nonconfidential june 2019 - madrigal pharma · 2019-06-19 · june 2019 1. 2 any statements, ......
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Nonconfidential
June 2019
1
2
Any statements, other than statements of historical facts, made in this presentation regarding our future financial or business performance, conditions, plans, prospects, trends, or strategies and other financial and business matters; our ability to obtainadditional financing; the estimated size of the market for our product candidates, the timing and success of our development and commercialization of our anticipated product candidates; and the availability of alternative therapies for our target market, are, or may be deemed, forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “could,” “should,” “would,” “anticipate,” “believe,” “estimate,” “continue,” “design,” “expect,” “intend,” “plan,” “potential,” “predict,” “seek” or the negative of these words and similar expressions and their variants may identify forward-looking statements.
These forward-looking statements reflect management’s current expectations, are based on certain assumptions and involve certain risks and uncertainties, which change over time. Our actual results may differ materially from the results discussed in these forward-looking statements due to various factors. Important factors that may cause actual results to differ materially from theresults discussed in these forward-looking statements include, but are not limited to, risks related to securing and maintainingrelationships with collaborators; risks relating to our clinical trials; risks relating to the commercialization, if any, of our proposed product candidates (such as marketing, regulatory, product liability, supply, competition, and other risks); dependence on the efforts of third parties; dependence on intellectual property; and risks related to our cash resources and ability to obtain working capital to fund our proposed operations. Further information regarding on the factors that could affect our business, financial conditions and results of operations are contained our filings with the U.S. Securities and Exchange Commission, which are available at www.sec.gov. These forward-looking statements represent management’s expectations as of the date hereof only, and we specifically disclaim any duty or obligation to update forward-looking statements as a result of subsequent events or developments, except as required by law.
Forward Looking Statements
Pipeline: Madrigal has Initiated the Phase 3 in NASH Fibrosis
Compound Indication Pre-Clinical Phase 1 Phase 2 Phase 3 Upcoming Catalysts
MGL-3196Thyroid Hormone Receptor-β (THR-β) Agonist
Nonalcoholic Steatohepatitis (NASH)With Fibrosis Stage 2-3
Phase 3 Initiated
Dyslipidemia Dyslipidemia Phase 3
study in NAFLD/NASH in planning stage
MGL-3745THR-β Agonist
NASH andDyslipidemia
3
Madrigal is focused on the development of its pipeline of THR-β agonists for the treatment of NASH and Dyslipidemia
Mechanism of Action: The Importance of Liver THR-β in NASH
4
Lowers LDL-cholesterol Lowers triglycerides Lowers liver fat, potentially reducing
lipotoxicity, NASH
No thyrotoxicosis (THR-α effect)
In humans, thyroid hormone receptor-β (THR-β) agonism:
Sinha and Yen Cell Biosci (2016) 6:46DOI 10.1186/s13578-016-0113-7; Autophagy, 11:8, 1341-1357, DOI: 10.1080/15548627.2015.1061849
MGL-3196 THR-β selective molecule with proven safety and efficacy in more than 300 subjects and
patients treated— No exposure outside the liver or activity at the systemic THR-α receptor
Pleiotropic effects with potential for addressing the underlying metabolic syndrome and hallmark features of NASH: steatosis/lipotoxicity, inflammation, ballooning, fibrosis (both directly and indirectly)
— Reduction of liver fat through breakdown of fatty acids, normalization of liver function
Thyroid Gland
Liver T4 T3
T3
Nucle
ar T
HR-α
, THR
-βThyroid Hormone Pathway
T4T4
T4, prohormoneT3, active hormone
