reported within 24 hours of discovery via the electronic data 
capture (EDC) system.
 


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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 2, Multi-Center, Single-Blind, Randomized, Placebo-Controlled Study of TVB-2640 in 
Subjects With Non-Alcoholic Steatohepatitis 
Study center(s): 
Coordinating Investigator: 
This study will be conducted at approximately 15 study centers in the United States (US) and China. 
The Coordinating Investigator is Rohit Loomba, MD, University of California, San Diego, CA. 
Studied period (years):  
Estimated date first subject enrolled: April 2019 
Estimated date last subject completed: August 2021 
Phase of development:  
2 
Objectives:   
Primary: 
 
To determine the effect of once daily (QD) TVB-2640 for 12 weeks versus placebo on the 
change in hepatic fat fraction by proton density fat fraction magnetic resonance imaging 
(MRI-PDFF) from baseline in subjects with non-alcoholic steatohepatitis (NASH). 
 
To determine the safety of QD TVB-2640 versus placebo in subjects with NASH, including 
the effects on alanine aminotransferase (ALT) and aspartate aminotransferase (AST). 
Secondary: 
 
To determine the effect of once-daily (QD) TVB-2640 for 12 weeks versus placebo in 
subjects with NASH on: 
- Lipid and lipoprotein parameters, including low-density lipoprotein cholesterol (LDL-C), 
non-LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, 
triglycerides, apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) particles. 
- NASH and fibrosis biomarkers including cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and 
enhanced liver function (ELF) or FIBROSpect 2 or ProC3 test. 
- Eicosanoid panel. 
Exploratory: 
 
To determine the effect of QD TVB-2640 for 12 weeks versus placebo in subjects NASH on 
clinical measures, including: 
- Liver fibrosis, as determined by vibration-controlled transient elastography (VCTE). 
- Metabolic and inflammatory parameters, including fasting glucose, insulin, homeostatic 
model assessment insulin resistance (HOMA2-IR), glycated hemoglobin (HbA1c), non-


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esterified fatty acid (NEFA), adipose tissue insulin resistance (adipo-IR), adiponectin, 
resistin, Interleukin 6 (IL-6), and gamma-glutamyl transpeptidase (GGT). 
- Anthropometric parameters, including weight, waist and hip circumference, waist-hip 
ratio, and blood pressure. 
- Lipidomic analyses for de novo lipogenesis (DNL). 
 
Explore the relationship of plasma drug exposure to changes in efficacy and safety 
biomarkers. 
 
Explore possible relationships between genomic markers of NASH and responses to 
treatment. 
Methodology:  
This is a multi-center, randomized, single-blind, placebo-controlled, dose-escalation study to evaluate 
the safety and efficacy of TVB-2640 in subjects with NASH. Male and female subjects aged 
≥18 years with either biopsy-proven NASH within 2 years before randomization and MRI-PDFF ≥8% 
or, if prior liver biopsy was not performed or results are not available, magnetic resonance 
elastography (MRE) ≥2.5 kpa and MRI-PDFF ≥8% during screening are planned to be enrolled. 
Approximately 117 unique subjects will be enrolled and randomized, with at least 90 subjects 
enrolled in the US and approximately 27 evaluable subjects (18 active, 9 placebo) enrolled in China. 
In the US, subjects will be enrolled and randomized to achieve 90 evaluable subjects (30 active and 
15 placebo in each of 2 dose cohorts). The 50 mg cohort will enroll and randomize approximately 
27 additional subjects from China. The US-only 75 mg cohort will enroll approximately 12 subjects 
(in order to ensure 10 active, evaluable subjects) who may have previously received placebo in the 25 
or 50 mg cohort. A subject is defined as evaluable if they receive study drug for at least 8 weeks and 
have a baseline and at least 1 post-baseline MRI-PDFF assessment on or after Week 8. 
Subjects will be screened for study eligibility within 60 days before randomization. Subjects must 
meet all of the inclusion criteria and none of the exclusion criteria to participate in the study. Subjects 
who are determined to be eligible for the study, based on screening assessments, are to be randomized 
into the study within 24 hours before baseline (Day 1, the first day of study drug administration). 
Subjects who are randomized are considered to be enrolled in the study. Initially, 2 TVB-2640 dose 
levels are planned to be evaluated in a sequential fashion:  25 mg and, if study suspension criteria are 
not met at the 25 mg dose level (see Section 7.2), 50 mg. At each of the 2 initial dose levels, subjects 
will be randomly assigned to TVB-2640 or placebo at a 2:1 ratio, with randomization stratified by 
type 2 diabetes mellitus status. The 50 mg dose level will also be stratified by country:  
 
Cohort 1, 25 mg dose level:  TVB-2640 (Planned N=30) and Placebo (Planned N=15) 
 
Cohort 2, 50 mg dose level:  US: TVB-2640 (Planned N=30) and Placebo (Planned N=15); 
China: TVB-2640 (Planned N=18) and Placebo (Planned N=9); Total: TVB-2640 (Planned 
N=48) and Placebo (Planned N=24) 
Subjects will receive TVB-2640 or placebo QD PO for 12 weeks, or until the time of the final on-
treatment MRI-PDFF if after Week 12, but for no longer than 16 weeks, with the first dose 
administered on Day 1. During the 12-week Treatment period, subjects are to attend study center 
visits at Week 1, Days 1 and 2, and Weeks 2, 4, 8, and 12. After completion of the 12-week 
Treatment period, subjects are to attend a Follow-up visit at Week 16 for post-treatment safety and 
efficacy assessments. 
All subjects must complete the 12-week treatment period at the 25 mg dose level, with review of all 
safety data and written approval by the Safety Review Committee and reviewed by the Food and 
Drug Administration before enrollment and treatment of subjects at the 50 mg dose level may 
commence.  


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After completion of Cohorts 1 and 2, and again if no stopping criteria are met upon review by the 
Independent Safety Review Committee (SRC), subjects assigned to placebo in either cohort are 
eligible to crossover to receive TVB-2640 75 mg in Open-label Cohort 3 (planned N=12 in order to 
obtain 10 evaluable subjects). Cohort 3 will be conducted at select sites in the US only. 
The Sponsor notes that the coronavirus disease-2019 (COVID-19) pandemic may impact the conduct 
of the 50 mg and 75 mg cohorts, with challenges potentially arising from quarantines and travel 
limitations affecting study subjects as well as clinic and imaging facility closures. Accordingly, safety 
assessments scheduled for the Week 12 and 16 visits, as identified in Table 2, including sample 
collection for clinical laboratory tests, physical examinations, and documentation of adverse events 
(AEs), may be performed at an alternate study center or by home health care visit. Furthermore, if the 
subject is unable to attend the Week 12 visit at the study center, one MRI-PDFF may be performed at 
any time between Week 11 and 16. If this scan is performed after Week 12, the subject must continue 
to receive study drug until the final scan is performed; however, study drug is not to be continued for 
>16 weeks. The safety of subjects who continue dosing beyond 12 weeks will be assessed during this 
continued dosing period by planning for blood sample collection at an alternate site or home visit at 
Week 12 and blood sample collection and physical examination on the last day of dosing. A 4-week 
off treatment safety assessment is to occur after the last dose, regardless of whether a subject receives 
treatment for 12 or 16 weeks. 
In Cohorts 1 and 2 study drug will be dispensed to subjects in a single-blinded fashion. All other 
study personnel, with the exception of personnel conducting/interpreting imaging studies (see 
Section 11.1) at each study center, will be unblinded to the subject’s treatment assignment. In 
Cohort 3, study drug will be dispensed in an open-label fashion. 
In Cohorts 1 and 2, subjects will undergo MRI-PDFF prior to the start of treatment (pre-dose), at the 
end of the initial 12 week Treatment Period (between 11 and 12 weeks after the start of treatment), 
and at Week 16. In accordance with the Food and Drug Administration (FDA) guidance for the 
conduct of clinical trials of medicinal products during the COVID-19 pandemic, if the subject is 
unable to attend the Week 12 visit at the study center, one MRI-PDFF may be performed at any time 
between Week 11 and 16. If this scan is performed after Week 12, the subject must continue to 
receive study drug until the final scan is performed. However, study drug is not to be continued for 
>16 weeks. In Cohort 3, subjects will undergo MRI-PDFF prior to the start of treatment (pre-dose) 
and at the end of the initial 12 week Treatment Period (between 11 and 12 weeks after the start of 
treatment). 
During the study, safety will be assessed by vital signs (oral temperature, pulse, respiratory rate, and 
blood pressure), 12-lead electrocardiogram (ECG), physical examination, including ophthalmologic 
examination, and clinical laboratory testing (hematology, chemistry, and urinalysis). Subjects will be 
evaluated for AEs and concomitant medication use throughout the study.  
Efficacy variables include MRI-PDFF as well as measurement of liver aminotransferases, lipid 
parameters, and markers of NASH and liver fibrosis. The primary efficacy endpoint is percent change 
from baseline in liver fat at Week 12, as determined by MRI-PDFF. The percentage of subjects with 
at least a 30% reduction in the primary efficacy endpoint is a key secondary efficacy endpoint.   
 
 


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Number of subjects (planned):  
Approximately 117 unique subjects will be enrolled and randomized in a 2:1 fashion to TVB-2640 or 
placebo in Cohorts 1 and 2. This includes at least 45 US subjects in the 25 mg cohort, and at least 45 
US subjects and approximately 27 Chinese subjects in the 50 mg cohort. Up to 12 subjects assigned 
to placebo in Cohorts 1 and 2 will be eligible to crossover and receive TVB-2640 75 mg in an open-
label fashion in Cohort 3 in the US.  
Diagnosis and main criteria for inclusion:  
The study population is male and female subjects aged ≥18 years with either biopsy-proven NASH 
within 2 years before randomization and MRI-PDFF ≥8% OR, if prior liver biopsy was not performed 
or results are not available, MRE ≥2.5 kpa and MRI-PDFF ≥8% during screening. 
Note that subjects who initially fail to meet all entrance criteria based on screening assessments (i.e., 
screen failures) may be submitted for re-screening once (see Section 8.5 for details). 
Inclusion Criteria: 
1. Must be willing to participate in the study and provide written informed consent. 
2. Aged ≥18 years with a body mass index (BMI) ≤40 kg/m2. 
3. If a female subject of child-bearing potential, must have a negative serum pregnancy (beta-
human chorionic gonadotropin [β-HCG]) test during screening and is not breastfeeding, does 
not plan to become pregnant during the study, and agrees to use two forms of birth control, 
one being a barrier method (i.e., condoms, diaphragm, non-hormonal intrauterine device 
[IUD]) throughout the study and for at least 3 months after the final study drug dose. 
Hormonal contraception (estrogens stable ≥3 months) and hormonal IUDs are permitted if 
used with a secondary barrier birth control method (e.g., condoms). 
4. If a female subject of non-child-bearing potential, must have documentation of surgical 
sterility (bilateral oophorectomy, hysterectomy, or tubal ligation) or natural sterility 
(>12 consecutive months without menses). 
5. If male, agrees to use adequate birth control throughout the study and for at least 3 months 
after the final study drug dose. 
6. Prior liver biopsy within 24 months of randomization with fibrosis Stage 1 to 3 and a non-
alcoholic fatty liver disease (NAFLD) activity score (NAS) of ≥4 with at least a score of 1 in 
each of the following NAS components: 
 
Steatosis. 
 
Ballooning degeneration. 
 
Lobular inflammation. 
AND 
 
Confirmation of ≥8% liver fat content on MRI-PDFF. 
OR, if prior biopsy is not available: 
 
Either overweight (BMI ≥25 and <30 kg/m2) or obese (BMI ≥30 kg/m2) or diabetic or 
ALT ≥30 U/L for men or ≥19 U/L for women or fatty liver on ultrasound and at least one 
more feature of metabolic syndrome by Adult Treatment Panel III (ATP III) criteria. 
AND 
 
MRE ≥2.5 kpa (Cohorts 1 and 2 only) and MRI-PDFF ≥8% during screening.  
 
 


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For Cohort 3 Only 
7. Subject may have previously participated in this study in Cohort 1 or 2 and is known to have 
received placebo by single-blind treatment assignment. 
Exclusion Criteria 
1. History of significant alcohol consumption for a period of more than 3 consecutive months 
within 1 year prior to screening, as assessed by the Investigator. 
Note: Significant alcohol consumption is defined as average of >20 g/day in female subjects 
and >30 g/day in male subjects. For reference, 14 grams of alcohol are contained in the 
following: 
 
12 fl oz regular beer containing ~5% alcohol. 
 
8-9 fl oz malt liquor containing ~7% alcohol. 
 
5 fl oz of table wine containing ~12% alcohol. 
 
1.5 fl oz of distilled spirits (e.g., gin, rum, vodka, whiskey) containing ~40% alcohol. 
2. Inability to reliably quantify alcohol consumption based upon judgment of the Investigator.  
3. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for 
more than 2 weeks in the year prior to screening. 
4. Weight gain or loss >5% in the 6 months prior to randomization or >10% in the 12 months 
prior to screening. 
5. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y 
gastric bypass). 
6. Type 1 diabetes. 
7. Uncontrolled Type 2 diabetes defined as: 
 
HbA1c ≥9.5% during screening. (Subjects with HbA1c ≥9.5% may be retested during 
screening). 
 
Basal insulin dose adjustment >10% within 60 days prior to enrollment. 
 
Requirement for glucagon-like peptide analogue or a complex oral anti-diabetic (OAD) 
regimen (3 or more OADs) within 6 months of screening. 
 
History of severe hypoglycemia (symptomatic hypoglycemia requiring outside assistance 
to regain normal neurologic status) within the previous year. 
Note: Individual diabetes regimens will be reviewed by Investigator and may be adjusted 
based on American Diabetes Association guidelines. 
8. Presence of cirrhosis on liver biopsy (Stage 4 fibrosis) or imaging (MRE ≥4.67 kpa). 
9. Platelet count <150×109/L. 
10. Clinical evidence of hepatic decompensation as defined by the presence of any of the 
following abnormalities:  
 
Serum albumin ≤3.5 g/dL, 
 
International normalized ratio (INR) ≥1.3 (a single retest is permitted if laboratory error is 
suspected), 
 
Total bilirubin >1.8 mg/dL and/or direct bilirubin >0.8 mg/dL (unless due to Gilbert’s 
syndrome, as documented in the subject’s medical history/records), or 
 
History of esophageal varices, ascites, or hepatic encephalopathy. 


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11. Evidence of other forms of chronic liver disease including the following:  
 
Hepatitis B, as defined by presence of hepatitis B surface antigen (HBsAg) at screening, 
 
Hepatitis C, as defined by presence of hepatitis C virus (HCV) antibody (anti-HCV), and 
HCV ribonucleic acid (RNA). Subjects with positive anti-HCV who test negative for 
HCV RNA at screening will be allowed to participate in the study,  
 
Evidence of ongoing autoimmune liver disease, 
 
Primary biliary cirrhosis, 
 
Primary sclerosing cholangitis, 
 
Wilson’s disease,  
 
Homozygous alpha-1-anti-trypsin deficiency, 
 
History of hemochromatosis or iron overload, 
 
Drug-induced liver disease,  
 
Known bile duct obstruction, 
 
Suspected or proven liver cancer, or 
 
Any other type of liver disease other than NASH. 
12. Serum ALT >5 × the upper limit of normal (ULN). 
13. Liver function tests (ALT/AST) > 5 × ULN at screening. One repeat test may be allowed 
within 7 days at the discretion of the Investigator. 
 
If AST or ALT is > than ULN at screening visit an additional ALT, AST, INR, and total 
bilirubin will be obtained at least 2 weeks after the screening laboratories are obtained. If 
the abnormal parameters increase by > 30% at the retesting visit, the subject may not be 
randomized. The test may then be repeated in 2-4 weeks and if there is no further increase 
in the abnormal laboratory parameter, the subject may be randomized. 
14. Estimated glomerular filtration rate <60 mL/min/1.73 m2, as determined using the 
Modification of Diet in Renal Disease Study equation. 
15. History of biliary diversion.  
16. Positive for human immunodeficiency virus infection. 
17. Active, serious medical disease with likely life expectancy <2 years. 
18. Active substance abuse, including inhaled or injected drugs, within 1 year prior to screening. 
(Note that recreational cannabis/tetrahydrocannabinol use is permissible.) 
19. Use of any excluded medications listed in Section 9.8.1.  
20. Participation in an investigational new drug study in the 30 days prior to randomization (with 
the exception of Cohort 3 in which participants are prior placebo recipients in Cohort 1 and 2 
of this study). 
21. History of clinically significant dry eye (xerophthalmia) or other corneal abnormality or, if a 
contact lens wearer, does not agree to abstain from contact lens use from baseline through the 
last study drug dose. 
22. Evidence of a clinically significant abnormality on slit-lamp examination or other clinically 
significant ophthalmologic finding, as determined by an ophthalmologist. 
23. Known allergy or hypersensitivity to components of TVB-2640. 
24. Prior history of hypersensitivity or drug/radiation-induced or other immune-mediated 
pneumonitis. 
25. Prior history of palmar-plantar erythrodysesthesia syndrome. 


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26. Any contraindication to MRI (e.g., claustrophobia, metal implants). 
27. Positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) polymerase chain 
reaction (PCR) test within 30 days before Baseline, history of hospitalization for COVID-19, 
or history of use of oxygen due to COVID-19. Note that previous COVID-19 infection alone 
is not exclusionary and vaccination against SARS-CoV-2 is allowed, but must be 
documented. 
28. 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 is supplied by the Sponsor as 25 and 50 mg strength tablets. 
Subjects randomly assigned to TVB-2640 will receive study drug PO QD. Each QD dose of study 
drug is to be taken at the same time of day with food; the study drug dose is to be taken in the 
morning on Days 1 to 8 and then in the evening on each day thereafter, with each dose separated by 
24 hours (±4 hours). (The Day 8 and 9 doses will be separated by 36 hours.) 
Duration of treatment:  
Subjects will receive treatment with TVB-2640 or placebo daily for 12 weeks according to their 
cohort and treatment assignment. 
Reference therapy, dosage and mode of administration:  
Subjects randomly assigned to placebo will receive placebo tablets PO QD under the same conditions 
and frequency as described for TVB-2640.  
Criteria for evaluation: 
Efficacy: 
Efficacy variables include hepatic fat fraction by MRI-PDFF (primary) as well as measurement of 
liver aminotransferases, lipid parameters, markers of NASH and liver fibrosis, and an eicosanoid 
panel. Metabolic and anthropometric parameters will be assessed as exploratory measures.  
 
 
 
  
Safety: 
Safety variables to be assessed include safety laboratory tests (hematology, clinical chemistry, and 
urinalysis), vital signs and anthropometrics, 12-lead ECGs, vital sign, physical examination findings, 
including ophthalmologic examination findings, AEs, and concomitant medications. 


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Sample size: 
The sample size is based on a fixed-sequence strategy which tests for a treatment difference in the 
primary endpoint (percent change from baseline in liver fat at Week 12, as determined by MRI-
PDFF) between each randomized TVB-2640 dose group (25 mg and 50 mg) versus placebo. The 
fixed-sequence strategy will start with the highest dose group comparison. If the high dose 
comparison is statistically significant, then testing will proceed to the low dose group comparison. 
Each randomized TVB-2640 dose group will be compared to the pooled placebo group using an F-
test test from an analysis of covariance (ANCOVA) model with fixed effects for diabetes status, 
treatment group, and baseline MRI-PDFF value as a covariate. The non-parametric Wilcoxon rank-
sum test is conservatively used, instead of the F-test, for power calculations. 
The sample size is based on a conservative assumption that the primary analysis is going to be 
performed in the US population only, resulting in 30 evaluable subjects in the placebo group, and 
30 evaluable subjects in each of the randomized TVB-2640 dose levels. Based on Patel (2016), it is 
conservatively assumed that the primary endpoint has a standard deviation of 30. Power calculations 
assume the primary endpoint is lognormally distributed with a standard deviation of 30, there are at 
least 30 evaluable subjects in each treatment group, and the two-sided Wilcoxon rank sum test will be 
used to test each pairwise treatment difference at the 0.05 Type I error level. Under the fixed-
sequence strategy which maintains an overall 0.05 Type I error rate, the study has at least 80% overall 
power to detect both treatment differences (i.e., both high dose [50 mg] versus placebo and low dose 
[25 mg] versus placebo), if each mean treatment difference is at least 24. If the study does not proceed 
to the high-dose level, (i.e., there are 30 evaluable subjects treated with 25 mg TVB-2640 and only 
15 with placebo), then the study has at least 77% power to detect a mean treatment difference of at 
least 24. The study will have more power if the subjects from China are included in the primary 
analysis and the same assumptions of treatment difference and variability hold. 
Statistical methods: 
The modified intent-to-treat population (mITT) is defined as all subjects who are randomized, receive 
study drug for at least 8 weeks, and have a baseline and at least 1 post-baseline MRI-PDFF 
assessment on or after Week 8. The mITT is the primary population for analysis of MRI-PDFF 
assessments. The intent-to-treat population (ITT) is defined as all subjects who are randomized and 
received at least 1 dose of study drug. The ITT will be used for analysis of secondary efficacy 
endpoints and supportive and sensitivity analyses of MRI-PDFF assessments. 
A test for country-by-treatment interaction with respect to the primary efficacy endpoint, percent 
change from baseline in hepatic fat fraction at Week 12, as determined by MRI-PDFF, will be 
performed in the 50 mg cohort. An ANCOVA model with fixed effects for the stratification factor 
(diabetes presence/absence), country (US/China), treatment group (TVB-2640 50 mg and pooled 
placebo), and country-by-treatment interaction and with the baseline MRI-PDFF value as a covariate 
including all subjects from US and China will be performed. If there is no interaction detected 
(p≥0.05), the primary efficacy endpoint will be analyzed using an ANCOVA model with fixed effects 
for the stratification factor (diabetes presence/absence) and treatment group (i.e., randomized 
TVB-2640 dose groups and pooled placebo) and with the baseline MRI-PDFF value as a covariate 
including all subjects from US and China. If the country-by-treatment interaction is significant 
(p<0.05) then the primary analysis will be conducted on US subjects and will maintain sufficient 
power with the 90 evaluable subjects in the US (30 active in each cohort and 30 combined placebo). 
A separate analysis would be performed on subjects from China in the 50 mg cohort. This analysis is 
not powered to detect a significant difference but would be supportive/descriptive in nature to 
evaluate trends. 
The primary efficacy analyses will be based on an F-test from the ANCOVA model in the mITT to 
compare each randomized TVB-2640 dose group individually with the placebo group. The fixed-


