GFT505, a PPAR agonist developed by Genfit for the treatment of NASH

The leading molecule being developed Genfit (GFT505) is a dual agonist of Peroxisome
Proliferator-Activated Receptors (PPAR), a family of Nuclear Receptors (NR) that govern how
living cells control the function of organs. I give here a simplified description of very complex
processes indeed which means that I have made approximations to the description of these
processes in order that non specialists can understand them.
PPARs are a subset of Nuclear Receptors (NR) that govern how cells function with respect to
external chemical signals. There are many families of NR some of which are specific in that they
only respond to certain signals such as hormone molecules. In response to a specific hormone
molecule entering a cell and bonding to an NR, the latter instructs genes in the DNA to express
(produce) new substances (mainly proteins) that affect how certain organs function.
PPARs are a more general form of NR in that they respond to a range of activating molecules with
varying intensity depending on the affinity for the molecule to bond to the PPAR. Three types of
PPAR were identified in 1990s and have been the subject of intense research which has resulted in
thousands of research articles. These are known as PPARa (apha), PPARd (delta) and PPARg
(gamma). PPAR beta (found in frogs) is a close relative of PPARd found in mammals. All PPARs
are very similar but vary in their affinity to bond to certain molecules and in the specific processes
and organs they control. There are also differences in how strongly they function in humans
compared to other mammals, like mice, but the principles remain the same for all mammals. These
differences have been studied in the finest detail and are well documented.
NRs and PPARs are large, very complex structures that attach themselves to the DNA helix at many
points and influence a large number or genes at once. They regulate how the DNA responds or fails
to respond, to a molecule entering the cell. Molecules entering the cell can only influence the DNA
if the NR accepts to bond with the incoming molecule, thus replacing any other molecule already
bonded. On bonding the NR instructs the genes to express specific substances (mainly proteins) that
will regulate how the cell functions until such time that the bonded molecule is replaced by
another in its turn. The activating molecule is called the agonist .. it activates the cell process. Other
molecules may be antagonists that block the process or reverse agonists that reverse the process. A
molecule that bonds to an NR is called a ligand in the bonded state.
GFT505 is described as an agonist that activates both PPARa and PPARd. However published
tables show that known natural PPAR agonists have similar affinity and promote similar levels of
activity in all three PPARs. This may suggest that GFT505 may also activate PPARg to a some
degree, but recent statements by the Chief Scientific Officer of Genfit suggest that GFT505 has no
action on PPARg. Furthermore GFT505 has 4 times more sensitivity to PPARa compared to
PPARd.
Our interest is therefore focused initially on the processes controlled by PPARa and PPARd by their
their natural agonists and the consequences that occur when the process fails to work properly.
PPARa
PPARa is the Master Regulator of lipid storage and metabolism in the liver.
PPARa mainly affects cells in the liver and to a lesser degree, the kidneys, intestines, heart and
muscle tissues. Any operation in liver cells that involves storage, metabolism, transfer and
conversion of lipids to other molecules is controlled by PPARa. In addition, PPARa has been
shown to regulate glucose metabolism, lipoprotein (cholesterol) metabolism, liver inflammation,
and amino acid metabolism. The initial natural agonists for PPARa are soluble highly unsaturated

