NO DOUBT THAT GENFIT'S DRUG CURES NASH       (by Albert Wright)

person-864804 1920

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.



On the basis of the analysis of data from clinical trials, Genfit has consistently argued that GFT505, now named Elafibranor, shows good efficacy to cure Nash. However, not all investors or analysts take the time to research the documents to build up a complete picture of the elements of doubt and conviction that help to make the case for a balanced opinion.

So let's look at the some of these elements that contribute to doubt or certitude, not only on the basis of statistical analysis but also on the basis of human conception of doubt, trust, confidence and conviction.


Doubt and Conviction

We feel CONVICTION when information from many sources CONVERGES towards the same conclusion and when we feel that the information is complete, relevant and precise. We see that the data is consistent with this conclusion and inconsistent with any other. In parallel, the source of all the information must be reliable and unbiased, which means that we TRUST the sources and the methods providing the information on the basis of past experience and knowledge.

DOUBT arises when information on an issue is DIVERGENT such that information from one source can lead to a conclusion that differs to that from other sources or when the information or methods are unreliable, irrelevant or imprecise.

The more precise, reliable and consistent are the elements and the sources, the greater will be our CONVICTION of the veracity of our conclusion, but there can never be absolute CERTAINTY, just a very strong belief.

Our doubts or conviction may also be influenced by the views of others who offer their opinions. We should be very wary of these opinions unless we can actually check on the methods and facts used to come to their opinions and what motivates them to share them with us. In short, we should not trust them unless we have very good reason to do so.

 

Reliable and trustworthy data

In this attempt to define areas of doubt and conviction, I will use information from a poster published at the AASLD conference in November 2015, signed by 17 authors from 14 different institutions and presented for discussion by the leading experts in liver diseases. This considerably increases the trust we can have in the data presented. I therefore consider that the data I will use is reliable and trustworthy. Some of this data is also given in Genfit's presentation for Investors and is certainly easier to read ( http://www.genfit.com/wp-content/uploads/2015/11/20151116-AASLD_Investor_Event.pdf )

 

Histological scores versus Biochemical tests

In the upcoming Phase III trial for Elafibranor, the primary outcome criterion is the resolution of NASH without worsening of fibrosis, based solely on histological measurements of liver biopsies in Elafibranor-treated patients versus placebo. The new consensual definition of the reversion of NASH is a score of 0 for ballooning (on a scale of 0-2) and 0-1 for inflammation (on a scale of 0-3).  Steatosis is no longer used to define the reversion of NASH, but remains a parameter in selecting patients with a score of at least 1 in steatosis (on a scale of 0-3). The previous phase IIB trial data have been analysed on the basis of these new criteria and compared to extensive biochemical tests from the same patients.

The aim of this article is to define if and where these sources of data converge or diverge and hence establish where lies the conviction or doubt. I will demonstrate that the biochemical data is more relevant, more consistent, more precise and more reliable than the histological data in measuring the beneficial effects of Elafibranor in the treatment of NASH which lead to its reversion.

 

Relevance

Liver biopsies are images of a stained slice of liver tissue at a given time. Since they are expensive and carry a health risk, they are taken at the beginning and end of a large time interval in order to identify changes in the physical state of the liver. They provide no information on the functional state of the liver. Since the liver is an organ whose job is to clean up toxins and store, convert and transfer sugars and lipids, its physical appearance is less relevant to the health of the patient than its capacity to function. Furthermore its physical state develops as a result of its incapacity to manage an overload of sugars and lipids over a very long period of time.

As with many chronic diseases, changes in physical appearance lag behind changes in functional capacity. NASH typically takes 15-20 years to develop during which time the functional capacity of the liver slowly declines. The reversion of NASH can only begin after the functional state starts to improve. The biopsy is lagging indicator of the progression of NASH whatever the direction of progression. Furthermore, the choice of “Reversion”, which is considered to be equivalent to “cure” is an odd choice for a chronic disease. For patients who suffer from a chronic disease, what matters is whether or not they are “getting better”. A patient whose treatment improves his health is usually quite satisfied with his progress. No one expects chronically ill patients to be cured by taking a pill. So is it relevant to use a cure test to see if a drug works on NASH ? What the patient wants to know is if the treatment is making him better.

Biochemical tests give information on the functional state of organs and on the overall health of the patient. NASH patients don't only have NASH. Many are also dyslipidemic and insulino-resistant. They are at high risk of developing diabetes and cardiovascular diseases. Indeed, NASH patients are at higher risk of dying from cardiovascular events than from liver disease. For the patient's overall health, treating NASH also means reducing the risk of cardiovascular disease and diabetes. The Chairman of Genfit repeated that in an interview this morning (4 December 2015) http://ow.ly/Vt5AV . Liver biopsies give no information on these which is also why Genfit has developed its bio-marker programme. The biochemical test reviewed in this data give information on the real-time progression of liver enzymes, diabetes, and cardiovascular risk. This is relevant to the NASH patient. These are the tests that practitioners will apply to NASH patients to check whether they are getting better or worse.

 

Precision

The measurement scale of biopsies for the phase III trials to check the progress of NASH is crude and misleading. Requiring a score of 0 for ballooning is an on/off result that takes no account of the starting point. Requiring a score of 0 or 1 for inflammation is a cut-off that ignores any partial progression. Furthermore, the biopsy is subject to sampling errors (2 biopsies cannot come from the same liver tissue) and to subjective interpretation. Genfit uses central reading to try to reduce errors of interpretation, but can do nothing about sampling errors.

