1
MGL-3196, a selective thyroid hormone receptor-beta agonist, significantly decreases hepatic fat in NASH patients at 12 weeks, the primary endpoint in a 36 week serial liver biopsy study
Stephen Harrison1 , Sam Moussa2 , Mustafa Bashir3 , Naim Alkhouri4 , Juan Frias5 , Seth Baum6 , Brent Tetri7 , Meena Bansal8 , Rebecca Taub9; 1Oxford University ; 2University of Arizona for Medical Sciences ; 3Duke University Medical Center ; 4 Texas Liver Institute, San Antonio, TX; 5University of California San Diego, Endocrinology, San Diego, United States ; 6Florida Atlantic University ; 7St Louis University School of Medicine ; 8Icahn School of Medicine at Mount Sinai ; 9Madrigal Pharmaceuticals
Mechanism of Action: The Importance of Liver THR-β in NASH
2
Thyroid Gland
Liver T4è T3
T4 T3
Nuc
Thyr
oid
Horm
one
Rece
ptor
α o
r β
TSH
Thyroid Hormone Pathway
T4
T4,prohormoneT3,ac/vehormoneTSH,thyroids/mula/nghormone
ê Lowers LDL-cholesterol
ê Lowers triglycerides
ê Lowers liver fat, potentially reducing
lipotoxicity, NASH
No thyrotoxicosis (THR-α effect)
In humans THR-β agonism:
Sinha and Yen Cell Biosci (2016) 6:46
DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8,
1341-1357, DOI: 10.1080/15548627.2015.1061849
n MGL-3196 has pleiotropic effects with potential for addressing the underlying metabolic syndrome and hallmark features
of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly)
n THR-β agonists reduce liver fat through breakdown of fatty acids, and stimulate mitochondrial biogenesis in the NASH liver,
thereby reducing lipotoxicity and improving liver function
n In human NASH, the liver has relatively low THR-β activity, exacerbating mitochondrial dysfunction and lipotoxicity
n THR-β may have direct hepatic anti-fibrotic effects in that THR agonism has been shown to dampen inflammation in vivo
and to inhibit TGF-β signaling in cell culture and in vivo
MGL-3196, a First-in-Class Liver-Directed THR- β Agonist
First bona fide THR-β selective molecule with key advantages
n Discovery of MGL-3196 utilized a novel in vitro functional assay
• Additional selectivity conferred by highly specific uptake into liver, avoiding any systemic thyroid
receptor effects
n in vivo preclinical and clinical data confirm MGL-3196’s high liver uptake and safety
• Avoids activity at the systemic THR-α receptor (no increased heart rate, osteoporosis)
• Long-term animal studies completed: no cartilage/bone findings in chronic toxicology
• Tested in more than 160 subjects in Phase 1 studies and 150 patients in Phase 2 studies
• MGL-3196 well-tolerated in clinical dosing, normal thyroid axis and vital signs, no liver enzyme increases
n Lipid lowering
• Robust, pleiotrophic anti-atherogenic lipid lowering properties
• In In Phase 1 healthy volunteer and Phase 2 heterozygous familial cholesterolemia (HeFH) studies
lowered LDL-cholesterol (LDL-C) up to 30%,apolipoprotein B (ApoB) 28%, lipoprotein(a) Lp(a) up to
40% and triglycerides (TGs) up to 40%
J Med Chem. 2014;57(10):3912-3923 3
Study Design: Randomized, Double-Blind, PBO Controlled Trial
4
D1 W2 W4 W8 W12 W24 W36 ExtensionScreening
MRI-PDFFLiver Biopsy
MRI-PDFFLiver BiopsyMRI-PDFF MRI-PDFF
W12
PK assessment
Comparator/Armsn 2:1 MGL-3196 to placebon 125 patients enrolled in USA, 18 sitesn MGL-3196 or placebo, once daily; starting dose 80 mg per day, +-20 mg dose
adjustment possible at Week 4
Inclusion/Exclusionn NASH on liver biopsy: NAS≥4 with fibrosis stage 1-3n ≥10% liver fat on MRI-PDFFn Includes diabetics, statin therapy, representative NASH population
Study Endpoints
5
n Primary endpoint
• Relative reduction of liver fat (MRI-PDFF) at 12 weeks
n Secondary, exploratory biomarker and imaging endpoints
• Numbers achieving ≥ 30% liver fat reduction at 12 weeks; absolute liver fat reduction• NASH, fibrosis biomarkers and lipids at 12, 36 weeks; multi-parametric imaging substudy• Repeat MRI-PDFF at 36 weeks
n Secondary, exploratory liver biopsy endpoints at 36 weeks
