Expert faculty summarize key NAFLD/NASH studies from this important annual conference. Use these slides to review data on noninvasive screening, clinical outcomes, emerging treatments.
Ira M. Jacobson, MD
Philip N. Newsome, PhD, FRCPE
Format: Microsoft PowerPoint (.ppt)
File Size: 421 KB
Released: December 3, 2018
Glomerular Filtration rate and its determinants.pptx
Clinical Impact of New NAFLD/NASH Data From San Francisco 2018
1. Clinical Impact of New NAFLD/NASH Data From
San Francisco 2018
This program is supported by educational grants from
AbbVie and Gilead Sciences
CCO Independent Conference Coverage*
of The Liver Meeting 2018; November 9-13, 2018; San Francisco, California
*CCO is an independent medical education company that provides state-of-the-art medical information to
healthcare professionals through conference coverage and other educational programs.
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About These Slides
Slide credit: clinicaloptions.com
3. Faculty
Ira M. Jacobson, MD
Director of Hepatology
Department of Medicine
NYU School of Medicine
New York, New York
Philip N. Newsome, PhD, FRCPE
Professor of Hepatology
University of Birmingham
Birmingham, United Kingdom
4. Disclosures
Ira M. Jacobson, MD, has disclosed that he has received funds for
research support and consulting fees from AbbVie, Bristol-Myers Squibb,
Enanta, Genfit, Gilead Sciences, Intercept, Janssen, Merck, Novo Nordisk,
Spring Bank, and Trek Therapeutics.
Philip N. Newsome, PhD, FRCPE, has disclosed that he has received
consulting fees from Afimmune, Boehringer Ingelheim, Gilead Sciences,
Intercept, Novo Nordisk, Pfizer, and Shire; has received funds for research
support from Boehringer Ingelheim; and has served on speaker bureaus
for Intercept and Norgine.
6. Detection of Active NASH and Advanced Fibrosis With
FibroScan-Based Scoring
Prospective, multicenter study of patients undergoing liver biopsy for
suspected NASH (N = 335)
Score based on fibrosis, steatosis, and inflammation (LSM, CAP, AST)
used to detect patients with active NASH and advanced fibrosis
(NAS ≥ 4, fibrosis level F ≥ 2)
‒ Performance assessed by AUROC
‒ Validated internally by bootstrap
‒ Cutoffs determined in derivation cohort
‒ External validation: French bariatric surgery, Malaysian NAFLD,
US screening cohorts
Sasso. AASLD 2018. Abstr 140. Slide credit: clinicaloptions.com
7. Validation of Score for Detection of Active NASH and
Advanced Fibrosis
Sasso. AASLD 2018. Abstr 140. Slide credit: clinicaloptions.com
Good performance in derivation and validation cohorts
‒ In multiple clinical settings (screening, bariatric surgery, NAFLD)
‒ In multiple geographical areas (Asia, Europe, United States)
Derivation Cohort External Validation Cohorts
Characteristic
Development
Population
(N = 335)
Bootstrap
Validation
(N = 335)
Malaysian
NAFLD Cohort
(N = 231)
US Screening
Cohort
(N = 193)
French Bariatric
Surgery Cohort
(N = 110)
All
(N = 534)
NASH, NAS ≥ 4, F ≥ 2
prevalence, n (%)
166 (50) (44-55)* 53 (23) 24 (12) 17 (15) 96 (18)
VCTE + CAP + AST
AUROC (95% CI)
0.83
(0.78-0.87)
0.83
(0.78-0.87)
0.85
(0.80-0.91)
0.91
(0.86-0.96)
0.93
(0.89-0.98)
0.88
(0.85-0.91)
*95% CI for prevalence.
