NO ! INTERMEDIATE RESULTS OF SELADELPAR IN NASH ARE NOT A FAILURE!

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Far from it!

I know that my articles are often against the current of the collective feeling; it is not a deliberate will but the simple consequence of a careful examination of the facts, and to seek what the appearances hide.

 

CYMABAY launched in May 2018 a phase 2b clinical trial targeting action of SELADELPAR in NASH.


The study planned to recruit 175 patients and has 4 arms

·       placebo arm.

·       3 arms with SELADELPAR (10, 20, 50 mg / day)

 

The primary endpoint of the study is the measurement of hepatic fat using the PDFF MRI technique measured at 12 weeks, 26 weeks and 52 weeks.

Patients will have a liver biopsy at baseline and at week 52 to measure histologic changes.

Hepatic serological parameters will also be monitored at each intermediate point and at the end of the study.

Patient recruitment was completed in February 2019.

On June 11, 2019 CYMABAY presented the first intermediate results of its study at 12 weeks.

The only thing the press and investors have learned from these results is the failure of SELADELPAR in lowering hepatic fat as measured by MRI-PDFF.

The share price of CYMABAY fell immediately by almost 50%.

 

And yet ...

 

These results must be put in context.

SELADELPAR is part of the PPAR family. There are three families of actions identified for PPARs. The receptors sensibility: alpha, delta (beta), and gamma.

Each of these components has a different mode of action and effects.

SELADELPAR is a pure PPAR delta;

There are other PPAR molecules in the race for NASH:

 

  • ELAFIBRANOR (GENFIT): PPAR alpha delta, in phase 3.
  • LANIFIBRANOR (INVENTIVA): PPAR alpha delta gamma, in phase 2b.
  • SAROGLITAZAR (ZYDUS): PPAR alpha gamma, in phase 2b.
  • BEZAFIBRATE (INTERCEPT): PPAR alpha delta gamma, status of studies unknown.

 

Examining the known and published effects of PPARs on NASH, we can rely on the only drug that has published all of its Phase 2b results, ELAFIBRANOR (GENFIT) a PPAR alpha delta .

ELAFIBRANOR had demonstrated in 2016 a reversion of NASH according to the currently consensual definition of the FDA, ie the histological finding of a decrease in inflammation and ballooning of hepatocytes.

ELAFIBRANOR however has a mechanism of complementary action in addition to that of SELADELPAR because instead to activating the delta receptors alones, it also activates the gamma receptors, which completes its action.

It should be noted that ELAFIBRANOR had no noticeable effect on steatosis (fat level in the liver).

However, if steatosis is the soil on which the NASH develops, the FDA does not make its decline an acceptable criterion to validate an anti NASH drug, the criteria selected are the disappearance of ballooning (grade 0) and the decline of inflammation has a grade of 0 or 1.

But now, clinical studies with biopsy are long and expensive and some laboratories, in their frantic race to catch up on the two leaders that are INTERCEPT and GENFIT have sought criteria more economical and less invasive to facilitate recruitment.

Those days, labs like to present intermediate results during trial in a way to create buzz and capture the attention of investors.

However it is not possible to practice multiple biopsies 12 weeks apart on a patient. Several laboratories have therefore decided to use a new non-invasive imaging technique (MRI-PDFF) that allows to evaluate with some accuracy the level of fat in the liver.

They are well aware that this technique is not accepted as a criterion by the regulatory agencies for the validation of a NASH treatment, however, some drugs such as MADRIGAL and VICKING molecules have used this technique during their studies because they know that their hormonal treatment specifically targets steatosis and this makes this measure relevant as an advanced indicator.

They of course know know that they will eventually have to go through the histological criteria and thus the biopsies to access the market.

In the case of SELADELPAR, it is incomprehensible, knowing the principle of action of PPAR on NASH that CYMABAY chose this imaging technique (MRI-PDFF ) measuring only steatosis as the main criterion, half of their outcomes mesures is based on that technique, but it is inappropriate for a family  of compound that never lowered liver fat in clinical trial.

They wanted to reproduce MADRIGAL's study profile without much thought, and this is, in my opinion, a huge misjudgment.

Because in the end, in their study, after 52 weeks, there will be an analysis of histological changes in the liver of patients (point 6 of secondary outcomes), in line with the expectations of the FDA. Mesuring liver fat is not stupid in terms of scientific research but the publication of those intermediate measures of steatosis was therefore useless and counterproductive.

They wanted to make the buzz and they are served.

 

What about published data at 12 weeks?

 

Well, if we dismiss this measure of steatosis totally incompatible with the known action of PPAR we have the serological results that are really excellent.


They are in line and even beyond what might be expected from intermediate outcomes of effective NASH treatment. They are also consistent with what is known about the effectiveness of PPARs.

For comparison, these results on liver enzymes at 12 weeks are much better than those of MADRIGAL after the same duration of study.

In my opinion, this suggests future good histological results for SELADELPAR at the end of the study and it confort reasonable hope in other PPARs compounds positive action on NASH.

CYMABAY made a huge strategic mistake in publishing interim results on steatosis and making this measure its primary criterion while the known's mechanisms of PPAR actions are elsewhere, but this is not to say that these intermediate results are a failure, far from it!


G Divry 2019

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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