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sequence method, as described below, will be used to maintain an overall 0.05 Type I error rate. 
Analyses with transformed data or rank-based methods may be substituted if required to meet model 
assumptions. Summary statistics will be displayed by treatment group along with the difference in 
least squares means (and the associated 95% confidence interval and p-value) for each randomized 
TVB-2640 dose group to pooled placebo comparison. 
Differences between each randomized TVB-2640 dose group (25 mg, 50 mg) and pooled placebo for 
the key secondary efficacy endpoint, the percentage of subjects achieving a 30% or greater reduction 
of liver fat as determined by MRI PDFF (i.e., a response), will be analyzed using Cochran-Mantel-
Haenszel (CMH) methods. The key secondary efficacy analyses will be based on a CMH test in the 
mITT to compare each randomized TVB-2640 dose group with placebo, adjusting for the 
stratification factor (diabetes presence/absence). If a country-by-treatment interaction is found in the 
primary efficacy endpoint, the subjects enrolled in the US and in China in the 50 mg cohort may be 
analyzed separately for the key secondary efficacy endpoint and analysis of the subjects from China 
will be viewed as supportive/descriptive. The estimated response rates and the corresponding exact 
95% confidence interval based on a binomial distribution will be calculated for each treatment group. 
The exact 95% confidence limit for the CMH estimate of the common risk difference will also be 
obtained. 
The primary and key secondary efficacy analyses will be tested using a fixed-sequence strategy to 
maintain the overall Type I error rate at 0.05. Each test in the fixed-sequence, uses a 2-sided test at the 
0.05 level of significance and starts with the primary efficacy analyses. The primary efficacy analyses 
start with a comparison of the highest randomized dose-group (50 mg) to placebo and if statistically 
significant, testing will proceed to the low dose group comparison. If both comparisons of the primary 
efficacy endpoint are significant, then testing will proceed to the key secondary efficacy endpoint. 
The key secondary efficacy analyses similarly start with a comparison of the highest dose-group with 
placebo and if statistically significant, testing will proceed to the low dose group comparison. 
Missing Week 12 values for MRI-PDFF, in the primary and key secondary analyses, will be imputed 
with the last post-baseline observation on or after Week 8 in the mITT. Secondary and sensitivity 
analyses using other methods for missing data and in different analysis populations will be described 
in the Statistical Analysis Plan (SAP). For other continuous secondary efficacy endpoints measured at 
multiple post-baseline visits, the changes at 12 weeks will be summarized for each treatment group 
and compared between each randomized TVB-2640 dose group and pooled placebo using a linear 
mixed-effects model for repeated measures in the ITT. The model will include the stratification factor 
(diabetes presence/absence), treatment group, visit, and treatment-by-visit interaction as the fixed 
effects, and baseline value as a covariate. The point estimates for the least-squares mean of the 
pairwise difference for each randomized TVB-2640 dose group and pooled placebo comparison at 
each visit and the corresponding 95% confidence interval and 2-sided p-value will be summarized. 
Additional details for handling of data from subjects enrolled in the US and in China will be 
described in the SAP. 
Similarly, a generalized linear mixed-effects model for repeated measures based on a logit link 
function will be used for comparing other categorical efficacy endpoints or derived categorical 
response rates for continuous endpoints at 12 weeks between each randomized TVB-2640 dose group 
and pooled placebo group in the ITT. 
No formal statistical testing will be conducted for the safety analyses. 
Data from Cohort 3 will be summarized descriptively. Further details will be provided in the SAP. 
Fewer samples will be collected for potential biomarker assays in the 75 mg cohort, as outlined in the 
Schedule of Events. 
Subset analyses will be performed on all safety and efficacy endpoints for subjects enrolled in China 
to evaluate the consistency of results between subjects enrolled in each country.  


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Schedule of events: 
The schedule of events is presented in Table 2. 


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Table 2 
Schedule of Events 
Evaluation 
 
Study Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening/baseline assessments 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
review 
X 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical and social history 
X 
 
 
 
 
 
 
 
 
Screening/baseline pregnancy test 
X3 
X3 
 
 
 
 
 
 
 
Alcohol breath test or blood 
alcohol test 
X 
X 
 
 
 
 
 
 
 
Confirmation of NASH diagnosis 
X4,5 
 
 
 
 
 
 
 
 
Screening serology 
X6 
 
 
 
 
 
 
 
 
Height, BMI, waist and hip 
circumference, and waist-hip ratio 
X 
 
 
 
 
 
 
 
 
Safety Assessments 
ECG 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
Vital signs8 
X 
X 
 
X 
X 
X 
X 
X 
X 
Complete physical examination 
X 
 
 
 
 
 
X 
X 
 


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Evaluation 
 
Study Visit 
Screening
(Day -60 
to -1) 
Baseline
(Day 1)1 
Day 2 
Week 2 
Week 4 
Week 8 
Week 
122 
Early 
Termin-
ation 
Visit2 
Week 
16 
(Follow-
up 
Visit)2 
Abbreviated physical examination, 
including examination of focused 
liver signs, skin, and extremities 
 
X 
 
X 
X 
X 
 
 
X 
Ophthalmologic examination9 
X 
 
 
X 
X 
X 
X 
X 
Safety Laboratory tests 
 
 
 
 
 
 
 
 
 
Hematology and coagulation 
studies10 
X 
X 
 
X 
X 
X 
X 
X 
X 
Liver aminotransferases11 
X12 
X 
 
X 
X 
X 
X 
X 
X 
Clinical chemistry13 
X 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis14 
X 
X 
 
 
 
 
X 
X 
 
Urine pregnancy testing15 
 
 
 
X 
X 
X 
X 
X 
 
Adverse events 
 
AEs occurring from screening (i.e., after the ICF is signed) through 28 days after the last study drug dose are to 
be documented. 
Prior / concomitant medications 
X 
All medications taken within 28 days prior to the first study drug dose through 28 days after the last study drug 
dose are to be documented. 
Efficacy, PD, and PK assessments 
MRI-PDFF 
X16 
 
 
 
 
 
X17 
X17 
X17 
(Cohorts 1 
& 2 Only) 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
Waist and hip circumference and 
waist-hip ratio 
 
X 
 
 
 
 
X 
X 
 


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Evaluation 
 
Study Visit 
Screening
(Day -60 
to -1) 
Baseline
(Day 1)1 
Day 2 
Week 2 
Week 4 
Week 8 
Week 
122 
Early 
Termin-
ation 
Visit2 
Week 
16 
(Follow-
up 
Visit)2 
MRE (Cohorts 1 and 2 only) 
X16,18 
 
 
 
 
 
 
 
 
MRI / FibroScan™ 
 
X16 
 
 
 
 
X 
X 
 
Blood sample collection for: 
 
 
 
 
 
 
 
 
 
Lipid panel19 
X 
X 
 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
 
 
 
 
X 
X 
 
Metabolic panel20 
 
X 
 
X 
X 
X 
X 
X 
X 
NASH / fibrosis biomarkers21 
 
X 
 
 
 
 
X 
X 
 
Eicosanoid panel (Cohorts 1 and 
2 only)22 
 
X 
 
 
X 
 
X 
X 
 
Inflammatory biomarkers 
(TNFα, IL-6, IL-8, Hs-CRP, 
MCP-1) (Cohorts 1 and 2 only)22 
 
X 
 
 
X 
 
X 
X 
 
Adiponectin, resistin, leptin 
(Cohorts 1 and 2 only)22 
 
X 
 
 
X 
 
X 
X 
 
Lipoprotein particle size analysis 
(NMR) (Cohorts 1 and 2 only)22 
 
X 
 
 
 
 
X 
X 
 
Lipidomic analyses for DNL 
 
X 
 
 
X 
(Cohort 3 
Only) 
 
X 
X 
 
Genomics pertaining to the 
disease under study23 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Evaluation 
 
Study Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory PD biomarkers 
(Cohorts 1 and 2 only)22 
 
X 
 
 
 
 
X 
X 
 
Lymphocyte subsets in 
peripheral blood mononuclear 
cells (Cohorts 1 and 2 only)22,26 
 
X 
 
 
 
 
X 
 
 
Sample for storage22,27 
 
X 
 
 
 
 
X 
X 
 
Spot urine sample collection for: 
 
 
 
 
 
 
 
 
 
Exploratory PD biomarkers22 
 
X 
 
 
 
 
X 
X 
 
Study Drug Administration 
 
 
 
 
 
 
 
 
 
Randomization 
 
X28 
 
 
 
 
 
 
 
Study drug dispensation 
 
X 
 
 
X 
X 
 
 
 
Study drug administration 
 
QD PO from Day 1 through Week 12 
 
 
Study drug accountability 
 
 
 
X 
X 
X 
X 
X 
 
Table footnotes appear on the following page. 


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1 
Baseline evaluations are to be performed pre-dose, unless otherwise specified. 
2 
At the time of this amendment, subject participation in the 25 mg cohort is complete, with participation in the 50 mg cohort fully enrolled but with subject participation 
ongoing. The Sponsor notes that the COVID-19 pandemic may impact the conduct of the 50 and 75 mg cohorts, with challenges potentially arising from quarantines and 
travel limitations affecting study subjects as well as clinic and imaging facility closures. Accordingly, safety assessments scheduled for the Week 12 and 16 visits, including 
sample collection for clinical laboratory tests, physical examinations, and documentation of AEs, may be performed at an alternate study center or by home health care visit. 
Furthermore, if the subject is unable to attend the Week 12 visit at the study center, one MRI-PDFF may be performed at any time between Week 11 and 16. If this scan is 
performed after Week 12, the subject must continue to receive study drug until the final scan is performed; however, study drug is not to be continued for >16 weeks. The 
safety of subjects who continue dosing beyond 12 weeks will be assessed during this continued dosing period by planning for blood sample collection at an alternate site or 
home visit at Week 12 and blood sample collection and physical examination on the last day of dosing. A 4-week off treatment safety assessment is to occur after the last 
dose, regardless of whether a subject receives treatment for 12 or 16 weeks. 
For subjects in Cohort 3, Week 16 assessments may serve as screening assessments if within the window before the Day 1 visit. 
3 
Serum beta-human chorionic gonadotropin (β-HCG) pregnancy testing is to be performed for all female subjects of child-bearing potential during screening and serum or 
urine β-HCG pregnancy testing is to be performed within 48 hours before first dose on Day 1; subjects with positive results are not eligible for study participation. Pregnancy 
testing is to be repeated during the study any time pregnancy is suspected; study drug is to be discontinued for any subject with a positive result. 
4 
Results of liver biopsy conducted within 24 months before randomization, with findings consistent with NASH diagnosis, must be collected and documented.  
5  
If prior biopsy was not performed or is not available, subjects must have a suspected diagnosis of NASH based on clinical presentation/historical assessments (see protocol 
Section 8.2) and must have MRE ≥2.5 kpa (Cohorts 1 and 2 only) and MRI-PDFF ≥8% during screening.  
6 
Screening serologies include HIV RNA, HBsAg, anti-HCV, and HCV RNA. Subjects with positive anti-HCV who test negative for HCV RNA at screening will be allowed to 
participate in the study. A PCR test for SARS-Cov-2 (the virus that causes COVID-19) also is to be performed; subjects with positive results are not eligible for study 
participation.   
7 
ECGs are to be performed before and 4 hours after the first study drug dose on Day 1. 
8 
Vital signs include oral temperature and supine 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. 
9 
Slit lamp and near and far visual acuity testing is to be performed. Baseline examinations may be performed within 28 days before Day 1. If a subject experiences a treatment-
emergent ophthalmologic abnormality, an ophthalmologic examination should be performed within 24 to 48 hours or next business day after symptom onset to evaluate the 
abnormality. 
10 Hematology parameters include hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white blood cell (WBC) count with differential, and absolute neutrophil 
count (ANC), and prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) and fibrinogen.  
11 Liver aminotransferases include AST and ALT. Liver aminotransferases collected as part of the clinical chemistry panel for safety are also applicable for efficacy 
assessments. 
12 Baseline liver aminotransferases are to be the mean of at least 2 values taken at least 4 to 12 weeks apart; the first measurement may be a historical measurement. 
13 Fasting clinical chemistries include chloride (Cl), carbon dioxide (CO2), sodium (Na), potassium (K), blood urea nitrogen (BUN), calcium, magnesium, creatinine, albumin, 
alkaline phosphatase (ALP), total bilirubin, indirect and direct bilirubin, and total protein. Creatine phosphokinase (CPK) (total and fractionated) is to be calculated during 
screening and at baseline. 
14 Urinalysis includes specific gravity, pH, blood, glucose, protein, ketones, and microscopic examination of sediment. 
15 For female subjects of child-bearing potential only; subjects with positive results are to discontinue study drug immediately. 
16 Baseline imaging studies may be performed within 28 days before Day 1. 
17 Due to the COVID-19 pandemic, if the subject is unable to attend both the Week 12 and Week 16 visit, one MRI-PDFF may be performed at any time between Week 11 and 
16. If this scan is performed after Week 12, the subject must continue to receive study drug until the final scan is performed. However, study drug is not to be continued for 
>16 weeks.  
18 Note that subjects without a biopsy performed within 24 months of randomization MUST have MRE performed during screening. 
19 Fasting lipid panel includes LDL-C, non-LDL-C, HDL-C, non-HDL-C, total cholesterol, triglycerides, ApoB, and Lp(a) particles. 


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20 Fasting metabolic panel includes glucose, insulin, NEFA, and GGT. HOMA2-IR and adipo-IR are to be calculated from fasting insulin, fasting glucose, and fasting NEFA, as 
applicable. 
21 NASH and fibrosis biomarkers include CK-18, FIB-4 Index, ELF (TIMP-1, PIIINP, HA), PROC3, and FIBROSpect 2. For Cohort 3 (75 mg), only PROC3 sample will be 
collected. 
22 For Cohort 3 (75 mg), these samples will not be collected as dedicated blood collections. Instead, assays for some of these parameters may be conducted retrospectively using 
additional aliquots collected from the “NASH/fibrosis markers sample” or from the “lipidomic analyses for DNL sample”. 
23 The genomics sample collection is optional for Cohort 3 (75 mg). 
24 
 
 
 
 
25 
 
 
26 Blood samples are to be collected from a subset of subjects enrolled at selected study centers at baseline and Week 12 for exploratory evaluation of change in 
CD4/Th17/regulatory T-cell populations and, potentially, natural killer-T and epigenetic or activation changes in peripheral blood mononuclear cells. 
27 Additional blood samples will be collected at specified time points and stored for potential future analysis for biomarkers relevant to NAFLD/NASH. These samples will 
neither be used for genetic analysis nor creation of cell lines. 
28 Randomization may be performed within 24 hours before baseline. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............20 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................24 
5. 
INTRODUCTION ......................................................................................................27 
5.1. 
TVB-2640 ...................................................................................................................28 
6. 
OBJECTIVES AND PURPOSE .................................................................................30 
6.1. 
Primary Objectives .....................................................................................................30 
6.2. 
Secondary Objective ...................................................................................................30 
6.3. 
Exploratory Objectives ...............................................................................................30 
6.4. 
Endpoints ....................................................................................................................31 
6.4.1. 
Efficacy Endpoints ......................................................................................................31 
6.4.2. 
Safety Endpoints .........................................................................................................31 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design ..................................................................................................32 
7.2. 
Study Suspension Criteria ...........................................................................................34 
7.3. 
Criteria for Study Termination by the Sponsor ..........................................................34 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................35 
8.1. 
Number of Subjects ....................................................................................................35 
8.2. 
Subject Inclusion Criteria ...........................................................................................35 
8.3. 
Subject Exclusion Criteria ..........................................................................................36 
8.4. 
Source of Subjects ......................................................................................................39 
8.5. 
Subject Identification and Randomization ..................................................................39 
8.6. 
Subject Withdrawal Criteria .......................................................................................39 
8.7. 
Safety Review Committee ..........................................................................................41 
8.8. 
Investigator Compliance .............................................................................................41 
8.9. 
Subject Adherence to Protocol Schedule ....................................................................41 
9. 
TREATMENT OF SUBJECTS ..................................................................................43 
9.1. 
Description of Study Drug ..........................................................................................43 


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9.1.1. 
TVB-2640 ...................................................................................................................43 
9.1.2. 
Placebo ........................................................................................................................43 
9.2. 
Study Drug Packaging and Labeling ..........................................................................43 
9.3. 
Study Drug Storage .....................................................................................................43 
9.4. 
Study Drug Accountability .........................................................................................43 
9.5. 
Study Drug Dose and Administration .........................................................................44 
9.6. 
Dose Reductions .........................................................................................................44 
9.7. 
Rationale for the Doses Selected ................................................................................44 
9.8. 
Concomitant Medications ...........................................................................................46 
9.8.1. 
Excluded Medications ................................................................................................46 
9.8.2. 
Permitted Medications ................................................................................................47 
9.8.3. 
Contraception ..............................................................................................................47 
9.9. 
Blinding ......................................................................................................................47 
10. 
BASELINE ASSESSMENTS ....................................................................................48 
10.1. 
Demographics .............................................................................................................48 
10.2. 
Medical and Social History ........................................................................................48 
10.3. 
Screening Serology .....................................................................................................48 
10.4. 
Pregnancy Testing ......................................................................................................48 
11. 
EFFICACY, PHARMACOKINETIC, AND PHARMACODYNAMIC 
ASSESSMENTS.........................................................................................................50 
11.1. 
Efficacy and Pharmacodynamic Assessments ............................................................50 
11.1.1. 
Magnetic Resonance Imaging Studies ........................................................................50 
11.1.1.1. 
Proton-density Fat Fraction by Magnetic Resonance Imaging (MRI-PDFF) ............50 
11.1.1.2. 
Liver Stiffness by Magnetic Resonance Elastography ...............................................50 
11.1.2. 
Liver Fibrosis by FibroScan .......................................................................................50 
11.1.3. 
Clinical Laboratory Tests ...........................................................................................50 
11.1.3.1. 
Lipid and Metabolic Panel, Glycated Hemoglobin, and Lipoprotein Particle 
Size .............................................................................................................................50 
11.1.3.2. 
NASH / Fibrosis Markers ...........................................................................................51 
11.1.3.3. 
Eicosanoid Panel .........................................................................................................51 
11.1.3.4. 
Inflammatory Biomarkers ...........................................................................................51 
11.1.3.5. 
Adiponectin, Resistin, Leptin .....................................................................................51 
11.1.4. 
Lipidomic Analyses ....................................................................................................51 


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11.1.5. 
Genomics ....................................................................................................................51 
11.1.6. 
Sample Collection for Storage ....................................................................................52 
11.1.7. 
Anthropometric Assessments .....................................................................................52 
11.1.8. 
Lymphocyte Subsets in Peripheral Blood Mononuclear Cells ...................................52 
11.2. 
 
