New Nash findings for Genfit : Extensive biological tests from phase IIb trial

seriously challenge the interpretation of liver biopsies and demonstrate the wide
efficacy of Elafibranor in treating Nash
At the recent AASLD Liver meeting in San Francisco, Genfit presented a scientific poster which,
because of its detailed scientific language has been entirely ignored by the financial analysts and the
market. This poster however provides a wealth of information extracted from the Genfit Golden
results, analysed on the basis of the recent consensual definition of the reversion of Nash and taking
into account an extensive range of serum-based markers of liver function, plasma lipids, and
glucose markers which seriously challenge the interpretation of the trial results based uniquely on
liver biopsies. The combined interpretation of liver biopsies and biological tests prove the excellent
efficacy of Elafibranor 120mg in treating a very wide range of Nash patients and demonstrate the
need to treat patients even in the early stages of the disease.
This document “THE HEPATIC AND EXTRA-HEPATIC PROFILE OF RESOLUTION OF
STEATOHEPATITIS INDUCED BY GFT-505 (ELAFIBRANOR) » is published on the Genfit web
site on the Elafibranor page.
http://www.genfit.com/wpcontent/uploads/2015/11/2015_11_17_Poster_AASLD_Arun_Sanyal.pdf

This poster goes a long way to explaining the phase IIB results and gives credence to Genfit's
confidence in launching the Phase III trial for Elafibranor. The poster deals with 2 main aspects of
the Golden trial : the distinction between patients who respond to Elafibranor and those who do not
based uniquely on histological results (called Responders and Non-responders) and the total lack of
coherence between the histological results and biological tests in two groups of patients :

(i) Responders treated with Elafibranor compared to Responders on placebo,
(ii) Responders treated with Elafibranor and compared to Non-responders treated with Elafibranor.
The basic interpretation of the histological data is that Responders are considered to be cured
whereas Non-responders simply failed to respond to treatment. The biological tests demonstrate that
this binary interpretation, based uniquely on liver biopsies is misleading, medically unsafe and
seriously distorts the results of the phase IIb trial.
Let's first of all look at look at G120 responders (Elafibranor 120 mg) compared to placebo
responders. (4th column of the poster).

Biochemistry shows that Placebo cures are false-positives
On the basis of the histological data alone, these placebo treated patients were considered to be
cured as a result of the conditions imposed by the phase IIB trial (diet and exercise). What do the
extensive analyses of blood samples tell us ?
The graphs in column 4 give the results for markers of liver function, plasma lipids, glucose levels,
inflammatory markers and the FGF21 hormone marker for both G120 Responders and Placebo
Responders. This is what the authors conclude :
“Whereas G120 responders all showed significant improvements in liver markers, plasma lipids,
diabetes and inflammatory markers, placebo-responders failed to show significant improvements
in any of these areas.
These biological tests, widely used by the medical profession to check the state of health of
patients, confirm that Elafibranor improves liver function as well as the associated conditions that
make up metabolic syndrome (plasma lipids and diabetes) in the Elafibranor Responder group and
give credence to the interpretation of the histological results that these patients really were cured.
In contrast, these same tests demonstrate that the medical condition of the Placebo-Responders was
not improved in any of these areas and discredit the interpretation of the histological result that
these patients were cured. In fact they were not cured at all. They just went under the threshold of
the binary histological test. It is well known that such biopsies are subject to sampling errors and
errors of visual interpretation, a limitation that is made worse by the binary (0/1) judgement applied
to Nash trials. In any case this binary interpretation is medically unsafe and if used in isolation, puts
patients at risk of the progression of Nash and of cardiovascular accidents due to the continued high
levels of plasma lipids.
This histological result for so-called Placebo Responders was a false positive that seriously
distorted the Genfit data. Correcting this error of interpretation by confronting the
histological data with plasma biochemistry leads to the unavoidable conclusion that the Genfit
Golden trial was a resounding success.
This result also shows that exercise and diet are not sufficient tot reverse Nash. Only treatment with
an effective medication such as Elafibranor will make a lasting improvement in liver function,
plasma lipids, glucose levels and liver inflammation. Under normal conditions, since their NAS
score would be unknown (no biopsies), such patients will have to rely on blood tests to check their
condition and would be given medication to control their NASH.

