Metabolic Dysfunction-assocated Steatohepatitis/ Nonalcoholic Fatty Liver Disease
Conditions
Keywords
NASH, Nonalcoholic Steatohepatitis, Fatty Liver Disease, Biopsy Confirmed, FASN, Fatty Liver, Liver Disease, Digestive System Diseases, MASH, Metabolic dysfunction-associated steatohepatitis
Brief summary
This is a Phase 2, multi-center, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy on TVB-2640 in subjects with non-alcoholic steatohepatitis (NASH). Subjects will be randomly assigned toTVB-2640 or matching placebo PO QD for 52 weeks, with the first dose administered on Day 1.
Detailed description
The indication nonalcoholic steatohepatitis \[NASH\]) is now referred to as metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by hepatocyte necrosis, chronic inflammation, and resultant fibrosis formation.
Interventions
DRUGTVB-2640
Oral dose, tablet
OTHERPlacebo
Oral dose, tablet
Sponsors
Sagimet Biosciences Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Subjects with liver fibrosis stage F2-F3, will be enrolled and randomized in a 2:1 ratio to receive TVB-2640, or placebo PO QD
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must be willing and able to participate in the study and provide written informed consent. * Male and female adults ≥18 years of age on the date that written informed consent to take part in the study is provided. * Body mass index (BMI) ≥23 kg/m2 for Asians and ≥25 kg/m2 for other races. * Female subjects must be either: * Not of childbearing potential OR * Women of childbearing potential (WOCBP) must have a negative serum pregnancy (beta-human chorionic gonadotropin \[β-HCG\]) test during Screening, a negative urine pregnancy test within 24 hours before the first dose of study drug on Day 1, and must agree to perform urine home pregnancy tests monthly between study visits. WOCBP must not be breastfeeding, not plan to become pregnant during the study, and must use birth control. * Must have liver stiffness measurement ≥8.5 kPa measured by FibroScan and CAP score measured by FibroScan ≥280 dB/m during the Screening period. * Histologic confirmation of NASH: must have had prior liver biopsy within 180 days before randomization (randomization is within 24 hours of Baseline \[Day1\]) with fibrosis stage F2-F3 and a NAS of ≥4 with at least a score of 1 in each of the following NAS components: steatosis, ballooning degeneration, and lobular inflammation.
Exclusion criteria
* History of harmful alcohol intake for a period of more than 3 consecutive months within 1 year prior to Screening in the judgement of the Investigator. * Active substance abuse. * Gain or loss of \>5% of body weight in the 6 months prior to Baseline (Day 1) or \>10% of body weight in the 12 months prior to Screening. * Type 1 diabetes mellitus by history. * Positive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) test within 30 days before Baseline, history of hospitalization for coronavirus disease-2019 (COVID-19) ), or history of use of oxygen due to COVID-19) \<6 months prior to the Screening visit date. Note that previous COVID-19 infection alone is not exclusionary and vaccination against SARS-CoV-2 is allowed. Infection and/or vaccination must be documented. * Uncontrolled T2DM, defined as HbA1c ≥9.5% at Screening. * Presence of cirrhosis on liver histology (stage 4 fibrosis), according to the judgement of the central reader, and/or cross sectional imaging evidence consistent with cirrhosis and/or portal hypertension. * Use of glucagon-like peptide-1 (GLP-1) agonists or a sodium-glucose co-transporter-2 (SGLT2) inhibitor, unless on a stable daily dose for at least 6 months prior to the Screening visit date, or on a complex oral anti-diabetic (OAD) regimen (3 or more OADs \[except for a GLP-1 agonist or an SGLT2 inhibitor\]), unless on a stable dose for at least 3 months prior to the Screening visit date. * Subjects with active or quiescent chronic liver disease of etiologies other than NASH (eg, viral or autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and 'autoimmune hepatitis-overlap' syndromes, hemochromatosis, Wilson's disease, alpha 1 antitrypsin deficiency, alcohol-related liver disease, drug-induced liver disease, and/or infiltrative conditions \[eg, sarcoidosis\]). * Current or historic clinically evident hepatic decompensation event (eg, ascites formation, variceal hemorrhage, hepatic encephalopathy). * Any subject who has sustained a clinically evident cardiovascular, cerebrovascular, and/or peripheral vascular event during the 12 months prior to anticipated Baseline (Day 1) visit date is not eligible for study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) Without Worsening of Fibrosis (by NASH Clinical Research Network [CRN] Fibrosis Score). | 52 Weeks | Histological improvement is defined as ≥2 points improvement in NAS with ≥1 point improvement in ballooning or inflammation |