12. 
ASSESSMENT OF SAFETY .....................................................................................54 
12.1. 
Safety Parameters .......................................................................................................54 
12.1.1. 
Vital Signs ..................................................................................................................54 
12.1.2. 
Physical Examination and Height ...............................................................................54 
12.1.3. 
Electrocardiogram (ECG) ...........................................................................................54 
12.1.4. 
Ophthalmologic Examinations ...................................................................................54 
12.1.5. 
Safety Laboratory Assessments ..................................................................................55 
12.2. 
Adverse and Serious Adverse Events .........................................................................56 
12.2.1. 
Definition of Adverse Events .....................................................................................56 
12.2.1.1. 
Adverse Events (AE) ..................................................................................................56 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................56 
12.2.2. 
Adverse Event Assessment .........................................................................................57 
12.2.2.1. 
Intensity ......................................................................................................................57 
12.2.2.2. 
Relationship to Study Drug ........................................................................................57 
12.2.2.3. 
Seriousness .................................................................................................................58 
12.2.3. 
Recording Adverse Events .........................................................................................58 
12.2.4. 
Reporting Serious Adverse Events .............................................................................59 
12.2.5. 
Follow-Up of Adverse Events ....................................................................................59 
12.2.6. 
Pregnancy ...................................................................................................................59 
12.2.7. 
Overdose .....................................................................................................................60 
12.2.8. 
Protocol Deviations Due to an Emergency or Adverse Event ....................................60 
13. 
STATISTICS ..............................................................................................................61 
13.1. 
Determination of Sample Size ....................................................................................61 
13.2. 
Statistical Analyses .....................................................................................................62 
13.2.1. 
Analysis Populations ..................................................................................................62 
13.2.2. 
Efficacy Analysis ........................................................................................................62 
13.2.3. 
Safety Analysis ...........................................................................................................64 


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14. 
ETHICS ......................................................................................................................65 
14.1. 
Good Clinical Practice Compliance............................................................................65 
14.2. 
Institutional Review Board (IRB) ...............................................................................65 
14.3. 
Ethical Conduct of the Study ......................................................................................65 
14.4. 
Written Informed Consent ..........................................................................................66 
14.5. 
Subject Confidentiality ...............................................................................................66 
15. 
ADMINISTRATIVE REQUIREMENTS ..................................................................67 
15.1. 
Study Monitoring ........................................................................................................67 
15.2. 
Case Report Form Completion ...................................................................................67 
15.3. 
Computerized Systems / Medical Records as Source Data ........................................68 
15.4. 
Retention of Records ..................................................................................................68 
15.5. 
Audits and Inspections ................................................................................................68 
15.6. 
Publication Policy .......................................................................................................68 
16. 
LIST OF REFERENCES ............................................................................................70 
17. 
APPENDICES ............................................................................................................72 
 
LIST OF TABLES 
Table 1 
Emergency Contact Information ...................................................................................3 
Table 2 
Schedule of Events .....................................................................................................14 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
15-HETE 
15-LOX–derived 15-hydroxyeicosatetraenoic acid 
ACC 
Acetyl-CoA carboxylase 
Adipo-IR 
Adipose tissue insulin resistance 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
ApoB 
Apolipoprotein B 
APRI 
AST to platelet ratio 
AST 
Aspartate aminotransferase 
ATP III 
Adult Treatment Panel III 
BMI 
Body mass index 
CAP 
Controlled attenuation parameter 
CFDA 
China Food and Drug Administration 
CK-18 
Cytokeratin-18 
CMH 
Cochran-Mantel-Haenszel 
CoA 
Coenzyme A 
COVID-19 
Coronavirus disease-2019 
CRA 
Clinical research associate 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP3A4 
Cytochrome P450 3A4 
DILI 
Drug-induced liver injury 
DLT 
Dose-limiting toxicity 
DNL 
De novo lipogenesis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ELF 
Enhanced liver function 
ELISA 
Enzyme-linked immunosorbent assay 
FASN 
Fatty acid synthase 
FIB-4 
Fibrosis-4 


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Abbreviation or Specialist Term 
Explanation 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
HbA1c 
Glycated hemoglobin 
HBsAg 
Hepatitis B surface antigen  
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HOMA2-IR 
Homeostatic model assessment insulin resistance 
Hs-CRP 
High-sensitivity C-reactive protein 
ICH 
International Council for Harmonisation 
IL 
Interleukin 
IL-6 
Interleukin 6 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IST 
Investigator-sponsored trial 
ITT 
Intent-to-treat population 
IUD 
Intrauterine device 
LDL-C 
Low-density lipoprotein cholesterol 
Lp(a) 
Lipoprotein(a) 
LTB4 
5-LOX–derived leukotriene B4 
LXA4 
Lipoxin A4 
MCP-1 
Monocyte chemoattractant protein-1 
mITT 
Modified intent-to-treat population 
MRE 
Magnetic resonance elastography 
MRI-PDFF 
Proton density fat fraction by magnetic resonance imaging 
MRS 
Magnetic resonance spectroscopy 
MTD 
Maximum tolerated dose 
NADPH 
Nicotinamide adenine dinucleotide phosphate 
NAFLD 
Non-alcoholic fatty liver disease 
NAS 
NAFLD activity score 
NASH 
Non-alcoholic steatohepatitis 
NCI 
National Cancer Institute 


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Abbreviation or Specialist Term 
Explanation 
NEFA 
Non-esterified fatty acid 
NMR 
Nuclear magnetic resonance 
NOAEL 
No observed adverse effect level 
OAD 
oral anti-diabetic 
PCR 
Polymerase chain reaction  
PD 
Pharmacodynamic 
PGE2 
prostaglandin E2 
PK 
Pharmacokinetic 
PO 
Orally 
PPE 
Palmar-plantar erythrodysesthesia 
QD 
Once daily 
RNA 
Ribonucleic acid 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus-2 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TNFα 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
US 
United States 
US FDA 
United States Food and Drug Administration 
VCTE 
Vibration-controlled transient elastography 
β-HCG 
Beta-human chorionic gonadotropin 
 


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5. 
INTRODUCTION 
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. 
Metabolic diseases spanning the continuum of metabolic syndrome, non-alcoholic fatty liver 
disease (NAFLD) and the more advanced disease of non-alcoholic steatohepatitis (NASH) can 
progress to significant liver diseases, including cirrhosis and hepatocellular carcinoma. In 
addition, NAFLD is associated with increased comorbidities, including cardiovascular diseases 
(Widya et al. 2016; Targher, Day, and Bonora 2010) and type 2 diabetes (Cusi 2016). Obesity 
and the metabolic syndrome are two key risk factors for NAFLD, which are characterized as 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. Over the next 5 years, NASH will overtake hepatitis as 
the most prevalent liver disease in the United States (US). 
Normal responses to feeding carbohydrate in meals include a transient increase in hepatic DNL, 
a FASN-dependent pathway, followed by a return to baseline levels upon fasting. In subjects 
with NAFLD, however, hepatic DNL is increased (Donnelly et al. 2005; Lambert et al. 2014), 
and FASN gene expression has been shown to be elevated in liver biopsies from NAFLD 
patients (Kohijimi, 2007; Mitsuyoshi, 2009), contributing to elevated liver stores of triglycerides 
(TG) and saturated fatty acid species, which in turn may contribute to liver inflammation (Wei 
2006), tissue damage, and fibrosis. 
There are currently no drugs licensed for the treatment of NASH. Inhibiting lipogenesis, with an 
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 NASH subjects have shown that inhibition of DNL with 
acetyl-CoA carboxylase (ACC) inhibitor GS-0976 (Stiede, 2017) results in a significant 
reduction of intrahepatic fat and surrogate markers of fibrosis and cell death (Loomba, 2017). 
Also, pioglitazone use has been shown to improve advanced fibrosis in NASH (Musso, 2017), 
which may be associated with a reduction in DNL (Beysen, 2008). Further studies are needed, 
however, to evaluate the full spectrum of treatment effects elicited by these drugs and 
management of their side-effects. 
Sagimet Biosciences (formerly 3-V Biosciences) has developed an oral, once-daily (QD) FASN 
inhibitor, TVB-2640. This drug has been evaluated in approximately160 humans to date 
including patients with solid tumors and healthy adults, some of whom had characteristics of 
metabolic syndrome. The safety, pharmacokinetic (PK) and pharmacodynamic (PD) parameters 
of TVB-2640 have been measured. Preliminary results demonstrated that once-daily, oral 
administration of TVB-2640 for 10 days decreased hepatic DNL in a dose-dependent manner 
and improved other markers of metabolic dysfunction in otherwise healthy subjects with 


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characteristics of the metabolic syndrome (Study 2006432, Syed-Abdul, 2019). These 
observations form the basis for evaluating the TVB-2640 as a novel therapy for subjects with 
NASH. 
5.1. 
TVB-2640 
The clinical safety profile to date for TVB-2640 is based primarily on one completed 
uncontrolled open-label Phase 1 study in humans (Study 3V2640-CLIN-002) in 136 patients 
with solid tumors, 76 treated with monotherapy (at doses ranging from 60 mg/m2 to a dose of 
240 mg/m2 (i.e., up to 600 mg) and 60 treated with TVB-2640 in combination with a taxane 
(paclitaxel or docetaxel).  
Overall, TVB-2640 demonstrated a favorable tolerability profile. Most treatment-emergent 
adverse events (TEAEs) were Grade 1 or 2 in intensity, non-serious, and manageable. 
As anticipated, based on nonclinical study findings, the principal toxicities associated with 
TVB-2640 as monotherapy were skin and ocular effects. With monotherapy, most skin events 
were Grade 1 or 2 in intensity, and all were non-serious. 
The maximum tolerated dose (MTD) of TVB-2640 monotherapy in patients with solid tumors 
was determined to be 100 mg/m2. Dose-limiting toxicities (DLTs) associated with TVB-2640 
monotherapy were skin and ocular events, including corneal edema, keratitis, and palmar-plantar 
erythrodysesthesia (PPE) syndrome. 
As monotherapy, the most common individual TEAEs were alopecia (61%), PPE syndrome 
(46%), fatigue (37%), decreased appetite (26%), and dry skin (22%).  
When TVB-2640 was administered in combination with a taxane (paclitaxel or docetaxel), skin 
and ocular effects also were common. Most skin events were Grade 1 or 2 in intensity, and all 
but 1 skin event were non-serious. 
As was the case with monotherapy, the MTD of TVB-2640 in combination with paclitaxel was 
determined to be 100 mg/m2. DLTs associated with TVB-2640 in combination included PPE 
syndrome and uveitis. The most common TEAEs with TVB-2640 in combination with paclitaxel 
were fatigue (53%), alopecia (46%), PPE syndrome (46%), nausea (40%), and peripheral 
neuropathy (36%). Peripheral neuropathy is known to be associated with paclitaxel. 
When TVB-2640 was administered in combination with paclitaxel, 6 episodes of serious 
pneumonitis were experienced by 5 patients, with all assessed by the Investigator as related to 
both TVB-2640 and paclitaxel. (No cases of pneumonitis were reported among monotherapy 
patients.) Given the occurrence of these events, respiratory events were identified as adverse 
events of special interest for patients receiving TVB-2640 in combination.  
Overall, among patients with solid tumors treated with TVB-2640, no apparent trends were seen 
over time or across TVB-2640 dose groups with regard to change from baseline in clinical 
laboratory or vital sign parameters. Furthermore, based on review of electrocardiogram (ECG) 
and Holter monitoring data, TVB-2640 was shown to have no clinically relevant QTc prolonging 
effect. 
A total of 12 subjects with features of the metabolic syndrome have been treated with TVB-2640 
at flat doses of 50 to 150 mg QD orally (PO) for 10 days in an Investigator-sponsored trial (IST). 


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TVB-2640 was well tolerated in this subject population. All TEAEs were Grade 1 in intensity 
and non-serious and none led to study drug discontinuation. The only TEAEs reported for 
>1 subjects were alopecia and PPE syndrome (each 2 subjects). In this study, QD PO 
administration of TVB-2640 for 10 days was shown to decrease hepatic DNL in a dose-
dependent manner and improved other markers of metabolic dysfunction in this population of 
otherwise healthy subjects with characteristics of the metabolic syndrome. These observations 
form the basis for evaluating the TVB-2640 as a novel therapy for subjects with NASH. 
Refer to the Investigator’s Brochure for more detailed information regarding TVB-2640. 


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6. 
OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The primary objectives are: 
 To determine the effect of QD TVB-2640 for 12 weeks versus placebo on the change 
in hepatic fat fraction by proton density fat fraction by magnetic resonance imaging 
(MRI-PDFF) from baseline in subjects with NASH. 
 To determine the safety of QD TVB-2640 versus placebo in subjects with NASH, 
including the effects on alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST). 
6.2. 
Secondary Objective 
The secondary objective is: 
 To determine the effect of QD TVB-2640 for 12 weeks versus placebo in subjects 
with NASH on: 
 Lipid and lipoprotein parameters, including low-density lipoprotein cholesterol 
(LDL-C), non-LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-
C, total cholesterol, TG, apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) 
particles. 
 NASH and fibrosis biomarkers including cytokeratin-18 (CK-18), fibrosis-4 (FIB-
4), and enhanced liver function (ELF) or FIBROSpect 2 or ProC3 test. 
 Eicosanoid panel. 
6.3. 
Exploratory Objectives 
The exploratory objectives are: 
 To determine the effect of QD TVB-2640 for 12 weeks versus placebo in subjects 
NASH on clinical measures, including: 
 Liver fibrosis, as determined by vibration-controlled transient elastography 
(VCTE).  
 Metabolic parameters, including fasting glucose, insulin, homeostatic model 
assessment insulin resistance (HOMA2-IR), HbA1c, non-esterified fatty acid 
(NEFA), adipose tissue insulin resistance (adipo-IR), adiponectin, resistin, 
Interleukin 6 (IL-6), and gamma-glutamyl transpeptidase (GGT). 
 Anthropometric parameters, including weight, waist and hip circumference, 
waist-hip ratio, and blood pressure. 
 Lipidomic analyses for DNL. 
 Explore the relationship of plasma drug exposure to changes in efficacy and safety 
biomarkers. 


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 Explore possible relationships between genomic markers of NASH and responses to 
treatment. 
6.4. 
Endpoints 
6.4.1. 
Efficacy Endpoints 
The primary efficacy endpoint is: 
 Percent change from baseline in liver fat at Week 12, as determined by MRI-PDFF. 
The key secondary efficacy endpoint is: 
 The percentage of subjects with at least a 30% reduction in liver fat at Week 12, as 
determined by MRI-PDFF. 
Additional efficacy endpoints are: 
 Percent change from baseline in liver fat at Week 16, as determined by MRI-PDFF. 
 Percentage of subjects with at least a 30% reduction in liver fat at Week 16, as 
determined by MRI-PDFF. 
 Change from baseline over the 12-week treatment period in:   
 Liver aminotransferases. 
 Lipid and lipoprotein parameters. 
 NASH and fibrosis markers. 
 Eicosanoids.  
Exploratory efficacy endpoints are: 
 Change from baseline over the 12-week treatment period in:   
 Liver fibrosis, as determined by VCTE.  
 Metabolic parameters. 
 Anthropometric parameters. 
 Lipidomic analyses for DNL. 
 Proportion of subjects with <5% liver fat (normalized) at Week 12. 
6.4.2. 
Safety Endpoints 
Safety endpoints are: 
 Proportion of subjects experiencing treatment-emergent adverse events (TEAEs), Grade 3 
or 4 TEAEs, and serious adverse events (SAEs). 
 Change from baseline in vital sign measurements, 12-lead electrocardiogram (ECG) 
findings, and clinical laboratory test results. 
 Proportion of subjects experiencing treatment-emergent ophthalmologic abnormalities. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multi-center, randomized, single-blind, placebo-controlled, dose-escalation study to 
evaluate the safety and efficacy of TVB-2640 in subjects with NASH. Male and female subjects 
aged ≥18 years with either biopsy-proven NASH within 2 years before randomization and MRI-
PDFF ≥8% or, if prior liver biopsy was not performed or results are not available, magnetic 
resonance elastography (MRE) ≥2.5 kpa (Cohorts 1 and 2 only) and MRI-PDFF ≥8% during 
screening are planned to be enrolled. Approximately 117 unique subjects will be enrolled and 
randomized, with at least 90 subjects enrolled in the US and approximately 27 evaluable subjects 
enrolled in China (18 active and 9 placebo). In the US, subjects will be enrolled and randomized 
to achieve 90 evaluable subjects (30 active and 15 placebo in each of 2 dose cohorts). The 50 mg 
cohort will enroll and randomize approximately 27 additional subjects from China. The US-only 
75 mg cohort will enroll approximately 10 active, evaluable subjects who previously received 
placebo in the 25 or 50 mg cohort. A subject is defined as evaluable if they receive study drug 
for at least 8 weeks and have a baseline and at least 1 post-baseline MRI-PDFF assessment on or 
after Week 8. 
Subjects will be screened for study eligibility within 60 days before randomization. Subjects 
must meet all of the inclusion criteria and none of the exclusion criteria to participate in the 
study. Note that subjects who initially fail to meet all entrance criteria based on screening 
assessments (i.e., screen failures) may be submitted for re-screening once (see Section 8.5 for 
details).  
Subjects who are determined to be eligible for the study, based on screening assessments, are to 
be randomized into the study within 24 hours before baseline (Day 1, the first day of study drug 
administration). Subjects who are randomized are considered to be enrolled in the study. 
Initially, 2 TVB-2640 dose levels are planned to be evaluated in a sequential fashion:  25 mg 
and, if study suspension criteria are not met at the 25 mg dose level (see Section 7.2), 50 mg. At 
each of the 2 initial dose levels, subjects will be randomly assigned to TVB-2640 or placebo at a 
2:1 ratio, with randomization stratified by type 2 diabetes mellitus status. The 50 mg dose level 
will also be stratified by country:  
 25 mg dose level:  TVB-2640 (Planned N=30) and Placebo (Planned N=15) 
 50 mg dose level:  US: TVB-2640 (Planned N=30) and Placebo (Planned N=15); 
China: TVB-2640 (Planned N=18) and Placebo (Planned N=9); Total: TVB-2640 
(Planned N=48) and Placebo (Planned N=24) 
Subjects will receive TVB-2640 or placebo QD PO for 12 weeks, or until the time of the final 
on-treatment MRI-PDFF if after Week 12, but for no longer than 16 weeks. During the 12-week 
Treatment period, subjects are to attend study center visits at Week 1, Days 1 and 2, and 
Weeks 2, 4, 8, and 12. After completion of the 12-week Treatment period, subjects are to attend 
a Follow-up visit at Week 16 for post-treatment safety and efficacy assessments.  
All subjects must complete the 12-week treatment period at the 25 mg dose level, with review of 
all safety data and written approval by the Safety Review Committee (SRC) and reviewed by the 


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Food and Drug Administration (FDA) before enrollment and treatment of subjects at the 50 mg 
dose level may commence.  
After completion of Cohorts 1 and 2, and again if no stopping criteria are met upon review by the 
Independent SRC, subjects assigned to placebo in either cohort are eligible to crossover to 
receive TVB-2640 75 mg in Open-label Cohort 3 (planned N=12 in order to obtain 10 evaluable 
subjects). Cohort 3 will be conducted at select sites only. 
The Sponsor notes that the coronavirus disease-2019 (COVID-19) pandemic may impact the 
conduct of the 50 mg and 75 mg cohorts, with challenges potentially arising from quarantines 
and travel limitations affecting study subjects as well as clinic and imaging facility closures. 
Accordingly, safety assessments scheduled for the Week 12 and 16 visits, as identified in 
Table 2, including sample collection for clinical laboratory tests, physical examinations, and 
documentation of adverse events (AEs), may be performed at an alternate study center or by 
home health care visit. Furthermore, if the subject is unable to attend the Week 12 visit at the 
study center, one MRI-PDFF may be performed at any time between Week 11 and 16. If this 
scan is performed after Week 12, the subject must continue to receive study drug until the final 
scan is performed; however, study drug is not to be continued for >16 weeks. The safety of 
subjects who continue dosing beyond 12 weeks will be assessed during this continued dosing 
period by planning for blood sample collection at an alternate site or home visit at Week 12 and 
blood sample collection and physical examination on the last day of dosing. A 4-week off 
treatment safety assessment is to occur after the last dose, regardless of whether a subject 
receives treatment for 12 or 16 weeks.  
In Cohorts 1 and 2, study drug will be dispensed to subjects in a single-blinded fashion. All other 
study personnel, with the exception of personnel conducting/interpreting imaging studies (see 
Section 11.1) at each study center, will be unblinded to the subject’s treatment assignment. In 
Cohort 3, study drug will be dispensed in an open-label fashion. 
Efficacy variables include MRI-PDFF as well as measurement of liver aminotransferases, lipid 
parameters, and markers of NASH and liver fibrosis. The primary endpoint is percent change 
from baseline in liver fat from baseline at Week 12, as determined by MRI-PDFF. The 
percentage of subjects with at least a 30% reduction in the primary endpoint is a key secondary 
efficacy endpoint.  
In Cohorts 1 and 2, subjects will undergo MRI-PDFF prior to the start of treatment (pre-dose), at 
the end of the initial 12-week Treatment Period (between 11 and 12 weeks after the start of 
treatment), and at Week 16. Due to the COVID-19 pandemic, if the subject is unable to attend 
the Week 12 visit, one MRI-PDFF may be performed at any time between Week 11 and 16. If 
this scan is performed after Week 12, the subject must continue to receive study drug until the 
final scan is performed. However, study drug is not to be continued for >16 weeks. In Cohort 3, 
MRI-PDFF will undergo MRI-PDFF prior to the start of treatment (pre-dose) and at the end of 
the initial 12 week Treatment Period (between 11 and 12 weeks after the start of treatment). 
During the study, safety will be assessed by vital signs (oral temperature, pulse, respiratory rate, 
and seated blood pressure), 12-lead ECG, physical examination, including ophthalmologic 
examination, and clinical laboratory testing (hematology, chemistry, and urinalysis). Subjects 
will be evaluated for AEs and concomitant medication use throughout the study.  


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Blood samples will be collected at specified times for the assessment of PK. 
An SRC will oversee the study to ensure subject safety and to advise if any dosing alterations are 
recommended. The SRC will review safety including liver-related events (i.e., clinically 
meaningful elevations in ALT, AST, and bilirubin), and other efficacy (lipid parameters) and 
safety data as needed. 
7.2. 
Study Suspension Criteria 
Treatment of ongoing subjects and enrollment of new subjects at a given dose level will be 
suspended in the event of any of the following:   
 One subject experiences a Grade 5 TEAE (i.e., TEAE with a fatal outcome). 
 Two subjects experience the same Grade 4 TEAE. 
 Three subjects experience the same Grade 3 TEAE.  
In such cases, the SRC will review unblinded data to determine the relationship of the TEAE(s) 
to TVB-2640 and make a determination whether enrollment and treatment of subjects may be 
resumed or is to be permanently discontinued.  
7.3. 
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 
8.1. 
Number of Subjects 
Approximately 117 unique subjects will be enrolled and randomized across 2 dosing cohorts (25 
and 50 mg). Up to 12 subjects assigned to placebo in Cohorts 1 and 2 will be eligible to 
crossover and receive TVB-2640 75 mg in an open-label fashion in Cohort 3. The study plans to 
enroll male and female subjects aged ≥18 years with either biopsy-proven NASH within 
24 months before randomization and MRI-PDFF ≥8% or, if prior liver biopsy was not performed 
or results are not available, MRE ≥2.5 kpa (Cohorts 1 and 2 only) and MRI-PDFF ≥8% during 
screening.  
8.2. 
Subject Inclusion Criteria 
Subjects meeting all of the following criteria are eligible for enrollment in the study. 
1. Must be willing to participate in the study and provide written informed consent. 
2. Aged ≥18 years with a body mass index (BMI) ≤40 kg/m2. 
3. If a female subject of child-bearing potential, must have a negative serum pregnancy 
(beta-human chorionic gonadotropin [β-HCG]) test during screening and is not 
breastfeeding, does not plan to become pregnant during the study, and agrees to use 
two forms of birth control, one being a barrier method (i.e., condoms, diaphragm, 
non-hormonal intrauterine device [IUD]) throughout the study and for at least 3 months 
after the final study drug dose.  
Hormonal contraception (estrogens stable ≥3 months) and hormonal IUDs are permitted 
if used with a secondary barrier birth control method (e.g., condoms). 
4. If a female subject of non-child-bearing potential, must have documentation of surgical 
sterility (bilateral oophorectomy, hysterectomy, or tubal ligation) or natural sterility 
(>12 consecutive months without menses). 
5. If male, agrees to use adequate birth control throughout the study and for at least 
3 months after the final study drug dose. 
6. Prior liver biopsy within 24 months of randomization with fibrosis Stage 1 to 3 and a 
NAFLD activity score (NAS) of ≥4 with at least a score of 1 in each of the following 
NAS components:  
 Steatosis. 
 Ballooning degeneration. 
 Lobular inflammation. 
AND 
 Confirmation of ≥8% liver fat content on MRI-PDFF. 


