Aramchol

Hepatobiliary lipids
...
‫נולד‬
‫טיפול‬
‫איך‬
from bench to bedside
Fred M Konikoff, MD, MSc, FAASLD
Institute of Gastroenterology and Hepatology,
Meir Medical Center, Kfar Saba, and Research
Laboratory of Cholesterol Gallstones and Lipid
Metabolism in the Liver, Tel Aviv University
GALLSTONE DISEASE
Among the most common and
costly digestive diseases:
Prevalence 10-20% of population
#2 GI cause of hospitalization (US)
~5% of the total health budget
Donovan JM, Konikoff FM. Schiff’s Diseases of the Liver, 10th Edition, 2006
Peery AF, Crockett SD et al Gastroenterology 2015, in press
LAP CHOLECYSTECTOMY
Morbidity 0.6-12% (major 2%)
Mortality (0.1%)
DiBaise JK. Clin Gastroenterol Hepatol 2003,9:818
MEDICAL
TREATMENT OF GALLSTONES
URSODEOXYCHOLATE (UDCA)
 Only ~3% suitable patients
 Prolonged treatment (6-18mos)
 Recurrence 50% in 5 years
Konikoff FM. Medscape General Medicine (Gastroenterology) 2003,5:1
cholesterol
Bile Acids
Micelles
cholesterol
Phospholipids
Vesicles
Admirand WH, Small DM. J Clin Invest 1968,47:1043
Peled Y, Halpern Z, Eitan B, Goldman G, Konikoff F, Gilat T. Biochim Biophys Acta 1989,1003:246
PHOSPHOLIPIDS
Candidates for gallstone
treatment?
 Broken by digestive enzymes
 Biliary phospholipids cannot be
controlled by dietary ingestion
Pakula R, Konikoff FM, et al. Lipids 1996,31:295
PHOSPHOLIPIDS IN BILE
16:0 Sn1
18:1
18:2
Sn2
18:3
20:4
Phosphatidylcholine (Lecithin)
Effect of Sn2 chain
on cholesterol crystallization
15
10
Crystal
observation
time (d)
5
0
Control
18:0
18:1
18:2
Ringel Y, Somjen GJ, Konikoff FM et al Biochim Biophys Acta 1998, 1390:293
Candidate for
Saturated
gallstone
treatment?
Pakula R, Konikoff FM, et al. Lipids 1996, 31: 295
FM Konikoff, T Gilat. Curr Drug Targets, Immune, Endocrine & Metabolic Disorders 2005, 5:171
Fatty Acid Bile Acid Conjugate
(FABAC)
OH
COOH
•Influence
•Secreted into bile
cholesterol
•Enterohepatic
solubility &
circulation
crystallization
CH
(CH ) CONH
OH
3
2 n
H
Fatty Acid
Bile Acid
SATURATED
T Gilat, G Somjen, Y Mazur, A Frenkel, R Rosenberg, Z Halpern, FM Konikoff. Gut 2001,48: 75
Effect
of
FABACs
on
cholesterol
C20-FABAC
=
Aramchol
crystallization (in vitro)
Crystal Observation Time
20
15
Time
(days) 10
5
0
Control
C16
C18
C20
C22
T Gilat, G Somjen, Y Mazur, A Frenkel, R Rosenberg, Z Halpern, FM Konikoff. Gut 2001,48: 75
Dissolution of crystals by Aramchol
(human bile, ex vivo)
14
days
3
2
Cholesterol
crystal mass
(mmoles)1
0
Control
10mM
30mM
Aramchol
T Gilat, I Goldiner, A Frenkel, H Laufer, Z Halpern, FM Konikoff. Lipids 2001,36: 1135
In vivo studies
Prevention of crystallization
Lithogenic diet
Aramchol
150/mg/kg/d
100
% with 75
crystals
Mice
50
25
0
0
14
Time (days)
Dissolution of crystals
Lithogenic diet
Aramchol
150/mg/kg/d
100
90
80
70
60
%%with
with
50
crystals
crystals
40
30
20
10
0
Mice
10
10
14
14
28
28
Time (days)
42
42
Prevention of gallstone formation
Lithogenic diet
Aramchol
150/mg/kg/d
100
STONES 75
(%)
Mice
50
25
0
25 50 150
0
Time (days)
20
mg/kg/d
Gallstone Dissolution
Aramchol:
25mg/kg
Lithogenic diet
150mg/kg
Regular diet + Saline/Aramchol
100
80
% of mice
60
with
stones
40
20
0
2
4
T Gilat, A Leikin-Frenkel, I Goldiner, Z Halpern, FM Konikoff. Hepatology, 35: 597-600, 2002
months
Aramchol:
 Prevents cholesterol crystallization
and gallstone formation
 Dissolves cholesterol crystals and
gallstones
Potential medical treatment
for gallstones!…
Pharmacodynamics
(after 150mg/kg/d by gavage)
In vivo concentration of Aramchol:
Bile:
1.0-5.2 µmol/l
In vitro:
2-30mM
Mechanism of action?
