A Single-center, Randomized, Double-blind, Multiple Ascending Dose, Placebo-controlled Phase Ib/IIa Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Early Pharmacodynamics of BGT-002 Tablets in Subjects With NASH
Phase: PHASE1
Conditions: NASH
Sponsor: Burgeon Therapeutics Co., Ltd.

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Protocol Synopsis
Study Title
A Single-center, Randomized, Double-blind, Multiple Ascending Dose, Placebo-controlled
Phase Ib/IIa Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Early
Pharmacodynamics of BGT-002 Tablets in Subjects with NASH
Objectives

Primary Objective:
To evaluate the safety and tolerability of BGT-002 Tablets in subjects with NASH after
oral administration;

Secondary Objectives:
1)
To evaluate the pharmacokinetics (PK) of BGT-002 Tablets in subjects with NASH
after oral administration;
2)
To evaluate the effect of BGT-002 on lipid metabolism in subjects with NASH;
3)
To evaluate the effect of BGT-002 on biochemical indicators related to liver
function in subjects with NASH.

Exploratory Objective:
To evaluate the biomarker profile of BGT-002 in subjects with NASH.
Protocol No.
BGT-002-004
Sponsor
Burgeon Therapeutics Co., Ltd.
Clinical Study
Approval No.
2023LP00117/ 2023LP00118
Registration
Category
Chemical Drug Class 1
Study Facility
The First Hospital of Jilin University
Phase of
Development
Phase Ib/IIa
Investigationa
l Products
Drug and
Storage
Conditions
Study Drug: BGT-002 Tablets
It was developed by Burgeon Therapeutics Co., Ltd. and manufactured by ApicHope
Pharmaceutical Co., Ltd.
Drug Batch No.: XXX
Dosage Form: Tablet
Strength: 50 mg/tablet;
Mode of Administration: Oral under fasting conditions
Shelf Life: MM/YYYY
Storage Condition: Sealed, stored in a dry place below 25°C
Control Drug: BGT-002 Placebo
It was developed by Burgeon Therapeutics Co., Ltd. and manufactured by ApicHope

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Pharmaceutical Co., Ltd.
Drug Batch No.: XXX
Dosage Form: Tablet
Strength: 50 mg/tablet;
Mode of Administration: Oral under fasting conditions
Shelf Life: MM/YYYY
Storage Condition: Sealed, stored in a dry place below 25°C
The batch number and shelf life of the above study drug and control drug shall be subject to
the packaging.
Key
Information
of Preclinical
Study
Pharmacodynamic Study:
The results of in vitro pharmacodynamic studies showed that the coenzyme A derivative
of BGT-002 (ZM326E-CoA) could notably decrease the catalytic activity of ACLY with an
IC50 of 5.31 ± 1.21 μM. BGT-002 could strongly inhibit the de novo synthesis of triglyceride
(IC50: 0.76 ± 0.20 μM) and cholesterol (IC50: 1.82 ± 1.89 μM) from sodium [1,2-14C]-acetate
in mouse primary hepatocytes in a significant dose-dependent manner. Similarly, using
[14C]-citrate as a substrate, BGT-002 could significantly inhibit the de novo synthesis of
triglyceride (IC50: 13.26 ± 1.89 μM) and cholesterol (IC50: 5.53 ± 2.49 μM) in mouse
primary hepatocytes in a significant dose-dependent manner. The inhibition of BGT-002 on
lipid synthesis could be partially reversed by Triacsin C (a long-chain acyl-CoA synthetase
indicator), indicating its active form, ZM326E-CoA, is necessary for ACLY inhibition.
Moreover, BGT-002 could effectively enhance fatty acid β-oxidation in mouse primary
hepatocytes, performing comparably to the commercially available drug ETC-1002
(bempedoic acid).
In the in vivo pharmacodynamic studies, it was found that long-term administration of
BGT-002 significantly reduced hyperlipidemia induced by a high-fat, high-glucose, and
high-cholesterol diet and hepatic lipid accumulation in NAFLD model (C57BL/6J mice) and
NASH model (ob/ob mice). Besides, it significantly reduced the degree of liver function
damage
caused
by
dietary
stress
(ALT
and
AST
significantly
reduced).
Immunohistochemical staining results showed that long-term administration of BGT-002
reduced
inflammatory
cell
infiltration;
picrosirius
red
staining
results
indicated
a
significantly reduced liver fibrosis compared to the model control group. The levels of
NASH-related plasma biomarkers such as FGF21 and TIMP-1 were significantly decreased
after long-term administration of BGT-002. We also saw that long-term administration of
BGT-002 could significantly ameliorate hepatic lipid accumulation, inflammation, and
fibrosis in the HFD-MCD diet-induced NASH model (C57BL/6J mice). The anti-fibrotic
pharmacodynamics of BGT-002 was evaluated in a CCl4-induced mouse model of liver
fibrosis. It was found that long-term administration of BGT-002 significantly reduced
collagen deposition, and the pathological score also showed that long-term administration of
BGT-002 significantly reduced CCl4-induced fibrosis. More importantly, we performed

