NAFLD/NASH

Present & Future Management options

By,
Agenda

 Introduction
 Epidemiology
 Pathogenesis

 Diagnosis

 Management of NAFLD
 Algorithm of the current treatment options of NASH
 Emerging Treatments for NAFLD/ NASH

2
Introduction
 Nonalcoholic fatty liver disease (NAFLD) is a worldwide
epidemic,
 With global prevalence increasing in parallel with rates of obesity,
diabetes, and the metabolic syndrome.
 Estimated to affect as many as a third of the general population and up to
70% of diabetic and obese subjects in the United States.

 NAFLD:- excessive fat (TG) accumulation in the liver (> 5% of

hepatocytes histologically).

 NASH:- NAFLD with liver cell injury and inflammation

 The spectrum of NAFLD:

 Simple steatosis (NAFL) – NASH -- cirrhosis

 Indian Journal of Endocrinology and Metabolism 2013;17(4):665-671,

 World Gastroenterology Organisation Global Guidelines July 2014
Global burden of NAFLD and NASH

 Nature Reviews Gastroenterology & Hepatology. volume 15, pages 11–20 (2018)
Prevalence Data of Non-alcoholic Fatty Liver
Disease in the General Population of India

Extrapolation of Indian data suggests that India may have at least 25 million
patients with NAFLD who may be at risk for significant liver disease.

 NAFLD: non-alcoholic fatty liver disease; BMI: body mass index; AST: aspartate aminotransferase;
ALT: alanine aminotransferase; CT: computed tomography; FBS: fasting blood sugar.

 Duseja et al. Nafld Position Paper . Journal of Clinical and Experimental Hepatology
| March 2015 | Vol. 5 | No. 1 | 51–68
Epidemiology
 In a recent meta-analysis, the worldwide prevalence of NAFLD was
estimated to be 25.24% (95% confidence interval [CI]: 22.10–28.65).
 As diagnosed by imaging in the absence of significant alcohol use.
 With the highest prevalence in the Middle East and South America and
the lowest prevalence in Africa.

 In the United States, data from the NHANES conducted between

1988 and 2008 estimate that
 The prevalence of NAFLD increased from 5.5% to 11%,
 With concurrent increased prevalence of obesity, type 2 diabetes mellitus,
insulin resistance, and hypertension.

 Interestingly, the prevalence of NAFLD in Asian countries seems to follow a

rural-to-urban gradient,
 With lower prevalence rates in the rural areas of India and China and higher prevalence in
the urban areas.

 Lindenmeyer, Christina C. et al. The Natural History of Nonalcoholic Fatty Liver Disease. Clinics in Liver Disease ,
Volume 22 , Issue 1 , 11 - 21
Epidemiology
 Metabolic comorbidities associated with a diagnosis of NAFLD
included
 Obesity (51.34%),
 Type 2 diabetes mellitus (22.51%),
 Hyperlipidemia (69.16%),
 Hypertension (39.34%), and
 The Metabolic syndrome (42.54%).

 NAFLD is increasingly diagnosed in the pediatric population,

with studies estimating prevalence rates of 3% to 18%.

 NAFLD is on track to be the most common indication for

liver transplantation by the year 2020.

 Lindenmeyer, Christina C. et al. The Natural History of Nonalcoholic Fatty Liver Disease. Clinics in Liver Disease ,
Volume 22 , Issue 1 , 11 - 21
The Economic Burden Of NAFLD
 A recent analysis of the Medicare database estimated
 That in the United States, there are more than 64 million people
with NAFLD
 With a potential annual direct medical cost of about $103
billion ($1613 per patient).

 In Europe, it was estimated that approximately 52 million

people may have NAFLD with an annual cost of about 35
billion Euro (from 354 to 1163 Euro per patient).

 If the analysis had focused only on patients with NASH and

fibrosis who are at the greatest for progression,
 An estimated 3 to 4 million patients in the United States with an
annual expenditure of $10 to 15 billion will fall into this category

 Younossi, Zobair M. et al. Clinical and Economic Burden of Nonalcoholic Fatty Liver Disease and Nonalcoholic
Steatohepatitis Clinics in Liver Disease , Volume 22 , Issue 1 , 1 - 10
The NAFLD Journey
NASH : overview

 Epidemiology and natural history of non-alcoholic steatohepatitis.ClinicalLiver

Disease.2009 Nov;13(4):511-31.
Mortality in NASH
 NASH patients are at risk of liver failure, cardiometabolic event, and
death.

 The disease is asymptomatic… until it is too late.

Clinical conditions associated with NAFLD

Torres DM, Williams CD, Harrison SA.Features, diagnosis, and treatment of nonalcoholic fatty liver disease.Clin 12
Gastroenterol Hepatol. 2012 Aug;10(8):837-58.
Links Between Metabolic Syndrome, NAFLD and
Insulin Resistance

 Ahmed MH, Abu EO, Byrne CD.Non-Alcoholic Fatty Liver Disease (NAFLD): new challenge for general 13
practitioners and important burden for health authorities?Prim Care Diabetes. 2010 Oct;4(3):129-37.
Pathophysiology of NAFLD