MGL-3196, First and Best-in-Class Liver-Directed THR-β Agonist
First bona fide THR-β selective molecule with key advantages
Discovery of MGL-3196 utilized a novel in vitro functional assay, 28 fold THR-β selective with virtually no THR-α activity
— Other thyromimetic compounds lacked beta selectivity in this assay
in vivo preclinical and clinical data confirm MGL-3196’s high liver uptake and safety
— Avoids activity at the systemic THR-αreceptor (no increased heart rate, osteoporosis)
— Long-term animal studies completed: no cartilage/bone findings in chronic toxicology
— Multiple Phase 1 studies completed, well-tolerated in clinical dosing, normal thyroid axis and vital signs, no liver enzyme increases (right panel)
J Med Chem. 2014;57(10):3912-3923; Atherosclerosis 230 (2013) 373e3805
Radiographic Tissue Distribution Demonstrates Liver Uptake
6
MGL-3196 is highly protein bound (>99%) and is taken up into the liver by hepatic transporters— Uptake is low to undetectable in heart, bone and brain at the Cmax and throughout the timecourse
The primary route of elimination after oral dose of [14C]MGL-3196 in rats, dogs and humans is feces via biliary excretion
Focused uptake in liver, with low to undetectable levels in heart, bone and brain, further support the safety of MGL-3196
0 5 10 15 20 25
Liver
Kidney (medulla)
Kidney (cortex)
Skeletal Muscle
Heart
Pituitary Gland
Brain (medula)
Brain (cerebrum)
Brain (cerebellum)
Bone Marrow
Bone (femur)
Ratio to BloodC14 MGL-3196 2h post dose
MGL-3196 Development Path Across the Spectrum of NAFLD/NASH
7
F3
F4Phase 3 NASH study: NASH Resolution (primary), LDL-C, fibrosis (key secondary); Phase 4 (post-approval): cirrhosis and MACE
F2
F1B
F1
F0
NAFLD with dyslipidemia, diabetics, metabolic syndrome
CV Benefits
Fatty liverLDL-CApoBTriglyceridesLp(a) Phase 3 Lipid study:
LDL-C (primary)(no liver biopsy requirement)Phase 4 (post-approval): MACE
2.0 million
3.5 million
15 million
6.3 million
3.4 million
1.3 million
NASH/NAFLD Spectrum1
PatientNumbers (US)
1 Estes et al; Hepatology, Vol. 67, No. 1, 2018
Phase 2 NASH Study Design: Randomized, Double-Blind, PBO Controlled
8
Extension Study
Screening
MRI-PDFFLiver Biopsy
MRI-PDFFLiver BiopsyMRI-PDFF MRI-PDFFPK
Comparator/Arms 2:1 MGL-3196 to placebo 125 patients enrolled in USA, 18 sites MGL-3196 or placebo, oral, once daily; dose 80 mg (+/-20 mg dose adjustment
possible at Week 4 )
Inclusion/Exclusion NASH on liver biopsy: NAS≥4 with fibrosis stage 1-3 ≥10% liver fat on MRI-PDFF Includes diabetics, statin therapy, representative NASH population
D1 W2 W4 W12 W36 W12 W36ExD136 Week Main Study
Study Endpoints
Primary endpoint — Relative reduction of liver fat (MRI-PDFF) at 12 weeks (at 36 weeks,
secondary)
Key secondary endpoints at 12, 36 weeks— Reduction (2-point on NAS) or resolution of NASH without worsening of
fibrosis with at least a 2-pt reduction in NAS in MGL-3196-treated compared to placebo patients
— One point reduction in fibrosis on liver biopsy— Numbers achieving ≥ 30% liver fat reduction at 12, 36 weeks; absolute
liver fat reduction— Liver enzymes, fibrosis biomarkers and lipids at 12, 36 weeks
Completed 36 week extension study in 30 patients who completed the main 36 week study
9
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)
PRO-C3 16.2 (8.3) 17.8 (10.3)
ELF 9.2 (1.0) 9.2 (0.88)
Mean LDL-C 116.9 (30.0) 111.3 (30.4)
Mean Triglycerides (TG) 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** 1, n (%) 19 (46.3) 47 (55.9)
2-3, n (%) 20 (48.8) 36 (42.8)
10
* Patients with both baseline and week 12 assessments; **F0 placebo=2 (4.9); MGL-3196=1 (1.2) were included in all analyses
Dose-related Sustained Reduction in Liver Fat on MRI-PDFF
11
Relative Fat Reduction (%)
Main, 36 Week Study Sustained statistically significant reduction in
hepatic fat Week 12 to Week 36 Placebo response generally related to weight
loss ≥5%
P value, placebo compared to MGL-3196; MGL-3196, n=78; placebo, n=38; extension study shown for former pbo patients, 3 took 100 mg, 11/14, 80 mg.