8. NIS4: Detection of Active NASH and Advanced Fibrosis
With Biomarker-Based Scoring
Sanyal. AASLD 2018. Abstr 142. Slide credit: clinicaloptions.com
NIS4: score based on biomarkers miR-34a, alpha-2-macroglobulin,
YKL-40, and A1C used to detect patients with active NASH and
advanced fibrosis (NAS ≥ 4, fibrosis level F ≥ 2)
Baseline data from GOLDEN and RESOLVE-IT trials (N = 714)
‒ Training set: 220 patients from GOLDEN trial
‒ Validation set: first 467 patients screened for inclusion in RESOLVE-IT
9. Validation of NIS4 for Detection of Active NASH and
Advanced Fibrosis
For overall population, NIS4 AUROC = 0.83 (95% CI: 0.80-0.86)
‒ Consistently good performance across the clinical spectrum of NAFLD,
regardless of obesity, metabolic syndrome, T2DM status, or sex
Sanyal. AASLD 2018. Abstr 142. Slide credit: clinicaloptions.com
Group Subgroup n
Prevalence
NAS ≥ 4 and F ≥ 2, %
AUC
(95% CI)
Obesity BMI ≤ 30 224 45 0.794 (0.733-0.849)
BMI > 30 490 54 0.838 (0.804-0.873); P = .204
Diabetes No 439 44 0.830 (0.790-0.867)
Yes 275 61 0.801 (0.748-0.854); P = .382
Age ≤ 55 yrs 361 42 0.804 (0.758-0.848)
> 55 yrs 353 59 0.833 (0.791-0.871); P = .358
Sex Female 369 50 0.841 (0.802-0.881)
Male 345 51 0.813 (0.767-0.855); P = .345
10. Sequential Algorithms to Detect Advanced Fibrosis due
to NASH
Study of baseline data from
STELLAR trials (N = 3202) to
determine performance of
sequential combinations of
noninvasive tests in diagnosing
F3/F4 liver fibrosis
Liver biopsy assessment
‒ 41% fibrosis stage F4 (n = 1283)
‒ 30% fibrosis stage F3 (n = 979)
Algorithm based on noninvasive
tests used low cutoff for
sensitivity (to rule in F0-F2) and
high cutoff for specificity (to
rule in F3/F4)
‒ Novel cutoffs from STELLAR
study: FIB-4 (1.23, 2.10), ELF
(9.35, 10.24), FibroScan (9.6,
14.53 kPa)
‒ Published cutoffs: FIB-4 (1.30,
2.67), ELF (9.8, 11.3), FibroScan
(9.9, 11.4 kPa)
Younossi. AASLD 2018. Abstr LB-10. Slide credit: clinicaloptions.com
11. Sequential Algorithms to Detect Advanced Fibrosis due
to NASH: Results
Single tests (either FIB-4, ELF, or FibroScan) led to up to 50%
indeterminate results
Algorithm using 3 sequential tests (FIB-4, then ELF, then FibroScan) led
to 9% to 10% indeterminate results
Younossi. AASLD 2018. Abstr LB-10. Slide credit: clinicaloptions.com
Outcome, % (95% CI)
Test Cutoffs F3/F4, % Sensitivity Specificity PPV NPV Indeterminate Misclassified
Novel cutoffs
(n = 639)
71 75 (71-79) 82 (76-87) 91 (88-94) 58 (52-64) 9 (7-11) 23 (20-26)
Published cutoffs
(n = 639)
71 64 (60-69) 93 (88-96) 95 (92-97) 52 (46-57) 10 (7-12) 28 (24-31)
13. NAFLD Prevalence in Lean vs Obese Adults With or
Without Metabolic Abnormalities
Slide credit: clinicaloptions.com
Study of adults in NHANES III from 1988-1994 followed through 2011
‒ Obese defined as BMI > 30 and high waist circumference
(> 102 cm for men, > 88 cm for women)
‒ Lean defined as BMI < 25 and normal waist circumference
(≤ 90 cm for men, ≤ 80 cm for women)
Golabi. AASLD 2018. Abstr 179.