| Subjects With Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score and Histological Improvement in NAS. | 52 Weeks | NASH resolution defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a score of either 0 or 1 for inflammation, 0 for ballooning and any value for steatosis and no worsening of liver fibrosis (by NASH CRN fibrosis score). Histological improvement defined as ≥2 point improvement in NAS (with ≥1 point improvement in ballooning or inflammation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 52 Weeks | Proportion of subjects experiencing fibrosis improvement of ≥1 stage by NASH CRN score Without worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at 52 weeks. |
| Proportion of Subjects Experiencing Resolution of Steatohepatitis and no Worsening of Liver Fibrosis (by NASH CRN Fibrosis Score) | 52 Weeks | Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis. |
| Proportion of Subjects With Improvement in Liver Fibrosis >=1 Stage by NASH CRN Fibrosis Score Without Worsening of Steatohepatitis at 52 Weeks OR Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score | 52 Weeks | No increase in NAS for ballooning, inflammation or steatosis. |
| Proportion of MRI-PDFF ≥30% Responders. | 52 Weeks | MRI PDFF ≥30% responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a relative reduction from Baseline in MRI-PDFF ≥30%. |
Countries
Canada, Poland, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TVB-2640 50 mg Subjects will receive TVB-2640 PO QD for 52 weeks, with the first dose administered on Day 1.
TVB-2640: Oral dose, tablet | 112 |
| Placebo Subjects will receive matching placebo PO QD for 52 weeks, with the first dose administered on Day 1.
Placebo: Oral dose, tablet | 56 |
| Total | 168 |
Baseline characteristics
| Characteristic | Placebo | Total | TVB-2640 50 mg |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 11.9 | 57.0 years STANDARD_DEVIATION 11 | 56.3 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 55 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 113 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 11 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 50 Participants | 150 Participants | 100 Participants |
| Sex: Female, Male Female | 34 Participants | 100 Participants | 66 Participants |
| Sex: Female, Male Male | 22 Participants | 68 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 112 | 0 / 56 |
| other Total, other adverse events | 79 / 112 | 36 / 56 |
| serious Total, serious adverse events | 13 / 112 | 3 / 56 |
Outcome results
Primary
Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) Without Worsening of Fibrosis (by NASH Clinical Research Network [CRN] Fibrosis Score).
Histological improvement is defined as ≥2 points improvement in NAS with ≥1 point improvement in ballooning or inflammation
Time frame: 52 Weeks
Population: ITT and mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ITT: TVB-2640 50 mg | Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) Without Worsening of Fibrosis (by NASH Clinical Research Network [CRN] Fibrosis Score). | 42 Participants |
| ITT: Placebo | Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) Without Worsening of Fibrosis (by NASH Clinical Research Network [CRN] Fibrosis Score). | 9 Participants |
| mITT: TVB-2640 50 mg | Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) Without Worsening of Fibrosis (by NASH Clinical Research Network [CRN] Fibrosis Score). | 42 Participants |
| mITT: Placebo | Histological Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) Without Worsening of Fibrosis (by NASH Clinical Research Network [CRN] Fibrosis Score). | 9 Participants |
Comparison: ITT Population analysisp-value: 0.0018Cochran-Mantel-Haenszel
Comparison: ITT Population Analysisp-value: 0.0035Cochran-Mantel-Haenszel
Comparison: mITT Population Analysisp-value: 0.0001t-test, 1 sided
Comparison: mITT Population Analysisp-value: 0.0003Cochran-Mantel-Haenszel
Primary
Subjects With Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score and Histological Improvement in NAS.
NASH resolution defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a score of either 0 or 1 for inflammation, 0 for ballooning and any value for steatosis and no worsening of liver fibrosis (by NASH CRN fibrosis score). Histological improvement defined as ≥2 point improvement in NAS (with ≥1 point improvement in ballooning or inflammation).