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OR, if prior biopsy is not available: 
 Either overweight (BMI ≥25 and <30 kg/m2) or obese (BMI ≥30 kg/m2) or diabetic or 
ALT ≥30 U/L for men or ≥19 U/L for women or fatty liver on ultrasound and at least 
one more feature of metabolic syndrome by Adult Treatment Panel III (ATP III) 
criteria. 
AND 
 MRE ≥2.5 kpa (Cohorts 1 and 2 only) and MRI-PDFF ≥8% during screening. 
For Cohort 3 Only 
7. Subject may have previously participated in this study in Cohort 1 or 2 and is known to 
have received placebo by single-blind treatment assignment. 
8.3. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for enrollment in the study. 
1. History of significant alcohol consumption for a period of more than 3 consecutive 
months within 1 year prior to screening, as assessed by the Investigator. 
Note: Significant alcohol consumption is defined as average of >20 g/day in female 
subjects and >30 g/day in male subjects. For reference, 14 grams of alcohol are contained 
in the following: 
 12 fl oz regular beer containing ~5% alcohol.  
 8-9 fl oz malt liquor containing ~7% alcohol. 
 5 fl oz of table wine containing ~12% alcohol. 
 1.5 fl oz of distilled spirits (e.g., gin, rum, vodka, whiskey) containing ~40% alcohol. 
2. Inability to reliably quantify alcohol consumption based upon judgment of the 
Investigator.  
3. Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for 
hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins) for 
more than 2 weeks in the year prior to screening. 
4. Weight gain or loss >5% in the 6 months prior to randomization or >10% in the 
12 months prior to screening. 
5. Prior or planned (during the study period) bariatric surgery (e.g., gastroplasty, roux-en-Y 
gastric bypass). 
6. Type 1 diabetes. 
7. Uncontrolled Type 2 diabetes defined as: 
 HbA1c ≥9.5% during screening. (Subjects with HbA1c ≥9.5% may be retested during 
screening). 


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 Basal insulin dose adjustment >10% within 60 days prior to enrollment. 
 Requirement for glucagon-like peptide analogue or a complex oral anti-diabetic 
(OAD) regimen (3 or more OADs) within 6 months of screening. 
 History of severe hypoglycemia (symptomatic hypoglycemia requiring outside 
assistance to regain normal neurologic status) within the previous year. 
Note: Individual diabetes regimens will be reviewed by Investigator and may be adjusted 
based on American Diabetes Association guidelines. 
8. Presence of cirrhosis on liver biopsy (Stage 4 fibrosis) or imaging (MRE ≥4.67 kpa). 
9. Platelet count <150×109/L. 
10. Clinical evidence of hepatic decompensation as defined by the presence of any of the 
following abnormalities:  
 Serum albumin ≤3.5 g/dL, 
 International normalized ratio (INR) ≥1.3 (a single retest is permitted if laboratory 
error is suspected), 
 Total bilirubin >1.8 mg/dL and/or direct bilirubin >0.8 mg/dL (unless due to Gilbert’s 
syndrome, as documented in the subject’s medical history/records), or 
 History of esophageal varices, ascites, or hepatic encephalopathy. 
11. Evidence of other forms of chronic liver disease including the following:  
 Hepatitis B, as defined by presence of hepatitis B surface antigen (HBsAg) at 
screening, 
 Hepatitis C, as defined by presence of hepatitis C virus (HCV) antibody (anti-HCV), 
and HCV ribonucleic acid (RNA). Subjects with positive anti-HCV who test negative 
for HCV RNA at screening will be allowed to participate in the study,  
 Evidence of ongoing autoimmune liver disease, 
 Primary biliary cirrhosis, 
 Primary sclerosing cholangitis, 
 Wilson’s disease,  
 Homozygous alpha-1-anti-trypsin deficiency, 
 History of hemochromatosis or iron overload, 
 Drug-induced liver disease,  
 Known bile duct obstruction, 
 Suspected or proven liver cancer, or 
 Any other type of liver disease other than NASH 
12. Serum ALT >5 × the upper limit of normal (ULN). 


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13. Liver function tests (ALT/AST) > 5 × ULN at screening. One repeat test may be allowed 
within 7 days at the discretion of the Investigator. 
 If AST or ALT is > than ULN at screening visit an additional ALT, AST, INR, and 
total bilirubin will be obtained at least 2 weeks after the screening laboratories are 
obtained. If the abnormal parameters increase by > 30% at the retesting visit, the 
subject may not be randomized. The test may then be repeated in 2-4 weeks and if 
there is no further increase in the abnormal laboratory parameter, the subject may be 
randomized. 
14. Estimated glomerular filtration rate <60 mL/min/1.73 m2, as determined using the 
Modification of Diet in Renal Disease Study equation. 
15. History of biliary diversion.  
16. Positive for human immunodeficiency virus infection. 
17. Active, serious medical disease with likely life expectancy <2 years. 
18. Active substance abuse, including inhaled or injected drugs, within 1 year prior to 
screening. (Note that recreational cannabis/tetrahydrocannabinol use is permissible.) 
19. Use of any excluded medications listed in Section 9.8.1.  
20. Participation in an investigational new drug study in the 30 days prior to randomization 
(with the exception of Cohort 3 in which participants are prior placebo recipients in 
Cohort 1 and 2 of this study). 
21. History of clinically significant dry eye (xerophthalmia) or other corneal abnormality or, 
if a contact lens wearer, does not agree to abstain from contact lens use from baseline 
through the last study drug dose. 
22. Evidence of a clinically significant abnormality on slit-lamp examination or other 
clinically significant ophthalmologic finding, as determined by an ophthalmologist. 
23. Known allergy or hypersensitivity to components of TVB-2640. 
24. Prior history of hypersensitivity or drug/radiation-induced or other immune mediated 
pneumonitis. 
25. Prior history of PPE syndrome. 
26. Any contraindication to MRI (e.g., claustrophobia, metal implants). 
27. Positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) polymerase 
chain reaction (PCR) test within 30 days before Baseline, history of hospitalization for 
COVID-19, or history of use of oxygen due to COVID-19. Note that previous COVID-19 
infection alone is not exclusionary and vaccination against SARS-CoV-2 is allowed, but 
must be documented. 
28. 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. 


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8.4. 
Source of Subjects 
This will be a multi-center study. Each study center is required to obtain Institutional Review 
Board (IRB) approval to conduct the study before enrollment of subjects may commence. 
Subjects meeting the entry criteria who are known by or referred to the study center will be 
eligible for enrollment. 
8.5. 
Subject Identification and Randomization 
Subjects who are candidates for enrollment into the study will be assigned a sequential and 
unique subject number by the Investigator after the subject has provided written informed 
consent. Once a subject number has been assigned, it cannot be reused. 
Subjects who have provided written informed consent will be evaluated for eligibility by the 
Investigator to ensure that the entry criteria (see Section 8.2 and Section 8.3) have been satisfied 
and that the subjects is eligible for participation in this clinical study.  
Note that subjects who initially fail to meet all entrance criteria based on screening assessments 
(i.e., screen failures) may be submitted for re-screening once, with each case handled on an 
individual subject basis. The subject must be submitted for review via electronic mail and only 
entered into the electronic data capture (EDC) system as a screening candidate with written 
approval from the medical monitor. Subjects who initially fail screening because of clinical 
laboratory tests may have laboratory tests repeated during screening, at the Investigator’s 
discretion, without being re-submitted for screening.  
Three TVB-2640 dose levels are planned to be evaluated in a sequential fashion:  25 mg and, if 
study suspension criteria are not met at the 25 mg dose level (see Section 7.2), 50 mg, and then, 
in an open-label fashion, 75 mg.  
At the 25 and 50 mg dose levels, subjects will be randomly assigned to TVB-2640 or placebo at 
a 2:1 ratio, with randomization stratified by type 2 diabetes mellitus status. The 50 mg dose level 
will also be stratified by country:  
 Cohort 1:  25 mg dose level:  TVB-2640 (Planned N=30) and Placebo (Planned N=15) 
 Cohort 2:  50 mg dose level:  US: TVB-2640 (Planned N=30) and Placebo (Planned 
N=15); China: TVB-2640 (Planned N=18) and Placebo (Planned N=9); Total: TVB-2640 
(Planned N=48) and Placebo (Planned N=24) 
Subjects are to receive their first study drug dose on Day 1 within 24 hours after randomization. 
At both dose levels, subjects will receive TVB-2640 or placebo QD PO for 12 weeks, or until the 
time of the final on-treatment MRI-PDFF if after Week 12, but for no longer than 16 weeks. 
After completion of Cohorts 1 and 2, subjects assigned to placebo in either cohort are eligible to 
crossover to receive TVB-2640 75 mg in Open-label Cohort 3 (Planned N=12 in order to obtain 
10 evaluable subjects). 
8.6. 
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 


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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 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. 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, pain, or dryness of the 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 should be undertaken. 
 Evidence of drug-induced liver injury (DILI); Study drug should be permanently 
discontinued for subjects with evidence of DILI; see Appendix A for details. 
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 >7 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. 
 Non-compliance. 
 Lost to follow-up. 
 Subject withdrawal of consent. 
 Sponsor request. 
At the time of withdrawal, all study procedures outlined for the Early Termination visit should be 
completed. The primary reason for a subject’s withdrawal from the study is to be recorded in the 
electronic case report form (eCRF). 


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8.7. 
Safety Review Committee 
An SRC will oversee the study to ensure subject safety and to advise if any dosing alterations are 
recommended. The SRC will review safety including liver-related events (i.e., clinically 
meaningful elevations in ALT, AST, and bilirubin), and other efficacy (lipid parameters) and 
safety data as needed.  
If study suspension criteria are met at any time (see Section 7.2), the SRC will review the 
relevant study data and make a determination whether enrollment and treatment of subjects may 
continue or be permanently terminated. In addition, the SRC will review all safety data from the 
25 mg dose level after all subjects at that dose level complete the 12-week treatment period. 
Enrollment and treatment of subjects at the 50 mg dose level may commence only with the 
written approval of the SRC and with US FDA review.  
8.8. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study. The Investigator at each 
study center is responsible for ensuring the accuracy and completeness of all research records, 
the accountability of study drug, and the conduct of clinical and laboratory evaluations as 
outlined in the protocol. 
8.9. 
Subject Adherence to Protocol Schedule 
All subjects are required to adhere to the protocol-specified visit schedule.  
Subjects will be evaluated for study eligibility during the screening period, within 60 days before 
randomization. All subjects must provide written informed consent before any study-related 
samples are collected or evaluations performed in this study.  
Subjects who are determined to be eligible for the study will be randomized within 24 hours 
before baseline (Day 1, the first day of study drug administration). Thereafter, subjects are to 
attend study center visits at Day 2 and Week 2, 4, 8, and 12. Subjects who discontinue study drug 
before completion of the Week 12 visit are to attend an Early Termination visit within 1 week 
after the last study drug dose. All study visits are to be conducted on an out-patient basis. 
Additional study center visits may be scheduled, as deemed necessary based on the subject’s 
clinical status.  
Permissible visit windows are specified in Table 2. 
A Follow-up visit will be conducted at Week 16 (±1 week) for MRI-PDFF, measurement of liver 
aminotransferases, and safety assessments. Additional safety follow-up may be required 
thereafter if drug-related AEs have not resolved at that time. 
Failure to attend scheduled study visits within the protocol-specified windows may result in 
discontinuation from the study.  
The Sponsor notes that the COVID-19 pandemic may impact the conduct of the 50 mg and 
75 mg cohorts, with challenges potentially arising from quarantines and travel limitations 
affecting study subjects as well as clinic and imaging facility closures. Accordingly, safety 
assessments scheduled for the Week 12 and 16 visits, as identified in Table 2, including sample 


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collection for clinical laboratory tests, physical examinations, and documentation of AEs, may be 
performed at an alternate study center or by home health care visit. Furthermore, if the subject is 
unable to attend the Week 12 visit at the study center, one MRI-PDFF may be performed at any 
time between Week 11 and 16. If this scan is performed after Week 12, the subject must continue 
to receive study drug until the final scan is performed; however, study drug is not to be continued 
for >16 weeks. The safety of subjects who continue dosing beyond 12 weeks will be assessed 
during this continued dosing period by planning for blood sample collection at an alternate site 
or home visit at Week 12 and blood sample collection and physical examination on the last day 
of dosing. A 4-week off treatment safety assessment is to occur after the last dose, regardless of 
whether a subject receives treatment for 12 or 16 weeks. 


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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 oral administration as 25 and 
50 mg strength tablets.  
9.1.2. 
Placebo 
A placebo tablet is available which conforms to the appearance, shape and size of the TVB-2640 
50-mg strength tablet. 
9.2. 
Study Drug Packaging and Labeling 
TVB-2640 will be packaged in bulk, screw-top plastic bottles. 
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.  
9.4. 
Study Drug Accountability 
The US FDA, Chinese Food and Drug Administration (CFDA) 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.  
Each study center is to use a study drug accountability log to document study drug disposition. 
All items on this form are to be completed in full. The Sponsor’s clinical research associate 
(CRA) is to approve the area where study drug is to be stored and accountability records are to 
be maintained. 
The investigator identification number and subject initials (as allowed by local regulations) and 
identification number are to be recorded on each study drug accountability log. Each time study 
personnel dispense study drug for a subject, he or she is to record the date dispensed, amount of 
study drug dispensed, and his or her initials. Study personnel are to monitor the inventory of 
clinical supplies and maintain a count of all used and unused study drug. The CRA is to review 
study drug accountability records and remaining drug supplies during routine monitoring visits. 


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9.5. 
Study Drug Dose and Administration 
All subjects will receive study drug QD PO for 12 weeks, or until the time of the final on-
treatment MRI-PDFF if after Week 12, but for no longer than 16 weeks, with the first dose 
administered on Day 1. 
Each QD dose of study drug is to be taken at the same time of day with food; the study drug dose 
is to be taken in the morning on Days 1 to 8 and then in the evening on each day thereafter, with 
each dose separated by 24 hours (±4 hours). (The Day 8 and 9 doses will be separated by 
36 hours.) Subjects will receive one of the following each day, based on their cohort and 
treatment assignment: 
 Placebo:  1 placebo tablet 
 TVB-2640 25 mg:  1 25-mg TVB-2640 tablet 
 TVB-2640 50 mg:  1 50-mg TVB-2640 tablet 
 TVB-2640 75 mg:  1 50-mg TVB-2640 tablet and 1 25-mg TVB-2640 tablet 
9.6. 
Dose Reductions 
Dose reductions for the management of other study drug-related toxicities are permissible for 
subjects assigned to TVB-2640 50 mg or 75 mg with the approval of the Medical Monitor.  
 Subjects assigned to 50 mg may have the dose reduced to 25 mg. In such cases, subjects 
will receive 1 25-mg tablet. 
 Subjects assigned to 75 mg may have the dose reduced to 50 mg. In such cases, subjects 
will receive 1 50-mg tablet. 
Subjects for whom the study drug dose is reduced are to continue treatment at the reduced dose 
for the remainder of the treatment period. At the time the dose is reduced, all study drug is to be 
returned and study drug will be redispensed according to the reduced dose. 
Subjects receiving 25 mg for whom a dose reduction is deemed necessary should be discontinued 
from the study. 
9.7. 
Rationale for the Doses Selected 
The following 3 dose levels have been selected for this study:  25 mg, 50 mg, and 75 mg, 
delivered in QD PO tablet(s) of strengths 25 mg and 50 mg.  
These doses are expected to span a range of effects on the primary endpoint, percentage of 
subjects achieving a 30% or greater reduction of liver fat determined by MRI-PDFF, as well as 
overall reduction of liver fat. This range also is expected to enable determination of minimal 
effective dose for future studies. In addition, the AE profile of the doses will be collected and 
used to assess dose optimization for future studies. 
In a Phase 1 study of 12 otherwise healthy men with characteristics of the metabolic syndrome 
(Study 2006432), 6 subjects received 50 mg of QD TVB-2640 for 10 days, the lowest dose 
tested. This 50 mg dose reduced hepatic lipogenesis by an average of 24% (95% confidence 
interval -4%, -39%, p=0.02) and reduction was observed in 100% of the 6 subjects. These data, 


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and similar observations with other hepatic lipogenesis inhibitors, suggest that 12 weeks of QD 
dosing with 50 mg or 75 mg of TVB-2640 will result in at least a 30% reduction of intrahepatic 
fat in a large percentage of NASH subjects.  
The safety of the 50 mg and 75 mg doses is supported by nonclinical Good Laboratory Practice 
(GLP) toxicology studies and prior human experience.  
 
 
 
 
 
 
 
 
 
 
 
Additionally, none of the 6 men with metabolic syndrome who 
received 50 mg of TVB-2640 experienced a TEAE. 
In Study 3V2640-CLIN-002, cancer patients received daily doses of 100 mg or greater of 
TVB-2640 and the blood exposure was reported to be linearly proportional to the oral dose. PK 
data from the Phase 1 study of 12 men with metabolic syndrome are consistent with this 
relationship. 
 
 
 
. 
Refer to the Investigator’s Brochure for a summary of safety data with TVB-2640. 
The existing nonclinical and clinical studies of TVB-2640 support the safety of the doses 
selected as well as the potential to differentiate the activity of the drug on the percent of subjects 
achieving a 30% or greater reduction of liver fat and an overall reduction of liver fat. These data 
will enable guidance of a minimal effective dose for future studies. 
Due to the COVID-19 pandemic, if the subject in the 50 mg and 75 mg cohorts is unable to 
attend the Week 12 visit, one MRI-PDFF may be performed at any time between Week 11 and 
16. If this scan is performed after Week 12, the subject must continue to receive study drug until 
the final scan is performed. However, study drug is not to be continued for >16 weeks.  
Nonclinical and clinical data obtained to date support daily dosing with TVB-2640 for 16 weeks, 
as follows:   
 Complete safety data from 30 subjects who received TVB-2640 25 mg for 12 weeks 
and available safety data from 30 subjects who received TVB-2640 50 mg for 4 to 
12 weeks (ongoing cohort) as reviewed by the SRC, support continued dosing beyond 
Week 12 and up to and including Week 16. Safety and PK data from these 2 doses 
demonstrate a proportional and expected plasma exposure of TVB-2640 in subjects, 
further providing confidence in continued dosing. 


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 Safety data are available from 136 patients with cancer who received either TVB-
2640 alone or in combination with a taxane of whom 72 received TVB-2640 at doses 
of 100 to 600 mg per day, with a mean and maximum time on treatment of 62 days 
(9 weeks) and 324 days (46 weeks), respectively. These doses and duration used in 
CLIN-002 far exceed those in the current study. 
 In addition to 2 previously completed 13-week GLP toxicity studies, the Sponsor is 
currently conducting 2 chronic toxicology studies. (
 
 
) 
a. The in-life portion of a 6-month chronic toxicity study in rats has been completed 
(SN19-1112); adverse in-life or clinical pathology toxicities were not observed in 
this study. Toxicokinetic results from this study were consistent with expected 
exposures. The AUC of TVB-2640 at the highest dose in this study 
, over 2.5-times higher than the 50 mg dose in humans. 
b. The in-life portion for the 9-month toxicity study in dogs has been completed 
through Week 36 of dosing (SN19-1113), with no in-life or clinical pathology 
toxicities observed through that time. The AUC of TVB-2640 at the highest dose 
was 
, over 2.4-times higher than the 50 mg dose in humans. 
9.8. 
Concomitant Medications 
All prescription and non-prescription medications and therapies, including pharmacologic doses 
of vitamins, herbal medicines, or other non-traditional medicines, taken from 28 days prior to the 
first dose of TVB-2640 through the Final Study Visit must be recorded in the eCRF.  
9.8.1. 
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 cytochrome P450 3A4 (CYP3A4). (Refer to the 
following for examples:  
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/drugin
teractionslabeling/ucm093664.htm.) 
 Drugs historically associated with NAFLD (amiodarone, methotrexate, systemic 
glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used 
for hormone replacement, anabolic steroids, valproic acid, and other known 
hepatotoxins). 
 Glucagon-like peptide analogue or a complex oral OAD regimen (3 or more OADs). 
 Insulin dose adjustment >10%. (Subjects receiving insulin at baseline who require a 
>10% dose adjustment for the management of Type 2 diabetes mellitus are to be 
discontinued from the study.) 


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 Introduction of new or changes in continuing oral diabetic medications (e.g., 
pioglitazone) is prohibited. Concomitant oral diabetic medications are permitted only 
if the dose has been stable for at least 3 months before screening and remains stable 
throughout study participation.  
Subjects requiring such treatment during study participation are to be discontinued. 
9.8.2. 
Permitted Medications 
Medications and treatments other than those specified in Section 9.8.1 are permitted during the 
study. Subjects should be closely monitored, and treatment is to be instituted for disease-related 
symptoms, as appropriate. 
9.8.3. 
Contraception 
 
 
 females of childbearing potentia must use 
two forms of birth control, one being a barrier method (i.e., condoms, diaphragm, non-hormonal 
IUD) throughout the study and for at least 3 months after the final study drug dose. Hormonal 
contraception (estrogens stable ≥3 months) and hormonal IUDs are permitted if used with a 
secondary barrier birth control method (e.g., condoms). 
9.9. 
Blinding 
In Cohorts 1 and 2, study drug will be dispensed to subjects in a single-blinded fashion. All other 
study personnel, with the exception of personnel conducting/interpreting imaging studies (see 
Section 11.1) at each study center, will be unblinded to the subject’s treatment assignment. In 
Cohort 3, TVB-2640 will be dispensed in an open-label fashion. 


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10. 
BASELINE ASSESSMENTS 
All subjects must provide written informed consent 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. 
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 score, APRI, NAFLD fibrosis score, and/or enhanced liver function (ELF) 
score, as well as abbreviated weight history, family history (siblings and subjects; particularly of 
obesity and liver disease), past medical/surgical events and illness history (including diabetes, 
gestational diabetes, hypertension, lipodystrophy, polycystic ovarian syndrome, and any history 
of Gilbert’s disease) and other associated co-morbid 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 SARS-CoV-2 should also be 
documented. 
Social history, including alcohol, tobacco, and caffeine use, also will be documented.  
10.3. 
Screening Serology 
Screening serologies include HIV RNA, HBsAg, anti-HCV, and HCV RNA. A PCR test for 
SARS-CoV-2 (the virus that causes COVID-19) also is to be performed.  
Subjects with positive anti-HCV who test negative for HCV RNA at screening will be allowed to 
participate in the study. 
10.4. 
Pregnancy Testing 
For women of child-bearing potential, a serum β-hCG pregnancy test will be performed during 
screening and a serum or urine β-hCG pregnancy test will be performed within 48 hours before 
baseline. Results must be available and confirmed to be negative before the subject is eligible for 
randomization in the study. Pregnancy testing is to be repeated during the study any time 
pregnancy is suspected. 
All subjects of reproductive potential must agree to adequate birth control from the time the 
screening pregnancy test is performed through 3 months after the final study drug dose. 