NAFLD Prevalence, % All
Obese
(n = 2952)
Lean
(n = 3242)
All patients 19.6 39.4 7.7
Any metabolic abnormalities 18.1 38.4 5.5
No metabolic abnormalities 1.5 1 2.2
14. Lean, Metabolically Normal Adults With NAFLD:
Mortality
Characteristic Deaths, n
Unadjusted
Mortality, % (95% CI)
P
Value*
Age-Adjusted Mortality,
% (95% CI)
P
Value*
Deaths among lean patients with
NAFLD
Without metabolic abnormalities
With metabolic abnormalities
57
8
49
13.83 (8.80 to 18.86)
8.72 (-0.37 to 17.81)
16.60 (11.16 to 22.03)
NA
NA
.1459
18.32 (12.09 to 24.56)
15.01 (3.09 to 26.92)
19.90 (13.19 to 26.61)
NA
NA
.4399
CV deaths among lean patients with
NAFLD
Without metabolic abnormalities
With metabolic abnormalities
13
0
13
2.89 (9.14 to 4.87)
0
4.46 (1.79 to 7.13)
NA
NA
.0020
3.71 (1.76 to 5.66)
0
3.71 (1.73 to 5.69)
NA
NA
.0005
*vs lean adults without metabolic abnormalities.
In lean NAFLD adults without any component of metabolic syndrome,
no increased overall or CV-related mortality vs lean non-NAFLD
controls
‒ Median follow up: 18.9 yrs
Golabi. AASLD 2018. Abstr 179. Slide credit: clinicaloptions.com
15. Poorer Patient-Reported Outcomes in NASH and With
More Advanced Fibrosis
Younossi. AASLD 2018. Abstr 1683. Slide credit: clinicaloptions.com
Design
Analysis of NASH patients with bridging
fibrosis or compensated cirrhosis (NASH CRN
stages F3-F4) enrolled in phase III STELLAR
trial evaluating ASK1 inhibitor selonsertib
(N = 1667)
PROs collected before treatment initiation
‒ Chronic Liver Disease Questionnaire (CLDQ
NAFLD-NASH)
‒ EQ-5D
‒ Short Form-36 (SF-36)
‒ Work Productivity and Activity Index
(WPAI:SHP)
Results
Physical health–related PROs significantly
worse with NASH patients vs population
norms (all P < .05)
F4 cohort had significantly poorer PROs vs F3
in most questionnaire components (P < .02)
‒ Average impairment difference for F4 vs F3
across all PROs: -1.6% to -4.7% (P < .05)
‒ Most pronounced impairment in CLDQ
NAFLD-NASH’s Activity and Worry domains
16. Independent Predictors of Poorer Patient-Reported
Outcomes in NASH
Younossi. AASLD 2018. Abstr 1683. Slide credit: clinicaloptions.com
Independent Predictors of
Poorer Scores in NASH Patients*
Beta, % of PRO
Range Size
Age, per yr 0.15 to 0.53
Male sex 2.1 to 9.8
Black vs white -14.9 to -7.8
Asian vs white 4.3 to 10.2
US enrollment 3.2 to 10.2
Current smoker -7.1 to -3.7
BMI, per kg/m2 -0.80 to -0.18
Diabetes mellitus -4.6 to -3.1
Asthenic conditions -7.5 to -6.1
GI disorders -7.3 to -2.8 *All P < .01 after stepwise selection in multiple models.
