FROM NAFLD TO MAFLD, LAST MOVES !



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What's new in the NASH world…    it's moving!

 

As a preamble, I would like to make it clear that I do not have privileged information from anyone and that to make my opinion, I have scrutinized the press releases of the financial analysts who may have contacted the company and I have delved into the recently published scientific literature. My analysis is therefore not intended to provide a truth, but rather to shed light on the situation.

Genfit's announcement that they were postponing the lifting of the double-blind in their RESOLV'IT phase 3 trial pending clarification from the FDA on the framework for statistical analysis did not seem understandable to many people who follow the NASH world closely.

It is in fact the tip of an iceberg that deserves some clarification.

Reading the various press releases from financial analysts who have been able to exchange directly with GENFIT management is full of lessons. I have left out the reading of certain analysts whom I will not name and who, frankly, understand nothing at all and do not even try to understand a minimum of the subject they are dealing with.

The background that led to the postponement of the lifting of the double-blind RESOLV'IT study seems to be as follows (I will use the conditional tense as much as possible because I have had no official confirmation of what happened)

In December, GENFIT had a working meeting with the FDA during which they requested the possibility of modifying the design of the ongoing Phase 3 study to add Key Secondary Endpoints.  The company wanted to be able to perform the analysis of these new endpoints as part of the ongoing study and not in post-hoc studies whose statistical power could have been questioned. To this end, it was necessary to obtain agreement on the modification of the study design before lifting the double-blinding. The FDA would have requested a study delay on their part to validate the new design, a delay that was initially compatible with the publication of the results in the first quarter of 2020.

With medical news having become a little busy at the beginning of the year, the FDA would have informed GENFIT that its opinion could not finally be received until the end of March 2020, which meant that GENFIT could no longer publish the results of the study in March 2020 as promised, hence the sibylline press release postponing the publication, which surprised many people.

So much for the history that I was able to reconstruct, but what is really interesting to dig into are the reasons for all this.

One piece of information given by some analysts would be that the new secondary endpoints would have metabolic components. They don't say whether they're going to be composite endpoints, but as we'll see later on, I think it seems very likely.

Which fly has stung GENFIT so that 3 months before the publication of the intermediate results of their study, they ask for a modification of the design of the study.

It should be remembered that modifying the design of an ongoing study is not very common, but that INTERCEPT had used it for its REGENERATE study by modifying the NASH definition of reversion to comply with the new FDA guidelines but above all to dissociate the two endpoints, reversion and fibrosis, previously linked. This saved the REGENERATE study because in the end only one of the two endpoints was reached, and without this design change, the study would have been a total failure.


To try to understand the motivations behind GENFIT, we must look at a recent publication in the journal Gastoenterology. 

"MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease." https://doi.org/10.1053/j.gastro.2019.11.312

This is based on consultation with an international panel of KOLS disease specialists.

I don't intend to repeat the whole of this fascinating article, but I invite all those interested in NASH to read it.

What does this article say :

It begins by recalling the origin of the acronym NAFLD and shows the semantic limitations with regard to the current knowledge on the disease. It reminds us of the ostracism of the term alcoholic in its definition, even if it is preceded by a negation. He also reminds us that NAFLDs are also present in patients who consume alcohol without the two being linked.

He indicated that, as knowledge of the disease has progressed, the definition of the disease by an exclusion (non-alcoholic) that was linked to a nebula of unknown causes can now be replaced by an inclusive cause.

After consultation with the entire panel of KOLs , the article proposes on behalf of the signatories that the name NAFLD (Non Alcoholic Fatty Liver Disease) be replaced by MAFLD (Metabolic Associated Fatty Liver Disease), in fact the full term would be: metabolic dysfunction associated fatty liver disease. supported by 72.4% of participants.

What is interesting is that the article does not limit itself to suggesting a name change but builds a compelling case for segmenting the disease into distinct subgroups.

The Article points out that about one billion people on earth suffer from LAMD and that the estimated medical costs directly attributable to LAMD exceed 35 billion euros in four major European countries (UK, France, Germany and Italy) and 100 billion dollars in the United States.

He also points out that the mixed effectiveness of various compounds under development is partly a reflection of imprecise definitions and the lack of precision in medicine, particularly with regard to the heterogeneity of the disease. And that this heterogeneity of the NAFLD population with respect to its major factors and coexisting disease modifiers represents a significant barrier to the discovery of highly effective drug therapies.