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pharmacodynamic evaluations for over 130 days on a non-human primate (cynomolgus
monkey) model for NASH that closely resembled human NASH onset characteristics. The
study results showed that long-term administration of BGT-002 had pharmacological effects
to significantly improve NASH and reverse fibrosis, with a significant increase in the
content of ketone bodies represented by β-hydroxybutyrate in serum and a significant
decrease in the hepatic inflammatory marker (hs-CRP), showing good tolerability. This
result demonstrates the favorable safety profile of BGT-002 in addition to its significant
efficacy. Therefore, BGT-002 has the pharmacological effects of significantly inhibiting de
novo lipid synthesis in the liver (cells), promoting fatty acid oxidation, significantly
improving NASH, and reversing hepatic fibrosis. This result demonstrates the favorable
safety profile of BGT-002 in addition to its
significant efficacy. The secondary
pharmacodynamic and safety pharmacology study data also demonstrate that BGT-002 has
good target selectivity and safety.
Pharmacokinetic Study:
BGT-002 had good pharmacokinetic profiles in mice and dogs, with an absolute
bioavailability of 92.7% and 53.8% by gavage or oral administration, respectively. BGT-002
was rapidly absorbed in mice, with the time to maximum plasma concentration (Tmax) of
0.083–0.5 h and the plasma elimination half-life (t1/2) of 1.89–8.07 h. The high exposure of
BGT-002 in plasma and liver was favorable for its efficacy. The major metabolite of
BGT-002 in hepatocytes from various species was the glucuronide conjugate M2, with
significantly higher levels produced in human, monkey, and dog hepatocytes compared to
those in rats and mice. BGT-002 was mainly catalyzed by UGT2B7 to generate glucuronide
conjugate M2. Within the tested concentration range (0.10–100 μM), BGT-002 had no
time-dependent inhibition on major CYP450 enzymes and did not induce CYP1A2,
CYP2B6, or CYP3A4. BGT-002 was highly permeable and efflux transporters in Caco-2
cells were not involved in its transportation.
Toxicology Study:
Safety pharmacology (ICR mice, Beagle dogs), single-dose toxicity (ICR mice, Beagle
dogs), repeated-dose toxicity (ICR mice, Beagle dogs), and genotoxicity results all suggest
that BGT-002 has a good safety profile. The specific findings are as follows:
(1)Within the observation range of pre-dose and 24 h post-dose in ICR mice, no
significant abnormality was observed in various test indicators related to involuntary
movement, autonomic nervous system, sensorimotor system, neuromuscular system and
behavior in BGT-002 30 mg/kg, 100 mg/kg and 300 mg/kg groups;
(2)Beagle dogs were administered with BGT-002 by single oral gavage and monitored
continuously for 24 h post-dose. No drug-related effects on cardiovascular and respiratory
systems were observed in the BGT-002 10 mg/kg, 30 mg/kg, and 100 mg/kg groups
compared with the vehicle control group and baseline measurements before administration;
(3)The maximum tolerated dose (MTD) of BGT-002 was 1000 mg/kg following single

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doses at 100, 300, and 1000 mg/kg by oral gavage in ICR mice;
(4)The maximum tolerated dose (MTD) of BGT-002 was 600 mg/kg following single
doses at 30, 200, and 600 mg/kg by oral gavage in Beagle dogs;
(5)The no observed adverse effect level (NOAEL) of BGT-002 was 30 mg/kg after oral
gavage (30, 100, and 300 mg/kg) once daily for 28 consecutive days in ICR mice;
(6)The no observed adverse effect level (NOAEL) of BGT-002 was 360 mg/kg after
oral gavage (30, 100, and 360 mg/kg) once daily for 28 consecutive days in Beagle dogs;
(7)BGT-002 did not induce reverse mutation in Salmonella typhimurium strains TA97,
TA98, TA100, TA102 and TA1535;
(8)No increase in the chromosomal structural aberration rate of CHL cells induced by
BGT-002 was observed after 4 h and 24 h treatment under -S9 conditions, and the result was
negative. Although the chromosomal aberration rate of BGT-002 in the 50 μg/mL dose group
was 6.67% (within 5%–10%) after 4 h treatment under + S9 conditions, which was a
suspicious positive result, BGT-002 did not induce an increase in the micronucleus rate of
bone marrow erythrocytes in KM mice at ≤1000 mg/(kg/d), confirming that BGT-002 has
no teratogenic toxicity. The result of the comet assay in SD rats also showed that BGT-002
did not induce DNA damage in liver and gastric cells at doses ≤600 mg/(kg/d).
In addition, during the long-term pharmacodynamic evaluation, no significant
abnormalities in body weight, food intake, and other vital signs were observed in mouse
models (ApoE-/- mice for 24 weeks, ob/ob mice for 9 weeks, C57BL/6J mice for up to 19
weeks) and cynomolgus monkey models (at a dose of 20 mg/kg), and no drug-related
abnormal clinical observations were observed. In terms of drug exposure, the plasma Cmax
was 148.7 μg/mL after 12 weeks of high dose administration (50 mg/kg) in ApoE-/- mice,
93.3 μg/mL after 6 weeks of high dose administration (60 mg/kg) in ob/ob mice, and 134.05
μg/mL after 1 week of administration (20 mg/kg) in cynomolgus monkeys. In the completed
long-term toxicity study in mice, Cmax was 62.7 μg/mL at 30 mg/kg; 210 μg/mL at 100
mg/kg, and 349 μg/mL at 300 mg/kg 28 days post-dose. In the completed long-term toxicity
study in Beagle dogs, Cmax was 199 μg/mL at 30 mg/kg; 382 μg/mL at 100 mg/kg, and 570
μg/mL at 300 mg/kg 28 days post-dose. The liver function evaluation results obtained during
the pharmacodynamic study found that the activities of ALT and AST in plasma did not
increase significantly with the prolongation of administration. However, due to the
improvement effect of long-term administration on NAFLD, liver function was significantly
improved. The above study results also further suggest the safety of the study drug in
long-term administration.
Key
Information
from Previous
Trials
Clinical Trials Conducted:
Till now, 3 single-center clinical trials have been carried out for BGT-002 tablets. The
specific information is summarized as follows:
Main Information on Clinical Trials Conducted for BGT-002 Tablets