Biological tests challenge the negative result for Non-responders to Elafibranor
Here we compare G120 responders (Elafibranor 120 mg) to G120 non-responders (columns 2 and 3
of the poster).
At baseline there was no significant difference in the mean histological readings for steatosis,
ballooning and inflammation between Responders and Non-responders to G120 Elafibranor. This
was also true for the biological tests for liver function, plasma lipids, glucose levels and liver
inflammation. The correlation between histological readings and biological analyses was good.
After 52 weeks treatment, two groups : Responders and Non-responders were identified based on
the histological responses to Elafibranor corresponding to the new definition of the reversal of
Nash.
According to the histological data, reversal of NASH in Responders was associated with a strong
reduction in NAS score of more than 2 and of the individual components steatosis, ballooning and
inflammation, while Non-responders did not show any significant improvement.
How does this correlate with the biological tests ?
This is what the authors write:
G120-Responders showed a strong reduction from baseline for all liver markers, reaching
statistical significance for ALT, ALP and CK18-M30. Non-responders also showed a significant
reduction in ALP and GGT with no effect or minimal trends on ALT, AST, CK18-M30 and CK18M65. In all cases the improvement was less for Non-responders compared to Responders.
Both Responders and Non-Responders were dyslipidemic and insulino-resistant at baseline. The
overall improvement of plasma lipid profile was higher in G120-Responders than in NonResponders, although the difference reached significance only for triglycerides.
Compared to Non responders, G120-Responders experienced an overall improvement of glucose
homeostasis and insulin sensitivity markers, the difference reaching significance for change in
Plasma glucose.
Both G120-Responders and G120-Non-Responders showed significant improvement from baseline
in Haptoglobin and Fibrinogen plasma levels. The decrease in Haptoglobin and Fibrinogen was
higher in G120-Responders than in G120-Non-Responders, the difference between groups reaching
significance for Fibrinogen.
Overall, whereas the Responders showed a marked improvement in all the biological tests, the Nonresponders showed a slower improvement, typically 40-70% of the improvement recorded for the
group Responders.
What can we conclude from these results ?
One aim of this poster was to show that responders were clearly being cured by Elafibranor. The
excellent correlation between positive histological results and positive biological tests is proof
that Elafibranor cures Nash and that patients can then be followed up using biological tests.

However whereas the histological data give a negative result for non-responders after 52 weeks
treatment, the biological data contrast with this binary interpretation and clearly show that
Elafibranor significantly improves liver function, plasma lipids and inflammation markers in all
patients. The level of response after 52 weeks in Non-Responders is simply lower than that for the
Responder group. These patients are clearly getting better, but at a slower rate than the Responder
group. The biological condition of the liver has improved as shown by the liver function markers,
but this improvement has not been translated into a significant physical impact on the liver that is
visible by histological reading. As with the placebo responders, the histological interpretation,
being based on threshold binary levels (0/1) is very much less sensitive to change than the
continuous scales used for the biological data..
These biological results clearly indicate that after 52 weeks treatment with Elafibranor, the nonresponders were on track to be cured over a longer period than 52 weeks. The biological data
indicate the real-time trend of the disease, whereas the histological readout is a trailing indicator of
the liver condition. The evidence suggests that this negative result on histology alone for nonresponders, becomes a false negative when all the data is taken into account. Non-responders are in
reality just slower responders.
Medical specialists will easily understand these results. Overall, the use of histological data alone
for Nash trials is misleading and dangerous. Histological data should be combined with selected
biological tests to eliminate false negatives and false positives which seriously distort the
interpretation of the trial results. Taking these factors into account, Genfit's Phase II b trial was not
just a success, it was a resounding success.
Albert Wright PhD,
Revised November 27 2015.

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