Torres DM, Williams CD, Harrison SA.Features, diagnosis, and treatment of nonalcoholic fatty liver disease.Clin 14
Gastroenterol Hepatol. 2012 Aug;10(8):837-58.
 Pathogenesis of NASH
NASH is histologically characterized by heptocyte ballooning, steatosis, inflammation
and fibrosis.
First Hit Second Hit(s) Stage 3

Insulin resistance • Oxidation stress

• Adipose tissue • Inflammation
• Liver • Lipotoxicity and
• Muscle peroxidation
• Mitochondrial
dysfunction Fibrosis &
ongoing injury
Cirrhosis

€ HCC
Consequence Consequence
• Increased • Kupffer cell
hepatic TG activation
Adipocytes synthesis Steatosis • Stellate cell NASH
• Hepatic fat activation
accumulation • Apopotosis
• Hepatocyte
Ballooning
• Fibrosis

NAFLD NASH

At present, there is no evidence based drug Approved for NAFLD/NASH

15  Chalasani N et al Hepatology. 2012:55:2005-2023[4]; Cusi K.Gastroenerology 2012:142:711-725.[5] “Non-alcoholic fatty liver disease1” by
Nephron – Own work. CC-SA-3.0 via Wikimedia Commons. “Liver steatosis fatty change” by Laboratory of Experimental Pathology, Division
of Intramural Research, NIEHS (NIH) via Wikimadia Commons
Diagnosis of NAFLD/NASH
Tools for Diagnosis of NAFLD
Method Sensitivity Specificity Comments
Liver enzymes
 GGT[1] 63% 65% Not reliable for diagnosis

Ultrasound[2] 85% 94% Inexpensive and accessible, but

 Any degree[3] 61% 100% cannot distinguish
 Cutoff ≥ 20%[3] 100% 90% fibrosis/steatosis
CT without contrast[4] Better in morbid obesity, but
 Cutoff > 30% 79% 97% affected by iron, fibrosis, and less
accurate with less steatosis
Detects mild steatosis, quantifies
MRI[5] hepatic fat most accurately
 Cutoff PDFF 6.4%, gr ≥ 1 86% 83%
 Cutoff PDFF 17.4%, gr ≥ 2 64% 96%
MRS[6]
 Cutoff ≥ 5% 90-96% 87-100%
 Cutoff > 33% 92-100% 92-97%
Liver biopsy Gold standard, but invasive and
subject to sampling error

 1) Alam S, et al. BSMMU J. 2015;8:61-67. 2) Hernaez R, et al. Hepatology. 2011;54:1082-1090. 3) Dasarathy S, et al. J Hepatol. 2009;51:1061-
1067. 4) Rogier J, et al. Liver Transpl. 2015;21:690-695. 5) Tang A, et al. Radiology. 2015;274:416-425. 6) McPherson S, et al. J Hepatol.
2009;51:389-397.
NAFLD: Diagnosis with Fibroscan
 NAFLD patients with hepatic steatosis were diagnosed using transient elastography
i.e., Fibroscan

 Fibroscan is based on Vibration Controlled Transient Elastography (VCTE) technology

 Measures two quantitative parameters

simultaneously
 – Liver stiffness to measure hepatic fibrosis
 – Controlled attenuation parameter (CAP) to measure
hepatic steatosis

 CAP has high diagnostic accuracy and is also

applicable on Asian patients

 Amount of steatosis can be measured based on the FOR SCIENTIFIC &

COMMERCIAL EVALUATION
CAP values

 1) Friedrich-Rust et al., Gastroenterology 2008;134:960-74. 2) Sasso et al., Journal of Viral Hepatitis 2012;19:244-53.
3) Chon et al., Liver Int 2014;34:102-9.
 The Role of Liver Biopsy
 Make diagnosis of NASH (surrogates insufficient)[1]
 Initiate drug therapy
 Assess prognosis: liver, cardiovascular, etc

 Stage fibrosis (if imaging or tests are indeterminate)[1]

 Rule out concomitant liver disease[1]
 Autoimmune, Wilson disease, DILI, iron overload (ferritin can be high in NAFLD
in absence of iron overload[2])

Isolated Steatosis Steatohepatitis/NASH

19  1. Rinella ME, et al. Gastroenterol Hepatol (NY). 2014 ;10:219-227.

 2. Camaschella C, Poggiali E. Haematologica. 2009;94:307-309.
Histological Features found in Liver Biopsies with
NASH
Quality Children Adult
Frequency in +++ +
children
Steatosis +++ +
Ballooning - +
Cirrhosis + +
Inflammation Portal Lobular
Fibrosis Portal or none Perisinusoidal/
Pericentral
Histology

20
Management of NAFLD/NASH
Treatment Targets for NASH

 Curr Opin Gastroenterol 2017, 33:134–141

Fibrosis stage-based treatment algorithm for
NASH/NAFLD

 Saroglitazar
 Elafibranor

 Yoshio Sumida and Masashi Yoneda. Current and future pharmacological therapies
for NAFLD/NASH. J Gastroenterol (2018) 53:362–376
Current Treatment of Nonalcoholic Fatty Liver
Disease/Nonalcoholic Steatohepatitis
 Body weight loss via physical activity and dieting is the
mainstay of treatment of NAFLD.

 Bariatric and endoscopic weight loss surgery can be effective

in obese patients with NAFLD, with and without metabolic
complications.

 There is no currently approved pharmacotherapy;

 Vitamin E and pioglitazone are available medications
 With the most evidence of efficacy in the treatment of patients with
NAFLD but have side effects and limitations.