36 Week Extension Study Thirty patients, 14 former placebo patients
were treated with MGL-3196, 80 mg for an additional 36 weeks
Well tolerated, excellent safety, lipid and liver enzyme responses
Absolute Fat Reduction (%)
Week 36: Sustained Robust Lipid Lowering
Significant sustained lowering effect in multiple atherogenic lipids
12
Lipids (% Change from Baseline)
MGL-3196 compared with placebo; all analyses and cutoffs were prespecified; based on prespecified mITT; placebo n=39; MGL-3196 n=79 (LOCF)
◼MGL-3196 is the only NASH therapeutic able to lower lipids, consistent with regulatory approval for dyslipidemia; an also reduces fatty liver, an independent CV risk factor
◼ApoB, not LDL-C is the major risk factor in CV disease
◼NASH patients die of CV disease more frequently than liver disease
Week 36: Liver Enzymes
ALT
AST
GGT
Statistically significant reductions in ALT, AST and GGT versus placebo; no change in bilirubin or alkaline phosphatase
Placebo MGL-3196
13All analyses were prespecified. Baseline elevated ALT =45 male, 30 female. GGT shown
as % change from baseline, females and males have different normal GGT ranges, placebo n=39; MGL-3196, n=79, LOCF
Week 36, 40% reduction in ALT in MGL-3196 with elevated baseline (p=0.01), and all MGL-3196 relative to placebo patients (p=0.002)
At Week 36, 60% of MGL-3196 patients with ALT <30 vs 37% of placebo (p=0.03)
Week 36, statistically significant AST reduction in MGL-3196 vs placebo (% change and absolute change) p=0.002
Week 36, statistically significant GGT reduction MGL-3196 vs placebo (% change and absolute change) p=0.002
Week 36: NASH Liver Biopsy Endpoints
14
2-pt reduction in NAS in placebo patients was correlated with body weight loss
PlaceboMGL-3196 (all)MGL-3196 (high exp)MGL-3196, MRI responder
In MGL-3196 treated patients with NASH resolution, 50% had fibrosis resolution (F=0) and 61% had ≥ 1 point fibrosis reduction; 39% had baseline NAS≥5 compared with 0 in placebo
2-Point NAS Reduction
with at least a 1-pt reduction in
ballooning or inflammation
(% of liver biopsies)
MRI Responder; ≥ 30% fat reduction on Week 12 MRI-PDFF High Exp,, n=44; 2-pt NAS reduction; MGL-3196, n=73, placebo n=34; NASH Resolution, prespecified endpoint: at least 2-pt reduction in NAS; ballooning=0, inflammation=0, 1; Prespecified: Excluded patients with >9.5% weight loss from NR
NASH Resolutionballooning=0,
inflammation =0, 1 with at least 2-point
reduction in NAS(% of liver biopsies)
NASH Resolution: Ballooning = 0; Inflammation = 0,1; No worsening of fibrosis stage
36 @72 5252
