The Paradox of Obeticholic Acid for the Treatment of NASH

In a previous note, I gave a simplified review of the functionality of the nuclear receptors PPAR
alpha and PPAR delta in respect to how GFT505 operates to reduce stored liver lipids and combat
NASH. I tried to explain how the two PPAR targets of GFT505 were the main operators in the
process of burning excess fat in the liver (PPAR alpha) and in other lipid tissues (PPAR delta) as
well as in the transport of fat from the liver to peripheral tissues when activated by GFT505. The
link between PPAR activation and their effect on lipid metabolism has been clearly established by
researchers in the field for some years. The choice of Genfit to target NASH by activating PPARs
was therefore rather logical and easy to understand.
In this note I try to do the same for the competitor of GFT505, Obeticholic acid (OCA) being
developed by INTERCEPT Pharmaceuticals. My conclusion is that the action of OCA in treating
NASH is much more complex and indirect than that of GFT50505 and may have dangerous side
effects for NASH patients. I will try to explain how I came to this conclusion, but I must emphasize
that, since the way OCA functions is very much more complex than for GFT505, I have had to
considerably simplify my explanations to make them understandable to the reader. That said, I
believe that my conclusions are pretty sound and based on clear evidence published by experts in
the field.
OCA is a bile acid activator of the Farnesoid X Nuclear Receptor, which goes by the name of FXR.
The FXR receptor was first identified some twenty years ago and has been the subject of many
research articles since then because of its role in moderating the process of converting cholesterol in
the liver into bile acid which is then delivered to the intestine via the bile duct for the purpose of
digesting fats. Bile acid is a corrosive and potentially toxic detergent which emulsifies fat to make it
soluble for transport into the blood and subsequent metabolism.
The Farnesoid X receptor plays a key role in the control of multiple metabolic pathways. When
activated by bile acids, FXR modulates bile acid synthesis and transport, as well as lipid and
glucose metabolism. In addition, FXR is activated by the bile acids it produces via a negative
feedback loop that serves to limit the production of bile acid and maintain a stable level in the
intestine in relation to the needs of the patient. Too much or too little delivery of bile acid into the
intestines lead to a range biliary disorders. One of these is primary biliary cirrhosis (PBC) which is
caused by a blockage of the ducts which transport bile from the liver to the intestine and a
subsequent build up of cholesterol in the liver. Most (95%) of the bile acid that enters the intestine
is recovered further down the intestine by a process whereby FXR stimulates its recovery and return
to the liver for reprocessing back into cholesterol. The 5% of bile acid that is lost corresponds to
about half of the cholesterol produced by the liver each day. As a consequence the recovery process
is a vital part of the mechanism to control cholesterol levels. OCA was initially proposed as an FXR
activator to reduce the production of bile acid by patients suffering from PBC. By reducing the flow
of bile acid from the liver, FXR reduces the pressure of excess bile acid in the bile duct and eases
the associated pain.
How can an FXR activator reduce the build up of fat in the liver ?
FXR activation also modulates blood cholesterol and the clearance of plasma triglycerides (soluble
fats in the blood). There are different mechanisms involved in the modulation of blood lipids and
triglycerides by FXR activation.
1) FXR activation suppresses the production of new bile acids, and accelerates their excretion
thus reducing the total concentration of bile acids in the intestines. This reduces the
efficiency of the intestine to digest lipids and transport them to the blood as triglycerides.

2) FXR also modulates the clearance (metabolism) of triglycerides in the blood.

3) FXR also stimulates PPAR alpha (like gft505) which controls the oxidation of fats in the
liver. FXR does not appear to activate PPAR in peripheral tissues, so has no role in burning
off fat in peripheral tissues and no effect on obesity.
However, as a consequence of FXR activation, since less cholesterol is converted into bile, there is
a build up of total cholesterol in both the liver and the blood.
The paradox of FXR activation is the simultaneous modulation of HDL cholesterol and triglycerides
in the same direction, an observation that is widely accepted by experts. If triglycerides are reduced,
so is HDL cholesterol.
FXR activation reduces triglycerides, but increases LDL (bad) cholesterol and decreases HDL
(good) cholesterol at the same time. It is a catch 22 situation for NASH patients. FXR activators
such as OCA may reduce lipid absorption and burn of some fat from the liver through PPAR
stimulation, but in doing so will reduce HDL (good) cholesterol and increase LDL (bad) cholesterol.
This effect is not new. It has been known for more than ten years.
Interestingly, the need for new drugs to treat dyslipidemia in specific patient groups could open
new avenues for the development of FXR mixed agonists. FXR is at the cross-road of bile acid
and lipid metabolism and because FXR modulation changes triglyceride and HDL cholesterol
levels in the same direction, a simple FXR agonist or antagonist will have undesired side effects
from a therapeutic point of view. (Ref : Thierry Claudel, Bart Staels and Folkert Kuipers
Arterioscler Thromb Vasc Biol. 2005;25:2020-2030)
How might this affect NASH patients ?
70% of NASH patients have high LDL cholesterol levels and low HDL cholesterol levels. This is
recognized as the key factor in cardiovascular disease that is the single largest cause of death in the
USA. So by treating NASH patients with the FXR agonist OCA, NASH patients will be more at
risk of cardiovascular disease and cardiovascular accidents.
Heart disease (which includes Heart Disease, Stroke and other Cardiovascular Diseases) is the No. 1
cause of death in the United States, killing nearly 787,000 people alone in 2011.
Chronic liver disease and cirrhosis caused 36,427 deaths in 2013 in the United States
NASH sufferers are therefore 21 times more likely to die from cardiovascular disease than
from NASH itself. One can therefore conclude that treating NASH patients with a medication that
increases the risk of cardiovascular disease would be a therapeutic error.
The results from the recent Flint trial showed that OCA significantly increased the level of LDL
cholesterol in patients being treated with OCA. Indeed, even patients already following a therapy of
statins showed a significant increase in LDL cholesterol levels due to OCA.
OCA therapy therefore significantly increases the cardiovascular risk of NASH patients,
many of whom are already known to be at risk of a cardiovascular accident.
Albert Wright PhD
10 April 2015