 Treatment of NAFLD should be individualized to each patient’s

comorbidities and unique situation.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver Disease , Volume 22 , Issue 1 , 175 - 187
http://dx.doi.org/10.1016/j.cld.2017.08.012
Weight Loss Associated With Histological
Improvement in NAFLD
 Analysis of data from 4 randomized studies
Weight loss ≥ 10%
Fibrosis
regression
(45% of pts)
Weight loss ≥ 7%
NASH resolution
(64% to 90% of pts)*

Weight loss ≥ 5%
Ballooning/inflammation
(41% to 100% of pts)*

Weight loss ≥ 3%
Steatosis
(35% to 100% of pts)*

*Depending on degree of weight loss.

 Hannah WN, et al. Clin Liver Dis. 2016;20:339-350. 25
Pharmacological Therapies for NAFLD/NASH
Class Agent Mechanisms of action

Dual PPAR Saroglitazar Diabetic dyslipidemia and insulin sensitizer

Elafibranor
Insulin sensitizers Metformin Insulin-sensitizing effects by AMPK
TZDs activation
Biguanides Insulin-sensitizing effects by
PPAR- γ agonism
Antioxidants Vitamin E Anti-oxidative effect (free radical
scavenger)
Cytoprotective agents UDCA Act on apoptosis
Cytoprotective effect
Dietary supplement Probiotics Reduction profibrotic agents and
increase
FFA catabolism
Dietary supplement PUFAs Insulin-sensitizing effects

 Vajro P, Lenta S, Socha P, Dhawan A, McKiernan P, Baumann U, Durmaz O, Lacaille F, McLin V, Nobili V.Diagnosis of nonalcoholic fatty
liver disease in children and adolescents: position paper of the ESPGHAN Hepatology Committee. J Pediatr Gastroenterol Nutr. 2012
26
May;54(5):700-13.
Pharmacologic Therapies
 No FDA approved pharmacologic therapies for the
treatment of NAFLD or NASH, to date.
 Treatment is available for associated metabolic disorders.

Dietary Supplements:
 Vitamin E is shown, in animals, to be an antioxidant that modulates
cell signaling and can prevent damage caused by free radicals.

 The largest human trial studying vitamin E is the PIVENS trial, which
compared pioglitazone, vitamin E, and placebo in 247 nondiabetic
patients.

 There was significant improvement, compared with placebo, in

steatosis, lobular inflammation, ballooning, and NAFLD activity score
in subjects receiving 800 IU/d of vitamin E for 96 weeks.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver Disease , Volume 22 , Issue 1 , 175 - 187
http://dx.doi.org/10.1016/j.cld.2017.08.012
Vitamin E
 Treated subjects also showed improvement in ALT activities and
liver histology.

 The resolution of NASH in 36% of vitamin E–treated patients,

however, compared with 21% of placebo recipients was not
statistically significant (P= .05), and, most importantly, fibrosis did not
improve.

 In the TONIC trial, where vitamin E was compared with metformin

and placebo in pediatric patients, improvements in ballooning and
NAS and histologic resolution of NASH were demonstrated.

 Serum ALT and hepatic fibrosis, however, did not meet the primary
endpoint of 50% improvement.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver
Disease , Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
Vitamin E
 Although vitamin E is well tolerated, meta-analyses show a
small increase in mortality (relative risk 1.04; CI, 1.01–
1.07).

 Others have also associated the use of vitamin E with an

increased risk of prostate cancer and hemorrhagic stroke
(relative risk 1.2; P= .5).

 The use of vitamin E should thus be tailored toward

individuals with histologically proven NASH.

 Patients should be made aware of these associated potential

adverse events.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver
Disease , Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
Silybum marianum
 The herbal supplement milk thistle (Silybum marianum) is
readily available and purported to have anti-inflammatory
properties that may be beneficial in NAFLD.

 A randomized trial for its use in NASH has been performed,

where milk thistle in a combination form with vitamin E and
phospholipids was compared with placebo.

 Although there were improvements in homeostatic serum

markers, liver enzyme levels, and histology in the intervention
group, it is unclear if the benefit is from milk thistle or
vitamin E.

 Further studies are warranted to assess the efficacy of this

herbal supplement.
 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver
Disease , Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
Coffee, probiotics, and omega-3 fatty acids.
 Coffee use is associated with a decreased risk of cirrhosis,
hepatocellular carcinoma, and mortality.

 Phenolic and chlorogenic acids among many other chemicals in

coffee are postulated to be beneficial.

 To date, no randomized controlled trials on the effects of

coffee on NAFLD are available.

 The gut microbiota has also been postulated to have a role in

obesity and the development of metabolic syndrome.

 A few small studies have evaluated noninvasive measures of steatosis

and their relationship to administration of probiotics but with
unclear and conflicting results.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver
Disease , Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
Insulin Sensitizers:
Metformin
 In several studies, including randomized trials,
 Metformin seemed to have some beneficial effect on ALT and NASH activity
score
 Likely due to weight loss and not the drug itself.

 A meta-analysis of 4 trials using metformin:

 Did not show any significant changes in hepatic steatosis, ballooning,
inflammation, fibrosis, or ALT.

