ELAFIBRANOR IN PBC, WHY ?


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GENFIT is starting a Phase 2 in the PBC, it makes me update this article to present the issues of this new trial.

PBC is not a big market and is not a completely virgin market, even if the existing generic covers only part of the need, many patients do not respond or there is allergic.

 

Genfit conference exctract


The maximum prevalence of the disease is, in publications, 300 patients per 1 million inhabitants.

In its conference, GENFIT evokes the figure of 0.05% or 500 patients per 1 million inhabitants and I have not yet found their source.

 

This makes anyway a limited market.

 

Initiate studies on such market, sub intends that we think have a serious chance of success; otherwise the game is not worth the candle.


 

If we look at the criteria recommended for a study on the PBC one can return to the criteria of the POISE Intercept study or, if we really want to delve deeper, take the time to read the anterior paper published in Gastroenterology in 2014 that analyzed and proposed these criteria.

 

The criteria for the intercept study are those recommended in the article

 

It is a mix endpoint:

  • Alkaline Phosphatase <1.67 times ULN (Upper Limit of Normal) except that my mistake is situated about 100 U / L but seems to vary between laboratories.
  • Down 15% Alkaline Phosphatase of mini vs. baseline
  • Total Bilirubin rate normal and constant.


Intercept announced that these criteria were achieved in POISE in 47% of patients treated with OCA 10 mg and 46% by the OCA 5mg - then 10 mg vs. 10% for placebo




It is difficult to extract data in non-dedicated to PBC studies, but I will try myself.

In Golden study, elafibranor 80 and 120 mg arms have been particularly effective in lowering Alkaline Phosphatase



The average patients had low ALP at baseline, which is understandable because there was no question of recruiting patients with PBC in a study of the NASH (column 1 placebo, 80 mg elafibranor 2, 3 elafibranor 120 mg)


It is therefore not possible to say whether the elafibranor would have decreased the ALP below 1.67 times the ULN, (around 100). 

Similarly, we have the bilirubin of patients at baseline ,  the article does not give its evolution but it does not speak of an increase of total bilirubin also.

We can see a decline of nearly 25% of the ALP in a few months, much better than what is required in the endpoint (-15%).

It should be noted that in the study FLINT, OCA did not lower the rate of ALP but, on the contrary, increase it, but they manage to make it drop of nearly 40% in the study on PBC.



GENFIT has access to total bilirubin evolution of GOLDEN patients and must think they have high chances to meet the criteria recommended by the agencies to the PBC.

GENFIT also has an advantage , Elafibranor would reduce pruritus which is one of the symptoms of the disease, while OCA increase it, 

7 patients (10%) in the OCA 10mg arm discontinued the POISE study because of pruritus, 0% for placebo.

The advisory meeting convened by the FDA for consideration of approval of the INTERCEPT OCA in PBC, following the incapacity of Intercept to recruit patients with elevated bilirubin in the POISE study, revealed that the FDA accepted the sole criterion of decline in ALP, without proof of the impact on total bilirubin, as valid .

The FDA concluded that a criterion requiring a 40% drop from the ALP, brought below a threshold 2x UNL, seemed to have a predictive character and this is what has allowed INTERCEPT to get his MA. The final opinion of the FDA on the study of INTERCEPT showed that for the FDA, these criteria are deemed sufficient for the development of a drug to market.

What is surprising is that GENFIT, in its announcement of 27 September 2016, has a small presentation of  the design of its PBC Phase 2a study, they seems to copy that of the POISE study, ie by integrating bilirubin total endpoint.

GENFIT seems to hold in his image of good student in the class by taking the original criteria recommended by the KOLs. It also means they also hope to be able to comply with the criterion of the decline in Total Bilirubin, in contrast to Intercept.

We must monitor results closely.





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