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Project No.
Phase
Population
Number of Subjects
Enrolled (BGT-002
Tablets: Placebo)
Dosing Regimen and
Design
BGT-002-0
01
Phase
Ia-SAD
Healthy
Subjects
59 (45:14)
12.5–300 mg, PO,
single dose,
randomized,
double-blind
BGT-002-0
02
Phase
Ia-MAD
36 (27:9)
25–75 mg/day, PO for
14 consecutive days,
randomized,
double-blind
BGT-002-0
03
Phase
Ia-FE
14 (without placebo)
100 mg (D1, D15),
PO, randomized,
open-label,
two-period,
two-sequence,
two-way crossover
Pharmacokinetics
Based on some available PK data, the exposure of BGT-002 in human plasma
demonstrated a good dose dependency after administration of BGT-002 tablets.
As of January 04, 2023, the mean Cmax after single doses of BGT-002 at 12.5 mg–300
mg
in
healthy
subjects
was
1.61
μg/mL–48.88
μg/mL,
the
AUClast
was
32.4
μg·h/mL–2703.12 μg·h/mL, the median Tmax (25 mg–300 mg groups) occurred at 1.00
h–1.75 h, and the mean T1/2 ranged from 25.0 h–75.1 h. The half-life at single doses in
healthy subjects showed a tendency to increase with higher doses.
As of December 08, 2022, a total of 12 subjects (11 males and 1 female) were enrolled
in the BGT-002 25 mg dose group of the multiple-dose trial for healthy subjects for 14
consecutive days. The Cmax was 14.1 μg/mL and AUC0-24h was 257.1 μg·h/mL on Day 14
after multiple-dose administration; there were 12 subjects (10 males and 2 females) in the 50
mg dose group. After 14 days of continuous administration, the drug concentration was close
to a steady state. On Day 14, after multiple-dose administration, the Cmax,ss was 27.1 μg/mL
and AUC0-24h,ss was 513.9 μg·h/mL. The pharmacokinetics exhibited good linearity after
continuous administration at 25 mg and 50 mg.
As of January 04, 2023, after administration with a high-fat meal in healthy subjects in
the food effect trial, the median Tmax was 3.50 h, Cmax was 12.18 μg/mL, AUClast was 571.31
μg·h/mL, and t1/2 was 41.27 h; after administration under fasting conditions, the median Tmax
was 1.50 h, Cmax was 16.64 μg/mL, AUClast was 579.70 μg·h/mL and t1/2 was 41.07 h. After
administration following a high-fat meal, the Tmax was delayed and the peak concentration
decreased slightly, but the degree of drug absorption hardly changed.
Safety Results
No SAEs, life-threatening TEAEs, or TEAEs leading to death occurred during the
Phase Ia single-dose clinical trial in healthy subjects. There were no TEAEs leading to
premature withdrawal of any subject from the study or discontinuation of the study drug. A
total of 58 subjects were enrolled in dose groups 1–8 (12.5 mg, 25 mg, 50 mg, 100 mg, 150
mg, 200 mg, 250 mg, and 300 mg), and a total of 24 (41.1%) subjects experienced 35

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TEAEs, including 31 drug-related AEs in 22 subjects. Apart from 1 case of white blood cell
decreased and 1 case of upper respiratory infection, both in Grade 2, all others were in Grade
1. Common AEs possibly related to the drug included bradycardia sinus (N=13, 22.4%),
shortened PR interval (N=4, 6.9%), and elevated AST (N=2, 3.4%). The incidence of
bradycardia sinus and specific heart rate values in each group were as follows: For the 50 mg
group: 37.5%, N = 3 (46 bpm, 46 bpm, and 44 bpm, respectively); 100 mg group: 37.5%, N
= 3 (46 bpm, 46 bpm, and 44 bpm, respectively); 150 mg group: 12.5%, N = 1 (48 bpm);
200 mg group: 25%, N = 2 (43 bpm and 49 bpm); 250 mg group: 12.5%, N=1 (40 bpm); 300
mg group: 37.5%, N=3 (45 bpm, 44 bpm, and 47 bpm, respectively). The frequency and
severity of bradycardia did not increase with increasing doses of BGT-002. The frequency
and severity of the remaining TEAEs did not increase with increasing doses of BGT-002 and
were not related to the dose level of BGT-002.
During the Phase Ia multiple-dose clinical trial in healthy subjects, a total of 24 subjects
were enrolled in 25 mg and 50 mg dose groups. After 2 weeks of administration, 15 subjects
(62.5%) experienced 21 AEs, including 8 drug-related AEs occurred in 6 subjects (25%), all
of which were in Grade 1; common drug-related AEs included diarrhea (N = 3, 12.5%),
triglycerides increased (N = 3, 12.5%) and high-sensitivity C-reactive protein increased (N =
2, 8.3%). The frequency and severity of TEAEs did not increase with increasing doses of
BGT-002 and were not related to the dose level of BGT-002.
During the Phase Ia clinical trial on food effect in healthy subjects, a total of 14 subjects
(13 males and 1 female) were enrolled, of which 6 subjects (42.9%) experienced 10 AEs,
including 1 in Grade 3, 2 in Grade 2, and the rest in Grade 1. No serious adverse events
occurred. A total of 5 drug-related AEs occurred in 4 subjects (28.1%), all of which were in
Grade 1; drug-related AEs included urine white blood cell increased (N = 1, 7.1%),
microscopic hematuria (N = 1, 7.1%), upper respiratory tract infection (N = 1, 7.1%), white
blood cell count increased (N = 1, 7.1%), and blood neutrophil count increased (N = 1,
7.1%).
Phase Ib/IIa Starting and Effective Dose Estimation
The results of preclinical chronic toxicity studies showed that the NOAEL of BGT-002
was 30 mg/kg in mice and 360 mg/kg in Beagle dogs, which corresponded to human
equivalent doses (HEDs) of 2.66 mg/kg and 209 mg/kg respectively. With a safety factor of
10, the maximum recommended starting doses (MRSDs) for humans were 16 mg and 1254
mg based on a body weight of 60 kg. Preclinical pharmacodynamic studies showed that the
observed effective dose of BGT-002 in mice was < 15 mg/kg, which was 1.33 mg/kg after
conversion to HED; the observed effective dose in rhesus monkeys was 20 mg/kg, which
was 8 mg/kg after conversion to HED.
Based on the analysis of preclinical pharmacodynamic data, it is found that the
pharmacological effect of BGT-002 in improving NAFLD is not weaker than ETC-1002,
while the clinical exposure of BGT-002 is about 2–3 times higher than that of ETC-1002.