Independent Predictors of
Poorer Scores in NASH Patients*
Beta, % of PRO
Range Size
Musculoskeletal and connective
tissue disorders
-11.6 to -2.4
Nervous system disorders -5.7 to -2.7
Psychiatric disorders -13.3 to -4.9
Albumin, per g/dL 4.7 to 10.9
Apolipoprotein A1, per mg/dL 0.05 to 0.07
CRP, per mg/dL -3.2 to -2.0
Haptoglobin, per mg/dL -0.03 to -0.02
A1C, per % -2.2 to -1.4
17. Bariatric Surgery in Patients With Cirrhosis, Including
NASH Cirrhosis
Single-center, longitudinal study of patients with compensated or
decompensated cirrhosis (N = 60,543)
Griffin. AASLD 2018. Abstr 218. Slide credit: clinicaloptions.com
Patient Characteristic, %
Cirrhosis With Bariatric Surgery
(n = 292)
Cirrhosis Without Bariatric Surgery
(n = 29,987)
Female 73 38
NASH cirrhosis 16 3
Alcoholic cirrhosis 31 31
Decompensated cirrhosis 71 72
18. Lower Survival With Bariatric Surgery in Patients With
Cirrhosis, Including NASH Cirrhosis
Bariatric surgery also a predictor of mortality among compensated and decompensated
cirrhotic patients (obesity not significant)
‒ HR: 1.3; 95% CI 1.12-1.62; P = .002
Slide credit: clinicaloptions.comGriffin. AASLD 2018. Abstr 218.
0
20
40
60
80
Survival(%)
57.9
62.8
100
Patients With Bariatric Surgery Patients Without Bariatric Surgery
P < .04
5-Yr Survival Among Patients With Cirrhosis
19. Bariatric Surgery and Regression of NASH Fibrosis
Multicenter, prospective study of long-term impact of bariatric surgery in morbidly
obese NASH patients (N = 190)
Lassally. AASLD 2018. Abstr 70. Slide credit: clinicaloptions.com
Patient Characteristic Patients
Median age, yrs (IQR) 46.5 (38.3-54.3)
Female, % 65.8
Median BMI (IQR) 46.9 (42.9-52.3)
Median ALT (IQR) 45 (32-62)
Median γGT (IQR) 53.5 (35-86.8)
Median A1C, mmol/mol (IQR) 6.9 (5.9-8.8)
Median liver fat amount, % (IQR) 60 (40-75)
Median NAS (IQR) 5 (4-5)
Median Score Patients, %
Brunt activity score
Mild (1)
Moderate (2)
Severe (3)
68.95
23.68
23.68
METAVIR fibrosis score
F0
F1
F2
F3
F4
37.36
30.77
16.46
11.54
3.85
20. Disappearance of NASH and Regression of Fibrosis
Following Bariatric Surgery
NASH disappearance in 85% of
patients at Yrs 1 and 5
Fibrosis by Brunt and METAVIR
score significantly reduced at
Yrs 1 and 5 vs baseline
Patients without fibrosis
regression experienced less
weight loss, higher insulin
resistance (HOMA-IR), and
higher NAS following surgery
Lassally. AASLD 2018. Abstr 70. Slide credit: clinicaloptions.com
METAVIR
Fibrosis Stage
Patients, %
BL Yr 1 Yr 5
F0 37.36 45.69 63.49
F1 30.77 30.17 22.22
F2 16.48 12.93 3.17
F3 11.54 9.48 9.52
F4 3.85 1.72 1.59
P = .01 baseline vs Yr 1; P = .003 Yr 1 vs Yr 5.
