BYZANTINES QUARRELS AN SEX OF ANGELS

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A recent article by Professor Vlad Ratziu: « Back to Byzantium: Querelles Byzantines over NASH and fibrosis» (doi: 10.1016 / j.jhep.2017.09.024)   

responds to a publication NAFLD fibrosis stage but not NASH predicted mortality and time to development of severe liver disease in biopsy-proven .   (Doi: 10.1016 / j.jhep.2017.07.027) which attempted to show that NASH is not a predictor of severe liver disease in patients with NASH but that only the grade of fibrosis is predictive.

His answer, though tinged with humor and historical references to the useless polemics of Byzantine theologians during the siege of Constantinople, is rather scathing, he wonders how can we arbitrarily distinguish predictive factors when they are intimately linked.

The text of the article by Professor Vlad Ratziu is easily understandable by everyone, so it would be pretentious to propose an extension, however it does not seem useless to place it in context, which is anything but harmless.

For two years, a sort of quarrel has emerged between two major strategies for treating patients with NASH. Those who think that the most urgent risk to treat is fibrosis of the liver that leads to cirrhosis, and those who think that it is necessary above all to treat the cause which is the inflammation and its metabolic origins causing this fibrosis.

 This quarrel is not insignificant because the future of many pharmaceutical companies depends on the treatment strategy that will be chosen.

To date, there is no treatment and the sixty or so laboratories that have embarked on the treatment race are all seeking to present their drug as the one that will be the most profitable and which, therefore, will target the market with the highest potential.

The quarrel between fibrosis and NASH is maintained by the financial strategies of these laboratories and the publications on the subject, sometimes contradicting each other, are not written without a second thought!

Patients with advanced fibrosis are patients with a short-term risk, so they have a profile that allows them to be prescribed expensive treatment even if it has significant side effects.

Treatments directly targeting liver fibrosis seek a rapid effect on this fibrosis without worrying about the original cause of fibrosis

It is a market that can grow quickly and be very lucrative, so many laboratories have bet on this treatment strategy and explain to investors that this is the future mainl treatment for patients with NASH.

Other laboratories work on the longer term and target the metabolic causes of NASH, they explain that several pathologies can induce a hepatic fibrosis such as hepatitis C (viral) and then, patients were never treated with anti-fibrotic drugs, but by treating the cause that, in this case, was viral.

They therefore bet on the fact that suppressing the cause of inflammation and necrosis of hepatocytes by treating the metabolic causes of NASH will enable the liver to activate its repair mechanisms which are the most powerful of all human organs, and therefore to resorb the fibrosis.

This mechanism of repair is long, can take several years and requires long-term treatments, maybe even ad vitam. The safety profile of the treatment is therefore essential and its price cannot be too high.

 

A quarrel over the sex of angels

As Professor Vlad Ratziu puts it, these are uninteresting Byzantine quarrels because all the specialists are convinced that the future of the treatment of NASH patients is in the combination of treatments adapted to the progress of the disease.

 

A basic treatment of metabolic causes will be proposed as "backbone treatment" and, depending on the progress of the fibrosis, will be completed a certain time by an anti-fibrotic, to act quickly on liver fibrosis, the time for the background treatment to have effect.

There is no incompatibility between these two therapeutic routes but a real complementarity.

 

But now, the world of science and the world of finance are bumping. 

The short-term economic logic is often inconsistent in terms of health! The world of finance and investors is not renowned for its depth of analysis, and few funds recruit skills that can seriously address the ins and outs of treatment strategies. 

In addition, the funds generally seek to finance the companies whose profitability will be as fast as possible.

It is therefore easy to understand that the majority of laboratories with molecules with supposed direct effects on fibrosis searching for funds to finance their development lean towards a short-term treatment strategy for the most affected patients.

 It is also not surprising that laboratories with molecules with severe side effects also target this population where the benefit / risk ratio is less restrictive.

These laboratories therefore have a regular need for publications supporting their short-term strategy and highlighting the need to treat fibrosis above all else. They know very well that this treatment strategy alone has no future but Manichaeism is always easier to sell and explain than the subtlety of therapeutic combinations.

This strategy is also supported by financial analysts who consider the NASH market as a big cake were each laboratory can take a slice to the detriment of other laboratories.

Even NASHBIOTECHS in its 'market forecast' , which has yet broken down the market into 20 segments to refine its projections, has not yet integrated the notion of overlay of therapeutics which makes that a patient can be treated a certain time with two apparently competing molecules. (This will soon evolve in the next NashBiotechs market forecast).

The statement that the treatment of fibrosis is the only 'bankable' market in the short and medium term, however, begins to crack with the gradual arrival in analyst's  reflection, of laboratories defending a global approach to the disease, as GENFIT , NOVONORDISK and more recently MADRIGAL.

In this context, the somewhat acid exchange of points of view between scientists, reflects the tensions on the economic future and the strategies of the laboratories.

Some laboratories do not hesitate to adapt their arguments as GILEAD who get the majority of its income from Sobosufir, that treats the viral cause of hepatitis C and not fibrosis (which is only its consequence), and now explains that in the case of NASH, it is necessary to treat fibrosis as priority, only because its most advanced drug in NASH has shown some antifibrotic effects (to be confirmed) but moreover because its potential drugs targeting the metabolic causes of NASH are still at early stages of clinical trials, and therefore very far from the market.

Professor Vlad Ratziu explains in a few words that it is not possible to state that the grade of fibrosis is the only predictor of severe liver diseases in patients with NAFLD, an that NASH would not be.

Rightly, one of the criteria being the consequence of the other, a simple transitive approach shows the weakness of the reasoning of the original article authors. article. In this case, the " post hoc, ego propter hoc " is no longer a fallacy but a proven reality.

To try to simplify their reasoning it would be like proclaiming that the presence of water at 40 ° C in a container is not predictive of its boiling, whereas the presence of water at 80 ° C and some bubbles would be. By neglecting the fact that to go from the ambient temperature to 80C ° it was necessary that the water goes through a phase at 40C °.


And to conclude on my fancy analogy regarding treatment strategies:

 

In NASH, those who swear by the treatment of fibrosis, regularly throw ice in hot water to prevent it from boiling, those who defend the treatment of the metabolic cause think it is more wise to extinguish the fire under the pan.

Ultimately the most effective will be to extinguish the fire under the pan, even to throw ice in the water at beginning to bring down the temperature faster.

 

G Divry


"Notice that I am neither a physician nor a biologist, my point of view is only that of an enlightened amateur, so it must be taken for what it is, a questionable point of view"


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