Recent Constellation Presentation

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biopearl123
Posts: 1665
Joined: Fri Jul 20, 2018 5:13 pm

Recent Constellation Presentation

Post by biopearl123 » Fri Feb 26, 2021 12:46 am

Mentioned in passing Are new studies suggesting genotoxicity of their Backbone therapy for MF. More later but thought we should look into it. bp

biopearl123
Posts: 1665
Joined: Fri Jul 20, 2018 5:13 pm

Re: Recent Constellation Presentation

Post by biopearl123 » Fri Feb 26, 2021 11:52 pm

I am not sure how relevant the studies cited in the recent Constellation earnings call that suggest CPI-0610, their BET inhibitor in trials for treatment of MF that show genotoxicity are. Rux has been shown not to be genotoxic and Imetelstat as far as I can find has not either. Here is a quote from the clinical trial site from an old study :

"Imetelstat animal and in vitro studies suggest it is not genotoxic or teratogenic. However, 13-cis-retinoic acid is known to be teratogenic. Pregnancy tests must be obtained in girls who are post menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two reliable contraceptive methods. Pregnant or breast-feeding females will not be entered on this study due to the potential fetal and teratogenic adverse effects."

Since MF is associated with a higher transformation to AML already, one might speculate that the use of a genotoxic agent might enhance this tendency. I don't know (hat tip to Hugh on Constellation YMB board). Some anticancer agents are genotoxic by nature and this is acceptable in some treatments. Imetelstat of course targets the CSC and I have asked the company to comment whether transformation to AML has been positively affected. I am extrapolating (my thoughts only) that given the much longer OS associated with Imetelstat treatment that perhaps it does impact transformation to AML. Wouldn't that be wonderful if true. While we fret about major competition (Constellation) this might be relevant. I suppose a BET inhibitor could result in a better but shorter life. Clearly Geron is quite happy to be given the opportunity to prove longevity with the latest PIII MF study and this may be one of the reasons why.

Recall that the FDA stopped Geron in its tracks several years ago for liver function abnormalities and set the entire program back at least 9 months despite opinions from liver experts as to appropriate management. I wonder how they will view the suggestion that there may be genotoxicity with CPI-0610. There is such disordered genetics in MF anyway that it might not be a big issue but with regard to transformation to AML it might. Pure speculation. here. bp

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