*included NAS=3; @ NASH resolution required at least a 2-pt NAS reduction in addition to ballooning 0; inf 0,1, no fibrosis worsening ; FXR, farnesoid X receptor; NASH, non-alcoholic steatohepatitis; NAS, NAFLD activity score; OCA, obeticholic acid; Pbo, placebo; PDFF, proton density fat fraction; PPAR, peroxisome proliferator-activated receptor; THR, thyroid hormone receptor. Younossi ZM. EASL 2019 (F1-F3 population); Ratziu Gastroenterology 2016;150:1147-1159; Ratziu AASLD 2018; Harrison AASLD 2018. For elafibrinor only enrolled patients with NAS>3 at baseline were evaluated for NASH resolution
Treatmentdose (n)
Weeks
OCA25 mg
(n=407)
Pbo0 mg
(n=34)
MGL-319660–80 mg
(n=73)
3196 PDFF+60–80 mg
(n=46)
Pbo0 mg
(n=40)
Aramchol600 mg(n=78)
Pbo0 mg
(n=76)
Elafibranor120 mg(n=75)
Pbo0 mg
(n=404)
0Biop
sies
with
reso
lutio
n (%
)
7.914.9 9
19
5
16.7
6
25
0
5
10
15
20
25
30
35
40
37
5
F1–3F1–3 F0–3
4.9* 4.8 4.9Baseline NAS
Baseline Fibrosis
Reduces NAS ≥2
Target THR-𝛽𝛽FXR Fatty/bile acid SCD inhPPAR𝛂𝛂δ
15
NASH Resolution: ”Non-NASH” or Ballooning=0; no worsening of fibrosis
GLP-1, glucagon-like peptide-1; Lira, liraglutide; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; Pbo, placebo; PPAR, peroxisome proliferator-activated receptor. sc, subcutaneous. Sanyal AJ et al. N Engl J Med. 2010;362:1675–85; Vilar-Gomez et al. Gastroenterology. 2015;149:367–78; Armstrong MJ et al. Lancet. 2016;387:679–90.
Biop
sies
with
reso
lutio
n (%
)
213 6
4 7
1 0
9 0
9
3 9
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
Target GLP-1Weight loss
Baseline NAS
Baseline Fibrosis
Reduces NAS ≥2
Pioglitazone30 mg(n=80)
Pbo0 mg
(n=23)
Lira1.8 mg sc
(n=22)
≥5% wt loss(n=205)
≥10% wt loss(n=29)
Treatment dose (n)
Vitamin E800 mg(n=84)
Pbo0 mg
(n=83)
5 4.8 4.94.85.14.8
F0–4F0 (61%)F0–4
Non-NASH at Baseline 28 1817
48 weeks96 weeks (PIVENS trial) 52 weeksWeeks
PPARγ Antioxidant
In older studies Inflammation score not considered
MRI-PDFF Absolute Fat Reduction (%)
Pbo0
(n=26)
GS-0976
20(n=46
)
Lira1.2 sc(n=68)
VK2809
10, 10 qod
(n=24)
Pbo0
(n=12)
OCA/pb25
(n=40/38)
Pbo0
(n=33)
Pbo0
(n=27)
NGM282
3 sc(n=27)
MGL-319660/80(n=74)
MGL-3196
80 ext(n=14
)
Pbo0
(n=26)
Peg10 sc
(n=25)
TargetDisease
FGF19 THR-𝛽𝛽 FXR FGF21 THR-𝛽𝛽GLP-1ACC
Weeks
Treatment dose (mg)
n
12 36 72 16 12 24 12
NASH NAFLD Early NAFLDNASH NASH NAFLD Early NAFLD
Abso
lute
fat
redu
ctio
n (%
)
ACC, acetyl-CoA carboxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; Lira, liraglutide; MRI-PDFF, magnetic resonance imaging – proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid; Pbo, placebo; Peg, pegbelfermin; sc, subcutaneous; THR, thyroid hormone receptor. Harrison SA. Lancet. 2018;391:1174–85; Harrison AASLD 2018; Loomba AASLD 2017; Sanyal AJ. Lancet. 2018;392:2705-717; Loomba R. Gastroenterology. 2018;155:1463–1473; Petit JM. J Clin Endocrinol Metab. 2017;102:407–15; Loomba AASLD 2018.