Effect on biliary lipids
Control
Aramchol
15
Cholesterol
(mM)
10
5
0
30
Phospholipids
(mM)
20
10
C57L/J mice
8w
0
180
Bile salts
(mM)
120
60
0
FM Konikoff, A Leikin-Frenkel, I Goldiner et al. Eur J Hepatol Gastroenterol, 15:1-8, 2003
Bile acid composition
+Aramchol
40
30
Hydrophobic
index
20
10
0
Regular
diet
Lithogenic
diet
Phospholipid composition
120
100
80
Saturation
(16:0/16:1)
60
40
20
0
RD
LD
LD+Aramchol
Aramchol – MODE OF ACTION
Bile salt
hydrophobicity
Cholesterol
Phospholipid
saturation
Crystallization
Y. Peled, Z. Halpern, B. Eitan, G. Goldman, F. Konikoff, T. Gilat. Biochim Biophys Acta, 1003: 246, 1989.
Mice on a high fat diet
Control
Fatty Liver
Aramchol+
Normal Liver
LIVER LIPID CONTENT
(21 days)
150
Mice
100
*
50
0
200
Hamsters
*
mg lipid/g liver 100
0
400
*
200
0
*p<0.05
Control
HFD
HFD+Armchol
Rats
Fatty acid synthesis in the liver
SCD1
Effect of Aramchol on SCD1
Mouse Liver Microsomes
200
160
120
Specific Activity
(pmol/min/mg)
80
40
0
0
0.5
5
Aramchol (µg/ml)
Inhibition of SCD1
25
Aramchol:
 Decreases bile lithogenicity via
Bile acid & Phospholipid composition
 Effective for cholesterol gallstones
 Effective for fatty liver
 Inhibits SCD1
Therapeutic agent…
Human trials
Phase I:
- 41 healthy volunteers
- Single dose up to 900mg
- Repeated doses of 300mg
No toxic effects
Phase II trial
- Randomized, double blind,
placebo controlled
- 60 pts with Bx proven NAFLD
- Aramchol:100mg/d, 300mg/d,
Placebo – 3mos
- Liver fat assessed by
MR spectroscopy
Safadi R, Konikoff FM, et al. Clin Gastroenterol Hepatol. 2014 , 12: 2085
Change in liver fat content
(after 3 mos of treatment)
No adverse effects
Safadi R, Konikoff FM, et al. Clin Gastroenterol Hepatol. 2014 , 12: 2085
Ongoing studies…
 Multicenter International
Phase II b fatty liver study
(NASH)
 Gallstone prevention study
after bariatric surgery
(proof of concept)
Conclusions
Observations on cholesterol crystallization
in bile…
Importance of Bile acids and Phospholipids
Aramchol - therapeutic potential for:
- Gallstones
- Fatty liver
…by a different mechanism than
originally planned…
Thanks
Israel
Tuvia Gilat
Alicia Leikin-Frenkel
Ilana Goldiner
Diana Gobbi
Zamir Halpern
Livna Shoefat
Ruth Rosenberg
Giora Somjen
Ishi Talmon
Ran Oren
Rifaat Safadi
Amsterdam
Albert Groen
Stockholm
Paolo Parini
Kurt Einarsson
Marseille
Huguette Lafont
Ulm
Michael Fuchs
Dietmar Klass
Galmed Medical
Minerva Center for Gallstones and Lipid Metabolism in the Liver, TAU