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The dosage of ETC-1002 is 180 mg once a day. Therefore, we expect that the clinically
effective dose of BGT-002 may be 60 mg–90 mg.
Pharmacodynamic Results
No data available up to now.
Study Design
Overall Design
This study is a single-center, randomized, double-blind, multiple ascending doses
(MAD), placebo-controlled phase Ib/IIa clinical trial of BGT-002 Tablets in subjects with
NASH
to
evaluate
the
safety,
tolerability,
pharmacokinetics
(PK)
and
early
pharmacodynamics (PD) of BGT-002 Tablets.
The number of subjects: A total of 48–60 subjects are planned to be enrolled in this
study.
Study Flow
Study Schedule:
This study includes the screening period (D-56–D-1), run-in period (D-56–-28–D-1),
treatment and observation period (D1–D29), and follow-up period (D30–D56). There will be
a total of 8 return visits in the 50 mg and 75 mg groups: Visit 1-D-56–D-1 in the Screening
Period, Visit 2-D-56–-28–D-1 in the Run-in Period, Visit 3-D-1 at the End of Run-in Period,
Visits 4–8-D15, D22, D26, and D27 in the Treatment and Efficacy Observation Period. The
Follow-up Period will be D56 ± 5 days and there will be 2 hospitalization periods: 9 days in
D-1–D8 and 3 days in D27–D29. In addition to the above visits, return visits will be required
for patients in the 100 mg, 150 mg, and 200 mg (alternative) groups on D31, D35, D38, and
D41. During the study, if necessary, additional visits may be added according to the
individual conditions of the subjects.
After signing the informed consent form, subjects will enter the screening period
(D-56–D-1) for preliminary eligibility evaluation. Subjects who pass the preliminary
screening will enter a 4 to 8-week run-in period (D-56–-28–D-1), during which subjects will
be required to maintain their previous living habits and diet structure. If subjects have
received one body weight measurement and MRI-PDFF examination and have obtained the
results before screening, they will be subject to another body weight measurement,
MRI-PDFF examination, and other screening tests at an interval of 4–8 weeks from the first
time. Subjects who meet the enrollment criteria will be admitted to the ward on D-1, receive
randomization in this trial, and enter the treatment and observation period (D1–D29). During
the treatment and observation period (D1–D28), subjects will be given BGT-002 tablets or a
placebo according to the randomization number every morning under fasting conditions.
After completing the corresponding visit, they can enter the follow-up period (D30–D56).
All adverse events should be observed and recorded from post-administration to the end

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of the trial, and appropriate treatment and handling measures should be adopted if necessary.
In case of any abnormal indicator with clinical significance during the trial, the subjects
should return to the hospital for re-examination as required by the investigator. After the
investigator judges that the abnormal value becomes normal and the abnormality is not
clinically significant or has become stable without the need for further tracking, they can be
discharged.
Dose Group Design
It is originally planned to set 3-4 dose groups in this study, and the dose ascending
design is as follows: 50 mg, 75 mg, 100 mg, and 125 mg (alternative). In this trial, it is
planned to start with 50 mg as the lowest dose group. During the study, whether to continue
to ascend to a higher dose group or adjust the dose ascending ratio will be determined based
on available data.
As of September 13, 2023, based on the results of the completed interim analysis for
three dose groups (50 mg, 75 mg and 100 mg), after discussion, the Sponsor and investigator
decided to add 150 mg and 200 mg (alternative) groups for a 28-day continuous
administration study, with 3 sentinels in the 150 mg and 200 mg (alternative) groups,
respectively (2 subjects in the test group, and 1 subject in the placebo group) and observe for
8 days. If the safety is good, the remaining subjects will continue to be enrolled in this dose
group (7 subjects in the test group and 2 subjects in the placebo group).
Dose
(mg)
50
75
100
150
200
(Alternative)
Number of Subjects
Study Drug +
Placebo
9+3
9+3
9+3
(Male:female =
close to 1:1)
9+3
9+3
Each dose group will randomly include 12 screened eligible subjects with NASH, with
9 taking the study drug orally and 3 taking the placebo orally. A total of 48-60 subjects will
be included in the study. Whether to conduct the dose expansion study will be based on the
results of the dose ascending stage.

Dose Ascending Principle:
1)
In this trial, it is planned to start with 50 mg as the lowest dose and 200 mg as an
alternative dose. A total of 4 to 5 dose groups will be selected from 50 mg, 75 mg,
100 mg, 150 mg, and 200 mg (alternative) groups, and the trial will be gradually
carried out according to the above set doses.
2)
After the investigator and sponsor determine that 50% of subjects in each dose
group have good results for 14-day safety evaluations, the trial can proceed to the
next dose group. If necessary, subsequent trial protocols may be appropriately
adjusted based on previous safety and PK analysis results (such as increasing or
decreasing administration observation time or dose).
3)
If the criteria for termination of dose ascending are met during dose ascending,
even if the predetermined maximum dose has not been reached, the dose
ascending should be terminated.