13.7 15.9 17.3 18.113.218–2019.816.8 18.1 20.6 18 21 18
Baseline fat fraction
17
Pbo0
(n=26)
GS-0976
20(n=46
)
Lira1.2 sc(n=68)
VK2809
10, 10 qod
(n=24)
Pbo0
(n=12)
OCA/pb25
(n=40/38)
Pbo0
(n=33)
Pbo0
(n=27)
NGM282
3 sc(n=27)
MGL-319660/80(n=74)
MGL-3196
80 ext(n=14
)
Pbo0
(n=26)
Peg10 sc
(n=25)
MRI-PDFF Relative Fat Reduction (%)
TargetDisease
Rela
tive
fat r
educ
tion
(%)
FGF19 THR-𝛽𝛽 FXR FGF21 THR-𝛽𝛽GLP-1ACC
Weeks
ACC, acetyl-CoA carboxylase; FGF, fibroblast growth factor; FXR, farnesoid X receptor; GLP-1, glucagon-like peptide-1; Lira, liraglutide; MRI-PDFF, magnetic resonance imaging – proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid; Pbo, placebo; Peg, pegbelfermin; sc, subcutaneous; THR, thyroid hormone receptor. Harrison SA. Lancet. 2018;391:1174–85; Harrison AASLD 2018; Loomba AASLD 2017; Sanyal AJ. Lancet. 2018;392:2705-717; Loomba R. Gastroenterology. 2018;155:1463–1473; Petit JM. J Clin Endocrinol Metab. 2017;102:407–15; Loomba AASLD 2018.
Treatment dose (mg)
12 36 72 16 12 24 12
NASH NAFLD Early NAFLDNASH NASH NAFLD Early NAFLD
13.7 15.9 17.3 18.113.218–2019.816.8 18.1 20.6 18 21 18
Baseline fat fraction
18
Correlation of Decrease in Hepatic Fat (MRI-PDFF) with Improvement in Ballooning and Inflammation on Liver Biopsy
19
Patients who were not MRI-PDFF Responders (≥30% fat reduction) had a low rate of NASH resolution (left panel)
In both MGL-3196 (correlation coefficient 0.42) (right panel) and placebo (correlation coefficient 0.58) % relative change in MRI-PDFF was correlated with reduction in ballooning plus inflammation scores on liver biopsy (steatosis score removed)
NASH Resolution (%); Biopsies with Both Ballooning and Inflammation
Improvement
MRI-PDFF Week 12, % Relative Change: Correlation with Change in
Ballooning and Inflammation Scores
MGL-3196-treated
Week 36: Reduction of Fibrosis, Biomarkers
20
ELF, CK-18 and Pro-C3 scores, biomarkers correlated with liver fibrosis stage, were statistically significantly reduced in MGL-3196 treated, especially in patients with advanced fibrosis at baseline
BL, baseline; compared with placebo; all, placebo n=38; MGL-3196 n=78; ELF≥9 placebo n=21; MGL-3196 n=40; Pro-C3 BL≥17.5, placebo n=12; MGL-3196 n=29; cutoffs (ELF, PRO-C3) were prespecified based on lab normal values; Pro-C3>10 baseline, was also stat sig
*Liver Int. 2015 Feb;35(2):429-37; Journal of Hepatology 2013 vol. 59 j 236–242;
MGL-3196 (all) MGL-3196 (high exp) F2/F3
ELF BL≥9 CK-18 (M30) U/L Pro-C3 (ng/ml)
week
% change
Week 36: Change in Fibrosis Score on Liver Biopsy
21
Second Harmonic Generation (SHG) microscopy provides automated fully quantitative assessment of fibrosis on liver biopsy slides based on unique architectural features of collagen
SHG score was generated and aligned with the pathologist baseline score (baseline, r=0.76), (left panel), blinded to treatment code
Using SHG, MGL-3196 treated compared with placebo showed a statistically significant ≥1-pt reduction in fibrosis score at Week 36. Based on pathology score, fibrosis was reduced by ≥ 1 point in 29% of MGL-3196 treated patients vs. 23% in placebo
≥1 pt reduction in fibrosis on liver biopsy (SHG)
Pathologist Score
SHG
(qfib
rosi
s)
https://doi.org/10.1371/journal.pone.0199166Week 36 pathology scores and treatment code were not provided to SHG
3
21
0
SHG Score
qSteatosis Scoring Correlation with Pathologist Scoring and Baseline and Week 36 MRI-PDFF
22
qSteatosis, an automated slide analysis technology (Histoindex), demonstrates, that like qFibrosis, there is a strong relationship to pathologist steatosis score; however, unlike the pathology steatosis socre, qSteatosisprovides a continuous variable score that correlates well with MRI-PDFF
In this study, qSteatosis and qfibrosis are reduced in the same regions of the liver lobule suggesting that lipotoxicitydrives fibrosis
Brunt et al (2018) demonstrated that fibrosis improvement is predicted by NASH resolution, NAS reduction, ballooning or steatosis decrease
Hepatology. 2018 Dec 14. doi: 10.1002/hep.30418.
