FGEN, speaking of safety data, I've been digging around trying to find studies that might support the remaining short thesis that there could be a bad MACE result. Indeed, chronic PHD inhibition seemed to produce cardiomyopathy in mice. But KO mice are not that good a model for humans on chronic treatment.
>> A number of small molecule PHD inhibitors are in various stages of development for the treatment of anemia and ischemia. Our findings suggest that the chronic use of such agents might cause cardiomyopathy. However, it remains possible that the threshold of HIF activity required for therapeutic effects (for example, induction of red blood cell production) is lower than the threshold required for deleterious effects. In this regard, several observations are perhaps noteworthy. First, PHD inhibitor use in the clinic will almost certainly lead to submaximal, non-continuous, PHD inhibition, in contrast to the genetic models described here. Second, the dose-response curves relating PHD activity to HIF-target gene induction are not stereotypical. Instead, they differ for different HIF target genes and in different tissues. For example, near maximal induction of erythropoietin in the kidney is achieved after PHD2 inactivation, whereas the maximal induction of some other HIF target genes requires the concurrent inactivation of other PHD paralogs and/or the HIF asparaginyl hydroxylase FIH1, which regulates HIF transactivation function 13. Finally, cardiomyopathy is not a conspicuous feature of patients with hypomorphic PHD2 mutations 43, 44 or with chronic hypoxemia and polycythemia from non-cardiac causes.<<
Loss of PHD Prolyl Hydroxylase Activity in Cardiomyocytes Phenocopies Ischemic Cardiomyopathy
And an article that cites the above notes the following:
>>Interestingly, as with most drugs, PHIs appear to be strongly concentrated in the liver and kidneys (the Epo-producing organs) 143, so at low doses they may indeed only produce modest, and potentially beneficial, activation of HIF in the heart. <<
HIF hydroxylase pathways in cardiovascular physiology and medicine
So either shorts aren't reading deeply enough, or they've found other more damning material that I haven't. I added today. With MACE the only real potential fly in the FGEN ointment, can anyone else support a bear case on MACE (even weakly)?
TIA & Cheers, Tuck |
