Non-alcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis
Conditions
Keywords
Non-alcoholic fatty liver disease, NAFLD, Non-alcoholic steatohepatitis, NASH, Platform design, LYS006, LJN452, Tropifexor
Brief summary
This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.
Detailed description
This was a Phase II, non-confirmatory, multicenter, open label, platform study in NAFLD participants with a NASH-like biomarker phenotype to examine the effects of single and combination therapies over 12 weeks of treatment. The study consisted of four distinct study periods: * Screening Period (Day -60 to -28): Lasted up to a maximum of 33 days where participants were assessed for inclusion and exclusion criteria prior the baseline assessments. * Baseline Period (Day -27 to -1): Lasted up to a maximum of 27 days and comprised baseline assessments and randomization. * Treatment Period (Day 1 to 85): Participants were randomized in a 1:1 ratio to LYS006 20 mg (twice a day) arm or to LYS006 20 mg (twice a day) and tropifexor 200ug (once a day). Participants were treated daily during 12 weeks. * Follow-up Period (Day 85 to 113): After completion of the treatment period, participants were observed until the End Of Study (EOS) visit at Day 113.
Interventions
DRUGLYS006
5 mg LYS006 capsules orally administered 20 mg b.i.d for 12 weeks
DRUGTropifexor
100 ug LJN452 capsules orally administered 200ug once daily for 12 weeks
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Phenotypic diagnosis of NASH based on the presence of all of the following: * ALT ≥ 43 IU/L (males) or ≥ 28 IU/L (females) * BMI ≥ 27 kg/m2 (race other than Asian) or ≥ 23 kg/m2 (Asian race) * History of type 2 diabetes mellitus with HbA1c ≤ 9% * ELF test score ≥ 8.5 and ≤ 10.5 * Liver fat ≥ 8% * Patients must weigh between 40 kg (88 lbs.) and 150 kg (330 lbs.)
Exclusion criteria
* Use of other investigational drugs within 5 half-lives of randomization or within 3 months, whichever is longer * Use of obeticholic acid (OCA) or pharmacologically-active weight loss drugs within 1 month of randomization * Use of strong CYP3A4/5 inhibitors or strong CYP3A4 inducers within 5 half-lives or 7 days of randomization, whichever is longer * History or presence of other concomitant liver diseases * History or current diagnosis of ECG abnormalities * Patients with contraindications to MRI imaging * Current or history of significant alcohol consumption * Clinical evidence of hepatic decompensation or severe liver impairment * Women of child bearing potential (unless on highly effective methods of contraception) * Presence of liver cirrhosis * Use of OAT3 inhibitors within 5 half-lives or 7 days of randomization, whichever is longer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 113 Days | Number of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters qualifying and reported as AEs. The number of participants in each category is reported in the table. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113) | Fasting lipid profile (total cholesterol) was examined as a cardiometabolic risk parameter. Total cholesterol was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates cardiovascular risk. |
| Change From Baseline in Percent Liver Fat at Day 85 | Baseline and Day 85 | Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction (MRIPDFF). Participants underwent magnetic resonance imaging twice during the course of the study (baseline and end of treatment) to quantitate liver fat. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in a component of NAFLD. |
| Change From Baseline in Total Body Weight | Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113) | Body weight (to the nearest 0.1 kilogram \[kg\] was measured on a calibrated scale. The measurement was performed with the study participant in underwear and without shoes; or while wearing minimal indoor clothing. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in obesity. |
| Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Day 85 | Baseline and Day 85 | HOMA-IR is a test that uses a simultaneous fasting blood glucose test and fasting insulin test to accurately estimate the degree of insulin resistance (IR) and β-cell function (the cells of the pancreas that produce insulin). HOMA-IR scores are classified as follows: Insulin sensitive is considered less than 1.0, Healthy is considered 0.5-1.4, Above 1.8 is early insulin resistance and Above 2.7 is considered significant insulin resistance HOMA-IR= \[Fasting glucose (mmol/L) x (fasting insulin (pmol/L)/6)\] / 22.5 Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity. |
| Change From Baseline in Fasting Glucose | Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113) | Fasting Glucose was examined as a cardiometabolic risk parameter. Total fasting glucose was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control. |
| Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | Baseline and Days 57, 85 and EOS (Day 113) | The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: \< 7.7: no to mild fibrosis; ≥ 7.7 - \< 9.8: Moderate fibrosis; ≥ 9.8 - \< 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates decreased fibrosis. |
| Change From Baseline in Hemoglobin A1c (HbA1c) | Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113) | HbA1c was examined as a cardiometabolic risk parameter. HbA1c was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control. |
| Change From Baseline in Alanine Aminotransferase (ALT) | Baseline and days 15, 29, 43, 57, 85 and EOS (Day 113) | Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver inflammation. Baseline is defined as the mean of the last 2 non-missing measurements taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation. |
| Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Baseline and Days 57, 85 and EOS (Day 113) | High-sensitivity C-reactive protein is a blood test marker for inflammation in the body. HsCRP was measured from a blood sample and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation. |
| LYS006 Plasma Concentration | pre-dose at Days 1, 29, 57 and 85 and post-dose (1, 2, 3 and 4 hours) at Days 29 and 57 | LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. No methods for imputation of missing data were used. |
| Maximum Observed Plasma Concentration (Cmax) of LYS006 | pre-dose and post-dose (1, 2, 3 and 4 hours) at Days 29 and 57 | LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Cmax of LYS006 was determined with Phoenix WinNonlin (Version 8.0 or higher). No methods for imputation of missing data were used. |
| Change From Baseline in Fasting Insulin at Day 85 | Baseline and Day 85 | Fasting insulin was examined as a cardiometabolic risk parameter. Total fasting insulin was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity. |
Countries
Argentina, Germany, United States
Participant flow
Recruitment details
Participants were recruited from 10 sites in 3 countries.
Pre-assignment details
Participants underwent a Screening period of up to 33 days followed by a Baseline assessment period of up to 27 days.
Participants by arm
| Arm | Count |
|---|---|
| LYS006 LYS006 20 mg was administered orally twice per day (b.i.d) for 12 weeks | 20 |
| LYS006 + LJN452 LYS006 20 mg was administered orally twice per day (b.i.d) in addition to LJN452 200ug administered orally once daily for 12 weeks | 21 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Study Terminated by Sponsor | 4 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | LYS006 | LYS006 + LJN452 | Total |
|---|---|---|---|
| Age, Continuous | 52.0 Year STANDARD_DEVIATION 9.23 | 54.9 Year STANDARD_DEVIATION 8.36 | 53.5 Year STANDARD_DEVIATION 8.81 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 17 Participants | 36 Participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 41 |
| other Total, other adverse events | 9 / 20 | 15 / 21 | 24 / 41 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 41 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with AEs and SAEs including significant changes from baseline in vital signs, electrocardiograms and laboratory parameters qualifying and reported as AEs. The number of participants in each category is reported in the table.
Time frame: From the start of treatment to 28 days after end of treatment, assessed up to maximum duration of 113 Days
Population: All participants who received at least one dose of study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LYS006 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 14 Participants |
| LYS006 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 2 Participants |
| LYS006 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| LYS006 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 0 Participants |
| LYS006 + LJN452 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs leading to discontinuation of study treatment | 3 Participants |
| LYS006 + LJN452 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 17 Participants |
| LYS006 + LJN452 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| LYS006 + LJN452 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AEs | 15 Participants |
Secondary
Change From Baseline in Alanine Aminotransferase (ALT)
Alanine aminotransferase (ALT) is an enzyme found primarily in the liver. ALT is increased with liver damage. In this study, the blood levels of ALT was used to detect liver inflammation. Baseline is defined as the mean of the last 2 non-missing measurements taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation.