Phase 3/4: MGL-3196 NASH Trial Design
Inclusion/Exclusion
NASH on liver biopsy: NAS≥4, high risk F1, F2/3
Comparator/Arms
MGL-3196 80 or 100 mg or Placebo, once daily
Primary Endpoint
Phase 3: Liver biopsy at 52 weeks - resolution of NASH associated with a ≥2 pt reduction in NAS and no worsening of fibrosis
Phase 4: reduction in liver related events or progression to cirrhosis
Key Secondary Endpoints
LDL-C lowering
≥1 pt reduction in fibrosis with no worsening of NAS
Other Secondary and Exploratory Endpoints
Additional NASH biopsy endpoints
Imaging MRI-PDFF
Fibrosis biomarkers
Design
Stage
Drug MGL-3196 (resmetirom)
Blinded 1:1:1
Phase 3/4
Number of Patients
Centers
Treatment Duration
Phase 3: 900 Phase 4: up to 2000
~100, USA; EU
52 Weeks; 4.5 years
Study Overview Study Details
23
Phase 3 Largely Replicates the Phase 2 Design at Higher Doses
Phase 2 NASH Phase 3 NASHLiver biopsy confirmed NASH; NAS≥4 F1-3 NAS≥4, F2-F3, primary assessment; F1B
MRI-PDFF≥10% fat fraction MRI-PDFF ≥8% fat fraction
Enrollment 125 1:2 placebo: resmetirom Enrollment 900 1:1:1 placebo: 2 doses
Dose: 60, 80 mg once daily Dose: 80, 100 mg once daily
36 Weeks 52 Weeks
Centers: USA, 30 Centers: Global, 150, primary USA
Primary endpoint: Relative reduction in liver fat on MRI-PDFF
Primary endpoint: NASH resolution with at least a 2-point reduction in NAS, no worsening of fibrosis powered >>90% to achieve endpoint
Secondary endpoints: 2-pt reduction in NAS Key secondary endpoints:
LDL-C, other lipids LDL-C powered>>90% to achieve endpoint
NASH resolution with at least a 2-point reduction in NAS and no worsening of fibrosis; 1 stage fibrosis reduction with no NAS worsening
At least a 1 stage reduction in fibrosis with no worsening of NASpowered>90% to achieve endpoint
Multiple exploratory biomarkers for fibrosis, inflammation, imaging assessed in Phase 2 and 3
Phase 4: Clinical benefit, reduction in cirrhosis, liver related outcomes up to 4.5 years
24
Catalysts: Our Expectations for Development Timing
Initiation of 12-week Phase 2 trial of MGL-3196 for HeFH
Positive topline 12-week data from Phase 2 trial of MGL-3196 for NASH
Positive topline data from Phase 2 trial of MGL-3196 for HeFH
Positive 36-week topline liver biopsy data from Phase 2 trial of MGL-3196 for NASH
Completed Milestones:
201920182017
Ongoing NASH Phase 3 milestones Potential initiation of Phase 3
dyslipidemia study in 2H 2019
25
Completion of 36 Week NASH Extension Study
Initiation of Phase 3 Study in NASH
