THE BIG PICTURE FOR GENFIT  
NASH PATIENTS WITH DIABETES AND CARDIOVASCULAR RISK (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.

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Since the publication of the preliminary results of Genfit's phase IIB clinical trial of GFT505 (now Elafibranor) in March 2015, many observers have been focused on certain details of the liver biopsy results, especially the positive reversion of patients with low NASH scores in the placebo group which biased the overall results. By focusing on these details, observers, investors and especially analysts are failing to see the Big Picture. This may well be deliberate on the part of some analysts who favour, or have interests in the US company Intercept, also in the race to treat NASH. These biopsy results for low NASH patients which are worst misleading due to their low accuracy are a diversion that hides the Big Picture for NASH patients.

 

1) Misleading Details : Biopsy data from low NASH patients is inaccurate

Several publications have demonstrated that biopsy data is inaccurate because of to sampling variation. A typical biopsy represents 1/50 000 of the volume of the liver and NASH varies depending on the sampling site. A study designed to measure sampling variations by taking two biopsies from the same patient, carried out by V Ratziu et al, one of the leading experts on NASH,   « Sampling variability of liver biopsy in nonalcoholic fatty liver disease » demonstrated a discordance of one stage or more for 41% of patients. Ballooning discordance was 24% between the two biopsies.

Since 41% of biopsies could be in error by at least one NASH stage due to sampling variation, it is not surprising that many low NASH patients treated with placebo were recorded as cured when second biopsies were taken at the end of the Genfit trial. This result is in total discordance with the blood tests of “cured” patients, which showed that were still just as much at risk from diabetes and CVD events. More on the misleading impact of histological variation can be found here or in the article New Genfit data challenge placebo positives … This subject of sampling variation is also discussed in the excellent article by Rosana Kapella, Setting The Pace In The Race To Treat NASH

 

 

2) The Big Picture : NASH patients have Diabetes and Cardiovascular Risk

 

The Big Picture is that most NASH patients need an effective global treatment not only for NASH, but also for insulin resistance, diabetes and cardiovascular risk and that Elafibranor is effective in treating all of these conditions.

It is well established that most NASH patients are pre-diabetic or diabetic (resistant to insulin) and dyslipidemic (unhealthy levels of lipids and triglycerides in the blood). These diseases are part of the Metabolic Syndrome and often occur together. Indeed most NASH patients are at much higher risk of dying from complications of diabetes or from heart disease and stroke than they are from NASH alone. 38% of NASH patients die from CVD (heart disease and stroke). CVD is the biggest killer in the US, with 85 million patients and 15% of deaths from all causes.

Metabolic Syndrome Risk Factors

The US National Heart Institute defines the Metabolic Syndrome as a group of risk factors that raises your risk for heart disease and other health problems, such as diabetes and stroke.

The conditions described below are metabolic risk factors. These risk factors tend to occur together. You must have at least three metabolic risk factors to be diagnosed with metabolic syndrome.

·    Obesity. Excess fat in the stomach area is a greater risk factor for heart disease than excess fat in other parts of the body, such as on the hips.

·    A high triglyceride level (or you're on medicine to treat high triglycerides). Triglycerides are a type of fat found in the blood.

·    A low level of HDL cholesterol (or you're on medicine to treat low HDL cholesterol). HDL sometimes is called "good" cholesterol. This is because it helps remove cholesterol from your arteries. A low level of HDL cholesterol raises your risk for heart disease.

·    High fasting blood sugar (or you're on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes. Insulin resistance also may increase your risk for metabolic syndrome. Insulin resistance is a condition in which the body can’t use its insulin properly.

Most NASH patients have all of the above risk factors. Indeed NASH is recognised as being caused by excessive levels of triglycerides in the blood which leads to excessive fat storage in the liver. NASH patients therefore need to be protected from all the factors of Metabolic syndrome as well as from NASH.

Elafibranor works by stimulating improved fat and sugar management

Elafibranor stimulates the nuclear receptors PPAR alpha and delta. These are the operators that control the transformation and storage of sugars and lipids in the blood, liver, fat storage cells and muscles. You can find an explanation of the Mechanism of  PPARs here . By stimulating better fat and sugar management, Elafibranor acts to correct the causes of both NASH and Metabolic Syndrome. The results taken from the latest phase IIB clinical trial are clear on this.

 

3) The Big Picture is that Elafibranor improves NASH + CVD risk + Insulin Resistance

For Cardiovascular Diseases

- Elafibranor significantly reduces plasma triglyceride levels

- Elafibranor significantly reduces Total and LDL (bad) Cholesterol and increases HDL
 (good) Cholesterol

For Insulin Resistance and Diabetes

- Elafibranor significantly reduces fasting plasma glucose levels

- Elafibranor significantly reduces HOMA-IR insulin resistance

For NASH

- Elafibranor significantly reduces markers of liver diseases : ALT, ALP, gGT

- Elafibranor significantly reduces histological NASH scores

- Elafibranor significantly reduces markers of fibrosis

- Elafibranor significantly reduces markers of inflammation

 

Conclusion : Elafibranor will be strongly recommended by doctors for all NASH and NAFLD patients since they are all potentially at risk from diabetes and CVD.

In comparison, Intercept's OCA increases both cardiovascular risks and insulin resistance which makes it counter-indicated for most NASH patients

 

Where can you check out this information ?

 Much of this information can be found in a poster displayed 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 poster gives information on Nash Patients treated with Elafibranor or with placebo during Genfit's phase IIB trial. The results compare histological NASH scores with results for liver enzymes, plasma lipids (triglycerides and cholesterol), plasma sugars, insulin sensitivity and other markers.

More information can also be found in Genfit's AASLD Investor presentation


Albert Wright PhD, 16 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.






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