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4)
After the maximum estimated dose is reached by dose ascending, the investigator
and the sponsor will discuss and analyze the existing safety and PK data before
deciding whether to continue the next dose exploration. Any continuation will be
subject to the approval of the Ethics Committee.

Stopping Criteria for Dose Ascending:
Within 14 days after the first dose, if any of the following criteria are met, the
investigator and the sponsor will discuss and analyze the reasons and judge the impact on
subsequent trials to decide whether to terminate dose ascending:
1)In the same dose group, more than 1/2 of subjects experience Grade 2 and above AEs
related to the study drug; or more than 1/3 of subjects experience Grade 3 and above AEs
related to the study drug;
2)The trial should be suspended if 1 case of serious adverse event (SAE) related to the
study drug occurs during the trial;
3)Based on the available PK data, the investigator agrees with the sponsor that there is
no need to continue the trial.
Dosing
Regimen
In this trial, the drug will be orally administered under fasting conditions, once in the
morning with warm water for 4 consecutive weeks. Subjects will be required to fast for at
least 10 h pre-dose on D1 and D28 and 4 h post-dose on the days of intensive blood
sampling (D1 and D28) (intolerant subjects can take food 30 min post-dose). For the rest of
the time (D2–D27), subjects should try to fast for 30 min post-dose. Except for water
deprivation 1 h pre-dose and 2 h post-dose on the days of intensive blood sampling (D1 and
D28), subjects can have free access to water in the rest time (D2–D27). Subjects will be
required to remain sitting and out-of-bed activities will be limited within 2 h post-dose on
D1 and D28 (transient lying position can be kept during ECG examination). Normal indoor
activities will be allowed for the rest of the time, while excessive activity or prolonged bed
rest should be avoided. Daily dosing shall be conducted at the same time as far as possible.
Treatment and Observation Period (4 weeks after treatment)
Study drug: Administered once daily in the morning under fasting conditions for 4
consecutive weeks.
Placebo: Administered once daily in the morning under fasting conditions for 4
consecutive weeks.
Examination
Items and
Time in
Screening
Period
The screening physical examination will be performed on D-56–D-1 of administration,
and the screening examination items include the following: Measurement of height and
weight; vital signs; physical examination; HbA1c (only in diabetics and when needed);
hematology; blood biochemistry; chest X-ray (PA view); urinalysis; four coagulation tests;
thyroid function; ANA test; blood pregnancy test (for females only); abdominal B-scan
ultrasonography (liver, gallbladder, pancreas, spleen and both kidneys); Fibroscan;
MRI-PDFF;
infectious
disease
screening;
and
12-lead
electrocardiogram
(ECG)

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examination.
Results
of
infectious
disease
screening,
chest
X-ray,
and
abdominal
B-scan
ultrasonography obtained within 1 month before screening will be considered valid.
MRI-PDFF results obtained within 8 weeks before screening will be regarded as screening
examination results and no additional examination will be required.
Examination
Items and
Time at the
End of Run-in
Period (D-1)
Examination items at the end of the run-in period (D-1) include the following: Vital
signs; physical examination; body weight measurement; hematology; blood biochemistry;
urinalysis; four coagulation tests; Fibroscan; MRI-PDFF; blood pregnancy test (for females
only); 12-lead ECG; urine drug screening; and alcohol breath test.
For patients with MRI-PDFF, Fibrocan, hematology, blood biochemistry, urinalysis,
and four coagulation test reports within 7 days before the first dose (D-7–D-1), it will be
unnecessary to perform these examinations again on D-1.
Inclusion
Criteria
Subjects are eligible for the study only if all of the following inclusion criteria are met:
1)
Subjects aged ≥18 and ≤65, male or female;
2)
Body mass index (BMI) ≥25 kg/m2 at screening;
3)
Subjects fulfilling the following criteria:
a)
ALT level exceeds the upper limit of normal once within 3 months (ALT elevation
without other obvious reasons);
b) Mean liver fat content ≥10% during screening and at the end of the run-in period
(MRI-PDFF);
4)
Stable body weight (defined as weight gain or loss ≤5%) 4–8 weeks pre-dose;
5)
Pre-dose blood pressure: Systolic blood pressure ≤160 mmHg and diastolic blood
pressure ≤95 mmHg (oral antihypertensive drugs can be taken regularly);
6)
Maintain the same medication and lifestyle (diet and/or exercise) as those at
enrollment during the trial;
7)
Subjects who have no birth plan from screening to 6 months after the last dose and
voluntarily take reliable contraceptive measures;
8)
Subjects who fully understand the purpose and requirements of the trial, voluntarily
participate in the clinical trial, and sign the written ICF, and are able to complete all
trial processes according to the trial requirements.
Exclusion
Criteria
Those who meet any of the following criteria cannot be enrolled in this study:
1)
Subjects with a known history of allergies to the test product, any of its components, or
related products; as well as those with allergic diseases or an allergic constitution;
2)
Subjects with heavy alcohol consumption for 3 consecutive months or above within 1
year before screening. "Heavy alcohol consumption" is defined as average daily
alcohol consumption of > 20 g for females and > 30 g for males, or uncontrollable
alcohol consumption;
3)
Subjects with cirrhosis suggested by liver biopsy or clinically diagnosed cirrhosis;