 Current clinical guidelines recommend against using metformin for

the treatment of NASH.
 TONIC Trial
 Metformin was not superior to placebo in reduction in ALT level in pediatric
NAFLD
 Only able to improve histological hepatocellular ballooning in NAFLD and
NASH

 Haukeland JW, Konopski Z, Eggesbo HB, et al. Metformin in patients with nonalcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol
2009;44(7):853–60.
 76. Loomba R, Lutchman G, Kleiner DE, et al. Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2009;
Insulin Sensitizers:
Thiazolidinediones
 In addition to improving insulin sensitivity and adiponectin production,
Thiazolidinedione leads to
 Increased uptake of fatty acids in adipose tissue, thus potentially drawing fat
deposition away from the liver.

 In the largest randomized PIVENS trial (30 mg daily for 96 weeks in

patients without diabetes),
 As with vitamin E, improvements in steatosis, lobular cellular inflammation,
ballooning, NAFLD activity score, and insulin resistance all met statistical
significance.

 The resolution of definite NASH also was significant, 47% in pioglitazone

users compared with 21% in placebo recipients (P = .001). Hepatic
fibrosis, however, did not decrease.

 Side effects were more common in subjects given pioglitazone compared

with those on vitamin E.

 1) Ratziu V, Goodman Z, Sanyal A. Current efforts and trends in the treatment of NASH. Hepatol 2015;62:S65–75.
 2) Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and
adolescents. JAMA 2011;305(16):1659–68.
Miscellaneous Agents
 Orlistat, which is a gastrointestinal lipase inhibitor for weight loss,
 Was shown to decrease serum ALT and sonographic hepatic steatosis in
one study but failed to improve histology or measures of insulin
resistance in another.

 Pentoxifylline, via its attenuation of TNF-a effect, has been studied

as a possible treatment of NASH.

 Two randomized trials, both using liver histology as an endpoint,

were done using a dose of 400 mg of pentoxifylline three times daily.
 One study showed an improvement in hepatic steatosis and ballooning,
whereas the other did not show any significant differences compared
with placebo.
 The administration of pentoxifylline was associated with significant
nausea.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver
Disease , Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
Miscellaneous Agents
 Ursodeoxycholic acid, which has been used in patients with cholestatic
liver diseases, has also been studied in patients with NAFLD.
 The only randomized trial to evaluate ursodeoxycholic acid at a dose of 13
mg/kg/d to 15 mg/kg/d in NASH patients did not show any difference in
histology in treated patients compared with placebo recipients.

 Statins are shown to be safe in most patients even with elevated liver
enzymes.
 There are 2 prospective, randomized studies on the use of statins for the
treatment of NASH.
 A meta-analysis of the findings shows a decrease in serum ALT levels and
sonographic hepatic echogenicity, but liver histology was not assessed.
 Other retrospective or cohort studies failed to show any benefit in fibrosis.

 Although statins are clearly beneficial for persons at risk of cardiovascular

disease and should be used for such, clinical practice guidelines recommend
against using statins specifically for NASH.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver
Disease , Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
Algorithm of the current treatment options of
NASH

The use of these agents should be highly individualized to each

individual’s specific circumstance and comorbidities.

Careful counseling should be provided when starting any of

these treatments, with patients made aware of potential side
effects and of the off-label use of these medications for NASH.

 With the increasing prevalence of NAFLD and NASH and

their complications , there is the need to develop additional
drugs with proved efficacy in patients with NASH.

 Hung, Chun Kit et al.. Treatment of Nonalcoholic Fatty Liver Disease. Clinics in Liver Disease ,
Volume 22 , Issue 1 , 175 - 187 http://dx.doi.org/10.1016/j.cld.2017.08.012
NASH drug pipelines

 Yoshio Sumida and Masashi Yoneda. Current and future pharmacological therapies
for NAFLD/NASH. J Gastroenterol (2018) 53:362–376
Targets of upcoming therapies for NASH/NAFLD

 Yoshio Sumida and Masashi Yoneda. Current and future pharmacological therapies
for NAFLD/NASH. J Gastroenterol (2018) 53:362–376
Emerging Treatments for NAFLD/ NASH
 Saroglitazar, Obeticholic acid, Elafibranor, and Liraglutide have
demonstrated variable beneficial effects on NASH histology in phase II
RCTs.

 The 1-year, midstudy interim analysis of Cenicriviroc’s phase IIb

study showed an encouraging improvement in hepatic fibrosis.
 Completed results after an additional 1 year of therapy are expected later
this year.

 Promising results from a phase II study of Selonsertib provided

impetus for initiating 2 large phase III trials
 To assess the efficacy of selonsertib in patients with NASH with bridging
fibrosis or cirrhosis.

