| | | OK, folks, I have delved into the pharmacological dose response studies a bit further. To clarify and expand on that knowledge of CR845 plasma exposures, drug half-life, kappa receptor activity and degree of receptor occupancy (based on the Needham April presentation, slide 31 eg), I further had a discussion with CEO Derek Chalmers (this morning) about the data, both shown in slides previously or otherwise available.
Here is the key data to make a decision as to whether efficacy will be seen in the revised trial dose group of 1ug/kg: Kappa receptor occupancy at peak drug levels achieves 98-99%. By the end of this initial dose, prior to the next dose, 825 levels are at 70% kappa receptor occupancy. PK exposures upon repeated IV doses are maintained (ie, no induction etc). Note also that 825 is a 140-150 pM agonist with no plasma protein binding, and drug is precisely dose-proportional. So as to the 0.5ug/kg dose, the upper limit of kappa receptor occupancy will be somewhere in the 90s% range (no precision here as it is on the upper sigmoidal part of the dose-response curve), and kappa receptor occupancy will be at 35% by the next dose.
So efficacy and dose-response relations data should be evident.
Another aside has to do with the hypernatremia. No effect has apparently been seen on plasma vasopressin levels, and Chalmers reasons that it is due to an acute effect on the kidney. I thought it could have been an effect on hypothalamic neurons involved in vasopressin secretion due to the limited nature of the blood-brain barrier at this site. Most important is the direct kidney effect, which would not occur with the tightened dose range in the revised pain trial, only occurred upon the initial dose in those affected patients, and then showed tachyphlaxis. With the revised 2 dose levels, no hyponatremia should be observed.
These are my opinions only and anyone interested in CARA as an investment needs to perform their own due diligence. |
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