GENFIT PHASE 3 DESIGN SECOND ANALYSIS
(by Gery DIVRY)

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The design of the  ELAFIBRANOR Phase 3 in NASH was announced by GENFIT the November 16th, 2015 after obtaining the approval from the FDA and EMA. and published on clinicaltrials.org the 10 of March 2016

This is an extremely favorable design GENFIT for several reasons as it accompanies the new consensus definition of NASH.

the recruitment asked for the GENFIT’s subpart H (1000) is lower than the ICPT’one (1400)

I mentioned this evolution of the definition of NASH in my previous articles citing the symposium speakers on NASH, which was held last June in Paris. 

A world expert questioned what defined him best the  NASH answered "the balloning and portal inflammation".

I recalled that on these two points, GENFIT announced very good results while the OCA Intercept had an efficiency almost zero on the balloning.

the design of the study announced is :

A total number of patients will be 1800 in total and two arms (the final design published refer to 2000 patients)

· An arm 120 mg / day elafibranor

· A placebo arm

What is interesting is that GENFIT has obtained eligibility for Subpart H on the basis of an interim study of 900 (1000 now) patients over 72 weeks only.

One histological criteria, the reversion of the NASH with no worsening of fibrosis. 

But it is a new definition of reversion criteria:

· A balloning score of 0

· Inflammation score between 0 and 1

This design is incredibly favorable for GENFIT

The relative small size of the sample means will drastically limit the cost of this first phase of part 3 before applying for a marketing authorization and therefore to start returning cash.

It is far from the $ 200 million initially announced, if one follows the current design statistical publications of this type, the Phase 3 cost should not exceed a total of $ 150 million and may be only $ 80 million for the first phase which would consistent with a cost assessable to 5 times the cost of Phase 2b which included 270 patients for 12 months.

The second point is the histological criterion which is cut exactly on the known performance of the ELAFIBRANOR (an important action on the balloning and inflammation) and which deviates steatosis as a criterion on which the elafibranor was iless efficient.

The chances of succes in this study are very good.


we can do some comparisons of known data’s on GENFIT and INTERCEPT studies in NASH regarding the new consensual definition of NASH 


This new consensual definition is  :

  • A ballooning score > 0
  • And a inflammation score >1

 

Regarding the data available in the FLINT Study’s annexes

  •  102 patients under OCA
  •  98 under placebo

 

Regarding balloning

  • Only 88 patients under OCA had a ballooning score > 0
  • Only 82 patients under placebo had a ballooning score > 0

 

  • On the 88 patients under OCA,  25 improved their score to 0 (28%)
  • On the 82 patients under placebo,  18 improved their score to 0 (22%)

 

We can’t calculate the p value but the RR value is  RR=1,29

 

Regarding Inflammation

 

  • Only 67 patients under OCA had an inflammation score > 1
  • Only 61 patients under placebo had an inflammation score > 1

 

  • On the 67 patients under OCA,  45 improved their score to 1 (67%) none to 0
  • On the 61 patients under placebo, 24 improved their score to 1 (39%), none to 0

 

We can’t calculate the p value but the RR value is  RR=1,70

 

Unfortunately the data’s availables do not allow to cross the two results case by case.

In the best case .. the two ensembles overlap and in the best configuration

The resolution of NASH with OCA is at a maximum of

28% OCA vs 22% placebo  RR = 1,29

but in facts the chance they completely overlap is very tiny ..

So regarding those data’s (relative risk factor of 1,29) , it is not easy to predict the OCA efficacy in the new consensual definition of reversion. We can hope that the phase 3 results will be better.


Regarding GOLDEN study on ELAFIBRANOR

We have less data at this time .. it will come soon.

But referring tho the last GENFIT presentation and abstracts published

« Compared to PLB, the 120 mg arm improved ballooning (45% vs. 23%, p=0.02),

inflammation (55% vs. 33%, p=0.05) and steatosis (35.5% vs. 18%, NS) »

It is interesting to see that the results are in line with the new consensual definition of reversion ( good results in inflammation and balloning, NS in steatosis

With the new consensual definition of NASH,  the GOLDEN study show significant results on reversion of NASH on the overall studied population (NAS 3 included) 

Elafibranor 19% vs 12% p = 0.045 placebo


Professor Arun Sanyal, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, commented: “The Phase 2b GOLDEN-505 study demonstrated that, in patients with clearly established NASH with high disease activity, Elafibranor safely led to resolution of steatohepatitis as well as improvement in cardiometabolic risk factors. Of particular importance is the efficacy of Elafibranor on the new consensual definition of resolution of NASH without worsening of fibrosis. Using this new consensual definition which emphasizes the role of cell injury and inflammation as the main drivers of fibrosis evolution, the GOLDEN-505 trial demonstrated that Elafibranor-treated patients who cleared their NASH also experienced a significant reduction in liver fibrosis. Thus, the design of the Phase 3 trial is optimal to confirm the good efficacy/safety ratio of Elafibranor on resolution of NASH at an interim analysis after 72 weeks, and on prevention of cirrhosis in the long-term.” 


This improve the chances of succes in the starting Phase 3



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