Do prior negative clinical results with CBAY's Seladelpar predict bad news for GNFT's Elafibranor in its upcoming NASH readout?
As we dig deeper into this question, we are interested in your thoughts. We are reminded of the upcoming (early Q2 2020) elafibranor NASH readout from our catalyst database, which we've made public on this web site. Both Elafibranor and seladalpar are PPAR agonists. These molecules, as well as key elafibranor metabolyte called CGF-B have similar structures:
Souce: CBAY poster
We were surprised when Seladelpar was pulled from clinical trials due to safety concerns last fall. Our initial thought regarding elafibranor, is that the safety issue should have reared its ugly head already in the elafibranor NASH trial, and other PPAR agonist trials, if it is a class issue for any PPAR agonist or PPAR delta agonist. Seladelpar is a specific PPAR delta agonist, whereas elafibranor is a dual PPAR alpha and delta agonist. We were pleased to see CBAY's biochemical results indicating that elafibranor and CGF-B have much lower affinity for PPAR delta than seladelpar.
Elefibranor has passed numerous DSMB safety checkpoints. Therefore, it seems to us that it is not very likely that the safety issue of Seladelpar will come up in elafibranor trials, such as the NASH trial whose interim is about to read out. However, looking at the similarity in structures causes us some hesitation. We need to look more closely because our recollection is that the issue came up fairly late in the Seladelpar NASH trial, upon liver biopsy review. Should GNFT's DSMB have seen biopsy data at a late enough timepoint that would have revealed this already? Please comment below if you have thoughts on this.
Seladelpar missed its NASH primary endpoint, week 12 reduction liver fat since the Seladelpar arms did not separate from placebo in a statistically signifant manner.
Source: CBAY Seladelpar NASH Ph2b readout
The upcoming interim for elafibranor is a 72 week timepoint, NASH resolution without worsening of fibrosis, not liver fat reduction. Seladelpar never made it to its NASH resolution readout at 52 weeks. The trial was stopped for safety concerns before that point because of atypical findings in some biopsies, as CBAY recently reiterated in a letter to shareholders (Jan 29, 2020):
The elafibranor trial data database was locked at the end of February after a 72 week timepoint. Therefore, we would expect that a safety signal like that seen with the Seladelpar trial would have been seen by now as biopsies were read. Do you agree? We would like to hear your thought?
Of course, there is the other major looming issue: Even if safety looks OK, how will efficacy for the primary endpoint look with seladelpar. We plan to dig deeper into its prior trials, as well as those of other PPAR alpha and delta inhibitors, if such data exists for other dual inhibitors. We've loaded links to some of the prior seladelpar data into our databases, which you can access from this site. Have a look and let us know what you think.
excellent question. I would have thought though that liver biopsies would be a standard safety component of such studies...with mandatory reports to the FDA if adverse/unexplained results occurred. The fact that the trial continued suggests that none were observed. Of course the delay in the readout, taken after consultation with the FDA MIGHT mean that such tests were not done as part of the trial...still 72 weeks is a very long time in terms of seeing if there were real adverse effects.....