WHAT IS THE IMPACT OF THE SELADELPAR MISADVENTURES ON THE PBC AND NASH MARKETS?

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This Monday, November 25, CYMABAY has created the surprise by announcing the discontinuation of SELADELPAR studies in NASH and PBC.

“The atypical histological findings in the NASH Phase 2b clinical study of seladelpar were observed in patients who demonstrated on-study improvement or stabilization of their biochemical measures of inflammation and liver injury and no liver-related adverse events after 52 weeks of treatment,” stated Sujal Shah, CEO of CymaBay. “These findings were also unexpected based on our preclinical and clinical experience with seladelpar to date.  However, in light of the findings, we have decided to terminate our NASH and PSC studies and place our PBC studies on hold pending further review and follow-up. We are very disappointed in having to halt the development of seladelpar at this time but patient safety and care is paramount. We would like to thank patients and their families, as well as the investigators and site personnel that have participated in these studies.”

We can only congratulate the CYMABAY team for quickly making this courageous decision, which was necessary in the interest of patient safety.

As always, some analysts in a hurry and not very conscientious immediately blamed this setback on the PPAR delta in general and, as SELADELPAR is defined as a PPAR delta, issued an alert on one of the other molecules with a PPAR delta component, ELAFIBRANOR.

Curiously, these same analysts have forgotten in their vindictiveness other molecules also having a PPAR delta component such as INVENTIVA's LANIFIBRANOR or INTERCEPT's BEZAFIBRATE.

GENFIT reacted immediately by recalling that ELAFIBRANOR had been tested on 10 times more patients/year than SELADELPAR without ever having been found to have interface hepatitis on patients' biopsies.  The problem therefore seems to be specific to SELADELPAR.


 


NUCLEAR RECEPTORS, A PRECISION TUNING


While it is clear that classes of drugs generally have similar clinical effects, the problem is a little more complex for cell nuclear receptor activators.

Nuclear receptor activators are small molecules whose composition and geometry allow them to bind to compatible cell nucleus receptors and, in doing so, activate or inhibit the expression of a gene in the cell. This action on the gene will slightly modify the cell's program, which will therefore modify its behaviour.

To try to simplify, imagine a railway station locker room with multiple lockers and therefore locks that represent the nuclear receivers of a cell, in each locker there is a switch that acts on the cell program that can be activated or not, which will influence part of the cell program. Developing a drug is about making a key that will open the right locker to act on the cell at the chosen location.

But here it is, organic life is complex and nothing is that simple. We all know that some keys can sometimes open several lockers, and that others have difficulty getting into the lock but sometimes they do so by forcing a little. The same applies to nuclear receptors. The key will be randomly tested on all locks and will, if it is well designed, finally open the targeted locker, but here it is, if it is not specific enough, it can also, without this being provided for in the design of the key, open another locker without anyone knowing anything about it and press the button that is not necessary.

Two keys can therefore be designed to open the same locker and yet have different actions by acting recklessly on adjacent lockers.

To add complexity and refer to computer programming, those who practice it know that the result of a program can be modified by acting at many points in the programming, the result will apparently be the same but not all modifications are the same, some have side effects on the program that are only detected in certain situations and sometimes very late, it is an induced bug.

The same is true for the genetic program of a cell, the complexity of the code is such that the interactions with epi-genetics are so poorly known that if one can give the impression that two keys have the same result, it happens that the method of action is completely different and the side effects too.

Returning to SELADELPAR, it is a molecule that, according to CYMABAY, specifically targets the PPAR beta/delta receptor. It's a key that's supposed to open only one locker. On the other hand, the ELAFIBRANOR is supposed to open the PPAR alpha and beta/delta trays, the LANIFIBRANOR and the BEZAFIBRATE would also open the PPAR gamma trays.

It may well be that SELADELPAR opens, without being identified, some other lockers and activates unexpected buttons. Given the number of receptors in a cell, it will take time to understand why and how.

That is why analysts who quickly proceed by association of ideas and criminalize all gamma PPARs without distinction, are in my opinion far from the point and do not do their work seriously.

Playing with nuclear receivers is precision tuning and few laboratories excel in this exercise. Announcing that a particular nuclear receptor is targeted is not enough, only well-conducted clinical studies with regular safety checks are a guarantee and confirm over time that the key has been well designed and only acts on the targeted lockers. 


WHAT ARE THE IMPLICATIONS OF SELADELPAR HANG-UP ON THE FUTURE MARKET OF NASH AND PBC.

I would say that for the NASH market, it doesn't change much. CYMABAY was quite far from the leaders in the process leading to the MA and its disappearance from the radars has almost no influence on the future market.

This is totally different for the PBC Market because the abandonment of SELADELPAR directly benefits two competitors.

At first, this logically benefits INTERCEPT, which gets a break of almost two years as it will remain alone with the UDCA on this market.

CYMABAY with its twice as effective would have eliminated them from the market within a few months of obtaining its MA.

This allows INTERCEPT to temporarily keep its turnover in the PBC as long as it manages to solve the problem of the price that will be raised by its possible MA in NASH.

Secondly, it opens a boulevard for GENFIT, which will find itself alone in three years' time facing INTERCEPT by offering treatment twice as effective and without dangerous side effects, which, in my opinion, will eliminate OCALIVA from the PBC market and allow GENFIT to earn an annual income of a few hundred million dollars.


CONCLUSION


I would like to point out that this episode highlights two fundamental points of clinical studies in NASH.

He recalled the usefulness of biopsies in NASH clinical studies, and analysts would do well to re-examine laboratories that claim to rely on imaging alone in their studies to save time and that announce dramatic results based solely on PDFF MRI imaging.

It also recalls the importance of the duration of clinical studies and the size of cohorts. Because SELADELPAR had not revealed its problem in previous studies, probably too short for that.

Therefore, caution and caution should be exercised with respect to candidates in NASH who show promising results, but based on studies of only 12 weeks duration while playing with thyroid or hormone receptors as complex as PPARs and whose mechanisms of action have in the past had late detected side effects that have had a significant impact on the history of pharmacy.

To conclude, the history of PPAR in the pharmacy is marked by failures, not because of their lack of efficacy, quite the contrary, but because of poor control of their side effects due to collateral action on unwanted receptors.

Fortunately, science is progressing and some laboratories have now become references in this very complex field of nuclear receptors, which will enable them to propose effective molecules with few side effects.

A good initial design, well-designed clinical studies and continuous safety monitoring are the keys to success!

Is not a locksmith who wants!


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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