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Study drug is to be discontinued for any subject with positive pregnancy test findings; see 
Section 12.2.6 for details regarding management of any pregnancies during the study.  
Women of non-child-bearing potential are to have this documented as part of the medical 
history. 


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11. 
EFFICACY, PHARMACOKINETIC, AND 
PHARMACODYNAMIC ASSESSMENTS 
11.1. 
Efficacy and Pharmacodynamic Assessments 
11.1.1. 
Magnetic Resonance Imaging Studies 
All imaging studies will be done by experienced research personnel according to a standard 
imaging protocol. Personnel reading imaging studies will be blinded to the subject’s treatment 
group allocation and clinical and biochemical data. A trained image analyst will assess all 
images at each study center; ideally, the same reviewer should review all scans at that study 
center for the duration of the study. All imaging studies also will be read centrally; the central 
reader also 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 read will be used in the 
analysis of imaging data. 
11.1.1.1. Proton-density Fat Fraction by Magnetic Resonance Imaging (MRI-PDFF) 
MRI-PDFF is a non-invasive, quantitative, and accurate measure of liver fat content to assess 
treatment response in early-phase of NASH studies (Caussy 2018). MRI-PDFF is to be 
determined at the time points designated in Table 2. Visceral adipose tissue measurement by 
MRI will be performed for all eligible subjects. Subjects who are randomized will have repeat 
visceral adipose tissue and liver fat measurements performed. 
11.1.1.2. Liver Stiffness by Magnetic Resonance Elastography 
MRE has been shown to be a robust, accurate biomarker for the quantitative, noninvasive 
evaluation of liver stiffness as a surrogate for liver fibrosis and for NASH detection. MRE is to 
be determined during screening, as per Table 2. Note that subjects without a biopsy performed 
within 24 months of randomization MUST have MRE performed during screening. 
11.1.2. 
Liver Fibrosis by FibroScan 
The degree of liver fibrosis, as indicated by the kpa, will be assessed using Fibroscan at the time 
points designated in Table 2.  
11.1.3. 
Clinical Laboratory Tests 
Refer to the Laboratory Manual for details regarding clinical efficacy/pharmacodynamic 
laboratory sample collection, processing, storage, and shipment. Note that in Cohort 3 (75 mg), 
some of the exploratory biomarker samples will not be collected or may be collected on an 
optional basis, as indicated in Table 2. 
11.1.3.1. Lipid and Metabolic Panel, Glycated Hemoglobin, and Lipoprotein Particle Size 
A fasting blood sample for lipid and metabolic panels as well as HbA1c is to be collected at the 
time points designated in Table 2. The following parameters are to be determined: 
 Lipid Panel:  LDL-C, non-LDL-C, HDL-C, non-HDL-C, total cholesterol, TG, ApoB, 
and Lp(a) particles 


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 Metabolic Panel:  Glucose, insulin, NEFA, and GGT. HOMA2-IR and adipo-IR are to 
be calculated from fasting insulin, fasting glucose, and fasting NEFA, as applicable 
 Hb1Ac 
 Lipoprotein Particle Size Analysis by nuclear magnetic resonance (NMR) 
Subjects are to fast overnight for at least 9 hours prior to collection of the fasting sample. (Water 
is permissible.) 
11.1.3.2. NASH / Fibrosis Markers 
A blood sample for NASH / fibrosis markers, including CK-18, FIB-4 Index, ELF (TIMP-1, 
PIIINP, HA), PROC3, and FIBROSpect 2, is to be collected at the time points designated in 
Table 2. Instructions regarding the calculation of indices are provided in the Operations Manual. 
11.1.3.3. Eicosanoid Panel 
A blood sample for an eicosanoid panel, including 5-LOX–derived leukotriene B4 (LTB4), 
COX-derived prostaglandin E2 (PGE2), and 15-LOX–derived 15-hydroxyeicosatetraenoic acid 
(15-HETE) and lipoxin A4 (LXA4), is to be collected at the time points designated in at the time 
points designated in Table 2. 
11.1.3.4. Inflammatory Biomarkers 
A blood sample for inflammatory biomarkers, including tumor necrosis factor-alpha (TNFα), 
interleukin (IL)-6, IL-8, high-sensitivity C-reactive protein (Hs-CRP), monocyte chemoattractant 
protein-1 (MCP-1), is to be collected according to the time points in Table 2. 
11.1.3.5. Adiponectin, Resistin, Leptin  
A blood sample for determination of adiponectin, resistin, and leptin, is to be collected according 
to the time points in Table 2, with these parameters determined using enzyme-linked 
immunosorbent assay (ELISA). 
11.1.4. 
Lipidomic Analyses 
In the current study, a fasting blood sample for fatty acid analyses will be collected according to 
the time points in Table 2. Plasma TG will be isolated from the blood. The quantity and 
composition of fatty acids in these TGs will be evaluated. The quantity and composition of fatty 
acids in these TGs will be evaluated. The quantity of palmitate (C16:0) in this fraction, 
representing hepatic synthesized lipid, will be compared to the quantity of omega-6-linoleic acid 
(C18:2n6), an essential fatty acid obtained through dietary sources. Decreased ratios of C16:0 / 
C18:2n6 are indicative of decreased hepatic lipogenesis (Hudgins, 1996).  
11.1.5. 
Genomics 
A blood sample for genomics pertaining to the disease under study will be collected at the time 
points designated in Table 2; subjects will be asked to provide separate written informed consent 
for the collection of such samples. 


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11.1.6. 
Sample Collection for Storage 
Blood and spot urine samples for storage will be collected at the time points designated in 
Table 2. 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 nor 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 the Regulatory Authorities will have access to the 
samples/data if they are ever used for a future research. 
The collection of blood and spot urine samples for storage is not voluntary and will be collected 
for all subjects randomized to the study. 
11.1.7. 
Anthropometric Assessments 
Anthropometric assessments are to be performed at the time points designated in Table 2, 
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 
11.1.8. 
Lymphocyte Subsets in Peripheral Blood Mononuclear Cells 
Blood samples are to be collected from a subset of subjects enrolled at selected study centers at 
baseline and Week 12 for exploratory evaluation of change in CD4/Th17/regulatory T-cell  
populations and, potentially, natural killer-T and epigenetic or activation changes in peripheral 
blood mononuclear cells. 
11.2. 
Pharmacokinetic Assessments 
 
 
 
 
 
 


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The times of study drug administration, the most recent meal prior to blood sample collection, 
and of blood sample collection ares to be documented in the eCRF. 
 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Vital Signs 
Vital signs, including oral temperature (ºC), pulse (bpm), systolic and diastolic blood pressure 
(mmHg), and respiration rate (breaths/minute), are to be measured and documented in the eCRF 
at the time points designated in Table 2. 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 the time points designated 
in Table 2. The complete physical is to include examination of general appearance, 
head/ears/eyes/nose/throat, lungs/chest, heart, abdomen, lymph nodes, musculoskeletal, 
extremities, skin, and neurological examination. Liver signs (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). 
Abbreviated (i.e., symptom-directed) physical examinations, including assessment of focused 
liver signs (presence or absence of edema, ascites, hepatomegaly, splenomegaly, asterixis), skin, 
and extremities, will be conducted at the time points designated in Table 2 to address any 
complaints or concerns verbalized by the subject at all other study visits. 
Any abnormal findings are to be documented as AEs. 
12.1.3. 
Electrocardiogram (ECG) 
Single 12-lead ECGs are to be performed for all subjects at the time points designated in Table 2. 
On Day 1, ECGs are to be performed before and 4 hours after the first study drug dose, with the 
ECG performed prior to PK blood sample collection. 
12.1.4. 
Ophthalmologic Examinations 
Ophthalmologic examinations are to be performed for all subjects at the time points designated 
in Table 2. 
Near and far visual acuity is to be assessed by an ophthalmologist 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.) Note that contact 
lens wearers are to abstain from contact lens use during study drug treatment. 
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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If a subject experiences a treatment-emergent ophthalmologic abnormality, an ophthalmologic 
examination should be performed within 24 to 48 hours or 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 
according to the time points designated in Table 2. The following safety laboratory parameters 
are to be measured: 
Hematology 
Hematocrit 
Platelet count 
Hemoglobin 
White blood cell count with differential 
Red blood cell count 
Absolute neutrophil count 
Coagulation Studies 
 
Prothrombin time 
Activated partial thromboplastin time 
INR 
 
Chemistry (Fasting) 
Chloride 
Carbon dioxide 
Sodium 
Potassium 
Blood urea nitrogen 
Calcium 
Creatinine 
Magnesium 
Albumin 
Glucose 
Total protein 
Alkaline phosphatase 
AST* 
ALT* 
Indirect and direct bilirubin 
 
Creatine phosphokinase (total and fractionated) 
(screening and baseline only) 
 
*AST and ALT collected as part of the clinical chemistry panel are also applicable for efficacy assessments. 
Urinalysis 
Specific gravity 
Protein 
pH 
Ketones 
Blood 
Microscopic examination of sediment 
Glucose 
 
 
LFTs determined as part of the clinical chemistry panel will be used for the assessment of the 
secondary efficacy endpoint. 
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. 


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Laboratory abnormalities that are considered by the Investigator to be clinically significant for a 
particular subject are to be reported as an AE. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Events (AE) 
An AE is any untoward medical occurrence in a patient 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. 
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 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 (SAE) 
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. 
 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. 


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 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 forms provided by Sagimet Biosciences, or designee.  
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), Version 5.0 (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 
 
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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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/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. 
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 examination, observations 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 reported 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.  


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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. 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 ProSciento, Inc., Medical Monitor/Safety team. (In the 
event the EDC system is not available, then SAE reports must be emailed to 
3VBIOSafety@ProSciento.com.) 
The Investigator must complete and electronically sign and date the SAE pages of the eCRF and 
verify the accuracy of the information recorded on the SAE pages with the corresponding source 
documents.  
Additional follow-up information, if required or available, should be submitted within the EDC 
system within one business day of receipt and this should be completed on a follow-up SAE 
form and placed with the original SAE information and kept with the appropriate section of the 
eCRF and/or study file. 
Sagimet Biosciences is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Investigator’s responsibility to notify the IRB of all SAEs that occur at his or her 
study center. Investigators will also be notified of all unexpected, serious, drug-related events 
(7/15 Day Safety Reports) that occur during the clinical study. Each study center is responsible 
for notifying its IRB of these additional SAEs.  
12.2.5. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all treatment-emergent SAEs and non-serious AEs 
considered to be at least possibly related to study drug either until resolution or the event is 
clearly determined to be stable or due to a subject’s stable or chronic condition or inter-current 
illness(es). This follow-up may extend after the end of the study. 
12.2.6. 
Pregnancy 
Pregnancies occurring in the subject or subject’s partner while the subject is receiving study drug 
or within 3 months after the subject’s last dose of study drug will not be considered serious, but 
are to be reported using the same procedures as for SAEs described in Section 12.2.4.  
Study drug must be discontinued immediately in the event of a pregnancy in the subject. The 
subject should be referred to an obstetrician/gynecologist experienced in reproductive toxicity 
for further evaluation and counseling. 
The Investigator will follow the subject / subject’s partner until completion of the pregnancy, and 
must notify the Medical Monitor of the outcome within 5 days. The Investigator will provide this 
information as a follow-up to the initial report. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., 
spontaneous abortion [any congenital anomaly detected in an aborted fetus is to be documented], 
stillbirth, neonatal death, or congenital anomaly), then the Investigator should report it as such. 


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Furthermore, all neonatal deaths that occur within 28 days of birth should be reported, without 
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 
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 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. 
STATISTICS 
13.1. 
Determination of Sample Size 
The sample size is based on a fixed-sequence strategy which tests for a treatment difference in 
the primary endpoint (percent change at Week 12 in liver fat from baseline as determined by 
MRI-PDFF) between each randomized TVB-2640 dose group (25 and 50 mg) versus placebo. 
The fixed-sequence strategy will start with the highest dose group comparison. If statistically 
significant, then testing will proceed to the low dose group comparison. Each TVB-2640 dose 
group will be compared to the pooled placebo group using an F-test test from an analysis of 
covariance (ANCOVA) model with fixed effects for the stratification factor (diabetes 
presence/absence) and treatment group (i.e., TVB-2640 dose groups and pooled placebo) and 
with the baseline MRI-PDFF value as a covariate. Since the primary efficacy endpoint may not 
be normally distributed, the non-parametric Wilcoxon rank-sum test is conservatively used, 
instead of the F-test, for power calculations. 
The sample size is based on a conservative assumption that the primary analysis is going to be 
performed in the US population only, resulting in 30 evaluable subjects in the placebo group, and 
30 evaluable subjects in each of the randomized TVB-2640 dose levels. Based on Patel (2016), it 
is conservatively assumed that the primary endpoint has a standard deviation of 30. Power 
calculations assume the primary endpoint is lognormally distributed with a standard deviation of 
30, there are at least 30 evaluable subjects in each treatment group, and the two-sided Wilcoxon 
rank sum test will be used to test each pairwise treatment difference at the 0.05 Type I error 
level. Under the fixed-sequence strategy which maintains an overall 0.05 Type I error rate, the 
study has at least 80% overall power to detect both treatment differences (i.e., both high dose 
[50 mg] versus placebo and low dose [25 mg] versus placebo), if each mean treatment difference 
is at least 24. If the study does not proceed to the high-dose level, (i.e., there are 30 evaluable 
subjects treated with 25 mg TVB-2640 and only 15 with placebo), then the study has at least 
77% power to detect a mean treatment difference of at least 24. The study will have more power 
if the subjects from China are included in the primary analysis and the same assumptions of 
treatment difference and variability hold. 
Power calculations for the key secondary endpoint (percentage of subjects with at least a 30% 
reduction in the primary endpoint) are based on pairwise comparisons with the placebo group 
using Fisher’s two-sided exact test [equivalent to Cochran-Mantel-Haenszel (CMH) without 
stratification] at the 0.05 significance level. Based on Loomba (2018), it is expected there will be 
less than 5 responses out of 30 evaluable subjects in the placebo group (i.e., less than 16.7%). 
With 30 evaluable subjects in each treatment group, there is at least 80% power to detect at least 
a 36.7% increase in the response rate (TVB-2640 treatment group minus placebo) when the 
placebo response rate is at most 16.7%. If the study does not proceed to the high-dose level, (i.e., 
30 evaluable subjects treated with 25 mg TVB-2640 and only 15 with placebo), then the study 
has at least 63% power to detect at least a 36.7% increase in the response rate (25 mg TVB-2640 
treatment group minus placebo) when the placebo response rate is at most 2 out of 15 evaluable 
subjects (i.e., 13.34%).With 30 subjects in each TVB-2640 treatment arm, there is at least a 95% 
probability of detecting at least 1 AE when the AE rate is 10% or more in the underlying 
population. The open label 75mg cohort is being assessed for safety only.  


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13.2. 
Statistical Analyses 
13.2.1. 
Analysis Populations 
The modified intent-to-treat population (mITT) is defined as all subjects who are randomized, 
receive study drug for at least 8 weeks, and have a baseline and at least 1 post-baseline MRI-
PDFF assessment on or after Week 8. The mITT is the primary population for analysis of MRI-
PDFF assessments and subjects will be analyzed according to the randomized treatment 
assignment. 
The intent-to-treat population (ITT) is defined as all subjects who are randomized and received at 
least 1 dose of study drug. The ITT will be used for analysis of secondary efficacy endpoints and 
supportive and sensitivity analyses of MRI-PDFF assessments. Subjects will be analyzed 
according to the randomized treatment assignment. Details will be provided in the Statistical 
Analysis Plan (SAP). 
The safety population is defined as all subjects who are randomized and received at least 1 dose 
of study drug and will be used for all analysis of safety. Subjects will be analyzed according to 
the treatment received. If all subjects were dosed according to randomized treatment assignment, 
then the safety population and ITT are identical.  
13.2.2. 
Efficacy Analysis 
A test for country-by-treatment interaction with respect to the primary efficacy endpoint, percent 
change from baseline in hepatic fat fraction at Week 12, as determined by MRI-PDFF, will be 
performed in the 50 mg cohort. An ANCOVA model with fixed effects for the stratification 
factor (diabetes presence/absence), country (US/China), treatment group (TVB-2640 50 mg and 
pooled placebo), and country-by-treatment interaction and with the baseline MRI-PDFF value as 
a covariate including all subjects from US and China will be performed. If there is no interaction 
detected (p≥0.05), the primary efficacy endpoint, percent change from baseline in hepatic fat 
fraction at Week 12, as determined by MRI PDFF, will be analyzed using an analysis of 
covariance (ANCOVA) model with fixed effects for the stratification factor (diabetes 
presence/absence) and treatment group (i.e., randomized TVB-2640 dose groups and pooled 
placebo) and with the baseline MRI-PDFF value as a covariate including all subjects from US 
and China. If the country-by-treatment interaction is significant (p<0.05) then the primary 
analysis will be conducted on subjects enrolled in the US and will maintain sufficient power with 
the 90 evaluable subjects in the US (30 active in each cohort and 30 combined placebo). A 
separate analysis would be performed on subjects enrolled in China in the 50 mg cohort. This 
analysis is not powered to detect a significant difference but would be supportive/descriptive in 
nature to evaluate trends. 
The primary efficacy analyses will be based on a F-test from the ANCOVA model in the mITT 
to compare each randomized TVB-2640 dose group individually with the placebo group. The 
fixed-sequence method, as described below, will be used to maintain an overall 0.05 Type I error 
rate. Data normality will be assessed and the appropriate data transformation will be applied to 
fulfill the underlying assumption of the ANCOVA model; if a suitable transformation cannot be 
determined the corresponding rank ANCOVA will become the primary analysis for this 
endpoint. Treatment interaction will be evaluated among the treatment groups, and if needed it 


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will be considered supportive of the primary efficacy analyses. Summary statistics will be 
displayed by treatment group along with the difference in least squares means (and the associated 
95% confidence interval and p-value) for each randomized TVB-2640 dose group to pooled 
placebo comparison. 
Differences between each randomized TVB-2640 dose group (25 mg, 50 mg) and pooled 
placebo for the key secondary efficacy endpoint, the percentage of subjects achieving a 30% or 
greater reduction of liver fat, as determined by MRI-PDFF (i.e., a response), will be analyzed 
using CMH methods. The key secondary efficacy analyses will be based on a CMH test in the 
mITT to compare each randomized TVB-2640 dose group with placebo, adjusting for the 
stratification factor (diabetes presence/absence). If a country-by-treatment interaction is found in 
the primary efficacy endpoint, the subjects from the US and China in the 50 mg cohort may be 
analyzed separately for the key secondary efficacy endpoint and analysis of the subjects from 
China will be viewed as supportive/descriptive. To check for other possible interactions, i.e., 
diabetes strata-dependent treatment effects, the Breslow-Day test will be performed; if the p-
value of the Breslow-Day test is ≥0.05, the treatment-by-strata interaction is deemed not 
significant. However, if the interaction effect is statistically significant (i.e., p-value <0.05), then 
the Gail and Simon test will be used to test for the qualitative interaction at a significance level 
of 0.05 and provided as an aid for interpretation of the CMH results. The estimated response 
rates and the corresponding exact 95% confidence interval based on a binomial distribution will 
be calculated for each treatment group. The exact 95% confidence limit for the CMH estimate of 
the common risk difference will also be obtained; a Wald asymptotic approximation with 
continuity correction is an acceptable substitute for the exact limits in the event of computational 
difficulties. Response level definitions other than 30% may be explored in additional supportive 
analyses. 
The primary and key secondary efficacy analyses will be conducted using a fixed-sequence 
strategy to maintain the overall Type I error rate at 0.05. The primary efficacy analyses will 
compare the primary efficacy endpoint between each randomized TVB-2640 dose group with the 
pooled placebo group, each using a 2-sided test at the 0.05 level of statistical significance with 
the goal of identifying the minimum effective dose. The primary efficacy analyses start with the 
highest dose-group comparison and if statistically significant, testing will proceed to the low 
dose group comparison. If both comparisons of the primary efficacy endpoint are significant, 
then testing will proceed to the key secondary efficacy analyses. The key secondary efficacy 
analyses will similarly compare the key secondary efficacy endpoint between each randomized 
TVB-2640 dose group with pooled placebo group, each using a 2-sided test at the 0.05 level of 
statistical significance. The key secondary efficacy analyses start with the highest dose-group 
comparison and if statistically significant, testing will proceed to the low dose group comparison. 
In the primary and key secondary analyses, missing Week 12 values for MRI-PDFF will be 
imputed with the last post-baseline observation on or after Week 8 in the mITT. Secondary and 
sensitivity analyses using other methods for missing data methods and in different analysis 
populations will be described in the SAP. 
For other continuous secondary efficacy endpoints measured at multiple post-baseline visits, the 
changes at 12 weeks will be summarized for each treatment group and compared between each 
randomized TVB-2640 dose group and pooled placebo using a linear mixed-effects model for 
repeated measures in the ITT. The model will include the stratification factor (diabetes 


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presence/absence), treatment group, visit, and treatment-by-visit interaction as the fixed effects, 
and baseline value as a covariate using an unstructured variance-covariance matrix. The point 
estimates for the least-squares mean of the pairwise difference for each randomized TVB-2640 
dose group and pooled placebo comparison at each visit and the corresponding 95% confidence 
interval and two-sided p-value will be summarized. Other variance-covariance structures may be 
substituted if convergence problems arise. 
Similarly, a generalized linear mixed-effects model for repeated measures based on a logit link 
function will be used for comparing other categorical efficacy endpoints at Week 12 between 
each randomized TVB-2640 dose group and pooled placebo in the ITT. The model will include 
the stratification factor (diabetes presence/absence), treatment group, visit, treatment-by-visit 
interaction as fixed effects and, depending on the nature of the data, the baseline result as fixed 
effect or covariate with an unstructured variance-covariance matrix. The point estimates for the 
least-squares mean of the pairwise difference for each randomized TVB-2640 dose group and 
pooled placebo comparison at each visit and the corresponding 95% confidence interval and two-
sided p-value will be summarized. Other variance-covariance structure may be substituted if 
convergence problems arise.  
Subset analyses will be performed on all efficacy endpoints for subjects enrolled in China to 
evaluate the consistency of results between subjects enrolled in each country.  
Efficacy data will be summarized descriptively for Cohort 3. 
Details for handling of data from the US and Chinese subjects will be described in the SAP. 
Additional details of analysis of other secondary efficacy endpoints and the analysis of 
exploratory and safety endpoints and pharmacokinetics will be described in the SAP. 
13.2.3. 
Safety Analysis 
No formal statistical testing will be conducted for the safety analyses. Analysis of safety will be 
detailed in the SAP. Subset analyses will be performed on all safety endpoints for subjects 
enrolled in China to evaluate the consistency of results between subjects enrolled in each 
country.  