 Cysteamine bitartrate and long-chain polyunsaturated fatty acids

did not achieve the primary end point of histologic improvement in
high-quality phase II RCTs.
 Gawrieh & Chalasani . Treatments for Nonalcoholic Fatty Liver Disease Clin Liver Dis - 2017
http://dx.doi.org/10.1016/j.cld.2017.08.013
Obeticholic Acid (OCA):
FXR-Mediated Pharmacological Actions
Emerging Treatments:
PPARs as Targets for NASH

PPAR-α PPAR-γ PPAR-α/δ

 Steatosis[2]
 β-oxidation[1]  β-oxidation[4]
 Insulin
 Steatosis[1]  Hepatic steatosis[5]
sensitivity[1]
 Insulin sensitivity[5]
Less effective for  Inflammation[1]
 Inflammation[4]
NAFLD in
 Adverse events[3]  Fibrosis[4]
humans
 ? Safety concerns  Dyslipidemia[4]

 Clinical data in
MetS[4]
 Clinical data in
NASH[5]

Exploitable drug targets: PPARα/∂ (Elafibranor) and PPARα/∂/γ (IVA337)

 1. Anderson N, et al. Pharmacol Rev. 2008;60:311-357. 2. Moran-Salvador E, et al. FASEB J. 2011;25:2538-2550. 3. Wright MB, et al. Mol
Endocrinol. 2014;28:1756-1768. 4. Ratziu V. Nat Rev Gastroenterol Hepatol. 2013;10:676-685. 5. Ratziu V, et al. Gastroenterology.
2016;150:1147-1159.
Saroglitazar:
A potent PPARα and optimal PPARγ agonist

Saroglitazar

Saroglitazar is a potent and predominantly PPARα agonist with

optimal PPARγ agonistic activity
Saroglitazar:
Combining the beneficial effects of Fibrates & Pioglitazone

No weight gain No edema No hypoglycemia

Phase III RCT (PRESS V & PRESS VI)

 In vitro PPAR Agonistic activity in HepG2 Cells

 Saroglitazar, an ideal agent for NAFLD & NASH
First Hit Second Hit(s) Stage 3
αg αg
Insulin resistance
• Adipose tissue g •
•
Oxidation stress
Inflammation
• Liver • Lipotoxicity and
• Muscle peroxidation
• Mitochondrial
dysfunction
Fibrosis
&
Cirrhosis
ongoing
injury
€ HCC
Saroglitazar Saroglitazar
Impact Impact
• Decreased • Kupffer cell
Adipocytes hepatic TG Steatosis activation NASH
synthesis Blocked
• Stellate cell
• Reduced
Hepatic fat
α activation αg
accumulation Blocked
• Hepatocyte
Ballooning NASH
NAFLD Reduced
• Fibrosis
Reversed

• In NASH condition, predominant PPARα effects of Saroglitazar specifically in liver has significant impact on hepatic fat &
associated lipotoxicity driven mechanisms.
• Saroglitazar reduces heptocyte ballooning, steatosis, inflammation and fibrosis, due to its insulin sensitizing, lipid lowering, anti-
inflammatory and anti-fibrotic properties, along with reduction of oxidative stress, improvement of mitochondrial function and
inhibition of Stellate cell activation.
AIMS
 (1)To determine if Saroglitazar administration could prevent
progression of NASH,
 (2)To compare the efficacy of Saroglitazar with benchmark
Pioglitazone and positive and negative natural history controls.
Serum Lipids and LFT Measurments
Left Panel: H&E and Sirius Red staining of PPFE liver sections.
Right Panel: Oil Red O staining of neutral lipids in frozen liver sections.
Oil Red O staining of neutral lipids
H&E and Sirius Red staining of PPFE liver sections
in frozen liver sections
Conclusions
 The pathogenesis of NASH and metabolic syndrome/diabetes
have mechanistic drivers in common.

 This study demonstrated that Saroglitazar inhibits steatosis,

inflammation, ballooning, and fibrosis in addition to lowering
body weight, serum LFTs and lipids.

 Saroglitazar ameliorated NASH development and progression

in addition to improving measures of insulin resistance and
diabetes.

 Saroglitazar met the primary study endpoint of preventing

NASH progression in the DIAMOND™ mouse model, and
the secondary endpoint of outperforming the efficacy of
benchmark Pioglitazone in the DIAMOND™ mouse model.
Effect on PA-induced oxidative stress, inflammation and
impaired mitochondrial biogenesis
In Vitro
Effect on activation of stellate cells
 CCL4 Model
Effect on Histological parameters
Olive Oil +Vehicle CCL4+Vehicle (DC) CCL4+Saroglitazar 4 mg/kg
(NC)

Fibrosis

Fibrosis

COL1A -SMA TGF1

Gene expression

1 .5 0
F o ld c h a n g e in C O L 1 A 1 e x p r e s s io n

F o ld c h a n g e T G F   -S M A e x p r e s s io n
1 .5 0
O liv e o il c o n tro l 1 .5 0
F o ld c h a n g e  -S M A e x p r e s s io n

# C C l 4 C o n tro l (D is e a s e ) O liv e o il c o n tro l

1 .2 5
1 .2 5 # O liv e o il c o n tro l
# C C l 4 C o n tro l (D is e a s e ) 1 .2 5
D -S a ro (3 ) C C l 4 C o n tro l (D is e a s e )
1 .0 0 D -S a ro (3 ) D -S a ro (3 )
1 .0 0
1 .0 0
V s D -C V

V s D -C V

V s D -C V
0 .7 5
0 .7 5
0 .7 5

0 .5 0 ** 0 .5 0 **
0 .5 0

0 .2 5 0 .2 5
0 .2 5

0 .0 0 0 .0 0
0 .0 0
# S ig n ific a n c e a t p < 0 .0 0 1 V s O liv e O il c o n tro l # S ig n ific a n c e a t p < 0 .0 0 1 V s O liv e O il c o n tro l
# S ig n ific a n c e a t p < 0 .0 0 1 V s O liv e O il c o n tro l
* * S ig n ific a n c e a t p < 0 .0 1 V s C C l 4 C o n tro l * * S ig n ific a n c e a t p < 0 .0 1 V s C C l 4 C o n tro l

