Download Effect of the FXR Agonist Obeticholic Acid on Portal Pressure in

Mookerjee
Yago-Baenas
1
M,
1
G,
2
T,
Mehta
Beecher-Jones
Hooshmand-Rad
1
2
2
Jalan R , Eliot L , Shapiro D
2
R,
Parihar
1
N,
Sharma
1
V,
Failure Group, UCL I nstitute of Liver and Digestive Health, Royal Free Cam pus, London, UK .; 2 I ntercept P harm aceuticals, I nc
Background
NO
intrahepatic
resistance
NOS
↓ DDAH
impacts
ADMA
metabolism
by increasing
portal
pressure via
↓ NO
ADMA
X
DDAH
Cirrhosis and
Inflammation
rf
FXR Agonists
promote transcription of
many genes, including
DDAH.
Hypothesis:
OCA lowers ADMA in
cirrhosis by increasing
hepatic DDAH, increasing
intra-hepatic NO and
lowering portal pressure
Aim
Open label, phase 2, proof of concept study to evaluate if short-term treatment
with OCA is well tolerated and can lower portal pressure in patients with cirrhosis
Study Design
A cohort of 12 patients with established alcoholic cirrhosis and portal hypertension were recruited based on clinical/histological
and radiological criteria. The first 4 patients were assessed for drug safety and tolerance; the subsequent 8 were evaluated for
hepatic venous pressure gradient (HVPG) before and after 7 days of oral OCA (10 mg/day).
Key Inclusion Criteria:
• Age: 18-70 yrs.; all female patients of child-bearing potential were screened for pregnancy and advised on contraception
• Efficacy cohort: significant portal hypertension (HVPG) ≥ 12 mmHg
• Patients with large/grade 3 varices identified by endoscopy within 6 months of screening were in a banding program at entry
Key Exclusion Criteria:
105
106
109
110
113
114
115
116
20
15
10
5
105
106
109
110
113
114
115
116
120
110
100
90
80
70
0
Baseline
HVPG measured pre-treatment and at the end of 7 days
OCA treatment (N=8):
Five of eight (5/8) patients in whom HVPG was measured, met the
protocol-specified criteria for a positive response (HVPG <12mm or
>15% fall). Six (6) patients had a mean reduction from 16 mmHg to
12 mmHg; a mean percent reduction of 24% (shown in blue).
Two (2) patients were non-responders, shown in black. One showed
no change. The other (with initial HVPG = 12 mmHg) had an HVPG
increase. Of interest, this patient was an in-patient and was
subsequently treated for decompensation with infection, though his
infection screen at the time of study was negative.
Total Bilirubin
Mean Arterial Pressure (MAP) measured at the time of
HVPG assessment:
In 6 patients, there was a mean increase in MAP from 84 mmHg at
baseline to 97 mmHg after treatment, including the 2 HVPG nonresponders (shown in black).
In 2 patients (shown in red), initial MAP is higher than anticipated
(based on the patients’ clinical records and measurement on
subsequent follow-up).
45
80
100
50
0
Screening/Baseline
End of Treatment
Normal range <21
60
40
20
0
Screening/Baseline
End of Treatment
Normal
Normal range:
Range:M<41;
M<41;F<33
F<33
Serum Creatinine
Serum Albumin
Alanine Aminotransferase
150
End
Baseline
End
Serum Creatinine (umol/L)
X
L-Arginine
130
25
Albumin (g/L)
hepatic blood flow
Mean Arterial Pressure - 7 days OCA 10mg
HVPG - 7 days OCA 10mg
ALT (IU/L)
Hypothesis
Twelve (12) out-patients (7 male; mean age 53 yrs.) were recruited with a mean Child-Pugh score of 7.6.
Nine (9) out of 12 patients dosed with10 mg OCA experienced at least one adverse event (AE). The most frequent AEs were nausea
(2 patients) and headache (2 patients). All AEs in this patient group were mild in severity, non-serious and resolved without sequelae.
Eight (8) patients had haemodynamic evaluation to determine the effect of short-term OCA therapy.
Total Bilirubin (umol/L)
• Portal hypertension is a major cause of morbidity and mortality in advanced cirrhosis and current
therapies are limited in both efficacy and tolerance.
• Obeticholic acid (OCA; 6 ethyl-chenodeoxycholic acid; INT-747) is a derivative of the natural FXR
ligand, the primary bile acid chenodeoxycholic acid (CDCA). OCA is ~100x a more potent FXR agonist
than CDCA.
• Preclinical studies show that 5 days of therapy with OCA in BDL rats reduces portal pressure,
mediated by an increase in eNOS activity and a reduction in hepatic concentrations of the endogenous
NOS inhibitor, asymmetric dimethylarginine (ADMA) [Hepatology 2009, Vol 50, 74A].
Results
MAP - mm Hg
1 Liver
1
RP ,
HVPG - mm Hg
Intercept Pharma Logo
UCL Institute of Liver and Digestive Health
Effect of the FXR Agonist Obeticholic Acid on Portal Pressure in Alcoholic
Cirrhosis: A Phase 2 Proof of Concept Study
40
35
30
25
Screening/Baseline
End of Treatment
Normal
(Normalrange:
Range:35-50
35-50)
120
90
60
30
0
Screening/Baseline
End of Treatment
NormalNormal
Rangerange:
male: M<66-112;
66 - 112; female:
F<59-9249 - 92
Biochemical characteristics are shown for the 12 patients receiving OCA therapy.
No significant change was noted in serum total bilirubin, ALT, albumin and creatinine between screening and posttherapy. Coagulation status (INR) and AST, ALP and GGT levels were also not different (data not shown) after therapy.
• Patients with active, high consumption of alcohol or prior non-compliance to therapy
Conclusion
• Concomitant vasoactive drugs (beta blockers, nitrates, vasopressin or analogues) ≤ 6 weeks prior to randomization
• Use of the following drugs within 3 months of randomization
– Systemic corticosteroids
– Pentoxifylline
– Ursodeoxycholic acid (UDCA)
– Potential hepato-toxins e.g. methyl-dopa, sodium valproic acid, isoniazid
• Alcoholic hepatitis or overt infection
• Co-existing disease (including cardiac, renal and pulmonary); HIV
• Hepatitis B or C virus treatment <12 months of randomization
HVPG:
• Measurements were made using standard balloon occlusion catheter techniques, in triplicate, with the same
interventionist;
• Response to therapy was defined as either: HVPG reduction <12 mmHg or ≥15% fall from baseline.
This pilot study demonstrated that short-term, low-dose OCA therapy was safe, well tolerated and
lowered HVPG as per protocol to <12 mmHg or ≥15% fall from baseline in 5 of 8 evaluated patients,
with one further patient manifesting a reduction in HVPG of over 14%.
 In patients manifesting a reduction in HVPG (6 /8 patients), the mean percent reduction was 24%.
In 2 non-responders, one showed no change in HVPG; the other an increase from 12 mmHg at baseline.
Mean arterial pressure (MAP) did not decrease across the whole cohort and aside form 2 patients with high
baseline MAP, the remainder of the group showed a net increase in MAP after therapy.
These data warrant further evaluation in a larger, controlled study over a longer duration to determine
if the effects of therapy are sustained.