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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://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_
R2__Step_4_2016_1109.pdf 
14.2. 
Institutional Review Board (IRB) 
The IRB 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 
approval has been obtained. The protocol, Investigator’s Brochure, informed consent, 
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 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 as appropriate. Written IRB 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 of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB 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 upon receipt of amendments and annually, as local regulations require. The 
Investigator is also responsible for providing the IRB 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 
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 15.5 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 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. 
The Investigator(s) must maintain the original, signed Informed Consent Form. 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 initials (as allowed by local regulations) and 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. 
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. Any 
electronic study data are to be entered into a secure, validated data processing system and a 
backup maintained. Any changes to electronic study data will be documented. 
15.4. 
Retention of Records 
The Investigator will maintain all study records according to ICH GCP and applicable regulatory 
requirement(s). Records will be retained for 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 the responsibility. The Sponsor must be notified immediately by telephone or e-mail and 
the notification confirmed in writing if a custodial change occurs. 
15.5. 
Audits and Inspections 
Authorized representatives of Sagimet Biosciences or designee, a regulatory authority, or IRB 
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. 
 
 
 
 
 
 
 
 
 
 
  
 
 


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16. 
LIST OF REFERENCES 
Andrade P, Rodrigues S, Rodrigues-Pinto E, Gaspar R, Lopes J, Lopes S, Macedo G. Diagnostic 
Accuracy of Controlled Attenuation Parameter for Detecting Hepatic Steatosis in Patients with 
Chronic Liver Disease. GE Port J Gastroenterol. 2017;24(4):161-168.  
Beysen C, Murphy EJ, Nagaraja H, Decaris M, Riiff T, Fong A, et al. A pilot study of the effects 
of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes. J Lipid Res 
2008;49(12):2657-63.  
Buckley D, Duke G, Heuer TS, O'Farrell M, Wagman AS, McCulloch W, Kemble G. Fatty acid 
synthase - Modern tumor cell biology insights into a classical oncology target. Pharmacol Ther. 
2017;177:23-31.  
Caussy C, Reeder SB, Sirlin CB, Loomba R. Non-invasive, quantitative assessment of liver fat 
by MRI-PDFF as an endpoint in NASH trials. Hepatology. 2018;68(2):763-772. 
Clinical Study Report for Project 2006432, “Evaluation of TVB-2640, a FASN Inhibitor, to 
reduce de novo lipogenesis in subjects with characteristics of the metabolic syndrome”. 
Cusi K. Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current 
approaches and future directions. Diabetologia. 2016;59(6):1112-20.  
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):1343-51. 
Duke G, Wagman AS, Buckley D, McCulloch W, Feigh M, Veidal S, 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. Abstract 1994. AASLD, 2017. 
Dulai PS, Sirlin CB, Loomba R. MRI and MRE for non-invasive quantitative assessment of 
hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J Hepatol. 
2016 Nov;65(5):1006-1016.  
Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and 
management of the metabolic syndrome: an American Heart Association/National Heart, Lung, 
and Blood Institute scientific statement: Executive Summary. Crit Pathw Cardiol 
2005;4(4):198-203. 
Hudgins LC, Hellerstein M, Seidman C, Neese R, Diakun J, Hirsch J. Human fatty acid synthesis 
is stimulated by a eucaloric low fat, high carbohydrate diet. J Clin Invest. 1996;97(9):2081-91. 
Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, et al. Re-evaluation of fatty 
acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med. 
2007;20(3):351-8. 
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):726-35.  


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Loomba et al. Oral Abstracts (Abstracts 1–263). Hepatology 201766:1–148.  
Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 Reduces 
Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease. 
Gastroenterology. 2018 Nov;155(5):1463-1473.e6.  
Mitsuyoshi H, Yasui K, Harano Y, Endo M, Tsuji K, Minami M, 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):366-73.  
Musso G, Cassader M, Paschetta E, Gambino R, Thiazolidinediones and advanced liver fibrosis 
in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 2017;177(5):633-640.  
Patel J, Bettencourt R, Cui J, Salotti J, Hooker J, Bhatt A, et al. Association of noninvasive 
quantitative decline in liver fat content on MRI with histologic response in nonalcoholic 
steatohepatitis. Ther Adv Gastroenterol 2016;9(5):692-701. 
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.  
Stiede K, Miao W, Blanchette HS, Beysen C, Harriman G, Harwood HJ, et al. Acetyl-coenzyme 
A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A 
randomized, double-blind, crossover study. Hepatology 2017;66:324–334.  
Syed-Abdul MM, Parks EJ, Gaballah AH, Bingham K, Hammoud GM, Kemble G, et al. First-in-
class fatty acid synthase inhibitor TVB-2640 reduces hepatic de novo lipogenesis in males with 
metabolic abnormalities. Hepatology. 2019 Oct 20. doi: 10.1002/hep.31000. [Epub ahead of 
print]. 
Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty 
liver disease. N Engl J Med. 2010 Sep 30;363(14):1341-50.  
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):E275-81. 
Widya RL, de Mutsert R, den Heijer M, le Cessie S, Rosendaal FR, Jukema JW, et al. 
Association between Hepatic Triglyceride Content and Left Ventricular Diastolic Function in a 
Population-based Cohort: The Netherlands Epidemiology of Obesity Study. Radiology. 
2016;279(2):443-50.  
Wilke MS, French MA, Goh YK, Ryan EA, Jones PJ, Clandinin MT. Synthesis of specific fatty 
acids contributes to VLDL-triacylglycerol composition in humans with and without type 2 
diabetes. Diabetologia. 2009;52(8):1628-37.  


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17. 
APPENDICES 


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Appendix A: Algorithm for Evaluating Subjects for a Potential Drug-induced Liver Injury 
(DILI) 
The mean of at least 2 liver aminotransferase values taken at least 4 to 12 weeks apart during 
screening should be used to establish baseline values; the first measurement may be a historical 
measurement.  
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 days. Monitor the subject 
as per “close observation” 
definition* in the DILI guidance. 
ALT or AST above normal 
range at baseline 
increase ≥3 × baseline levels and 
no liver related symptoms 
ALT or AST above normal 
range at baseline 
increase ≥3x baseline + subject 
experiences liver related 
symptoms (nausea, vomiting, 
right upper quadrant pain) 
Interrupt study drug. Initiate 
potential DILI evaluation for 
alternative etiologies and repeat 
liver profile and PT/INR within 
48-72 hours and closely observe 
the subject. 
*Close observation as defined in the FDA DILI guidance i.e., laboratory testing and physical examination 
2-3 times per week. Study drug is to be restarted only if a firm alternative etiology is “identified” and the 
liver tests return to baseline. 
2. Elevation of aminotransferase and total bilirubin or cholestatic markers: 
Analyte 
Event during the study 
Action 
TB + AST or ALT 
↑ TB >2 mg/dL 
and 
↑ ALT or ALT ≥3x baseline or 
5x ULN (whichever comes first) 
Interrupt study drug. 
Initiate potential DILI evaluation 
for alternative etiologies.  
Repeat liver profile and PT/INR 
within 48-72 hours and place 
subject under “close 
observation” as defined in the 
DILI guidance. 
Study drug can be restarted only 
if a firm competing etiology is 
identified and the liver tests 
return to baseline. 
TB, ALP, or GGT  
↑ TB >2 mg/dL  
and 
ALP or GGT ↑ >2X ULN 


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Analyte 
Event during the study 
Action 
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 
nausea, vomiting, right upper 
quadrant pain (symptoms 
consistent with clinical hepatitis) 
Permanently discontinue study 
drug.  
Initiate potential DILI evaluation 
for alternative etiologies.  
Repeat liver profile and PT/INR 
within 48-72 hours and place 
subject under “close 
observation” as defined in the 
DILI guidance. 
 
Note the following: 
1. If a subject lives in a remote area, they can be tested locally, with the results 
communicated to the Investigator promptly. 
2. For subjects with Gilbert’s syndrome, a doubling of direct bilirubin instead of total 
bilirubin should be used for close monitoring and TVB-2640 discontinuation. 
3. If 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: 
 If close monitoring of a subject is not possible. 
 In the presence of total bilirubin elevation (>2 × ULN or >1.5 × baseline); 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 degree of total bilirubin, ALT, or AST elevation recurs following re-challenge 
with study drug. 

SAP_001.pdf: 
 
 
PROTOCOL 3V2640-CLIN-005 
 
A PHASE 2, MULTI-CENTER, SINGLE-BLIND, 
RANDOMIZED, PLACEBO CONTROLLED STUDY OF 
TVB 2640 (ASC40) IN SUBJECTS WITH NON-
ALCOHOLIC STEATOHEPATITIS 
Statistical Analysis Plan 
 
 
 
FINAL VERSION 1 
DATE OF PLAN: 
02June2020 
 
 
STUDY DRUG:  
TVB-2640 
 
 
PREPARED FOR: 
Sagimet Biosciences 
 
 


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Version and Date: Final Version 1, 02June2020 
 
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Date 
 
 
 
 


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Approval Signature Page: Sagimet Biosciences 
 
 
 
 
 
 
 
  
 
 
Date 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 


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Contents 
ABBREVIATIONS ......................................................................................................................... 6 
1. 
Introduction ............................................................................................................................. 8 
2. 
Study Objectives and Endpoints .............................................................................................. 8 
2.1. 
Primary .............................................................................................................................. 8 
2.2. 
Secondary .......................................................................................................................... 8 
2.3. 
Exploratory ....................................................................................................................... 8 
3. 
Study Design ............................................................................................................................ 9 
3.1. 
Study Design and Population ............................................................................................ 9 
3.2. 
Randomization and Blinding .......................................................................................... 10 
3.3. 
Sample Size Considerations ............................................................................................ 10 
3.4. 
Safety Review Committee .............................................................................................. 11 
3.5. 
Timing of Analyses ......................................................................................................... 12 
4. 
Study Endpoints ..................................................................................................................... 12 
4.1. 
Efficacy ........................................................................................................................... 12 
4.2. 
Safety .............................................................................................................................. 13 
5. 
Analysis Populations/Sets ...................................................................................................... 13 
6. 
Definitions ............................................................................................................................. 14 
7. 
General Data Handling Considerations ................................................................................. 14 
7.1. 
Stratification and Covariates ........................................................................................... 15 
7.2. 
Evaluation of Subgroups ................................................................................................. 15 
7.3. 
Multiple Comparisons and Multiplicity .......................................................................... 15 
7.4. 
Reference Dates .............................................................................................................. 15 
7.5. 
Baseline and Post-Baseline Changes .............................................................................. 16 
7.6. 
Imputation of Partial Dates ............................................................................................. 16 
7.7. 
Multiple Assessments and Visit Windows ..................................................................... 17 
7.8. 
Missing Data ................................................................................................................... 18 
8. 
Analysis Methods .................................................................................................................. 18 
8.1. 
Study Subject Data .......................................................................................................... 18 
8.1.1. 
Subject Disposition ..................................................................................................... 18 
8.1.2. 
Protocol Deviations ..................................................................................................... 18 
8.1.3. 
Demographic and Baseline Characteristics ................................................................. 19 
8.1.4. 
Medical History ........................................................................................................... 19 


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8.1.5. 
Prior and Concomitant Medication ............................................................................. 19 
8.2. 
Study Drug Exposure and Compliance ........................................................................... 20 
8.3. 
Efficacy ........................................................................................................................... 20 
8.3.1. 
Primary Efficacy Endpoint and Analyses ................................................................... 20 
8.3.1.1. 
Primary Analysis of the Primary Efficacy Endpoint ............................................... 20 
8.3.1.2. 
Additional Analyses of the Primary Efficacy Endpoint .......................................... 21 
8.3.2. 
Secondary Efficacy Endpoints and Analyses .............................................................. 22 
8.3.3. 
Exploratory Efficacy Endpoints and Analyses ............................................................ 25 
8.4. 
Pharmacokinetics (PK) ................................................................................................... 25 
8.5. 
Safety .............................................................................................................................. 25 
8.5.1. 
Adverse Events ............................................................................................................ 26 
8.5.2. 
Clinical Laboratory Evaluations .................................................................................. 27 
8.6. 
Other Safety Evaluations ................................................................................................ 28 
8.6.1. 
Vital Signs ............................................................................................................... 28 
8.6.2. 
Electrocardiogram (ECG) ........................................................................................ 28 
8.6.3. 
Ophthalmologic Examinations ................................................................................ 28 
8.6.4. 
Physical Examinations ............................................................................................. 28 
9. 
Changes to the planned analyses ........................................................................................... 29 
Appendix 1. COVID-19 Impact and Data Handling ..................................................................... 30 
Appendix 2. Planned Tables, Listings, and Figures ...................................................................... 31 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Explanation 
15-HETE 
15-LOX–derived 15-hydroxyeicosatetraenoic acid 
Adipo-IR 
Adipose tissue insulin resistance 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoB 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
ATC 
Anatomic therapeutic class 
ATP 
As-Treated Population 
BMI 
Body mass index 
CI 
Confidence interval 
CK-18 
Cytokeratin-18 
cm 
Centimeter 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DM 
Diabetes mellitus 
DNL 
De novo lipogenesis 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ELF 
Enhanced liver function 
FASN 
Fatty acid synthase 
FDA 
Food and Drug Association 
FIB-4 
Fibrosis-4 
GGT 
Gamma-glutamyl transpeptidase 
HbA1c 
Glycated hemoglobin 
HDL-C 
High-density lipoprotein cholesterol 
HOMA-IR 
Homeostatic model assessment insulin resistance 
ICH 
International Council for Harmonisation 
IL-6 
Interleukin 6 
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 
LOCF 
Last Observation Carried Forward 
Lp(a) 
Lipoprotein(a) 
LTB4 
5-LOX–derived leukotriene B4 
LXA4 
Lipoxin A4 
m  
Meter 
max  
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Explanation 
min 
Minimum 
mITT 
Modified intent-to-treat population 
mmHg 
Millimeters of mercury 
MMRM 
Mixed model for repeated measures 
MRE 
Magnetic resonance elastography 
ms 
Millisecond 
N or n 
Number of subjects 
NASH 
Non-alcoholic steatohepatitis 
NCI 
National Cancer Institute 
NEFA 
Non-esterified fatty acid 
MRI-PDFF 
Proton density fat fraction by magnetic resonance imaging 
PGE2 
prostaglandin E2 
PK 
Pharmacokinetic 
PO 
Orally 
PP 
Per-protocol 
PT 
Preferred term 
Q1 
First quartile 
Q3 
Third quartile 
QD 
Once daily 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SI 
International System of Units 
SOC 
System organ class 
SRC 
Safety Review Committee 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings, and figures 
TG 
Triglycerides 
TNFα 
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 
VCTE 
Vibration-controlled transient elastography 
β-HCG 
Beta-human chorionic gonadotropin 
 
 
 


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1. INTRODUCTION 
The statistical analysis plan (SAP) details the planned analysis required to satisfy the Clinical 
Study Report (CSR) of Sagimet Biosciences, Inc. (Sagimet) study number 3V2640-CLIN-005: A 
Phase 2, Multi-Center, Single-Blind, Randomized, Placebo-Controlled Study of TVB-2640 in 
Subjects With Non-Alcoholic Steatohepatitis (NASH).  The content of this SAP is based on the 
protocol version 6.0 dated 29Apr2020. 
SAP Revision Chronology: 
 
 
Final Version 1 
02June2020 
Original 
 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Primary 
The primary objectives of the study are: 
• To determine the effect of once daily (QD) TVB-2640 for 12 weeks versus placebo on 
the change in hepatic fat fraction by proton density fat fraction by magnetic resonance 
imaging (MRI-PDFF) from baseline in subjects with NASH. 
• To determine the safety of QD TVB-2640 versus placebo in subjects with NASH, 
including the effects on alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST). 
2.2. Secondary 
The secondary objective is: 
• To determine the effect of QD TVB-2640 for 12 weeks versus placebo in subjects 
with NASH on: 
- Lipid and lipoprotein parameters, including low-density lipoprotein cholesterol 
(LDL-C), non-LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-
C, total cholesterol, triglycerides (TG), apolipoprotein B (ApoB), and 
lipoprotein(a) (Lp[a]) particles. 
- NASH and fibrosis biomarkers including cytokeratin-18 (CK-18), fibrosis-4 (FIB-
4), and enhanced liver function (ELF) or FIBROSpect 2 or ProC3 test. 
- Eicosanoid panel. 
2.3. Exploratory 
The exploratory objectives are: 
• To determine the effect of QD TVB-2640 for 12 weeks versus placebo in subjects 
NASH on clinical measures, including: 
- Liver fibrosis, as determined by vibration-controlled transient elastography 
(VCTE).  


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- Metabolic parameters, including fasting glucose, insulin, homeostatic model 
assessment insulin resistance (HOMA2-IR), glycated hemoglobin (HbA1c), non-
esterified fatty acid (NEFA), adipose tissue insulin resistance (adipo-IR), 
adiponectin, resistin, Interleukin 6 (IL-6), and gamma-glutamyl transpeptidase 
(GGT). 
- Anthropometric parameters, including weight, waist and hip circumference, 
waist-hip ratio, and blood pressure. 
- Lipidomic analyses for de novo lipogenesis (DNL). 
• Explore the relationship of plasma drug exposure to changes in efficacy and safety 
biomarkers. 
• Explore possible relationships between genomic markers of NASH and responses to 
treatment. 
3. STUDY DESIGN 
3.1. Study Design and Population 
This is a multi-center, randomized, single-blind, placebo-controlled, dose-escalation study to 
evaluate the safety and efficacy of TVB-2640 in subjects with NASH. Male and female subjects 
aged ≥18 years with either biopsy-proven NASH within 2 years before randomization and MRI-
PDFF ≥8% or, if prior liver biopsy was not performed or results are not available, magnetic 
resonance elastography (MRE) ≥2.5 kpa and MRI-PDFF ≥8% during screening are planned to be 
enrolled. Approximately 117 subjects will be enrolled and randomized, with at least 90 subjects 
enrolled in the US and approximately 27 subjects enrolled in China (18 active and 9 placebo). In 
the US, subjects will be enrolled and randomized to achieve 90 evaluable subjects (30 active and 
15 placebo in each of 2 dose cohorts). The 50 mg cohort will enroll and randomize 
approximately 27 additional subjects from China. A subject is defined as evaluable if they 
receive study drug for at least 8 weeks and have a baseline and at least 1 post-baseline MRI-
PDFF assessment on or after Week 8. 
Subjects will receive TVB-2640 or placebo QD orally (PO) for 12 weeks. During the 12-week 
Treatment period, subjects are to attend study center visits on Days 1 and 2, and Weeks 2, 4, 8, 
and 12. After completion of the 12-week Treatment period, subjects are to attend a Follow-up 
visit at Week 16 for post-treatment safety and efficacy assessments.  
All subjects must complete the 12-week treatment period at the 25 mg dose level, with review of 
all safety data and written approval by the Safety Review Committee (SRC) and reviewed by the 
Food and Drug Administration (FDA) before enrollment and treatment of subjects at the 50 mg 
dose level may commence.  
Due to the impact of COVID-19, several subjects were unable to have their Week 12 end of 
treatment visit performed within the protocol defined window. These subjects received extended 
dosing of study product and will have their end of treatment visit collected more than 12 weeks 
post first dose of study product, with allowable ranges between Week 11 and Week 16. Study 


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drug was not permitted to be continued for more than 16 weeks. For these subjects, the End of 
Study Visit was scheduled for 4 weeks after the last dose of study drug.  For purposes of 
consistent terminology in context of the COVID changes, the following terminology will be 
used,  
End of Treatment Visit: Visit performed following the end of study treatment. This will be the 
Week 12 visit for subjects who completed the treatment period as planned. For subjects who 
entered extended dosing, the visit will be performed on or prior to Week 16. For subjects who 
received less than 12 weeks of study treatment, the visit will be prior to the scheduled Week 12 
visit. 
End of Study Visit: Visit corresponding to 4 weeks after the end of treatment visit. This will be 
the Week 16 visit for subjects who completed the treatment period as planned. 
3.2. Randomization and Blinding 
Subjects who are candidates for enrollment into the study will be assigned a sequential and 
unique subject number by the Investigator after the subject has provided written informed 
consent. Once a subject number has been assigned, it cannot be reused. 
Subjects who have provided written informed consent will be evaluated for eligibility by the 
Investigator to ensure that the entry criteria (see Protocol Sections 8.2 and 8.3) have been 
satisfied and that the subjects is eligible for participation in this clinical study.  
Two TVB-2640 dose levels are planned to be evaluated in a sequential fashion:  25 mg and, if 
study suspension criteria are not met at the 25 mg dose level (see Protocol Section 7.2), 50 mg. 
At each dose level, subjects will be randomly assigned to TVB-2640 or placebo at a 2:1 ratio, 
with randomization stratified by type 2 diabetes mellitus (DM) status. The 50 mg dose level will 
also be stratified by country:  
• 25 mg dose level:  TVB-2640 (Planned N=30) and Placebo (Planned N=15) 
• 50 mg dose level:  US: TVB-2640 (Planned N=30) and Placebo (Planned N=15); China: 
TVB-2640 (Planned N=18) and Placebo (Planned N=9); Total: TVB-2640 (Planned 
N=48) and Placebo (Planned N=24) 
Randomization will be done via Interactive Web Response System (IWRS). Subjects are to 
receive their first study drug dose on Day 1 within 24 hours after randomization. 
At both dose levels, subjects will receive TVB-2640 or placebo QD PO for 12 weeks. 
Study drug will be dispensed to subjects in a single-blinded fashion. All other study personnel, 
with the exception of personnel conducting/interpreting imaging studies (see Protocol Section 
11.1) at each study center, will be unblinded to the subject’s treatment assignment. 
3.3. Sample Size Considerations 
The sample size is based on a fixed-sequence strategy which tests for a treatment difference in 
the primary endpoint (percent change at Week 12 in liver fat from baseline as determined by 