52
 CDAHFD model
Effect on NASH Biomarkers
ALT AST MCP-1 TG

700 # # N -C V
400 450 #
Serum Markers

N -C V 100
D -C V N -C V
600
D -C V 350 N -C V
D -S a ro (3 ) 375 D -C V
D -S a ro (3 ) 80
D -C V
500 300
D -S a ro (3 ) D -S a ro (3 )

M C P -1 (p g /m l)
A L T ( U /L )

300

A S T ( U /L )
250

T G (m g /d l)
400
60
200
300 225
150 *** ***
*** 40 **
200 150
100

100 50 20
75

0 0
# S ig n ifica n c e at p < 0 .0 0 0 1 V s N -C V
* * S ig n ific an c e a t p < 0 .0 0 0 1 ,* p < 0 .0 5 V s D -C V
# S ig n ific a n c e a t p < 0 .0 0 0 1 V s N -C V 0 0
* * * S ig n ific a n c e a t p < 0 .0 0 0 1 V s D -C V * * S ig n ific a n c e a t p < 0 .0 1 ,* p < 0 .0 5 V s D -C V
# S ig n ific a n c e a t p < 0 .0 0 0 1 V s N -C V
* * S ig n ific a n c e a t p < 0 .0 0 1 ,* p < 0 .0 5 V s D -C V

L-TG Hydroxyproline COL1A1 gene

100
# 250 # 1 .5 0
N -C V
Liver Markers

N -C V N -C V
(m g /g o f liv e r tis s u e )

D -C V 225
O H p r o ( µ g /g o f liv e r t is s u e )

80
D -C V 1 .2 5 #
D -C V
D -S a ro (3 )

F o ld c h a n g e V s D -C V
200
D -S a ro (3 ) D -S a ro (3 )
175 1 .0 0
60
150

125 0 .7 5
40 **
*** **
100
0 .5 0
75
T G

20
50 0 .2 5
25
0
# S ig n ifica n c e at p < 0 .0 0 0 1 V s N -C V 0 0 .0 0
* * S ig n ifican ce at p < 0 .0 0 0 1 V s D -C V # S ig n if ic a n c e a t p < 0 .0 1 V s N -C V # S ig n ific a n c e a t p < 0 .0 0 1 V s N -C V
* S ig n ific a n c e a t p < 0 .0 1 V s D -C V * * S ig n ific a n c e a t p < 0 .0 1 ,* p < 0 .0 5 V s D -C V

53
 CDAHFD model
Effect on Inflammation Markers
MMP-9 1 .5 0
TIMP-1 1 .5 0
#
F o ld c h a n g e in M M P -9 e x p r e s s io n

N -C V

F o ld c h a n g e T I M P - 1 e x p r e s s io n
#
N -C V
1 .2 5 D -C V 1 .2 5
D -C V
D -S a r o (3 )
D -S a ro (3 )
1 .0 0 1 .0 0

V s D -C V
V s D -C V

0 .7 5 0 .7 5

0 .5 0 0 .5 0
**
**
0 .2 5
0 .2 5

0 .0 0
0 .0 0
# S ig n if ic a n c e a t p < 0 .0 0 1 V s N - C V
# S ig n if ic a n c e a t p < 0 .0 0 1 V s N - C V
* * S ig n if ic a n c e a t p < 0 .0 1 ,* p < 0 .0 5 V s D - C V
* * S ig n if ic a n c e a t p < 0 .0 1 V s D - C V

TNF-α MCP-1 1 .5 0

fo ld c h a n g e in M C P - 1 e x p r e s s io n
1 .5 0 1 .2 5 #
F o ld c h a n g e T N F - e x p r e s s io n

N -C V
1 .2 5 # D -C V 1 .0 0

D -S a ro (3 )
1 .0 0 0 .7 5
*
V s D -C V

0 .7 5 0 .5 0

0 .5 0
0 .2 5

0 .2 5
0 .0 0
# S ig n if ic a n c e a t p < 0 .0 0 1 v s N - C V
0 .0 0
* S ig n if ic a n c e a t p < 0 .0 0 1 v s D - C V
# S ig n if ic a n c e a t p < 0 .0 0 1 v s N - C V
 CDAHFD model
Effect on Histological parameters

Normal control Disease Control Disease +Saro (3)

L iv e r h is to lo g y -to ta l N A S H S c o r e

15
D -C V

12
D -S a r o (3 )

T otal N A S H sco re
9

3
**

G r a p h s h o w in g th e e f f e c t o f S a r o g lita z a r o n liv e r h is to lo g y ( T o ta l N A S H s c o r e )
a f te r 8 w e e k tr e a tm e n t in C D A H F D f e d m a le C 5 7 m ic e ( n = 6 ) ,
* * S ig n if ic a n c e a t p < 0 .0 0 0 1 V s D - C V
Saroglitazar: Clinical Studies
Saroglitazar has been evaluated in a number of
clinical trials