21. Cirrhosis and HCC Risk: Association With Steatosis
and ALT
Retrospective study of adults with > 1 ALT test and abdominal imaging within
VA hospital system (N = 78,892)
‒ Excluded patients with:
‒ Cirrhosis or HCC before or within 1 yr of first ALT test
‒ HCV or HBV infection
‒ Excessive alcohol use
‒ Rare hepatic conditions (including Wilson’s disease, primary biliary cirrhosis,
primary sclerosing cholangitis, autoimmune hepatitis, or hereditary
hemochromatosis)
Subjects followed to end of 2015 or to HCC, cirrhosis, or death
Natarjan. AASLD 2018. Abstr 143. Slide credit: clinicaloptions.com
22. Characteristic No Steatosis, Normal ALT Steatosis, Normal ALT Steatosis, High ALT
Age, mean (SD) 58.1 (10.7) 56.4 (10.3) 53.3 (12.1)
Male, n (%) 22,711 (92.2) 10,478 (91.8) 39,664 (92.6)
Race/ethnicity, n (%)
White
Black
Hispanic
Other
16,062 (65.2)
4719 (19.2)
1078 (4.4)
483 (2.0)
7532 (66.0)
1752 (15.4)
850 (7.5)
271 (2.4)
30,404 (71.0)
4061 (9.5)
3512 (8.2)
1362 (3.2)
BMI, n (%)
< 30
≥ 30
15,539 (63.1)
9097 (36.9)
5188 (45.5)
6221 (54.5)
15,298 (35.7)
25,748 (64.3)
Comorbidity, n (%)
DM
Hypertension
Dyslipidemia
CAD
6363 (25.8)
17,794 (72.2)
16,317 (66.2)
5538 (22.5)
3867 (33.9)
8576 (75.2)
8135 (71.3)
2588 (22.7)
14,490 (33.8)
31,467 (73.4)
30,524 (71.2)
8273 (19.3)
Healthcare use, n (%) 21,987 (89.2) 10,340 (90.6) 40,430 (94.4)
Baseline Characteristics
Natarjan. AASLD 2018. Abstr 143. Slide credit: clinicaloptions.com
23. Outcome
Cirrhosis HCC
Patients,
n
Incidence,
n
Follow-up,
PYs
Adjusted Risk
(95% CI)
Incidence,
n
Follow-up,
PYs
Adjusted Risk
(95% CI)
No steatosis,
normal ALT
24,638 445 184,591 Ref 18 186,484 Ref
Steatosis,
normal ALT
11,409 225 343,688 1.1 (1.0-1.3) 9 91,542 1.0 (0.3-3.0)
Steatosis,
high ALT
42,845 1694 90,388 2.2 (2.0-2.5) 117 350,398 3.8 (1.9-7.4)
Risk of Cirrhosis and HCC in Patients With Steatosis and
Normal ALT
Natarjan. AASLD 2018. Abstr 143. Slide credit: clinicaloptions.com
Cumulative Incidence/1000 PYs
(95% CI)
No Steatosis,
Normal ALT
Steatosis,
Normal ALT
Steatosis,
High ALT
Cirrhosis 2.41 (2.19-2.65) 2.16 (2.18-2.84) 4.93 (4.70-5.17)
HCC 0.1 (0.06-0.15) 0.1 (0.05-0.19) 0.33 (0.28-0.40)
30. CONTROL: Obeticholic Acid in Patients With NASH
Double-blind, placebo-controlled,
phase II study
‒ Obeticholic acid: FXR agonist
Through Wk 16, patients with vs
without cirrhosis (F4 vs F1-F3)
showed no trend for differences in:
‒ ALT
‒ Bilirubin
‒ Platelets
‒ INR
‒ Change in C4 from baseline
Halegoua-De Marzio. AASLD 2018. Abstr 71. Slide credit: clinicaloptions.com
Adults with NASH,
F1-F4 fibrosis,
without hepatic
decompensation
(N = 84)
Obeticholic Acid 5 mg/day*
(n =20)
Obeticholic Acid 25 mg/day*
(n = 22)
Obeticholic Acid 10 mg/day*
(n = 21)
Placebo*
(n = 21)
Wk 16
*Plus atorvastatin 10 mg Wk 4 through Wk 8, then 20 mg through Wk 12,
then titrated up or down depending on clinical signs until Wk 16
32. FLIGHT-FXR: Tropifexor (TXR) in Patients With NASH
FLIGHT-FXR: 3-part randomized, placebo-controlled,
double-blind, dose-ranging phase IIb study
‒ TXR: FXR agonist
Current analysis reports pooled
data from Parts A and B
‒ Part C (not shown) ongoing
Sanyal. AASLD 2018. Abstr LB-23. Slide credit: clinicaloptions.com
Part A
Adults with NASH*, weighing
40-150 kg with liver fat ≥ 10%
by MRI-PDFF
(N = 77)
TXR 10 μg QD (n = 14)
Wk 12
TXR 30 μg QD (n = 16)
TXR 60 μg QD (n = 16)
TXR 90 μg QD (n = 15)
Placebo QD (n = 16)
Part B
Adults with NASH*, weighing
40-150 kg with liver fat ≥ 10%
by MRI-PDFF
(N = 121)
TXR 60 μg QD (n = 21)
TXR 90 μg QD (n = 70)
Placebo QD (n = 30)
*NASH defined as F1-F3 on biopsy obtained within 2 yrs of randomization, no other chronic liver disease, with
elevated ALT; or by phenotype (elevated ALT, BMI ≥ 27 in non-Asians or ≥ 23 in Asians, with T2DM).