Time frame: Baseline and days 15, 29, 43, 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 15 | 0.97 U / L | Standard Deviation 18.255 |
| LYS006 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 29 | -6.92 U / L | Standard Deviation 22.166 |
| LYS006 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 43 | -11.13 U / L | Standard Deviation 21.624 |
| LYS006 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 57 | -12.09 U / L | Standard Deviation 25.401 |
| LYS006 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 85 | -7.21 U / L | Standard Deviation 34.702 |
| LYS006 | Change From Baseline in Alanine Aminotransferase (ALT) | EOS | -14.50 U / L | Standard Deviation 29.619 |
| LYS006 + LJN452 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 85 | -11.14 U / L | Standard Deviation 26.318 |
| LYS006 + LJN452 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 15 | -19.75 U / L | Standard Deviation 25.617 |
| LYS006 + LJN452 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 57 | -17.04 U / L | Standard Deviation 12.841 |
| LYS006 + LJN452 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 29 | -9.63 U / L | Standard Deviation 13.774 |
| LYS006 + LJN452 | Change From Baseline in Alanine Aminotransferase (ALT) | EOS | -8.05 U / L | Standard Deviation 14.57 |
| LYS006 + LJN452 | Change From Baseline in Alanine Aminotransferase (ALT) | Day 43 | -8.68 U / L | Standard Deviation 14.573 |
Secondary
Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint
Fasting lipid profile (total cholesterol) was examined as a cardiometabolic risk parameter. Total cholesterol was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates cardiovascular risk.
Time frame: Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 15 | -0.025 mmol / L | Standard Deviation 0.5814 |
| LYS006 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 29 | -0.058 mmol / L | Standard Deviation 0.6058 |
| LYS006 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 43 | -0.109 mmol / L | Standard Deviation 0.6758 |
| LYS006 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 57 | -0.246 mmol / L | Standard Deviation 0.6341 |
| LYS006 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 85 | 0.001 mmol / L | Standard Deviation 0.8558 |
| LYS006 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | EOS | -0.283 mmol / L | Standard Deviation 1.1182 |
| LYS006 + LJN452 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 85 | 0.754 mmol / L | Standard Deviation 0.9915 |
| LYS006 + LJN452 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 15 | 0.086 mmol / L | Standard Deviation 0.8825 |
| LYS006 + LJN452 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 57 | 0.463 mmol / L | Standard Deviation 1.3026 |
| LYS006 + LJN452 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 29 | 0.431 mmol / L | Standard Deviation 1.0688 |
| LYS006 + LJN452 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | EOS | 0.249 mmol / L | Standard Deviation 0.5175 |
| LYS006 + LJN452 | Change From Baseline in Cholesterol: Fasting Lipid Profile Endpoint | Day 43 | 0.474 mmol / L | Standard Deviation 1.0364 |
Secondary
Change From Baseline in Fasting Glucose
Fasting Glucose was examined as a cardiometabolic risk parameter. Total fasting glucose was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control.
Time frame: Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in Fasting Glucose | Day 15 | 0.26 mmol / L | Standard Deviation 2.609 |
| LYS006 | Change From Baseline in Fasting Glucose | Day 29 | -0.04 mmol / L | Standard Deviation 3.541 |
| LYS006 | Change From Baseline in Fasting Glucose | Day 43 | -0.53 mmol / L | Standard Deviation 3.655 |
| LYS006 | Change From Baseline in Fasting Glucose | Day 57 | -0.82 mmol / L | Standard Deviation 3.176 |
| LYS006 | Change From Baseline in Fasting Glucose | Day 85 | -1.74 mmol / L | Standard Deviation 3.81 |
| LYS006 | Change From Baseline in Fasting Glucose | EOS | -1.01 mmol / L | Standard Deviation 3.627 |
| LYS006 + LJN452 | Change From Baseline in Fasting Glucose | Day 85 | 0.41 mmol / L | Standard Deviation 2.023 |
| LYS006 + LJN452 | Change From Baseline in Fasting Glucose | Day 15 | 0.26 mmol / L | Standard Deviation 2.402 |
| LYS006 + LJN452 | Change From Baseline in Fasting Glucose | Day 57 | 0.84 mmol / L | Standard Deviation 1.96 |
| LYS006 + LJN452 | Change From Baseline in Fasting Glucose | Day 29 | 0.61 mmol / L | Standard Deviation 2.362 |
| LYS006 + LJN452 | Change From Baseline in Fasting Glucose | EOS | -0.40 mmol / L | Standard Deviation 1.563 |
| LYS006 + LJN452 | Change From Baseline in Fasting Glucose | Day 43 | 1.05 mmol / L | Standard Deviation 2.449 |
Secondary
Change From Baseline in Fasting Insulin at Day 85
Fasting insulin was examined as a cardiometabolic risk parameter. Total fasting insulin was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity.