Phase 1 RCT in healthy volunteers

Phase 2 RCT

Phase 3 RCT in diabetic dyslipidemia

Phase 2 RCT in HIV Lipodystrophy

Phase 2 RCT in NAFLD

Note: 1. Prospective Randomized Efficacy & Safety study of Saroglitazar (PRESS)

Saroglitazar Evidences:
Phase II study in patient with NASH showed improvement
in liver enzymes with favorable effects on lipids

A prospective, multi-centric, open-label, single arm

Clinical Endpoints
Study study to evaluate the safety and efficacy of 4 mg of
Title: Saroglitazar in non-alcoholic Steatohepatitis
Primary End-points:
(NASH)
•Change in alanine
Phase: Phase II aminotransferase (ALT) from
baseline to Week 6 and Week
CTRI No.: CTRI/2010/091/000108, Registered on 22/07/2010 12

Study Secondary End-points:

Prospective, multicenter, open-label, single arm study •Assessment of sustained
Design:
reduction in ALT level
Study (<1.5UNL)
Biopsy proven NASH patients •Changes in C-peptide as
Population:
endogenous insulin marker and
triglyceride (TG) (≥150 mg/dL
Sample Size: Planned 30; Analyzed: 32 and ≤150 mg/dL).
•Exploratory endpoints of
Treatment change in lipid levels were
12 weeks
Duration: also assessed in the trial
program.
Study Sites: 10 sites across India
 Saroglitazar 4 mg treatment for 12 weeks has a
beneficial effect on liver function tests
• Saroglitazar 4 mg
Summary of Alanine Aminotransferase (U/L) for treatment demonstrated
Saroglitazar 4 mg (N=19) statistically significant
Week 0 Week 6 Week 12 reduction in the ALT
Alanine levels from baseline
95.86±37.6 week 6 and week-12
aminotransfer 5
52.79±28.42 44.37±35.43
(p-value <.0001)
ase (U/L)
Absolute
- -43.07±28.60* -51.49±32.79* • The mean percentage
change
change from baseline
Percent ALT at week 6 and 12
- -42.78±23.25* -54.35±21.83* was -42.78% and -54.35,
change
respectively
Abbreviations: SD = standard deviation; N = number
of subjects in the treatment group; Note : * indicates • Reduction in
significant as compare to Week 0; Data are Triglycerides and LDL-c
Mean±SD was also observed.

 Data on file
 Saroglitazar:
Evidence III
60
A Randomized, Parallel Group, Placebo Controlled Phase III Trial in
India

Study Title: A Prospective, Multi-centre, Double-blind, Randomized

Trial of Saroglitazar 4 mg versus Placebo in Patients
With Non-Alcoholic Steato hepatitis.
Phase: Phase III
Study Design: Randomized, Parallel Group, Placebo Controlled Trial

Study Population: Histologically diagnosed patients suffering from NASH

Sample Size: 102

Treatment Duration: 52 weeks
Saroglitazar:
Evidence III
Objective:
To evaluate the safety and efficacy of 4 mg of Saroglitazar vs placebo in
NASH patients

Primary Endpoints:
 To assess the decrease in NAFLD Activity Score (Time frame 52 weeks)

Secondary Endpoints:
 Percentage of responders, defined by the disappearance of steatohepatitis (Time
frame: 52 weeks).
 Stage of steatosis, lobular inflammation and ballooning (Time frame: 52 weeks)
 Stage of fibrosis (Time frame: 52 weeks)
 Area of fibrosis (Time frame: 52 weeks)
 Liver function test (Time frame: 52 weeks)
 Lipid profile and lipoprotein (Time frame: 52 weeks)
 Insulin resistance and glycemic control
Saroglitazar when added to anti-diabetic drug Dapagliflozin
(SGLT2) for 24 Weeks resulted in statistically significant
reduction in Triglycerides and Liver Fat content

Variables Group 1 Group 2 P value

(Dapagliflozin only) (Dapagliflozin+Saroglitazar) between
groups
Baseline 24 weeks Change Baseline 24 weeks Change
N=28 N=28 N=28 N=28
HbA1c (%) 7.9±0.6 7.1±0.4 -0.87 8.2±1.0 7.1±0.4 -1.2 0.8 (ns)

Triglycerides 373.9±16 230.7±62. -143.2 399.2±83 183.3±47.4 -215.9 0.002

(mg/dL) 4.8 8

Liver fat 324±29 250.2±30 -73.8 335.6±36. 204.8±26.1 -130.7 0.001

content 6
(dB/m)

Abnormal N= N=11/28 35% N=18/28 N=5/28 72%

Transaminas 17/28 (39.3%) (64.28%) (17.9%)
es (60.7%)
Parameters Group-1 (Exenatide only) Group-2 (Exenatide+ Saroglitazar) P Value
(changes
between
Baseline Group-1 Change Baseline Group-2 Change groups)
Week 24 Group 1 Week 24 Group-2

HbA1c (%) 7.9±0.54 7.09±0.29 -0.81 8.1±1.01 6.94±0.40 -1.16 0.09 (NS)

HDL-C 35.8±9.8 38.1±8.9 +6.4% 31.6±10.5 38.4±10.3 +21.5% 0.003

(mg/dL)

TG (mg/dL) 362.9±167. 233.8±60.8 -35.6% 390.4±96.6 180.3±51.6 -53.8% 0.01

2

Liver Fat 319.3±31.4 248.3±30.5 -22.2% 330.4±36.1 202.8±28.3 -38.7% <0.001

Content
(dB/m)

 Kiran Pal Singh et al, Poster no., 134-LB; 75th Scientific Session - ADA, June 5-9,
2015 • Boston, MA, USA
Abstract #1311
SAROGLITAZAR IN NON-ALCOHOLIC FATTY LIVER
DISEASE

 Shashank Joshi,Banshi Saboo,Rajeev Chawla,Sudheer Bhandari

Results
At 24 weeks follow-up:
 TG : reduced from 321 to 129 mg/dL(p<0.001).
 HbA1c : reduced from 8.9 to 8.1%
 ALT : reduced from 89 to 21 U/L
 39% patients showed improvement in fatty liver on fibroscan
evaluation.