Efficacy
endpoints
Safety
endpoints
33. Efficacy of TXR in Overall Population and in Subgroup of
Patients With Biopsy-Proven NASH at Wk 12
AEs similar among arms; TXR well tolerated with few grade 3/4 AEs or SAEs
‒ 9% of pts on TXR 90 μg QD discontinued or reduced dose for AEs
‒ TXR associated with mild dose-related rise in LDL-C and mild reduction in HDL-C
Sanyal. AASLD 2018. Abstr LB-23. Slide credit: clinicaloptions.com
Relative Change
vs BL,* % (n)
Biopsy-Proven NASH Only Phenotypic and Biopsy-Proven NASH
Placebo
(n = 18)
TXR 60 μg
(n = 12)
TXR 90 μg
(n = 35)
Placebo
(n = 46)
TXR 60 μg
(n = 37)
TXR 90 μg
(n = 85)
FGF19 +46 (12) +232 (10) +556 (34) + 37 (37) + 319 (34) +528 (74)
ALT -15.5 (17) -23.7 (12) -26.9 (32) -15.5 (45) -21.2 (36) -24.0 (73)
GGT -10.5 (17) -46.5 (12) -56.5 (34) -9.2 (45) -43.3 (36) -56.6 (78)
Liver fat content
by MRI-PDFF
-1.8 (14) -7.2 (12) -12.5 (28) -9.8 (41) -16.9 (36) -15.6 (63)
*Change in ALT, GGT, HFF reported as geometric mean of relative change at Wk 12 vs BL, FGF19 as 4 hrs post-dose vs pre-dose at Wk 6.
35. NGM282 in Patients With NASH
Multicenter, dose-finding phase II study of NGM282
‒ NGM282: FGF19 analogue
Harrison. AASLD 2018. Abstr 104. Slide credit: clinicaloptions.com
Patients with biopsy-confirmed
NASH, NAS ≥ 4*, stage 1-3 fibrosis,
liver fat ≥ 8% by MRI-PDFF
(N = 43)
*≥ 1 point in each component of NAS.
NGM282
1 mg SC QD†
Followed through
Wk 18
Wk 12
NGM282
3 mg SC QD†
†Option for rosuvastatin 20 mg at
Wk 2 if 10 mg/dL LDL-C increase
observed; titrated up to 40 mg in
Wks 4-8 if LDL-C remained above BL.
36. NGM282: Liver Fat Content by MRI-PDFF at Wk 12
Harrison. AASLD 2018. Abstr 104. Slide credit: clinicaloptions.com
Change in Liver Fat Content From BL, %
NGM282 1 mg*
(n = 24)
NGN282 3 mg*
(n = 19)
Absolute change -10.9 -11.2
≥ 5% absolute reduction 92 100
Normalized LFC† 33 63
Relative change -57 -67
≥ 30% relative reduction 92 100
*All absolute and relative changes P < .001 vs baseline.
†Normalized LFC defined as absolute MRI-PDFF ≤ 5%.