 

But here's what becomes most interesting:

"The phenotypic manifestation of NAFLD probably reflects the sum of the dynamic and complex interactions of these factors at the systems level. It follows that effective treatment requires that they be precisely targeted, based on a person's phenotype and genetic background, and this is a problem because many pathways lead to the same histology.

However, trial recruitment is currently based on histological and phenotypic classification, without dissection of the predominant pathogenic pathways. It is perhaps not surprising that response rates to current experimental agents range from 20-40%, with a difference of 10-20% from placebo. Thus, a "one-size-fits-all" approach would seem inappropriate when dealing with a very heterogeneous liver disease .../...

We now recognize that metabolic fatty liver disease is a phenotype with complex and disparate causes; the current terminology (NAFLD) represents an umbrella term for the multiple underlying subtypes of severity and natural history, as well as substantial interpatient variability across the spectrum. »

 

This is followed by an analysis of the different factors  that can lead to the disease.

These are described in detail in separate chapters:

  • - Age and gender,
  • - Ethnicity,
  • - Moderate alcohol consumption,
  • - Food consumption, intestinal microbiota and bile acids,
  • - Obesity and Metabolic Health
  • - The Lean NAFDL of Thin People (Lean NAFLD)
  • - Family risk
  • - Genetic variation
  • - Epigenetic factors


They conclude that all these parameters must have an impact on :

  • - The assessment of the risk of fibrosis
  • - The choice of animal models which are more or less representative according to the phenotypes sought.

 

And above all, what interests us the most:

Impact on clinical trial design and the ability to find treatments...

"The standard design of a clinical trial that does not take into account the heterogeneity of the disease may not be the best option for studying a complex disease. Thus, future clinical trials will likely target patients with specific characteristics (gender, hormonal status, genetic predisposition, metabolic and microbiotic signatures, and presence or absence of co-morbidity) once the relationships between characteristics and treatment targets are understood. This trial design is likely to include rational combination approaches .../... Designs that provide flexibility to modify one or more aspects of the basic characteristics of the study design based on responses given in previous phases are also an option, although this adds substantial complexity to the interpretation of the data.

In particular, given the heterogeneity of NAFLDs by ethnicity and geographic region, regional stratification or conducting separate trials in different geographic areas should be considered for pivotal trials."

The conclusion refers to a table of recommendations:

"Nomenclature and definition of Metabolism-Associated Fatty Liver Disease (MAFLD)

  • - We suggest that the NAFLD nomenclature be updated to MAFLD.
  • - The diagnosis of MAFLD should be based on the presence of metabolic dysfunction and not the absence of other conditions.
  • - MAFLD can coexist with other liver diseases
  • - A reference to alcohol should not be included in the acronym MAFLD.
  • - Patients with both MAFLD and a contribution of alcohol to their liver disease are an important group that requires further study and characterization.


Heterogeneity of MAFLD

  • - The MAFLD is a heterogeneous entity
  • - Appropriate patient stratification should be considered when non-invasive fibrosis scores are developed and during clinical trial design.
  • - Studies are needed to map the MAFLD landscape and to precisely define the subtypes of the disease.


Clinical Trials for MAFLD

  • - Detailed stratification of patients and tailoring clinical trial inclusion criteria to disease factors is likely to yield more informative and meaningful results.
  • - Innovative clinical trial designs and tailored combination therapy approaches are likely to be needed to overcome the challenges of disease heterogeneity and for optimal clinical efficacy."

 

Let's be clear that this is not the delusion of a few researchers but the synthesis work of 31 of the world's most renowned KOLS working on NASH.

GENFIT had imperatively to take this into account and probably asked the FDA to add Endpoints integrating metabolic factors allowing a segmentation of the action of ELAFIBRANOR according to phenotypes or comorbidities (for example diabetes, hyperlipidemia, obesity, etc.), we will soon see what these Endpoints are.

The fact of adding endpoints, beyond a success or not on the primary endpoint which will not be modified, will then make it possible to apply for marketing authorisation on a typology of patients for which results have been conclusive without having to restart new studies. 

As an example, if the molecule is effective on diabetic patients only, it is about 30% of NASH patients, but these are the easiest to identify in a few months, which will have a strong impact on the market.

As with Intercept at the time, this design change therefore increases the chances of success for the RESOLV'IT study in terms of market access. It is therefore well worth waiting a few more weeks for the results.


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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