Time frame: 52 Weeks
Population: ITT and mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ITT: TVB-2640 50 mg | Subjects With Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score and Histological Improvement in NAS. | 29 Participants |
| ITT: Placebo | Subjects With Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score and Histological Improvement in NAS. | 6 Participants |
| mITT: TVB-2640 50 mg | Subjects With Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score and Histological Improvement in NAS. | 29 Participants |
| mITT: Placebo | Subjects With Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score and Histological Improvement in NAS. | 6 Participants |
Comparison: ITT Population Analysisp-value: 0.0087Cochran-Mantel-Haenszel
Comparison: ITT Population Analysisp-value: 0.0173Cochran-Mantel-Haenszel
Comparison: mITT Population Analysisp-value: 0.0022Cochran-Mantel-Haenszel
Comparison: mITT Population Analysisp-value: 0.0044Cochran-Mantel-Haenszel
Secondary
Proportion of MRI-PDFF ≥30% Responders.
MRI PDFF ≥30% responder is defined as a subject with ≥8% liver fat content at Baseline who achieves a relative reduction from Baseline in MRI-PDFF ≥30%.
Time frame: 52 Weeks
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ITT: TVB-2640 50 mg | Proportion of MRI-PDFF ≥30% Responders. | 69 Participants |
| ITT: Placebo | Proportion of MRI-PDFF ≥30% Responders. | 38 Participants |
Comparison: mITT Population Analysisp-value: <0.0001Cochran-Mantel-Haenszel
Secondary
Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis
Proportion of subjects experiencing fibrosis improvement of ≥1 stage by NASH CRN score Without worsening of steatohepatitis (defined as no increase in NAS for ballooning, inflammation, or steatosis) at 52 weeks.
Time frame: 52 Weeks
Population: mITT Population and Subgroups
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ITT: TVB-2640 50 mg | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 33 Participants |
| ITT: Placebo | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 8 Participants |
| mITT: TVB-2640 50 mg | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 10 Participants |
| mITT: Placebo | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 5 Participants |
| Subgroup: Fibrosis Stage F3; TVB-2640 | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 23 Participants |
| Subgroup: Fibrosis Stage F3; Placebo | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 3 Participants |
| Subgroup: T2DM; TVB-2640 | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 22 Participants |
| Subgroup: T2DM; Placebo | Proportion of Subjects Experiencing Fibrosis Improvement of ≥1 Stage by NASH CRN Score Without Worsening of Steatohepatitis | 5 Participants |
Comparison: mITT Population Analysisp-value: 0.0102Cochran-Mantel-Haenszel
Comparison: Subgroup Fibrosis Stage F2 at Baseline Population Analysisp-value: 0.59Cochran-Mantel-Haenszel
Comparison: Subgroup Fibrosis Stage F3 at Baseline Population Analysisp-value: 0.0032Cochran-Mantel-Haenszel
Comparison: Subgroup Type 2 Diabetes Mellitus at Baseline Population Analysisp-value: 0.0764Cochran-Mantel-Haenszel
Secondary
Proportion of Subjects Experiencing Resolution of Steatohepatitis and no Worsening of Liver Fibrosis (by NASH CRN Fibrosis Score)
Resolution of steatohepatitis is defined as absence of fatty liver disease or isolated or simple steatosis without steatohepatitis and a NAS of 0 or 1 for inflammation, 0 for ballooning, and any value for steatosis.
Time frame: 52 Weeks
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ITT: TVB-2640 50 mg | Proportion of Subjects Experiencing Resolution of Steatohepatitis and no Worsening of Liver Fibrosis (by NASH CRN Fibrosis Score) | 31 Participants |
| ITT: Placebo | Proportion of Subjects Experiencing Resolution of Steatohepatitis and no Worsening of Liver Fibrosis (by NASH CRN Fibrosis Score) | 7 Participants |
Comparison: mITT Population Analysisp-value: 0.0043Cochran-Mantel-Haenszel
Secondary
Proportion of Subjects With Improvement in Liver Fibrosis >=1 Stage by NASH CRN Fibrosis Score Without Worsening of Steatohepatitis at 52 Weeks OR Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score
No increase in NAS for ballooning, inflammation or steatosis.
Time frame: 52 Weeks
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ITT: TVB-2640 50 mg | Proportion of Subjects With Improvement in Liver Fibrosis >=1 Stage by NASH CRN Fibrosis Score Without Worsening of Steatohepatitis at 52 Weeks OR Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score | 45 Participants |
| ITT: Placebo | Proportion of Subjects With Improvement in Liver Fibrosis >=1 Stage by NASH CRN Fibrosis Score Without Worsening of Steatohepatitis at 52 Weeks OR Resolution of Steatohepatitis and No Worsening of Liver Fibrosis by NASH CRN Fibrosis Score | 12 Participants |
Comparison: mITT Population Analysisp-value: 0.0018Cochran-Mantel-Haenszel