• Reduction (2-point on NAS) or resolution of NASH without worsening of fibrosis in MGL-3196-treated compared to placebo
• One point reduction in fibrosis• Reduction in components of NASH
n Ongoing exploratory endpoint extension study in a subset of patients who completed the main 36 week study
Baseline Characteristics
Placebo (41) MGL-3196 (84)
Mean age, years (SD) 47.3 (11.7) 51.8 (10.4)
Male, n (%) 24 (58.5) 38 (45.2)
White 37 (90.2) 79 (94.0)
Hispanic/Latino 22 (53.7) 37 (44.0)
Diabetic, n (%) 13 (31.7) 35 (41.7)
Mean BMI (SD) 33.6 (5.8) 35.8 (6.2)
Mean ALT 60.1 (32.8) 50.0 (29.2)
Mean AST 38.2 (21.2) 35.7 (17.8)
Mean LDL-C 116.9 (30.0) 111.3 (30.4)
Mean TGs 161.1 (75.2) 178.5 (82.4)
Mean MRI-PDFF* 19.8 (6.7) 20.7 (7.0)
Mean NAS 4.8 (1.1) 4.9 (1.0)
Fibrosis stage n, % 0-1 21 (51.2) 48 (57.1)
n, % 2-3 20 (48.8) 36 (42.8)
6* Patients with both baseline and week 12 assessments
-9.6
-36.3
-42.0
-22.5
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0p=0.02 p<0.0001 p<0.0001 p<0.0001
n=38 n=78 n=44 n=34
Placebo MGL-3196High MGL-
3196Low MGL-
3196
Relative Change in MRI-PDFF (%)
18.4
60.3
75.0
41.2
0
10
20
30
40
50
60
70
80Placebo MGL-3196
High MGL-3196
Low MGL-3196
≥30% Fat Reduction (%)
-2.4
-7.6-8.8
-5.0
-12
-10
-8
-6
-4
-2
0p=0.02 p<0.0001 p<0.0001 p<0.0001
n=38 n=78 n=44 n=34
Placebo MGL-3196High
MGL-3196Low MGL-
3196
Absolute Change MRI-PDFF
Primary Endpoint Achieved
7
p<0.0001
p<0.0001
*p<0.02
*compared with placebo **within group p-value
p<0.0001
p<0.0001
*p<0.04
n Primary endpoint was met: Relative change in MRI-PDFF (% change from baseline (median)) and absolute fat reduction were both highly significant
n Prespecified high exposure MGL-3196 patients achieved a 75% response for ≥30% liver fat reduction
n No effect of MGL-3196 on body weight; 5 out of the 7 placebo patients who achieved ≥ 30% fat reduction lost ≥5% body weight
p<0.0001
*p<0.02
p<0.0001
**
Fat Reduction Relative to NAS/Fibrosis Stage
8
n MGL-3196 reduces liver fat effectively in both early and advanced NASH fibrosis
26.3
60.0
10.5
60.6
20.0
52.9
16.7
65.9
0
10
20
30
40
50
60
70
n=19 n=45 n=19 n=33 n=20 n=34 n=18 n=44
Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196
Fibrosis ≤ 1 Fibrosis 2-3 NAS ≤ 4 NAS > 4
≥30% Fat Reduction (%)
-45
-40
-35
-30
-25
-20
-15
-10
-5
0p=0.0009 p<0.0001 NS p<0.0001 NS p<0.0001 p=0.01 p<0.0001
n=19 n=45 n=19 n=33 n=20 n=34 n=18 n=44
Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196 Placebo MGL-3196
Fibrosis ≤ 1 Fibrosis 2-3 NAS ≤ 4 NAS > 4
Relative Change in MRI-PDFF (%)
**within group p-value
**
p=0.0007 p=0.002 p=0.005p=0.01
p=0.002 p=0.001p=0.02
p=0.02
Reductions in Multiple Atherogenic Lipids
9
Lp(a), % change from baseline, other lipids absolute reductions (ng/ml); LDL-C>100 mg/dL, BL; Lp(a) >10 nmol BL; TGs Week 4, MGL-3196 patients on 80 mg dose; SE shown; ND, not determined
n Extension study: Open label study of eligible week 36 completers, all patients on MGL-3196
• Dose adjustment based on biomarkers
• Significant lipid lowering, correlating with sex hormone binding globulin (SHBG) increase
• ApoB lowering equal to LDL-C, reflects lowering of LDL and VLDL particles; ApoBcorrelates with CV risk more than LDL-C level
-30
-25
-20
-15
-10
-5
0
5ApoB TGs LDL-CNASH ExtensionStudy
0
10
20
30
40
50
60
70
80
90
100
SHBG
% C
hang
e fr
om B
asel
ine
Biomarker Monitoring in Patients:Extension Study
n Significant (p<0.0001) reductions relative to placebo in multiple atherogenic lipids including LDL-cholesterol, Lp(a), Apo B and TGs
n Average reductions in LDL-C, ApoB and triglyceride reductions not maximal, many patients had drug exposures consistent with half-maximal lipid lowering effect
-50
-40
-30
-20
-10
0
10
20
30(n=39) (n=79) (n=44)
Placebo MGL-3196 High MGL-3196
Lipids
LDL-C Lp(a) non-HDL-C ApoB TGs
Cha
nge
from
bas
elin
e ng
/dL
ND ND
Multiparametric MRI Substudy
10
n Multiparametric MRI has been validated as a predictive test for NASH, and the CT1 predicts NAS on liver biopsy, particularly correlating with inflammation*
n Measures inflammation and liver fat across the whole liver