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4)
Subjects with other concomitant liver diseases, including but not limited to
drug-induced liver disease, alcoholic liver disease, autoimmune liver disease,
hemochromatosis, Wilson's disease, suspected or confirmed liver cancer;
5)
Subjects who have received liver transplantation surgery or plan to have this surgery:
6)
Subjects who have received bariatric surgery or plan to have this surgery during the
study;
7)
Subjects with type 1 diabetes and poorly controlled type 2 diabetes (HbA1c > 10.5% at
screening);
8)
Patients with diabetes who use hypoglycemic drugs other than metformin;
9)
Subjects with a history of malignant tumor within 5 years before screening (Note: 1.
Subjects with cervical carcinoma in situ whose lesions have been resected and with no
evidence of recurrence or metastasis for at least 3 years may participate in this study. 2.
Subjects with basal cell or squamous cell carcinoma whose lesions have been
completely resected and with no recurrent lesions for at least 3 years can participate in
this study;
10)
Subjects with serious cardiovascular and cerebrovascular events within 6 months
before screening, including but not limited to uncontrolled or serious arrhythmia
(ventricular fibrillation, atrial fibrillation, etc.), angina unstable, acute myocardial
infarction, cardiac failure congestive, coronary intervention (including coronary artery
stent implantation, intracoronary thrombectomy, and percutaneous transluminal
coronary angioplasty, etc) or coronary artery bypass surgery, peripheral vascular
intervention, stroke (except lacunar infarction), and transient ischaemic attack;
11)
Subjects with gastrointestinal diseases or postoperative conditions affecting drug
absorption;
12)
Subjects who are taking drugs that may cause steatosis/steatohepatitis;
13)
Subjects who have used ACLY-targeted drugs (Nexletol, etc.) and other study drugs,
are
taking
statins
(lovastatin,
simvastatin,
pravastatin,
mevastatin,
fluvastatin,
atorvastatin, cerivastatin, rosuvastatin, pitavastatin, etc.), fibric acids (such as
fenofibrate, gemfibrozil), probucol, warfarin, systemic steroids, cyclosporin or other
immunosuppressants, or have taken these drugs less than 1 month or 5 half-lives of the
drug (whichever is longer) from the first administration of the study drug;
14)
Subjects who have used drugs with potential therapeutic effects on NASH (such as
GLP-1 receptor agonists, DPP4 inhibitors, SGLT2 inhibitors, or other drugs known to
affect liver function and cause steatosis at the discretion of the investigator) during the
trial period and within less than 1 month from the screening;
15)
Subjects with a TG > 6.0 mmol/L, direct bilirubin > 2 × ULN, creatinine clearance <
60 mL/min (calculated using the Cockcroft-Gault formula);
16)
Platelet count < 75 × 109/L;
17)
Subjects with confirmed positive and clinically significant results for antinuclear

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antibody (ANA) at screening;
18)
Subjects with a history of hypothyroidism, hyperthyroidism, or subclinical thyroid
disease (except for those with TSH levels < 10 mu/l, normal free T3 and T4 levels, and
no symptoms of hypothyroidism);
19)
Subjects with contraindications to MRI scan;
20)
Subjects with blood donation or blood loss ≥400 mL within 3 months before
screening;
21)
Subjects who have participated in other drug clinical trials within 1 month prior to the
screening;
22)
Pregnant/lactating women or subjects confirmed positive in serum pregnancy test
(female);
23)
Subjects with positive results in urinary drug screening (morphine, marijuana);
24)
Subjects who have consumed any food or beverage containing alcohol (or positive
alcohol breath test result), grapefruit juice/grapefruit juice, methylxanthine (such as
coffee, tea, cola, chocolate, and energy drink) within 1 day pre-dose, or have strenuous
exercise or other factors affecting drug absorption, distribution, metabolism, and
excretion;
25)
Subjects with other severe systemic diseases unrelated to NASH;
26)
Subjects infected with viral hepatitis (including hepatitis B and C), AIDS, or syphilis;
27)
Subjects with high-risk factors of torsades de pointes (hypokalemia, hypomagnesemia,
heart rate < 45 bpm), and ECG QTc interval longer than 490 ms during screening;
28)
Subjects with other factors deemed by investigators as not suitable for the trial.
Concomitant
Medication/T
herapy
Prohibited Drugs during the Study
During the administration period of clinical studies, the following medications are
specifically prohibited unless required for adverse events:
1)
All medications for the treatment of NASH other than this study drug are
prohibited during the study.
2)
During the study, other lipid-lowering drugs are prohibited (including but not
limited to the following: Statins (lovastatin, simvastatin, pravastatin, mevastatin,
fluvastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, etc.), fibric acids
(such
as
fenofibrate,
gemfibrozil),
probucol,
warfarin,
systemic
steroids,
cyclosporin or other immunosuppressants).
Concomitant Drugs and Treatments as Appropriate in the Study
In addition to prohibited medications, the following medications/treatments are allowed
as appropriate during the study:
1)
Long-term medications required due to concomitant diseases before enrollment;
2)
Symptomatic treatments for toxic reactions of drugs.
Criteria for
Subjects may withdraw from the trial at any time without providing a reason. Subjects