Conclusion
 Saroglitazar can be a potential therapeutic option for the treatment of
NAFLD and NASH associated with metabolic syndrome.

 A biopsy driven randomized, controlled clinical trial is required to establish

the efficacy of saroglitazar in patients with NAFLD and NASH.
Efficacy and Safety of Saroglitazar in Indian diabetics - 2 year data

SHASHANK R. JOSHI1, RUBY SOUND2, BANSHI D. SABOO3

1. Consultant Endocrinologist, Joshi Clinic*, Lilavati & Bhatia Hospital, Mumbai, India;

40-LB
Results
 41% reduction (P < 0.001) in triglycerides,
 12% reduction in LDL-C,
 16.3% reduction in TC,
 28% reduction in non HDL-C
 Significant absolute reduction of 0.7 % in HbA1C
 Significant improvement in Fasting and PP plasma glucose.
 Renal, hepatic and cardiac functions were monitored every 3
months and no serious adverse events were seen.
 No edema or weight gain was reported during 2 years follow-up
Efficacy of Saroglitazar:
PRESS V & VI TRIALS
 TG lowering – 45-46.7%

 Non HDL-C lowering – 32.5%

 Apo B reduction – 32%

 HbA1C reduction – 0.3% (vs. 0.4% reduction in Pioglitazone arm)

 Effect on body weight:

 -0.1 kg in Saro 4mg arm (vs. 1.6kg gain in pioglitazone arm)

 J Diabetes Sci Technol. 2014 Jan 16;8(1):132-141

 Diabetes Technol Ther. 2014 Feb;16(2):63-71
Safety of Saroglitazar:
PRESS V & PRESS VI studies(24 & 12 weeks studies)
Saroglitazar was found to be safe and well tolerated

 Most commonly reported adverse events:

 Gastritis
 Dyspepsia
 Pyrexia
 Asthenia

 Mild to moderate in nature, did not result in discontinuation of

study medication

 J Diabetes Sci Technol. 2014 Jan 16;8(1):132-141

 Diabetes Technol Ther. 2014 Feb;16(2):63-71
Saroglitazar Abstract

Abstract P02-08,
2017 EASL NAFLD Summit,
Rome, Italy

Abstract P02-08, EASL NAFLD Summit, Rome, Italy

Elafibranor:
A PPAR Alpha/Delta Agonist:
ALP reduction induced by Elafibranor

Elafibranor in NASH :
 Effects on ALP and GGT increase with the level at baseline
 Effects consistent in all Phase 2 trials in cardiometabolic patients
IVA337:
Next generation pan PPAR profile

IVA337 next
generation pan
PPAR profile
(PPARa/d/g) could
combine in a
single drug the
efficacy of
pioglitazone
(PPARg) and
elafibranor
(PPARa/d)

 CusiK et al, Annals of Internal Medicine, 2016; Ratziu V et al, Gastroenterology, 2016
 The Liraglutide Efficacy and Action in Non-
alcoholic steatohepatitis (LEAN)

Results of the LEAN trial

a P<.05; b P = .05, remaining comparisons P>.05.
LI, lobular inflammation

 Gawrieh & Chalasani . Treatments for Nonalcoholic Fatty Liver Disease Clin Liver
Dis - (2017) http://dx.doi.org/10.1016/j.cld.2017.08.013
Summary of interventions for NASH

 Merola et al. NAFLD following liver transplant. Clin Transplant 2015: 29: 728–737
DOI: 10.1111/ctr.12585
Summary
 NASH can progress to cirrhosis and liver cancer and has
become a leading cause for chronic liver disease worldwide.

 Vitamin E and pioglitazone currently remain the first-line off label

drugs for NASH.

 Of the emerging promising compounds, Saroglitazar, OCA,

elafibranor, and liraglutide have evidence from phase II RCTs of
variable beneficial effects on NASH histology.

 For all these promising compounds in different stages of

development, the establishment of long-term safety, efficacy, and
tolerability will be key for their approvals as therapies for
patients with NASH.
Saroglitazar:
A potential agent for managing NAFLD & NASH
 Shows strong Lipid lowering effect (Reduce TG, TC, LDL), Clears chylomicrons

 Has Insulin sensitizing & anti-hyperglycemic effects

 Reduces NASH Markers (ALT, AST), Shows strong hepatic lipid lowering effect

 Reduces inflammatory markers , and fibrogenic markers

 Reduces oxidative stress and Improves

mitochondrial function

 Improves in liver histological (Reduce steatosis,

inflammation, balloning & fibrosis)

 Abrogate stellate cell activation

Thank You