Time frame: Baseline and Day 85
Population: The overall number of participants analyzed includes all participants in the PD analysis set with evaluable data for the endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LYS006 | Change From Baseline in Fasting Insulin at Day 85 | -28.36 pmol / L | Standard Deviation 139.23 |
| LYS006 + LJN452 | Change From Baseline in Fasting Insulin at Day 85 | 14.23 pmol / L | Standard Deviation 63.875 |
Secondary
Change From Baseline in Hemoglobin A1c (HbA1c)
HbA1c was examined as a cardiometabolic risk parameter. HbA1c was measured on blood samples under fasted conditions and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in glycemic control.
Time frame: Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 29 | 0.03 Percentage | Standard Deviation 0.431 |
| LYS006 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 57 | -0.11 Percentage | Standard Deviation 0.73 |
| LYS006 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 15 | 0.10 Percentage | Standard Deviation 0.194 |
| LYS006 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 85 | -0.48 Percentage | Standard Deviation 0.834 |
| LYS006 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 43 | -0.02 Percentage | Standard Deviation 0.544 |
| LYS006 | Change From Baseline in Hemoglobin A1c (HbA1c) | EOS | -0.59 Percentage | Standard Deviation 0.961 |
| LYS006 + LJN452 | Change From Baseline in Hemoglobin A1c (HbA1c) | EOS | 0.34 Percentage | Standard Deviation 0.359 |
| LYS006 + LJN452 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 15 | 0.08 Percentage | Standard Deviation 0.338 |
| LYS006 + LJN452 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 29 | 0.21 Percentage | Standard Deviation 0.487 |
| LYS006 + LJN452 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 43 | 0.31 Percentage | Standard Deviation 0.884 |
| LYS006 + LJN452 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 57 | 0.36 Percentage | Standard Deviation 0.68 |
| LYS006 + LJN452 | Change From Baseline in Hemoglobin A1c (HbA1c) | Day 85 | -0.03 Percentage | Standard Deviation 0.863 |
Secondary
Change From Baseline in High-sensitivity C-reactive Protein (hsCRP)
High-sensitivity C-reactive protein is a blood test marker for inflammation in the body. HsCRP was measured from a blood sample and analyzed at a central laboratory. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in liver inflammation.
Time frame: Baseline and Days 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Day 57 | -0.32 mg / L | Standard Deviation 2.192 |
| LYS006 | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Day 85 | -0.62 mg / L | Standard Deviation 2.18 |
| LYS006 | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | EOS | 0.19 mg / L | Standard Deviation 3.432 |
| LYS006 + LJN452 | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Day 57 | -7.78 mg / L | Standard Deviation 27.5 |
| LYS006 + LJN452 | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | Day 85 | 0.24 mg / L | Standard Deviation 1.692 |
| LYS006 + LJN452 | Change From Baseline in High-sensitivity C-reactive Protein (hsCRP) | EOS | 0.05 mg / L | Standard Deviation 1.015 |
Secondary
Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Day 85
HOMA-IR is a test that uses a simultaneous fasting blood glucose test and fasting insulin test to accurately estimate the degree of insulin resistance (IR) and β-cell function (the cells of the pancreas that produce insulin). HOMA-IR scores are classified as follows: Insulin sensitive is considered less than 1.0, Healthy is considered 0.5-1.4, Above 1.8 is early insulin resistance and Above 2.7 is considered significant insulin resistance HOMA-IR= \[Fasting glucose (mmol/L) x (fasting insulin (pmol/L)/6)\] / 22.5 Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in insulin sensitivity.