37. Patients with NASH resolution (n = 19): 16% Patients with NASH resolution (n = 19): 11%
NGM282: Fibrosis at Wk 12
Harrison. AASLD 2018. Abstr 104. Slide credit: clinicaloptions.com
NGM282 1 mg NGM282 3 mg
Fibrosis Stage at Baseline
Patients, % (n = 24)
16%
42%
38%
4%
F1
F2
F3
F4
Fibrosis Response at Wk 12
Patients, %
25%
58%
17%
Improved
Worsened
No Change
Fibrosis Stage at Baseline
Patients, % (n = 19)
16%
26%
53%
5%
F1
F2
F3
F4
Fibrosis Response at Wk 12
Patients, %
42%
47%
11%
ImprovedWorsened
No Change
38. NGM282: Safety
All Adverse Events
No new safety signals observed;
most events were mild or resolved
on treatment
Gastrointestinal Events
Most common treatment-emergent
adverse event was mild
gastrointestinal symptoms consisting
of nausea and loose, frequent stools
2 patients discontinued due to
diarrhea
Gastrointestinal symptoms improved
by separating dosing from mealtimes
and reducing meal size
Harrison. AASLD 2018. Abstr 104. Slide credit: clinicaloptions.com
Patients, n
NGM282
1 mg
NGM282
3mg
Serious adverse events
• Treatment related
1*
0
4†
0
*Renal mass.
†Cardiac arrest (nonmyocardial infarction), chest
pain (musculoskeletal), pleurisy, pneumonia.
43. MGL-3196 in Patients With NASH
Multicenter, randomized, double-blind, placebo-controlled phase II trial
‒ MGL-3196: THR-β agonist
*20-mg dose adjustment up or down
allowed at Wk 4.
Patients with biopsy-confirmed
NASH, NAS ≥ 4, F1-3 fibrosis, ≥ 10%
liver fat by MRI-PDFF
(N = 125)
MGL-3196 80 mg PO QD*
(n = 84)
Placebo PO QD
(n = 41)
Wk 36
Primary Endpoint
Wk 12
Harrison. AASLD 2018. Abstr 14. Slide credit: clinicaloptions.com
Open-label
extension study
44. MGL-3196: Efficacy at Wks 12, 36
Ongoing open-label extension suggests improvements of change in liver fat content are maintained
Harrison. AASLD 2018. Abstr 14. Slide credit: clinicaloptions.com
*P < .0001 vs placebo.
Reduction in Fibrosis Score ≥ 1 Point, % Placebo MGL-3196 P Value
Second harmonic generation score 12 32 .03
Pathology score 23 29 NS
MGL-3196*
Change in Liver Fat Content, %
Placebo
(n = 38)
All Patients
(n = 78)
High Exposure
(n = 44)
Wk 12 Wk 36 Wk 12 Wk 36 Wk 12 Wk 36
Relative -10 -8 -36 -37 -42 -49
Absolute -1.6 -2.3 -7.6 -8.5 -8.8 -9.4
≥ 30% relative reduction 18 30 60 68 75 77
Liver Fat Content by MRI-PDFF
Fibrosis at Wk 36
45. MGL-3196: Efficacy at Wks 12, 36
Ongoing open-label extension suggests improvements of change in liver fat content are maintained
Harrison. AASLD 2018. Abstr 14. Slide credit: clinicaloptions.com
*P < .0001 vs placebo.