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Treatment
Discontinuatio
n/Withdrawal
may withdraw from the trial under the following cases:
1)
The subject requests to be withdrawn from the trial;
2)
Serious violation of the protocol;
3)
The subject becomes pregnant;
4)
Subjects experience severe clinical or laboratory changes or intolerable adverse
events, and continuing the trial will not be conducive to their health. These
subjects may withdraw from the trial prematurely upon mutual agreement between
the investigator and the sponsor;
5)
Other
circumstances
warranting
withdrawal
as
deemed
necessary
by
the
investigator, including subjects' poor adherence to medication intake or PK blood
sampling.
Regardless of the reason, safety and efficacy data for subjects who discontinued and
withdrew from treatment should be obtained as much as possible. In any case, the reason for
withdrawal from the study should be recorded in the study medical records and case report
forms (CRFs), and all end-of-treatment assessments should be performed if the subject is
willing and compliant.
Termination
Criteria
Premature termination of trial means that the clinical trial is not completed for all
subjects as per the protocol and the entire trial is stopped halfway. Termination mainly aims
to protect the rights and interests of subjects, ensure the quality of the trial, and avoid
unnecessary economic losses.
Under normal circumstances, the trial will not be terminated prematurely at will.
However, the entire trial may be terminated prematurely in any of the following cases:
1)
New information is obtained, which leads to an unfavorable risk-benefit evaluation
of the study drug, including sufficient evidence for lack of efficacy or
unacceptable safety;
2)
The sponsor believes that it is inappropriate to continue the clinical trial for
medical, ethical or business reasons;
3)
The enrollment of subjects is suboptimal, as a result, it is impossible to complete
the trial within an acceptable time period;
4)
NMPA or the Ethics Committee orders to terminate the trial for certain reasons.
If the clinical trial is terminated prematurely, all parties involved (Sponsor, Investigator,
Ethics Committee, clinical trial institution, and administrative authority) shall be notified in
writing in a timely manner.
Elimination
Criteria
Before statistical analysis of the data, statisticians and principal investigators should
discuss whether to exclude individual cases. In any of the following circumstances, the
principal investigator should comprehensively judge whether to reject the subject according
to the degree of completion of the trial, reasons for withdrawal, and other factors, and make
relevant explanations:

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1)
The selection of individual subjects violates the inclusion/exclusion criteria; the
investigator and the sponsor should jointly discuss whether the subject needs to be
excluded.
2)
During the trial, the subject fails to follow the trial protocol and has poor
compliance; for example, the subject does not take the study drug or fails in
sampling for pharmacokinetic, pharmacodynamic, and safety evaluation as
required by trial protocol, or presents no data.
3)
During the trial, the investigator considers that subjects have other factors
indicating unsuitability for further trial and terminates their participation.
PK Sampling
and
Assessment
PK Blood Collection Points:
On D1, 0 h pre-dose (within 60 min pre-dose) and 10 min (±0.5 min), 20 min (±0.5
min), 40 min (±1 min), 1 h (±1 min), 1.5 h (±1.5 min), 2 h (±1.5 min), 3 h (±3 min), 4 h (±3
min), 6 h (±6 min), 8 h (±6 min), 12 h (±12 min) and 24 h (±36 min) post-dose;
Within 60 min pre-dose on D8, D15, D22, D26 and D27;
On D28, 0 h pre-dose (within 60 min pre-dose) and 10 min (±0.5 min), 20 min (±0.5
min), 40 min (±1 min), 1 h (±1 min), 1.5 h (±1.5 min), 2 h (±1.5 min), 3 h (±3 min), 4 h (±3
min), 6 h (±6 min), 8 h (±6 min), 12 h (±12 min) and 24 h (±36 min).
According to the PK data results of the completed dose groups in this project, the
sponsor and the investigator decided after discussion to adjust the blood collection time
points for 100 mg, 150 mg, and 200 mg (alternative) dose groups by adding 4 new PK blood
collection points: 72 h (±1 h, D31), 168 h (±2 h, D35), 240 h (±2 h, D38) and 312 h (±2 h,
D41) post-dose on D28.
PK Assessment
Evaluation of PK parameters for BGT-002 and its metabolites (if applicable) will
include:
Evaluation of PK parameters on Day 1 (D1): Cmax, Tmax,AUC0-24h, etc.;
Evaluation of steady-state PK parameters (D28): Cmax,ss, Tmax,ss, AUCss, CLss/F, Cmin,ss,
Rac, etc.
Collection and
Assessment of
PD and
Exploratory
Indicators
Imaging PD Indicators and Examination Time Points:
MRI-PDFF: D-1 (for subjects with results within 7 days pre-dose, examination may be
omitted on D-1), D29/early withdrawal (+5 days), and D56 (± 5 days).
CAP and LSM: D-1 (for subjects with results within 7 days pre-dose, examination may
be omitted on D-1), D29/early withdrawal, and D56 (± 5 days).
Other PD Indicators and Collection Points:
BMI, ALT, AST, TG, LDL, and TC: D-1, D29/early withdrawal, and D56 (± 5 days);
Exploratory Indicators (Test Indicators Adjusted According to the Actual Situation of
Testing Unit) and Collection Points:
CK18, FGF21, IP10, hsCRP, TIMP1, and β-HB: 0 h pre-dose on D1 (within 60 min
pre-dose), 24 h (+36 min) post-dose on D28, and D56 (± 5 days).