Time frame: Baseline and Day 85
Population: The overall number of participants analyzed includes all participants in the PD analysis set with evaluable data for the endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LYS006 | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Day 85 | -3.74 HOMA-IR score | Standard Deviation 9.865 |
| LYS006 + LJN452 | Change From Baseline in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) at Day 85 | 1.67 HOMA-IR score | Standard Deviation 7.741 |
Secondary
Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score
The markers of fibrosis assessed in this test comprised hyaluronic acid (HA), tissue inhibitor of metalloproteinase (TIMP1) and procollagen III N-terminal peptide (PIIINP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during fibrogenesis as a result of activation of the hepatic stellate cell. The ELF test is a composite score: \< 7.7: no to mild fibrosis; ≥ 7.7 - \< 9.8: Moderate fibrosis; ≥ 9.8 - \< 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates decreased fibrosis.
Time frame: Baseline and Days 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | Day 57 | -0.25 Scores on a scale | Standard Deviation 0.564 |
| LYS006 | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | Day 85 | -0.12 Scores on a scale | Standard Deviation 0.78 |
| LYS006 | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | EOS | 0.01 Scores on a scale | Standard Deviation 0.713 |
| LYS006 + LJN452 | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | Day 57 | 0.29 Scores on a scale | Standard Deviation 0.286 |
| LYS006 + LJN452 | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | Day 85 | 0.18 Scores on a scale | Standard Deviation 0.687 |
| LYS006 + LJN452 | Change From Baseline in Non-invasive Markers of Hepatic Fibrosis: Enhanced Liver Fibrosis Test (ELF) Score | EOS | 0.09 Scores on a scale | Standard Deviation 0.461 |
Secondary
Change From Baseline in Percent Liver Fat at Day 85
Percent (%) Liver fat was measured by Magnetic Resonance Imaging Proton Density Liver Fat Fraction (MRIPDFF). Participants underwent magnetic resonance imaging twice during the course of the study (baseline and end of treatment) to quantitate liver fat. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates a reduction in a component of NAFLD.
Time frame: Baseline and Day 85
Population: The overall number of participants analyzed includes all participants in the PD analysis set with evaluable data for the endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LYS006 | Change From Baseline in Percent Liver Fat at Day 85 | -3.74 Percentage of Liver Fat | Standard Deviation 3.47 |
| LYS006 + LJN452 | Change From Baseline in Percent Liver Fat at Day 85 | -7.52 Percentage of Liver Fat | Standard Deviation 5.846 |
Secondary
Change From Baseline in Total Body Weight
Body weight (to the nearest 0.1 kilogram \[kg\] was measured on a calibrated scale. The measurement was performed with the study participant in underwear and without shoes; or while wearing minimal indoor clothing. Baseline is defined as the last non-missing measurement taken at the Screening and Baseline visits (prior to the first dose of study drug administered at the Day 1). A negative change from Baseline indicates improvement in obesity.
Time frame: Baseline and Days 15, 29, 43, 57, 85 and EOS (Day 113)
Population: The overall number of participants analyzed includes all participants in the PD analysis set. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Change From Baseline in Total Body Weight | Day 43 | -0.24 kg | Standard Deviation 1.664 |
| LYS006 | Change From Baseline in Total Body Weight | Day 57 | -0.48 kg | Standard Deviation 1.548 |
| LYS006 | Change From Baseline in Total Body Weight | Day 29 | -0.27 kg | Standard Deviation 1.513 |
| LYS006 | Change From Baseline in Total Body Weight | Day 85 | -0.54 kg | Standard Deviation 2.334 |
| LYS006 | Change From Baseline in Total Body Weight | EOS | 0.17 kg | Standard Deviation 2.753 |
| LYS006 | Change From Baseline in Total Body Weight | Day 15 | -0.21 kg | Standard Deviation 1.412 |
| LYS006 + LJN452 | Change From Baseline in Total Body Weight | EOS | -2.56 kg | Standard Deviation 2.789 |
| LYS006 + LJN452 | Change From Baseline in Total Body Weight | Day 15 | -1.09 kg | Standard Deviation 2.03 |
| LYS006 + LJN452 | Change From Baseline in Total Body Weight | Day 29 | -1.17 kg | Standard Deviation 2.455 |
| LYS006 + LJN452 | Change From Baseline in Total Body Weight | Day 85 | -3.33 kg | Standard Deviation 2.892 |
| LYS006 + LJN452 | Change From Baseline in Total Body Weight | Day 43 | -1.94 kg | Standard Deviation 2.78 |
| LYS006 + LJN452 | Change From Baseline in Total Body Weight | Day 57 | -2.97 kg | Standard Deviation 3.144 |
Secondary
LYS006 Plasma Concentration
LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. No methods for imputation of missing data were used.