Change in Fibrosis or NASH by Biopsy, % Placebo MGL-3196 P Value
Reduction in Fibrosis Score ≥ 1 Point
Second harmonic generation score
Pathology score
12
23
32
29
.03
NS
Resolution of NASH 6 27 .02
MGL-3196*
Change in Liver Fat Content by
MRI-PDFF, %
Placebo
(n = 38)
All Patients
(n = 78)
High Exposure
(n = 44)
Wk 12 Wk 36 Wk 12 Wk 36 Wk 12 Wk 36
Relative -10 -8 -36 -37 -42 -49
Absolute -1.6 -2.3 -7.6 -8.5 -8.8 -9.4
≥ 30% relative reduction 18 30 60 68 75 77
46. MGL-3196: Lipids, Safety
Lipids Safety
AEs generally mild and balanced
between groups, except increase in
loose stools at beginning of
treatment, usually 1 episode
‒ Some AEs moderate
Laboratory abnormalities balanced
between groups
Serious AEs (n = 7) balanced between
groups with none related to
treatment
Harrison. AASLD 2018. Abstr 14. Slide credit: clinicaloptions.com
Change in Lipids
From BL to Wk 36 % Change P Value
LDL-C -22.3 < .0001
ApoB -21.9 < .0001
Triglycerides -36 < .0001
Lp(a) -36.8 < .001
ApoCIII -36.5 < .0001
52. Semaglutide in Obese Patients With No Diabetes
Post hoc analysis of multicenter, randomized, double-blind phase II trial
Newsome. AASLD 2018. Abstr 105. Slide credit: clinicaloptions.com
Adults with BMI ≥ 30,
≥ 1 unsuccessful attempt at
weight loss, no diabetes
(N = 957)
Semaglutide .05 mg QD escalated Q4W* (n = 103)
Wk 52
Semaglutide .1 mg QD escalated Q4W* (n = 102)
Semaglutide .2 mg QD escalated Q4W* (n = 103)
Semaglutide .3 mg QD escalated Q4W* (n = 103)
Semaglutide .4 mg QD escalated Q4W* (n = 102)
Placebo* (n = 136)
Current
post hoc analysis
*Plus diet of -500 kcal/day and increased physical activity.
Semaglutide .3 mg QD escalated Q2W* (n = 102)
Semaglutide .4 mg QD escalated Q2W* (n = 103)
Liraglutide 3 mg QD escalated QW* (n = 103)
53. Semaglutide in Obese Patients With No Diabetes:
Baseline Characteristics
Newsome. AASLD 2018. Abstr 105. Slide credit: clinicaloptions.com
BL Characteristic
With Elevated BL ALT
(n = 499)
Without Elevated BL ALT
(n = 458)
Age, yrs (range) 48 (18-76) 47 (19-86)
Male, n (%) 187 (37.5) 151 (33.0)
Weight, kg (range) 106.9 (70.5-216.3) 107.8 (70.2-243.7)
BMI (range) 37.4 (29.7-77.1) 37.9 (29.7-80.3)
A1C, % (range) 5.5 (4.3-6.6) 5.5 (4.2-7.0)
Lipids, mmol/L (range)
Total cholesterol
LDL cholesterol
HDL cholesterol
Triglycerides
5.2 (2.7-9.7)
3.2 (1.1-6.2)
1.2 (0.5-2.4)
1.6 (0.5-11.9)
5.0 (2.6-10.3)
3.0 (0.8-7.2)
1.3 (0.7-2.9)
1.4 (0.4-9.9)
Liver enzymes, IU/L (range)
ALT
AST
34 (20-313)
24 (12-272)
17 (3-30)
16 (8-62)
Impaired fasting glucose (≥ 6.1 mmol/L), n/N (%) 76/499 (15.2) 57/457 (12.5)
*Elevated ALT defined as > 30 IU/L for men, > 19 IU/L for women.
54. Semaglutide in Obese Patients With Elevated ALT and
No Diabetes: Change in ALT Through 52 Wks
Newsome. AASLD 2018. Abstr 105. Slide credit: clinicaloptions.com
MeanALTRatiotoBaseline
Semaglutide 0.05 mg
Semaglutide 0.1 mg
Semaglutide 0.2 mg
Semaglutide 0.3 mg
Semaglutide 0.4 mg
Placebo
Wk 4 Wk 16 Wk 28 Wk 40 Wk 52
0.7
0.8
0.9
1.0
1.1
1.2
55. clinicaloptions.com/hepatitis
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