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MRI-PDFF) between each TVB-2640 dose group versus placebo. The fixed-sequence strategy 
will start with the highest dose group comparison. If statistically significant, then testing will 
proceed to the low dose group comparison. Each TVB-2640 dose group will be compared to the 
pooled placebo group using an F-test test from an analysis of covariance (ANCOVA) model with 
fixed effects for the stratification factor (diabetes presence/absence) and treatment group (i.e., 
TVB-2640 dose groups and pooled placebo) and with the baseline MRI-PDFF value as a 
covariate. Since the primary efficacy endpoint may not be normally distributed, the non-
parametric Wilcoxon rank-sum test is conservatively used, instead of the F-test, for power 
calculations. 
The sample size is based on a conservative assumption that the primary analysis is going to be 
performed in the US population only, resulting in 30 evaluable subjects in the placebo group, and 
30 evaluable subjects in each of the TVB-2640 dose levels. Based on Patel (2016), it is 
conservatively assumed that the primary endpoint has a standard deviation of 30. Power 
calculations assume the primary endpoint is lognormally distributed with a standard deviation of 
30, there are at least 30 evaluable subjects in each treatment group, and the two-sided Wilcoxon 
rank sum test will be used to test each pairwise treatment difference at the 0.05 Type I error 
level. Under the fixed-sequence strategy which maintains an overall 0.05 Type I error rate, the 
study has at least 80% overall power to detect both treatment differences (i.e., both high dose 
versus placebo and low dose versus placebo), if each mean treatment difference is at least 24. If 
the study does not proceed to the high-dose level, (i.e., there are 30 evaluable subjects treated 
with 25 mg TVB-2640 and only 15 with placebo), then the study has at least 77% power to 
detect a mean treatment difference of at least 24. The study will have more power if the subjects 
from China are included in the primary analysis and the same assumptions of treatment 
difference and variability hold. 
Power calculations for the key secondary endpoint (percentage of subjects with at least a 30% 
reduction in the primary endpoint) are based on pairwise comparisons with the placebo group 
using Fisher’s two-sided exact test [equivalent to Cochran-Mantel-Haenszel (CMH) without 
stratification] at the 0.05 significance level. Based on Loomba (2018), it is expected there will be 
less than 5 responses out of 30 evaluable subjects in the placebo group (i.e., less than 16.7%). 
With 30 evaluable subjects in each treatment group, there is at least 80% power to detect at least 
a 36.7% increase in the response rate (TVB-2640 treatment group minus placebo) when the 
placebo response rate is at most 16.7%. If the study does not proceed to the high-dose level, (i.e., 
30 evaluable subjects treated with 25 mg TVB-2640 and only 15 with placebo), then the study 
has at least 63% power to detect at least a 36.7% increase in the response rate (25 mg TVB-2640 
treatment group minus placebo) when the placebo response rate is at most 2 out of 15 evaluable 
subjects (i.e., 13.34%).With 30 subjects in each TVB-2640 treatment arm, there is at least a 95% 
probability of detecting at least 1 AE when the AE rate is 10% or more in the underlying 
population. 
3.4. Safety Review Committee 
An SRC will oversee the study to ensure subject safety and to advise if any dosing alterations are 
recommended. The SRC will review safety including liver-related events (i.e., clinically 


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meaningful elevations in ALT, AST, and bilirubin), and other efficacy (lipid parameters) and 
safety data as needed.  
If study suspension criteria are met at any time (see Protocol Section 7.2), the SRC will review 
the relevant study data and make a determination whether enrollment and treatment of subjects 
may continue or be permanently terminated. In addition, the SRC will review all safety data from 
the 25 mg dose level after all subjects at that dose level complete the 12-week treatment period. 
Enrollment and treatment of subjects at the 50 mg dose level may commence only with the 
written approval of the SRC and with FDA review.  The SRC may also review data from the 50 
mg cohort, if performed, upon request (see below). 
Additional details on the SRC can be found in the SRC Plan. The SRC Plan includes details on 
membership, purpose, organization, data requirements, logistics, and reporting requirements. 
3.5. Timing of Analyses 
An interim analysis for SRC review will be performed after all of the subjects in the 25 mg dose 
level complete the 12-week treatment period. Details on data requirements and outputs required 
will be maintained in the SRC Plan or other related documents. 
An additional SRC analysis was performed during the COVID pandemic to confirm safety prior 
to allowing the option for extended 50 mg cohort dosing.  
The primary analysis of efficacy will be performed when all subjects in the US 50 mg cohort 
finish their final visit. The primary analysis will not include any data from China, due to delays 
and uncertainty of enrollment in the Chinese cohort.   
An End of Study final analysis will be performed when the final subject completes the study and 
will include cumulative data from the US and China as applicable. 
4. STUDY ENDPOINTS 
4.1. Efficacy 
The primary efficacy endpoint is: 
• Percent change from baseline in liver fat at Week 12, as determined by MRI-PDFF. 
The key secondary efficacy endpoint is: 
• The percentage of subjects with at least a 30% reduction in liver fat at Week 12, as 
determined by MRI-PDFF. 
Additional secondary efficacy endpoints are: 
• Percent change from baseline in liver fat at End of Treatment and End of Study, as 
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• Percentage of subjects with at least a 30% reduction in liver fat at End of Treatment and End 
of Study, as determined by MRI-PDFF. 
• Change from baseline over the treatment period in:   
o Liver aminotransferases. 
o Lipid and lipoprotein parameters. 
o NASH and fibrosis markers. 
o Eicosanoids.  
Exploratory efficacy endpoints are: 
• Change from baseline over the treatment period in:   
o Liver fibrosis, as determined by VCTE.  
o Metabolic parameters. 
o Anthropometric parameters. 
o Lipidomic analyses for DNL. 
• Proportion of subjects with <5% liver fat (normalized) at Week 12. 
4.2. Safety 
Safety endpoints are: 
• Proportion of subjects experiencing treatment-emergent adverse events (TEAEs), Grade 3 
• or 4 TEAEs, and serious adverse events (SAEs). 
• Change from baseline in vital sign measurements, 12-lead ECG findings, and clinical 
laboratory test results. 
• Proportion of subjects experiencing treatment-emergent ophthalmologic abnormalities. 
5. ANALYSIS POPULATIONS/SETS 
The modified intent-to-treat population (mITT) is defined as all subjects who are randomized, 
receive study drug for at least 8 weeks, and have a baseline and at least 1 post-baseline MRI-
PDFF assessment on or after Week 8. The mITT is the primary population for analysis of MRI-
PDFF assessments and subjects will be analyzed according to the randomized treatment 
assignment. 
The intent-to-treat population (ITT) is defined as all subjects who are randomized and received at 
least 1 dose of study drug. The ITT will be used for analysis of a subset of secondary efficacy 
endpoints and supportive and sensitivity analyses of MRI-PDFF assessments. Subjects will be 
analyzed according to the randomized treatment assignment.  
The as-treated population (ATP) is defined as all subjects who are randomized and received at 
least 1 dose of study drug. The ATP will be used for analysis of secondary efficacy endpoints 
and supportive and sensitivity analyses of MRI-PDFF assessments. Subjects will be analyzed 
according to the treatment received.  
The safety population is defined as all subjects who are randomized and received at least 1 dose 
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the treatment received. If all subjects were dosed according to randomized treatment assignment, 
then the safety population and ITT are identical. 
A per-protocol (PP) population may be defined for sensitivity analyses of the efficacy endpoints. 
The PP population will be based on subjects in the mITT population with data excluded from 
subjects who have important protocol violations deemed to possibly affect the efficacy 
measurements or integrity of any other key study data. Subjects will be analyzed according to the 
actual treatment received.  If a PP population is implemented, details on subjects excluded will 
be provided in the CSR. 
 
6. DEFINITIONS 
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, and maximum (max) value.  
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 2-sided testing with a 5% 
significance level (i.e. 95% confidence intervals [CI] will be produced). 
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. 


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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 Harmonisation (ICH) E3 
whenever possible. 
7.1. Stratification and Covariates 
At each dose level, subjects will be randomly assigned to TVB-2640 or placebo at a 2:1 ratio, 
with randomization stratified by type 2 diabetes mellitus status (present/absent). The 50 mg dose 
level will also be stratified by country (US/China) for the final analysis. 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. 
This is a multi-center trial. However, adjustment for study center will not be made in the 
statistical tests. 
7.2. Evaluation of Subgroups 
All analyses will be performed separately by country (US and China) in addition to overall. 
Selected analyses of liver fat reduction may also be repeated based on the following subgroups: 
• ALT: Baseline ≥1.5 x ULN vs <1.5 x ULN 
• DM status: present vs absent 
• Baseline MRI-PDFF: ≥ median vs < median 
• Baseline MRE: ≥ median vs < median 
• Liver stiffness based on fibrosis stage: Stage 1 vs Stage 2/3 
• Baseline triglycerides: ≥ median vs < median 
• Weight change: >=5% loss vs <5% loss (or a gain) 
7.3. Multiple Comparisons and Multiplicity 
In order to control for multiple comparisons, the primary and key secondary efficacy analyses 
will be tested using a fixed-sequence strategy to maintain the overall Type I error rate at 0.05. 
Each test in the fixed-sequence, uses a 2-sided test at the 0.05 level of significance and starts 
with the primary efficacy analyses. The first comparison to be assessed for significance is the 
primary efficacy endpoint analysis of the high-dose group (50 mg TVB-2640) compared to 
placebo and if statistically significant, testing will proceed to the low-dose group (25 mg TVB-
2640) comparison. If both comparisons of the primary efficacy endpoint are significant, then 
testing will proceed to the key secondary efficacy endpoint. The key secondary efficacy analyses 
will be tested in a similar fashion, first comparing the high dose group (50 mg TVB-2640) with 
placebo and if statistically significant, testing will proceed to the low dose group (25 mg TVB-
2640) comparison. 
7.4. Reference Dates 
• Screening date is defined as the electronic case report form (eCRF) provided date on 
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• 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 screening 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.  Date imputation will 
be performed as identified in Section 7.6. 
 
7.5. 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%. 
7.6. Imputation of Partial Dates 
Imputed dates will be used to classify treatment emergent AEs (TEAEs) and prior and 
concomitant medications. 
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 


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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 
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. 
7.7. 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, and (4) subject data listings. 


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7.8. Missing Data 
Imputation will only be performed on the primary and selected secondary efficacy endpoints 
using MRI-PDFF data. 
In the primary and key secondary analyses, missing Week 12 values for MRI-PDFF will be 
imputed with the last post-baseline observation on or after Week 8. For sensitivity analyses that 
include subjects with extended dosing, the End of Treatment values for MRI-PDFF will be 
imputed with the last post-baseline observation on or after Week 8. 
MRI-PDFF analyses at other timepoints (e.g., End of Study) will follow similar conventions and 
use the last-post baseline observation on or after Week 8. Missing MRI-PDFF data before Week 
8 will not be imputed. 
Sensitivity analyses will be performed excluding data from subjects with missing data (i.e., 
observed cases approach).  
Additional details are provided in the relevant analysis sections below. 
 
8. ANALYSIS METHODS 
8.1. Study Subject Data 
8.1.1. Subject Disposition 
Summaries of analysis population membership and final subject status (completed or 
withdrawn), including reasons for withdrawal, 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. 
8.1.2. 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 
Important protocol deviations deemed to possibly affect the efficacy measurements or integrity 
of any other key study data may be identified prior to database lock to support defining the PP 
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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 protocol deviations will be provided. 
8.1.3. Demographic and Baseline Characteristics 
 
Subject demographics will be summarized and listed.  Age, sex (Male / Female), ethnicity 
(Hispanic or Latino / Not Hispanic or Latino), race (American Indian or Alaska Native / Asian / 
Black or African American / Native Hawaiian or Other Pacific Islander / White / Other), baseline 
height (cm), baseline weight (kg), body mass index (BMI) (kg/m2), Type 2 Diabetes Mellitus 
status (Yes / No), waist circumference (cm), hip circumference (cm), waste-hip ratio (cm) and 
country (US / China).  Age will also be categorized as a categorical variable (< 65, 65 ≤ age < 
75, 75 ≤ age < 85, ≥85) for reporting.  Data will be presented by treatment group as well as 
overall for the study.   
The following conversions and equations will be used as applicable: 
BMI (kg/m2) = weight(kg)/[height(m)2] 
Demographic and baseline characteristics summaries will be provided for the mITT, and safety 
populations. Subgroup analyses will be produced by region (US/China). 
Baseline characteristics including social history (tobacco, alcohol, and caffeine use) will be 
listed. Pregnancy test, breath/blood alcohol test, and beta-human chorionic gonadotropin 
(β-HCG) data will be listed. NASH confirmation data collected at screening will be presented in 
a data listing. 
8.1.4. Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 22.0 Mar 2019 for reporting by system organ class (SOC) and preferred term (PT). 
Medical history data will be presented in a listing. 
8.1.5. Prior and Concomitant Medication  
The incidence of medication use will be summarized by WHO Drug Dictionary 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.  


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All prior and concomitant medication data will be listed including the verbatim and preferred 
drug name and ATC Level 2. 
8.2. 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 < 2 weeks; 2 weeks - <4 weeks; 4 weeks - <8 
weeks; 8 weeks - <12 weeks; ≥12 weeks. 
Drug accountability is captured in the eCRF at each visit. The eCRF captures the number of pills 
dispensed, the number 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 
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 
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.  
8.3. Efficacy  
8.3.1. Primary Efficacy Endpoint and Analyses 
The primary efficacy endpoint is the percent change from baseline in liver fat at Week 12, as 
determined by MRI-PDFF.  In the primary analysis, missing Week 12 values for MRI-PDFF will 
be imputed with the last post-baseline observation on or after Week 8 in the mITT (i.e., last 
observation carried forward [LOCF]). 
8.3.1.1. Primary Analysis of the Primary Efficacy Endpoint 
The initial analysis of the primary efficacy endpoint will be performed using an ANCOVA 
model with fixed effects for the stratification factor (diabetes presence/absence),  and treatment 
group (TVB-2640 50 mg and pooled placebo)with the baseline MRI-PDFF value as a covariate 
including all subjects in the mITT from the US.  


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The primary efficacy analyses will be based on a F-test from the ANCOVA model in the mITT 
to compare each TVB-2640 dose group individually with the placebo group. Data normality will 
be assessed and the appropriate data transformation will be applied to fulfill the underlying 
assumption of the ANCOVA model. Model residuals will be calculated and plotted to visually 
inspect the model assumptions of homoscedasticity and normality for the primary efficacy 
analysis.  If, upon visual inspection, the model assumptions of homoscedasticity or normality are 
not met, then the primary efficacy analysis will be repeated after making an appropriate 
transformation (e.g., log transformation) of the data. If a suitable transformation cannot be 
determined the corresponding rank ANCOVA will become the primary analysis for this 
endpoint. 
The equal slopes assumption for the primary analysis will be assessed by including a term for the 
treatment by baseline MRI-PDFF interaction.  If the equal slope assumption is not met (p-value 
for interaction less than 0.05), then the primary analysis will be repeated with the interaction 
term included in the model and the LS Means and treatment difference in the LS Means will be 
tested and summarized at the 25th, 50th, and 75th percentile for the baseline MRI-PDFF.  This 
analysis will be considered secondary and supportive of the primary analysis. 
Summary statistics will be displayed by treatment group along with the difference in least 
squares means (and the associated 95% confidence interval and p-value) for each TVB-2640 
dose group to pooled placebo comparison. If data is transformed for analysis, then LS means will 
be back transformed to the original scale where appropriate. 
The fixed-sequence method, as described in Section 7.3, will be used to maintain an overall 0.05 
Type I error rate for the final analysis.  
In the primary analysis, missing Week 12 values for MRI-PDFF will be imputed with the last 
post-baseline observation on or after Week 8 in the mITT.  
Subjects who required extended dosing beyond 12 weeks will be excluded from the primary 
efficacy analysis. See Appendix 1 for additional details on COVID-19 impacts and data handling 
considerations. 
The primary analysis will be based on the mITT population.  
8.3.1.2. Additional Analyses of the Primary Efficacy Endpoint 
The primary efficacy analysis will be repeated using the ITT population, ATP, and PP 
population.   Analyses will be conducted with LOCF from Week 8 onward and repeated 
excluding missing data (no LOCF). 
In addition to the primary analysis of Week 12 that includes all subjects who had no more than 
12 weeks of study treatment, an analysis of the End of Treatment MRI-PDFF data including data 
from the extended dosing subjects will be performed in the mITT, ITT, ATP, and PP 
populations.  
An analysis of MRI-PDFF data in the log scale will be performed in the mITT population. The 
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ANCOVA mode. In the event that model assumptions are not met for the primary efficacy 
analysis noted above, the analysis in the log scale will become primary. 
At the time of the final analysis, the above analyses will be repeated using all data from the US 
and China.  Subset analyses will be performed on the primary efficacy endpoints for subjects 
enrolled in US and China to evaluate the consistency of results between subjects enrolled in each 
country.   The ANCOVA model will incorporate fixed effects for the stratification factor 
(diabetes presence/absence), country (US/China), treatment group (TVB-2640 50 mg and pooled 
placebo), and country-by-treatment interaction and with the baseline MRI-PDFF value as a 
covariate including all subjects in the mITT from US and China who received 50 mg or placebo.  
A test for country-by-treatment interaction will be performed. If there is no interaction detected 
(p≥0.05), the primary efficacy endpoint, percent change from baseline in hepatic fat fraction at 
Week 12, as determined by MRI PDFF, will be analyzed using an ANCOVA model with fixed 
effects for the stratification factor (diabetes presence/absence) and treatment group (i.e., TVB-
2640 dose groups and pooled placebo) and with the baseline MRI-PDFF value as a covariate 
including all subjects from US and China (with no fixed effect for country). If the country-by-
treatment interaction is significant (p<0.05) then a separate analysis will be performed on 
subjects enrolled in China in the 50 mg cohort. This analysis is not powered to detect a 
significant difference but would be supportive/descriptive in nature to evaluate trends. 
Analyses of absolute reduction from baseline to week 12 in liver fat will be performed in the 
mITT, ITT, ATP, and PP populations. Similar methodology as used for the primary efficacy 
analysis will be used. 
In order to determine if the effect on liver fat persists after study treatment, the absolute and 
percent change in liver fat from End of Treatment to End of Study will be performed in the mITT 
population with missing data excluded. The analysis will be run with and without dosing 
extenders.  Methodology similar to that described for the primary efficacy analysis will be used. 
 
8.3.2. Secondary Efficacy Endpoints and Analyses 
MRI-PDFF Endpoints 
Week 12 data for the secondary efficacy endpoints will be handled similarly to the handling used 
for the primary efficacy endpoint. That is, analyses will be performed both excluding data from 
subjects who required extended dosing beyond 12 weeks and including data from the extended 
dosing subjects as supplemental analyses. 
The key secondary efficacy endpoint is the percentage of subjects with at least a 30% reduction 
in liver fat at Week 12, as determined by MRI-PDFF. Note that due to data collection precision, 
subjects with a reduction of at least 29.5% from baseline will count as responders. Differences 
between each TVB-2640 dose group (25 mg, 50 mg) and pooled placebo for the key secondary 
efficacy endpoint will be analyzed using CMH methods. The key secondary efficacy analyses 
will be based on a CMH test in the mITT population to compare each TVB-2640 dose group 
with placebo, adjusting for the stratification factor (diabetes presence/absence). For the final end 


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of study analysis, if a country-by-treatment interaction is found in the primary efficacy endpoint, 
the subjects from the US and China in the 50 mg cohort will be analyzed separately for the key 
secondary efficacy endpoint.  
To check for other possible interactions, i.e., diabetes strata-dependent treatment effects, the 
Breslow-Day test will be performed; if the p-value of the Breslow-Day test is ≥0.05, the 
treatment-by-strata interaction is deemed not significant. However, if the interaction effect is 
statistically significant (i.e., p value <0.05), then the Gail and Simon test will be used to test for 
the qualitative interaction at a significance level of 0.05 and provided as an aid for interpretation 
of the CMH results. The estimated response rates and the corresponding exact 95% confidence 
interval based on a binomial distribution will be calculated for each treatment group. The exact 
95% confidence limit for the CMH estimate of the common risk difference will also be obtained; 
a Wald asymptotic approximation with continuity correction is an acceptable substitute for the 
exact limits in the event of computational difficulties.  
Similar responder analyses will be performed using response level definitions of 20%, 40%, and 
50%. As done for the key secondary endpoint efficacy endpoint, subjects with a reduction of at 
least 19.5%, 39.5%, and 49.5% from baseline, respectively, will count as responders. Analyses 
will be repeated in the ITT, ATP, and PP populations. Analyses of the key secondary endpoint 
performed in the ATP populations will include summaries of all subjects in the analysis 
population, as well as the subset of subjects that have at least 8 weeks of treatment and an 
evaluable assessment on/after 8 weeks (i.e., the same subjects in the mITT population).  
Similar responder analyses will be performed using reduction in liver fat at End of Study in the 
mITT, ITT, and ATP populations.  
A scatter plot of End of Treatment body weight changes versus End of Treatment liver fat 
changes will graphed by treatment and overall in the ATP.  A subset will also be run in subjects 
with at least a 30% reduction in liver fat at Week 12. 
In the key secondary analysis, missing Week 12 values for MRI-PDFF will be imputed with the 
last post-baseline observation on or after Week 8 in the mITT population. Sensitivity analyses 
excluding subjects with missing data will also be performed.   
 