Let's look at the statistical issues that this raises. On a histological readout for NASH you cannot have a score of 2,5. For a given patient, the histologist has to choose between 2 or 3 even if he has several tissue samples with different results. For this reason you have to have many patients to get an average score. If we take biopsies from a large group of patients with an average score of NASH of 4,5, you will get a spread of results from say 2 to 6, each patient with his proper score. If you repeat this with a new biopsy on the same group of patients with a double blind analysis you will come close to the same average score of 4,5 but because of the errors of sampling and interpretation, some patients will have a different score. Patient A could have changed from 3 to 2, patient B could have changed from 2 to 3. Patient C could have changed from 4 to 2. Does this mean that Patient B has got worse and Patient C has been cured ? Of course not, this is just a result of the error of the technique. To get a clear picture of whether a drug is effective in treating NASH you have to look at the whole spread of the scores before and after treatment irrespective of the response of individual patients. An effective drug will cause the whole envelope of results to move to lower levels. The use of a cut-off point which designates individual patients as being cured as in the original phase IIB analysis (NAS >3) is bound to lead to distortion of the results. It does not take into account that the results of other individual patients could have moved to higher levels. This was very clearly demonstrated on the results for patients on placebo (see below).

Biochemical blood tests are far more precise than biopsies. They are measured on precise extended scales and the patient variations and measurement errors are known to the analysts. There is no need to make a choice between two integer values. Interpretation can be made in terms of a trend towards higher or lower levels and correlated with other biochemical tests known to be related. Furthermore such tests can be repeated at short intervals to confirm any doubtful results. One may argue that they are only indirectly related to the state of NASH, but they are directly related to the patient's health and the risk of complication. Small changes are often meaningful and send a clear message to the practitioner.


 Convergence and divergence

The document below  “THE HEPATIC AND EXTRA-HEPATIC PROFILE OF RESOLUTION OF STEATOHEPATITIS INDUCED BY GFT-505 (ELAFIBRANOR) » was presented at the AASLD conference in November 2015. It is signed by 17 authors from 14 different institutions and presented for discussion by the leading experts in liver diseases. It is also published on the Genfit web site on the Elafibranor page.




This poster shows results comparing histological data and biochemical data taken during the Genfit phase IIB trial.

Columns 2 and 3 present these results for two groups of patients, so-called “Responders” that passed the new histological cut-off for reversion of NASH and Non-Responders that failed to meet the cut-off histological criteria.

For the Responder group, we have excellent convergence between histological results and all the biochemical data for liver enzymes, plasma lipids, glucose homeostasis and markers of inflammation (16 biological measurements). The biochemical markers clearly show that the patients' liver function has very significantly improved in parallel with the improvement in the physical appearance of the liver biopsies. This is accompanied by improvements in plasma lipids and insulin resistance. The histological data and the biochemical data are consistent and convergent for this group of patients and clearly indicate that Elafibranor has efficacy in the treatment of NASH.

For the Non-responder patients, the data shows low convergence between histology and biochemical tests. There is however high consistency between all four groups of biological tests: liver enzymes, plasma lipids, glucose homeostasis and markers of inflammation, most of which record between 40 and 70% improvement compared to the responder group, whereas the histological test show no significant improvement. This gives credence to significant improvement in the overall health of the patients in this group and a consequent reduction of risk from Nash related diseases, diabetes and cardiovascular disease.

What can we deduce from this low convergence between histology and biochemical tests ?

For these patients, the low relevance of the histological tests in terms of the cut-off level after 52 weeks of treatment could be the cause. Whereas the biological tests are real-time, precise measurements of relevance to the patients' health, the histological measurements are time-lagged and subject to a cut-off that may not be sensitive the true development of the disease.

Now let's look at column 4 which looks at the convergence/divergence between Responders treated with Elafibranor and Responders on placebo.

Once again, the 16 biological measurements are compared in the two groups. In the placebo group, 13% passed the criteria for reversion of NASH according to their histological readouts compared to 22% on Elafibranor. On the basis of histological data, both of these groups are considered to be cured, either by simply following the restrictions imposed by the clinical trial (diet and exercise) or as a result of the treatment with Elafibranor.

The biochemical data fails to support this conclusion. There is in fact total divergence between Placebo responders and Elafibranor responders. Placebo responders show no significant change in the four conditions measured by the biochemical tests compared to the beginning of the trial. These patients are just as much at risk of progression of their NASH and remain at high risk for diabetes and cardiovascular disease. The positive placebo responders are in fact false positives.

This observation concerning the placebo responder group is extremely important. It confirms that the histological method used to measure the efficacy of Elafibranor carries a high degree of doubt and the cut-off criteria to be used in the phase III trial may seriously bias the results. These criteria create a systematic placebo trap that produces false positive results.

No Doubt that Elafibranor cures NASH, but real doubt about the histological method.

These results show that there is no doubt that patients treated by Elafibranor whose histological tests met the trial criteria were effectively cured of NASH over 52 weeks. All the tests converge to this conclusion.

For hose patients on Elafibranor who did not meet the trial criteria, there low convergence between the histological data and the biochemical data. This raises doubts about the relevance of the histological method and cut-off criteria used in the trial.

The false positives of the placebo group would appear to discredit the histological method and criteria used.

If these same criteria are to be used for the Phase III trials, then Genfit must take into account the weakness of the histological methods used when selecting patients so as to avoid the systematic placebo trap. A review of these criteria to include biochemical tests as part of the primary outcome should be considered.

 

Albert Wright PhD, 4 december 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.






Share on StockTwits

WWW.NASHBIOTECHS.COM  -  Copyright G DIVRY 2015-2016  - Contact and TERMS OF USE