Acknowledgements
We are grateful to the patients and staff who made the Phase 2 NASH study possible and are participating in the Phase 3 NASH study
Phase 2 InvestigatorsDr. Stephen A. Harrison, Dr. Cynthia D. Guy, Dr. Mustafa Bashir, Dr. Juan Pablo Frias, Dr. Naim Alkhouri, Dr. Seth Baum, Dr. Cynthia A. Moylan, Dr. Meena B. Bansal, Dr. Brent A. Neuschwander-Tetri, Dr. Sam Moussa and the rest of the team
26
Safety and Additional Biomarkers
27
AEs, mostly mild, a few moderate, balance between groups. Increase in MGL-3196 treated relative to placebo in loose stools, typically a single episode, only at the beginning of therapy
No lab abnormalities or other AEs were increased in MGL-3196 compared with placebo patients
7 SAEs, distributed between placebo and drug-treated, all single occurrences, none related
AEs
Inflammation Biomarker
Safety Biomarkers
No effects on TSH, bone mineral density, heart rate, QTc, other CV biomarkers or diabetes biomarkers
Small (<3%, not statistically significant) reduction in diastolic BP at Week 36 in MGL-3196 patients, consistent with reduced liver fat
Sustained statistically significant reduction in reverse T3 — Reverse T3 is a marker of inflammation. Elevations in reverse T3 may be
indicative of high hepatic thyroid hormone degradation, in NASH, potentially caused by activated stellate cells
Conclusions
In a Phase 2 36 week serial liver biopsy study in patients with NASH fibrosis stage 1-3, patients treated with MGL-3196 as compared with placebo showed
◼ Sustained statistically significant reduction in liver fat on MRI-PDFF in MGL-3196 treated as compared with placebo patients
◼ Sustained statistically significant lowering of multiple atherogenic lipids including LDL-C, ApoB, triglycerides, ApoCIII and Lp(a)
◼ Statistically significant lowering and normalization of liver enzymes; overall safety
◼ Statistically significant resolution of NASH that is correlated with reduction in liver fat on MRI-PDFF and provides evidence for efficacy at a registrational endpoint for Phase 3 development in NASH
28
CV Risk in NASH and NAFLD
◼ Strong association between NAFLD and increased risk of CVD events and mortality
◼ Patients with NAFLD have a pro-atherogenic lipid profile: — Increased triglycerides— Increased apolipoprotein B— Higher concentration of small dense LDL
◼ Patients with NAFLD are at high risk for cardiovascular morbidity and mortality. Thus, aggressive modification of CVD risk factors is mandatory in all patients with NAFLD.