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Primary Efficacy Variables:
Changes from baseline in ALT, AST, BMI and blood lipid levels at Week 4 and Week
8;
Change from baseline in liver fat content measured by MRI-PDFF at Week 4 and Week
8;
Proportion of subjects with a relative reduction of at least 30% in liver fat content
measured by MRI-PDFF at Week 4 and Week 8;
Secondary Efficacy Variables:
Changes from baseline in CAP and LSM at Week 4 and Week 8;
Exploratory Evaluation Indicators:
Changes from baseline in biomarkers (CK18, FGF21, IP10, hsCRP, TIMP1, β-HB) at
Week 4 and Week 8.
Tolerability
and Safety
Evaluation
Indicators
The safety and tolerability of BGT-002 in subjects after administration will be
evaluated.
Adverse events (AEs) throughout the study will be evaluated and graded according to
CTCAE 5.0.
The indicators will include symptoms and physical examination, clinical laboratory
tests (hematology, coagulation function, blood chemistry and urinalysis), vital signs (blood
pressure, pulse, respiration and body temperature) and 12-lead ECG.
C-QTc Study: To investigate the effect of BGT-002 in 75 mg, 100 mg, 150 mg, and
200 mg (alternative) dose groups on QT/QTc interval in subjects, a C-QTc study will be
conducted for 36-48 subjects on D1 and D28.
Statistical
Analysis
Analysis Population
Full Analysis Set (FAS): Randomized subjects who received at least 1 dose of the study
drug with safety data available.
Safety Set (SS): Randomized subjects who received at least 1 dose of the study drug.
Pharmacokinetics Set (PKS): Randomized subjects who received at least 1 dose of the
study drug with at least one evaluable PK concentration data. The inclusion of subjects in the
PKS will be determined on a case-by-case basis at the data verification meeting.
Pharmacodynamics Set (PDS): Randomized subjects who received at least 1 dose of the
study drug with at least one valid PD evaluation data. The inclusion of subjects in the PDS
will be determined on a case-by-case basis at the data verification meeting.
Statistical Methods
Descriptive statistical analysis will be mainly adopted for the trial results. For
quantitative indicators, the mean, standard deviation, median, maximum, and minimum
values will be listed. Frequency (constituent ratio) will be presented for enumeration data
and ranked data. The inclusion, completion, and early withdrawal of subjects in each dose
group
will
be
described,
and
the
demographic
and
baseline
characteristics
of

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randomized/enrolled subjects will be summarized. The number and percentage of subjects
included in different analysis data sets will be calculated for each dose group.
Statistical Analysis of C-QTC Study:
Exploratory statistical analysis will be performed on C-QTc based on PK and QT
interval changes. Descriptive analysis will be performed for QT/QTc intervals and changes
from baseline at each time point, and line charts will be used to depict the changes at each
time point and between groups. Baseline correction (ΔQTc) and placebo correction (ΔΔQTc)
will be applied to the obtained QT/QTc intervals, with ΔQTc as the dependent variable to
measure the degree of drug effect on QT/QTc. The changes in drug concentration and
QT/QTc intervals will be considered for model-based exploratory analysis.
Tolerability and Safety Evaluation:
Statistical analysis will be performed using SAS (v9.4 or above).
Adverse events (AEs) will be coded as per the Medical Dictionary for Regulatory
Activities (MedDRA). The AEs observed during the trial will be described by system organ
class (SOC) and preferred term (PT) for each dose group. Descriptive statistics of clinical
laboratory tests, 12-lead ECGs, C-QTc study, vital signs, and physical examination results
will be performed for each dose group. Clinically significant changes in clinical laboratory
findings from baseline will be presented in the shift table.
Evaluation of the C-QTc study: The threshold of concern is a ΔΔQTc interval
prolongation exceeding 5 ms. Based on the C-QTc study results, it can be confirmed whether
the conditions for conducting a TQT study are met. According to the C-QTc model, if the
upper limit of two-sided 90% CI for ΔΔQTcF corresponding to the highest clinical exposure
is ≤10 ms, it can be considered that the mean QT/QTc effect of the drug is not more than 5
ms, and the C-QTc study result is negative. However, if the upper limit of two-sided 90% CI
for ΔΔQTcF corresponding to low clinical exposure is > 10 ms by model calculation, the
C-QTc study result will be positive. When the upper limit of two-sided 90% CI for ΔΔQTcF
corresponding to low clinical exposure is ≤10 ms and the upper limit of two-sided 90% CI
for ΔΔQTcF corresponding to the highest clinical exposure is > 10 ms, the dose range for
negative ΔΔQTcF (≤10 ms) can be obtained with the model.
Pharmacokinetic Analysis:
Plasma concentrations will be summarized by dose group and scheduled sampling time
point, including the number of subjects, the number of subjects below the quantification
limit (BQL), arithmetic mean, standard deviation, coefficient of variation, median,
minimum, maximum, geometric mean, and geometric coefficient of variation. Individual and
mean plasma concentration-time (C-T) curves will be plotted separately.
Based on the non-compartmental model, Phoenix WinNonlin software (Certara USA
Inc, version 8.2 or above) will be used to calculate PK parameters (main PK parameters
include Tmax, Cmax, and AUC). PK parameters will be summarized by dose group, including
the number of subjects, arithmetic mean, standard deviation, median, minimum, and

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maximum. For PK parameters, other than Tmax, the coefficient of variation (CV, based on the
arithmetic mean), geometric mean, and geometric CV will also be derived.
Descriptive statistics of main PK parameters post-dose will be performed using the
Statistical Analysis Software (SAS, v9.4 or above) for each dose group, including a
comparison of Tmax between groups using a non-parametric test. An exploratory analysis of
PK parameters (AUC and Cmax) versus dose will be conducted for potential dose
proportionality.
The
relationship
of
log-transformed
PK
parameters
against
the
log-transformed dose (fixed effect) will be fitted using the Power model to calculate the
slope (β) and its 90% confidence interval (CI) on the log scale.
Pharmacodynamic Analysis
Descriptive statistics will be used to calculate and summarize the changes from
baseline in liver fat content measured by MRI-PDFF at 4 weeks and 8 weeks, the proportion
of subjects with a relative reduction of at least 30% in liver fat content measured by
MRI-PDFF, the changes from baseline in ALT, AST, BMI, blood lipid levels, and the
changes from baseline in CAP and LSM for each group.
Analysis of Exploratory Indicators
Descriptive analysis will be performed for exploratory biomarker indicators (CK18,
FGF21, IP10, hsCRP, TIMP1, and β-HB) after administration in each dose group to explore
the relationship between dose/exposure and effect of BGT-002.
The specific statistical methods are specified in the Statistical Analysis Plan.