fatty acids that are produced by the digestion of unsaturated fats (vegetable oils, omega-3 oils) in
the digestive system. The partially oxidized fatty acids in liver tissue are even more efficient
agonists for PPARa so that fatty acid oxidization accelerates the regulation process leading to faster
energy burning and reduced fat storage in the liver. This positive feedback system is designed to
avoid storing too much fat in the liver. During fasting, when no fat is provided by food intake,
PPARa, continues to be activated by partially oxidized fatty acids to instruct the liver to oxidize its
stored lipids to purge the liver and maintain blood glucose levels constant. This lipid management
process has the capacity to temporarily store a large amount of fat in the liver ready for immediate
use to maintain blood glucose levels, but is designed to operate with alternating periods of high fat
intake and intervals of fasting during which the liver can be purged of its excess fat. The system
fails when fat intake (especially saturated fats) exceeds energy needs and normal storage capacity
over a long period of time so that the liver gets overloaded with fat and becomes damaged. The
damaged liver then has reduced capacity for fatty acid oxidation which in turn leads to reduced
availability of the more efficient partially-oxidized fatty acid agonists. With a lower supply of the
most efficient agonists, liver damage continues to increase.
Sugar intake also makes matters much worse. Sugar is made up of glucose and fructose molecules.
Whereas glucose can be directly used as fuel for muscles, fructose must first be converted and
stored as fat in the liver. Unlike direct fat intake, fructose intake does not deliver a fatty acid agonist
to the PPARa to instruct the liver to burn off fat. The combination of a high fat / high sugar diet is a
disaster for the liver. High fructose corn syrup (HFCS), used as a cheap substitute for natural sugar
in the industrial food business (especially in the USA), is particularly unhealthy when combined
with a high saturated fat diet.
PPARd
Researchers appear to know less about PPARd than about PPARa. Recent research indicates that
PPARd also regulates lipid and cholesterol metabolism but seems to concentrate its activity in cells
outside the liver. PPARd activates an array of genes required for fatty acid combustion, but not
those genes involved in lipogenesis and storage. PPARd is a key regulator of fat burning in
peripheral tissues by coordinating fatty acid oxidation. PPARd activation thus reduces obesity by
burning excess fat, but also moderates fat absorption. PPARd is the main agent responsible for
insulin sensitivity and the regulation of blood glucose levels. Expression of PPARd also protects the
heart muscle from excessive fat accumulation. PPARd is also activated by unsaturated fatty acids.
PPARd has also been reported to be actively involved in the repair and regrowth of wounded skin
tissue. This may be related to the process of the reversal of fibrosis in mice by GFT505.
PPARg
PPARg has three types (g1, g2 and g3) which play a complementary role to those of PPARa and
PPARd. They are involved in regulating the storage of fat in the liver and also in non-liver tissue.
PPARg controls the storage and transport of lipids to apidose tissue and protects non-apidose tissue
from excessive fat overload to maintain normal organ function. PPARg2 regulates the response to
nutrient intake and obesity. PPARg is also involved in maintaining glucose levels and insulin
sensitivity. The natural agonists include the same unsaturated fatty acids as for the other PPARs.
Key processes and the Genfit strategy
Given the partial overlap of the physiological roles of PPARs, there appears to be a large degree of
redundancy in the functions provided by PPARs to regulate fat metabolism. A substantial overload
of continuous high fat and/or high sugar intake over a long period of time is therefore required to

cause chronic PPAR dysfunction and liver damage. The key factor in the failure to regulate lipid
overload is the progressive insensitivity to natural unsaturated fatty acid agonists, leading to a lower
supply of more efficient oxidized unsaturated fatty acid agonists from the damaged liver .
If this analysis is correct, one can now see the pertinence of the Genfit strategy. The primary target
is to boost the Master Regulator of lipid metabolism in the liver : the PPAR alpha.
Given that the liver of Nash patients has reduced ability to deliver enough of its most efficient
natural agonist - partially oxidized unsaturated fatty acids, the first priority is to supplement or
replace the natural agonists by a synthetic molecule offering high affinity and high activity to
stimulate lipid oxidation by the PPARa. The aim here is to burn off excess liver fat and
simultaneously boost the production of partially-oxidized unsaturated fatty acids which in turn
boost the PPARa activity.
As a secondary objective, Genfit targets the activation of PPAR delta to boost fat burning and the
regulation of lipid and cholesterol metabolism in non-liver cells so as to reduce obesity, increase
insulin sensitivity and regulate blood glucose levels. PPARg which regulates lipid storage is not
targeted directly, possibly because of historical safety concerns about synthetic PPARg agonists.
However, if the PPARa and PPARd function correctly to burn off fat and regenerate an adequate
supply of partially oxidized unsaturated fatty acids, PPARg will then function properly and no
further action will be needed.
Originally, Genfit began developing GFT505 as a drug candidate for diabetes, only later changing
its use as a drug candidate for NASH. On the basis of the analysis stated above, even though
GFT505 may be effective against diabetes through the activation of PPARd, this change of
orientation was an excellent decision on medical grounds and in terms of the the development of the
company. Indeed its dual activation of both PPARa and PPARd in reactivating the regulation both
liver and non-liver fat should make it a very potent drug to treat the growing problem of obesity and
helping to reduce insulin resistance thus treating the source of NASH. Genfit's current strategy for
GFT505, both in terms of therapeutic potency and commercial returns is very well thought out and
logical.