Other Efficacy Endpoints 
Other efficacy endpoints will be summarized using the ATP.  A limited set of endpoints will be 
repeated in the ITT. 
Liver aminotransferases will be evaluated using observed values and changes from baseline by 
study visit. Summaries will be performed for ALT and AST and will be presented by treatment 
group.  
The changes at 12 weeks will be summarized for each treatment group and compared between 
each TVB-2640 dose group and pooled placebo using a linear mixed-effects model for repeated 
measures (MMRM). The model will include the stratification factor (diabetes presence/absence), 


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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 pairwise difference for each TVB-2640 dose group 
and pooled placebo comparison 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. 
For the end of study final analysis, if a country-by-treatment interaction is found in the primary 
efficacy endpoint, the subjects from the US and China in the 50 mg cohort will be analyzed 
separately. However, if no country-by-treatment interaction is found in the primary efficacy 
endpoint, the interaction may be explored within the secondary endpoints in a similar manner in 
order to determine if there is a significant interaction for any of the other endpoints (e.g., ALT or 
AST). 
The model produces asymptotically consistent estimates when data are missing at random. No 
imputation of missing data will be required for these analyses. By definition, subjects without a 
baseline and at least 1 post-baseline value will be excluded from the MMRM analyses. Model 
assumptions (normality of residuals and parallel slopes) may be assessed. If assumptions are not 
met, then transformations will be done analogous to the primary efficacy analyses described 
above. 
Similar analyses will be performed for: 
• Lipid and lipoprotein parameters including low-density lipoprotein cholesterol (LDL-C), 
non-LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total 
cholesterol, TG, apolipoprotein B (ApoB), and lipoprotein(a) (Lp[a]) particles, total 
Cholesterol:HDL ratio, LDL:HDL ratio (Note that the cholesterol and LDL to HDL ratios 
will be derived and do not come directly from the laboratory 
• NASH and fibrosis biomarkers including cytokeratin-18 (CK-18), fibrosis-4 (FIB-4), and 
enhanced liver function (ELF) or FIBROSpect 2 or ProC3 test. 
• Eicosanoids including 5-LOX–derived leukotriene B4 (LTB4), COX-derived 
prostaglandin E2 (PGE2), and 15-LOX–derived 15-hydroxyeicosatetraenoic acid (15-
HETE) and lipoxin A4 (LXA4). For eicosanoids, descriptive statistics will be presented 
without any statistical testing.  
The number and percentage of subjects with normalized ALT will be summarized by study visit 
and treatment group. Differences between each TVB-2640 dose group (25 mg, 50 mg) and 
pooled placebo for ALT normalization will be analyzed using CMH methods. The analyses will 
be based on a CMH test to compare each TVB-2640 dose group with placebo, adjusting for the 
stratification factor (diabetes presence/absence). Only subjects with ALT>ULN at baseline will 
be included in the ALT normalization analyses. 
Similar analyses will be performed for AST. 
A scatter plot of End of Treatment TG changes versus End of Treatment liver fat changes will 
graphed by treatment and overall in the ATP.  A subset will also be run in subjects with at least a 
30% reduction in liver fat at Week 12 


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Subset analyses will be performed on relevant secondary efficacy endpoints for subjects enrolled 
in the US and China to evaluate the consistency of results between subjects enrolled in each 
country.  The specific analyses performed by region will depend on the data that are ultimately 
collected in China. In the event that some efficacy parameters are not able to be evaluated in 
China, those analyses will not be performed. 
8.3.3. Exploratory Efficacy Endpoints and Analyses 
Analysis of exploratory endpoints will be based on the ATP. Exploratory efficacy endpoints 
include the change from baseline over the treatment period in following continuous 
measurements: 
• Liver fibrosis, as determined by VCTE 
• Metabolic parameters 
• Anthropometric parameters including weight, waist and hip circumference, waist-hip 
ratio, and blood pressure 
• Lipidomic analyses for DNL 
Analyses will be performed similarly to those described in the secondary efficacy analysis 
section above. 
The proportion of subjects with <5% liver fat (normalized) at Week 12 will be summarized by 
treatment group. Analyses similar to those described for the key secondary efficacy endpoint will 
be used.  
Subset analyses will be performed on all exploratory efficacy endpoints for subjects enrolled in 
the US and China to evaluate the consistency of results between subjects enrolled in each 
country.   
 
8.4. Pharmacokinetics (PK)  
Blood samples for determination of TVB-2640 PK are to be collected immediately before and 
then at 2, 4, 6, and 24 hours after the first study drug dose; the 24-hour post-dose sample is to be 
collected on Day 2, immediately before the second study drug dose. Blood samples for PK also 
are to be collected immediately pre-dose and at 2, 4, and 6 hours post-dose at Week 2 (i.e., Day 
8). 
PK samples will be collected from 12 active subjects/cohort in the US and 8 active subjects in 
the 50 mg cohort in China. 
PK analyses will be performed by a separate vendor and described outside of this SAP (i.e., in a 
separate PK SAP or other document). 
8.5. Safety  
Safety will be evaluated based on data collected for adverse events, vital signs, physical 
examinations, electrocardiogram (ECG), ophthalmologic examinations, and laboratory data. No 


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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. 
Subset analyses will be performed on all safety endpoints for subjects enrolled in China to 
evaluate the consistency of results between subjects enrolled in each country.  
All safety analysis reporting will be based on the Safety Analysis Set. All safety data will be 
listed by treatment group and subject. 
8.5.1. Adverse Events 
An AE is any untoward medical occurrence in a patient 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. 
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 22.0 Mar 2019 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. 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 be “possible”, 
“probable”, or “definite”, the event will be considered to be treatment-related for the safety 
analyses. 
Any missing severity assessments will be assumed to be Grade 3 (severe) and missing 
relationship assessments will be assumed to be related. All AE summaries will be produced 
using the safety population and displayed by treatment group and overall.  


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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, SAEs, and fatal SAEs. The number of AEs will also be 
included on 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 
• TEAEs leading to treatment discontinuation by SOC and 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. 
A comprehensive listing of all AEs will be provided in a by-subject data listing. AEs that began 
after 84 days of dosing will be identified on the listing. In addition, the following listings will be 
provided:  
• TEAEs related to study treatment 
• SAEs 
• TEAEs leading to treatment discontinuation; and 
• Fatal AEs. 
8.5.2. 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: 
• Chemistry: Chloride, Carbon dioxide, Sodium, Potassium, Blood urea nitrogen, Calcium, 
Creatinine, Magnesium, Albumin, Glucose, Total protein, Alkaline phosphatase, AST, ALT, 
Indirect and direct bilirubin, 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, Platelet count, White blood cell 
count with differential, Absolute neutrophil count. 
• Coagulation Studies: Prothrombin time, 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 include the most extreme change from baseline. The percent change from 


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baseline at each visit and the most extreme percent change from baseline will also be 
summarized. 95% confidence intervals for the change and percent change will be included. 
Laboratory data will also be summarized in shift tables of baseline to each visit and 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. 
8.6. Other Safety Evaluations 
8.6.1. Vital Signs 
Vital signs include: respiratory rate (breaths/minute); temperature (oC); and pulse rate 
(beats/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. 
Summaries will be provided for the safety population and displayed by treatment group. 
8.6.2. Electrocardiogram (ECG) 
Electrocardiogram (ECG) parameters include:  HR (bpm), PR (ms), QRS (ms), QT (ms), QTcF 
(ms), QTcB (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. 
8.6.3. 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. 
8.6.4. Physical Examinations 
Physical examination results will be presented in subject data listings. 


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9. CHANGES TO THE PLANNED ANALYSES 
 
The timing of the primary efficacy analysis will be based on completion of the US 50 mg cohort. 
The protocol indicated the initial analysis of the primary efficacy endpoint would be performed 
using subjects from US and China and include country as an effect in the ANCOVA model. 
Given the delays in enrollment in China due to COVID-19, the primary analysis has been 
adjusted to only include the US cohorts and a modified ANCOVA model as described above. 
The treatment group used for the presentation of data based on the mITT population has been 
modified from the protocol. Per the study protocol, the data were to be analyzed based on 
randomized treatment.  
As a point of clarification and as noted for the key secondary efficacy analysis above, due to data 
collection precision, subjects with a reduction of at least 29.5% from baseline will count as 
responders. Similar conventions were used for the sensitivity analyses of that endpoint using 
different responder definitions. 
Since one subject received the incorrect study treatment (active instead of placebo), an as-treated 
population (ATP) has been added to the SAP. The ATP will be used to evaluate the treatment 
differences in efficacy endpoints using treatment received instead of randomized treatment. 
Due to the impact of COVID-19, all efficacy endpoints will be analyzed at End of Treatment and 
End of Study. The definition of those timepoints are described in section 3.1. Per the protocol, 
endpoints were evaluated at Week 12 and Week 16 but the differences in duration of treatment 
require further evaluation given the visits may not correspond to the number of weeks specified 
in the protocol visit schedule.  
An additional SRC analysis was performed during the COVID-19 pandemic to confirm safety 
prior to allowing the option of extended 50mg cohort dosing. If additional SRC reviews are 
performed, they will be discussed in the CSR. 
Additional supplementary and sensitivity analyses related to the protocol-planned analyses have 
been added to the SAP. Specifically, the absolute change from baseline in MRI-PDFF has been 
added in addition to the planned percent change. The change from Week 12 to Week 16 in MRI-
PDFF has been added. ALT and AST normalization has been added as an additional analysis of 
the liver aminotransferases.  
Analyses and data presentations described in the protocol have been expanded upon, but no other 
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. 


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APPENDIX 1. COVID-19 IMPACT AND DATA HANDLING  
 
COVID-19 impacts on 3V2640-CLIN-005 include, but are not limited to, missed visits, inability 
to complete certain assessments per the protocol including Week 12 MRI-PDFF data which 
constitutes the data for the primary efficacy endpoint. In order to collect as much efficacy data 
on all randomized subjects, subjects were allowed to continue on their treatment beyond Week 
12 and have their end of treatment MRI-PDFF performed at any time between Week 11 and 
Week 16 per protocol Amendment 5. Study drug was not permitted to be continued for more 
than 16 weeks. The End of Study Visit was scheduled for 4 weeks after the last dose of study 
drug. 
Given the uncertainty of the impact of extended dosing beyond Week 12 on efficacy, the primary 
and secondary efficacy analyses will be performed excluding subjects who entered extended 
dosing beyond 12 weeks. Sensitivity analyses that include these subjects will be performed to 
evaluate the end of treatment efficacy. 
The analysis of safety will include all collected data regardless of treatment extension.   
An addendum to this SAP will be developed that documents all additional data handling 
techniques employed to manage COVID impacted data, if needed.  
 
 


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APPENDIX 2. PLANNED TABLES, LISTINGS, AND FIGURES  
 
The table of contents and mock tables, listings, and figures (TLF) are maintained in a separate 
document. 
 
 


 
 
PROTOCOL 3V2640-CLIN-005 
 
A PHASE 2, MULTI-CENTER, SINGLE-BLIND, 
RANDOMIZED, PLACEBO CONTROLLED STUDY OF 
TVB-2640 (ASC40) IN SUBJECTS WITH 
NONALCOHOLIC STEATOHEPATITIS 
Statistical Analysis Plan Addendum 
 
 
VERSION 1 
DATE OF PLAN: 
14Mar2022 
 
 
STUDY DRUG:  
TVB-2640 
 
 
PREPARED FOR: 
Sagimet Biosciences 
 
 


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Approval Signature Page: 
 
 
 
 
 
 
 
 
   
 
 
Date 
 
 
 
 


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Approval Signature Page: Sagimet Biosciences 
 
 
 
 
 
 
 
  
  
 
Date 
 
 
 
 


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Contents 
1. 
Introduction ............................................................................................................................. 5 
2. 
Description of Analyses for Cohort 3 ...................................................................................... 5 
Appendix 2. Planned Tables, Listings, and Figures ........................................................................ 6 
 
 
 
 


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1. INTRODUCTION 
This document serves as an addendum to the statistical analysis plan (SAP) version 1 dated 
02June2020. The SAP Addendum is focused on details pertaining to the planned analyses for the 
TVB-2640 75mg Open-Label Cohort 3 and should be read along with the primary study SAP 
that detailed the primary analyses of data from Cohort 1 and Cohort 2. 
The content of this SAP Addendum is based on the protocol version 7.0 dated 17Mar2021. 
SAP Revision Chronology: 
 
 
Final Version 1 
02June2020 
Original 
Addendum 1 
14Mar2022 
Addendum to Original SAP 
 
2. DESCRIPTION OF ANALYSES FOR COHORT 3 
Data collected for the thirteen subjects in safety Cohort 3 will be summarized similarly to data 
collected for the first two study cohorts. Data collected via the EDC (CRF data) and from 
external vendors (laboratory data and MRI-PDFF) will be summarized, graphically presented, 
and listed. All summaries will be based on descriptive statistics. Continuous data will be 
summarized using descriptive statistics including number of subjects (n), mean, median, standard 
deviation (SD), first quartile (Q1), third quartile (Q3), minimum (min) value, and maximum 
(max) value.  
Categorical data will be summarized 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. 
Statistical significance will not be assessed for this study cohort. If any p-values are generated, 
they will be evaluated in order to assess study trends and not to assess statistical significance. 
Statistical outputs will follow the design of those prepared for prior analyses but will include 
only a single column for the Cohort 3 (75mg) dose group. 
Details on the analysis results and any changes from the protocol and/or prior SAP will be 
described in the clinical study report (CSR). 
 
 


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APPENDIX 2. PLANNED TABLES, LISTINGS, AND FIGURES  
 
 
 


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Type 
Number 
Title 
Population 
Table 
14.1.1 
Summary of Subject Disposition 
All Subjects 
Table 
14.1.2.1 
Summary of Subject Demographics 
Modified Intent-to-Treat Population 
Table 
14.1.2.2 
Summary of Subject Demographics 
Safety Population 
Table 
14.1.3.1 
Summary of Subject Baseline Characteristics 
Modified Intent-to-Treat Population 
Table 
14.1.3.3 
Summary of Subject Baseline Characteristics 
Safety Population 
Table 
14.1.4.1 
Summary of NASH History 
Modified Intent-to-Treat Population 
Table 
14.1.4.3 
Summary of NASH History 
Safety Population 
Table 
14.1.5 
Summary of Protocol Deviations 
Intent-to-Treat Population 
Table 
14.1.6 
Summary of Concomitant Medications 
Safety Population 
Table 
14.1.7 
Summary of Study Drug Exposure and Compliance 
Safety Population 
Table 
14.2.1.1.1 
Summary of Liver Fat (%) Based on MRI-PDFF 
Modified Intent-to-Treat Population 
Table 
14.2.1.7 
Summary of Liver Fat (%) Based on MRI-PDFF Log Ratio Versus Baseline 
Modified Intent-to-Treat Population 
Table 
14.2.2.1.1 
Summary of Liver Fat (%) Based on MRI-PDFF  - Responder Analysis 
Modified Intent-to-Treat Population 
Table 
14.2.3.1.1 
Summary of Liver Aminotransferase Results and Change from Baseline 
As-Treated Population 
Table 
14.2.3.4 
Summary of Percentage of ALT and AST Normalization by Visit: Missing Data 
Excluded 
As-Treated Population 
Table 
14.2.4.1.1 
Summary of Lipid and Lipoprotein Results and Change from Baseline 
As-Treated Population 
Table 
14.2.7 
Summary of Liver Fibrosis Results as Determined by VCTE 
As-Treated Population 
Table 
14.2.8.1.1 
Summary of Metabolic Parameter Results and Change from Baseline 
As-Treated Population 
Table 
14.2.9 
Summary of Anthropometric Body Measurement Parameter Results and Change 
from Baseline 
As-Treated Population 
Table 
14.3.1 
Overall Summary of Adverse Events 
Safety Population 
Table 
14.3.2 
Summary of Treatment Emergent Adverse Events by SOC and PT 
Safety Population 
Table 
14.3.3 
Summary of Treatment Related Treatment Emergent Adverse Events by SOC and 
PT 
Safety Population 
Table 
14.3.5 
Summary of Treatment Emergent Adverse Events Leading to Treatment 
Discontinuation of Study Treatment by SOC and PT 
Safety Population 
Table 
14.3.7 
Summary of Treatment Emergent Adverse Events by SOC, PT, and CTCAE 
Grade 
Safety Population 
Table 
14.3.8 
Summary of Treatment Related Treatment Emergent Adverse Events by SOC, PT, 
and CTCAE Grade 
Safety Population 
Table 
14.3.9 
Summary of Treatment Emergent Adverse Events by SOC, PT, and Relationship 
to Treatment 
Safety Population 
Table 
14.3.10 
Summary of Selected Clinical Laboratory Results and Changes from Baseline 
Safety Population 
Table 
14.3.14 
Summary of Clinical Chemistry Shifts from Baseline 
Safety Population 
Table 
14.3.18 
Summary of Vital Signs Results and Changes from Baseline 
Safety Population 


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Type 
Number 
Title 
Population 
Table 
14.3.19 
Summary of ECG Results and Changes from Baseline 
Safety Population 
Table 
14.3.20 
Summary of Clinically Significant Ophthalmologic Examination Abnormalities 
Safety Population 
  
  
  
  
Listing 
16.2.1.1 
Patient Disposition 
All Subjects 
Listing 
16.2.1.2 
Informed Consent and Randomization 
All Subjects 
Listing 
16.2.2 
Protocol Deviations   
All Subjects 
Listing 
16.2.4.1 
Demographics 
All Subjects 
Listing 
16.2.4.2 
Social History 
All Subjects 
Listing 
16.2.4.3 
Baseline Internal Laboratory Results 
All Subjects 
Listing 
16.2.4.4 
Medical History 
All Subjects 
Listing 
16.2.4.5 
NASH Confirmation Results 
All Subjects 
Listing 
16.2.4.6 
Physical Examination Results 
All Subjects 
Listing 
16.2.4.7 
Prior and Concomitant Medications 
All Subjects 
Listing 
16.2.5.1 
Study Drug Accountability 
All Subjects 
Listing 
16.2.5.2 
Study Drug Administration 
All Subjects 
Listing 
16.2.5.3 
Study Drug Dosing Adjustments 
All Subjects 
Listing 
16.2.6.1 
MRI-PDFF Results    
All Subjects 
Listing 
16.2.6.2 
Lipid and Lipoprotein Parameter Results 
All Subjects 
Listing 
16.2.7.1 
All Adverse Events 
All Subjects 
Listing 
16.2.7.2 
Treatment Related Treatment Emergent Adverse Events 
All Subjects 
Listing 
16.2.7.3 
Serious Adverse Events 
All Subjects 
Listing 
16.2.7.4 
Treatment Emergent Adverse Events Leading to Treatment Discontinuation 
All Subjects 
Listing 
16.2.7.5 
Treatment Emergent Adverse Events of Special Interest 
All Subjects 
Listing 
16.2.7.6 
Fatal Adverse Events 
All Subjects 
Listing 
16.2.8 
Selected Laboratory Results 
All Subjects 
Listing 
16.2.8.1 
Clinical Chemistry Results 
All Subjects 
Listing 
16.2.8.2 
Hematology Results 
All Subjects 
Listing 
16.2.8.3 
Coagulation and Urinalysis Results 
All Subjects 
Listing 
16.2.8.4 
Other Laboratory Results 
All Subjects 
Listing 
16.2.8.5 
Vital Signs 
All Subjects 
Listing 
16.2.8.6 
ECG Results 
All Subjects 
Listing 
16.2.8.7 
Ophthalmologic Examination Results 
All Subjects 
Listing 
16.2.8.8 
Anthropometric Body Measurements 
All Subjects 
Listing 
16.2.8.9 
FibroScan Results 
All Subjects 
  
  
  
  
Figure 
14.2.1.2.1 
Mean (SE) Percent Change from Baseline in Liver Fat (%) Based on MRI-PDFF 
Modified Intent-to-Treat Population 


Sponsor: Sagimet Biosciences 
Protocol Number: 3V2640-CLIN-005 
Version and Date: Final Addendum 1, 14Mar2022 
 
9 of 9 
 
Type 
Number 
Title 
Population 
Figure 
14.2.1.3 
Mean (SE) Change from Baseline in Liver Fat (%) Based on MRI-PDFF   
Modified Intent-to-Treat Population 
Figure 
14.2.2.5 
Plot of MRI-PDFF Responder Percentage Week 12 LOCF 
Modified Intent-to-Treat Population 
Figure 
14.2.3.2.1 
Mean (SE) ALT Over Time 
As-Treated Population 
Figure 
14.2.3.2.2 
Mean (SE) ALT Over Time 
As-Treated Population with Baseline, Week 
12 and Week 16 Data 
Figure 
14.2.3.5 
Percentage of Subjects with ALT Normalization Over Time 
As-Treated Population with Baseline 
ALT>ULN 
Figure 
14.2.3.3 
Mean (SE) AST (U/L) Over Time 
As-Treated Population 
Figure 
14.2.3.6 
Percentage of Subjects with AST Normalization Over Time 
As-Treated Population with Baseline 
AST>ULN 
Figure 
14.2.4.2 
Mean (SE) Triglycerides (mg/dL) Over Time 
As-Treated Population 
Figure 
14.2.4.3 
Box and Whisker Plot of Triglycerides (mg/dL) Over Time 
As-Treated Population 
Figure 
14.2.4.4 
Scatter Plot of End of Treatment Triglyceride (mg/dL) Changes versus Liver Fat 
Absolute Changes (%) 
As-Treated Population 
Figure 
14.2.4.5 
Scatter Plot of End of Treatment Triglyceride (mg/dL) Changes versus Liver Fat 
Absolute Changes (%) 
As-Treated Population with At Least a 30% 
Reduction in Liver Fat at End of Treatment 
Figure 
14.2.4.6.1 
Scatter Plot of End of Treatment ALT Changes (%) versus Liver Fat Absolute 
Changes (%) 
As-Treated Population 
Figure 
14.2.4.6.2 
Scatter Plot of End of Treatment ALT Changes (%) versus Liver Fat Percentage 
Changes 
As-Treated Population 
Figure 
14.2.4.7 
Scatter Plot of End of Treatment ALT Changes (%) versus Liver Fat Changes (%) 
As-Treated Population with At Least a 30% 
Reduction in Liver Fat at End of Treatment 
Figure 
14.2.4.8 
Scatter Plot of End of Treatment Weight (kg) Changes versus Liver Fat Changes 
(%)  
As-Treated Population 
Figure 
14.2.4.9 
Scatter Plot of End of Treatment Weight (kg) Changes versus Liver Fat Changes 
(%) 
As-Treated Population with At Least a 30% 
Reduction in Liver Fat at End of Treatment 
 
Output numbers and titles may vary slightly in the final outputs. Any significant changes from the main study SAP to the Cohort 3 
analyses will be described in the CSR.