RE:targeted BETi vs pan BETi Apabetalone is a targetted, specific BETi and has to date a very good safety profile. My understanding is that zen3694 and perhaps other compounds in the Zenith portfolio are pan BETi's. I understand that some pan BETi drugs directed at cancers do not have good safety profiles.
Am I correct in my assumptions?
Yes, apabetalone/RVX-208 is a BET inhibitor selective for the second bromodomain, whereas ZEN-3694 is a pan-BET inhibitor that binds both bromodomains 1 and 2 without selectivity for either one. Both Resverlogix and Zenith have their own independent BET inhibitor libraries of thousands of compounds generated from their respective platforms. It is my understanding that both companies have in their libraries BET inhibitors that are pan-inhibitors, BD-1 selective, or BD-2 selective. With the exception of RVX-208, all BET inhibitors in clinical trials are pan-inhibitors being used in oncology indications.
The first generation of pan BET inhibitors that have completed or still ongoing Phase 1 clinical trials seem to achieve some efficacy, but with common toxic effects reported as thrombocytopenia, anaemia, neutropenia, diarrhoea, fatigue and nausea. Therefore, these studies have adopted an intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects. Zenith has already found their maximally tolerated dose for their daily administration of ZEN-3694 and disclosed a couple months ago that they were exploring an intermittent dosing schedule as well. Is this because they see these same side effects? This hasn't been disclosed yet, so we just don't know. Zenith has mentioned that they see an on-target safety profile for ZEN-3694, but I am not sure exactly what that means. Zenith has also mentioned that they see a superior safety profile for ZEN-3694 in their pre-clinical studies. There are other next generation BET inhibitors in cancer clinical trials now as well, and their safety profiles haven't been disclosed yet either. So until this info is disclosed, questions will remain regarding the safety of ZEN-3694 and other next generation pan-BET inhibitors.
If so, (asking for speculation here) and given that Zenith is in very early stages of development, does anyone have opinions on the best bet of success between Zenith and RVX? (I am not implying they are in competition)
Are you asking likelihood of success between RVX-208 and ZEN-3694 at this stage of the game? If so, then my opinion is that with the information available right now, RVX-208 has is a more proven molecule that has a higher likelihood of success.
Could it be possible that some Zenith compounds could have high safety profiles and is there any evidence?
Yes, its possible that Zenith compounds have great safety profiles. But to the best of my knowledge no evidence of this has been publicly disclosed.
And then, I guess the question on the Zenith side (RVX as well but it seems like less so) is the ratio of risk to reward. If zen3694 in the mCRPC trial turns out to have safety issues and yet it turns out to have a very positive impact on patients with mCRPC in terms of extending their lives might it actually have a chance of making it to market?
Yes, I think that even if pan-BET inhibitors have some safety issues that they still have a chance of making it to the market as cancer therapies. I expect ZEN-3694 to have some side effects/safety issues. But will ZEN-3694 elicit better efficacy and less severe side effects than other first- and next-generation pan-BET inhibitors in trials right now? If so, then ZEN-3694 may be able to rise to the top. However, there is not enough publicly available info to know this answer at this time.