MGL-3196, a selective thyroid hormone receptor-beta agonist, - - PowerPoint PPT Presentation

▶
mgl 3196 a selective thyroid hormone receptor beta
SMART_READER_LITE
LIVE PREVIEW

MGL-3196, a selective thyroid hormone receptor-beta agonist, - - PowerPoint PPT Presentation

May 24, 2023 611 likes •767 views

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 Harrison 1 , Sam Moussa 2 , Mustafa Bashir 3 , Naim

slide-1
SLIDE 1

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

slide-2
SLIDE 2

Mechanism of Action: The Importance of Liver THR-β in NASH

2

Thyroid Gland Liver T4è T3 T4 T3 Nuc Thyroid Hormone Receptor α or β

TSH

Thyroid Hormone Pathway T4 T4, prohormone T3, ac/ve hormone TSH, thyroid s/mula/ng hormone

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

  • f 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

slide-3
SLIDE 3

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

slide-4
SLIDE 4

Study Design: Randomized, Double-Blind, PBO Controlled Trial

4

D1 W2 W4 W8 W12 W24 W36 Extension Screening MRI-PDFF Liver Biopsy MRI-PDFF Liver Biopsy MRI-PDFF MRI-PDFF W12 PK assessment

Comparator/Arms n 2:1 MGL-3196 to placebo n 125 patients enrolled in USA, 18 sites n MGL-3196 or placebo, once daily; starting dose 80 mg per day, +-20 mg dose adjustment possible at Week 4 Inclusion/Exclusion n NASH on liver biopsy: NAS≥4 with fibrosis stage 1-3 n ≥10% liver fat on MRI-PDFF n Includes diabetics, statin therapy, representative NASH population

slide-5
SLIDE 5

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

slide-6
SLIDE 6

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

slide-7
SLIDE 7
  • 9.6
  • 36.3
  • 42.0
  • 22.5
  • 50
  • 45
  • 40
  • 35
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

p=0.02 p<0.0001 p<0.0001 p<0.0001 n=38 n=78 n=44 n=34 Placebo MGL-3196 High MGL- 3196 Low MGL- 3196

Relative Change in MRI-PDFF (%)

18.4 60.3 75.0 41.2

10 20 30 40 50 60 70 80

Placebo 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

p=0.02 p<0.0001 p<0.0001 p<0.0001 n=38 n=78 n=44 n=34 Placebo MGL-3196 High MGL-3196 Low 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

**

slide-8
SLIDE 8

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

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

p=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=0.005 p=0.01 p=0.002 p=0.001 p=0.02 p=0.02

slide-9
SLIDE 9

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; ApoB correlates with CV risk more than LDL-C level

  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

5

ApoB TGs LDL-C NASH ExtensionStudy

10 20 30 40 50 60 70 80 90 100

SHBG % Change from Baseline

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

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

Change from baseline ng/dL

ND ND

slide-10
SLIDE 10

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)

Change in CT1

  • 95.3
  • 18.8
  • 120
  • 100
  • 80
  • 60
  • 40
  • 20

MGL-3196 Placebo

p=0.03

*Liver International. 2017;37:1065–1073

slide-11
SLIDE 11
  • 7.7
  • 13.5
  • 21
  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

NS p=0.002 p<0.0001 n=29 n=47 n=29 Placebo MGL-3196 High MGL- 3196

ALT

  • 1.6
  • 7.4
  • 9.2
  • 14
  • 12
  • 10
  • 8
  • 6
  • 4
  • 2

NS p=0.001 p=0.0002 n=38 n=78 n=44 Placebo MGL-3196 High 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, T3 Reverse T3 (inactivated thyroid hormone) NASH Inflammation

  • 6
  • 5
  • 4
  • 3
  • 2
  • 1

p=0.08 p<0.0001 n=37 n=76 Placebo MGL-3196

U/L

Reverse T3

**within group p-value ** **

slide-12
SLIDE 12
  • 10
  • 8
  • 6
  • 4
  • 2

2 4

p=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-C3 ng/ml

Pro-C3

  • 0.5
  • 0.4
  • 0.3
  • 0.2
  • 0.1

0.1 0.2

p=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

slide-13
SLIDE 13
  • 8
  • 6
  • 4
  • 2

2 4 6

NS 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*

* Study is blinded; 3 SAEs, all unrelated

p=0.005 p=0.002

mm Hg

** **within group p-value

slide-14
SLIDE 14

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