Time frame: pre-dose at Days 1, 29, 57 and 85 and post-dose (1, 2, 3 and 4 hours) at Days 29 and 57
Population: The overall number of participants analyzed includes all participants. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | LYS006 Plasma Concentration | Day 29 (2 h) | 224 ng / mL | Standard Deviation 113 |
| LYS006 | LYS006 Plasma Concentration | Day 1 (0 h) | 0.162 ng / mL | Standard Deviation 0.648 |
| LYS006 | LYS006 Plasma Concentration | Day 29 (0 h) | 78.9 ng / mL | Standard Deviation 74 |
| LYS006 | LYS006 Plasma Concentration | Day 29 (1 h) | 174 ng / mL | Standard Deviation 89.6 |
| LYS006 | LYS006 Plasma Concentration | Day 29 (3 h) | 188 ng / mL | Standard Deviation 89.8 |
| LYS006 | LYS006 Plasma Concentration | Day 29 (4 h) | 149 ng / mL | Standard Deviation 73.6 |
| LYS006 | LYS006 Plasma Concentration | Day 57 (0 h) | 58.0 ng / mL | Standard Deviation 57.2 |
| LYS006 | LYS006 Plasma Concentration | Day 57 (1 h) | 200 ng / mL | Standard Deviation 118 |
| LYS006 | LYS006 Plasma Concentration | Day 57 (2 h) | 222 ng / mL | Standard Deviation 80.3 |
| LYS006 | LYS006 Plasma Concentration | Day 57 (3 h) | 188 ng / mL | Standard Deviation 74.3 |
| LYS006 | LYS006 Plasma Concentration | Day 57 (4 h) | 140 ng / mL | Standard Deviation 83.3 |
| LYS006 | LYS006 Plasma Concentration | Day 85 (0 h) | 15.2 ng / mL | Standard Deviation 17.6 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 57 (4 h) | 126 ng / mL | Standard Deviation 54.1 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 57 (0 h) | 24.0 ng / mL | Standard Deviation 21.4 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 1 (0 h) | 0.00 ng / mL | Standard Deviation 0 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 57 (3 h) | 156 ng / mL | Standard Deviation 59.2 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 29 (0 h) | 53.5 ng / mL | Standard Deviation 74.9 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 57 (1 h) | 123 ng / mL | Standard Deviation 123 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 29 (1 h) | 169 ng / mL | Standard Deviation 105 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 29 (2 h) | 189 ng / mL | Standard Deviation 105 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 85 (0 h) | 10.2 ng / mL | Standard Deviation 18.7 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 29 (3 h) | 145 ng / mL | Standard Deviation 54.9 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 57 (2 h) | 198 ng / mL | Standard Deviation 88.7 |
| LYS006 + LJN452 | LYS006 Plasma Concentration | Day 29 (4 h) | 110 ng / mL | Standard Deviation 31.8 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of LYS006
LYS006 plasma concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Cmax of LYS006 was determined with Phoenix WinNonlin (Version 8.0 or higher). No methods for imputation of missing data were used.
Time frame: pre-dose and post-dose (1, 2, 3 and 4 hours) at Days 29 and 57
Population: The overall number of participants analyzed includes all participants. The number analyzed per row represents participants with evaluable data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LYS006 | Maximum Observed Plasma Concentration (Cmax) of LYS006 | Day 29 | 264 ng / mL | Standard Deviation 87.7 |
| LYS006 | Maximum Observed Plasma Concentration (Cmax) of LYS006 | Day 57 | 271 ng / mL | Standard Deviation 71.1 |
| LYS006 + LJN452 | Maximum Observed Plasma Concentration (Cmax) of LYS006 | Day 57 | 228 ng / mL | Standard Deviation 88.1 |
| LYS006 + LJN452 | Maximum Observed Plasma Concentration (Cmax) of LYS006 | Day 29 | 215 ng / mL | Standard Deviation 98.8 |