◼ Chalasani N et al. NAFLD Treatment Guidance, Hepatology 2018;67:328-357
Fatty Liver Associates with Overall CVD Mortality
30Pisto P et al. BMJ Open 2014;4:e004973. doi:10.1136/bmjopen-2014-004973
MGL-3196: Potential of a Dyslipidemia Indication in NASH/NAFLD
◼MGL-3196 is the only NASH therapeutic able to lower lipids, consistent with regulatory approval for dyslipidemia; an also reduces fatty liver, an independent CV risk factor
◼Significant dyslipidemia opportunity exists in early NASH / NAFLD (>30M people in the US) and diabetes populations (~70% have dyslipidemia)
—Potential target population includes early NASH / NAFLD patients not eligible for most NASH clinical trials or NASH drugs in development
—50% to 67% of diabetics on statins do not reach their LDL-c target and also have elevated triglycerides; CV outcome studies consistently show that lower LDL-c/ApoB leads to better CV disease risk reduction: “lower is better”
◼Possibility of regulatory approval based on LDL-c (and ApoB) reduction, with a post-approval Phase 4 clinical trial demonstrating CV disease benefit
—Reduction of ApoB, Lp(a), ApoCIII/triglycerides, and liver fat in addition to CV benefit conferred by LDL-c lowering
31
Phase 3: MGL-3196 Dyslipidemia Trial
32
Inclusion/Exclusion
NASH/NAFLD, metabolic syndrome, diabetics, primary dyslipidemia patients not at target on current lipid therapy
Fatty liver disease patients
Comparator/Arms
MGL-3196 80 mg or Placebo, once daily
Primary Endpoint
LDL cholesterol/Apo B lowering
Key Secondary Endpoints
TGs, Lp(a), ApoCIII, hsCRP lowering
MRI-PDFF (subset)
Safety
Design
Stage
Drug MGL-3196
2:1
Phase 3
Number of Patients
Centers
Treatment Duration
2000
USA, Europe, ROW
12 months
Study Overview Study Details
MGL-3196 is Inactive in in vivo Heart Studies
MGL-3196 is the only negative analogue, even given at very high doses (no increase vs untreated control)
Confirms selectivity and lack of heart penetration
No adverse heart findings reported in efficacy or toxicology studies (histopathology)
In vivo assessment of marker of THR-α activity in the heart
THR-α signal from T3 (control) and putative THR-β analogues demonstrates heart penetration and confirms lack of functional THR-β selectivity
Hypothyroid rats treated with compound for 6 hrs
mRNA isolated and α-MHC quantified by RT-PCR
Results relative to T3 Exposure MGL-3196:
— 5 mg/kg at 6 hr: 15.4 uM— 20 mg/kg at 6 hr: 57 uM— 37.5 mg/kg at 6 hr: 94 uM
Rela
tive
alph
a-M
HC m
RNA
0
30
5
10
15
20
25
Untreated Euthyroid T31ug
GC-13ug
Eprotirome1mg
MGL-31965mg/kg
MGL-319620mg/kg
MGL-319640mg/kg
NASH Extension Study
34
◼ Former placebo patient, diabetic on multiple medications whose ALT was ~200 IU/L during the Main study
◼ Following initiation of MGL-3196 at Week 36, rapid decrease in liver fat, improvement in liver imaging (Perspectum) normalized corrected T1 (measure of liver inflammation), 85% decrease in liver enzymes
MGL-3196
BaselinecT1 894 ms
Week 12cT1 883 ms
Week 36cT1 884 ms
Week 12 ExtcT1 836 ms
Week 36 ExtcT1 811 ms
% Fat MRI-PDFF
0 12 36 12 Ext 36 Ext
Importance of Steatosis Response in Improving Fibrosis and NAS
◼ Hepatic fat is most accurately measure by MRI-PDFF, not the steatosis score on liver biopsy, which is a crude measure, that only generally correlates with MRI-PDFF
— Steatosis =1 includes 5-33% of hepatocytes with fat and does not effectively distinguish between a liver fat content that is normal ~5% and abnormal ~20%
— Both placebo (weight loss) and MGL-3196 treated patients show an association between MRI-PDFF response and reduction in other NAS components, ballooning and inflammation
◼ Recent publication Brunt et al (NASH CRN, Hepatology 2019) demonstrated that fibrosis response on liver biopsy was associated most strongly with
— Resolution of NASH (PIVENS OR=3.9, 95% CI 2.0-7.6, p<0.001; FLINT OR=8.0, 95% CI 3.1-20.9, P<0.001), and improved NAS by ≥ 2 (PIVENS OR=2.4, 95% CI 1.3-4.3, p=0.003; FLINT OR=4.2, 95% CI 2.1-8.3, P<0.001).
— Improvement in histologic features associated with improved fibrosis for both studies included steatosis and ballooning, but not lobular, inflammation.
35Hepatology. 2018 Dec 14. doi: 10.1002/hep.30418.