n MGL-3196 NASH substudy: evaluation of 17 patients with paired baseline and week 12 multiparametric scans
n MGL-3196 treated patients showed statistically significant improvements in MRI-PDFF and CT1
Improvement 44%; deterioration 0%BL CT1 926 ms Week 12 CT1 840 ms
MGL-3196 treated patient (nl CT1 826 ms)
Chan
ge in
CT1
-95.3
-18.8
-120
-100
-80
-60
-40
-20
0MGL-3196 Placebo
p=0.03
*Liver International. 2017;37:1065–1073
-7.7
-13.5
-21
-30
-25
-20
-15
-10
-5
0NS p=0.002 p<0.0001
n=29 n=47 n=29
Placebo MGL-3196High MGL-
3196
ALT
-1.6
-7.4
-9.2
-14
-12
-10
-8
-6
-4
-2
0NS p=0.001 p=0.0002
n=38 n=78 n=44
Placebo MGL-3196High MGL-
3196
AST
Reduction at Week 12 of Liver Enzymes and Reverse T3, Markers of Inflammation
11
n Decrease in liver enzymes is correlated with improvement in NASH on serial liver biopsy
n Significant decrease in ALT, AST (within group MGL-3196); significant decrease in ALT (patients with ALT*
elevations at baseline) and AST (p=0.04, 0.02, respectively) compared with placebo in high MGL-3196 patients
n Significant decrease in reverse T3 (p<0.0001), an inflammatory biomarker that is relatively increased in patients with NASH, particularly advanced NASH (doi: 10.1210/en.2014-1302) Clinical Gastroenterology and Hepatology 2018;16:123–131
*Baseline ALT, >=45 males; >=30 females
T4, T3Reverse T3 (inactivated thyroid hormone)
NASH Inflammation
-6
-5
-4
-3
-2
-1
0p=0.08 p<0.0001
n=37 n=76
Placebo MGL-3196
U/L
Reverse T3
**within group p-value
**
**
-10
-8
-6
-4
-2
0
2
4p=NS 0.057 p=NS 0.0019
n=38 n=78 n=12 n=29
Placebo MGL-3196 Placebo MGL-3196
All Elevated BL Pro-C3ng/m
l
Pro-C3
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2p=NS p=.12 p=NS p<0.0001
n=32 n=64 n=22 n=40
Placebo MGL-3196 Placebo MGL-3196
All Elevated BL ELF
ELF
Reduction of Fibrosis Biomarkers by MGL-3196
12
n Pro-C3 and ELF scores have been correlated with the liver fibrosis score on liver biopsy in NASH patients*
n MGL-3196 significantly decreases ELF and Pro-C3 (up to 40% relative to placebo) fibrosis biomarkers particularly in patients with > normal level at baseline reflective of more advanced baseline liver fibrosis
p=0.002
p=0.08
p=0.009
p=0.05
BL, baseline; elevated BL Pro-C3>=17.5 ngl/ml; elevated BL ELF >= 9 **within group p-value
** **
*Liver Int. 2015 Feb;35(2):429-37; Journal of Hepatology 2013 vol. 59 j 236–242
-8
-6
-4
-2
0
2
4
6NS p=<0.0001 NS p=0.0004
n=39 n=79 n=39 n=79
Placebo MGL-3196 Placebo MGL-3196
Diastolic Systolic
Blood Pressure
Safety Results
13
n Study remains blinded, completion of dosing and follow up in 36 week study by end of April 2018
n Very good all subject tolerability: mostly mild and a few moderate AEs, the numbers of which are balanced between placebo and drug-treated groups; 3 reported SAEs all unrelated to drug
n Only 2/9 discontinuations secondary to AEs
n No change in heart rate or other vital signs, significant decrease in blood pressure in MGL-3196-treated
n No change in thyroid axis
Adverse Events
Placebo MGL-3196
Mild n (%) 19 (46.3) 55 (65.5)
Moderate n (%) 7 (17.1) 18 (21.4)
Severe* 0 0
* Study is blinded; 3 SAEs, all unrelated
p=0.005p=0.002
mm
Hg
**
**within group p-value
Conclusions
n Once daily MGL-3196 for 12 weeks compared with placebo significantly decreased hepatic fat in patients relative to placebo
n Results from liver enzyme, inflammatory and fibrosis biomarker data, including a multiparametric MRI substudy are suggestive of an impact of MGL-3196 to reduce NASH and fibrosis
n MGL-3196 significantly reduced blood pressure and multiple atherogenic lipids which provides support for potential cardiobeneficial effects in NASH patients who most frequently die of cardiovascular disease
n MGL-3196 appeared safe and was well-tolerated
n Histopathologic assessment by 36 week liver biopsy will allow for correlations with the baseline biopsy in addition to multiple 12 week and 36 week non-invasive imaging and biomarker assessments
J Med Chem. 2014;57(10):3912-3923 14
Top Related