NEW NASH FINDINGS FOR GENFIT                  (by Albert Wright)

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by Albert Wright  PhD, a retired British research scientist with investments in life science and biotech companies. His approach is to try to understand the complexe science underlying the development of biotech companies and to make this information available to readers in a form that they can most easily understand. In some cases the science is new to him and requires considerable research before publishing an article. Please fell free to contact him on wriga38@gmail.com.


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 is published on the Genfit web site on the Elafibranor page entitled :

 “THE HEPATIC AND EXTRA-HEPATIC PROFILE OF RESOLUTION OF STEATOHEPATITIS INDUCED BY GFT-505 (ELAFIBRANOR) "




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 CK18-M65. 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 Non-Responders, 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 Non-responders 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 non-responders 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 non-responders, 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, November 2015

revised Novemeber 27 2015



Disclaimer

This document contains interpretations and extrapolations that are entirely the work of the author and may or may not be close to the real situation. They are however based on referenced published data and analysed in good faith according to the author's experience as a scientific researcher and author. The author invites the reader to make his own research and interpretation and to draw his own conclusions. The author is open to modification of this text after discussion with the reader. Please fell free to contact him on wriga38@gmail.com

 

The author is a small shareholder in Genfit.



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